Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/dailymed/clinicalPharmacology
| Subject | Predicate | Object | Context |
|---|---|---|---|
| dailymed-instance:clinicalP... | rdf:type | rdf:Property | lld:dailymed |
| dailymed-drugs:643 | dailymed-instance:clinicalP... | Pharmacokinetics: | lld:dailymed |
| dailymed-drugs:926 | dailymed-instance:clinicalP... | Please refer to the package insert for ProstaScint or Zevalin for this information on the final drug product. | lld:dailymed |
| dailymed-drugs:1 | dailymed-instance:clinicalP... | Following IV administration of 1, 2, and 3 gram doses of Cefizox to normal volunteers, the following serum levels were obtained. A serum half���life of approximately 1.7 hours was observed after IV or IM administration. Cefizox is 30% protein bound. Cefizox is not metabolized, and is excreted virtually unchanged by the kidneys in 24 hours. This provides a high urinary concentration. Concentrations greater than 6000��g/mL have been achieved in the urine by 2 hours after a 1 gram dose of Cefizox intravenously. Probenecid slows tubular secretion and produces even higher serum levels, increasing the duration of measurable serum concentrations. Cefizox achieves therapeutic levels in various body fluids, e.g., cerebrospinal fluid (in patients with inflamed meninges), bile, surgical wound fluid, pleural fluid, aqueous humor, ascitic fluid, peritoneal fluid, prostatic fluid and saliva, and in the following body tissues: heart, gallbladder, bone, biliary, peritoneal, prostatic, and uterine. In clinical experience to date, no disulfiram���like reactions have been reported with Cefizox.<br/>Microbiology: The bactericidal action of Ceftizoxime results from inhibition of cell���wall synthesis. Ceftizoxime is highly resistant to a broad spectrum of beta���lactamases (penicillinase and cephalosporinase), including Richmond types I, II, III, TEM, and IV, produced by both aerobic and anaerobic gram���positive and gram���negative organisms. Ceftizoxime has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:<br/>Aerobic Gram-Positive Microorganisms: Staphylococcus aureus (including penicillinase producing strains) NOTE: Methicillin��resistant staphylococci are resistant to cephalosporins, including ceftizoxime. Staphylococcus epidermidis (including penicillinase producing strains) Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes NOTE: A streptococcal isolate that is susceptible to penicillin can be considered susceptible to ceftizoxime. NOTE: Ceftizoxime is usually inactive against most strains of Enterococcus faecalis.<br/>Aerobic Gram-Negative Microorganisms: Enterobacter spp. Escherichia coli Haemophilus influenzae (including ampicillin��resistant strains) Klebsiella pneumoniae Morganella morganii Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Providencia rettgeri Pseudomonas aeruginosa Serratia marcescens<br/>Anaerobic Microorganisms: Bacteroides spp. Peptococcus spp. Peptostreptococcus spp. The following in vitro data are available, but their clinical significance is unknown. At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for ceftizoxime. However, the safety and effectiveness of ceftizoxime in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.<br/>Aerobic Gram-Negative Microorganisms: Aeromonas hydrophila Citrobacter spp. Moraxellacatarrhalis Neisseria meningitidis Providencia stuartii<br/>Susceptibility Testing Methods::<br/>Dilution techniques:: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method(broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ceftizoxime powder. The MIC values should be interpreted according to the following criteria: A report of���Susceptible���indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of���Intermediate���indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of���Resistant���indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable, other therapy should be selected. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard ceftizoxime powder should provide the following MIC values:<br/>Diffusion Techniques:: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedurerequires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30-��g ceftizoxime to test the susceptibility of microorganisms to ceftizoxime. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-��g ceftizoxime disk should be interpreted according to the following criteria: Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ceftizoxime. As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30-��g ceftizoxime disk should provide the following zone diameters in these laboratory test quality control strains:<br/>Anaerobic Techniques:: For anaerobic bacteria, the susceptibility to ceftizoxime as MICs can be determined by standardized test methods. Agar dilution results can vary widely when using ceftizoxime. It is recommended that broth microdilution method be used when possible.The MIC values obtained should be interpreted according to the following criteria: Interpretation is identical to that described in Susceptibility Testing: Dilution Techniques. As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized ceftizoxime powder should provide the following MIC values:<br/>Susceptibility Testing for Pseu domonas in Urinary Tract Infections: Most strains of Pseudomonas aeruginosa are moderately susceptible to ceftizoxime. Ceftizoxime achieves high levels in the urine (greater than 6000 mcg/mL at 2 hours with 1 gram IV) and, therefore, the following zone sizes should be used when testing ceftizoxime for treatment of urinary tract infections caused by Pseudomonas aeruginosa. Susceptible organisms produce zones of 20 mm or greater, indicating that the test organism is likely to respond to therapy. Organisms that produce zones of 11 to 19 mm are expected to be susceptible when the infection is confined to the urinary tract (in which high antibiotic levels are attained). Resistant organisms produce zones of 10 mm or less, indicating that other therapy should be selected. | lld:dailymed |
| dailymed-drugs:2 | dailymed-instance:clinicalP... | Mechanism of Action: Fluticasone propionate is a synthetic trifluorinated corticosteroid with potent anti-inflammatory activity. In vitro assays using human lung cytosol preparations have established fluticasone propionate as a human corticosteroid receptor agonist with an affinity 18 times greater than dexamethasone, almost twice that of beclomethasone-17-monopropionate (BMP), the active metabolite of beclomethasone dipropionate, and over 3 times that of budesonide. Data from the McKenzie vasoconstrictor assay in man are consistent with these results. The clinical significance of these findings is unknown. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to inhibit multiple cell types (e.g., mast cells, eosinophils, basophils, lymphocytes, macrophages, neutrophils) and mediator production or secretion (e.g., histamine, eicosanoids, leukotrienes, cytokines) involved in the asthmatic response. These anti-inflammatory actions of corticosteroids contribute to their efficacy in asthma. Though effective for the treatment of asthma, corticosteroids do not affect asthma symptoms immediately. Individual patients will experience a variable time to onset and degree of symptom relief. Maximum benefit may not be achieved for 1 to 2 weeks or longer after starting treatment. When corticosteroids are discontinued, asthma stability may persist for several days or longer. Studies in patients with asthma have shown a favorable ratio between topical anti-inflammatory activity and systemic corticosteroid effects with recommended doses of orally inhaled fluticasone propionate. This is explained by a combination of a relatively high local anti-inflammatory effect, negligible oral systemic bioavailability (<1%), and the minimal pharmacological activity of the only metabolite detected in man.<br/>Pharmacokinetics:<br/>Absorption: Fluticasone propionate acts locally in the lung; therefore, plasma levels do not predict therapeutic effect. Studies using oral dosing of labeled and unlabeled drug have demonstrated that the oral systemic bioavailability of fluticasone propionate is negligible (<1%), primarily due to incomplete absorption and presystemic metabolism in the gut and liver. In contrast, the majority of the fluticasone propionate delivered to the lung is systemically absorbed. The systemic bioavailability of fluticasone propionate from the DISKUS device in healthy volunteers averages 18%. Peak steady-state fluticasone propionate plasma concentrations in adult patients with asthma (N = 11) ranged from undetectable to 266 pg/mL after a 500-mcg twice-daily dosage of fluticasone propionate inhalation powder using the DISKUS device. The mean fluticasone propionate plasma concentration was 110 pg/mL.<br/>Distribution: Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg. The percentage of fluticasone propionate bound to human plasma proteins averages 91%. Fluticasone propionate is weakly and reversibly bound to erythrocytes and is not significantly bound to human transcortin.<br/>Metabolism: The total clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17��-carboxylic acid derivative of fluticasone propionate, which is formed through the cytochrome P450 3A4 pathway. This metabolite had less affinity (approximately 1/2,000) than the parent drug for the corticosteroid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.<br/>Elimination: Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites.<br/>Special Populations:<br/>Drug Interactions: Fluticasone propionate is a substrate of cytochrome P450 3A4. Coadministration of fluticasone propionate and the highly potent cytochrome P450 3A4 inhibitor ritonavir is not recommended based upon a multiple-dose, crossover drug interaction study in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable (<10 pg/mL) in most subjects, and when concentrations were detectable, peak levels (C) averaged 11.9 pg/mL (range, 10.8 to 14.1 pg/mL) and AUCaveraged 8.43 pg���hr/mL (range, 4.2 to 18.8 pg���hr/mL). Fluticasone propionate Cand AUCincreased to 318 pg/mL (range, 110 to 648 pg/mL) and 3,102.6 pg���hr/mL (range, 1,207.1 to 5,662.0 pg���hr/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate concentration resulted in a significant decrease (86%) in plasma cortisol area under the plasma concentration versus time curve (AUC). Caution should be exercised when other potent cytochrome P450 3A4 inhibitors are coadministered with fluticasone propionate. In a drug interaction study, coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in increased plasma fluticasone propionate concentration and reduced plasma cortisol AUC, but had no effect on urinary excretion of cortisol. In another multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.<br/>Pharmacodynamics: In clinical trials with fluticasone propionate inhalation powder using dosages up to and including 250 mcg twice daily, occasional abnormal short cosyntropin tests (peak serum cortisol<18 mcg/dL assessed by radioimmunoassay) were noted both in patients receiving fluticasone propionate and in patients receiving placebo. The incidence of abnormal tests at 500 mcg twice daily was greater than placebo. In a 2-year study carried out with the DISKHALER' inhalation device in 64 patients with mild, persistent asthma (mean FEV91% of predicted) randomized to fluticasone propionate 500 mcg twice daily or placebo, no patient receiving fluticasone propionate had an abnormal response to 6-hour cosyntropin infusion (peak serum cortisol<18 mcg/dL). With a peak cortisol threshold<35 mcg/dL, 1 patient receiving fluticasone propionate (4%) had an abnormal response at 1 year; repeat testing at 18 months and 2 years was normal. Another patient receiving fluticasone propionate (5%) had an abnormal response at 2 years. No patient on placebo had an abnormal response at 1 or 2 years. In a placebo-controlled clinical study conducted in patients 4 to 11 years of age, a 30-minute cosyntropin stimulation test was performed in 41 patients after 12 weeks of dosing with 50 or 100 mcg twice daily of fluticasone propionate via the DISKUS device. One patient receiving fluticasone propionate via DISKUS had a prestimulation plasma cortisol concentration<5 mcg/dL, and 2 patients had a rise in cortisol of<7 mcg/dL. However, all poststimulation values were>18 mcg/dL. The potential systemic effects of inhaled fluticasone propionate on the hypothalamic-pituitary��adrenal (HPA) axis were also studied in patients with asthma. Fluticasone propionate given by inhalation aerosol at dosages of 220, 440, 660, or 880 mcg twice daily was compared with placebo or oral prednisone 10 mg given once daily for 4 weeks. For most patients, the ability to increase cortisol production in response to stress, as assessed by 6-hour cosyntropin stimulation, remained intact with inhaled fluticasone propionate treatment. No patient had an abnormal response (peak serum cortisol<18 mcg/dL) after dosing with placebo or fluticasone propionate 220 mcg twice daily. For patients treated with 440, 660, and 880 mcg twice daily, 10%, 16%, and 12%, respectively, had an abnormal response as compared to 29% of patients treated with prednisone. To confirm that systemic absorption does not play a role in the clinical response to inhaled fluticasone propionate, a double-blind clinical study comparing inhaled fluticasone propionate powder and oral fluticasone propionate was conducted. Inhaled fluticasone propionate powder in dosages of 100 and 500 mcg twice daily was compared to oral fluticasone propionate 20,000 mcg once daily and placebo for 6 weeks. Plasma levels of fluticasone propionate were detectable in all 3 active groups, but the mean values were highest in the oral group. Both doses of inhaled fluticasone propionate were effective in maintaining asthma stability and improving lung function, while oral fluticasone propionate and placebo were ineffective. This demonstrates that the clinical effectiveness of inhaled fluticasone propionate is due to its direct local effect and not to an indirect effect through systemic absorption. | lld:dailymed |
| dailymed-drugs:3 | dailymed-instance:clinicalP... | Nadolol is a nonselective beta-adrenergic receptor blocking agent. Clinical pharmacology studies have demonstrated beta-blocking activity by showing (1) reduction in heart rate and cardiac output at rest and on exercise, (2) reduction of systolic and diastolic blood pressure at rest and on exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia. Nadolol specifically competes with beta-adrenergic receptor agonists for available beta-receptor sites; it inhibits both the beta1 receptors located chiefly in cardiac muscle and the betareceptors located chiefly in the bronchial and vascular musculature, inhibiting the chronotropic, inotropic, and vasodilator responses to beta-adrenergic stimulation proportionately. Nadolol has no intrinsic sympathomimetic activity and, unlike some other beta-adrenergic blocking agents, nadolol has little direct myocardial depressant activity and does not have an anesthetic-like membrane-stabilizing action. Animal and human studies show that nadolol slows the sinus rate and depresses AV conduction. In dogs, only minimal amounts of nadolol were detected in the brain relative to amounts in blood and other organs and tissues. Nadolol has low lipophilicity as determined by octanol/water partition coefficient, a characteristic of certain beta-blocking agents that has been correlated with the limited extent to which these agents cross the blood-brain barrier, their low concentration in the brain, and low incidence of CNS-related side effects. In controlled clinical studies, nadolol at doses of 40 to 320 mg/day has been shown to decrease both standing and supine blood pressure, the effect persisting for approximately 24 hours after dosing. The mechanism of the antihypertensive effects of beta-adrenergic receptor blocking agents has not been established; however, factors that may be involved include (1) competitive antagonism of catecholamines at peripheral (non-CNS) adrenergic neuron sites (especially cardiac) leading to decreased cardiac output, (2) a central effect leading toreduced tonic-sympathetic nerve outflow to the periphery, and (3) suppression of renin secretion by blockade of the beta-adrenergic receptors responsible for renin release from the kidneys. While cardiac output and arterial pressure are reduced by nadolol therapy, renal hemodynamics are stable, with preservation of renal blood flow and glomerular filtration rate. By blocking catecholamine-induced increases in heart rate, velocity and extent of myocardial contraction, and blood pressure, nadolol generally reduces the oxygen requirements of the heart at any given level of effort, making it useful for many patients in the long-term management of angina pectoris. On the other hand, nadolol can increase oxygen requirements by increasing left ventricular fiber length and end diastolic pressure, particularly in patients with heart failure Although beta-adrenergic receptor blockade is useful in treatment of angina and hypertension, there are also situations in which sympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. Beta-adrenergic blockade may worsen AV block by preventing the necessary facilitating effects of sympathetic activity on conduction. Beta-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients. Absorption of nadolol after oral dosing is variable, averaging about 30 percent. Peak serum concentrations of nadolol usually occur in three to four hours after oral administration and the presence of food in the gastrointestinal tract does not affect the rate or extent of nadolol absorption. Approximately 30 percent of the nadolol present in serum is reversibly bound to plasma protein. Unlike many other beta-adrenergic blocking agents, nadolol is not metabolized by the liver and is excreted unchanged, principally by the kidneys. The half-life of therapeutic doses of nadolol is about 20 to 24 hours, permitting once-daily dosage. Because nadolol is excreted predominantly in the urine, its half-life increases in renal failure (see PRECAUTIONS and DOSAGE AND ADMINISTRATION). Steady-state serum concentrations of nadolol are attained in six to nine days with once-daily dosage in persons with normal renal function. Because of variable absorption and different individual responsiveness, the proper dosage must be determined by titration. Exacerbation of angina and, in some cases, myocardial infarction and ventricular dysrhythmias have been reported after abrupt discontinuation of therapy with beta-adrenergic blocking agents in patients with coronary artery disease. Abrupt withdrawal of these agents in patients without coronary artery disease has resulted in transient symptoms, including tremulousness, sweating, palpitation, headache, and malaise. Several mechanisms have been proposed to explain these phenomena, among them increased sensitivity to catecholamines because of increased numbers of beta receptors. | lld:dailymed |
| dailymed-drugs:4 | dailymed-instance:clinicalP... | Mechanism of Action: Keratinocyte growth factor (KGF) is an endogenous protein in the fibroblast growth factor (FGF) family that binds to the KGF receptor. Binding of KGF to its receptor has been reported to result in proliferation, differentiation, and migration of epithelial cells. The KGF receptor, one of four receptors in the FGF family, has been reported to be present on epithelial cells in many tissues examined including the tongue, buccal mucosa, esophagus, stomach, intestine, salivary gland, lung, liver, pancreas, kidney, bladder, mammary gland, skin (hair follicles and sebaceous gland), and the lens of the eye. The KGF receptor has been reported to not be present on cells of the hematopoietic lineage. Endogenous KGF is produced by mesenchymal cells and is upregulated in response to epithelial tissue injury. In mice and rats, Kepivance enhanced proliferation of epithelial cells (as measured by Ki67 immunohistochemical staining and BrDU uptake) and demonstrated an increase in tissue thickness of the tongue, buccal mucosa, and gastrointestinal tract. Kepivance has been studied in murine models of chemotherapy and radiation-induced gastrointestinal injury. In such models, administration of Kepivance prior to and/orafter the cytotoxic insult improved survival and reduced weight loss compared to control animals. Kepivance has been shown to enhance the growth of human epithelial tumor cell lines in vitro at concentrations���10 mcg/mL (>15-fold higher than average therapeutic concentrations in humans). In nude mouse xenograft models, three consecutive daily treatments of Kepivance at doses of 1,500 and 4,000 mcg/kg (25- and 67-fold higher than the recommended human dose, respectively) repeated weekly for 4 to 6 weeks were associated with a dose-dependent increase in the growth rate of 1 of 7 KGF receptor-expressing human tumor cell lines.<br/>Pharmacokinetics: The pharmacokinetics of Kepivance were studied in healthy subjects and patients with hematologic malignancies. After single IV doses of 20 to 250 mcg/kg (healthy subjects) and 60 mcg/kg (cancer patients), Kepivance concentrations declined rapidly (over 95% decrease) in the first 30 minutes post-dose. A slight increase or plateau in concentration occurred at approximately 1 to 4 hours, followed by a terminal decline phase. Kepivance exhibited linear pharmacokinetics with extravascular distribution. On average, total body clearance (CL) appeared to be 2- to 4-fold higher, and volume of distribution at steady state (Vss) to be 2-fold higher in cancer patients compared with healthy subjects after a 60 mcg/kg single dose of Kepivance. The elimination half-life was similar between healthy subjects and cancer patients (average 4.5 hours with a range of 3.3 to 5.7 hours). No accumulation of Kepivance occurred after 3 consecutive daily doses of 20 and 40 mcg/kg in healthy volunteers or 60 mcg/kg in cancer patients.<br/>Pharmacodynamics: Epithelial cell proliferation was assessed by Ki67 immunohistochemical staining in healthy subjects. A 3-fold or greater increase in Ki67 staining was observed in buccal biopsies from 3 of 6 healthy subjects given Kepivance at 40 mcg/kg/day IV for 3 days, when measured 24 hours after the third dose. Dose-dependent epithelial cell proliferation was observed in healthy subjects given single IV doses of 120 to 250 mcg/kg 48 hours post-dosing.<br/>Special Populations: No gender-related differences were observed in the pharmacokinetics of Kepivance at doses���60 mcg/kg. The pharmacokinetic profile in pediatric populations , or in patients with hepatic insufficiency, has not been assessed. Geriatric Use: No age-related differences were observed in the pharmacokinetics of Kepivance���180 mcg/kg. Renal Impairment: Results from a pharmacokinetics study in 24 subjects with varying degrees of renal impairment demonstrated that renal impairment has little or no influence on Kepivance pharmacokinetics. No dose adjustment is recommended for patients with renal impairment. | lld:dailymed |
| dailymed-drugs:5 | dailymed-instance:clinicalP... | Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: pain, temperature, touch, proprioception, and skeletal muscle tone. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems. At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block and ultimately to cardiac arrest. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation is manifested as restlessness, tremors, and shivering, progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited stage. A clinical study using 15 mL of 2% epidural mepivacaine at the T 9-10 interspace in 62 patients, 20-79 years of age, demonstrated a 40% decrease in the amount of mepivacaine required to block a given number of dermatomes in the elderly (60-79 years, N=13) as compared to young adults 20-39 years). Another study using 10mL of 2% lumbar epidural mepivacaine in 161 patients, 19-75 years of age, demonstrated a strong inverse relationship between patient age and the number of dermatomes blocked per cc of mepivacaine injected.<br/>Pharmacokinetics: The rate of systemic absorption of local anesthetics is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of epinephrine (1:200,000 or 5��g/mL) usually reduces the rate of absorption and plasma concentration of mepivacaine, however, it has been reported that vasoconstrictors do not significantly prolong anesthesia with mepivacaine. Onset of anesthesia with mepivacaine is rapid, the time of onset for sensory block ranging from about 3 to 20 minutes depending upon such factors as the anesthetic technique, the type of block, the concentration of the solution, and the individual patient. The degree of motor blockade produced is dependent on the concentration of the solution. A 0.5% solution will be effective in small superficial nerve blocks while the 1% concentration will block sensory and sympathetic conduction without loss of motor function. The 1.5% solution will provide extensive and often complete motor block and the 2% concentration of mepivacaine hydrochloride will produce complete sensory and motor block of any nerve group. The duration of anesthesia also varies depending upon the technique and type of block, the concentration, and the individual. Mepivacaine will normally provide anesthesia which is adequate for 2 to 2/hours of surgery. Local anesthetics are bound to plasma proteins in varying degrees. Generally, the lower the plasma concentration of drug, the higher the percentage of drug bound to plasma. Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by the degree of plasma protein binding, the degree of ionization, and the degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. Mepivacaineis approximately 75% bound to plasma proteins. The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation. Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain. Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of drug administration, and the age of the patient. The half-life of mepivacaine in adults is 1.9 to 3.2 hours and in neonates 8.7 to 9 hours. Mepivacaine, because of its amide structure, is not detoxified by the circulating plasma esterases. It is rapidly metabolized, with only a small percentage of the anesthetic (5 percent to 10 percent) being excreted unchanged in the urine. The liver is the principal site of metabolism, with over 50% of the administered dose being excreted into the bile as metabolites. Most of the metabolized mepivacaine is probably resorbed in the intestine and then excreted into the urine since only a small percentage is found in the feces. The principal route of excretion is via the kidney. Most of the anesthetic and its metabolites are eliminated within 30 hours. It has been shown that hydroxylation and N-demethylation, which are detoxification reactions, play important roles in the metabolism of the anesthetic. Three metabolites of mepivacaine have been identified from human adults: two phenols, which are excreted almost exclusively as their glucuronide conjugates, and the N-demethylated compound (2���,6���-pipecoloxylidide). Mepivacaine does not ordinarily produce irritation or tissue damage, and does not cause methemoglobinemia when administered in recommended doses and concentrations. | lld:dailymed |
| dailymed-drugs:6 | dailymed-instance:clinicalP... | Mechlorethamine, a biologic alkylating agent, has a cytotoxic action which inhibits rapidly proliferating cells.<br/>Pharmacokinetics and Metabolism: In water or body fluids, mechlorethamine undergoes rapid chemical transformation and combines with water or reactive compounds of cells, so that the drug is no longer present in active form a few minutes after administration. | lld:dailymed |
| dailymed-drugs:7 | dailymed-instance:clinicalP... | Pharmacokinetics and Metabolism: The pharmacokinetic properties of fluconazole are similar following administration by the intravenous or oral routes. In normal volunteers, the bioavailability of orally administered fluconazole is over 90% compared with intravenous administration. Peak plasma concentrations (Cmax) in fasted normal volunteers occur between 1 and 2 hours with a terminal plasma elimination half-life of approximately 30 hours (range: 20 to 50 hours) after oral administration. In fasted normal volunteers, administration of a single oral 400 mg dose of fluconazole leads to a mean Cmax of 6.72 mcg/mL (range: 4.12 to 8.08 mcg/mL) and after single oral doses of 50 to 400 mg, fluconazole plasma concentrations and AUC (area under the plasma concentration-time curve) are dose proportional. Administration of a single oral 150 mg tablet of fluconazole to ten lactating women resulted in a mean Cmax of 2.61 mcg/mL (range: 1.57 to 3.65 mcg/mL). Steady-state concentrations are reached within 5 to 10 days following oral doses of 50 to 400 mg given once daily. Administration of a loading dose (on day 1) of twice the usual daily dose results in plasma concentrations close to steady-state by the second day. The apparent volume of distribution of fluconazole approximates that of total body water. Plasma protein binding is low (11 to 12%). Following either single- or multiple-oral doses for up to 14 days, fluconazole penetrates into all body fluids studied (see table below). In normal volunteers, saliva concentrations of fluconazole were equal to or slightly greater than plasma concentrations regardless of dose, route, or duration of dosing. In patients with bronchiectasis, sputum concentrations of fluconazole following a single 150 mg oral dose were equal to plasma concentrations at both 4 and 24 hours post dose. In patients with fungal meningitis, fluconazole concentrations in the CSF are approximately 80% of the corresponding plasma concentrations. A single oral 150 mg dose of fluconazole administered to 27 patients penetrated into vaginal tissue, resulting in tissue:plasma ratios ranging from 0.94 to 1.14 over the first 48 hours following dosing. A single oral 150 mg dose of fluconazole administered to 14 patients penetrated into vaginal fluid, resulting in fluid:plasma ratios ranging from 0.36 to 0.71 over the first 72 hours following dosing. In normal volunteers, fluconazole is cleared primarily by renal excretion, with approximately 80% of the administered dose appearing in the urine as unchanged drug. About 11% of the dose is excreted in the urine as metabolites. The pharmacokinetics of fluconazole are markedly affected by reduction in renal function. There is an inverse relationship between the elimination half-life and creatinine clearance. The dose of fluconazole may need to be reduced in patients with impaired renal function. A 3-hour hemodialysis session decreases plasma concentrations by approximately 50%. In normal volunteers, fluconazole administration (doses ranging from 200 mg to 400 mg once daily for up to 14 days) was associated with small and inconsistent effects on testosterone concentrations, endogenous corticosteroid concentrations, and the ACTH-stimulated cortisol response.<br/>Pharmacokinetics in Children: In children, the following pharmacokinetic data (Mean(%cv)) have been reported: Clearance corrected for body weight was not affected by age in these studies. Mean body clearance in adults is reported to be 0.23 (17%) mL/min/kg. In premature newborns (gestational age 26 to 29 weeks), the mean (%cv) clearance within 36 hours of birth was 0.180 (35%, N=7) mL/min/kg, which increased with time to a mean of 0.218 (31%, N=9) mL/min/kg six days later and 0.333 (56%, N=4) mL/min/kg 12 days later. Similarly, the half-life was 73.6 hours, which decreased with time to a mean of 53.2 hours six days later and 46.6 hours 12 days later.<br/>Pharmacokinetics in Elderly: A pharmacokinetic study was conducted in 22 subjects, 65 years of age or older receiving a single 50 mg oral dose of fluconazole. Ten of these patients were concomitantly receiving diuretics. The Cmax was 1.54 mcg/mL and occurred at 1.3 hours post dose. The mean AUC was 76.4+ 20.3 mcg���h/mL, and the mean terminal half-life was 46.2 hours. These pharmacokinetic parameter values are higher than analogous values reported for normal young male volunteers. Coadministration of diuretics did not significantly alter AUC or Cmax. In addition, creatinine clearance (74 mL/min), the percent of drug recovered unchanged in urine (0 to 24 hr, 22%) and the fluconazole renal clearance estimates (0.124 mL/min/kg) for the elderly were generally lower than those of younger volunteers. Thus, the alteration of fluconazole disposition in the elderly appears to be related to reduced renal function characteristic of this group. A plot of each subject's terminal elimination half-life versus creatinine clearance compared with the predicted half-life���creatinine clearance curve derived from normal subjects and subjects with varying degrees of renal insufficiency indicated that 21 of 22 subjects fell within the 95% confidence limit of the predicted half-life���creatinine clearance curves. These results are consistent with the hypothesis that higher values for the pharmacokinetic parameters observed in the elderly subjects compared with normal young male volunteers are due to the decreased kidney function that is expected in the elderly.<br/>Drug Interaction Studies: Oral contraceptives: Oral contraceptives were administered as a single dose both before and after the oral administration of fluconazole 50 mg once daily for 10 days in 10 healthy women. There was no significant difference in ethinyl estradiol or levonorgestrel AUC after the administration of 50 mg of fluconazole. The mean increase in ethinyl estradiol AUC was 6% (range: -47 to 108%) and levonorgestrel AUC increased 17% (range: -33 to 141%). In a second study, twenty-five normal females received daily doses of both 200 mg fluconazole tablets or placebo for two, ten-day periods. The treatment cycles were one month apart with all subjects receiving fluconazole during one cycle and placebo during the other. The order of study treatment was random. Single doses of an oral contraceptive tablet containing levonorgestrel and ethinyl estradiol were administered on the final treatment day (day 10) of both cycles. Following administration of 200 mg of fluconazole, the mean percentage increase of AUC for levonorgestrel compared to placebo was 25% (range: -12 to 82%) and the mean percentage increase for ethinyl estradiol compared to placebo was 38% (range: -11 to 101%). Both of these increases were statistically significantly different from placebo. A third study evaluated the potential interaction of once weekly dosing of fluconazole 300 mg to 21 normal females taking an oral contraceptive containing ethinyl estradiol and norethindrone. In this placebo-controlled, double-blind, randomized, two-way crossover study carried out over three cycles of oral contraceptive treatment, fluconazole dosing resulted in small increases in the mean AUCs of ethinyl estradiol and norethindrone compared to similar placebo dosing. The mean AUCs of ethinyl estradiol and norethindrone increased by 24% (95% C.I. range 18 to 31%) and 13% (95% C.I. range 8 to 18%), respectively relative to placebo. Fluconazole treatment did not cause a decrease in the ethinyl estradiol AUC of any individual subject in this study compared to placebo dosing. The individual AUC individual values of norethindrone decreased very slightly (<5%) in 3 of the 21 subjects after fluconazole treatment. Cimetidine: Fluconazole 100 mg was administered as a single oral dose alone and two hours after a single dose of cimetidine 400 mg to six healthy male volunteers. After the administration of cimetidine, there was a significant decrease in fluconazole AUC and Cmax. There was a mean��SD decrease in fluconazole AUC of 13%��11% (range: -3.4 to -31 %) and Cmax decreased 19%��14% (range: -5 to -40%). However, the administration of cimetidine 600 mg to 900 mg intravenously over a four-hour period (from one hour before to 3 hours after a single oral dose of fluconazole 200 mg) did not affect the bioavailability or pharmacokinetics of fluconazole in 24 healthy male volunteers. Antacid: Administration of Maalox' (20 mL) to 14 normal male volunteers immediately prior to a single dose of fluconazole 100 mg had no effect on the absorption or elimination of fluconazole. Hydrochlorothiazide: Concomitant oral administration of 100 mg fluconazole and 50 mg hydrochlorothiazide for 10 days in 13 normal volunteers resulted in a significant increase in fluconazole AUC and Cmax compared to fluconazole given alone. There was a mean��SD increase in fluconazole AUC and Cmax of 45%��31% (range: 19 to 114%) and 43%��31% (range: 19 to 122%), respectively. These changes are attributed to a mean��SD reduction in renal clearance of 30%��12% (range: -10 to -50%). Rifampin: Administration of a single oral 200 mg dose of fluconazole after 15 days of rifampin administered as 600 mg daily in eight healthy male volunteers resulted in a significant decrease in fluconazole AUC and a significant increase in apparent oral clearance of fluconazole. There was a mean��SD reduction in fluconazole AUC of 23%��9% (range: -13 to -42%). Apparent oral clearance of fluconazole increased 32%��17% (range: 16 to 72%). Fluconazole half-life decreased from 33.4��4.4 hours to 26.8��3.9 hours. Warfarin: There was a significant increase in prothrombin time response (area under the prothrombin time-time curve) following a single dose of warfarin (15 mg) administered to 13 normal male volunteers following oral fluconazole 200 mg administered daily for 14 days as compared to the administration of warfarin alone. There was a mean��SD increase in the prothrombin time response (area under the prothrombin time-time curve) of 7%��4% (range: -2 to 13%). Mean is based on data from 12 subjects as one of 13 subjects experienced a 2-fold increase in his prothrombin time response. Phenytoin: Phenytoin AUC was determined after 4 days of phenytoin dosing (200 mg daily, orally for 3 days followed by 250 mg intravenously for one dose) both with and without the administration of fluconazole (oral fluconazole 200 mg daily for 16 days) in 10 normal male volunteers. There was a significant increase in phenytoin AUC. The mean��SD increase in phenytoin AUC was 88%��68% (range: 16 to 247%). The absolute magnitude of this interaction is unknown because of the intrinsically nonlinear disposition of phenytoin. Cyclosporine: Cyclosporine AUC and Cmax were determined before and after the administration of fluconazole 200 mg daily for 14 days in eight renal transplant patients who had been on cyclosporine therapy for at least 6 months and on a stable cyclosporine dose for at least 6 weeks. There was a significant increase in cyclosporine AUC, Cmax, Cmin (24-hour concentration), and a significant reduction in apparent oral clearance following the administration of fluconazole. The mean��SD increase in AUC was 92%��43% (range: 18 to 147%). The Cmax Increased 60%��48% (range:���5 to 133%). The Cmin increased 157%��96% (range: 33 to 360%). The apparent oral clearance decreased 45%��15% (range:���15 to���60%). Zidovudine: Plasma zidovudine concentrations were determined on two occasions (before and following fluconazole 200 mg daily for 15 days) in 13 volunteers with AIDS or ARC who were on a stable zidovudine dose for at least two weeks. There was a significant increase in zidovudine AUC following the administration of fluconazole. The mean��SD increase in AUC was 20%��32% (range:���27 to 104%). The metabolite, GZDV, to parent drug ratio significantly decreased after the administration of fluconazole, from 7.6��3.6 to 5.7��2.2. Theophylline: The pharmacokinetics of theophylline were determined from a single intravenous dose of aminophylline (6 mg/kg) before and after the oral administration of fluconazole 200 mg daily for 14 days in 16 normal male volunteers. There were significant increases in theophylline AUC, Cmax, and half-life with a corresponding decrease in clearance. The mean��SD theophylline AUC increased 21%��16% (range:���5 to 48%). The Cmax increased 13%��17% (range:���13 to 40%). Theophylline clearance decreased 16%��11% (range:���32 to 5%). The half-life of theophylline increased from 6.6��1.7 hours to 7.9��1.5 hours. Terfenadine: Six healthy volunteers received terfenadine 60 mg BID for 15 days. Fluconazole 200 mg was administered daily from days 9 through 15. Fluconazole did not affect terfenadine plasma concentrations. Terfenadine acid metabolite AUC increased 36%��36% (range: 7 to 102%) from day 8 to day 15 with the concomitant administration of fluconazole. There was no change in cardiac repolarization as measured by Holter QTc intervals. Another study at a 400 mg and 800 mg daily dose of fluconazole demonstrated that fluconazole taken in doses of 400 mg per day or greater significantly increases plasma levels of terfenadine when taken concomitantly. Oral hypoglycemics: The effects of fluconazole on the pharmacokinetics of the sulfonylurea oral hypoglycemic agents tolbutamide, glipizide, and glyburide were evaluated in three placebo-controlled studies in normal volunteers. All subjects received the sulfonylurea alone as a single dose and again as a single dose following the administration of fluconazole 100 mg daily for 7 days. In these three studies 22/46 (47.8%) of fluconazole treated patients and 9/22 (40.1%) of placebo treated patients experienced symptoms consistent with hypoglycemia. Tolbutamide: In 13 normal male volunteers, there was significant increase in tolbutamide (500 mg single dose) AUC and Cmax following the administration of fluconazole. There was a mean��SD increase in tolbutamide AUC of 26%��9% (range: 12 to 39%). Tolbutamide Cmax increased 11%��9% (range:���6 to 27%). Glipizide: The AUC and Cmax of glipizide (2.5 mg single dose) were significantly increased following the administration of fluconazole in 13 normal male volunteers. There was a mean��SD increase in AUC of 49%��13% (range: 27 to 73%) and an increase in Cmax of 19%��23% (range:���11 to 79%). Glyburide: The AUC and Cmax of glyburide (5 mg single dose) were significantly increased following the administration of fluconazole in 20 normal male volunteers. There was a mean��SD increase in AUC of 44%��29% (range:���13 to 115%) and Cmax increased 19%��19% (range:���23 to 62%). Five subjects required oral glucose following the ingestion of glyburide after 7 days of fluconazole administration. Rifabutin: There have been published reports that an interaction exists when fluconazole is administered concomitantly with rifabutin, leading to increased serum levels of rifabutin. Tacrolimus: There have been published reports that an interaction exists when fluconazole is administered concomitantly with tacrolimus, leading to increased serum levels of tacrolimus. Cisapride: A placebo-controlled, randomized, multiple-dose study examined the potential interaction of fluconazole with cisapride. Two groups of 10 normal subjects were administered fluconazole 200 mg daily or placebo. Cisapride 20 mg four times daily was started after 7 days of fluconazole or placebo dosing. Following a single dose of fluconazole, there was a 101% increase in the cisapride AUC and a 91% increase in the cisapride Cmax. Following multiple doses of fluconazole, there was a 192% increase in the cisapride AUC and a 154% increase in the cisapride Cmax. Fluconazole significantly increased the QTc interval in subjects receiving cisapride 20 mg four times daily for 5 days. Midazolam: The effect of fluconazole on the pharmacokinetics and pharmacodynamics of midazolam was examined in a randomized, cross-over study in 12 volunteers. In the study, subjects ingested placebo or 400 mg fluconazole on Day 1 followed by 200 mg daily from Day 2 to Day 6. In addition, a 7.5 mg dose of midazolam was orally ingested on the first day, 0.05mg/kg was administered intravenously on the fourth day, and 7.5 mg orally on the sixth day. Fluconazole reduced the clearance of IV midazolam by 51%. On the first day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 150%, respectively. On the sixth day of dosing, fluconazole increased the midazolam AUC and Cmax by 259% and 74%, respectively. The psychomotor effects of midazolam were significantly increased after oral administration of midazolam but not significantly affected following intravenous midazolam. A second randomized, double-dummy, placebo-controlled, cross-over study in three phases was performed to determine the effect of route of administration of fluconazole on the interaction between fluconazole and midazolam. In each phase the subjects were given oral fluconazole 400 mg and intravenous saline; oral placebo and intravenous fluconazole 400 mg; and oral placebo and IV saline. An oral dose of 7.5 mg of midazolam was ingested after fluconazole/placebo.The AUC and Cmax of midazolam were significantly higher after oral than IV administration of fluconazole. Oral fluconazole increased the midazolam AUC and Cmax by 272% and 129%, respectively. IV fluconazole increased the midazolam AUC and Cmax by 244% and 79%, respectively. Both oral and IV fluconazole increased the pharmacodynamic effects of midazolam. Azithromycin: An open-label, randomized, three-way crossover study in 18 healthy subjects assessed the effect of a single 800 mg oral dose of fluconazole on the pharmacokinetics of a single 1200 mg oral dose of azithromycin as well as the effects of azithromycin on the pharmacokinetics of fluconazole. There was no significant pharmacokinetic interaction between fluconazole and azithromycin.<br/>Microbiology: Mechanism of Action Fluconazole is a highly selective inhibitor of fungal cytochrome P-450 dependent enzyme lanosterol 14-��-demethylase. This enzyme functions to convert lanosterol to ergosterol. The subsequent loss of normal sterols correlates with the accumulation of 14-��-methyl sterols in fungi and may be responsible for the fungistatic activity of fluconazole. Mammalian cell demethylation is much less sensitive to fluconazole inhibition. Activity In Vitro and In Clinical Infections Fluconazole has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections. Candida albicans Candida glabrata (Many strains are intermediately susceptible)* Candida parapsilosis Candida tropicalis Cryptococcus neoformans *In a majority of the studies fluconazole MICvalues against C. glabrata were above the susceptible breakpoint (���16 mcg/mL). Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as intermediate (16 to 32 mcg/mL, see Table 1: Susceptibility Interpretive Criteria for Fluconazole ), the highest dose is recommended . For resistantisolatesalternative therapy is recommended. The following in vitro data are available, but their clinical significance is unknown. Fluconazole exhibits in vitro minimum inhibitory concentrations (MIC values) of 8 mcg/mL or less against most (���90%) strains of the following microorganisms, however, the safety and effectiveness of fluconazole in treating clinical infections due to these microorganisms have not been established in adequate and well controlled trials. Candida dubliniensis Candida guilliermondii Candida kefyr Candida lusitaniae Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g., Candida krusei). Such cases may require alternative antifungal therapy. Susceptibility Testing Methods Cryptococcus neoformans and filamentous fungi: No interpretive criteria have been established for Cryptococcus neoformans and filamentous fungi. Candida species: Broth Dilution Techniques: Quantitative methods are used to determine antifungal minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of Candida spp. to antifungal agents. MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method (broth)with standardized inoculum concentrations of fluconazole powder. The MIC values should be interpreted according to the criteria provided in Table 1. Diffusion Techniques: Qualitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of Candida spp. to an antifungal agent. One such standardized procedurerequires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 25 mcg of fluconazole to test the susceptibility of yeasts to fluconazole. Disk diffusion interpretive criteria are also provided in Table 1. * Isolates of C. krusei are assumed to be intrinsically resistant to fluconazole and their MICs and/or zone diameters should not be interpreted using this scale. ** The intermediate category is sometimes called Susceptible-Dose Dependent (SDD) and both categories are equivalent for fluconazole. The susceptible category implies that isolates are inhibited by the usually achievable concentrations of antifungal agent tested when the recommended dosage is used. The intermediate category implies that an infection due to the isolate may be appropriately treated in body sites where the drugs are physiologically concentrated or when a high dosage of drug is used. The resistant category implies that isolates are not inhibited by the usually achievable concentrations ofthe agent with normal dosage schedules and clinical efficacy of the agent against the isolate has not been reliably shown in treatment studies. Quality Control Standardized susceptibility test procedures require the use of quality control organisms to control the technical aspects of the test procedures. Standardized fluconazole powder and 25 mcg disks should provide the following range of values noted in Table 2. NOTE: Quality control microorganisms are specificstrains of organisms with intrinsic biological properties relating to resistance mechanisms and their genetic expression within fungi; the specific strains used for microbiological control are not clinically significant. ---* Quality control ranges have not been established for this strain/antifungal agent combination due to their extensive interlaboratory variation during initial quality control studies. Activity In Vivo Fungistatic activity has also been demonstrated in normal and immunocompromised animal models for systemic and intracranial fungal infections due to Cryptococcus neoformans and for systemic infections due to Candida albicans. In common with other azole antifungal agents, most fungi show a higher apparent sensitivity to fluconazole in vivo than in vitro. Fluconazole administered orally and/or intravenously was active in a variety of animal models of fungal infection using standard laboratory strains of fungi. Activity has been demonstrated against fungal infections caused by Aspergillus flavus and Aspergillus fumigatus in normal mice. Fluconazole has also been shown to be active in animal models of endemic mycoses, including one model of Blastomyces dermatitidis pulmonary infections in normal mice; one model of Coccidioides immitis intracranial infections in normal mice; and several models of Histoplasma capsulatum pulmonary infection in normal and immunosuppressed mice. The clinical significance of results obtained in these studies is unknown. Oral fluconazole has been shown to be active in an animal model of vaginal candidiasis. Concurrent administration of fluconazole and amphotericin B in infected normal and immunosuppressed mice showed the following results: a small additive antifungal effect in systemic infection with C. albicans, no interaction in intracranial infection with Cryptococcus neoformans, and antagonism of the two drugs in systemic infection with A. fumigatus. The clinical significance of results obtained in these studies is unknown. Drug Resistance Fluconazole resistance may arise from a modification in the quality or quantity of the target enzyme (lanosterol 14-��-demethylase), reduced access to the drug target, or some combination of these mechanisms. Point mutations in the gene (ERG11) encoding for the target enzyme lead to an altered target with decreased affinity for azoles. Overexpression of ERG11 results in the production of high concentrations of the target enzyme, creating the need for higher intracellular drug concentrations to inhibit all of the enzyme molecules in the cell. The second major mechanism of drug resistance involves active efflux of fluconazole out of the cell through the activation of two types of multidrug efflux transporters; the major facilitators (encoded by MDR genes) and those of the ATP-binding cassette superfamily (encoded by CDR genes). Upregulation of the MDR gene leads to fluconazole resistance, whereas, upregulation of CDR genes may lead to resistance to multiple azoles. Resistance in Candida glabrata usually includes upregulation of CDR genes resulting in resistance to multiple azoles. For an isolate where the MIC is categorized as Intermediate (16 to 32 mcg/mL), the highest fluconazole dose is recommended. Candida krusei should be considered to be resistant to fluconazole. Resistance in C. krusei appears to be mediated by reduced sensitivity of the target enzyme to inhibition by the agent. There have been reports of cases of superinfection with Candida species other than C. albicans, which are often inherently not susceptible to fluconazole (e.g., Candida krusei). Such cases may require alternative antifungal therapy. | lld:dailymed |
| dailymed-drugs:8 | dailymed-instance:clinicalP... | Prednisolone acetate is a glucocorticoid that, on the basis of weight, has 3 to 5 times the anti-inflammatory potency of hydrocortisone. Glucocorticoids inhibit the edema, fibrin deposition, capillary dilation, and phagocytic migration of the acute inflammatory response, as well as capillary proliferation, deposition of collagen, and scar formation. | lld:dailymed |
| dailymed-drugs:1230 | dailymed-instance:clinicalP... | Prednisolone acetate is a glucocorticoid that, on the basis of weight, has 3 to 5 times the anti-inflammatory potency of hydrocortisone. Glucocorticoids inhibit the edema, fibrin deposition, capillary dilation, and phagocytic migration of the acute inflammatory response, as well as capillary proliferation, deposition of collagen, and scar formation. | lld:dailymed |
| dailymed-drugs:9 | dailymed-instance:clinicalP... | Leuprolide acetate is a long-acting GnRH analog. A single monthly injection of LUPRON DEPOT 3.75 mg results in an initial stimulation followed by a prolonged suppression of pituitary gonadotropins. Repeated dosing at monthly intervals results in decreased secretion of gonadal steroids; consequently, tissues and functions that depend on gonadal steroids for their maintenance become quiescent. This effect is reversible on discontinuation of drug therapy. Leuprolide acetate is not active when given orally. Intramuscular injection of the depot formulation provides plasma concentrations of leuprolide over a period of one month.<br/>Pharmacokinetics:<br/>Absorption: A single dose of LUPRON DEPOT 3.75 mg was administered by intramuscular injection to healthy female volunteers. The absorption of leuprolide was characterized by an initial increase in plasma concentration, with peak concentration ranging from 4.6 to 10.2 ng/mL at four hours postdosing. However, intact leuprolide and an inactive metabolite could not be distinguished by the assay used in the study. Following the initial rise, leuprolide concentrations started to plateau within two days after dosing and remained relatively stable for about four to five weeks with plasma concentrations of about 0.30 ng/mL.<br/>Distribution: The mean steady-state volume of distribution of leuprolide following intravenous bolus administration to healthy male volunteers was 27 L. In vitro binding to human plasma proteins ranged from 43% to 49%.<br/>Metabolism: In healthy male volunteers, a 1 mg bolus of leuprolide administered intravenously revealed that the mean systemic clearance was 7.6 L/h, with a terminal elimination half-life of approximately 3 hours based on a two compartment model. In rats and dogs, administration ofC-labeled leuprolide was shown to be metabolized to smaller inactive peptides, a pentapeptide (Metabolite I), tripeptides (Metabolites II and III) and a dipeptide (Metabolite IV). These fragments may be further catabolized. The major metabolite (M-I) plasma concentrations measured in 5 prostate cancer patients reached maximum concentration 2 to 6 hours after dosing and were approximately 6% of the peak parent drug concentration. One week after dosing, mean plasma M-I concentrations were approximately 20% of mean leuprolide concentrations.<br/>Excretion: Following administration of LUPRON DEPOT 3.75 mg to 3 patients, less than 5% of the dose was recovered as parent and M-I metabolite in the urine.<br/>Special Populations: The pharmacokinetics of the drug in hepatically and renally impaired patients have not been determined.<br/>Drug Interactions: No pharmacokinetic-based drug-drug interaction studies have been conducted with LUPRON DEPOT. However, because leuprolide acetate is a peptide that is primarily degraded by peptidase and not by cytochrome P-450 enzymes as noted in specific studies, and the drug is only about 46% bound to plasma proteins, drug interactions would not be expected to occur. | lld:dailymed |
| dailymed-drugs:10 | dailymed-instance:clinicalP... | Timolol is a non-selective beta-adrenergic antagonist.It blocks both beta-and beta-adrenergic receptors. Timolol does not have significant intrinsic sympathomimetic activity, local anesthetic (membrane-stabilizing) or direct myocardial depressant activity. Timolol, when applied topically in the eye, reduces normal and elevated intraocular pressure (IOP) whether or not accompanied by glaucoma. Elevated intraocular pressure is a major risk factor in the pathogenesis of glaucomatous visual field loss. The higher the level of IOP, the greater the likelihood of glaucomatous visual field loss and optic nerve damage. The predominant mechanism of ocular hypotensive action of topical beta-adrenergic blocking agents is likely due to a reduction in aqueous humor production. In general, beta-adrenergic blocking agents reduce cardiac output both in healthy subjects and patients with heart diseases. In patients with severe impairment of myocardial function, beta-adrenergic receptor blocking agents may inhibit sympathetic stimulatory effect necessary to maintain adequate cardiac function. In the bronchi and bronchioles, beta-adrenergic receptor blockade may also increase airway resistance because of unopposed parasympathetic activity.<br/>Pharmacokinetics: When given orally, timolol is well absorbed and undergoes considerable first pass metabolism. Timolol and its metabolites are primarily excreted in the urine. The half-life of timolol in plasma is approximately 4 hours.<br/>Clinical Studies: In two controlled multicenter studies in the U.S., Betimol 0.25% and 0.5% were compared with respective timolol maleate eyedrops. In these studies, the efficacy and safety profile of Betimol was similar to that of timolol maleate. | lld:dailymed |
| dailymed-drugs:11 | dailymed-instance:clinicalP... | Succimer is a lead chelator; it forms water soluble chelates and, consequently, increases the urinary excretion of lead.<br/>Preclinical Toxicology: In an ongoing six month chronic oral toxicity study in dogs, thrombocytopenia was observed in animals receiving succimer at 80 or 140 mg/kg/day after three months of dosing. Preliminary gross pathology findings in the affected dogs included ecchymoses in a number of organs. No depressed platelet counts were observed in dogs receiving succimer at 10 mg/kg/day for three months. Platelets were not enumerated in previous oral toxicity studies up to 28 days. In those studies, daily doses of succimer up to 200 mg/kg/day did not produce any significant overt toxicity in rats and dogs. However, six and twenty-eight day oral toxicity studies in dogs have shown that doses of 300 mg/kg/day or higher were toxic and lethal to some dogs. Kidney and gastrointestinal tract were the major target organs for succimer toxicity. Toxicity was manifested by anorexia, emesis, mucoid and/or bloody diarrhea, increased blood urea nitrogen concentration, increased SGPT, SGOT and alkaline phosphatase levels, renal tubular necrosis, purulent nephritis and severe gastrointestinal bleeding and ulceration. Deathswere due to renal failure.<br/>Pharmacokinetics: In a study performed in healthy adult volunteers, after a single dose ofC-succimer at 16, 32, or 48 mg/kg, absorption was rapid but variable with peak blood radioactivity levels between one and two hours. On average, 49% of the radiolabeled dose was excreted: 39% in the feces, 9% in the urine and 1% as carbon dioxide from the lungs. Since fecal excretion probably represented nonabsorbed drug, most of the absorbed drug was excreted by the kidneys. The apparent elimination half-life of the radiolabeled material in the blood was about two days. In other studies of healthy adult volunteers receiving a single oral dose of 10 mg/kg, the chemical analysis of succimer and its metabolites in the urine showed that succimer was rapidly and extensively metabolized. Approximately 25% of the administered dose was excreted in the urine with the peak blood level and urinary excretion occurring between two and four hours. Of the total amount of drug eliminated in the urine, approximately 90% was eliminated in altered form as mixed succimer-cysteine disulfides; the remaining 10% was eliminated unchanged. The majority ofmixed disulfides consisted of succimer in disulfide linkages with two molecules of L-cysteine, the remaining disulfides contained one L-cysteine per succimer molecule.<br/>Pharmacodynamics: Dose ranging studies were performed in 18 men with blood lead levels of 44-96��g/dL. Three groups of 6 patients received either 10.0, 6.7 or 3.3 mg/kg succimer orally every 8 hours for 5 days. After five days the mean blood levels of the three groups decreased 72.5%, 58.3% and 35.5% respectively. The mean urinary lead excretions in the initial 24 hours were 28.6, 18.6 and 12.3 times the pretreatment 24 hour urinary lead excretion. As the chelatable pool was reduced during therapy, urinary lead output decreased. A mean of 19 mg of lead was excreted during a five-day course of 30 mg/kg/day succimer. Clinical symptoms, such as headache and colic, and biochemical indices of lead toxicity also improved. Decrease in urinary excretion of d-aminole-vulinic acid (ALA) and coproporphyrin paralleled the improvement in erythrocyte d-aminolevulinic acid dehydratase (ALA-D). Three control patients with lead poisoning of similar severity received CaNaEDTA intravenously at a dose of 50 mg/kg/day for five days. The mean blood lead level decreased 47.4% and the mean urinary lead excretion was 21 mg in the control patients.<br/>Effect on Essential Minerals: In the above studies succimer had no significant effect on the urinary elimination of iron, calcium or magnesium. Zinc excretion doubled during treatment. The effect of succimer on the excretion of essential minerals was small compared to that of CaNaEDTA, which can induce more than a ten-fold increase in urinary excretion of zinc and doubling of copper and iron excretion.<br/>Efficacy: A dose ranging study was performed in 15 pediatric patients aged 2 to 7 years with blood lead levels of 30-49��g/dL and positive CaNaEDTA lead mobilization tests. Each group of five patients received 350, 233 or 116 mg/msuccimer every 8 hours for 5 days. These doses corresponded to 10, 6.7 and 3.3 mg/kg. Six control patients received 1000 mg/m/day CaNaEDTA intravenously for 5 days. Following therapy, the mean blood lead levels decreased 78, 63 and 42% respectively in the three groups treated with succimer. The response of the 350 mg/mevery 8 hours (10 mg/kg q 8 hr) group was significantly better than that of the other succimer treated groups as well as that of the control group, whose mean blood lead level fell 48%. No adverse reactions or changes in essential mineral excretion were reported in the succimer treated groups. In the CaNaEDTA treated group, the cumulative amount of urinary lead excreted was slightly but significantly greater than in the succimer group. After CaNaEDTA, the urinary excretion of copper, zinc, iron and calcium were significantly increased. As with other chelators, both adults and pediatric patients experienced a rebound in blood lead levels after discontinuation of CHEMET. In these studies, after treatment with a dose of 350 mg/m(10 mg/kg) every 8 hours for five days, the mean lead level rebounded and plateaued at 60-85% of pretreatment levels two weeks after therapy. The rebound plateau was somewhat higher with lower doses of succimer and with intravenous CaNaEDTA. In an attempt to control rebound of blood lead levels, 19 pediatric patients, ages 1-7 years, with blood lead levels of 42-67��g/dL, were treated with 350 mg/msuccimer every 8 hours for five days and then divided into three groups. One group was followed for two weeks with no further therapy, the second group was treated for two weeks with 350 mg/mdaily, and the third with 350 mg/mevery 12 hours. After the initial 5 days of therapy, the mean blood lead level in all subjects declined 61%. While the untreated group and the group treated with 350 mg/mdaily experienced rebound during the ensuing two weeks, the group who received the 350 mg/mevery 12 hours experienced no such rebound during the treatment period and less rebound following cessation of therapy. In another study, ten pediatric patients, ages 21 to 72 months, with blood lead levels of 30-57��g/dL were treated with succimer 350 mg/mevery eight hours for five days followed by an additional 19-22 days of therapy at a dose of 350 mg/mevery 12 hours. The mean blood lead levels decreased and remained stable at under 15��g/dL during the extended dosing period. In addition to the controlled studies, approximately 250 patients with lead poisoning have been treated with succimer either orally or parenterally in open U.S. and foreign studies with similar results reported. Succimer has been used for the treatment of lead poisoning in one patient with sickle cell anemia and in five patients with glucose-6-phosphodehydrogenase (G6PD) deficiency without adverse reactions.<br/>Lead Encephalopathy: Three adults with lead encephalopathy have been reported in the literature to have improved with succimer therapy. However, data are not available regarding the use of succimer for the treatment of this rare and sometimes fatal complication of lead poisoning in pediatric patients.<br/>Other Heavy Metal Poisoning: No controlled clinical studies have been conducted with succimer in poisoning with other heavy metals. A limited number of patients have received succimer for mercury or arsenic poisoning. These patients showed increased urinary excretion of the heavy metal and varying degrees of symptomatic improvement. | lld:dailymed |
| dailymed-drugs:12 | dailymed-instance:clinicalP... | Pharmacodynamics: The mechanism of action of REMERON' (mirtazapine) Tablets, as with other drugs effective in the treatment of major depressive disorder, is unknown. Evidence gathered in preclinical studies suggests that mirtazapine enhances central noradrenergic and serotonergic activity. These studies have shown that mirtazapine acts as an antagonist at central presynaptic��adrenergic inhibitory autoreceptors and heteroreceptors, an action that is postulated to result in an increase in central noradrenergic and serotonergic activity. Mirtazapine is a potent antagonist of 5-HTand 5-HTreceptors. Mirtazapine has no significant affinity for the 5-HTand 5-HTreceptors. Mirtazapine is a potent antagonist of histamine (H) receptors, a property that may explain its prominent sedative effects. Mirtazapine is a moderate peripheral��adrenergic antagonist, a property that may explain the occasional orthostatic hypotension reported in association with its use. Mirtazapine is a moderate antagonist at muscarinic receptors, a property that may explain the relatively low incidence of anticholinergic side effects associated with its use.<br/>Pharmacokinetics: REMERON' (mirtazapine) Tablets are rapidly and completely absorbed following oral administration and have a half-life of about 20���40 hours. Peak plasma concentrations are reached within about 2 hours following an oral dose. The presence of food in the stomach has a minimal effect on both the rate and extent of absorption and does not require a dosage adjustment. Mirtazapine is extensively metabolized after oral administration. Major pathways of biotransformation are demethylation and hydroxylation followed by glucuronide conjugation. In vitro data from human liver microsomes indicate that cytochrome 2D6 and 1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas cytochrome 3A is considered to be responsible for the formation of the N-desmethyl and N-oxide metabolite. Mirtazapine has an absolute bioavailability of about 50%. It is eliminated predominantly via urine (75%) with 15% in feces. Several unconjugated metabolites possess pharmacological activity but are present in the plasma at very low levels. The (���) enantiomer has an elimination half-life that is approximately twice as long as the (+) enantiomer and therefore achieves plasma levels that are about three times as high as that of the (+) enantiomer. Plasma levels are linearly related to dose over a dose range of 15���80 mg. The mean elimination half-life of mirtazapine after oral administration ranges from approximately 20���40 hours across age and gender subgroups, with females of all ages exhibiting significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males). Steady state plasma levels of mirtazapine are attained within 5 days, with about 50% accumulation (accumulation ratio = 1.5). Mirtazapine is approximately 85% bound to plasma proteins over a concentration range of 0.01 - 10��g/mL.<br/>Special Populations:<br/>Geriatric: Following oral administration of REMERON' (mirtazapine) Tablets 20 mg/day for 7 days to subjects of varying ages (range, 25���74), oral clearance of mirtazapine was reduced in the elderly compared to the younger subjects. The differences were most striking in males, with a 40% lower clearance in elderly males compared to younger males, while the clearance in elderly females was only 10% lower compared to younger females. Caution is indicated in administering REMERON' to elderly patients (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).<br/>Pediatrics: Safety and effectiveness of mirtazapine in the pediatric population have not been established .<br/>Gender: The mean elimination half-life of mirtazapine after oral administration ranges from approximately 20���40 hours across age and gender subgroups, with females of all ages exhibiting significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males) (see Pharmacokinetics).<br/>Race: There have been no clinical studies to evaluate the effect of race on the pharmacokinetics of REMERON'.<br/>Renal Insufficiency: The disposition of mirtazapine was studied in patients with varying degrees of renal function. Elimination of mirtazapine is correlated with creatinine clearance. Total body clearance of mirtazapine was reduced approximately 30% in patients with moderate (Clcr = 11���39 mL/min/1.73 m) and approximately 50% in patients with severe (Clcr =<10 mL/min/1.73 m) renal impairment when compared to normal subjects. Caution is indicated in administering REMERON' to patients with compromised renal function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).<br/>Hepatic Insufficiency: Following a single 15 mg oral dose of REMERON', the oral clearance of mirtazapine was decreased by approximately 30% in hepatically impaired patients compared to subjects with normal hepatic function. Caution is indicated in administering REMERON' to patients with compromised hepatic function (see PRECAUTIONS and DOSAGE AND ADMINISTRATION).<br/>Clinical Trials Showing Effectiveness: The efficacy of REMERON' (mirtazapine) Tablets as a treatment for major depressive disorder was established in four placebo-controlled, 6-week trials in adult outpatients meeting DSM-III criteria for major depressive disorder. Patients were titrated with mirtazapine from a dose range of 5 mg up to 35 mg/day. Overall, these studies demonstrated mirtazapine to be superior to placebo on at least three of the following four measures: 21-Item Hamilton Depression Rating Scale (HDRS) total score; HDRS Depressed Mood Item; CGI Severity score; and Montgomery and Asberg Depression Rating Scale (MADRS). Superiority of mirtazapine over placebo was also found for certain factors of the HDRS, including anxiety/somatization factor and sleep disturbance factor. The mean mirtazapine dose for patients who completed these four studiesranged from 21���32 mg/day. A fifth study of similar design utilized a higher dose (up to 50 mg) per day and also showed effectiveness. Examination of age and gender subsets of the population did not reveal any differential responsiveness on the basis of these subgroupings. In a longer-term study, patients meeting (DSM-IV) criteria for major depressive disorder who had responded during an initial 8���12 weeks of acute treatment on REMERON' were randomized to continuation of REMERON' or placebo for up to 40 weeks of observation for relapse. Response during the open phase was defined as having achieved a HAM-D 17 total score of���8 and a CGI-Improvement score of 1 or 2 at two consecutive visits beginning with week 6 of the 8���12 weeks in the open-label phase of the study. Relapse during the double-blind phase was determined by the individual investigators. Patients receiving continued REMERON' treatment experienced significantly lower relapse rates over the subsequent 40 weeks compared to those receiving placebo. This pattern was demonstrated in both male and female patients. | lld:dailymed |
| dailymed-drugs:14 | dailymed-instance:clinicalP... | An in vitro percutaneous penetration study comparing BenzaClin Topical Gel and topical 1% clindamycin gel alone, demonstrated there was no statistical difference in penetration between the two drugs. Mean systemic bioavailability of topical clindamycin in BenzaClin Topical Gel is suggested to be less than 1%. Benzoyl peroxide has been shown to be absorbed by the skin where it is converted to benzoic acid. Less than 2% of the dose enters systemic circulation as benzoic acid. It is suggested that the lipophilic nature of benzoyl peroxide acts to concentrate the compound into the lipid-rich sebaceous follicle.<br/>Microbiology: The clindamycin and benzoyl peroxide components individually have been shown to have in vitro activity against Propionibacterium acnes an organism which has been associated with acne vulgaris; however, the clinical significance of this activity against P. acnes was not examined in clinical trials with this product. | lld:dailymed |
| dailymed-drugs:2267 | dailymed-instance:clinicalP... | An in vitro percutaneous penetration study comparing BenzaClin Topical Gel and topical 1% clindamycin gel alone, demonstrated there was no statistical difference in penetration between the two drugs. Mean systemic bioavailability of topical clindamycin in BenzaClin Topical Gel is suggested to be less than 1%. Benzoyl peroxide has been shown to be absorbed by the skin where it is converted to benzoic acid. Less than 2% of the dose enters systemic circulation as benzoic acid. It is suggested that the lipophilic nature of benzoyl peroxide acts to concentrate the compound into the lipid-rich sebaceous follicle.<br/>Microbiology: The clindamycin and benzoyl peroxide components individually have been shown to have in vitro activity against Propionibacterium acnes an organism which has been associated with acne vulgaris; however, the clinical significance of this activity against P. acnes was not examined in clinical trials with this product. | lld:dailymed |
| dailymed-drugs:15 | dailymed-instance:clinicalP... | General: Penicillin G benzathine has an extremely low solubility and, thus, the drug is slowly released from intramuscular injection sites. The drug is hydrolyzed to penicillin G. This combination of hydrolysis and slow absorption results in blood serum levels much lower but much more prolonged than other parenteral penicillins. Intramuscular administration of 300,000 units of penicillin G benzathine in adults results in blood levels of 0.03 to 0.05 units per mL, which are maintained for 4 to 5 days. Similar blood levels may persist for 10 days following administration of 600,000 units and for 14 days following administration of 1,200,000 units. Blood concentrations of 0.003 units per mL may still be detectable 4 weeks following administration of 1,200,000 units. Approximately 60% of penicillin G is bound to serum protein. The drug is distributed throughout the body tissues in widely varying amounts. Highest levels are found in the kidneys with lesser amounts in the liver, skin, and intestines. Penicillin G penetrates into all other tissues and the spinal fluid to a lesser degree. With normal kidney function, the drug is excreted rapidly by tubular excretion. In neonates and young infants and in individuals with impaired kidney function, excretion is considerably delayed.<br/>Microbiology: Penicillin G exerts a bactericidal action against penicillin-susceptible microorganisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell-wall mucopeptide. It is not active against the penicillinase-producing bacteria, which include many strains of staphylococci. The following in vitro data are available, but their clinical significance is unknown. Penicillin G exerts high in vitro activity against staphylococci (except penicillinase-producing strains), streptococci (Groups A, C, G, H, L, and M), and pneumococci. Other organisms susceptible to penicillin G are Neisseria gonorrhoeae, Corynebacterium diphtheriae, Bacillus anthracis, Clostridia species, Actinomyces bovis, Streptobacillus moniliformis, Listeria monocytogenes, and Leptospira species. Treponema pallidum is extremely susceptible to the bactericidal action of penicillin G. Susceptibility Test: If the Kirby-Bauer method of disc susceptibility is used, a 20-unit penicillin disc should give a zone greater than 28 mm when tested against a penicillin-susceptible bacterial strain. | lld:dailymed |
| dailymed-drugs:16 | dailymed-instance:clinicalP... | Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. | lld:dailymed |
| dailymed-drugs:3389 | dailymed-instance:clinicalP... | Potassium Chloride in 5% Dextrose and Sodium Chloride Injection, USP has value as a source of water, electrolytes and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. | lld:dailymed |
| dailymed-drugs:17 | dailymed-instance:clinicalP... | Pharmacodynamics:<br/>Mechanism of Action: Antiviral: The mechanism by which amantadine exerts its antiviral activity is not clearly understood. It appears to mainly prevent the release of infectious viral nucleic acid into the host cell by interfering with the function of the transmembrane domain of the viral M2 protein. In certain cases, amantadine is also known to prevent virus assembly during virus replication. It does not appear to interfere with the immunogenicity of inactivated influenza A virus vaccine.<br/>Antiviral Activity:: Amantadine inhibits the replication of influenza A virus isolates from each of the subtypes, i.e., H1N1, H2N2 and H3N2. It has very little or no activity against influenza B virus isolates. A quantitative relationship between the in vitro susceptibility of influenza A virus to amantadine and the clinical response to therapy has not been established in man. Sensitivity test results, expressed as the concentration of amantadine required to inhibit by 50% the growth of virus (ED) in tissue culture vary greatly (from 0.1��g/mL to 25.0��g/mL) depending upon the assay protocol used, size of virus inoculum, isolates of influenza A virus strains tested, and the cell type used. Host cells in tissue culture readily tolerated amantadine up to a concentration of 100��g/mL.<br/>Drug Resistance:: Influenza A variants with reduced in vitro sensitivity to amantadine have been isolated from epidemic strains in areas where adamantane derivatives are being used. Influenza viruses with reduced in vitro sensitivity have been shown to be transmissible and to cause typical influenza illness. The quantitative relationship between the in vitro sensitivity of influenza A variants to amantadine and the clinical response to therapy has not been established.<br/>Mechanism of Action: Parkinson's Disease: The mechanism of action of amantadine in the treatment of Parkinson's disease and drug-induced extrapyramidal reactions is not known. Data from earlier animal studies suggest that Amantadine Hydrochloride may have direct and indirect effects on dopamine neurons. More recent studies have demonstrated that amantadine is a weak, non-competitive NMDA receptor antagonist (Ki = 10��M). Although amantadine has not been shown to possess direct anticholinergic activity in animal studies, clinically, it exhibits anticholinergic-like side effects such as dry mouth, urinary retention, and constipation.<br/>Pharmacokinetics: Amantadine Hydrochloride is well absorbed orally. Maximum plasma concentrations are directly related to dose for doses up to 200 mg/day. Doses above 200 mg/day may result in a greater than proportional increase in maximum plasma concentrations. It is primarily excreted unchanged in the urine by glomerular filtration and tubular secretion. Eight metabolites of amantadine have been identified in human urine. One metabolite, an N-acetylated compound, was quantified in human urine and accounted for 5-15% of the administered dose. Plasma acetylamantadine accounted for up to 80% of the concurrent amantadine plasma concentration in 5 of 12 healthy volunteers following the ingestion of a 200 mg dose of amantadine. Acetylamantadine was not detected in the plasma of the remaining seven volunteers. The contribution of this metabolite to efficacy or toxicity is not known. There appears to be a relationship between plasma amantadine concentrations and toxicity. As concentration increases toxicity seems to be more prevalent, however absolute values of amantadine concentrations associated with adverse effects have not been fully defined. Amantadine pharmacokinetics were determined in 24 normal adult male volunteers after the oral administration of a single amantadine hydrochloride 100 mg soft gel capsule. The mean��SD maximum plasma concentration was 0.22��0.03��g/mL (range: 0.18 to 0.32��g/mL). The time to peak concentration was 3.3��1.5 hours (range: 1.5 to 8.0 hours). The apparent oral clearance was 0.28��0.11 L/hr/kg (range: 0.14 to 0.62 L/hr/kg). The half-life was 17��4 hours (range: 10 to 25 hours). Across other studies, amantadine plasma half-life has averaged 16��6 hours (range: 9 to 31 hours) in 19 healthy volunteers. After oral administration of a single dose of 100 mg of amantadine oral solution to five healthy volunteers, the mean��SD maximum plasma concentration Cwas 0.24��0.04��g/mL and ranged from 0.18 to 0.28��g/mL. After 15 days of amantadine 100 mg b.i.d. the Cwas 0.47��0.11��g/mL in four of five volunteers. Plasma amantadine clearance ranged from 0.2 to 0.3 L/hr/kg after the administration of 5 mg to 25 mg intravenous doses of amantadine to 15 healthy volunteers. In six healthy volunteers, the ratio of amantadine renal clearance to apparent oral plasma clearance was 0.79��0.17 (mean��SD). The volume of distribution determined after the intravenous administration of amantadine to 15 healthy subjects was 3 to 8 L/kg, suggesting tissue binding. Amantadine, after single oral 200 mg doses to 6 healthy young subjects and to 6 healthy elderly subjects has been found in nasal mucus at mean��SD concentrations of 0.15��0.16, 0.28��0.26, and 0.39��0.34��g/g at 1, 4, and 8 hours after dosing, respectively. These concentrations represented 31��33%, 59��61%, and 95��86% of the corresponding plasma amantadine concentrations. Amantadine is approximately 67% bound to plasma proteins over a concentration range of 0.1 to 2.0��g/mL. Following the administration of amantadine 100 mg as a single dose, the mean��SD red blood cell to plasma ratio ranged from 2.7��0.5 in 6 healthy subjects to 1.4��0.2 in 8 patients with renal insufficiency. The apparent oral plasma clearance of amantadine is reduced and the plasma half-life and plasma concentrations are increased in healthy elderly individuals age 60 and older. After single dose administration of 25 to 75 mg to 7 healthy, elderly male volunteers, the apparent plasma clearance of amantadine was 0.10��0.04 L/hr/kg (range 0.06 to 0.17 L/hr/kg) and the half-life was 29��7 hours (range 20 to 41 hours). Whether these changes are due to decline in renal function or other age related factors is not known. In a study of young healthy subjects (n=20), mean renal clearance of amantadine, normalized for body mass index, was 1.5 fold higher in males compared to females (p<0.032). Compared with otherwise healthy adult individuals, the clearance of amantadine is significantly reduced in adult patients with renal insufficiency. The elimination half-life increases two to three fold or greater when creatinine clearance is less than 40 mL/min/1.73 mand averages eight days in patients on chronic maintenance hemodialysis. Amantadine is removed in negligible amounts by hemodialysis. The pH of the urine has been reported to influence the excretion rate of Amantadine Hydrochloride. Since the excretion rate of Amantadine Hydrochloride increases rapidly when the urine is acidic, the administration of urine acidifying drugs may increase the elimination of the drug from the body. | lld:dailymed |
| dailymed-drugs:18 | dailymed-instance:clinicalP... | It is believed that platelet reactivity and interaction with prosthetic cardiac valve surfaces, resulting in abnormally shortened platelet survival time, is a significant factor in thromboembolic complications occurring in connection with prosthetic heart valve replacement. Dipyridamole USP tablets have been found to lengthen abnormally shortened platelet survival time in a dose-dependent manner. In three randomized controlled clinical trials involving 854 patients who had undergone surgical placement of a prosthetic heart valve, dipyridamole USP tablets, in combination with warfarin, decreased the incidence of postoperative thromboembolic events by 62 to 91 % compared to warfarin treatment alone. Theincidence of thromboembolic events in patients receiving the combination of dipyridamole USP tablets and warfarin ranged from 1.2 to 1.8%. In three additional studies involving 392 patients taking dipyridamole USP tablets and coumarin-like anticoagulants, the incidence of thromboembolic events ranged from 2.3 to 6.9%. In these trials, the coumarin anticoagulant was begun between 24 hours and 4 days postoperatively, and the dipyridamole USP tablets were begun between 24 hours and 10 days postoperatively. The length of follow-up in these trials varied from 1 to 2 years. Dipyridamole USP tablets do not influence prothrombin time or activity measurements when administered with warfarin.<br/>Mechanism of Action: Dipyridamole inhibits the uptake of adenosine into platelets, endothelial cells and erythrocytes in vitro and in vivo; the inhibition occurs in a dose-dependent manner at therapeutic concentrations (0.5-1.9��g/mL). This inhibition results in an increase in local concentrations of adenosine which acts on the platelet A2-receptor thereby stimulating platelet adenylate cyclase and increasing platelet cyclic-3',5'-adenosine monophosphate (cAMP) levels. Via this mechanism, platelet aggregation is inhibited in response to various stimuli such as platelet activating factor (PAF), collagen and adenosine diphosphate (ADP). Dipyridamole inhibits phosphodiesterase (PDE) in various tissues. While the inhibition of cAMP-PDE is weak, therapeutic levels of dipyridamole inhibit cyclic-3',5'-guanosine monophosphate-PDE (cGMP-PDE), thereby augmenting the increase in cGMP produced by EDRF (endothelium-derived relaxing factor, now identified as nitric oxide).<br/>Hemodynamics: In dogs intraduodenal doses of dipyridamole of 0.5 to 4.0 mg/kg produced dose-related decreases in systemic and coronary vascular resistance leading to decreases in systemic blood pressure and increases in coronary blood flow. Onset of action was in about 24 minutes and effects persisted for about 3 hours. Similar effects were observed following IV dipyridamole USP in doses ranging from 0.025 to 2.0 mg/kg. In man the same qualitative hemodynamic effects have been observed. However, acute intravenous administration of dipyridamole USP may worsen regional myocardial perfusion distal to partial occlusion of coronary arteries.<br/>Pharmacokinetics and Metabolism: Following an oral dose of dipyridamole USP tablets, the average time to peak concentration is about 75 minutes. The decline in plasma concentration following a dose of Dipyridamole USP tablets fits a two-compartment model. The alpha half-life (the initial decline following peak concentration) is approximately 40 minutes. The beta half-life (the terminal decline in plasma concentration) is approximately 10 hours. Dipyridamole is highly bound to plasma proteins. It is metabolized in the liver where it is conjugated as a glucuronide and excreted with the bile. | lld:dailymed |
| dailymed-drugs:19 | dailymed-instance:clinicalP... | Penicillin G procaine is an equimolecular compound of procaine and penicillin G, administered intramuscularly as a suspension. It dissolves slowly at the site of injection, giving a plateau type of blood level at about 4 hours which falls slowly over a period of the next 15 to 20 hours. Approximately 60% of penicillin G is bound to serum protein. The drug is distributed throughout the body tissues in widely varying amounts. Highest levels are found in the kidneys with lesser amounts in the liver, skin, and intestines. Penicillin G penetrates into all other tissues to a lesser degree with a very small level found in the cerebrospinal fluid. With normal kidney function, the drug is excreted rapidly by tubular excretion. In neonates and young infants and in individuals with impaired kidney functions, excretion is considerably delayed. Approximately 60 to 90 percent of a dose of parenteral penicillin G is excreted in the urine within 24 to 36 hours. Microbiology: Penicillin G exerts a bactericidal action against penicillin-susceptible microorganisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell-wall mucopeptide. It is not active against the penicillinase-producing bacteria, which include many strains of staphylococci. Whilein vitro studies have demonstrated the susceptibility of most strains of the following organisms, clinical efficacy for infections other than those included in the INDICATIONS AND USAGE section has not been documented. Penicillin G exerts highin vitro activity against staphylococci (except penicillinase-producing strains), streptococci (Groups A, C, G, H, L, and M), and pneumococci. Other organisms susceptible to penicillin G are Corynebacterium diphtheriae, Bacillus anthracis, Clostridium species, Actinomyces bovis, Streptobacillus moniliformis, Listeria monocytogenes, and Leptospira species. Treponemapallidum is extremely susceptible to the bactericidal action of penicillin G.<br/>Susceptibility Testing: Ten unit Penicillin G Susceptibility Discs may be used to determine microbial susceptibility to penicillin G using one of the followingstandard methods recommended by the National Committee for Laboratory Standards: M2-T4,���Performance Standards for Antimicrobial Disc Susceptibility Tests��� M7-T2,���Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically��� Tests should be interpreted by the following criteria: Interpretations of susceptible, intermediate, and resistant correlate zone size diameters with MIC values. A laboratory report of���susceptible���indicates that the suspected causative microorganism most likely will respond to therapy with penicillin G. A laboratory report of���resistant���indicates that the infecting microorganism most likely will not respond to therapy. A laboratory report of���moderately susceptible���indicates that the microorganism is most likely susceptible if a high dosage of penicillin G is used, or if the infection is such that high levels of penicillin G may be attained as in urine. A report of���intermediate���using the disc diffusion method may be considered an equivocal result, and dilution tests may be indicated. Control organisms are recommended for susceptibility testing. Each time the test is performed the following organism should be included. The range for zones of inhibition is shown below: | lld:dailymed |
| dailymed-drugs:20 | dailymed-instance:clinicalP... | Mechanism of Action:: Quinapril is deesterified to the principal metabolite, quinaprilat, which is an inhibitor of ACE activity in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The effect of quinapril in hypertension appears to result primarily from theinhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation. Quinapril inhibits the elevation in blood pressure caused by intravenously administered angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine or epinephrine. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex, thereby facilitating renal sodium and fluid reabsorption. Reduced aldosterone secretion by quinapril may result in a small increase inserum potassium. In controlled hypertension trials, treatment with quinapril hydrochloride alone resulted in mean increases in potassium of 0.07 mmol/L (see PRECAUTIONS). Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA). While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with low renin hypertension. Quinapril hydrochloride was an effective antihypertensive in all races studied, although it was somewhat less effective in blacks (usually a predominantly low renin group) than in nonblacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of quinapril remains to be elucidated.<br/>Pharmacokinetics and Metabolism:: Following oral administration, peak plasma quinapril concentrations are observed within one hour. Based on recovery of quinapril and its metabolites in urine, the extent of absorption is at least 60%. The rate and extent of quinapril absorption are diminished moderately (approximately 25 to 30%) when quinapril tablets are administered during a high-fat meal. Following absorption, quinapril is deesterified to its major active metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites. Following multiple oral dosing of quinapril hydrochloride, there is an effective accumulation half-life of quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed approximately 2 hours post-dose. Quinaprilat is eliminated primarily by renal excretion, up to 96% of an IV dose, and has an elimination half-life in plasma of approximately 2 hours and a prolonged terminal phase with a half-life of 25 hours. The pharmacokinetics of quinapril and quinaprilat are linear over a single-dose range of 5 to 80 mg doses and 40 to 160 mg in multiple daily doses. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins. In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine clearance decreases. There is a linear correlation between plasma quinaprilat clearance and creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or continuous ambulatory peritoneal dialysis has little effect on the elimination of quinapril and quinaprilat. Elimination of quinaprilat may be reduced in elderly patients (���65 years) and in those with heart failure; this reduction is attributable to decrease in renal function (see DOSAGE AND ADMINISTRATION). Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril. Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier.<br/>Pharmacodynamics and Clinical Effects:<br/>Hypertension:: Single doses of 20 mg of quinapril hydrochloride provide over 80% inhibition of plasma ACE for 24 hours. Inhibition of the pressor response to angiotensin I is shorter-lived, with a 20 mg dose giving 75% inhibition for about 4 hours, 50% inhibition for about 8 hours, and 20% inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of angiotensin II levels at 24 hours by doses of 20 to 80 mg. Administration of 10 to 80 mg of quinapril hydrochloride to patients with mild to severe hypertension results in a reduction of sitting and standing blood pressure to about the same extent with minimal effect on heart rate. Symptomatic postural hypotension is infrequent although it can occur in patients who are salt-and/or volume-depleted (see WARNINGS). Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after dosing. During chronic therapy, most of the blood pressure lowering effect of a given dose is obtained in 1 to 2 weeks. In multiple-dose studies, 10 to 80 mg per day in singleor divided doses lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect of about 5 to 11/3 to 7 mm Hg. The trough effect represents about 50% of the peak effect. While the dose-response relationship is relatively flat, doses of 40 to 80 mg were somewhat more effective at trough than 10 to 20 mg, and twice daily dosing tended to give a somewhat lower trough blood pressure than once daily dosing with the same total dose. The antihypertensive effect of quinaprilhydrochloride continues during long-term therapy, with no evidence of loss of effectiveness. Hemodynamic assessments in patients with hypertension indicate that blood pressure reduction produced by quinapril is accompanied by a reduction in total peripheral resistance and renal vascular resistance with little or no change in heart rate, cardiac index, renal blood flow, glomerular filtration rate, or filtration fraction. Use of quinapril hydrochloride with a thiazide diuretic gives a blood-pressure lowering effect greater than that seen with either agent alone. In patients with hypertension, quinapril hydrochloride 10 to 40 mg was similar in effectiveness to captopril, enalapril, propranolol, and thiazide diuretics. Therapeutic effects appear to be the same for elderly (���65 years of age) and younger adult patients given the same daily dosages, with no increase in adverse events in elderly patients. | lld:dailymed |
| dailymed-drugs:21 | dailymed-instance:clinicalP... | Dipivefrin hydrochloride is a member of a class of drugs known as prodrugs. Prodrugs are usually not active in themselves and require biotransformation to the parent compound before therapeutic activity is seen. These modifications are undertaken to enhance absorption, decrease side effects and enhance stability and comfort, thus making the parent compound a more useful drug. Enhanced absorption makes the prodrug a more efficient delivery system for the parent drug because less drug will be needed to produce the desired therapeutic response. Dipivefrin is a prodrug of epinephrine formed by the diesterification of epinephrine and pivalic acid. The addition of pivaloyl groups to the epinephrine molecule enhances its lipophilic character and, as a consequence, its penetration into the anterior chamber. Dipivefrin is converted to epinephrine inside the human eye by enzyme hydrolysis. The liberated epinephrine, an adrenergic agonist, appears to exert its action by decreasing aqueous production and by enhancing outflow facility. The dipivefrin hydrochloride prodrug delivery system is a more efficient way of delivering the therapeutic effects of epinephrine, with fewer side effects than are associated with conventional epinephrine therapy. The onset of action with one drop of dipivefrin hydrochloride ophthalmic solution occurs about 30 minutes after treatment, with maximum effect seen at about one hour. Using a prodrug means that less drug is needed for therapeutic effect since absorption is enhanced with the prodrug. Dipivefrin hydrochloride, 0.1% was judged less irritating than a 1% solution of epinephrine hydrochloride or bitartrate. In addition, only 8 of 455 patients (1.8%) treated with dipivefrin reported discomfort due to photophobia, glare or light sensitivity. | lld:dailymed |
| dailymed-drugs:22 | dailymed-instance:clinicalP... | Ringer's Injection USP provides electrolytes and is a source of water for hydration. It is capable of inducing diuresis depending on the clinical condition of the patient. Sodium, the major cation of the extracellular fluid, functions primarily in the control of water distribution, fluid balance, and osmotic pressure of body fluids. Sodium is also associated with chloride and bicarbonate in the regulation of the acid-base equilibrium of body fluid. Potassium, the principal cation of intracellular fluid, participates in carbohydrate utilization and protein synthesis, and is critical in the regulation of nerve conduction and muscle contraction, particularly in the heart. Chloride, the major extracellular anion, closely follows the metabolism of sodium, and changes in the acid-base balance of the body are reflected by changes in the chloride concentration. Calcium, an important cation, provides the framework of bones and teeth in the form of calcium phosphate and calcium carbonate. In the ionized form, calcium is essential for the functional mechanism of the clotting of blood, normal cardiac function, and regulation of neuromuscular irritability. | lld:dailymed |
| dailymed-drugs:23 | dailymed-instance:clinicalP... | Combination hormonal contraceptives act by suppression of gonadotropins. Although the primary effect of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation). Receptor binding studies, as well as studies in animals, have shown that etonogestrel, the biologically active metabolite of desogestrel, combines high progestational activity with low intrinsic androgenicity. The relevance of this latter finding in humans is unknown.<br/>Pharmacokinetics:<br/>Absorption: Etonogestrel: Etonogestrel released by NuvaRing' is rapidly absorbed. The bioavailability of etonogestrel after vaginal administration is approximately 100%. The serum etonogestrel and ethinyl estradiol concentrations observed during three weeks of NuvaRing' use are summarized in Table I. Ethinyl estradiol: Ethinyl estradiol released by NuvaRing' is rapidly absorbed. The bioavailability of ethinyl estradiol after vaginal administration is approximately 56%, which is comparable to that with oral administration of ethinyl estradiol. The serum ethinyl estradiol concentrations observed during three weeks of NuvaRing' use are summarized in Table I. The pharmacokinetic profile of etonogestrel and ethinyl estradiol during use of NuvaRing' is shown in Figure 1. The pharmacokinetic parameters of etonogestrel and ethinyl estradiol were determined during one cycle of NuvaRing' use in 16 healthy female subjects and are summarized in Table II.<br/>Distribution: Etonogestrel: Etonogestrel is approximately 32% bound to sex hormone-binding globulin (SHBG) and approximately 66% bound to albumin in blood. Ethinyl estradiol: Ethinyl estradiol is highly but not specifically bound to serum albumin (98.5%) and induces an increase in the serum concentrations of SHBG.<br/>Metabolism: In vitro data shows that both etonogestrel and ethinyl estradiol are metabolized in liver microsomes by the cytochrome P450 3A4 isoenzyme. Ethinyl estradiol is primarily metabolized by aromatic hydroxylation, but a wide variety of hydroxylated and methylated metabolites are formed. These are present as free metabolites and as sulfate and glucuronide conjugates. The hydroxylated ethinyl estradiol metabolites have weak estrogenic activity. The biological activity of etonogestrel metabolites is unknown.<br/>Excretion: Etonogestrel and ethinyl estradiol are primarily eliminated in urine, bile and feces.<br/>Special Populations:<br/>Race: No formal studies were conducted to evaluate the effect of race on the pharmacokinetics of NuvaRing'.<br/>Hepatic Insufficiency: No formal studies were conducted to evaluate the effect of hepatic disease on the pharmacokinetics, safety, and efficacy of NuvaRing'. However, steroid hormones may be poorly metabolized in women with impaired liver function .<br/>Renal Insufficiency: No formal studies were conducted to evaluate the effect of renal disease on the pharmacokinetics, safety, and efficacy of NuvaRing'.<br/>Drug-Drug Interactions: Interactions between contraceptive steroids and other drugs have been reported in the literature (see PRECAUTIONS). The drug interactions of NuvaRing' were evaluated in several studies. A single-dose vaginal administration of an oil-based 1200 mg miconazole nitrate capsule increased the serum concentrations of etonogestrel and ethinyl estradiol by approximately 17% and 16%, respectively. Following multiple doses of 200 mg miconazole nitrate by vaginal suppository or vaginal cream, the mean serum concentrations of etonogestrel and ethinyl estradiol increased by up to 40%. A single-dose vaginal administration of 100 mg water-based nonoxynol-9 spermicide gel did not affect the serum concentrations of etonogestrel or ethinyl estradiol. The serum concentrations of etonogestrel and ethinyl estradiol were not affected by concomitant administration of oral amoxicillin or doxycycline in standard dosages during 10 days of antibiotic treatment.<br/>Tampon Use: The use of tampons had no effect on serum concentrations of etonogestrel and ethinyl estradiol during use of NuvaRing'. | lld:dailymed |
| dailymed-drugs:24 | dailymed-instance:clinicalP... | Nystatin is an antifungal antibiotic which is both fungistatic and fungicidal in vitro against a wide variety of yeasts and yeast-like fungi. It probably acts by binding to sterols in the cell membrane of the fungus with a resultant change in membrane permeability allowing leakage of intracellular components. Nystatin is a polyene antibiotic that is obtained from Streptomyces noursei, and is the first well tolerated antifungal antibiotic of dependable efficacy for the treatment of cutaneous, oral and intestinal infections caused by Candida [Monilia]albicans and other Candida species. It exhibits no appreciable activity against bacteria. Nystatin provides specific therapy for all localized forms of candidiasis. Symptomatic relief is rapid, often occurring within 24 to 72 hours after the initiation of treatment. Cure is effected both clinically and mycologically in most cases of localized candidiasis. | lld:dailymed |
| dailymed-drugs:25 | dailymed-instance:clinicalP... | Surmontil is an antidepressant with an anxiety-reducing sedative component to its action. The mode of action of Surmontil on the central nervous system is not known. However, unlike amphetamine-type compounds it does not act primarily by stimulation of the central nervous system. It does not act by inhibition of the monoamine oxidase system. The single-dose pharmacokinetics of trimipramine were evaluated in a comparative study of 24 elderly subjects and 24 younger subjects; no clinically relevant differences were demonstrated based on age or gender. | lld:dailymed |
| dailymed-drugs:26 | dailymed-instance:clinicalP... | Pharmacodynamics: LACRISERT acts to stabilize and thicken the precorneal tear film and prolong the tear film breakup time which is usually accelerated in patients with dry eye states. LACRISERT also acts to lubricate and protect the eye. LACRISERT usually reduces the signs and symptoms resulting from moderate to severe dry eye syndromes, such as conjunctival hyperemia, corneal and conjunctival staining with rose bengal, exudation, itching, burning, foreign body sensation, smarting, photophobia, dryness and blurred or cloudy vision. Progressive visual deterioration which occurs in some patients may be retarded, halted, or sometimes reversed. In a multicenter crossover study the 5 mg LACRISERT administered once a day during the waking hours was compared to artificial tears used four or more times daily. There was a prolongation of tear film breakup time and a decrease in foreign body sensation associated with dry eye syndrome in patients during treatment with inserts as compared to artificial tears; these findings were statistically significantly different between the treatment groups. Improvement, as measured by amelioration of symptoms, by slit lamp examination and by rose bengal staining of the cornea and conjunctiva, was greater in most patients with moderate to severe symptoms during treatment with LACRISERT. Patient comfort was usually better with LACRISERT than with artificial tears solution, and most patients preferred LACRISERT. In most patients treated with LACRISERT for over one year, improvement was observed as evidenced by amelioration of symptoms generally associated with keratoconjunctivitis sicca such as burning, tearing, foreign body sensation, itching, photophobia and blurred or cloudy vision. During studies in healthy volunteers, a thickened precorneal tear film was usually observed through the slit-lamp while LACRISERT was present in the conjunctival sac.<br/>Pharmacokinetics and Metabolism: Hydroxypropyl cellulose is a physiologically inert substance. In a study of rats fed hydroxypropyl cellulose or unmodified cellulose at levels up to 5% of their diet, it was found that the two were biologically equivalent in that neither was metabolized. Studies conducted in rats fedC-labeled hydroxypropyl cellulose demonstrated that when orally administered, hydroxypropyl cellulose is not absorbed from the gastrointestinal tract and is quantitatively excreted in the feces. Dissolution studies in rabbits showed that hydroxypropyl cellulose inserts became softer within 1 hour after they were placed in the conjunctival sac. Most of the inserts dissolved completely in 14 to 18 hours; with a single exception, all had disappeared by 24 hours after insertion. Similar dissolution of the inserts was observed during prolonged administration (up to 54 weeks). | lld:dailymed |
| dailymed-drugs:27 | dailymed-instance:clinicalP... | Pharmacodynamics:<br/>Pharmacokinetics:<br/>Systemic Bioavailability:<br/>Metabolism:<br/>Protein Binding:<br/>Pediatric Pharmacokinetics:<br/>Age:<br/>Liver Disease:<br/>Renal Disease:<br/>Clinical Trials:<br/>Major Depressive Disorder: | lld:dailymed |
| dailymed-drugs:28 | dailymed-instance:clinicalP... | Sodium chloride in water dissociates to provide sodium (Na) and chloride (Cl) ions. These ions are normal constituents of the body fluids (principally extracellular) and are essential for maintaining electrolyte balance. Sodium is the principal cation of extracellular fluid. It comprises more than 90% of the total cations at its normal plasma concentration of approximately 142 mEq/liter. While the sodium ion can diffuse across cell membranes, intracellular sodium is maintained at a much lower concentration than extracellular sodium through the expenditure of energy by the cell (so called���sodium cation pump���). Loss of intracellular potassium ion is usually accompanied by an increase in intracellular sodium ion. When serum sodium concentration is low, the secretion of antidiuretic hormone (ADH) by the pituitary is inhibited, thereby preventing water reabsorption by the distal renal tubules. On the other hand, adrenal secretion of aldosterone increases renal tubular reabsorption of sodium in an effort to re-establish normal serum sodium concentration. Chloride (Cl) has an integral role in buffering action when oxygen and carbon dioxide exchange occurs in the red blood cells. The distribution and excretion of sodium (Na) and chloride (Cl) are largely under the control of the kidney which maintains a balance between intake and output. | lld:dailymed |
| dailymed-drugs:29 | dailymed-instance:clinicalP... | Propoxyphene is a centrally acting narcotic analgesic agent. Equimolar doses of propoxyphene hydrochloride or napsylate provide similar plasma concentrations. Following administration of 65, 130, or 195 mg of propoxyphene hydrochloride, the bioavailability of propoxyphene is equivalent to that of 100, 200, or 300 mg respectively of propoxyphene napsylate. Peak plasma concentrations of propoxyphene are reached in 2 to 2 1/2 hours. After a 65-mg oral dose of propoxyphene hydrochloride, peak plasma levels of 0.05 to 0.1��g/mL are achieved. Repeated doses of propoxyphene at 6-hour intervals lead to increasing plasma concentrations, with a plateau after the ninth dose at 48 hours. Propoxyphene is metabolized in the liver to yield norpropoxyphene. Propoxyphene has a half-life of 6 to 12 hours, whereas that of norpropoxyphene is 30 to 36 hours. Norpropoxyphene has substantially less central-nervous-system-depressant effect than propoxyphene but a greater local anesthetic effect, which is similar to that of amitriptyline and antiarrhythmic agents, such as lidocaine and quinidine. In animal studies in which propoxyphene and norpropoxyphene were continuously infused in large amounts, intracardiac conduction time (PR and QRS intervals) was prolonged. Any intracardiac conduction delay attributable to high concentrations of norpropoxyphene may be of relatively long duration. | lld:dailymed |
| dailymed-drugs:30 | dailymed-instance:clinicalP... | Mechanism of Action: Clopidogrel is an inhibitor of platelet aggregation. A variety of drugs that inhibit platelet function have been shown to decrease morbid events in people with established cardiovascular atherosclerotic disease as evidenced by stroke or transient ischemic attacks, myocardial infarction, unstable angina or the need for vascular bypass or angioplasty. This indicates that platelets participate in the initiation and/or evolution of these events and that inhibiting them can reduce the event rate.<br/>Pharmacodynamic Properties: Clopidogrel selectively inhibits the binding of adenosine diphosphate (ADP) to its platelet receptor and the subsequent ADP-mediated activation of the glycoprotein GPIIb/IIIa complex, thereby inhibiting platelet aggregation. Biotransformation of clopidogrel is necessary to produce inhibition of platelet aggregation, but an active metabolite responsible for the activity of the drug has not been isolated. Clopidogrel also inhibits platelet aggregation induced by agonists other than ADP by blocking the amplification of platelet activation by released ADP. Clopidogrel does not inhibit phosphodiesterase activity. Clopidogrel acts by irreversibly modifying the platelet ADP receptor. Consequently, platelets exposed to clopidogrel are affected for the remainder of their lifespan. Dose dependent inhibition of platelet aggregation can be seen 2 hours after single oral doses of PLAVIX. Repeated doses of 75 mg PLAVIX per day inhibit ADP-induced platelet aggregation on the first day, and inhibition reaches steady state between Day 3 and Day 7. At steady state, the average inhibition level observed with a dose of 75 mg PLAVIX per day was between 40% and 60%. Platelet aggregation and bleeding time gradually return to baseline values after treatment is discontinued, generally in about 5 days.<br/>Pharmacokinetics and Metabolism: After repeated 75-mg oral doses of clopidogrel (base), plasma concentrations of the parent compound, which has no platelet inhibiting effect, are very low and are generally below the quantification limit (0.00025 mg/L) beyond 2 hours after dosing. Clopidogrel is extensively metabolized by the liver. The main circulating metabolite is the carboxylic acid derivative, and it too has no effect on platelet aggregation. It represents about 85% of the circulating drug-related compounds in plasma. Following an oral dose ofC-labeled clopidogrel in humans, approximately 50% was excreted in the urine and approximately 46% in the feces in the 5 days after dosing. The elimination half-life of the main circulating metabolite was 8 hours after single and repeated administration. Covalent binding to platelets accounted for 2% of radiolabel with a half-life of 11 days.<br/>Effect of Food:: Administration of PLAVIX (clopidogrel bisulfate) with meals did not significantly modify the bioavailability of clopidogrel as assessed by the pharmacokinetics of the main circulating metabolite.<br/>Absorption and Distribution:: Clopidogrel is rapidly absorbed after oral administration of repeated doses of 75 mg clopidogrel (base), with peak plasma levels (3 mg/L) of the main circulating metabolite occurring approximately 1 hour after dosing. The pharmacokinetics of the main circulating metabolite are linear (plasma concentrations increased in proportion to dose) in the dose range of 50 to 150 mg of clopidogrel. Absorption is at least 50% based on urinary excretion of clopidogrel-related metabolites. Clopidogrel and the main circulating metabolite bind reversibly in vitro to human plasma proteins (98% and 94%, respectively). The binding is nonsaturable in vitro up to a concentration of 100��g/mL.<br/>Metabolism and Elimination:: In vitro and in vivo, clopidogrel undergoes rapid hydrolysis into its carboxylic acid derivative. In plasma and urine, the glucuronide of the carboxylic acid derivative is also observed.<br/>Special Populations:<br/>Geriatric Patients:: Plasma concentrations of the main circulating metabolite are significantly higher in elderly (���75 years) compared to young healthy volunteers but these higher plasma levels were not associated with differences in platelet aggregation and bleeding time. No dosage adjustment is needed for the elderly.<br/>Renally Impaired Patients:: After repeated doses of 75 mg PLAVIX per day, plasma levels of the main circulating metabolite were lower in patients with severe renal impairment (creatinine clearance from 5 to 15 mL/min) compared to subjects with moderate renal impairment (creatinine clearance 30 to 60 mL/min) or healthy subjects. Although inhibition of ADP-induced platelet aggregation was lower (25%) than that observed in healthy volunteers, the prolongation of bleeding time was similar to healthy volunteers receiving 75 mg of PLAVIX per day.<br/>Gender:: No significant difference was observed in the plasma levels of the main circulating metabolite between males and females. In a small study comparing men and women, less inhibition of ADP-induced platelet aggregation was observed in women, but there was no difference in prolongation of bleeding time. Inthe large, controlled clinical study (Clopidogrel vs. Aspirin in Patients at Risk of Ischemic Events; CAPRIE), the incidence of clinical outcome events, other adverse clinical events, and abnormal clinical laboratory parameters was similar in men and women.<br/>Race:: Pharmacokinetic differences due to race have not been studied. | lld:dailymed |
| dailymed-drugs:31 | dailymed-instance:clinicalP... | Pharmacokinetics: Nystatin is not absorbed from intact skin or mucous membrane.<br/>Microbiology: Nystatin is an antibiotic which is both fungistatic and fungicidal in vitro against a wide variety of yeasts and yeast-like fungi, including Candida albicans, C. parapsilosis, C. tropicalis, C. guilliermondi, C. pseudotropicalis, C. krusei, Torulopsis glabrata, Tricophyton rubrum, T. mentagrophytes. Nystatin acts by binding to sterols in the cell membrane of susceptible species resulting in a change in membrane permeability and the subsequent leakage of intracellular components. On repeated subculturing with increasing levels of nystatin, Candida albicans does not develop resistance to nystatin. Generally, resistance to nystatin does not develop during therapy.However, other species of Candida (C. tropicalis, C. guilliermondi, C. krusei, and C. stellatoides) become quite resistant on treatment with nystatin and simultaneously become cross resistant to amphotericin as well. This resistance is lost when the antibiotic is removed. Nystatin exhibits no appreciable activity against bacteria, protozoa, or viruses. | lld:dailymed |
| dailymed-drugs:32 | dailymed-instance:clinicalP... | Mechanisms of Action: Amiodarone is generally considered a class III antiarrhythmic drug, but it possesses electrophysiologic characteristics of all four Vaughan Williams classes. Like class I drugs, amiodarone blocks sodium channels at rapid pacing frequencies, and like class II drugs, it exerts a non-competitive antisympathetic action. One of its main effects, with prolonged administration, is to lengthen the cardiac action potential, a class III effect. The negative chronotropic effect of amiodarone in nodal tissues is similar to the effect of class IV drugs. In addition to blocking sodium channels, amiodarone blocks myocardial potassium channels, which contributes to slowing of conduction and prolongation of refractoriness. The antisympathetic action and the block of calcium and potassium channels are responsible for the negative dromotropic effects on the sinus node and for the slowing of conduction and prolongation of refractoriness in the atrioventricular (AV) node. Its vasodilatory action can decrease cardiac workload and consequently myocardial oxygen consumption. Amiodarone administration prolongs intranodal conduction (Atrial-His, AH) and refractoriness of the atrioventricular node (ERP AVN), but has little or no effect on sinus cycle length (SCL), refractoriness of the right atrium and right ventricle (ERP RA and ERP RV), repolarization (QTc), intraventricular conduction (QRS), and infranodal conduction (His-ventricular, HV). A comparison of the electrophysiologic effects of amiodarone and oral amiodarone is shown in the table below. At higher doses (>10 mg/kg) of amiodarone, prolongation of the ERP RV and modest prolongation of the QRS have been seen. These differences between oral and intravenous administration suggest that the initial acute effects of amiodarone may be predominantly focused on the AV node, causing an intranodal conduction delay and increased nodal refractoriness due to slow channel blockade (class IV activity) and noncompetitive adrenergic antagonism (class II activity).<br/>PHARMACOKINETICS AND METABOLISM: Amiodarone exhibits complex disposition characteristics after intravenous administration. Peak serum concentrations after single 5 mg/kg 15-minute intravenous infusions in healthy subjects range between 5 and 41 mg/L. Peak concentrations after 10-minute infusions of 150 mg amiodarone in patients with ventricular fibrillation (VF) or hemodynamically unstable ventricular tachycardia (VT) range between 7 and 26 mg/L. Due to rapid distribution, serum concentrations decline to 10% of peak values within 30 to 45 minutes after the end of the infusion. In clinical trials, after 48 hours of continued infusions (125, 500, or 1000 mg/day) plus supplemental (150 mg) infusions (for recurrent arrhythmias), amiodarone mean serum concentrations between 0.7 to 1.4 mg/L were observed (n=260). N-desethylamiodarone (DEA) is the major active metabolite of amiodarone in humans. DEA serum concentrations above 0.05 mg/L are not usually seen until after several days of continuous infusion but with prolonged therapy reach approximately the same concentration as amiodarone. The enzymes responsible for the N-deethylation are believed to be the cytochrome P-450 3A (CYP3A) subfamily, principally CYP3A4. This isozyme is present in both the liver and intestines. The highly variable systemicavailability of oral amiodarone may be attributed potentially to large interindividual variability in CYP3A4 activity. Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable. Amiodarone and DEA cross the placenta and both appear in breast milk. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEA's precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular class III effects after oral amiodarone administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation. On the other hand (see Clinical Trials), after amiodarone administration, there is evidence of activity well before significant concentrations of DEA are attained. The following table summarizes the mean ranges of pharmacokinetic parameters of amiodarone reported in single dose I.V. (5 mg/kg over 15 min) studies of healthy subjects. Desethylamiodarone clearance and volume involve an unknown biotransformation factor. The systemic availability of oral amiodarone in healthy subjects ranges between 33% and 65%. From in vitro studies, the protein binding of amiodarone is>96%. In clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients with VT and VF ranged between 220 and 440 mL/h/kg. Age, sex, renal disease, and hepatic disease (cirrhosis) do not have marked effects on the disposition of amiodarone or DEA. Renal impairment does not influence the pharmacokinetics of amiodarone. After a single dose of amiodarone in cirrhotic patients, significantly lowered Cand average concentration values are seen for DEA, but mean amiodarone levels are unchanged. Normal subjects over 65 years of age show lower clearances (about 100 mL/hr/kg) than younger subjects (about 150 mL/hr/kg) and an increase in tfrom about 20 to 47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition tof DEA is prolonged. Although no dosage adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with oral amiodarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction. There is no established relationship between drug concentration and therapeutic response for short-term intravenous use. Steady-state amiodarone concentrations of 1 to 2.5 mg/L have been associated with antiarrhythmic effects and acceptable toxicity following chronic oral amiodarone therapy.<br/>Pharmacodynamics: Amiodarone has been reported to produce negative inotropic and vasodilatory effects in animals and humans. In clinical studies of patients with refractory VF or hemodynamically unstable VT, treatment-emergent, drug-related hypotension occurred in 288 of 1836 patients (16%) treated with amiodarone. No correlations were seen between the baseline ejection fraction and the occurrence of clinically significant hypotension during infusion of amiodarone.<br/>Clinical Trials: Apart from studies in patients with VT or VF, described below, there are two other studies of amiodarone showing an antiarrhythmic effect before significant levels of DEA could have accumulated. A placebo-controlled study of i.v. amiodarone (300 mg over 2 hours followed by 1200 mg/day) in postcoronary artery bypass graft patients with supraventricular and 2- to 3- consecutive-beat ventricular arrhythmias showed a reduction in arrhythmias from 12 hours on. A baseline-controlled study using a similar i.v. regimen in patients with recurrent, refractory VT/VF also showed rapid onset of antiarrhythmic activity; amiodarone therapy reduced episodes of VT by 85% compared to baseline. The acute effectiveness of amiodarone in suppressing recurrent VF or hemodynamically unstable VT is supported by two randomized, parallel, dose-response studies of approximately 300 patients each. In these studies, patients with at least two episodes of VF or hemodynamically unstable VT in the preceding 24 hours were randomly assigned to receive doses of approximately 125 or 1000 mg over the first 24 hours, an 8-fold difference. In one study, a middle dose of approximately 500 mg was evaluated. The dose regimen consisted of an initial rapid loading infusion, followed by a slower 6-hour loading infusion, and then an 18-hour maintenance infusion. The maintenance infusion was continued up to hour 48. Additional 10-minute infusions of 150 mg amiodarone were given for "breakthrough" VT/VF more frequently to the 125-mg dose group, thereby considerably reducing the planned 8-fold differences in total dose to 1.8- and 2.6- fold, respectively, in the two studies. The prospectively defined primary efficacy end point was the rate of VT/VF episodes per hour. For both studies, the median rate was 0.02 episodes per hour in patients receiving the high dose and 0.07 episodes per hour in patients receiving the low dose, or approximately 0.5 versus 1.7 episodes per day (p= 0.07, 2-sided, in both studies). In one study, the time to first episode of VT/VF was significantly prolonged (approximately 10 hours in patients receiving the low dose and 14 hours in patients receiving the high dose). In both studies, significantly fewer supplemental infusions were given to patients in the high-dose group. Mortality was not affected in these studies; at the end of double-blind therapy or after 48 hours, all patients were given open access to whatever treatment (including amiodarone) was deemed necessary. | lld:dailymed |
| dailymed-drugs:33 | dailymed-instance:clinicalP... | Pharmacokinetics: Gastrointestinal absorption of nystatin is insignificant. Most orally administered nystatin is passed unchanged in the stool. In patients with renal insufficiency receiving oral therapy with conventional dosage forms, significant plasma concentrations of nystatin may occasionally occur.<br/>Microbiology: Nystatin is both fungistatic and fungicidal in vitro against a wide variety of yeasts and yeast-like fungi. Candida albicans demonstrates no significant resistance to nystatin in vitro on repeated subculture in increasing levels of nystatin; other Candida species become quite resistant. Generally, resistance does notdevelop in vivo. Nystatin acts by binding to sterols in the cell membrane of susceptible Candida species with a resultant change in membrane permeability allowing leakage of intracellular components. Nystatin exhibits no appreciable activity against bacteria, protozoa, or viruses. | lld:dailymed |
| dailymed-drugs:34 | dailymed-instance:clinicalP... | Pharmacokinetics and Metabolism: | lld:dailymed |
| dailymed-drugs:35 | dailymed-instance:clinicalP... | Pharmacodynamics: Etodolac is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of etodolac, like that of other NSAIDs, is not completely understood, but may be related to prostaglandin synthetase inhibition. Etodolac is a racemic mixture of [-]R- and [+]S-etodolac. As with other NSAIDs, it has been demonstrated in animals that the [+]S-form is biologically active. Both enantiomers are stable and there is no [-]R to [+]S conversion in vivo.<br/>Pharmacokinetics:<br/>Absorption: The systemic bioavailability of etodolac from etodolac capsules and tablets are 100% as compared to solution and at least 80% as determined from mass balance studies. Etodolac is well absorbed and had a relative bioavailability of 100% when 200 mg capsules were compared with a solution of etodolac. Based on mass balance studies, the systemic availability of etodolac from either the tablet or capsule formulation is at least 80%. Etodolac does not undergo significant first-pass metabolism following oral administration. Mean (��1 SD) peak plasma concentrations (C) range from approximately 14��4 to 37��9��g/mL after 200 to 600 mg single doses and are reached in 80��30 minutes (see Table 1 for summary of pharmacokinetic parameters). The dose-proportionality based on the area under the plasma concentration-time curve (AUC) is linear following doses up to 600 mg every 12 hours. Peak concentrations are dose proportional for both total and free etodolac following doses up to 400 mg every 12 hours, but following a 600 mg dose, the peak is about 20% higher than predicted on the basis of lower doses. The extent of absorption of etodolac is not affected when etodolac is administered after a meal. Food intake, however, reduces the peak concentration reached by approximately one-half and increases the time to peak concentration by 1.4 to 3.8 hours.<br/>Distribution: The mean apparent volume of distribution (Vd/F) of etodolac is approximately 390 mL/kg. Etodolac is more than 99% bound to plasma proteins, primarily to albumin. The free fraction is less than 1% and is independent of etodolac total concentration over the dose range studied. It is not known whether etodolac is excreted in human milk; however, based on its physical-chemical properties, excretion into breast milk is expected. Data from in vitro studies, using peak serum concentrations at reported therapeutic doses in humans, show that the etodolac free fraction is not significantly altered by acetaminophen, ibuprofen, indomethacin, naproxen, piroxicam, chlorpropamide, glipizide, glyburide, phenytoin, and probenecid.<br/>Metabolism: Etodolac is extensively metabolized in the liver. The role, if any, of a specific cytochrome P450 system in the metabolism of etodolac is unknown. Several etodolac metabolites have been identified in human plasma and urine. Other metabolites remain to be identified. The metabolites include 6-, 7-, and 8-hydroxylated-etodolac and etodolac glucuronide. After a single dose of 14C-etodolac, hydroxylated metabolites accounted for less than 10% of total drug in serum. On chronic dosing, hydroxylated-etodolac metabolite does not accumulate in the plasma of patients with normal renal function. The extent of accumulation of hydroxylated-etodolac metabolites in patients with renal dysfunction has not been studied. The hydroxylated-etodolac metabolites undergo further glucuronidation followed by renal excretion and partial elimination in the feces.<br/>Excretion: The mean oral clearance of etodolac following oral dosing is 49 (��16) mL/h/kg. Approximately 1% of a etodolac dose is excreted unchanged in the urine with 72% of the dose excreted into urine as parent drug plus metabolite: Although renal elimination is a significant pathway of excretion for etodolac metabolites, no dosing adjustment in patients with mild to moderate renal dysfunction is generally necessary. The terminal half-life (t) of etodolac is 6.4 hours (22% CV). In patients with severe renal dysfunction or undergoing hemodialysis, dosing adjustment is not generally necessary. Fecal excretion accounted for 16% of the dose.<br/>Special Populations:<br/>Geriatric: In etodolac clinical studies, no overall differences in safety or effectiveness were observed between these patients and younger patients. In pharmacokinetic studies, age was shown not to have any effect on etodolac half-life or protein binding, and there was no change in expected drug accumulation. Therefore, no dosage adjustment is generally necessary in the elderly on the basis of pharmacokinetics (see PRECAUTIONS, Geriatric Use). Etodolac is eliminated primarily by the kidney. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see WARNINGS, Renal Effects).<br/>Pediatric: Safety and effectiveness in pediatric patients below the age of 18 years have not been established.<br/>Race: Pharmacokinetic differences due to race have not been identified. Clinical studies included patients of many races, all of whom responded in a similar fashion.<br/>Hepatic Insufficiency: Etodolac is predominantly metabolized by the liver. In patients with compensated hepatic cirrhosis, the disposition of total and free etodolac is not altered. Patients with acute and chronic hepatic diseases do not generally require reduced doses of etodolac compared to patients with normal hepatic function. However, etodolac clearance is dependent on liver function and could be reduced in patients with severe hepatic failure. Etodolac plasma protein binding did not change in patients with compensated hepatic cirrhosis given etodolac.<br/>Renal Insufficiency: Etodolac pharmacokinetics have been investigated in subjects with renal insufficiency. Etodolac renal clearance was unchanged in the presence of mild-to-moderate renal failure (creatinine clearance 37 to 88 mL/min). Furthermore, there were no significant differences in the disposition of total and free etodolac in these patients. However, etodolac should be used with caution in such patients because, as with other NSAIDs, it may further decrease renal function in some patients. In patients undergoing hemodialysis, there was a 50% greater apparent clearance of total etodolac, due to a 50% greater unbound fraction. Free etodolac clearance was not altered, indicating the importance of protein binding in etodolac's disposition. Etodolac is not significantly removed from the blood in patients undergoing hemodialysis. | lld:dailymed |
| dailymed-drugs:36 | dailymed-instance:clinicalP... | Free carbenicillin is the predominant pharmacologically active fraction of Geocillin. Carbenicillin exerts its antibacterial activity by interference with final cell wall synthesis of susceptible bacteria. Geocillin is acid stable, and rapidly absorbed from the small intestine following oral administration. It provides relatively low plasma concentrations of antibiotic and is primarily excreted in the urine. After absorption, Geocillin is rapidly converted to carbenicillin by hydrolysis of the ester linkage. Following ingestion of a single 500 mg tablet of Geocillin, a peak carbenicillin plasma concentration of approximately 6.5 mcg/ml is reached in 1 hour. About 30% of this dose is excreted in the urine unchanged within 12 hours, with another 6% excreted over the next 12 hours. In a multiple dose study utilizing volunteers with normal renal function, the following mean urine and serum levels of carbenicillin were achieved:<br/>Microbiology: The antibacterial activity of Geocillin is due to its rapid conversion to carbenicillin by hydrolysis after absorption. Though Geocillin provides substantial in vitro activity against a variety of both gram-positive and gram-negative microorganisms, the most important aspect of its profile is in its antipseudomonal and antiproteal activity. Because of the high urine levels obtained following administration, Geocillin has demonstrated clinical efficacy in urinary infections due to susceptible strains of: Escherichia coliProteus mirabilisProteus vulgarisMorganella morganii (formerly Proteus morganii)Pseudomonas speciesProvidencia rettgeri (formerly Proteus rettgeri)Enterobacter speciesEnterococci (S. faecalis) In addition, in vitro data, not substantiated by clinical studies, indicate the following pathogens to be usually susceptible to Geocillin: Staphylococcus species (nonpenicillinase producing)Streptococcus species<br/>Resistance: Most Klebsiella species are usually resistant to the action of Geocillin. Some strains of Pseudomonas species have developed resistance to carbenicillin.<br/>Susceptibility Testing: Geopen (carbenicillin disodium) Susceptibility Powder or 100��g Geopen Susceptibility Discs may be used to determine microbial susceptibility to Geocillin using one of the following standard methods recommended by the National Committee for Clinical Laboratory Standards: M2-A3, "Performance Standards for Antimicrobial Disk Susceptibility Tests" M7-A, "Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically" M11-A, "Reference Agar Dilution Procedure for Antimicrobial Susceptibility Testing of Anaerobic Bacteria" M17-P, "Alternative Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria" Tests should be interpreted by the following criteria: Interpretations of susceptible, intermediate, and resistant correlate zone size diameters with MIC values. A laboratory report of "susceptible" indicates that the suspected causative microorganism most likely will respond to therapy with carbenicillin. A laboratory report of "resistant" indicates that the infecting microorganism most likely will not respond to therapy. A laboratory report of "moderately susceptible" indicates that the microorganism is most likely susceptible if a high dosage of carbenicillin is used, or if the infection is such that high levels of carbenicillin may be attained as in urine. A report of "intermediate" using the disk diffusion method may be considered an equivocal result, and dilution tests may be indicated. | lld:dailymed |
| dailymed-drugs:37 | dailymed-instance:clinicalP... | Pharmacodynamics: The mechanism of action of mirtazapine tablets, as with other drugs effective in the treatment of major depressive disorder, is unknown. Evidence gathered in preclinical studies suggests that mirtazapine enhances central noradrenergic and serotonergic activity. These studies have shown that mirtazapine acts as an antagonist at central presynaptic��adrenergic inhibitory autoreceptors and heteroreceptors, an action that is postulated to result in an increase in central noradrenergic and serotonergic activity. Mirtazapine is a potent antagonist of 5-HTand 5-HTreceptors. Mirtazapine has no significant affinity for the 5-HTand 5-HTreceptors. Mirtazapine is a potent antagonist of histamine (H) receptors, a property that may explain its prominent sedative effects. Mirtazapine is a moderate peripheral��adrenergic antagonist, a property that may explain the occasional orthostatic hypotension reported in association with its use. Mirtazapine is a moderate antagonist at muscarinic receptors, a property that may explain the relatively low incidence of anticholinergic side effects associated with its use.<br/>Pharmacokinetics: Mirtazapine is rapidly and completely absorbed following oral administration and has a half-life of about 20-40 hours. Peak plasma concentrations are reached within about 2 hours following an oral dose. The presence of food in the stomach has a minimal effect on both the rate and extent of absorption and does not require a dosage adjustment. Mirtazapine is extensively metabolized after oral administration. Major pathways of biotransformation are demethylation and hydroxylation followed by glucuronide conjugation. In vitro data from human liver microsomes indicate that cytochrome 2D6 and 1A2 are involved in the formation of the 8-hydroxy metabolite of mirtazapine, whereas cytochrome 3A is considered to be responsible for the formation of the N-desmethyl and N-oxide metabolite. Mirtazapine has an absolute bioavailability of about 50%. It is eliminated predominantly via urine (75%) with 15% in feces. Several unconjugated metabolites possess pharmacological activity but are present in the plasma at very low levels. The (-) enantiomer has an elimination half-life that is approximately twice as long as the (+) enantiomer and therefore achieves plasma levels that are about three times as high as that of the (+) enantiomer. Plasma levels are linearly related to dose over a dose range of 15 to 80 mg. The mean elimination half-life of mirtazapine after oral administration ranges from approximately 20-40 hours across age and gender subgroups, with females of all ages exhibiting significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males). Steady state plasma levels of mirtazapine are attained within 5 days, with about 50% accumulation (accumulation ratio = 1.5). Mirtazapine is approximately 85% bound to plasma proteins over a concentration range of 0.01 to 10 mcg/mL.<br/>Special Populations:<br/>Geriatric: Following oral administration of mirtazapine tablets 20 mg/day for 7 days to subjects of varying ages (range, 25-74), oral clearance of mirtazapine was reduced in the elderly compared to the younger subjects. The differences were most striking in males, with a 40% lower clearance in elderly males compared to younger males, while the clearance in elderly females was only 10% lower compared to younger females. Caution is indicated in administering mirtazapine to elderly patients .<br/>Pediatrics: Safety and effectiveness of mirtazapine in the pediatric population have not been established .<br/>Gender: The mean elimination half-life of mirtazapine after oral administration ranges from approximately 20-40 hours across age and gender subgroups, with females of all ages exhibiting significantly longer elimination half-lives than males (mean half-life of 37 hours for females vs. 26 hours for males) (see Pharmacokinetics).<br/>Race: There have been no clinical studies to evaluate the effect of race on the pharmacokinetics of mirtazapine.<br/>Renal Insufficiency: The disposition of mirtazapine was studied in patients with varying degrees of renal function. Elimination of mirtazapine is correlated with creatinine clearance. Total body clearance of mirtazapine was reduced approximately 30% in patients with moderate (Clcr = 11-39 mL/min/1.73 m) and approximately 50% in patients with severe (Clcr =<10 mL/min/1.73 m) renal impairment when compared to normal subjects. Caution is indicated in administering mirtazapine to patients with compromised renal function .<br/>Hepatic Insufficiency: Following a single 15 mg oral dose of mirtazapine, the oral clearance of mirtazapine was decreased by approximately 30% in hepatically impaired patients compared to subjects with normal hepatic function. Caution is indicated in administering mirtazapine to patients with compromised hepatic function .<br/>Clinical Trials Showing Effectiveness: The efficacy of mirtazapine as a treatment for major depressive disorder was established in four placebo-controlled, 6-week trials in adult outpatients meeting DSM-III criteria for major depressive disorder. Patients were titrated with mirtazapine from a dose range of 5 mg up to 35 mg/day. Overall, these studies demonstrated mirtazapine to be superior to placebo on at least three of the following four measures: 21-Item Hamilton Depression Rating Scale (HDRS) total score; HDRS Depressed Mood Item; CGI Severity score; and Montgomery and Asberg Depression Rating Scale (MADRS). Superiority of mirtazapine over placebo was also found for certain factors of the HDRS, including anxiety/somatization factor and sleep disturbance factor. The mean mirtazapine dose for patients who completed these four studies ranged from 21 to 32 mg/day. A fifth study of similar design utilized a higher dose (up to 50 mg) per day and also showed effectiveness. Examination of age and gender subsets of the population did not reveal any differential responsiveness on the basis of these sub-groupings. In a longer-term study, patients meeting (DSM-IV) criteria or major depressive disorder who had responded during an initial 8 to 12 weeks of acute treatment on mirtazapine were randomized to continuation of mirtazapine or placebo for up to 40 weeks of observation for relapse. Response during the open phase was defined as having achieved a HAM-D 17 total score of<8 and a CGI-Improvement score of 1 or 2 at two consecutive visits beginning with week 6 of the 8-12 weeks in the open-label phase of the study. Relapse during the double-blind phase was determined by the individual investigators. Patients receiving continued mirtazapine treatment experience significantly lower relapse rates over the subsequent 40 weeks compared to those receiving placebo. This pattern was demonstrated in both male and female patients. | lld:dailymed |
| dailymed-drugs:38 | dailymed-instance:clinicalP... | Irinotecan is a derivative of camptothecin. Camptothecins interact specifically with the enzyme topoisomerase I which relieves torsional strain in DNA by inducing reversible single-strand breaks. Irinotecan and its active metabolite SN-38 bind to the topoisomerase I-DNA complex and prevent religation of these single-strand breaks. Current research suggests that the cytotoxicity of irinotecan is due to double-strand DNA damage produced during DNA synthesis when replication enzymes interact with the ternary complex formed by topoisomerase I,DNA, and either irinotecan or SN-38. Mammalian cells cannot efficiently repair these double-strand breaks. Irinotecan serves as a water-soluble precursor of the lipophilic metabolite SN-38. SN-38 is formed from irinotecan by carboxylesterase-mediated cleavage of the carbamate bond between the camptothecin moiety and the dipiperidino side chain. SN-38 is approximately 1000 times as potent as irinotecan as an inhibitor of topoisomerase I purified from human and rodent tumor cell lines. In vitro cytotoxicity assays show that the potency of SN-38 relative to irinotecan varies from 2- to 2000-fold. However, the plasma area under the concentration versus time curve (AUC) values for SN-38 are 2% to 8% of irinotecan and SN-38 is 95% bound to plasma proteins compared to approximately 50% bound to plasma proteins for irinotecan (see Pharmacokinetics). The precise contribution of SN-38 to the activity of Irinotecan Hydrochloride Injection is thus unknown. Both irinotecan and SN-38 exist in an active lactone form and an inactive hydroxy acid anion form. A pH-dependent equilibrium exists between the two forms such that an acid pH promotes the formation of the lactone, while a more basic pH favors the hydroxy acid anion form. Administration of irinotecan has resulted in antitumor activity in mice bearing cancers of rodent origin and in human carcinoma xenografts of various histological types.<br/>Pharmacokinetics: After intravenous infusion of irinotecan in humans, irinotecan plasma concentrations decline in a multiexponential manner, with a mean terminal elimination half-life of about 6 to 12 hours. The mean terminal elimination half-life of the active metabolite SN-38 is about 10 to 20 hours. The half-lives of the lactone (active) forms of irinotecan and SN-38 are similar to those of total irinotecan and SN-38, as the lactone and hydroxy acid forms are in equilibrium. Over the recommended dose range of 50 to 350 mg/m, the AUC of irinotecan increases linearly with dose; the AUC of SN-38 increases less than proportionally with dose. Maximum concentrations of the active metabolite SN-38 are generally seen within 1 hour following the end of a 90-minute infusion of irinotecan. Pharmacokinetic parameters for irinotecan and SN-38 following a 90-minute infusion of irinotecan at dose levels of 125 and 340 mg/mdetermined in two clinical studies in patients with solid tumors are summarized in Table 1: Irinotecan exhibits moderate plasma protein binding (30% to 68% bound). SN-38 is highly bound to human plasma proteins (approximately 95% bound). The plasma protein to which irinotecan and SN-38 predominantly binds is albumin. Metabolism and Excretion: The metabolic conversion of irinotecan to the active metabolite SN-38 is mediated by carboxylesterase enzymes and primarily occurs in the liver. SN-38 is subsequently conjugated predominantly by the enzyme UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite. UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity such as the UGT1A1*28 polymorphism. Approximately 10% of the North American population is homozygous for the UGT1A1*28 allele. In a prospective study, in which irinotecan was administered as a single-agent on a once-every-3-week schedule, patients who were homozygous for UGT1A1*28 had a higher exposure to SN-38 than patients with the wild-type UGT1A1 allele . SN-38 glucuronide had 1/50 to 1/100 the activity of SN-38 in cytotoxicity assays using two cell lines in vitro. The disposition of irinotecan has not been fully elucidated in humans. The urinary excretion of irinotecan is 11% to 20%; SN-38,<1%; and SN-38 glucuronide, 3%. The cumulative biliary and urinary excretion of irinotecan and its metabolites (SN-38 and SN-38 glucuronide) over a period of 48 hours following administration of irinotecan in two patients ranged from approximately 25% (100 mg/m) to 50% (300 mg/m).<br/>Pharmacokinetics in Special Populations: Geriatric: In studies using the weekly schedule, the terminal half-life of irinotecan was 6.0 hours in patients who were 65 years or older and 5.5 hours in patients younger than 65 years. Dose-normalized AUCfor SN-38 in patients who were at least 65 years of age was 11% higher than in patients younger than 65 years. No change in the starting dose is recommended for geriatric patients receiving the weekly dosage schedule of irinotecan. The pharmacokinetics of irinotecan given once every 3 weeks has not been studied inthe geriatric population; a lower starting dose is recommended in patients 70 years or older based on clinical toxicity experience with this schedule . Pediatric: See Pediatric Use under PRECAUTIONS. Gender: The pharmacokinetics of irinotecan do not appear to be influenced by gender. Race: The influence of race on the pharmacokinetics of irinotecan has not been evaluated. Hepatic Insufficiency: Irinotecan clearance is diminished in patients with hepatic dysfunction while exposure to the active metabolite SN-38 is increased relative to that in patients with normal hepatic function. The magnitude of these effects is proportional to the degree of liver impairment as measured by elevations in total bilirubin and transaminase concentrations. However, the tolerability of irinotecan in patients with hepatic dysfunction (bilirubin greater than 2 mg/dl) has not been assessed sufficiently, and no recommendations for dosing can be made. See DOSAGE AND ADMINISTRATION and PRECAUTIONS: Patients at Particular Risk Sections. Renal Insufficiency: The influence of renal insufficiency on the pharmacokinetics of irinotecan has not been evaluated. Therefore, caution should be undertaken in patients with impaired renal function. Irinotecan is not recommended for use in patients on dialysis.<br/>Drug-Drug Interactions: Anticonvulsants: Exposure to irinotecan and its active metabolite SN-38 is substantially reduced in adult and pediatric patients concomitantly receiving the CYP3A4 enzyme-inducing anticonvulsants phenytoin, phenobarbital or carbamazepine. The appropriate starting dose for patients taking these anticonvulsants has not been formally defined. The following drugs are also CYP3A4 inducers: rifampin, rifabutin. For patients requiring anticonvulsant treatment, consideration should be given to substituting non-enzyme inducing anticonvulsants at least 2 weeks prior to initiation of irinotecan therapy. Dexamethasone does not appear to alter the pharmacokinetics of irinotecan. St. John's Wort: St. John's Wort is an inducer of CYP3A4 enzymes. Exposure to the active metabolite SN-38 is reduced in patients receiving concomitant St. John's Wort. St. John's Wort should be discontinued at least 2 weeks prior to the first cycle of irinotecan, and St. John's Wort is contraindicated during irinotecan therapy. Ketoconazole: Ketoconazole is a strong inhibitor of CYP3A4 enzymes. Patients receiving concomitant ketoconazole have increased exposure to irinotecan and its active metabolite SN-38. Patients should discontinue ketoconazole at least 1 week prior to starting irinotecan therapy and ketoconazole is contraindicated during irinotecan therapy. Neuromuscular blocking agents. Interaction between irinotecan and neuromuscular blocking agents cannot be ruled out. Irinotecan has anticholinesterase activity which may prolong the neuromuscular blocking effects of suxamethonium and the neuromuscular blockade of non-depolarizing drugs may be antagonized. Atazanavir sulfate: Coadministration of atazanavir sulfate, a CYP3A4 and UGT1A1 inhibitor has the potential to increase systemic exposure of SN-38, the active metabolite of irinotecan. Physicians should take this into consideration when co-administering these drugs. | lld:dailymed |
| dailymed-drugs:39 | dailymed-instance:clinicalP... | PROMETRIUM Capsules are an oral dosage form of micronized progesterone which is chemically identical to progesterone of ovarian origin. The oral bioavailability of progesterone is increased through micronization.<br/>Pharmacokinetics: Absorption: After oral administration of progesterone as a micronized soft-gelatin capsule formulation, maximum serum concentrations were attained within 3 hours. The absolute bioavailability of micronized progesterone is not known. Table 1 summarizes the mean pharmacokinetic parameters in postmenopausal women after five oral daily doses of PROMETRIUM Capsules 100 mg as a micronized soft-gelatin capsule formulation. Serum progesterone concentrations appeared linear and dose proportional following multiple dose administration of PROMETRIUM Capsules 100 mg over the dose range 100 mg/day to 300 mg/day in postmenopausal women. Although doses greater than 300 mg/day were not studied in females, serum concentrations from a study in male volunteers appeared linear and dose proportional between 100 mg/day and 400 mg/day. The pharmacokinetic parameters in male volunteers were generally consistent with those seen in postmenopausal women. Distribution: Progesterone is approximately 96% to 99% bound to serum proteins, primarily to serum albumin (50% to 54%) and transcortin (43% to 48%). Metabolism: Progesterone is metabolized primarily by the liver largely to pregnanediols and pregnanolones. Pregnanediols and pregnanolones are conjugated in the liver to glucuronide and sulfate metabolites. Progesterone metabolites which are excreted in the bile may be deconjugated and may be further metabolized in the gut via reduction, dehydroxylation, and epimerization. Excretion: The glucuronide and sulfate conjugates of pregnanediol and pregnanolone are excreted in the bile and urine. Progesterone metabolites which are excreted in the bile may undergo enterohepatic recycling or may be excreted in the feces. Special Populations: The pharmacokinetics of PROMETRIUM Capsules have not been assessed in low body weight or obese patients. Food���Drug Interaction: Concomitant food ingestion increased the bioavailability of PROMETRIUM Capsules relative to a fasting state when administered to postmenopausal women at a dose of 200 mg. Drug���Drug Interaction: The metabolism of progesterone by human liver microsomes was inhibited by ketoconazole (IC<0.1��M). Ketoconazole is a known inhibitor of cytochrome P450 3A4, hence these data suggest that ketoconazole or other known inhibitors of this enzyme may increase the bioavailability of progesterone. The clinical relevance of the in vitro findings is unknown. Coadministration of conjugated estrogens and PROMETRIUM Capsules to 29 postmenopausal women over a 12-day period resulted in an increase in total estrone concentrations (Cmax 3.68 ng/mL to 4.93 ng/mL) and total equilin concentrations (Cmax 2.27 ng/mL to 3.22 ng/mL) and a decrease in circulating 17��estradiol concentrations (Cmax 0.037 ng/mL to 0.030 ng/mL). The half-life of the conjugated estrogens was similar with coadministration of PROMETRIUM Capsules. Table 2 summarizes the pharmacokinetic parameters.<br/>Clinical Studies: Endometrial Protection: In a randomized, double-blind clinical trial, 358 postmenopausal women, each with an intact uterus, received treatment for up to 36 months. The treatment groups were: PROMETRIUM Capsules at the dose of 200 mg/day for 12 days per 28-day cycle in combination with conjugated estrogens 0.625 mg/day (n=120); conjugated estrogens 0.625 mg/day only (n=119); or placebo (n=119). The subjects in all three treatment groups were primarily Caucasian women (87% or more of eachgroup). The results for the incidence of endometrial hyperplasia in women receiving up to 3 years of treatment are shown in Table 3. A comparison of the PROMETRIUM Capsules plus conjugated estrogens treatment group to the conjugated estrogens only group showed a significantly lower rate of hyperplasia (6% combination product vs. 64% estrogen alone) in the PROMETRIUM Capsules plus conjugated estrogens treatment group throughout 36 months of treatment. The times to diagnosis of endometrial hyperplasia over 36 months of treatment are shown in Figure 1. This figure illustrates graphically that the proportion of patients with hyperplasia was significantly greater for the conjugated estrogens group (64%) compared to the conjugated estrogens plus PROMETRIUM Capsules group (6%). The discontinuation rates due to hyperplasia over the 36 months of treatment are as shown in Table 4. For any degree of hyperplasia, the discontinuation rate for patients who received conjugated estrogens plus PROMETRIUM Capsules was similar to that of the placebo only group, while the discontinuation rate for patients who received conjugated estrogensalone was significantly higher. Women who permanently discontinued treatment due to hyperplasia were similar in demographics to the overall study population. In the same 3-year clinical trial, postmenopausal women were treated with PROMETRIUM Capsules in combination with conjugated estrogens, conjugated estrogens only, or placebo. There was no statistically significant difference between the PROMETRIUM Capsules plus conjugated estrogens group and the conjugated estrogens only group in increases of HDL-C and triglycerides, or in decreases of LDL-C. The changes observed in lipid profiles are shown in Table 5.<br/>Women's Health Initiative Studies: The Women's Health Initiative (WHI) enrolled a total of 27,000 predominantly healthy postmenopausal women to assess the risks and benefits of either the use of oral 0.625 mg conjugated estrogens (CE) per day alone or the use of oral 0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate (MPA) per day compared to placebo in the prevention of certain chronic diseases. The primary endpoint was the incidence of coronary heart disease (CHD) (nonfatal myocardial infarction and CHD death), with invasive breast cancer as the primary adverse outcome studied. A���global index���included the earliest occurrence of CHD, invasive breast cancer, stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip fracture, or death due to other cause. The study did not evaluate the effects of CE or CE/MPA on menopausal symptoms. The CE/MPA substudy was stopped early because, according to the predefined stopping rule, the increased risk of breast cancer and cardiovascular events exceeded the specified benefits included in the���global index.���Results of the CE/MPA substudy, which included 16,608 women (average age of 63 years, range 50 to 79; 83.9% White, 6.5% Black, 5.5% Hispanic), after an average follow-up of 5.2 years are presented in Table 6 below. For those outcomes included in the "global index," the absolute excess risks per 10,000 women-years in the group treated with CE/MPA were 7 more CHD events, 8 more strokes, 8 more PEs, and 8 more invasive breast cancers, while the absolute risk reductions per 10,000 women-years were 6 fewer colorectal cancers and 5 fewer hip fractures. The absolute excess risk of events included in the���global index���was 19 per 10,000 women-years. There was no difference between the groups in terms of all-cause mortality.<br/>Women's Health Initiative Memory Study: The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, enrolled 4,532 predominantly healthy postmenopausal women 65 years of age and older (47% were age 65 to 69 years, 35% were 70 to 74 years, and 18% were 75 years of age and older) to evaluate the effects of CE/MPA (0.625 mg conjugated estrogens plus 2.5 mg medroxyprogesterone acetate) on the incidence of probable dementia (primary outcome) compared with placebo. After an average follow-up of 4 years, 40 women in the estrogen/progestin group (45 per 10,000 women-years) and 21 in the placebo group (22 per 10,000 women-years) were diagnosed with probable dementia. The relative risk of probable dementia in the hormone therapy group was 2.05 (95% CI, 1.21 to 3.48) compared to placebo. Differences between groups became apparent in the first year of treatment. It is unknown whether these findings apply to younger postmenopausal women. | lld:dailymed |
| dailymed-drugs:40 | dailymed-instance:clinicalP... | Mechanism of Action: TIKOSYN (dofetilide) shows Vaughan Williams Class III antiarrhythmic activity. The mechanism of action is blockade of the cardiac ion channel carrying the rapid component of the delayed rectifier potassium current, I. At concentrations covering several orders of magnitude, dofetilide blocks only Iwith no relevant block of the other repolarizing potassium currents (e.g., I, I). At clinically relevant concentrations, dofetilide has no effect on sodium channels (associated with Class I effect), adrenergic alpha-receptors, or adrenergic beta-receptors.<br/>Electrophysiology: TIKOSYN (dofetilide) increases the monophasic action potential duration in a predictable, concentration-dependent manner, primarily due to delayed repolarization. This effect, and the related increase in effective refractory period, is observed in the atria and ventricles in both resting and paced electrophysiology studies. The increase in QT interval observed on the surface ECG is a result of prolongation of both effective and functional refractory periods in the His-Purkinje system and the ventricles. Dofetilide did not influence cardiac conduction velocity and sinus node function in a variety of studies in patients with or without structural heart disease. This is consistent with a lack of effect of dofetilide on the PR interval and QRS width in patients with pre-existing heart block and/or sick sinus syndrome. In patients, dofetilide terminates induced re-entrant tachyarrhythmias (e.g., atrial fibrillation/flutter and ventricular tachycardia) and prevents their re-induction. TIKOSYN does not increase the electrical energy required to convert electrically-induced ventricular fibrillation, and it significantly reduces the defibrillation threshold in patients with ventricular tachycardia and ventricular fibrillation undergoing implantation of a cardioverter-defibrillator device.<br/>Hemodynamic Effects: In hemodynamic studies, TIKOSYN had no effect on cardiac output, cardiac index, stroke volume index, or systemic vascular resistance in patients with ventricular tachycardia, mild to moderate congestive heart failure or angina and either normal or low left ventricular ejection fraction. There was no evidence of a negative inotropic effect related to TIKOSYN therapy in patients with atrial fibrillation. There was no increase in heart failure in patients with significantleft ventricular dysfunction (see Safety in Patients with Structural Heart Disease: DIAMOND Studies). In the overall clinical program, TIKOSYN did not affect blood pressure. Heart rate was decreased by 4-6 bpm in studies in patients.<br/>Pharmacokinetics, General:<br/>Absorption and Distribution: The oral bioavailability of dofetilide is>90%, with maximal plasma concentrations occurring at about 2���3 hours in the fasted state. Oral bioavailability is unaffected by food or antacid. The terminal half life of TIKOSYN is approximately 10 hours; steady state plasma concentrations are attained within 2���3 days, with an accumulation index of 1.5 to 2.0. Plasma concentrations are dose proportional. Plasma protein binding of dofetilide is 60���70%, is independent of plasma concentration, and is unaffected by renal impairment. Volume of distribution is 3 L/kg.<br/>Metabolism and Excretion: Approximately 80% of a single dose of dofetilide is excreted in urine, of which approximately 80% is excreted as unchanged dofetilide with the remaining 20% consisting of inactive or minimally active metabolites. Renal elimination involves both glomerular filtration and active tubular secretion (via the cation transport system, a process that can be inhibited by cimetidine, trimethoprim, prochlorperazine, megestrol and ketoconazole). In vitro studies with human liver microsomes show that dofetilide can be metabolized by CYP3A4, but it has a low affinity for this isoenzyme. Metabolites are formed by N-dealkylation and N-oxidation. There are no quantifiable metabolites circulating in plasma, but 5 metabolites have been identified in urine.<br/>Pharmacokinetics in Special Populations:<br/>Renal Impairment: In volunteers with varying degrees of renal impairment and patients with arrhythmias, the clearance of dofetilide decreases with decreasing creatinine clearance. As a result, and as seen in clinical studies, the half-life of dofetilide is longer in patients with lower creatinine clearances. Because increase in QT interval and the risk of ventricular arrhythmias are directly related to plasma concentrations of dofetilide, dosage adjustment based on calculated creatinine clearance is critically important . Patients with severe renal impairment (creatinine clearance<20 mL/min) were not included in clinical or pharmacokinetic studies .<br/>Hepatic Impairment: There was no clinically significant alteration in the pharmacokinetics of dofetilide in volunteers with mild to moderate hepatic impairment (Child-Pugh class A and B) compared to age- and weight-matched healthy volunteers. Patients with severe hepatic impairment were not studied.<br/>Patients with Heart Disease: Population pharmacokinetic analyses indicate that the plasma concentration of dofetilide in patients with supraventricular and ventricular arrhythmias, ischemic heart disease, or congestive heart failure are similar to those of healthy volunteers, after adjusting for renal function.<br/>Elderly: After correction for renal function, clearance of dofetilide is not related to age.<br/>Women: A population pharmacokinetic analysis showed that women have approximately 12���18% lower dofetilide oral clearances than men (14���22% greater plasma dofetilide levels), after correction for weight and creatinine clearance. In females, as in males, renal function was the single most important factor influencing dofetilide clearance. In normal female volunteers, hormone replacement therapy (a combination of conjugated estrogens and medroxyprogesterone) did not increase dofetilide exposure.<br/>Drug-Drug Interactions:<br/>Dose-Response and Concentration Response for Increase in QT Interval: Increase in QT interval is directly related to dofetilide dose and plasma concentration. Figure 1 shows that the relationship in normal volunteers between dofetilide plasma concentrations and change in QTc is linear, with a positive slope of approximately 15���25 msec/(ng/mL) after the first dose and approximately 10���15 msec/(ng/mL) at Day 23 (reflecting a steady state of dosing). A linear relationship between mean QTc increase and dofetilide dose was also seen in patients with renal impairment, in patients with ischemic heart disease, and in patients with supraventricular and ventricular arrhythmias. Note: The range of dofetilide plasma concentrations achieved with the 500 mcg BID dose adjusted for creatinine clearance is 1���3.5 ng/mL. The relationship between dose, efficacy and the increase in QTc from baseline at steady state for the two randomized, placebo-controlled studies (described further below) is shown in Figure 2. The studies examined the effectiveness of TIKOSYN in conversion to sinus rhythm and maintenance of normal sinus rhythm after conversion in patients with atrial fibrillation/flutter of>1 week duration. As shown, both the probability of a patient's remaining in sinus rhythm at six months and the change in QTc from baseline at steady state of dosing increased in an approximately linear fashion with increasing dose of TIKOSYN. Note that in these studies doses were modified by results of creatinine clearance measurement and in-hospital QTc prolongation. Number of patients evaluated for maintenance of NSR: 503 TIKOSYN, 174 placebo.Number of patients evaluated for QTc change: 478 TIKOSYN, 167 placebo. Figure 2: Relationship Between TIKOSYN Dose, QTc Increase and Maintenance of NSR. | lld:dailymed |
| dailymed-drugs:41 | dailymed-instance:clinicalP... | Aminosyn, Sulfite-Free, (a crystalline amino acid solution) provides crystalline amino acids to promote protein synthesis and wound healing, and to reduce the rate of endogenous protein catabolism. Aminosyn, given by central venous infusion in combination with concentrated dextrose, electrolytes, vitamins, trace metals, and ancillary fat supplements, constitutes total parenteral nutrition (TPN). Aminosyn can also be administered by peripheral vein with dextrose and maintenance electrolytes. Intravenous fat emulsion may be substituted for part of the carbohydrate calories during either TPN or peripheral vein administration of Aminosyn. | lld:dailymed |
| dailymed-drugs:42 | dailymed-instance:clinicalP... | Dexamethasone sodium phosphate injection has a rapid onset but short duration of action when compared with less soluble preparations. Because of this, it is suitable for the treatment of acute disorders responsive to adrenocortical steroid therapy. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs, including dexamethasone, are primarily used for their potent anti-inflammatory effects in disorders of many organ systems. Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli. At equipotent anti-inflammatory doses, dexamethasone almost completely lacks the sodium-retaining property of hydrocortisone and closely related derivatives of hydrocortisone. | lld:dailymed |
| dailymed-drugs:43 | dailymed-instance:clinicalP... | Local anesthetics block the generation and the conduction of nerve impulses, presumably by increasing the threshold for electrical excitation in the nerve, by slowing the propagation of the nerve impulse, and by reducing the rate of rise of the action potential. In general, the progression of anesthesia is related to the diameter, myelination, and conduction velocity of affected nerve fibers. Clinically, the order of loss of nerve function is as follows: (1) pain, (2) temperature,(3) touch, (4) proprioception, and (5) skeletal muscle tone. Systemic absorption of local anesthetics produces effects on the cardiovascular and central nervous systems (CNS). At blood concentrations achieved with normal therapeutic doses, changes in cardiac conduction, excitability, refractoriness, contractility, and peripheral vascular resistance are minimal. However, toxic blood concentrations depress cardiac conduction and excitability, which may lead to atrioventricular block, ventricular arrhythmias, and cardiac arrest, sometimes resulting in fatalities. In addition, myocardial contractility is depressed and peripheral vasodilation occurs, leading to decreased cardiac output and arterial blood pressure. Recent clinical reports and animal research suggest that these cardiovascular changes are more likely to occur after unintended intravascular injection of bupivacaine. Therefore, incremental dosing is necessary. Following systemic absorption, local anesthetics can produce central nervous system stimulation, depression, or both. Apparent central stimulation is manifested as restlessness, tremors and shivering progressing to convulsions, followed by depression and coma progressing ultimately to respiratory arrest. However, the local anesthetics have a primary depressant effect on the medulla and on higher centers. The depressed stage may occur without a prior excited state. Pharmacokinetics: The rate of systemic absorption of local anesthetics is dependent upon the total dose and concentration of drug administered, the route of administration, the vascularity of the administration site, and the presence or absence of epinephrine in the anesthetic solution. A dilute concentration of epinephrine (1:200,000 or 5 mcg/mL) usually reduces the rate of absorption and peak plasma concentration of Bupivacaine Hydrochloride, permitting the use of moderately larger total doses and sometimes prolonging the duration of action. The onset of action with Bupivacaine Hydrochloride is rapid and anesthesiais long lasting. The duration of anesthesia is significantly longer with Bupivacaine Hydrochloride than with any other commonly used local anesthetic. It has also been noted that there is a period of analgesia that persists after the return of sensation, during which time the need for strong analgesics is reduced. Local anesthetics are bound to plasma proteins in varying degrees. Generally, the lower the plasma concentration of drug the higher the percentage of drug bound to plasma proteins. Local anesthetics appear to cross the placenta by passive diffusion. The rate and degree of diffusion is governed by (1) the degree of plasma protein binding, (2) the degree of ionization, and (3) the degree of lipid solubility. Fetal/maternal ratios of local anesthetics appear to be inversely related to the degree of plasma protein binding, because only the free, unbound drug is available for placental transfer. Bupivacaine Hydrochloride with a high protein binding capacity (95%) has a low fetal/maternal ratio (0.2 to 0.4). The extent of placental transfer is also determined by the degree of ionization and lipid solubility of the drug. Lipid soluble, nonionized drugs readily enter the fetal blood from the maternal circulation. Depending upon the route of administration, local anesthetics are distributed to some extent to all body tissues, with high concentrations found in highly perfused organs such as the liver, lungs, heart, and brain. Pharmacokinetic studies on the plasma profile of Bupivacaine Hydrochloride after direct intravenous injection suggest a three-compartment open model. The first compartment is represented by the rapid intravascular distribution of the drug. The second compartment represents the equilibration of the drug throughout the highly perfused organs such as the brain, myocardium, lungs, kidneys, and liver. The third compartment represents an equilibration of the drug with poorly perfused tissues, such as muscle and fat. The elimination of drug from tissue distribution depends largely upon the ability of binding sites in the circulation to carry it to the liver where it is metabolized. After injection of Bupivacaine Hydrochloride for caudal, epidural, or peripheral nerve block in man, peak levels of bupivacaine in the blood are reached in 30 to 45 minutes, followed by a decline to insignificant levels during the next three to six hours. Various pharmacokinetic parameters of the local anesthetics can be significantly altered by the presence of hepatic or renal disease, addition of epinephrine, factors affecting urinary pH, renal blood flow, the route of drug administration, and the age of the patient. The half-life of Bupivacaine Hydrochloride in adults is 2.7 hours and in neonates 8.1 hours. In clinical studies, elderly patients reached the maximal spread of analgesia and maximal motor blockade more rapidly than younger patients. Elderly patients also exhibited higher peak plasma concentrations following administration of this product. The total plasma clearance was decreased in these patients. Amide-type local anesthetics such as Bupivacaine Hydrochloride are metabolized primarily in the liver via conjugation with glucuronic acid. Patients with hepatic disease, especially those with severe hepatic disease, may be more susceptible to the potential toxicities of the amide-type local anesthetics. Pipecoloxylidine is the major metabolite of Bupivacaine Hydrochloride. The kidney is the main excretory organ for most local anesthetics and their metabolites. Urinary excretion is affected by urinary perfusion and factors affecting urinary pH. Only 6% of bupivacaine is excreted unchanged in the urine. When administered in recommended doses and concentrations, Bupivacaine Hydrochloride does not ordinarily produce irritation or tissue damage and does not cause methemoglobinemia. | lld:dailymed |
| dailymed-drugs:45 | dailymed-instance:clinicalP... | Pharmacodynamics: The antidepressant, antiobsessive-compulsive, and antibulimic actions of fluoxetine are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and��-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs.<br/>Absorption, Distribution, Metabolism, and Excretion:<br/>Systemic Bioavailability: In man, following a single oral 40 mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. The capsule, tablet, and oral solution dosage forms of fluoxetine are bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, fluoxetine may be administered with or without food.<br/>Protein Binding: Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and��-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important .<br/>Enantiomers: Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady-state.<br/>Metabolism: Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney.<br/>Clinical Issues Related to Metabolism/Elimination: The complexity of the metabolism of fluoxetine has several consequences that may potentially affect fluoxetine's clinical use.<br/>Variability in Metabolism: A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as "poor metabolizers" of drugs such as debrisoquin, dextromethorphan, and the TCAs. In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S-fluoxetine at a slower rate and thus achieved higher concentrations of S-fluoxetine. Consequently, concentrations of S-norfluoxetine at steady-state were lower. The metabolism of R-fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady-state of the plasma concentrations of the four active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non-2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady-state concentration rather than increasing without limit. Because fluoxetine's metabolism, like that of a number of other compounds including TCAs and other selective serotonin reuptake inhibitors (SSRIs), involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions .<br/>Accumulation and Slow Elimination: The relatively slow elimination of fluoxetine (elimination half-life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half-life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady-state, even when a fixed dose is used. After 30 days of dosing at 40 mg/day, plasma concentrations offluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single-dose studies, because fluoxetine's metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half-life after a single-dose was 8.6 days and after multiple-dosing was 9.3 days. Steady-state levels after prolonged dosing are similar to levels seen at 4 to 5weeks. The long elimination half-lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of fluoxetine.<br/>Liver Disease: As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a loweror less frequent dose should be used .<br/>Renal Disease: In depressed patients on dialysis (N = 12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients .<br/>Age:<br/>Clinical Trials:<br/>Major Depressive Disorder:<br/>Obsessive-Compulsive Disorder:<br/>Bulimia Nervosa: The effectiveness of fluoxetine for the treatment of bulimia was demonstrated in two 8 week and one 16 week, multicenter, parallel group studies of adult outpatients meeting DSM-III-R criteria for bulimia. Patients in the 8 week studies received either 20 or 60 mg/day of fluoxetine or placebo in the morning. Patients in the 16 week study received a fixed fluoxetine dose of 60 mg/day (once a day) or placebo. Patients in these three studies had moderate to severe bulimia with median binge eating and vomiting frequencies ranging from 7 to 10 per week and 5 to 9 per week, respectively. In these three studies, fluoxetine 60 mg, but not 20 mg, was statistically significantly superior to placebo in reducing the number of binge eating and vomiting episodes per week. The statistically significantly superior effect of 60 mg vs. placebo was present as early as Week 1 and persisted throughout each study. The fluoxetine relatedreduction in bulimic episodes appeared to be independent of baseline depression as assessed by the Hamilton Depression Rating Scale. In each of these three studies, the treatment effect, as measured by differences between fluoxetine 60 mg, and placebo on median reduction from baseline in frequency of bulimic behaviors at endpoint, ranged from 1 to 2 episodes per week for binge eating and 2 to 4 episodes per week for vomiting. The size of the effect was related to baseline frequency, with greater reductionsseen in patients with higher baseline frequencies. Although some patients achieved freedom from binge eating and purging as a result of treatment, for the majority, the benefit was a partial reduction in the frequency of binge eating and purging. In a longer-term trial, 150 patients meeting DSM-IV criteria for bulimia nervosa, purging subtype, who had responded during a single-blind, 8 week acute treatment phase with fluoxetine 60 mg/day, were randomized to continuation of fluoxetine 60 mg/day or placebo, for up to 52 weeks of observation for relapse. Response during the single-blind phase was defined by having achieved at least a 50% decrease in vomiting frequency compared with baseline. Relapse during the double-blind phase was defined as a persistent return to baseline vomiting frequency or physician judgement that the patient had relapsed. Patients receiving continued fluoxetine 60 mg/day experienced a significantly longer time to relapse over the subsequent 52 weeks compared with those receiving placebo.<br/>Panic Disorder: The effectiveness of fluoxetine in the treatment of panic disorder was demonstrated in 2 double-blind, randomized, placebo-controlled, multicenter studies of adult outpatients who had a primary diagnosis of panic disorder (DSM-IV), with or without agoraphobia. Study 1 (N = 180 randomized) was a 12 week flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in the range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 42% vs. 28%, respectively. Study 2 (N = 214 randomized) was a 12 week flexible-dose study. Fluoxetine was initiated at 10 mg/day for the first week, after which patients were dosed in a range of 20 to 60 mg/day on the basis of clinical response and tolerability. A statistically significantly greater percentage of fluoxetine-treated patients were free from panic attacks at endpoint than placebo-treated patients, 62% vs. 44%, respectively. | lld:dailymed |
| dailymed-drugs:46 | dailymed-instance:clinicalP... | Granisetron is a selective 5-hydroxytryptamine(5-HT) receptor antagonist with little or no affinity for other serotonin receptors, including 5-HT; 5-HT; 5-HT; 5-HT; for alpha, alpha, or beta-adrenoreceptors; for dopamine-D; or for histamine-H; benzodiazepine; picrotoxin or opioid receptors. Serotonin receptors of the 5-HTtype are located peripherally on vagal nerve terminals and centrally in the chemoreceptor trigger zone of the area postrema. During chemotherapy that induces vomiting, mucosal enterochromaffin cells release serotonin, which stimulates 5-HTreceptors. This evokes vagal afferent discharge, inducing vomiting. Animal studies demonstrate that, in binding to 5-HTreceptors, granisetron blocks serotonin stimulation and subsequent vomiting after emetogenic stimuli such as cisplatin. In the ferret animal model, a single granisetron injection prevented vomiting due to high-dose cisplatin or arrested vomiting within 5 to 30 seconds. In most human studies, granisetron has had little effect on blood pressure, heart rate or ECG. No evidence of an effect on plasma prolactin or aldosterone concentrations has been found in other studies. Following single and multiple oral doses, granisetron hydrochloride tablets slowed colonic transit in normal volunteers. However, granisetron hydrochloride had no effect on oro-cecal transit time in normal volunteers when given as a single intravenous (IV) infusion of 50 mcg/kg or 200 mcg/kg.<br/>Pharmacokinetics: In healthy volunteers and adult cancer patients undergoing chemotherapy, administration of granisetron hydrochloride tablets produced mean pharmacokinetic data shown in Table 1.<br/>Absorption: When granisetron tablets were administered with food, AUC was decreased by 5% and Cincreased by 30% in non-fasted healthy volunteers who received a single dose of 10 mg.<br/>Distribution: Plasma protein binding is approximately 65% and granisetron distributes freely between plasma and red blood cells.<br/>Metabolism: Granisetron metabolism involves N-demethylation and aromatic ring oxidation followed by conjugation. In vitro liver microsomal studies show that granisetron's major route of metabolism is inhibited by ketoconazole, suggestive of metabolism mediated by the cytochrome P-450 3A subfamily. Animal studies suggest that some of the metabolites may also have 5-HTreceptor antagonist activity.<br/>Elimination: Clearance is predominantly by hepatic metabolism. In normal volunteers, approximately 11% of the orally administered dose is eliminated unchanged in the urine in 48 hours. The remainder of the dose is excreted as metabolites, 48% in the urine and 38% in the feces.<br/>Subpopulations: | lld:dailymed |
| dailymed-drugs:47 | dailymed-instance:clinicalP... | Intravascular injection of a radiopaque diagnostic agent opacifies those vessels in the path of the flow of the contrast medium, permitting radiographic visualization of the internal structures of the human body until significant hemodilution occurs. At physiologic pH, the water-soluble contrast media are completely dissociated into a radiopaque anion and a solubilizing cation. While circulating in tissue fluids, the compound remains ionized. However, it is not metabolized but excreted unchanged in the urine, each diatrizoate molecule remaining "obligated" to its sodium moiety. Following intravenous injection, the radiopaque diagnostic agents are immediately diluted in the circulating plasma. Equilibrium is reached with the extracellular compartment at about 10 minutes. Hence, the plasma concentration at 10 minutes is closely related to the dose corrected to body size. The pharmacokinetics of the intravenously administered radiopaque contrast media are usually best described by a two compartment model with a rapid alpha phase for drug distribution and a slow beta phase for drug elimination. In patients with normal renal function, the alpha and beta half-lives were respectively 30 minutes and 120 minutes for diatrizoate. But in patients with renal functional impairment, the elimination half-life for the beta phase can be prolonged up to several days. Injectable radiopaque diagnostic agents are excreted either through the liver or through the kidneys. These two excretory pathways are not mutually exclusive, but the main route of excretion seems to be governed by the affinity of the contrast medium for serum albumin. From 0% to 10% of diatrizoate sodium is bound to serum protein. Diatrizoate salts are excreted unchanged predominantly through the kidneys by glomerular filtration. The amount excreted by the kidney during any period of time is determined by the filtered load; ie, the product of plasma contrast media concentration and glomerular filtration rate. The plasma concentration is dependent upon the dose administered and the body size. The glomerular filtration rate varies with the body size, sex, age, circulatory dynamics, diuretic effect of the drug, and renal function. In patients with normal renal function the maximum urinary concentration of diatrizoate sodium occurs within 10 minutes with 12 percent ofthe administered dose being excreted. The mean values of cumulative urinary excretion for diatrizoate sodium expressed as percentage of administered dose are 38 percent at 60 minutes, 45 percent at 3 hours, and 94 to 100 percent at 24 hours. Urinary excretion of contrast media is delayed in infants younger than 1 month and in patients with urinary tract obstruction. The urinary iodine concentration is higher with the sodium salt of diatrizoic acid than with the meglumine salt. The liver and small intestine provide the major alternate route of excretion for diatrizoate. In patients free of severe renal disease, the fecal recovery is less than 2 percent of the administered dose. In patients with severe renal impairment the excretion of these contrast media through the gallbladder and into the small intestine sharply increases; up to 20 percent of the administered dose has been recovered in the feces in 48 hours. Saliva is a minor secretory pathway for injectable radiopaque diagnostic agents. In patients with normal renal function, minimal amounts of contrast media are secreted unchanged. However, in uremic patients small amounts of free iodides resulting from deiodination prior to administration or in vivo, have been detected in the saliva. Diatrizoate salts cross the placental barrier in humans by simple diffusion and appear to enter fetal tissue passively. No apparent harm to the fetus was observed when diatrizoate sodium and diatrizoate meglumine were injected intravenously 24 hours prior to delivery. However, abnormal neonatal opacification of the small intestine and colon were detected 4 to 6 days after delivery. Procedures including radiation involve a certain risk related to the exposure of the fetus. Injectable radiopaque diagnostic agents are excreted unchanged in human milk.<br/>Computerized Tomography: HYPAQUE sodium 50 percent can be administered as an intravenous bolus for brain tissue enhancement using computerized tomography. Increased tissue contrast differential for the scan is achieved either because of increased vascular (arterial, venous, or capillary bed) contrast or by blood brain barrier penetration of the medium (or its absence) in certain localized areas of disrupted vascular permeability. The degree of tissue enhancement caused by increased blood contrast is directly related to blood iodine content. However, the degree of enhancement due to extravascular accumulation of iodine resulting from blood brain barrier disruption will depend on the extent of disruption, the blood level of iodine, and the time delay prior to scanning. The nature of the pathology will determine whether an immediate or delayed scan is optimal.<br/>Effects of Steroid Therapy: The anti-inflammatory and antiedema effects in patients receiving steroid therapy have interfered with the expected distribution of CT tissue enhancement on the scan in certain diseases. | lld:dailymed |
| dailymed-drugs:48 | dailymed-instance:clinicalP... | Axid is a competitive, reversible inhibitor of histamine at the histamine H-receptors, particularly those in the gastric parietal cells. Antisecretory Activity���1. Effects on Acid Secretion: Axid significantly inhibited nocturnal gastric acid secretion for up to 12 hours. Axid also significantly inhibited gastric acid secretion stimulated by food, caffeine, betazole, and pentagastrin (Table 1). 2. Effects on Other Gastrointestinal Secretions���Pepsin:Oral administration of 75 to 300 mg of Axid did not affect pepsin activity in gastric secretions. Total pepsin output was reduced in proportion to the reduced volume of gastric secretions. Intrinsic Factor: Oral administration of 75 to 300 mg of Axid increased betazole-stimulated secretion of intrinsic factor. Serum Gastrin Concentration: Axid had no effect on basal serum gastrin concentration. No rebound of gastrin secretion was observed when food was ingested 12 hours after administration of Axid. 3. Other Pharmacologic Actions- 4. Pharmacokinetics���The absolute oral bioavailability of nizatidine exceeds 70%. Peak plasma concentrations (700 to 1,800��g/L for a 150-mg dose and 1,400 to 3,600��g/L for a 300-mg dose) occur from 0.5 to 3 hours following the dose. A concentration of 1,000��g/L is equivalent to 3��mol/L; a dose of 300 mg is equivalent to 905��moles. Plasma concentrations 12 hours after administration are less than 10��g/L. The elimination half-life is 1 to 2 hours, plasma clearance is 40 to 60 L/h, and the volume of distribution is 0.8 to 1.5 L/kg. Because of the short half-life and rapid clearance of nizatidine, accumulation of the drug would not be expected in individuals with normal renal function who take either 300 mg once daily at bedtime or 150 mg twice daily. Axid exhibits dose proportionality over the recommended dose range. The oral bioavailability of nizatidine is unaffected by concomitant ingestion of the propantheline. Antacids consisting of aluminum and magnesium hydroxides with simethicone decrease the absorption of nizatidine by about 10%. With food, the AUC and Cincrease by approximately 10%. In humans, less than 7% of an oral dose is metabolized as N2-monodes-methylnizatidine, an H-receptor antagonist, which is the principal metabolite excreted in the urine. Other likely metabolites are the N2-oxide (less than 5% of the dose) and the S-oxide (less than 6% of the dose). More than 90% of an orally administered dose of nizatidine is excreted in the urine within 12 hours. About 60% of an oral dose is excreted as unchanged drug. Renal clearance is about 500 mL/min, which indicates excretion by active tubular secretion. Less than 6% of an administered dose is eliminated in the feces. Moderate to severe renal impairment significantly prolongs the half-life and decreases the clearance of nizatidine. In individuals who are functionally anephric, the half-life is 3.5 to 11 hours, and the plasma clearance is 7 to 14 L/h. To avoid accumulation of the drug in individuals with clinically significant renal impairment, the amount and/or frequency of doses of Axid should be reduced in proportion to the severity of dysfunction (see Dosage and Administration). Approximately 35% of nizatidine is bound to plasma protein, mainly to��-acid glycoprotein. Warfarin, diazepam, acetaminophen, propantheline, phenobarbital, and propranolol did not affect plasma protein binding of nizatidine in vitro. Clinical Trials���1. Active Duodenal Ulcer: In multicenter, double-blind, placebo-controlled studies in the United States, endoscopically diagnosed duodenal ulcers healed more rapidly following administration of Axid, 300 mg h.s. or 150 mg b.i.d., than with placebo (Table 2). Lower doses, such as 100 mg h.s., had slightly lower effectiveness. *P<0.01 as compared with placebo.���P<0.05 as compared with placebo. 2. Maintenance of Healed Duodenal Ulcer: Treatment with a reduced dose of Axid has been shown to be effective as maintenance therapy following healing of active duodenal ulcers. In multicenter, double-blind, placebo-controlled studies conducted in the United States, 150 mg of Axid taken at bedtime resulted in a significantly lower incidence of duodenal ulcer recurrence in patients treated for up to 1 year (Table 3). *P<0.001 as compared with placebo. 3. Gastroesophageal Reflux Disease (GERD): In 2 multi-center, double-blind, placebo-controlled clinical trials performed in the United States and Canada, Axid was more effective than placebo in improving endoscopically diagnosed esophagitis and in healing erosive and ulcerative esophagitis. In patients with erosive or ulcerative esophagitis, 150 mg b.i.d. of Axid given to 88 patients compared with placebo in 98 patients in Study 1 yielded a higher healing rate at 3 weeks (16% vs 7%) and at 6 weeks (32% vs 16%, P<0.05). Of 99 patients on Axid and 94 patients on placebo, Study 2 at the same dosage yielded similar results at 6 weeks (21% vs 11%, P<0.05) and at 12 weeks (29% vs 13%, P<0.01). In addition, relief of associated heartburn was greater in patients treated with Axid. Patients treated with Axid consumed fewer antacids than did patients treated with placebo. 4. Active Benign Gastric Ulcer: In a multicenter, double-blind, placebo-controlled study conducted in the United States and Canada, endoscopically diagnosed benign gastric ulcers healed significantly more rapidly following administration of nizatidine than of placebo (Table 4). In a multicenter, double-blind, comparator-controlled study in Europe, healing rates for patients receiving nizatidine (300 mg h.s. or 150 mg b.i.d.) were equivalent to rates for patients receiving a comparator drug, and statistically superior to historical placebo control rates. | lld:dailymed |
| dailymed-drugs:49 | dailymed-instance:clinicalP... | Dextrose Injections, USP have value as a source of water and calories. They are capable of inducing diuresis depending on the clinical condition of the patient. | lld:dailymed |
| dailymed-drugs:1791 | dailymed-instance:clinicalP... | Dextrose Injections, USP have value as a source of water and calories. They are capable of inducing diuresis depending on the clinical condition of the patient. | lld:dailymed |
| dailymed-drugs:51 | dailymed-instance:clinicalP... | 1. General Pharmacologic Properties: Minoxidil is an orally effective direct acting peripheral vasodilator that reduces elevated systolic and diastolic blood pressure by decreasing peripheral vascular resistance. Microcirculatory blood flow in animals is enhanced or maintained in all systemic vascular beds. In man, forearm and renal vascular resistance decline; forearm blood flow increases while renal blood flow and glomerular filtration rate are preserved. Because it causes peripheral vasodilation, minoxidil elicits a number of predictable reactions. Reduction of peripheral arteriolar resistance and the associated fall in blood pressure trigger sympathetic, vagal inhibitory, and renal homeostatic mechanisms, including an increase in renin secretion, that lead to increased cardiac rate and output and salt and water retention. These adverse effects can usually be minimized by concomitant administration of a diuretic and a beta-adrenergic blocking agent or other sympathetic nervous system suppressant. Minoxidil does not interfere with vasomotor reflexes and therefore does not produce orthostatic hypotension. The drug does not enter the central nervous system in experimental animals in significant amounts, and it does not affect CNS function in man.<br/>2. Effects on Blood Pressure and Target Organs: The extent and time-course of blood pressure reduction by minoxidil do not correspond closely to its concentration in plasma. After an effective single oral dose, blood pressure usually starts to decline within one-half hour, reaches a minimum between 2 and 3 hours and recovers at an arithmetically linear rate of about 30%/day. The total duration of effect is approximately 75 hours. When minoxidil is administered chronically, once or twice aday, the time required to achieve maximum effect on blood pressure with a given daily dose is inversely related to the size of the dose. Thus, maximum effect is achieved on 10 mg/day within 7 days, on 20 mg/day within 5 days, and on 40 mg/day within 3 days. The blood pressure response to minoxidil is linearly related to the logarithm of the dose administered. The slope of this log-linear dose-response relationship is proportional to the extent of hypertension and approaches zero at a supine diastolic blood pressure of approximately 85 mm Hg. When used in severely hypertensive patients resistant to other therapy, frequently with an accompanying diuretic and beta-blocker, minoxidil tablets usually decreased the blood pressure and reversed encephalopathy and retinopathy.<br/>3. Absorption and Metabolism: Minoxidil is at least 90% absorbed from the GI tract in experimental animals and man. Plasma levels of the parent drug reach maximum within the first hour and decline rapidly thereafter. The average plasma half-life in man is 4.2 hours. Approximately 90% of the administered drug is metabolized, predominantly by conjugation with glucuronic acidat the N-oxide position in the pyrimidine ring, but also by conversion to more polar products. Known metabolites exert much less pharmacologic effect than minoxidil itself; all are excreted principally in the urine. Minoxidil does not bind to plasma proteins, and its renal clearance corresponds to the glomerular filtration rate. In the absence of functional renal tissue, minoxidil and its metabolites can be removed by hemodialysis.<br/>4. Cardiac Lesions in Animals: Minoxidil produces several cardiac lesions in animals. Some are characteristic of agents that cause tachycardia and diastolic hypotension (beta-agonists like isoproterenol, arterial dilators like hydralazine) while others are produced by a narrower range of agents with arterial dilating properties. The significance of these lesions for humans is not clear, as they have not been recognized in patients treated with oral minoxidil at systemically active doses, despite formal review of over 150 autopsies of treated patients. Autopsies of over 150 patients who died of various causes after receiving minoxidil for hypertension have not revealed the characteristic hemorrhagic (especially atrial) lesions seen in dogs and minipigs. While areas of papillary muscle and subendocardial necrosis were occasionally seen, they occurred in the presence of known pre-existing coronary artery disease and were also seen in patients never exposed to minoxidil in another series using similar, but not identical, autopsy methods. | lld:dailymed |
| dailymed-drugs:52 | dailymed-instance:clinicalP... | Phenytoin is an anticonvulsant which may be useful in the treatment of status epilepticus of the grand mal type. The primary siteof action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of grand mal seizures. The plasma half-life in man after intravenous administration ranges from 10 to 15 hours. Optimum control without clinical signs of toxicity occurs most often with serum levels between 10 and 20 mcg/mL. A fall in plasma levels may occur when patients are changed from oral to intramuscular administration. The drop is caused by slower absorption, as compared to oral administration, due to the poor water solubility of phenytoin. Intravenous administration is the preferred route for producing rapid therapeutic serum levels. There are occasions when intramuscular administration may be required, i.e., postoperatively, in comatose patients, for GI upsets. During these periods, a sufficient dose must be administered intramuscularly to maintain the plasma level within the therapeutic range. Where oral dosage is resumed following intramuscular usage, the oral dose should be properly adjusted to compensate for the slow, continuing IM absorption to avoid toxic symptoms. Patients stabilized on a daily oral regimen of phenytoin experience a drop in peak blood levels to 50-60 percent of stable levels if crossed over to an equal dose administered intramuscularly. However, the intramuscular depot of poorly soluble material is eventually absorbed, as determined by urinary excretion of 5-(p-hydroxyphenyl)-5-phenylhydantoin (HPPH), the principal metabolite, as well as the total amount of drug eventually appearing in the blood. A short-term (one week) study indicates that patients do not experience the expected drop in blood levels when crossed over to the intramuscular route if the phenytoin IM dose is increased by 50 percent over the previously established oral dose. To avoid drug cumulation due to absorption from the muscle depots, it is recommended that for the first week back on oral phenytoin, the dose be reduced to half of the original oral dose (one third of the IM dose). Experience for periods greater than oneweek is lacking and blood level monitoring is recommended. For administration of phenytoin in patients who cannot take oral medication for periods greater than a week, gastric intubation may be considered. | lld:dailymed |
| dailymed-drugs:53 | dailymed-instance:clinicalP... | Mechanism of Action: CASODEX is a non-steroidal antiandrogen. It competitively inhibits the action of androgens by binding to cytosol androgen receptors in the target tissue. Prostatic carcinoma is known to be androgen sensitive and responds to treatment that counteracts the effect of androgen and/or removes the source of androgen. When CASODEX is combined with luteinizing hormone-releasing hormone (LHRH) analogue therapy, the suppression of serum testosterone induced by the LHRH analogue is not affected. However, in clinical trials with CASODEX as a single agent for prostate cancer, rises in serum testosterone and estradiol have been noted. In a subset of patients who have been treated with CASODEX and an LHRH agonist, and who discontinue CASODEX therapy due to progressive advanced prostate cancer, a reduction in Prostate Specific Antigen (PSA) and/or clinical improvement (antiandrogen withdrawal phenomenon) may be observed.<br/>Pharmacokinetics:<br/>Absorption:: Bicalutamide is well-absorbed following oral administration, although the absolute bioavailability is unknown. Co-administration of bicalutamide with food has no clinically significant effect on rate or extent of absorption.<br/>Distribution:: Bicalutamide is highly protein-bound (96%). See Drug-Drug Interactions below.<br/>Metabolism/Elimination:: Bicalutamide undergoes stereospecific metabolism. The S (inactive) isomer is metabolized primarily by glucuronidation. The R (active) isomer also undergoes glucuronidation but is predominantly oxidized to an inactive metabolite followed by glucuronidation. Both the parent and metabolite glucuronides are eliminated in the urine and feces. The S-enantiomer is rapidly cleared relative to the R-enantiomer, with the R-enantiomer accounting for about 99% of total steady-state plasma levels.<br/>Special Populations::<br/>Clinical Studies:<br/>CASODEX 50 mg Daily in Combination with an LHRH-A: In a multicenter, double-blind, controlled clinical trial, 813 patients with previously untreated advanced prostate cancer were randomized to receive CASODEX 50 mg once daily (404 patients) or flutamide 250 mg (409 patients) three times a day, each in combination with LHRH analogues (either goserelin acetate implant or leuprolide acetate depot). In an analysis conducted after a median follow-up of 160 weeks was reached, 213 (52.7%) patients treated with CASODEX-LHRH analogue therapy and 235 (57.5%) patients treated with flutamide-LHRH analogue therapy had died. There was no significant difference in survival between treatment groups (see Figure 1). The hazard ratio for time to death (survival) was 0.87 (95% confidence interval 0.72 to 1.05). Figure 1 - The Kaplan-Meier probability of death for both antiandrogen treatment groups. There was no significant difference in time to objective tumor progression between treatment groups (see Figure 2). Objective tumor progression was defined as the appearance of any bone metastases or the worsening of any existing bone metastases on bone scan attributable to metastatic disease, or an increase by 25% or more of any existing measurable extraskeletal metastases. The hazard ratio for time to progression of CASODEXplus LHRH analogue to that of flutamide plus LHRH analogue was 0.93 (95% confidence interval, 0.79 to 1.10). Figure 2 - Kaplan-Meier curve for time to progression for both antiandrogen treatment groups Quality of life was assessed with self-administered patient questionnaires on pain, social functioning, emotional well-being, vitality, activity limitation, bed disability, overall health, physical capacity, general symptoms, and treatment related symptoms. Assessment of the Quality of Life questionnaires did not indicate consistent significant differences between the two treatment groups.<br/>Safety Data from Clinical Studies using CASODEX 150 mg: CASODEX 150 mg is not approved for use either alone or with other treatments. Two identical multicenter, randomized, open label trials comparing CASODEX 150 mg daily monotherapy to castration were conducted in patients that had locally advanced (T3-4, NX, MO) or metastatic (M1) prostate cancer. | lld:dailymed |
| dailymed-drugs:54 | dailymed-instance:clinicalP... | Oral Administration: Rifampin is readily absorbed from the gastrointestinal tract. Peak serum concentrations in healthy adults and pediatric populations vary widely from individual to individual. Following a single 600 mg oral dose of rifampin in healthy adults, the peak serum concentration averages 7 mcg/mL but may vary from 4 to 32 mcg/mL. Absorption of rifampin is reduced by about 30% when the drug is ingested with food. Rifampin is widely distributed throughout the body. It is present in effective concentrations in many organs and body fluids, including cerebrospinal fluid. Rifampin is about 80% protein bound. Most of the unbound fraction is not ionized and, therefore, diffuses freely into tissues. In healthy adults, the mean biological half-life of rifampin in serum averages 3.35��0.66 hours after a 600 mg oral dose, with increases up to 5.08��2.45 hours reported after a 900 mg dose. With repeated administration, the half-life decreases and reaches average values of approximately 2 to 3 hours. The half-life does not differ in patients with renal failure at doses not exceeding 600 mg daily, and consequently, no dosage adjustment is required. Following a single 900 mg oral dose of rifampin in patients with varying degrees of renal insufficiency, the mean half-life increased from 3.6 hours in healthy adults to 5.0, 7.3, and 11.0 hours in patients with glomerular filtration rates of 30 to 50 mL/min, less than 30 mL/min, and in anuric patients, respectively. Refer to the WARNINGS section for information regarding patients with hepatic insufficiency. Rifampin is rapidly eliminated in the bile, and an enterohepatic circulation ensues. During this process, rifampin undergoes progressive deacetylation so that nearly all the drug in the bile is in this form in about 6 hours. This metabolite is microbiologically active. Intestinal reabsorption is reduced by deacetylation, and elimination is facilitated. Up to 30% of adose is excreted in the urine, with about half of this being unchanged drug.<br/>Intravenous Administration: After intravenous administration of a 300 or 600 mg dose of rifampin infused over 30 minutes to healthy male volunteers (n=12), mean peak plasma concentrations were 9.0��3.0 and 17.5��5.0 mcg/mL, respectively. Total body clearances after the 300 and 600 mg IV doses were 0.19��0.06 and 0.14��0.03 L/hr/kg, respectively. Volumes of distribution at steady state were 0.66��0.14 and 0.64��0.11 L/kg for the 300 and 600 mg IV doses, respectively. After intravenous administration of 300 or 600 mg doses, rifampin plasma concentrations in these volunteers remained detectable for 8 and 12 hours, respectively (see Table). Plasma concentrations after the 600 mg dose, which were disproportionately higher (up to 30% greater than expected) than those found after the 300 mg dose, indicated that the elimination of larger doses was not as rapid. After repeated once-a-day infusions (3 hr duration) of 600 mg in patients (n=5) for 7 days, concentrations of IV rifampin decreased from 5.81��3.38 mcg/mL 8 hours after the infusion on day 1 to 2.6��1.88 mcg/mL 8 hours after the infusion on day 7. Rifampin is widely distributed throughout the body. It is present in effective concentrations in many organs and body fluids, including cerebrospinal fluid. Rifampin is about 80% protein bound. Most of the unbound fraction is not ionized and therefore diffuses freely into tissues. Rifampin is rapidly eliminated in the bile and undergoes progressive enterohepatic circulation and deacetylation to the primary metabolite, 25���desacetyl-rifampin. This metabolite is microbiologically active. Less than 30% of the dose is excreted in the urine as rifampin or metabolites. Serum concentrations do not differ in patients with renal failure at a studied dose of 300 mg and consequently, no dosage adjustment is required.<br/>Pediatrics:<br/>Oral Administration: In one study, pediatric patients 6 to 58 months old were given rifampin suspended in simple syrup or as dry powder mixed with applesauce at a dose of 10 mg/kg body weight. Peak serum concentrations of 10.7��3.7 and 11.5��5.1 mcg/mL were obtained 1 hour after preprandial ingestion of the drug suspension and the applesauce mixture, respectively. After the administration of either preparation, the tof rifampin averaged 2.9 hours. It should be noted that in other studies in pediatric populations, at doses of 10 mg/kg body weight, mean peak serum concentrations of 3.5 mcg/mL to 15 mcg/mL have been reported.<br/>Intravenous Administration: In pediatric patients 0.25 to 12.8 years old (n=12), the mean peak serum concentration of rifampin at the end of a 30 minute infusion of approximately 300 mg/mwas 25.9��1.3 mcg/mL; individual peak concentrations 1 to 4 days after initiation of therapy ranged from 11.7 to 41.5 mcg/mL; individual peak concentrations 5 to 14 days after initiation of therapy were 13.6 to 37.4 mcg/mL. The individual serum half-life of rifampin changed from 1.04 to 3.81 hours early in therapy to 1.17 to 3.19 hours 5 to 14 days after therapy was initiated.<br/>Microbiology: Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. Rifampin at therapeutic levels has demonstrated bactericidal activity against both intracellular and extracellular Mycobacterium tuberculosis organisms. Organisms resistant to rifampin are likely to be resistant to other rifamycins. Rifampin has bactericidal activity against slow and intermittently growing M tuberculosis organisms. It also has significant activity against Neisseria meningitidis isolates . In the treatment of both tuberculosis and the meningococcal carrier state , the small number of resistant cells present within large populations of susceptible cells can rapidly become predominant. In addition, resistance to rifampin has been determined to occur as single-step mutations of the DNA-dependent RNA polymerase. Since resistance can emerge rapidly, appropriate susceptibility tests should be performed in the event of persistent positive cultures. Rifampin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. The following in vitro data are available, but their clinical significance is unknown. Rifampin exhibits in vitro activity against most strains of the following microorganisms; however, the safety and effectiveness of rifampin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials. ��-lactamase production should have no effect on rifampin activity.<br/>Susceptibility Tests: Prior to initiation of therapy, appropriate specimens should be collected for identification of the infecting organism and in vitro susceptibility tests. In vitro testing for Mycobacterium tuberculosis isolates: Two standardized in vitro susceptibility methods are available for testing rifampin against M tuberculosis organisms. The agar proportion method (CDC or NCCLSM24-P) utilizes Middlebrook 7H10 medium impregnated with rifampin at a final concentration of 1.0 mcg/mL to determine drug resistance. After three weeks of incubation MICvalues are calculated by comparing the quantity of organisms growing in the medium containing drug to the control cultures. Mycobacterial growth in the presence of drug, of at least 1% of the growth in the control culture, indicates resistance. The radiometric broth method employs the BACTEC 460 machine to compare the growth index from untreated control cultures to cultures grown in the presence of 2.0 mcg/mL of rifampin. Strict adherence to the manufacturer's instructions for sample processing and data interpretation is required for this assay. Susceptibility test results obtained by the two different methods can only be compared if the appropriate rifampin concentration is used for each test method as indicated above. Both procedures require the use of M tuberculosis H37Rv ATCC 27294 as a control organism. The clinical relevance of in vitro susceptibility test results for mycobacterial species other than M tuberculosis using either the radiometric or the proportion method has not been determined. In vitro testing for Neisseria meningitidis isolates:<br/>Dilution Techniques: Quantitative methods that are used to determine minimum inhibitory concentrations provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized dilution method(broth, agar, or microdilution) or equivalent with rifampin powder. The MIC values obtained should be interpreted according to the following criteria for Neisseria meningitidis: A report of "susceptible" indicates that the pathogen is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in the blood. A report of "intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where the maximum acceptable dose of drug can be used. This category also provides a buffer zone that prevents small-uncontrolled technical factors from causing major discrepancies in interpretation. A report of "resistant" indicates that usually achievable concentrations of the antimicrobial compound in the blood are unlikely to be inhibitory and that other therapy should be selected. Measurement of MIC or minimum bactericidal concentrations (MBC) and achieved antimicrobial compound concentrations may be appropriate to guide therapy in some infections. (See CLINICAL PHARMACOLOGY section for further information on drug concentrations achieved in infected body sites and other pharmacokinetic properties of this antimicrobial drug product.) Standardized susceptibility test procedures require the use of laboratory control microorganisms. The use of these microorganisms does not imply clinical efficacy ; they are used to control the technical aspects of the laboratory procedures. Standard rifampin powder should give the following MIC values:<br/>Diffusion Techniques: Quantitative methods that require measurement of zone diameters provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedurethat has been recommended for use with disks to test the susceptibility of microorganisms to rifampin uses the 5 mcg rifampin disk. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for rifampin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg rifampin disk should be interpreted according to the following criteria for Neisseria meningitidis: Interpretation should be as stated above for results using dilution techniques. As with standard dilution techniques, diffusion methods require the use of laboratory control microorganisms. The use of these microorganisms does not imply clinical efficacy ; they are used to control the technical aspects of the laboratory procedures. The 5 mcg rifampin disk should provide the following zone diameters in these quality control strains: | lld:dailymed |
| dailymed-drugs:55 | dailymed-instance:clinicalP... | Human Pharmacology: Cephalexin Capsules, USP is acid stable and may be given without regard to meals. It is rapidly absorbed after oral administration. Following doses of 250 mg, 500 mg, and 1 g, average peak serum levels of approximately 9, 18, and 32 mcg/mL respectively were obtained at 1 hour. Measurable levels were present 6 hours after administration. Cephalexin is excreted in the urine by glomerular filtration and tubular secretion. Studies showed that over 90% of the drug was excreted unchanged in the urine within 8 hours. During this period, peak urine concentrations following the 250-mg, 500-mg, and 1-g doses were approximately 1,000, 2,200, and 5,000 mcg/mL respectively.<br/>Microbiology: In vitro tests demonstrate that the cephalosporins are bactericidal because of their inhibition of cell-wall synthesis. Cephalexin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Aerobes, Gram-positive: Aerobes, Gram-negative: Note���Methicillin-resistant staphylococci and most strains of enterococci (Enterococcus faecalis [formerly Streptococcus faecalis]) are resistant to cephalosporins, including cephalexin. It is not active against most strains of Enterobacter spp, Morganella morganii, and Proteus vulgaris. It has no activity against Pseudomonas spp or Acinetobacter calcoaceticus.<br/>Susceptibility Tests: Diffusion techniques���Quantitative methods that require measurement of zone diameters provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedurethat has been recommended for use with disks to test the susceptibility of micro-organisms to cephalexin uses the 30-mcg cephalothin disk. Interpretation involves correlation of the diameter obtained in the disk test with the minimal inhibitory concentration (MIC) for cephalexin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-mcg cephalothin disk should be interpreted according to the following criteria: A report of "Susceptible" indicates that the pathogen is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in blood. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that usually achievable concentrations of the antimicrobial compound in the blood are unlikely to be inhibitory and that other therapy should be selected. Measurement of MIC or MBC and achieved antimicrobial compound concentrations may be appropriate to guide therapy in some infections. (See CLINICAL PHARMACOLOGY section for information on drug concentrations achieved in infected body sites and other pharmacokinetic properties of this antimicrobial drug product.) Standardized susceptibility test procedures require the use of laboratory control microorganisms. The 30-mcg cephalothin disk should provide the following zone diameters in these laboratory test quality control strains: Dilution techniques���Quantitative methods that are used to determine MICs provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized dilution method(broth, agar, microdilution) or equivalent with cephalothin powder. The MIC values obtained should be interpreted according to the following criteria: Interpretation should be as stated above for results using diffusion techniques. As with standard diffusion techniques, dilution methods require the use of laboratory control microorganisms. Standard cephalothin powder should provide the following MIC values: | lld:dailymed |
| dailymed-drugs:56 | dailymed-instance:clinicalP... | Nifedipine is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) and inhibits the transmembrane influx of calcium ions into cardiac muscle and smooth muscle. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. Nifedipine selectively inhibits calcium ion influx across the cell membrane of cardiac muscle and vascular smooth muscle without altering serum calcium concentrations.<br/>Mechanism of Action:<br/>Angina: The precise mechanisms by which inhibition of calcium influx relieves angina has not been fully determined, but includes at least the following two mechanisms:<br/>Hypertension: The mechanism by which nifedipine reduces arterial blood pressure involves peripheral arterial vasodilatation and the resulting reduction in peripheral vascular resistance. The increased peripheral vascular resistance that is an underlying cause of hypertension results from an increase in active tension in the vascular smooth muscle. Studies have demonstrated that the increase in active tension reflects an increase in cytosolic free calcium. Nifedipine is a peripheral arterial vasodilator which acts directly on vascular smooth muscle. The binding of nifedipine to voltage-dependent and possibly receptor-operated channels in vascular smooth muscle results in an inhibition of calcium influx through these channels. Stores of intracellular calcium in vascular smooth muscle are limited and thus dependent upon the influx of extracellular calcium for contraction to occur. The reduction in calcium influx by nifedipine causes arterial vasodilation and decreased peripheral vascular resistance which results in reduced arterial blood pressure.<br/>Pharmacokinetics and Metabolism: Nifedipine is completely absorbed after oral administration. Plasma drug concentrations rise at a gradual, controlled rate after a nifedipine extended-release tablet dose and reach a plateau at approximately six hours after the first dose. For subsequent doses, relatively constant plasma concentrations at this plateau are maintained with minimal fluctuations over the 24-hour dosing interval. About a four-fold higher fluctuation index (ratio of peak to trough plasma concentration) was observed with the conventional immediate-release nifedipine capsule at t.i.d. dosing than with once daily nifedipine extended-release tablet. At steady-state the bioavailability of the nifedipine extended-release tablet is 86% relative to immediate-release nifedipine capsules. Administration of the nifedipine extended-release tablet in the presence of food slightly alters the early rate of drug absorption, but does not influence the extent of drug bioavailability. Markedly reduced GI retention time over prolonged periods (i.e., short bowel syndrome), however, may influence the pharmacokinetic profile of the drug which could potentially result in lower plasma concentrations. Pharmacokinetics of nifedipine extended-releasetablets are linear over the dose range of 30 to 180 mg in that plasma drug concentrations are proportional to dose administered. There was no evidence of dose dumping either in the presence or absence of food for over 150 subjects in pharmacokinetic studies. Nifedipine is extensively metabolized to highly water-soluble, inactive metabolites accounting for 60 to 80% of the dose excreted in the urine. The elimination half-life of nifedipine is approximately two hours. Only traces (less than 0.1% of the dose) of unchanged form can be detected in the urine. The remainder is excreted in the feces in metabolized form, most likely as a result of biliary excretion. Thus, the pharmacokinetics of nifedipine are not significantly influenced by the degree of renal impairment. Patients in hemodialysis or chronic ambulatory peritoneal dialysis have not reported significantly altered pharmacokinetics of nifedipine. Since hepatic biotransformation is the predominant route for the disposition of nifedipine, the pharmacokinetics may be altered in patients with chronic liver disease. Patients with hepatic impairment (liver cirrhosis) have a longer disposition half-life and higher bioavailability of nifedipine than healthy volunteers. The degree of serum protein binding of nifedipine is high (92���98%). Protein binding may be greatly reduced in patients with renal or hepatic impairment.<br/>Hemodynamics: Like other slow-channel blockers, nifedipine exerts a negative inotropic effect on isolated myocardial tissue. This is rarely, if ever, seen in intact animals or man, probably because of reflex responses to its vasodilating effects. In man, nifedipine decreases peripheral vascular resistance which leads to a fall in systolic and diastolic pressures, usually minimal in normotensive volunteers (less than 5���10 mm Hg systolic), but sometimes larger. With nifedipine extended-release tablets, these decreases in blood pressure are not accompanied by any significant change in heart rate. Hemodynamic studies in patients with normal ventricular function have generally found a small increase in cardiac index without major effects on ejection fraction, left ventricular end diastolic pressure (LVEDP) or volume (LVEDV). In patients with impaired ventricular function, most acute studies have shown some increase in ejection fraction and reduction in left ventricular filling pressure.<br/>Electrophysiologic Effects: Although, like other members of its class, nifedipine causes a slight depression of sinoatrial node function and atrioventricular conduction in isolated myocardial preparations, such effects have not been seen in studies in intact animals or in man. In formal electrophysiologic studies, predominantly in patients with normal conduction systems, nifedipine has had no tendency to prolong atrioventricular conduction or sinus node recovery time, or to slow sinus rate. | lld:dailymed |
| dailymed-drugs:58 | dailymed-instance:clinicalP... | Mechanism of Action: Glipizide and metformin hydrochloride tablets combine glipizide and metformin hydrochloride, two antihyperglycemic agents with complementary mechanisms of action, to improve glycemic control in patients with type 2 diabetes. Glipizide appears to lower blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. Extrapancreatic effects may play a part in the mechanism of action of oral sulfonylurea hypoglycemic drugs. The mechanism by which glipizide lowers blood glucose during long-term administration hasnot been clearly established. In man, stimulation of insulin secretion by glipizide in response to a meal is undoubtedly of major importance. Fasting insulin levels are not elevated even on long-term glipizide administration, but the post prandial insulin response continues to be enhanced after at least 6 months of treatment. Metformin hydrochloride is an antihyperglycemic agent that improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Metformin hydrochloride decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization.<br/>Pharmacokinetics:<br/>Absorption and Bioavailability:<br/>Distribution:<br/>Metabolism and Elimination:<br/>Special Populations:<br/>Patients With Type 2 Diabetes: In the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see Table 1), nor is there any accumulation of metformin in either group at usual clinical doses.<br/>Hepatic Insufficiency: The metabolism and excretion of glipizide may be slowed in patients with impaired hepatic function (see PRECAUTIONS). No pharmacokinetic studies have been conducted in patients with hepatic insufficiency for metformin.<br/>Renal Insufficiency: The metabolism and excretion of glipizide may be slowed in patients with impaired renal function (see PRECAUTIONS). In patients with decreased renal function (based on creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see Table 1; also, see WARNINGS).<br/>Geriatrics: There is no information on the pharmacokinetics of glipizide in elderly patients. Limited data from controlled pharmacokinetic studies of metformin in healthy elderly subjects suggest that total plasma clearance is decreased, the half-life is prolonged, and Cis increased, compared to healthy young subjects. From these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see Table 1). Metformin treatment should not be initiated in patients���80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced.<br/>Pediatrics: No data from pharmacokinetic studies in pediatric subjects are available for either glipizide or metformin.<br/>Gender: There is no information on the effect of gender on the pharmacokinetics of glipizide. Metformin pharmacokinetic parameters did not differ significantly in subjects with or without type 2 diabetes when analyzed according to gender (males = 19, females = 16). Similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin was comparable in males and females.<br/>Race: No information is available on race differences in the pharmacokinetics of glipizide. No studies of metformin pharmacokinetic parameters according to race have been performed. In controlled clinical studies of metformin in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n = 249), blacks (n = 51), and Hispanics (n = 24).<br/>Clinical Studies:<br/>Initial Therapy: In a 24 week, double-blind, active-controlled, multicenter international clinical trial, patients with type 2 diabetes, whose hyperglycemia was not adequately controlled with diet and exercise alone (hemoglobin A[HbA]>7.5% and���12% and fasting plasma glucose [FPG]<300 mg/dL) were randomized to receive initial therapy with glipizide 5 mg, metformin 500 mg, glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg, or glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg. After two weeks, the dose was progressively increased (up to the 12 week visit) to a maximum of four tablets daily in divided doses as needed to reach a target mean daily glucose (MDG) of���130 mg/dL. Trial data at 24 weeks are summarized in Table 2. After 24 weeks, treatment with glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg and 2.5 mg/500 mg resulted in significantly greater reduction in HbAcompared to glipizide and to metformin therapy. Also, glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg therapy resulted in significant reductions in FPG versus metformin therapy. Increases above fasting glucose and insulin levels were determined at baseline and final study visits by measurement of plasma glucose and insulin for three hours following a standard mixed liquid meal. Treatment with glipizide and metformin hydrochloride tablets lowered the three-hour postprandial glucose AUC, compared to baseline, to a significantly greater extent than did the glipizide and the metformin therapies. Compared to baseline, glipizide and metformin hydrochloride tablets enhanced the postprandial insulin response, but did not significantly affect fasting insulin levels. There were no clinically meaningful differences in changes from baseline for all lipid parameters between glipizide and metformin hydrochloride tablet therapy and either metformin therapy or glipizide therapy. The adjusted mean changes from baseline in body weight were: glipizide and metformin hydrochloride tablets, 2.5 mg/250 mg, -0.4 kg; glipizide and metformin hydrochloride tablets, 2.5 mg/500 mg, -0.5 kg; glipizide, -0.2 kg; and metformin, -1.9 kg. Weight loss was greater with metformin than with glipizide and metformin hydrochloride tablets.<br/>Second-Line Therapy: In an 18 week, double-blind, active-controlled U.S. clinical trial, a total of 247 patients with type 2 diabetes not adequately controlled (HbA���7.5% and���12% and FPG<300 mg/dL) while being treated with at least one-half the maximum labeled dose of a sulfonylurea (e.g., glyburide 10 mg, glipizide 20 mg) were randomized to receive glipizide (fixed dose, 30 mg), metformin (500 mg), or glipizide and metformin hydrochloride tablets, 5 mg/500 mg. The doses of metformin and glipizide and metformin hydrochloride tablets were titrated (up to the eight week visit) to a maximum of four tablets daily as needed to achieve MDG���130 mg/dL. Trial data at 18 weeks are summarized in Table 3. After 18 weeks, treatment with glipizide and metformin hydrochloride tablets at doses up to 20 mg/2000 mg per day resulted in significantly lower mean final HbAand significantly greater mean reductions in FPG compared to glipizide and to metformin therapy. Treatment with glipizide and metformin hydrochloride tablets lowered the three-hour postprandial glucose AUC, compared to baseline, to a significantly greater extent than did the glipizide and the metformin therapies. Glipizide and metformin hydrochloride tablets did not significantly affect fasting insulin levels. There were no clinically meaningful differences in changes from baseline for all lipid parameters between glipizide and metformin hydrochloride tablet therapy and either metformin therapy or glipizide therapy. The adjusted mean changes from baseline in body weight were: glipizide and metformin hydrochloride tablets, 5 mg/500 mg, -0.3 kg; glipizide, -0.4 kg; and metformin, -2.7 kg. Weight loss was greater with metformin than with glipizide and metformin hydrochloride tablets. | lld:dailymed |
| dailymed-drugs:59 | dailymed-instance:clinicalP... | Mechanism of Action: Busulfan is a bifunctional alkylating agent in which two labile methanesulfonate groups are attached to opposite ends of a four-carbon alkyl chain. In aqueous media, busulfan hydrolyzes to release the methanesulfonate groups. This produces reactive carbonium ions that can alkylate DNA. DNA damage is thought to be responsible for much of the cytotoxicity of busulfan.<br/>Pharmacokinetics: The pharmacokinetics of BUSULFEX were studied in 59 patients participating in a prospective trial of a BUSULFEX-cyclophosphamide preparatory regimen prior to allogeneic hematopoietic progenitor stem cell transplantation. Patients received 0.8 mg/kg BUSULFEX every six hours, for a total of 16 doses over four days. Fifty-five of fifty-nine patients (93%) administered BUSULFEX maintained AUC values below the target value (<1500��M���min). BUSULFEX pharmacokinetics showed consistency between dose 9 and dose 13 as demonstrated by reproducibility of steady state Cmax and a low coefficient of variation for this parameter. In a pharmacokinetic study of BUSULFEX in 24 pediatric patients, the population pharmacokinetic (PPK) estimates of BUSULFEX for clearance (CL) and volume of distribution (V) were determined. For actual body weight, PPK estimates of CL and V were 4.04 L/hr/20 kg (3.37 ml/min/kg; interpatient variability 23%); and 12.8 L/20 kg (0.64 L/kg; interpatient variability 11%). Distribution, Metabolism, Excretion: Studies of distribution, metabolism, and elimination of BUSULFEX have not been done; however, the literature on oral busulfan is relevant. Additionally, for modulating effects on pharmacodynamic parameters see Drug Interactions. Distribution:Busulfan achieves concentrations in the cerebrospinal fluid approximately equal to those in plasma. Irreversible binding to plasma elements, primarily albumin, has been estimated to be 32.4��2.2% which is consistent with the reactive electrophilic properties of busulfan. Metabolism:Busulfan is predominantly metabolized by conjugation with glutathione, both spontaneously and by glutathione S-transferase (GST) catalysis. This conjugate undergoes further extensive oxidative metabolism in the liver. Excretion:Following administration ofC- labeled busulfan to humans, approximately 30% of the radioactivity was excreted into the urine over 48 hours; negligible amounts were recovered in feces. The incomplete recovery of radioactivity may be due to the formation of long-lived metabolites or due to nonspecific alkylation of macromolecules. | lld:dailymed |
| dailymed-drugs:60 | dailymed-instance:clinicalP... | Magnesium (Mg) is an important cofactor for enzymatic reactions and plays an important role in neurochemical transmission and muscular excitability. Magnesium prevents or controls convulsions by blocking neuromuscular transmission and decreasing the amount of acetylcholine liberated at the end plate by the motor nerve impulse. Magnesium is said to have a depressant effect on the central nervous system, but it does not adversely affect the mother, fetus or neonate when used as directed in eclampsia or pre-eclampsia. Normal serum magnesium levels range from 1.3 to 2.1 mEq/liter. As serum magnesium rises above 4 mEq/liter, the deep tendon reflexes are first decreased and then disappear as the serum level approaches 10 mEq/liter. At this level respiratory paralysis may occur. Heart block also may occur at this or lower serum levels of magnesium. Magnesium acts peripherally to produce vasodilation. With low doses only flushing and sweating occur, but larger doses cause lowering of blood pressure. The central and peripheral effects of magnesium poisoning are antagonized to some extent by intravenous administration of calcium. With intravenous administration the onset of anticonvulsant action is immediate and lasts about 30 minutes. Following intramuscular administration the onset of action occurs in about one hour and persists for three to four hours. Effective anticonvulsant serum levels range from 2.5 to 7.5 mEq/liter. Pharmacokinetics: Absorption: Intravenously administered magnesium is immediately absorbed. Distribution: Approximately 1-2% of total body magnesium is located in the extracellular fluid space. Magnesium is 30% bound to albumin. Metabolism: Magnesium is not metabolized. Excretion: Magnesium is excreted solely by the kidney at a rate proportional to the serum concentration and glomerular filtration. Special Populations: Renal Insufficiency: Magnesium is excreted solely by the kidney. In patients with severe renal insufficiency, the dose should be lower and frequent serum magnesium levels must be obtained (see Dosage and Administration). Hepatic Insufficiency: Magnesium is excreted solely by the kidney. No dosing adjustments are necessary in hepatic insufficiency. Drug-Drug Interactions: Drug induced renal losses of magnesium occur with the following drugs or drug classes: | lld:dailymed |
| dailymed-drugs:61 | dailymed-instance:clinicalP... | Pharmacodynamics: The efficacy of paroxetine in the treatment of major depressive disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD), and generalized anxiety disorder (GAD) is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate that paroxetine has little affinity for muscarinic, alpha-, alpha-, beta-adrenergic-, dopamine (D)-, 5-HT-, 5-HT-, and histamine (H)-receptors; antagonism of muscarinic, histaminergic, and alpha-adrenergic receptors has been associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. Because the relative potencies of paroxetine's major metabolites are at most 1/50 of the parent compound, they are essentially inactive.<br/>Pharmacokinetics: Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets of paroxetine daily for 30 days. Paroxetine is extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).<br/>Absorption and Distribution: Paroxetine is equally bioavailable from the oral suspension and tablet. Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of C, T, C, and Twere 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%), and 21.0 hours (CV 32%), respectively. The steady-state Cand Cvalues were about 6 and 14 times what would be predicted from single-dose studies. Steady-state drug exposure based on AUCwas about 8 times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is a consequence of the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable. The effects of food on the bioavailability of paroxetine were studied in subjects administered a single dose with and without food. AUC was only slightly increased (6%) when drug was administered with food but the Cwas 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours. Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma. Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin.<br/>Metabolism and Excretion: The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of paroxetine hydrochloride. In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to Cvalues after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled. Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions (see PRECAUTIONS). Approximately 64% of a 30 mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10 day post-dosing period. About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10 day post-dosing period.<br/>Other Clinical Pharmacology Information:<br/>Specific Populations:<br/>Clinical Trials:<br/>Major Depressive Disorder: The efficacy of paroxetine hydrochloride as a treatment for major depressive disorder has been established in 6 placebo-controlled studies of patients with major depressive disorder (aged 18 to 73). In these studies, paroxetine hydrochloride was shown to be significantly more effective than placebo in treating major depressive disorder by at least 2 of the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of Illness. Paroxetine hydrochloride was significantly better than placebo in improvement of the HDRS sub-factor scores, including the depressed mood item, sleep disturbance factor, and anxiety factor. A study of outpatients with major depressive disorder who had responded to paroxetine hydrochloride (HDRS total score<8) during an initial 8 week open-treatment phase and were then randomized to continuation on paroxetine hydrochloride or placebo for 1 year demonstrated a significantly lower relapse rate for patients taking paroxetine hydrochloride (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients.<br/>Obsessive Compulsive Disorder: The effectiveness of paroxetine hydrochloride in the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 12 week multicenter placebo-controlled studies of adult outpatients (Studies 1 and 2). Patients in all studies had moderate to severe OCD (DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale (YBOCS) total score ranging from 23 to 26. Study 1, a dose-range finding study where patients were treated with fixed doses of 20, 40, or 60 mg of paroxetine/day demonstrated that daily doses of paroxetine 40 and 60 mg are effective in the treatment of OCD. Patients receiving doses of 40 and 60 mg paroxetine experienced a mean reduction of approximately 6 and 7 points, respectively, on the YBOCS total score which was significantly greater than the approximate 4 point reduction at 20 mg and a 3 point reduction in the placebo-treated patients. Study 2 was a flexible-dose study comparing paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg daily). In this study, patients receiving paroxetine experienced a mean reduction of approximately 7 points on the YBOCS total score, which was significantly greater than the mean reduction of approximately 4 points in placebo-treated patients. The following table provides the outcome classification by treatment group on Global Improvement items of the Clinical Global Impression (CGI) scale for Study 1. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. The long-term maintenance effects of paroxetine hydrochloride in OCD were demonstrated in a long-term extension to Study 1. Patients who were responders on paroxetine during the 3 month double-blind phase and a 6 month extension on open-label paroxetine (20 to 60 mg/day) were randomized to either paroxetine or placebo in a 6 month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo.<br/>Panic Disorder: The effectiveness of paroxetine hydrochloride in the treatment of panic disorder was demonstrated in three 10 to 12 week multicenter, placebo-controlled studies of adult outpatients (Studies 1 through 3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia. In these studies, paroxetine hydrochloride was shown to be significantly more effective than placebo in treating panic disorder by at least 2 out of 3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score. Study 1 was a 10 week dose-range finding study; patients were treated with fixed paroxetine doses of 10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed only for the 40 mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were free of panic attacks, compared to 44% of placebo-treated patients. Study 2 was a 12 week flexible-dose study comparing paroxetine (10 to 60 mg daily) and placebo. At endpoint, 51% of paroxetine patients were free of panic attacks compared to 32% of placebo-treated patients. Study 3 was a 12 week flexible-dose study comparing paroxetine (10 to 60 mg daily) to placebo in patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the paroxetine-treated patients showed a reduction to 0 or 1 panic attacks compared to 14% of placebo patients. In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was approximately 40 mg/day of paroxetine. Long-term maintenance effects of paroxetine hydrochloride in panic disorder were demonstrated in an extension to Study 1. Patients who were responders during the 10 week double-blind phase and during a 3 month double-blind extension phase were randomized to either paroxetine (10, 20, or 40 mg/day) or placebo in a 3 month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.<br/>Social Anxiety Disorder: The effectiveness of paroxetine hydrochloride in the treatment of social anxiety disorder was demonstrated in three 12 week, multicenter, placebo-controlled studies (Studies 1, 2, and 3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the effectiveness of paroxetine hydrochloride compared to placebo was evaluated on the basis of (1) the proportion of responders, as defined by a Clinical Global Impression (CGI) Improvement score of 1 (very much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social Anxiety Scale (LSAS). Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 to 50 mg daily) and placebo. Paroxetine demonstrated statistically significant superiority over placebo on both the CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In Study 1, for patients who completed to week 12, 69% of paroxetine-treated patients compared to 29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI Improvement responders were 77% and 42% for the paroxetine- and placebo-treated patients, respectively. Study 3 was a 12 week study comparing fixed paroxetine doses of 20, 40, or 60 mg/day with placebo. Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the LSAS Total Score and the CGI Improvement responder criterion; there were trends for superiority over placebo for the 40 and 60 mg/day dose groups. There was no indication in this study of any additional benefit for doses higher than 20 mg/day. Subgroup analyses generally did not indicate differences in treatment outcomes as a function of age, race, or gender.<br/>Generalized Anxiety Disorder: The effectiveness of paroxetine hydrochloride in the treatment of Generalized Anxiety Disorder (GAD) was demonstrated in two 8 week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients with Generalized Anxiety Disorder (DSM-IV). Study 1 was an 8 week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with placebo. Doses of 20 mg or 40 mg of paroxetine were both demonstrated to be significantly superior to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not sufficient evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to the 20 mg/day dose. Study 2 was a flexible-dose study comparing paroxetine (20 mg to 50 mg daily) and placebo. Paroxetine demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. A third study, also flexible-dose comparing paroxetine (20 mg to 50 mg daily), did not demonstrate statistically significant superiority of paroxetine over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome. Subgroup analyses did not indicate differences in treatment outcomes as a function of race or gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age. In a longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety Disorder, who had responded during a single-blind, 8 week acute treatment phase with 20 to 50 mg/day of paroxetine, were randomized to continuation of paroxetine hydrochloride at their same dose, or to placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase was defined by having a decrease of���2 points compared to baseline on the CGI-Severity of Illness scale, to a score of���3. Relapse during the double-blind phase was defined as an increase of���2 points compared to baseline on the CGI-Severity of Illness scale to a score of���4, or withdrawal due to lack of efficacy. Patients receiving continued paroxetine hydrochloride experienced a significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo. | lld:dailymed |
| dailymed-drugs:62 | dailymed-instance:clinicalP... | Diphenoxylate is rapidly and extensively metabolized in man by ester hydrolysis to diphenoxylic acid (difenoxine), which is biologically active and the major metabolite in the blood. After a 5 mg oral dose of carbon-14 labeled diphenoxylate hydrochloride in ethanolic solution was given to three healthy volunteers, an average of 14% of the drug plus its metabolites was excreted in the urine and 49% in the feces over a four-day period. Urinary excretion of the unmetabolized drug constituted less than 1% of the dose, and diphenoxylic acid plus its glucuronide conjugate constituted about 6% of the dose. In a sixteen-subject cross-over bioavailability study, a linear relationship in the dose range of 2.5 to 10 mg was found between the dose of diphenoxylate hydrochloride (given as Diphenoxylate HCl and Atropine Sulfate Oral Solution) and the peak plasma concentration, the area under the plasma concentration-time curve, and the amount of diphenoxylic acid excreted in the urine. In the same study the bioavailability of the tablet compared with an equal dose of theliquid was approximately 90%. The average peak plasma concentration of diphenoxylic acid following ingestion of four 2.5 mg tablets was 163 ng/mL at about 2 hours, and the elimination half-life of diphenoxylic acid was approximately 12 to 14 hours. In dogs, diphenoxylate hydrochloride has a direct effect on circular smooth muscle of the bowel that conceivably results in segmentation and prolongation of gastrointestinal transit time. The clinical antidiarrheal action of diphenoxylate hydrochloride may thus be a consequence of enhanced segmentation that allows increased contact of the intraluminal contents with the intestinal mucosa. | lld:dailymed |
| dailymed-drugs:63 | dailymed-instance:clinicalP... | Pharmacodynamics: The efficacy of paroxetine in the treatment of major depressive disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD), generalized anxiety disorder (GAD), and posttraumatic stress disorder (PTSD) is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studiesindicate that paroxetine has little affinity for muscarinic, alpha-, alpha-, beta-adrenergic-, dopamine (D)-, 5-HT-, 5-HT-, and histamine (H)-receptors; antagonism of muscarinic, histaminergic, and alpha-adrenergic receptors has been associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. Because the relative potencies of paroxetine's major metabolites are at most 1/50 of the parent compound, they are essentially inactive.<br/>Pharmacokinetics: Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets of paroxetine daily for 30 days. Paroxetine is extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediated in part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).<br/>Absorption and Distribution: Paroxetine is equally bioavailable from the oral suspension and tablet. Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of C, T,C, and Twere 61.7 ng/mL (CV 45%), 5.2 hours (CV 10%), 30.7 ng/mL (CV 67%), and 21.0 hours (CV 32%), respectively. The steady-state Cand Cvalues were about 6 and 14 times what would be predicted from single-dose studies. Steady-state drug exposure based on AUCwas about 8 times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is a consequence of the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable. The effects of food on the bioavailability of paroxetine were studied in subjects administered a single dose with and without food. AUC was only slightly increased (6%) when drug was administered with food but the Cwas 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours. Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma. Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin.<br/>Metabolism and Excretion: The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of paroxetine. In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison to Cvalues after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled. Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions (see PRECAUTIONS). Approximately 64% of a 30 mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period. About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10-day post-dosing period.<br/>Other Clinical Pharmacology Information:<br/>Specific Populations:<br/>Clinical Trials:<br/>Major Depressive Disorder: The efficacy of paroxetine as a treatment for major depressive disorder has been established in 6 placebo-controlled studies of patients with major depressive disorder (aged 18 to 73). In these studies, paroxetine was shown to be significantly more effective than placebo in treating major depressive disorder by at least 2 of the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of Illness. Paroxetine was significantly better than placebo in improvement of the HDRS sub-factor scores, including the depressed mood item, sleep disturbance factor, and anxiety factor. A study of outpatients with major depressive disorder who had responded to paroxetine (HDRS total score<8) during an initial 8-week open-treatment phase and were then randomized to continuation on paroxetine or placebo for 1 year demonstrated a significantly lower relapse rate for patients taking paroxetine (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients.<br/>Obsessive Compulsive Disorder: The effectiveness of paroxetine in the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 12-week multicenter placebo-controlled studies of adult outpatients (Studies 1 and 2). Patients in all studies had moderate to severe OCD (DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale (YBOCS) total score ranging from 23 to 26. Study 1, a dose-range finding study where patients were treated with fixed doses of 20, 40, or 60 mg of paroxetine/day demonstrated that daily doses of paroxetine 40 and 60 mg are effective in the treatment of OCD. Patients receiving doses of40 and 60 mg paroxetine experienced a mean reduction of approximately 6 and 7 points, respectively, on the YBOCS total score which was significantly greater than the approximate 4-point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a flexible-dose study comparing paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg daily). In this study, patients receiving paroxetine experienced a mean reduction of approximately 7 points on the YBOCS total score, which wassignificantly greater than the mean reduction of approximately 4 points in placebo-treated patients. The following table provides the outcome classification by treatment group on Global Improvement items of the Clinical Global Impression (CGI) scale for Study 1. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. The long-term maintenance effects of paroxetine in OCD were demonstrated in a long-term extension to Study 1. Patients who were responders on paroxetine during the 3-month double-blind phase and a 6-month extension on open-label paroxetine (20 to 60 mg/day) were randomized to either paroxetine or placebo in a 6-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo.<br/>Panic Disorder: The effectiveness of paroxetine in the treatment of panic disorder was demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1-3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia. In these studies, paroxetine was shown to be significantly more effective than placebo in treating panic disorder by at least 2 out of 3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score. Study 1 was a 10-week dose-range finding study; patients were treated with fixed paroxetine doses of 10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed only for the 40 mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were free of panic attacks, compared to 44% of placebo-treated patients. Study 2 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) and placebo. At endpoint, 51% of paroxetine patients were free of panic attacks compared to 32% of placebo-treated patients. Study 3 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) to placebo in patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the paroxetine-treated patients showed a reduction to 0 or 1 panic attacks compared to 14% of placebo patients. In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was approximately 40 mg/day of paroxetine. Long-term maintenance effects of paroxetine in panic disorder were demonstrated in an extension to Study 1. Patients who were responders during the 10-week double-blind phase and during a 3-month double-blind extension phase were randomized to either paroxetine (10, 20, or 40 mg/day) or placebo in a 3-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.<br/>Social Anxiety Disorder: The effectiveness of paroxetine in the treatment of social anxiety disorder was demonstrated in three 12-week, multicenter, placebo-controlled studies (Studies 1, 2, and 3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the effectiveness of paroxetine compared to placebo was evaluated on the basis of (1) the proportion of responders, as defined by a Clinical Global Impression (CGI) Improvement score of 1 (very much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social Anxiety Scale (LSAS). Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 to 50 mg daily) and placebo. Paroxetine demonstrated statistically significant superiority over placebo on both the CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In Study 1, for patients who completed to week 12, 69% of paroxetine-treated patients compared to 29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI Improvement responders were 77% and 42% for the paroxetine- and placebo-treated patients, respectively. Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40, or 60 mg/day with placebo. Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the LSAS Total Score and the CGI Improvement responder criterion; there were trends for superiority over placebo for the 40 mg and 60 mg/day dose groups. There was no indication in this study of any additional benefit for doses higher than 20 mg/day. Subgroup analyses generally did not indicate differences in treatment outcomes as a function of age, race, or gender.<br/>Generalized Anxiety Disorder: The effectiveness of paroxetine in the treatment of Generalized Anxiety Disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients with Generalized Anxiety Disorder (DSM-IV). Study 1 was an 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with placebo. Doses of 20 mg or 40 mg of paroxetine were both demonstrated to be significantly superior to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not sufficient evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to the 20 mg/day dose. Study 2 was a flexible-dose study comparing paroxetine (20 mg to 50 mg daily) and placebo. Paroxetine demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. A third study, also flexible-dose comparing paroxetine (20 mg to 50 mg daily), did not demonstrate statistically significant superiority of paroxetine over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome. Subgroup analyses did not indicate differences in treatment outcomes as a function of race or gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age. In a longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety Disorder, who had responded during a single-blind, 8-week acute treatment phase with 20 to 50 mg/day of paroxetine, were randomized to continuation of paroxetine at their same dose, or to placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase was defined by having a decrease of���2 points compared to baseline on the CGI-Severity of Illness scale, to a score of���3. Relapse during the double-blind phase was defined as an increase of���2 points compared to baseline on the CGI-Severity of Illness scale to a score of���4, or withdrawal due to lack of efficacy. Patients receiving continued paroxetine experienced a significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo.<br/>Posttraumatic Stress Disorder: The effectiveness of paroxetine in the treatment of Posttraumatic Stress Disorder (PTSD) was demonstrated in two 12-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients who met DSM-IV criteria for PTSD. The mean duration of PTSD symptoms for the 2 studies combined was 13 years (ranging from .1 year to 57 years). The percentage of patients with secondary major depressive disorder or non-PTSD anxiety disorders in the combined 2 studies was 41% (356 out of 858 patients) and 40% (345 out of 858 patients), respectively. Study outcome was assessed by (i) the Clinician-Administered PTSD Scale Part 2 (CAPS-2) score and (ii) the Clinical Global Impression-Global Improvement Scale (CGI-I). The CAPS-2 is amulti-item instrument that measures 3 aspects of PTSD with the following symptom clusters: Reexperiencing/intrusion, avoidance/numbing and hyperarousal. The 2 primary outcomes for each trial were (i) change from baseline to endpoint on the CAPS-2 total score (17 items), and (ii) proportion of responders on the CGI-I, where responders were defined as patients having a score of 1 (very much improved) or 2 (much improved). Study 1 was a 12-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day to placebo. Doses of 20 mg and 40 mg of paroxetine were demonstrated to be significantly superior to placebo on change from baseline for the CAPS-2 total score and on proportion of responders on the CGI-I. There was not sufficient evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to the 20 mg/day dose. Study 2 was a 12-week flexible-dose study comparing paroxetine (20 to 50 mg daily) to placebo. Paroxetine was demonstrated to be significantly superior to placebo on change from baseline for the CAPS-2 total score and on proportion of responders on the CGI-I. A third study, also a flexible-dose study comparing paroxetine (20 to 50 mg daily) to placebo, demonstrated paroxetine to be significantly superior to placebo on change from baseline for CAPS-2 total score, but not on proportion of responders on the CGI-I. The majority of patients in these trials were women (68% women: 377 out of 551 subjects in Study 1 and 66% women: 202 out of 303 subjects in Study 2). Subgroup analyses did not indicate differences in treatment outcomes as a function of gender. There were an insufficient number of patients who were 65 years and older or were non-Caucasian to conduct subgroup analyses on the basis of age or race, respectively. | lld:dailymed |
| dailymed-drugs:64 | dailymed-instance:clinicalP... | Heparin inhibits reactions that lead to the clotting of blood and the formation of fibrin clots both invitro and in vivo. Heparin acts at multiple sites in the normal coagulation system. Small amounts of heparin in combination with antithrombin III (heparin cofactor) can inhibit thrombosis by inactivating activated Factor X and inhibiting the conversion of prothrombin to thrombin. Once active thrombosis has developed,larger amounts of heparin can inhibit further coagulation by inactivating thrombin and preventing the conversion of fibrinogen to fibrin. Heparin also prevents the formation of a stable fibrin clot in inhibiting the activation of the fibrin stabilizing factor. Bleeding time is usually unaffected by heparin. Clotting time is prolonged by full therapeutic doses of heparin; in most cases, it is not measurably affected by low doses of heparin. Patients over 60 years of age, following similar doses of heparin, may have higher plasma levels of heparin and longer activated partial thromboplastin times (APTTs) compared with patients under 60 years of age. Peak plasma levels of heparin are achieved 2 to 4 hours following subcutaneous administration, although there are considerable individual variations. Loglinear plots of heparin plasma concentrations with time for a wide range of dose levels are linear which suggests the absence of zero order processes. Liver and the reticuloendothelial system are the site of biotransformation. The biphasic elimination curve, a rapidly declining alpha phase (��= 10') and after the age of 40 a slower beta phase, indicates uptake in organs. The absence of a relationship between anticoagulant half-life and concentration half-life may reflect factors such as protein binding of heparin. Heparin does not have fibrinolytic activity; therefore, it will not lyse existing clots. Hypotonic concentrations of sodium chloride are suited for parenteral maintenance of water requirements when only small quantities of salt are desired. Sodium chloride in water dissociates to provide sodium (Na) and chloride (Cl��) ions. Sodium (Na) is the principal cation of the extracellular fluid and plays a large part in the therapy of fluid and electrolyte disturbances. Chloride (Cl��) has an integral role in buffering action when oxygen and carbon dioxide exchange occurs in the red blood cells. The distribution and excretion of sodium (Na) are largely under the control of the kidney which maintains a balance between intake and output. Water is an essential constituent of all body tissues and accounts for approximately 70% of total body weight. Average normal adult daily requirements range from two to three liters (1.0 to 1.5 liters each for insensible water loss by perspiration and urine production). Water balance is maintained by various regulatory mechanisms. Water distribution depends primarily on the concentration of electrolytes in the body compartments and sodium (Na) plays a major role in maintaining physiologic equilibrium. | lld:dailymed |
| dailymed-drugs:65 | dailymed-instance:clinicalP... | Levocarnitine is a naturally occurring substance required in mammalian energy metabolism. It has been shown to facilitate long-chain fatty acid entry into cellular mitochondria, thereby delivering substrate for oxidation and subsequent energy production. Fatty acids are utilized as an energy substrate in all tissues except the brain. In skeletal and cardiac muscle, fatty acids are the main substrate for energy production. Primary systemic carnitine deficiency is characterized by low concentrations of levocarnitine in plasma, RBC, and/or tissues. It has not been possible to determine which symptoms are due to carnitine deficiency and which are due to the underlying organic acidemia, as symptoms of both abnormalities may be expected to improve with carnitine. The literature reports that carnitine can promote the excretion of excess organic or fatty acids in patients with defects in fatty acid metabolism and/or specific organic acidopathies that bioaccumulate acyl CoA esters. Secondary levocarnitine deficiency can be a consequence of inborn errors of metabolism. Levocarnitine may alleviate the metabolic abnormalities of patients with inborn errors that result in accumulation of toxic organic acids. Conditions for which this effect was demonstrated are: glutaric aciduria II, methyl malonic aciduria, propionic acidemia, and medium chain fatty acyl CoA dehydrogenase deficiency.Autointoxication occurs in these patients due to the accumulations of acyl CoA compounds that disrupt intermediary metabolism. The subsequent hydrolysis of the acyl CoA compound to its free acid results in acidosis that can be life-threatening. Levocarnitine clears the acyl CoA compound by formation of acyl carnitine which is quickly excreted. Levocarnitine deficiency is defined biochemically as abnormally low plasma levels of free carnitine, less than 20 micromole/L at one week post term and may be associated with low tissue and/or urine concentrations. Further, this condition may be associated with a plasma concentration ratio of acylcarnitine/levocarnitine greater than 0.4 or abnormally elevated concentrations of acylcarnitine in the urine. In premature infants and newborns, secondary deficiency is defined as plasma free levocarnitine levels below age-related normal levels.<br/>Pharmacokinetics: In a relative bioavailability study in 15 healthy adult male volunteers Levocarnitine Tablets were found to be bio-equivalent to Levocarnitine Oral Solution. Following 4 days of dosing with 6 tablets of levocarnitine 330 mg bid or 2 g of levocarnitine oral solution bid, the maximum plasma concentration (C) was about 80 micromole/L and the time to maximum plasma concentration (T) occurred at 3.3 hours. The plasma concentration profiles of levocarnitine after a slow 3 minute intravenous bolus dose of 20 mg/kg of levocarnitine were described by a two-compartment model. Following a single IV administration, approximately 76% of the levocarnitine dose was excreted in urine during the 0 to 24h interval. Using plasma concentrations uncorrected for endogenous levocarnitine, the meandistribution half-life was 0.585 hours and the mean apparent terminal elimination half-life was 17.4 hours. The absolute bioavailability of levocarnitine from the two oral formulations of levocarnitine, calculated after correction for circulating endogenous plasma concentrations of levocarnitine, was 15.1��5.3% for levocarnitine tablets and 15.9��4.9% for levocarnitine oral solution. Total body clearance of levocarnitine (Dose/AUC including endogenous baseline concentrations) was a mean of 4.00 L/h. Levocarnitine was not bound to plasma protein or albumin when tested at any concentration or with any species including the human.<br/>Metabolism and Excretion: In a pharmacokinetic study where five normal adult male volunteers received an oral dose of [H-methyl]-L-carnitine following 15 days of a high carnitine diet and additional carnitine supplement, 58 to 65% of the administered radioactive dose was recovered in the urine and feces in 5 to 11 days. Maximum concentration of [H-methyl]-L-carnitine in serum occurred from 2 to 4.5 hr after drug administration. Major metabolites found were trimethylamine N-oxide, primarily in urine (8% to 49% of the administered dose) and [H]-y-butyrobetaine, primarily in feces (0.44% to 45% of the administered dose). Urinary excretion of levocarnitine was about 4 to 8% of the dose. Fecal excretion of total carnitine was less than 1% of the administered dose. After attainment of steady state following 4 days of oral administration of levocarnitine tablets (1980 mg q 12h) or oral solution (2000 mg q 12h) to 15 healthy male volunteers, the mean urinary excretion of levocarnitine during a single dose interval (12h) was about 9% of the orally administered dose (uncorrected for endogenous urinary excretion). | lld:dailymed |
| dailymed-drugs:66 | dailymed-instance:clinicalP... | Aminosyn-HF 8% (amino acid injection 8%) provides a mixture of essential and nonessential amino acids with high concentrations of the branched chain amino acids (isoleucine, leucine, and valine) and low concentrations of methionine and the aromatic amino acids (phenylalanine and tryptophan) relative to general purpose amino acid injections. This amino acid composition has beenspecifically formulated to provide a well tolerated nitrogen source for nutritional support and therapy of patients with liver disease who have hepatic encephalopathy. The precise mechanisms which produce the therapeutic effects of Aminosyn-HF 8% are not known. The etiopathology of hepatic encephalopathy is also unknown and is thought to be of multifactorial origin. The rationale for Aminosyn-HF 8% is based on observations of plasma amino acid imbalances in patients with liver diseaseand on theories which postulate that these abnormal patterns are causally related to the development of hepatic encephalopathy. Clinical studies in patients with hepatic encephalopathy showed that infusion of a solution identical to Aminosyn-HF 8% reversed the abnormal plasma amino acid pattern characterized by decreased levels of branched chain amino acids and elevated levels of aromatic amino acids and methionine. The trend toward normalization of these amino acids was generally associated with an improvement in mental status and EEG patterns. This clinical response was observed in the majority of patients studied. Nitrogen balance was significantly improved and mortality reduced in these typically protein-intolerant patients who received substantial amounts of protein equivalent from the amino acid solution. When infused with hypertonic dextrose as a calorie source, supplemented with electrolytes, vitamins, and minerals, Aminosyn-HF 8% provides total parenteral nutrition in patients with liver disease, with the exception of essential fatty acids. Phosphate is a major intracellular anion which participates in providing energy for metabolism of substrates and contributes to significant metabolic and enzymatic reactions in all organs and tissues. It exerts a modifying influence on calcium levels, a buffering effect on acid-base equilibrium, and has a primary role in the renal excretion of hydrogen ions. It is thought that the acetate from lysine acetate and acetic acid, under the conditions of parenteral nutrition, does not impact net acid-base balance when renal and respiratory functions are normal. Clinical evidence seems to support this thinking; however, confirmatory experimental evidence is not available. The amounts of sodium and chloride present are not of clinical significance. | lld:dailymed |
| dailymed-drugs:67 | dailymed-instance:clinicalP... | Pharmacokinetics and Metabolism: NOTE: The plasma concentrations reported below were measured by high-performance liquid chromatography (HPLC) specific for itraconazole. When itraconazole in plasma is measured by a bioassay, values reported may be higher than those obtained by HPLC due to the presence of the bioactive metabolite, hydroxyitraconazole. The pharmacokinetics of SPORANOX (itraconazole) Injection (200 mg b.i.d. for two days, then 200 mg q.d. for five days) followed by oral dosing of SPORANOX Capsules were studied in patients with advanced HIV infection. Steady-state plasma concentrations were reached after the fourth dose for itraconazole and by the seventh dose for hydroxyitraconazole. Steady-state plasma concentrations were maintained by administration of SPORANOX Capsules, 200 mg b.i.d. Pharmacokinetic parameters for itraconazole and hydroxyitraconazole are presented in the table below: The estimated mean��SD half-life at steady-state of itraconazole after intravenous infusion was 35.4��29.4 hours. In previous studies, the mean elimination half-life for itraconazole at steady-state after daily oral administration of 100 to 400 mg was 30���40 hours. Approximately 93���101% of hydroxypropyl-��-cyclodextrin was excreted unchanged in the urine within 12 hours after dosing. The plasma protein binding of itraconazole is 99.8% and that of hydroxyitraconazole is 99.5%. Following intravenous administration, the volume of distribution of itraconazole averaged 796��185 L. Itraconazole is metabolized predominately by the cytochrome P450 3A4 isoenzyme system (CYP3A4), resulting in the formation of several metabolites, including hydroxyitraconazole, the major metabolite. Results of a pharmacokinetics study suggest that itraconazole may undergo saturable metabolism with multiple dosing. Fecal excretion of the parent drug varies between 3���18% of the dose. Renal excretion of the parent drug is less than 0.03% of the dose. About 40% of the dose is excreted as inactive metabolites in the urine. No single excreted metabolite represents more than 5% of a dose. Itraconazole total plasma clearance averaged 381��95 mL/min following intravenous administration. Approximately 80���90% of hydroxypropyl-��-cyclodextrin is eliminated through the kidneys.<br/>Special Populations:<br/>Renal Insufficiency: Plasma concentrations of itraconazole in patients with mild to moderate renal insufficiency were comparable to those obtained in healthy subjects. The majority of the 8-gram dose of hydroxypropyl-��-cyclodextrin was eliminated in the urine during the 120-hour collection period in normal subjects and in patients with mild to severe renal insufficiency. Following a single intravenous dose of 200 mg to subjects with severe renal impairment (creatinine clearance���19 mL/minute), clearance of hydroxypropyl-��-cyclodextrin was reduced six-fold compared with subjects with normal renal function. SPORANOX Injection should not be used in patients with creatinine clearance<30 mL/min. In patients with mild (creatinine clearance 50���80 mL/min) and moderate (creatinine clearance 30���49 mL/min) renal impairment, SPORANOX Injection should be used with caution. Serum creatinine levels should be closely monitored and, if renal toxicity is suspected, consideration should be given to changing to SPORANOX Capsules, if clinically indicated and consistent with approved indications.<br/>Hepatic Insufficiency: Patients with impaired hepatic function should be carefully monitored when taking itraconazole. The prolonged elimination half-life of itraconazole observed in a clinical trial with itraconazole capsules in cirrhotic patients should be considered when deciding to initiate therapy with other medications metabolized by CYP3A4.<br/>Decreased Cardiac Contractility: When itraconazole was administered intravenously to anesthetized dogs, a dose-related negative inotropic effect was documented. In a healthy volunteer study of SPORANOX Injection (intravenous infusion), transient, asymptomatic decreases in left ventricular ejection fraction were observed using gated SPECT imaging; these resolved before the next infusion, 12 hours later. If signs or symptoms of congestive heart failure appear during administration of SPORANOX Injection, monitor carefully and consider other treatment alternatives which may include discontinuation of SPORANOX Injection administration. | lld:dailymed |
| dailymed-drugs:68 | dailymed-instance:clinicalP... | Mechanism of Action: Temozolomide is not directly active but undergoes rapid nonenzymatic conversion at physiologic pH to the reactive compound MTIC. The cytotoxicity of MTIC is thought to be primarily due to alkylation of DNA. Alkylation (methylation) occurs mainly at the Oand Npositions of guanine.<br/>Pharmacokinetics: Temozolomide is rapidly and completely absorbed after oral administration; peak plasma concentrations occur in 1 hour. Food reduces the rate and extent of temozolomide absorption. Mean peak plasma concentration and AUC decreased by 32% and 9%, respectively, and Tincreased 2-fold (from 1.1 to 2.25 hours) when temozolomide was administered after a modified high-fat breakfast. Temozolomide is rapidly eliminated with a mean elimination half-life of 1.8 hours and exhibits linear kinetics over the therapeutic dosing range. Temozolomide has a mean apparent volume of distribution of 0.4 L/kg (%CV=13%). It is weakly bound to human plasma proteins; the mean percent bound of drug-related total radioactivity is 15%.<br/>Metabolism and Elimination: Temozolomide is spontaneously hydrolyzed at physiologic pH to the active species, 3-methyl-(triazen-1-yl)imidazole-4-car-boxamide (MTIC) and to temozolomide acid metabolite. MTIC is further hydrolyzed to 5-amino-imidazole-4-carboxamide (AIC) which is known to be an intermediate in purine and nucleic acid biosynthesis and to methylhydrazine, which is believed to be the active alkylating species. Cytochrome P450 enzymes play only a minor role in the metabolism of temozolomide and MTIC. Relative to the AUC of temozolomide, the exposure to MTIC and AIC is 2.4% and 23%, respectively. About 38% of the administered temozolomide total radioactive dose is recovered over 7 days; 37.7% in urine and 0.8% in feces. The majority of the recovery of radioactivity in urine is as unchanged temozolomide (5.6%), AIC (12%), temozolomide acid metabolite (2.3%), and unidentified polar metabolite(s) (17%). Overall clearance of temozolomide is about 5.5 L/hr/m.<br/>Special Populations:<br/>Age: Population pharmacokinetic analysis indicates that age (range 19 to 78 years) has no influence on the pharmacokinetics of temozolomide. In the anaplastic astrocytoma study population, patients 70 years of age or older had a higher incidence of Grade 4 neutropenia and Grade 4 thrombocytopenia in the first cycle of therapy than patients under 70 years of age .<br/>Gender: Population pharmacokinetic analysis indicates that women have an approximately 5% lower clearance (adjusted for body surface area) for temozolomide than men. Women have higher incidences of Grade 4 neutropenia and thrombocytopenia in the first cycle of therapy than men .<br/>Race: The effect of race on the pharmacokinetics of temozolomide has not been studied.<br/>Tobacco Use: Population pharmacokinetic analysis indicates that the oral clearance of temozolomide is similar in smokers and nonsmokers.<br/>Creatinine Clearance: Population pharmacokinetic analysis indicates that creatinine clearance over the range of 36���130 mL/min/mhas no effect on the clearance of temozolomide after oral administration. The pharmacokinetics of temozolomide have not been studied in patients with severely impaired renal function (CLcr<36 mL/min/m). Caution should be exercised when TEMODAR Capsules are administered to patients with severe renal impairment. TEMODAR has not been studied in patients on dialysis.<br/>Hepatically Impaired Patients: In a pharmacokinetic study, the pharmacokinetics of temozolomide in patients with mild-to-moderate hepatic impairment (Child's-Pugh Class I���II) were similar to those observed in patients with normal hepatic function. Caution should be exercised when temozolomide is administered to patients with severe hepatic impairment.<br/>Drug-Drug Interactions: In a multiple-dose study, administration of TEMODAR Capsules with ranitidine did not change the Cor AUC values for temozolomide or MTIC. Population analysis indicates that administration of valproic acid decreases the clearance of temozolomide by about 5% . Population analysis failed to demonstrate any influence of coadministered dexamethasone, prochlorperazine, phenytoin, carbamazepine, ondansetron, H-receptor antagonists, or phenobarbital on the clearance of orally administered temozolomide. | lld:dailymed |
| dailymed-drugs:70 | dailymed-instance:clinicalP... | Typical serum and urine levels following a single 150 mg dose of Coly-Mycin M Parenteral IM or IV in normal adult subjects are shown in Figure 1. Higher serum levels were obtained at 10 minutes following IV administration. Serum concentration declined with a half-life of 2���3 hours following either intravenous or intramuscular administration in adults and in the pediatric population, including premature infants. Average urine levels ranged from about 270 mcg/mL at 2 hours to about 15 mcg/mL at 8 hours after intravenous administration and from 200 to about 25 mcg/mL during a similar period following intramuscular administration. Microbiology:Colistimethate sodium is a surface active agent which penetrates into and disrupts the bacterial cell membrane. It has been shown to have bactericidal activity against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Aerobic gram-negative microorganisms: Enterobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Susceptibility Tests: Colistimethate sodium is no longer listed as an antimicrobial for routine testing and reporting by clinical microbiology laboratories. | lld:dailymed |
| dailymed-drugs:71 | dailymed-instance:clinicalP... | Pharmacodynamics: The mechanism of action of citalopram HBr as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro and in vivo studies in animals suggest that citalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake. Tolerance to the inhibition of 5-HT uptake is not induced by long-term (14-day) treatment of rats with citalopram. Citalopram is a racemic mixture (50/50), and the inhibition of 5-HT reuptake by citalopram is primarily due to the (S)-enantiomer. Citalopram has no or very low affinity for 5-HT, 5-HT, dopamine Dand D,��-,��-, and��-adrenergic, histamine H, gamma aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors. Antagonism of muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of other psychotropic drugs.<br/>Pharmacokinetics: The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10-60 mg/day. Biotransformation of citalopram is mainly hepatic, with a mean terminal half-life of about 35 hours. With once daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be 2.5 times the plasma concentrations observedafter a single dose. Absorption and Distribution Following a single oral dose (40 mg tablet) of citalopram, peak blood levels occur at about 4 hours. The absolute bioavailability of citalopram was about 80% relative to an intravenous dose, and absorption is not affected by food. The volume of distribution of citalopram is about 12 L/kg and the binding of citalopram (CT), demethylcitalopram (DCT) and didemethylcitalopram (DDCT) to human plasma proteins is about 80%. Metabolism and Elimination Following intravenous administrations of citalopram, the fraction of drug recovered in the urine as citalopram and DCT was about 10% and 5%, respectively. The systemic clearance of citalopram was 330 mL/min, with approximately 20% of that due to renal clearance. Citalopram is metabolized to demethylcitalopram (DCT), didemethylcitalopram (DDCT), citalopram-N-oxide, and a deaminated propionic acid derivative. In humans, unchanged citalopram is the predominant compound in plasma. At steady state, the concentrations of citalopram's metabolites, DCT and DDCT, in plasma are approximately one-half and one-tenth, respectively, that of the parent drug. In vitro studies show that citalopram is at least 8 times more potent than its metabolites in the inhibition of serotonin reuptake, suggesting that the metabolites evaluated do not likely contribute significantly to the antidepressant actions of citalopram. In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of citalopram. Population Subgroups Age - Citalopram pharmacokinetics in subjects���60 years of age were compared to younger subjects in two normal volunteer studies. In a single-dose study, citalopram AUC and half-life were increased in the elderly subjects by 30% and 50%, respectively, whereas in a multiple-dose study they were increased by 23% and 30%, respectively. 20 mg is the recommended dose for most elderly patients . Gender - In three pharmacokinetic studies (total N=32), citalopram AUC in women was one and a half to two times that in men. This difference was not observed in five other pharmacokinetic studies (total N=114). In clinical studies, no differences in steady state serum citalopram levels were seen between men (N=237) and women (N=388). There were no gender differences in the pharmacokinetics of DCT and DDCT. No adjustment of dosage on the basis of gender is recommended. Reduced hepatic function - Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects. 20 mg is the recommended dose for most hepatically impaired patients . Reduced renal function - In patients with mild to moderate renal function impairment, oral clearance of citalopram was reduced by 17% compared to normal subjects. No adjustment of dosage for such patients is recommended. No information is available about the pharmacokinetics of citalopram in patients with severely reduced renal function (creatinine clearance<20 mL/min). Drug-Drug Interactions In vitro enzyme inhibition data did not reveal an inhibitory effect of citalopram on CYP3A4, -2C9, or -2E1, but did suggest that it is a weak inhibitor of CYP1A2, -2D6, and -2C19. Citalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. However, in vivo data to address this question are limited. Since CYP3A4 and 2C19 are the primary enzymes involved in the metabolism of citalopram, it is expected that potent inhibitors of 3A4 (e.g., ketoconazole, itraconazole, and macrolide antibiotics) and potent inhibitors of CYP2C19 (e.g., omeprazole) might decrease the clearance of citalopram. However, coadministration of citalopram and thepotent 3A4 inhibitor ketoconazole did not significantly affect the pharmacokinetics of citalopram. Because citalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease citalopram clearance. Citalopram steady state levels were not significantly different in poor metabolizers and extensive 2D6 metabolizers after multiple-dose administration of citalopram, suggesting that coadministration, with citalopram, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on citalopram metabolism. See Drug Interactions under PRECAUTIONS for more detailed information on available drug interaction data.<br/>Clinical Efficacy Trials: The efficacy of citalopram as a treatment for depression was established in two placebo-controlled studies (of 4 to 6 weeks in duration) in adult outpatients (ages 18-66) meeting DSM-III or DSM-III-R criteria for major depression. Study 1, a 6-week trial in which patients received fixed citalopram doses of 10, 20, 40, and 60 mg/day, showed that citalopram at doses of 40 and 60 mg/day was effective as measured by the Hamilton Depression Rating Scale (HAMD) total score, the HAMD depressed mood item (Item 1), the Montgomery Asberg Depression Rating Scale, and the Clinical Global Impression (CGI) Severity scale. This study showed no clear effect of the 10 and 20 mg/day doses, and the 60 mg/day dose was not more effective than the 40 mg/day dose. In study 2, a 4-week, placebo-controlled trial in depressed patients, of whom 85% met criteria for melancholia, the initial dose was 20 mg/day, followed by titration to the maximum tolerated dose or a maximum dose of 80 mg/day. Patients treated with citalopram showed significantly greater improvement than placebo patients on the HAMD total score, HAMD item 1, and the CGI Severity score. Inthree additional placebo-controlled depression trials, the difference in response to treatment between patients receiving citalopram and patients receiving placebo was not statistically significant, possibly due to high spontaneous response rate, smaller sample size, or, in the case of one study, too low a dose. In two long-term studies, depressed patients who had responded to citalopram HBr during an initial 6 or 8 weeks of acute treatment (fixed doses of 20 or 40 mg/day in one study and flexible doses of 20-60 mg/day in the second study) were randomized to continuation of citalopram or to placebo. In both studies, patients receiving continued citalopram treatment experienced significantly lower relapse rates over the subsequent 6 months compared to those receiving placebo. In the fixed-dose study, the decreased rate of depression relapse was similar in patients receiving 20 or 40 mg/day of citalopram. Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics. Comparison of Clinical Trial Results Highly variable results have been seen in the clinical development of all antidepressant drugs. Furthermore, in those circumstances when the drugs have not been studied in the same controlled clinical trial(s), comparisons among the results of studies evaluating the effectiveness of different antidepressant drug products are inherently unreliable. Because conditions of testing (e.g., patient samples, investigators, doses of the treatments administered and compared, outcome measures, etc.) vary among trials, it is virtually impossible to distinguish a difference in drug effect from a difference due to one of the confounding factors just enumerated. | lld:dailymed |
| dailymed-drugs:72 | dailymed-instance:clinicalP... | Promethazine is a phenothiazine derivative which differs structurally from the antipsychotic phenothiazines by the presence of a branched side chain and no ring substitution. It is thought that this configuration is responsible for its relative lack (1/10 that of chlorpromazine) of dopamine antagonist properties. Promethazine is an Hreceptor blocking agent. In addition to its antihistaminic action, it provides clinically useful sedative and antiemetic effects. Promethazine is well absorbed from the gastrointestinal tract. Clinical effects are apparent within 20 minutes after oral administration and generally last four to six hours, although they may persist as long as 12 hours. Promethazine is metabolized by the liver to a variety of compounds; the sulfoxides of promethazine and N-demethylpromethazine are the predominant metabolites appearing inthe urine. | lld:dailymed |
| dailymed-drugs:73 | dailymed-instance:clinicalP... | Carbachol is a potent cholinergic (parasympathomimetic) agent which produces constriction of the iris and ciliary body resulting in reduction in intraocular pressure. The exact mechanism by which carbachol lowers intraocular pressure is not precisely known. | lld:dailymed |
| dailymed-drugs:4107 | dailymed-instance:clinicalP... | Carbachol is a potent cholinergic (parasympathomimetic) agent which produces constriction of the iris and ciliary body resulting in reduction in intraocular pressure. The exact mechanism by which carbachol lowers intraocular pressure is not precisely known. | lld:dailymed |
| dailymed-drugs:74 | dailymed-instance:clinicalP... | Verapamil hydrochloride extended-release is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) which exerts its pharmacologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile myocardial cells. Normal sinus rhythm is usually not affected by verapamil hydrochloride. However in patients with sick sinus syndrome, verapamil hydrochloride may interfere with sinus node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in patients without preexisting conduction defects. Verapamil hydrochloride does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization and conduction in depressed atrial fibers. Verapamil hydrochloride may shorten the antegrade effective refractory period of accessory bypass tracts. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration of verapamil. Verapamil hydrochloride has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man.<br/>Mechanism of Action:<br/>Essential Hypertension: Verapamil hydrochloride exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/minute is uncommon). Verapamil hydrochloride regularly reduces arterial pressure at rest and at a given level of exercise by dilating peripheral arterioles and reducing the total peripheral resistance (afterload) against which the heart works.<br/>Pharmacokinetics and Metabolism: With the immediate-release formulations, more than 90% of the orally administered dose is absorbed, and peak plasma concentrations of verapamil are observed 1 to 2 hours after dosing. Because of rapid biotransformation of verapamil during its first pass through the portal circulation, the absolute bioavailability ranges from 20% to 35%. Chronic oral administration of the highest recommended dose (120 mg every 6 hours) resulted in plasma verapamil levels ranging from 125 to 400 ng/mL with higher values reported occasionally. A nonlinear correlation between the verapamil hydrochloride dose administered and verapamil plasma levels does exist. During initial dose titration with verapamil a relationship exists between verapamil plasma concentrations and the prolongation of the PR interval. However, during chronic administration this relationship may disappear. The quantitative relationship between plasma verapamil concentrations and blood pressure reduction has not been fully characterized. In a multiple dose pharmacokinetic study, peak concentrations for a single daily dose of verapamil hydrochloride extended-release 240 mg were approximately 65% of those obtained with an 80 mg t.i.d. dose of the conventional immediate-release tablets, and the 24-hour post-dose concentrations were approximately 30% higher. At a total daily dose of 240 mg, verapamil hydrochloride extended-release was shown to have a similar extent of verapamil bioavailability based on the AUC-24 as that obtained with the conventional immediate-release tablets. Inthis same study verapamil hydrochloride extended-release doses of 120 mg, 240 mg and 360 mg once daily were compared after multiple doses. The ratios of the verapamil and norverapamil AUCs for verapamil hydrochloride extended-release 120 mg, 240 mg and 360 mg once daily doses are 1 (565 ng���hr/mL):3 (1660 ng���hr/mL):5 (2729 ng���hr/mL) and 1 (621 ng���hr/mL):3 (1614 ng���hr/mL):4 (2535 ng���hr/mL), respectively, indicating that the AUC increased non-proportionately with increasing doses. Food does not affect the extent or rate of the absorption of verapamil from the verapamil hydrochloride extended-release capsule. The verapamil hydrochloride extended-release 240 mg capsule when administered with food had a Cof 77 ng/mL which occurred 9.0 hours after dosing, and an AUC(0���inf) of 1387 ng���hr/mL. Verapamil hydrochloride extended-release 240 mg under fasting conditions had a Cof 77 ng/mL which occurred 9.8 hours after dosing, and an AUC(0���inf) of 1541 ng���hr/mL. The bioequivalence of verapamil hydrochloride extended-release 240 mg, administered as the beads sprinkled on applesauce and as the intact capsule, was demonstrated in a single-dose, cross-over study in 32 healthy adults. Comparative ratios (sprinkled/intact) of verapamil were 0.95, 1.02, and 1.01 for C, T, and AUC(0���inf) respectively. Similar results were observed with norverapamil. The time to reach maximum verapamil concentrations (T) with verapamil hydrochloride extended-release has been found to be approximately 7 to 9 hours in each of the single dose (fasting), single dose (fed), the multiple dose (steady-state) studies, and dose proportionality pharmacokinetic studies. Similarly the apparent half-life (t) has been found to be approximately 12 hours independent of dose. Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly. In healthy man, orally administered verapamil hydrochloride undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. Norverapamil can reach steady-state plasma concentrations approximately equal to those of verapamil itself. The biologic activity of norverapamil appears to be approximately 20% that of verapamil. Approximately 70% of an administered dose of verapamil hydrochloride is excreted as metabolites in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted in the urine as unchanged drug. Approximately 90% is bound to plasma proteins. In patients with hepatic insufficiency, metabolism is delayed and elimination half-life prolonged up to 14 to 16 hours , the volume of distribution is increased, and plasma clearance reduced to about 30% of normal. Verapamil clearance values suggest that patients with liver dysfunction may attain therapeutic verapamil plasma concentrations with one-third of the oral daily dose required for patients with normal liver function. After four weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid with estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil. In 10 healthy males, administration of oral verapamil (80 mg every 8 hours for 6 days) and a single oral dose of ethanol (0.8 g/kg), resulted in a 17% increase in mean peak ethanol concentrations (106.45��21.40 to 124.23��24.74 mg/dL) compared with placebo. The area under the blood ethanol concentration versus time curve (AUC over 12 hours) increased by 30% (365.67��93.52 to 475.07��97.24 mg���hr/dL). Verapamil AUCs were positively correlated (r=0.71) to increased ethanol blood AUC values.<br/>Hemodynamics and Myocardial Metabolism: Verapamil hydrochloride reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with IHSS and those with coronary heart disease has also been observed with verapamil hydrochloride therapy. In most patients, including those with organic cardiac disease, the negative inotropic action of verapamil hydrochloride is countered by reduction of afterload and cardiac index is usually not reduced. In patients with severe left ventricular dysfunction however, (e.g., pulmonary wedge pressure above 20 mm Hg or ejection fraction lower than 30%), or in patients on beta-adrenergic blocking agents or other cardiodepressant drugs, deterioration of ventricular function may occur.<br/>Pulmonary Function: Verapamil hydrochloride does not induce bronchoconstriction and hence, does not impair ventilatory function. | lld:dailymed |
| dailymed-drugs:75 | dailymed-instance:clinicalP... | Absorption: Ethionamide is essentially completely absorbed following oral administration and is not subjected to any appreciable first pass metabolism. Ethionamide tablets may be administered without regard to the timing of meals. The pharmacokinetic parameters of ethionamide following single oral-dose administration of 250 mg of Trecator film-coated tablets under fasted conditions to 40 healthy adult volunteers are provided in Table 1. Trecator tablets have been reformulated from a sugar-coated tablet to a film-coated tablet. The Cfor the film-coated tablets (2.16��g/mL) was significantly higher than that of sugar-coated tablets (1.48��g/mL) .<br/>Distribution: Ethionamide is rapidly and widely distributed into body tissues and fluids following administration of a sugar-coated tablet, with concentrations in plasma and various organs being approximately equal. Significant concentrations are also present in cerebrospinal fluid following administration of a sugar-coated tablet. Distribution of ethionamide into the same body tissues and fluids, including cerebrospinal fluid following administration of the film-coated tablet, has not been studied, but is not expected to differ significantly from that of the sugar-coated tablet. The drug is approximately 30% bound to proteins. The mean (SD) apparent oral volume of distribution observed in 40 healthy volunteers following a 250 mg oral dose of film-coated tablets was 93.5 (19.2) L.<br/>Metabolism: Ethionamide is extensively metabolized to active and inactive metabolites. Metabolism is presumed to occur in the liver and thus far 6 metabolites have been isolated: 2-ethylisonicotinamide, carbonyl-dihydropyridine, thiocarbonyl-dihydropyridine, S-oxocarbamoyl dihydropyridine, 2-ethylthioiso-nicotinamide, and ethionamide sulphoxide. The sulphoxide metabolite has been demonstrated to have antimicrobial activity against Mycobacterium tuberculosis.<br/>Elimination: The mean (SD) half-life observed in 40 healthy volunteers following a 250 mg oral dose of film-coated tablets was 1.92 (0.27) hours. Less than 1% of the oral dose is excreted as ethionamide in urine.<br/>Mechanism of Action: Ethionamide may be bacteriostatic or bactericidal in action, depending on the concentration of the drug attained at the site of infection and the susceptibility of the infecting organism. The exact mechanism of action of ethionamide has not been fully elucidated, but the drug appears to inhibit peptide synthesis in susceptible organisms.<br/>Microbiology:<br/>In Vitro Activity: Ethionamide exhibits bacteriostatic activity against extracellular and intracellular Mycobacterium tuberculosis organisms. The development of ethionamide resistant M. tuberculosis isolates can be obtained by repeated subculturing in liquid or on solid media containing increasing concentrations of ethionamide. Multi-drug resistant strains of M. tuberculosis may have acquired resistance to both isoniazid and ethionamide. However, the majority of M. tuberculosisisolates that are resistant to one are usually susceptible to the other. There is no evidence of cross-resistance between ethionamide and para-aminosalicylic acid (PAS), streptomycin, or cycloserine. However, limited data suggest that cross-resistance may exist between ethionamide and thiosemicarbazones (i.e., thiacetazone) as well as isoniazid.<br/>In Vivo Activity: Ethionamide administered orally initially decreased the number of culturable Mycobacterium tuberculosis organisms from the lungs of H37Rv infected mice. Drug resistance developed with continued ethionamide monotherapy, but did not occur when mice received ethionamide in combination with streptomycin or isoniazid. | lld:dailymed |
| dailymed-drugs:76 | dailymed-instance:clinicalP... | Pharmacokinetics:<br/>Adults: A clinical pharmacology study was performed with ZOVIRAX Cream in adult volunteers to evaluate the percutaneous absorption of acyclovir. In this study, which included 6 male volunteers, the cream was applied to an area of 710 cmon the backs of the volunteers 5 times daily at intervals of 2 hours for a total of 4 days. The weight of cream applied and urinary excretion of acyclovir were measured daily. Plasma concentration of acyclovir was assayed 1 hour after the final application. The average daily urinary excretion of acyclovir was approximately 0.04% of the daily applied dose. Plasma acyclovir concentrations were below the limit of detection (0.01��M) in 5 subjects and barely detectable (0.014��M) in 1 subject. Systemic absorption of acyclovir from ZOVIRAX Cream is minimal in adults.<br/>Pediatric Patients: The systemic absorption of acyclovir following topical application of cream has not been evaluated in patients<18 years of age. | lld:dailymed |
| dailymed-drugs:77 | dailymed-instance:clinicalP... | Topical corticosteroids share anti-inflammatory, antipruritic and vasoconstrictive actions. The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potencyand therapeutic efficacy in man.<br/>Pharmacokinetics: The extent of percutaneous absorption to topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses. Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. Pharmacokinetic studies in men with Desoximetasone Cream 0.25% with tagged desoximetasone showed a total of 5.2%��2.9% excretion in urine (4.1%��2.3%) and feces (1.1%��0.6%) and no detectable level (limit of sensitivity: 0.005��g/mL) in the blood when it was applied topically on the back followed by occlusion for 24 hours. Seven days after application, no further radioactivity was detected in urine or feces. The half-life of the material was 15��2 hours (for urine) and 17��2 hours (for feces) between the third and fifth trial day. Studies with other similarly structured steroids have shown that predominant metabolite reaction occurs through conjugation to form the glucuronide and sulfate ester. | lld:dailymed |
| dailymed-drugs:78 | dailymed-instance:clinicalP... | Like other topical corticosteroids, fluticasone propionate has anti-inflammatory, antipruritic and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase Ainhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A. Fluticasone propionate is lipophilic and has a strong affinity for the glucocorticoid receptor. It has weak affinity for the progesterone receptor, and virtually no affinity for the mineralocorticoid, estrogen, or androgen receptors. The therapeutic potency of glucocorticoids is related to the half-life of the glucocorticoid-receptor complex. The half-life of the fluticasone propionate-glucocorticoid receptor complex is approximately 10 hours. Studies performed with fluticasone propionate ointment indicate that it is in the medium range of potency as compared with other topical corticosteroids.<br/>Pharmacokinetics:: Absorption: The activity of fluticasone propionate is due to the parent drug, fluticasone propionate. The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier. Occlusive dressing enhances penetration. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. In a study of 6 healthy volunteers applying 25 g of fluticasone propionate ointment 0.005% twice daily to the trunk and legs for up to 5 days under occlusion, plasma levels of fluticasone ranged from 0.08 to 0.22 ng/mL. In an animal study using radiolabeled 0.05% fluticasone propionate cream and ointment preparations, rats received a topical dose of 1 g/kg for a 24-hour period. Total recovery of radioactivity was approximately 80% at the end of the 7 days. The majority of the dose (73%) was recovered from the surface of the application site. Less than 1% of the dose was recovered in the skin at the application site. Approximately 5% of the dose was absorbed systemically through the skin. Absorption from the skin continued for the duration of the study (7 days), indicating a long retention time at the application site. Distribution: Following intravenous administration of 1 mg of fluticasone propionate in healthy volunteers, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The apparent volume of distribution averaged 4.2 L/kg (range, 2.3-16.7 L/kg). The percentage of fluticasone propionate bound to human plasma proteins averaged 91%. Fluticasone propionate is weakly and reversibly bound to erythrocytes. Fluticasone propionate is not significantly bound to human transcortin. Metabolism: No metabolites of fluticasone propionate were detected in an in vitro study of radiolabeled fluticasone propionate incubated in human skin homogenate. The total blood clearance of systemically absorbed fluticasone propionate averages 1093 mL/min (range, 618-1702 mL/min) after a 1-mg intravenous dose, with renal clearance accounting for less than 0.02% of the total. Fluticasone propionate is metabolized in the liver by cytochrome P450 3A4-mediated hydrolysis of the 5-fluoromethyl carbothioate grouping. This transformation occurs in 1 metabolic step to produce the inactive 17-�����carboxylic acid metabolite, the only known metabolite detected in man. This metabolite has approximately 2000 times less affinity than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man. Excretion: Following an intravenous dose of 1 mg in healthy volunteers, fluticasone propionate showed polyexponential kinetics and had an average terminal half-life of 7.2 hours (range, 3.2-11.2 hours). | lld:dailymed |
| dailymed-drugs:79 | dailymed-instance:clinicalP... | Pharmacokinetics:<br/>Ribavirin: Single- and multiple-dose pharmacokinetic properties in adults are summarized in TABLE 1. Ribavirin was rapidly and extensively absorbed following oral administration. However, due to first-pass metabolism, the absolute bioavailability averaged 64% (44%). There was a linear relationship between dose and AUC(AUC from time zero to last measurable concentration) following single doses of 200���1200 mg ribavirin. The relationship between dose and Cwas curvilinear, tending to asymptote above single doses of 400���600 mg. Upon multiple oral dosing, based on AUC12, a sixfold accumulation of ribavirin was observed in plasma. Following oral dosing with 600 mg BID, steady-state was reached by approximately 4 weeks, with mean steady-state plasma concentrations of 2200 (37%) ng/mL. Upon discontinuation of dosing, the mean half-life was 298 (30%) hours, which probably reflects slow elimination from nonplasma compartments.<br/>Effect of Food on Absorption of Ribavirin: Both AUCand Cincreased by 70% when REBETOL' Capsules were administered with a high-fat meal (841 kcal, 53.8 g fat, 31.6 g protein, and 57.4 g carbohydrate) in a single-dose pharmacokinetic study. There are insufficient data to address the clinical relevance of these results. Clinical efficacy studies with REBETOL/INTRON' A were conducted without instructions with respect to food consumption. During clinical studies with REBETOL/PegIntron���, all subjects were instructed to take REBETOL Capsules with food .<br/>Effect of Antacid on Absorption of Ribavirin: Coadministration of REBETOL Capsules with an antacid containing magnesium, aluminum, and simethicone (Mylanta) resulted in a 14% decrease in mean ribavirin AUC. The clinical relevance of results from this single-dose study is unknown. Ribavirin transport into nonplasma compartments has been most extensively studied in red blood cells, and has been identified to be primarily via an e-type equilibrative nucleoside transporter. This type of transporter is present on virtually all cell types and may account for the extensive volume of distribution. Ribavirin does not bind to plasma proteins. Ribavirin has two pathways of metabolism: (i) a reversible phosphorylation pathway in nucleated cells; and (ii) a degradative pathway involving deribosylation and amide hydrolysis to yield a triazole carboxylic acid metabolite. Ribavirin and its triazole carboxamide and triazole carboxylic acid metabolites are excreted renally. After oral administration of 600 mg ofC-ribavirin, approximately 61% and 12% of the radioactivity was eliminated in the urine and feces, respectively, in 336 hours. Unchanged ribavirin accounted for 17% of the administered dose. Results of in vitro studies using both human and rat liver microsome preparations indicated little or no cytochrome P450 enzyme-mediated metabolism of ribavirin, with minimal potential for P450 enzyme-based drug interactions. No pharmacokinetic interactions were noted between INTRON A for Injection and REBETOL Capsules in a multiple-dose pharmacokinetic study.<br/>Drug Interactions: Ribavirin has been shown in vitro to inhibit phosphorylation of zidovudine and stavudine which could lead to decreased antiretroviral activity. Exposure to didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased when didanosine is co-administered with ribavirin, which could cause or worsen clinical toxicities .<br/>Special Populations:<br/>Renal Dysfunction: The pharmacokinetics of ribavirin were assessed after administration of a single oral dose (400 mg) of ribavirin to non HCV-infected subjects with varying degrees of renal dysfunction. The mean AUCvalue was threefold greater in subjects with creatinine clearance values between 10 to 30 mL/min when compared to control subjects (creatinine clearance>90 mL/min). In subjects with creatinine clearance values between 30 to 60 mL/min, AUCwas twofold greater when compared to control subjects. The increased AUCappears to be due to reduction of renal and non-renal clearance in these patients. Phase III efficacy trials included subjects with creatinine clearance values>50 mL/min. The multiple-dose pharmacokinetics of ribavirin cannot be accurately predicted in patients with renal dysfunction. Ribavirin is not effectively removed by hemodialysis. Patients with creatinine clearance<50 mL/min should not be treated with REBETOL .<br/>Hepatic Dysfunction: The effect of hepatic dysfunction was assessed after a single oral dose of ribavirin (600 mg). The mean AUCvalues were not significantly different in subjects with mild, moderate, or severe hepatic dysfunction (Child-Pugh Classification A, B, or C) when compared to control subjects. However, the mean Cvalues increased with severity of hepatic dysfunction and was twofold greater in subjects with severe hepatic dysfunction when compared to control subjects.<br/>Elderly Patients: Pharmacokinetic evaluations in elderly subjects have not been performed.<br/>Gender: There were no clinically significant pharmacokinetic differences noted in a single-dose study of eighteen male and eighteen female subjects.<br/>Pediatric Patients: Multiple-dose pharmacokinetic properties for REBETOL Capsules and INTRON A in pediatric patients with chronic hepatitis C between 5 and 16 years of age are summarized in TABLE 2. The pharmacokinetics of REBETOL and INTRON A (dose-normalized) are similar in adults and pediatric patients. Complete pharmacokinetic characteristics of REBETOL Oral Solution have not been determined in pediatric patients. Ribavirin Cvalues were similar following administration of REBETOL Oral Solution or REBETOL Capsules during 48 weeks of therapy in pediatric patients (3 to 16 years of age). * In this section of the label, numbers in parenthesis indicate % coefficient of variation. | lld:dailymed |
| dailymed-drugs:80 | dailymed-instance:clinicalP... | Mechanism of Action: The pharmacological activity of oxcarbazepine is primarily exerted through the 10-monohydroxy metabolite (MHD) of oxcarbazepine (see Metabolism and Excretion). The precise mechanism by which oxcarbazepine and MHD exert their antiseizure effect is unknown; however, in vitro electrophysiological studies indicate that they produce blockade of voltage-sensitive sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminution of propagation of synaptic impulses. These actions are thought to be important in the prevention of seizure spread in the intact brain. In addition, increased potassium conductance and modulation of high-voltage activated calcium channels may contribute to the anticonvulsant effects of the drug. No significant interactions of oxcarbazepine or MHD with brain neurotransmitter or modulator receptor sites have been demonstrated.<br/>Pharmacodynamics: Oxcarbazepine and its active metabolite (MHD) exhibit anticonvulsant properties in animal seizure models. They protected rodents against electrically induced tonic extension seizures and, to a lesser degree, chemically induced clonic seizures, and abolished or reduced the frequency of chronically recurring focal seizures in Rhesus monkeys with aluminum implants. No development of tolerance (i.e., attenuation of anticonvulsive activity) was observed in the maximal electroshock test when mice and rats were treated daily for five days and four weeks, respectively, with oxcarbazepine or MHD.<br/>Pharmacokinetics: Following oral administration of oxcarbazepine tablets, oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD). The half-life of the parent is about two hours, while the half-life of MHD is about nine hours, so that MHD is responsible for most antiepileptic activity. Based on MHD concentrations, oxcarbazepine tablets and suspension were shown to have similar bioavailability. After single-dose administration of oxcarbazepine tablets to healthy male volunteers under fasted conditions, the median twas 4.5 (range 3 to 13) hours. In a mass balance study in people, only 2% of total radioactivity in plasma was due to unchanged oxcarbazepine, with approximately 70% present as MHD, and the remainder attributable to minor metabolites.<br/>Effect of Food: Food has no effect on the rate and extent of absorption of oxcarbazepine from oxcarbazepine tablets. Therefore, oxcarbazepine tablets can be taken with or without food. Steady-state plasma concentrations of MHD are reached within 2 to 3 days in patients when oxcarbazepine is given twice a day. At steady-state the pharmacokinetics of MHD are linear and show dose proportionality over the dose range of 300 to 2400 mg/day.<br/>Distribution: The apparent volume of distribution of MHD is 49 L. Approximately 40% of MHD is bound to serum proteins, predominantly to albumin. Binding is independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein.<br/>Metabolism and Excretion: Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to its 10-monohydroxy metabolite, MHD, which is primarily responsible for the pharmacological effect of oxcarbazepine. MHD is metabolized further by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidized to the pharmacologically inactive 10,11-dihydroxy metabolite (DHD). Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95% of the dose appears in the urine, with less than 1% as unchanged oxcarbazepine. Fecal excretion accounts for less than 4% of the administered dose. Approximately 80% of the dose is excreted in the urine either as glucuronides of MHD (49%) or as unchanged MHD (27%); the inactive DHD accounts for approximately 3% and conjugates of MHD and oxcarbazepine account for 13% of the dose.<br/>Special Populations: | lld:dailymed |
| dailymed-drugs:81 | dailymed-instance:clinicalP... | Mechanism of Action: The precise mechanism by which hydroxyurea produces its antineoplastic effects cannot, at present, be described. However, the reports of various studies in tissue culture in rats and humans lend support to the hypothesis that hydroxyurea causes an immediate inhibition of DNA synthesis by acting as a ribonucleotide reductase inhibitor, without interfering with the synthesis of ribonucleic acid or of protein. This hypothesis explains why, under certain conditions, hydroxyurea may induce teratogenic effects. Three mechanisms of action have been postulated for the increased effectiveness of concomitant use of hydroxyurea therapy with irradiation on squamous cell (epidermoid) carcinomas of the head and neck. In vitro studies utilizing Chinese hamster cells suggest that hydroxyurea (1) is lethal to normally radioresistant S-stage cells, and (2) holds other cells of the cell cycle in the G1 or pre-DNA synthesis stage where they are most susceptible to the effects of irradiation. The third mechanism of action has been theorized on the basis of in vitro studies of HeLa cells: it appears that hydroxyurea, by inhibition of DNA synthesis, hinders the normal repair process of cells damaged but not killed by irradiation, thereby decreasing their survival rate; RNA and protein syntheses have shown no alteration.<br/>Pharmacokinetics:<br/>Absorption: Hydroxyurea is readily absorbed after oral administration. Peak plasma levels are reached in 1 to 4 hours after an oral dose. With increasing doses, disproportionately greater mean peak plasma concentrations and AUCs are observed. There are no data on the effect of food on the absorption of hydroxyurea.<br/>Distribution: Hydroxyurea distributes rapidly and widely in the body with an estimated volume of distribution approximating total body water. Plasma to ascites fluid ratios range from 2:1 to 7.5:1. Hydroxyurea concentrates in leukocytes and erythrocytes.<br/>Metabolism: Up to 60% of an oral dose undergoes conversion through metabolic pathways that are not fully characterized. One pathway is probably saturable hepatic metabolism. Another minor pathway may be degradation by urease found in intestinal bacteria. Acetohydroxamic acid was found in the serum of three leukemic patients receiving hydroxyurea and may be formed from hydroxylamine resulting from action of urease on hydroxyurea.<br/>Excretion: Excretion of hydroxyurea in humans is likely a linear first-order renal process.<br/>Special Populations:<br/>Geriatric, Gender, Race: No information is available regarding pharmacokinetic differences due to age, gender, or race.<br/>Pediatric: No pharmacokinetic data are available in pediatric patients treated with hydroxyurea.<br/>Renal Insufficiency: As renal excretion is a pathway of elimination, consideration should be given to decreasing the dosage of hydroxyurea in patients with renal impairment. In adult patients with sickle cell disease, an open-label, non-randomized, single-dose, multicenter study was conducted to assess the influence of renal function on the pharmacokinetics of hydroxyurea. Patients in the study with normal renal function (creatinine clearance [CrCl]>80 mL/min), mild (CrCl 50���80 mL/min), moderate (CrCl = 30���<50 mL/min), or severe (<30 mL/min) renal impairment received hydroxyurea as a single oral dose of 15 mg/kg, achieved by using combinations of the 200 mg, 300 mg, or 400 mg capsules. Patients with end-stage renal disease (ESRD) received two doses of 15 mg/kg separated by 7 days, the first was given following a 4-hour hemodialysis session, the second prior to hemodialysis. In this study the mean exposure (AUC) in patients whose creatinine clearance was<60 mL/min (or ESRD) was approximately 64% higher than in patients with normal renal function. The results suggest that the initial dose of hydroxyurea should be reduced when used to treat patients with renal impairment. Close monitoring of hematologic parameters is advised in these patients.<br/>Hepatic Insufficiency: There are no data that support specific guidance for dosage adjustment in patients with hepatic impairment. Close monitoring of hematologic parameters is advised in these patients.<br/>Drug Interactions: There are no data on concomitant use of hydroxyurea with other drugs in humans.<br/>Animal Pharmacology and Toxicology: The oral LDof hydroxyurea is 7330 mg/kg in mice and 5780 mg/kg in rats, given as a single dose. In subacute and chronic toxicity studies in the rat, the most consistent pathological findings were an apparent dose-related mild to moderate bonemarrow hypoplasia as well as pulmonary congestion and mottling of the lungs. At the highest dosage levels (1260 mg/kg/day for 37 days then 2520 mg/kg/day for 40 days), testicular atrophy with absence of spermatogenesis occurred; in several animals, hepatic cell damage with fatty metamorphosis was noted. In the dog, mild to marked bone marrow depression was a consistent finding except at the lower dosage levels. Additionally, at the higher dose levels (140 to 420 mg or 140 to 1260 mg/kg/week given 3 or 7 days weekly for 12 weeks), growth retardation, slightly increased blood glucose values, and hemosiderosis of the liver or spleen were found; reversible spermatogenic arrest was noted. In the monkey, bone marrow depression, lymphoid atrophy of the spleen, and degenerative changes in the epithelium of the small and large intestines were found. At the higher, often lethal, doses (400 to 800 mg/kg/day for 7 to 15 days), hemorrhage and congestion were found in the lungs, brain, and urinary tract. Cardiovascular effects (changes in heart rate, blood pressure, orthostatic hypotension, EKG changes) and hematological changes (slight hemolysis, slight methemoglobinemia) were observed in some species of laboratory animals at doses exceeding clinical levels. | lld:dailymed |
| dailymed-drugs:82 | dailymed-instance:clinicalP... | Phenytoin is an antiepileptic drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activity of brain stem centers responsible for the tonic phase of tonic-clonic (grand mal) seizures. The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours. Steady-state therapeutic levels are achieved at least 7 to 10 days (5���7 half-lives) after initiation of therapy with recommended doses of 300 mg/day. When serum level determinations are necessary, they should be obtained at least 5���7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved. Trough levels provide information about clinically effective serum level range and confirm patient compliance and are obtained just prior to the patient's next scheduled dose. Peak levels indicate an individual's threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. For Dilantin-125 Suspension, peak levels occur 1�����3 hours after administration. Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 and 20 mcg/mL, although some mild cases of tonic-clonic (grand mal) epilepsy may be controlled with lower serum levels of phenytoin. In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, congenital enzyme deficiency, or drug interactions which result in metabolic interference. The patient with large variations in phenytoin plasma levels, despite standard doses, presents a difficult clinical problem. Serum level determinations in such patients may be particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high plasma levels, small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more. | lld:dailymed |
| dailymed-drugs:83 | dailymed-instance:clinicalP... | In vitro and in vivo animal studies have shown that cromolyn sodium inhibits the degranulation of sensitized mast cells which occurs after exposure to specific antigens. Cromolyn sodium acts by inhibiting the release of histamine and SRS-A (slow-reacting substance of anaphylaxis) from the mast cell. Another activity demonstrated in vitro is the capacity of cromolyn sodium to inhibit the degranulation of non-sensitized rat mast cells by phospholipase A and the subsequent release of chemical mediators. Another study showed that cromolyn sodium did not inhibit the enzymatic activity of released phospholipase A on its specific substrate. Cromolyn sodium has no intrinsic vasoconstrictor, antihistamine, or anti-inflammatory activity. Cromolyn sodium is poorly absorbed. When multiple doses of cromolyn sodium ophthalmic solution are instilled into normal rabbit eyes, less than 0.07% of the administered dose of cromolyn sodium is absorbed into the systemic circulation (presumably by way of the eye, nasal passages, buccal cavity, and gastrointestinal tract). Trace amounts (less than 0.01%) of the cromolyn sodium dose penetrate into the aqueous humor and clearance from this chamber is virtually complete within 24 hours after treatment is stopped. In normal volunteers, analysis of drug excretion indicates that approximately 0.03% of cromolyn sodium is absorbed following administration to the eye. | lld:dailymed |
| dailymed-drugs:85 | dailymed-instance:clinicalP... | Intramuscular penicillin G benzathine is absorbed very slowly into the blood stream from the intramuscular site and converted by hydrolysis to penicillin G. This combination of hydrolysis and slow absorption results in blood serum levels much lower than those of other parenteral penicillins. Approximately 60% of penicillin G is bound to serum protein. The drug is distributed throughout the body tissues in widely varying amounts. Highest levels are found in the kidneys with lesser amounts in the liver, skin, and intestines. Penicillin G penetrates into all other tissues and the spinal fluid to a lesser degree. With normal kidney function the drug is excreted rapidly by tubular excretion. A small amount is secreted into the bile. In neonates and young infants, and in individuals with impaired kidney function, excretion is considerably delayed.<br/>Microbiology: Penicillin G exerts a bactericidal action against penicillin-susceptible microorganisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell wall mucopeptide. It is not active against the penicillinase-producing bacteria, which includes many strains of staphylococci. While in vitro studies have demonstrated the susceptibility of most strains of the following organisms, clinical efficacy for infections other than those included in the INDICATIONS AND USAGE section has not been documented. Penicillin G exerts high in vitro activity against staphylococci (except penicillinase-producing strains), streptococci (groups A, C, G, H, L, and M), and pneumococci. Other organisms sensitive to penicillin G are: Corynebacterium diphtheriae, Bacillus anthracis, Clostridia, Actinomyces bovis, Streptobacillus moniliformis, Listeria monocytogenes, and Leptospira. Treponema pallidum is extremely sensitive to the bactericidal action of penicillin G. Penicillin acts synergistically with gentamicin or tobramycin against many strains of enterococci. | lld:dailymed |
| dailymed-drugs:87 | dailymed-instance:clinicalP... | Pharmacodynamics: ClomiPRAMINE is presumed to influence obsessive and compulsive behaviors through its effects on serotonergic neuronal transmission. The actual neurochemical mechanism is unknown, but ClomiPRAMINE's capacity to inhibit the reuptake of serotonin (5-HT) is thought to be important.<br/>Pharmacokinetics:<br/>Absorption/Bioavailability: ClomiPRAMINE from ClomiPRAMINE hydrochloride capsules is as bioavailable as ClomiPRAMINE from a solution. The bioavailability of ClomiPRAMINE from capsules is not significantly affected by food. In a dose proportionality study involving multiple ClomiPRAMINE doses, steady-state plasma concentrations (C) and area-under-plasma-concentration-time curves (AUC) of ClomiPRAMINE and ClomiPRAMINE's major active metabolite, desmethylclomipramine, were not proportional to dose over the ranges evaluated, i.e., between 25 to 100 mg/day and between 25 to 150 mg/day, although Cand AUC are approximately linearly related to dose between 100 to 150 mg/day. The relationship between dose and ClomiPRAMINE/desmethylclomipramine concentrations at higher daily doses has not been systematically assessed, but if there is significant dose dependency at doses above 150 mg/day, there is the potential for dramatically higher Cand AUC even for patients dosed within the recommended range. This may pose a potential risk to some patients (see WARNINGS and PRECAUTIONS, Drug Interactions). After a single 50 mg oral dose, maximum plasma concentrations of ClomiPRAMINE occur within 2 to 6 hours (mean, 4.7 hr) and range from 56 ng/mL to 154 ng/mL (mean, 92 ng/mL). After multiple daily doses of 150 mg of ClomiPRAMINE, steady-state maximum plasma concentrations range from 94 ng/mL to 339 ng/mL (mean, 218 ng/mL) for ClomiPRAMINE and from 134ng/mL to 532 ng/mL (mean, 274 ng/mL) for desmethylclomipramine. Additional information from a rising dose study of doses up to 250 mg suggests that desmethylclomipramine may exhibit nonlinear pharmacokinetics over the usual dosing range. At a dose of ClomiPRAMINE hydrochloride capsule 200 mg, subjects who had a single blood sample taken approximately 9 to 22 hours, (median 16 hours), after the dose had plasma concentrations of up to 605 ng/mL for ClomiPRAMINE, 781 ng/mL for desmethylclomipramine, and 1386 ng/mL for both.<br/>Distribution: ClomiPRAMINE distributes into cerebrospinal fluid (CSF) and brain and into breast milk. Desmethylclomipramine also distributes into CSF, with a mean CSF/plasma ratio of 2.6. The protein binding of ClomiPRAMINE is approximately 97%, principally to albumin, and is independent of ClomiPRAMINE concentration. The interaction between ClomiPRAMINE and other highly protein-bound drugs has not been fully evaluated, but may be important (see PRECAUTIONS, Drug Interactions).<br/>Metabolism: ClomiPRAMINE is extensively biotransformed to desmethylclomipramine and other metabolites and their glucuronide conjugates. Desmethylclomipramine is pharmacologically active, but its effects on OCD behaviors are unknown. These metabolites are excreted in urine and feces, following biliary elimination. After a 25 mg radiolabeled dose of ClomiPRAMINE in twosubjects, 60% and 51%, respectively, of the dose were recovered in the urine and 32% and 24%, respectively, in feces. In the same study, the combined urinary recoveries of ClomiPRAMINE and desmethylclomipramine were only about 0.8% to 1.3% of the dose administered. ClomiPRAMINE does not induce drug-metabolizing enzymes, as measured by antipyrine half-life.<br/>Elimination: Evidence that the Cand AUC for ClomiPRAMINE and desmethylclomipramine may increase disproportionately with increasing oral doses suggests that the metabolism of ClomiPRAMINE and desmethylclomipramine may be capacity limited. This fact must be considered in assessing the estimates of the pharmacokinetic parameters presented below, as these were obtained in individuals exposed to doses of 150 mg. If the pharmacokinetics of ClomiPRAMINE and desmethylclomipramine are nonlinear at doses above 150 mg, their elimination half-lives may be considerably lengthened at doses near the upper end of the recommended dosing range (i.e., 200 mg/day to 250 mg/day). Consequently, ClomiPRAMINE and desmethylclomipramine may accumulate, and this accumulation may increase the incidence of any dose- or plasma-concentration-dependent adverse reactions, in particular seizures (see WARNINGS). After a 150 mg dose, the half-life of ClomiPRAMINE ranges from 19 hours to 37 hours (mean, 32 hr) and that of desmethylclomipramine ranges from 54 hours to 77 hours (mean, 69 hr). Steady-state levels after multiple dosing are typically reached within 7 to 14 days for ClomiPRAMINE. Plasma concentrations of the metabolite exceed the parent drug on multiple dosing. After multiple dosing with 150 mg/day, the accumulation factor for ClomiPRAMINE is approximately 2.5 and for desmethylclomipramine is 4.6. Importantly, it may take two weeks or longer to achieve this extent of accumulation at constant dosing because of the relatively long elimination half-lives of ClomiPRAMINE and desmethylclomipramine (see DOSAGE AND ADMINISTRATION). The effects of hepatic and renal impairment on the disposition of ClomiPRAMINE have not been determined.<br/>Interactions: Coadministration of haloperidol with ClomiPRAMINE increases plasma concentrations of ClomiPRAMINE. Coadministration of ClomiPRAMINE with phenobarbital increases plasma concentrations of phenobarbital (see PRECAUTIONS, Drug Interactions). Younger subjects (18 to 40 years of age) tolerated ClomiPRAMINE better and had significantly lower steady-state plasma concentrations, compared with subjects over 65 years of age. Children under 15 years of age had significantly lower plasma concentration/dose ratios, compared with adults. Plasma concentrations of ClomiPRAMINE were significantly lower in smokers than in nonsmokers. | lld:dailymed |
| dailymed-drugs:88 | dailymed-instance:clinicalP... | Although the exact mechanism of action through which indomethacin causes closure of a patent ductus arteriosus is not known, it is believed to be through inhibition of prostaglandin synthesis. Indomethacin has been shown to be a potent inhibitor of prostaglandin synthesis, both in vitro and in vivo. In human newborns with certain congenital heart malformations, PGE 1 dilates the ductus arteriosus. In fetal and newborn lambs, E type prostaglandins have also been shown to maintain the patency of the ductus, and as in human newborns, indomethacin causes its constriction. Studies in healthy young animals and in premature infants with patent ductus arteriosus indicated that, after the first dose of intravenous indomethacin, there was a transient reduction in cerebral blood flow velocity and cerebral blood flow. Similar decreases in mesenteric blood flow and velocity have been observed. The clinical significance of these effects has not been established. In double-blind, placebo-controlled studies of INDOCIN I.V. in 460 small pre-term infants, weighing 1750 g or less, the neonates treated with placebo had a ductus closure rate after 48 hours of 25 to 30 percent, whereas those treated with INDOCIN I.V. had a 75 to 80 percent closure rate. In one of these studies, a multicenterstudy, involving 405 pre-term infants, later re-opening of the ductus arteriosus occurred in 26 percent of neonates treated with INDOCIN I.V., however, 70 percent of these closed subsequently without the need for surgery or additional indomethacin.<br/>Pharmacokinetics and Metabolism: The disposition of indomethacin following intravenous administration (0.2 mg/kg) in pre-term neonates with patent ductus arteriosus has not been extensively evaluated. Even though the plasma half-life of indomethacin was variable among premature infants, it was shown to vary inversely with postnatal age and weight. In one study, of 28 neonates who could be evaluated, the plasma half-life in those lessthan 7 days old averaged 20 hours (range: 3-60 hours, n=18). In neonates older than 7 days, the mean plasma half-life of indomethacin was 12 hours (range: 4-38 hours, n=10). Grouping the neonates by weight, mean plasma half-life in those weighing less than 1000 g was 21 hours (range: 9-60 hours, n=10); in those neonates weighing more than 1000 g, the mean plasma half-life was 15 hours (range: 3-52 hours, n=18). Following intravenous administration in adults, indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. The mean plasma half-life of indomethacin is 4.5 hours. In the absence of enterohepatic circulation, it is 90 minutes. Indomethacin has been found to cross the blood-brain barrier and the placenta. In adults, about 99 percent of indomethacin is bound to protein in plasma over the expected range of therapeutic plasma concentrations. The percent bound in neonates has not been studied. In controlled trials in premature infants, however, no evidence of bilirubin displacement has been observed as evidenced by increased incidence of bilirubin encephalopathy (kernicterus). | lld:dailymed |
| dailymed-drugs:89 | dailymed-instance:clinicalP... | Mechanism of Action: The mechanism of action of Tigan as determined in animals is obscure, but may involve the chemoreceptor trigger zone (CTZ), an area in the medulla oblongata through which emetic impulses are conveyed to the vomiting center; direct impulses to the vomiting center apparently are not similarly inhibited. In dogs pretreated with trimethobenzamide HCl, the emetic response to apomorphine is inhibited, while little or no protection is afforded against emesis induced by intragastric copper sulfate.<br/>Pharmacokinetics: The pharmacokinetics of trimethobenzamide have been studied in healthy adult subjects. Following administration of 200 mg (100 mg/mL) Tigan I.M. injection, the time to reach maximum plasma concentration (T) was about half an hour, about 15 minutes longer for Tigan 300 mg oral capsule than an I.M. injection. A single dose of Tigan 300 mg oral capsule provided a plasma concentration pro���le of trimethobenzamide similar to Tigan 200 mg I.M. The relative bioavailability of the capsule formulation compared to the solution is 100%. The mean elimination half-life of trimethobenzamide is 7 to 9 hours.<br/>Special Populations:<br/>Gender: Systemic exposure to trimethobenzamide was similar between men (N=40) and women (N=28).<br/>Race: Pharmacokinetics appeared to be similar for Caucasians (N=53) and African Americans (N=12). | lld:dailymed |
| dailymed-drugs:90 | dailymed-instance:clinicalP... | Pharmacodynamics: SEROQUEL is an antagonist at multiple neurotransmitter receptors in the brain: serotonin 5HTand 5HT(IC=717&148nM respectively), dopamine Dand D(IC=1268&329nM respectively), histamine H(IC=30nM), and adrenergic��and��receptors (IC=94&271nM, respectively). SEROQUEL has no appreciable affinity at cholinergic muscarinic and benzodiazepine receptors (IC>5000 nM). The mechanism of action of SEROQUEL, as with other drugs having efficacy in the treatment of schizophrenia and bipolar disorder, is unknown. However, it has been proposed that the efficacy of SEROQUEL in schizophrenia and its mood stabilizing properties in bipolar depression and mania are mediated through a combination of dopamine type 2 (D) and serotonin type 2 (5HT) antagonism. Antagonism at receptors other than dopamine and 5HTwith similar receptor affinities may explain some of the other effects of SEROQUEL. SEROQUEL's antagonism of histamine Hreceptors may explain the somnolence observed with this drug. SEROQUEL's antagonism of adrenergic��receptors may explain the orthostatic hypotension observed with this drug.<br/>Pharmacokinetics: Quetiapine fumarate activity is primarily due to the parent drug. The multiple-dose pharmacokinetics of quetiapine are dose-proportional within the proposed clinical dose range, and quetiapine accumulation is predictable upon multiple dosing. Elimination of quetiapine is mainly via hepatic metabolism with a mean terminal half-life of about 6 hours within the proposed clinical dose range. Steady-state concentrations are expected to be achieved within two days of dosing. Quetiapine is unlikely to interfere with the metabolism of drugs metabolized by cytochrome P450 enzymes.<br/>Absorption:: Quetiapine fumarate is rapidly absorbed after oral administration, reaching peak plasma concentrations in 1.5 hours. The tablet formulation is 100% bioavailable relative to solution. The bioavailability of quetiapine is marginally affected by administration with food, with Cand AUC values increased by 25% and 15%, respectively.<br/>Distribution:: Quetiapine is widely distributed throughout the body with an apparent volume of distribution of 10��4 L/kg. It is 83% bound to plasma proteins at therapeutic concentrations. In vitro, quetiapine did not affect the binding of warfarin or diazepam to human serum albumin. In turn, neither warfarin nor diazepam altered the binding of quetiapine<br/>Metabolism and Elimination:: Following a single oral dose ofC-quetiapine, less than 1% of the administered dose was excreted as unchanged drug, indicating that quetiapine is highly metabolized. Approximately 73% and 20% of the dose was recovered in the urine and feces, respectively. Quetiapine is extensively metabolized by the liver. The major metabolic pathways are sulfoxidation to the sulfoxide metabolite and oxidation to the parent acid metabolite; both metabolites are pharmacologically inactive. In vitro studies using human liver microsomes revealed that the cytochrome P450 3A4 isoenzyme is involved in the metabolism of quetiapine to its major, but inactive, sulfoxide metabolite.<br/>Population Subgroups:: Age: Oral clearance of quetiapine was reduced by 40% in elderly patients (���65 years, n=9) compared to young patients (n=12), and dosing adjustment may be necessary .<br/>Clinical Efficacy Data:<br/>Bipolar Disorder: Depression The efficacy of SEROQUEL for the treatment of depressive episodes associated with bipolar disorder was established in 2 identical 8-week, randomized, double-blind, placebo-controlled studies (N=1045). These studies included patients with either bipolar I or II disorder and those with or without a rapid cycling course. Patients randomized to SEROQUEL were administered fixed doses of either 300 mg or 600 mg once daily. The primary rating instrument used to assess depressive symptoms in these studies was the Montgomery-Asberg Depression Rating Scale (MADRS), a 10 item clinician-rated scale with scores ranging from 0 to 60. The primary endpoint in both studies was the change from baseline in MADRS score at week 8. In both studies, SEROQUEL was superior to placebo in reduction of MADRS score. Improvement in symptoms, as measured by change in MADRS score relative to placebo, was seen in both studies at Day 8 (week 1)and onwards. In these studies, no additional benefit was seen with the 600 mg dose. For the 300 mg dose group, statistically significant improvements over placebo were seen in overall quality of life and satisfaction related to various areas of functioning, as measured using the Q-LES-Q(SF). Mania The efficacy of SEROQUEL in the treatment of acute manic episodes was established in 3 placebo-controlled trials in patients who met DSM-IV criteria for Bipolar I disorder with manic episodes. These trials included patients with or without psychotic features and excluded patients with rapid cycling and mixed episodes. Of these trials, 2 were monotherapy (12 weeks) and 1 was adjunct therapy (3 weeks) to either lithium or divalproex. Key outcomes in these trials were change from baseline in the Young Mania Rating Scale (YMRS) score at 3 and 12 weeks for monotherapy and at 3 weeks for adjunct therapy. Adjunct therapy is defined as the simultaneous initiation or subsequent administration of SEROQUEL with lithium or divalproex. The primary rating instrument used for assessing manic symptoms in these trials was YMRS, an 11-item clinician-rated scale traditionally used to assess the degree of manic symptomatology (irritability, disruptive/aggressive behavior, sleep, elevated mood, speech, increased activity, sexual interest, language/thought disorder, thought content, appearance, and insight) in a range from 0 (no manic features) to 60 (maximum score). The results of the trials follow:<br/>Monotherapy: In two 12-week trials (n=300, n=299) comparing SEROQUEL to placebo, SEROQUEL was superior to placebo in the reduction of the YMRS total score at weeks 3 and 12. The majority of patients in these trials taking SEROQUEL were dosed in a range between 400 and 800 mg per day.<br/>Adjunct Therapy: In this 3-week placebo-controlled trial, 170 patients with acute bipolar mania (YMRS���20) were randomized to receive SEROQUEL or placebo as adjunct treatment to lithium or divalproex. Patients may or may not have received an adequate treatment course of lithium or divalproex prior to randomization. SEROQUEL was superior to placebo when added to lithium or divalproex alone in the reduction of YMRS total score. The majority of patients in this trial taking SEROQUEL were dosed in a range between 400 and 800 mg per day. In a similarly designed trial (n=200), SEROQUEL was associated with an improvement in YMRS scores but did not demonstrate superiority to placebo, possibly due to a higher placebo effect.<br/>Schizophrenia: The efficacy of SEROQUEL in the treatment of schizophrenia was established in 3 short-term (6-week) controlled trials of inpatients with schizophrenia who met DSM III-R criteria for schizophrenia. Although a single fixed dose haloperidol arm was included as a comparative treatment in one of the three trials, this single haloperidol dose group was inadequate to provide a reliable and valid comparison of SEROQUEL and haloperidol. Several instruments were used for assessing psychiatric signs and symptoms in these studies, among them the Brief Psychiatric Rating Scale (BPRS), a multi-item inventory of general psychopathology traditionally used to evaluate the effects of drug treatment in schizophrenia. The BPRS psychosis cluster (conceptual disorganization, hallucinatory behavior, suspiciousness, and unusual thought content) is considered a particularly useful subset for assessing actively psychotic schizophrenic patients. A second traditional assessment, the Clinical Global Impression (CGI), reflects the impression of a skilled observer, fully familiarwith the manifestations of schizophrenia, about the overall clinical state of the patient. In addition, the Scale for Assessing Negative Symptoms (SANS), a more recently developed but less well evaluated scale, was employed for assessing negative symptoms. The results of the trials follow: Examination of population subsets (race, gender, and age) did not reveal any differential responsiveness on the basis of race or gender, with an apparently greater effect in patients under the age of 40 compared to those older than 40. The clinical significance of this finding is unknown. | lld:dailymed |
| dailymed-drugs:91 | dailymed-instance:clinicalP... | When administered in recommended oral dosage to children or adults, Cystadane acts as a methyl group donor in the remethylation of homocysteine to methionine in patients with homocystinuria. As a result, toxic blood levels of homocysteine are reduced in these patients, usually to 20-30 percent or less of pre-treatment levels. Elevated homocysteine blood levels are associated with clinical problems such as a cardiovascular thrombosis, osteoporosis, skeletal abnormalities, and optic lens dislocation. Plasma levels of homocysteine were decreased in nearly all patients treated with betaine. In observational studies without concurrent controls, clinical improvement was reported by the treating physicians in about three-fourths of patients taking betaine. Many of these patients were also taking other therapies such as vitamin B(pyridoxine), vitamin B(cobalamin), and folate with variable biochemical responses. In most cases studied, adding betaine resulted in a further reduction of homocysteine. Betaine was observed to lower plasma homocysteine levels in the three types of homocystinuria, i.e., cystathionine beta-synthase (CBS) deficiency; 5,10-methylenetetrahydrofolate reductase (MTHFR) deficiency; and cobalamin cofactor metabolism (cbl) defect. Betaine has also been demonstrated to increase low plasma methionine and S-adenosylmethionine (SAM) levels in patients with MTHFR deficiency and cbl defect. In CBS-deficient patients, large increases in methionine levels over baseline have been observed. Betaine occurs naturally in the body. It is a metabolite of choline and is present in small amounts in foods such as beets, spinach, cereals, and seafood. Pharmacokinetic studies of betaine are not available. Plasma levels of betaine have not been measured in patients and have not been correlated to homocysteine levels. However, pharmacodynamic measurements, i.e., monitoring of plasma homocysteine levels, have demonstrated that the onset of action of betaine is within several days and that a steady state in response to dosage is achieved within several weeks. Patients have taken betaine for many years without evidence of tolerance. | lld:dailymed |
| dailymed-drugs:92 | dailymed-instance:clinicalP... | Biologically inactive clindamycin phosphate is rapidly converted to active clindamycin. By the end of short-term intravenous infusion, peak serum levels of active clindamycin are reached. Biologically inactive clindamycin phosphate disappears rapidly from the serum; the average elimination half-life is 6 minutes; however, the serum elimination half-life of active clindamycin is about 3 hours in adults and 2��hours in pediatric patients. After intramuscular injection of clindamycin phosphate, peak levels of active clindamycin are reached within 3 hours in adults and 1 hour in pediatric patients. Serum level curves may be constructed from IV peak serum levels as given in Table 1 by application of elimination half-lives listed above. Serum levels of clindamycin can be maintained above the in vitro minimum inhibitory concentrations for most indicated organisms by administration of clindamycin phosphate every 8 to 12 hours in adults and every 6 to 8 hours in pediatric patients, or by continuous intravenous infusion. An equilibrium state is reached by the third dose. The elimination half-life of clindamycin is increased slightly in patients with markedly reduced renal or hepatic function. Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum. Dosage schedules need not be modified in the presence of mild or moderate renal or hepatic disease. No significant levels of clindamycin are attained in the cerebrospinal fluid even in the presence of inflamed meninges. Pharmacokinetic studies in elderly volunteers (61���79 years) and younger adults (18���39 years) indicate that age alone does not alter clindamycin pharmacokinetics (clearance, elimination half-life, volume of distribution, and area under the serum concentration-time curve) after IV administration of clindamycin phosphate. After oral administration of clindamycin hydrochloride, elimination half-life is increased to approximately 4.0 hours (range 3.4���5.1 h) in the elderly compared to 3.2 hours (range 2.1���4.2 h) in younger adults. The extent of absorption, however, is not different between age groups and no dosage alteration is necessary for the elderly with normal hepatic function and normal (age-adjusted) renal function. Serum assays for active clindamycin require an inhibitor to prevent in vitro hydrolysis of clindamycin phosphate.<br/>Microbiology: Although clindamycin phosphate is inactive in vitro, rapid in vivo hydrolysis converts this compound to the antibacterially active clindamycin. Clindamycin has been shown to have in vitro activity against isolates of the following organisms: Aerobic gram positive cocci, including: Anaerobic gram negative bacilli, including: Anaerobic gram positive nonsporeforming bacilli, including: Anaerobic and microaerophilic gram positive cocci, including: Clostridia: Clostridia are more resistant than most anaerobes to clindamycin. Most Clostridium perfringens are susceptible, but other species, e.g., Clostridium sporogenes and Clostridium tertium are frequently resistant to clindamycin. Susceptibility testing should be done. Cross resistance has been demonstrated between clindamycin and lincomycin. Antagonism has been demonstrated between clindamycin and erythromycin.<br/>In vitro Susceptibility Testing:<br/>Disk diffusion technique: Quantitative methods that require measurement of zone diameters give the most precise estimates of antibiotic susceptibility. One such procedurehas been recommended for use with disks to test susceptibility to clindamycin. Reports from a laboratory using the standardized single-disk susceptibility testwith a 2 mcg clindamycin disk should be interpreted according to the following criteria: Susceptible organisms produce zones of 17 mm or greater, indicating that the tested organism is likely to respond to therapy. Organisms of intermediate susceptibility produce zones of 15���16 mm, indicating that the tested organism would be susceptible if a high dosage is used or if the infection is confined to tissues and fluids (e.g., urine), in which high antibiotic levels are attained. Resistant organisms produce zones of 14 mm or less, indicating that other therapy should be selected. Standardized procedures require the use of control organisms. The 2 mcg clindamycin disk should give a zone diameter between 24 and 30 mm for S. aureus ATCC 25923.<br/>Dilution techniques: A bacterial isolate may be considered susceptible if the minimum inhibitory concentration (MIC) for clindamycin is not more than 1.6 mcg/mL. Organisms are considered moderately susceptible if the MIC is greater than 1.6 mcg/mL and less than or equal to 4.8 mcg/mL. Organisms are considered resistant if the MIC is greater than 4.8 mcg per mL. The range of MICs for the control strains are as follows: S. aureus ATCC 29213, 0.06���0.25 mcg/mL. E. faecalis ATCC 29212, 4.0���16 mcg/mL. For anaerobic bacteria the minimum inhibitory concentration (MIC) of clindamycin can be determined by agar dilution and broth dilution (including microdilution) techniques.If MICs are not determined routinely, the disk broth method is recommended for routine use. THE KIRBY-BAUER DISK DIFFUSION METHOD AND ITS INTERPRETIVE STANDARDS ARE NOT RECOMMENDED FOR ANAEROBES. | lld:dailymed |
| dailymed-drugs:93 | dailymed-instance:clinicalP... | Pharmacokinetics:<br/>Absorption: The absolute oral bioavailability of mefloquine has not been determined since an intravenous formulation is not available. The bioavailability of the tablet formation compared with an oral solution was over 85%. The presence of food significantly enhances the rate and extent of absorption, leading to about a 40% increase in bioavailability. In healthy volunteers, plasma concentrations peak 6 to 24 hours (median, about 17 hours) after a single dose of mefloquine. In a similar group of volunteers, maximum plasma concentrations in��g/L are roughly equivalent to the dose in milligrams (for example, a single 1000 mg dose produces a maximum concentration of about 1000��g/L). In healthy volunteers, a dose of 250 mg once weekly, produces maximum steady-state plasma concentrations of 1000 to 2000��g/L, which are reached after 7 to 10 weeks.<br/>Distribution: In healthy adults, the apparent volume of distribution is approximately 20 L/kg, indicating extensive tissue distribution. Mefloquine may accumulate in parasitized erythrocytes. Experiments conducted in vitro with human blood using concentrations between 50 and 1000 mg/mL showed a relatively constant erythrocyte-to-plasma concentration ratio of about 2 to 1. The equilibrium reached in less than 30 minutes, was found to be reversible. Protein binding is about 98%. Mefloquine crosses the placenta. Excretion into breast milk appears to be minimal .<br/>Metabolism: Two metabolites have been identified in humans. The main metabolite, 2,8-bis-trifluoromethyl-4-quinoline carboxylic acid, is inactive in Plasmodium falciparum. In a study in healthy volunteers, the carboxylic acid metabolite appeared in plasma 2 to 4 hours after a single oral dose. Maximum plasma concentrations, which were about 50% higher than those of mefloquine, were reached after 2 weeks. Thereafter, plasma levels of the main metabolite and mefloquine declined at a similar rate. The area under the plasma concentration-time curve (AUC) of the main metabolite was 3 to 5 times larger than that of the parent drug. The other metabolite, an alcohol, was present in minute quantities only.<br/>Elimination: In several studies in healthy adults, the mean elimination half-life of mefloquine varied between 2 and 4 weeks, with an average of about 3 weeks. Total clearance, which is essentially hepatic, is in the order of 30 mL/min. There is evidence that mefloquine is excreted mainly in the bile and feces. In volunteers, urinary excretion of unchanged mefloquine and its main metabolite under steady-state condition accounted for about 9% and 4% of the dose, respectively. Concentrations of other metabolites could not be measured in the urine.<br/>Pharmacokinetics in Special Clinical Situations:<br/>Children and the Elderly: No relevant age-related changes have been observed in the pharmacokinetics of mefloquine. Therefore, the dosage for children has been extrapolated from the recommended adult dose. No pharmacokinetic studies have been performed in patients with renal insufficiency since only a small proportion of the drug is eliminated renally. Mefloquine and its main metabolite are not appreciably removed by hemodialysis. No special chemoprophylactic dosage adjustments are indicated for dialysis patients to achieve concentrations in plasma similar to those in healthy persons. Although clearance of mefloquine may increase in late pregnancy, in general, pregnancy has no clinically relevant effect on the pharmacokinetics of mefloquine. The pharmacokinetics of mefloquine may be altered in acute malaria. Pharmacokinetic differences have been observed between various ethnic populations. In practice, however, these are of minor importance compared with host immune status and sensitivity of the parasite. During long-term prophylaxis (>2 years), the trough concentrations and the elimination half-life of mefloquine were similar to those obtained in the same population after 6 months of drug use, which is when they reached steady state. In vitro and in vivo studies showed no hemolysis associated with glucose-6-phosphate dehydrogenase deficiency .<br/>Microbiology:<br/>Mechanism of Action: Mefloquine is an antimalarial agent which acts as a blood schizonticide. Its exact mechanism of action is not known.<br/>Activity In Vitro and In Vivo: Mefloquine is active against the erythrocytic stages of Plasmodium species . However, the drug has no effect against the exoerythrocytic (hepatic) stages of the parasite. Mefloquine is effective against malaria parasites resistant to chloroquine .<br/>Drug Resistance: Strains of P. falciparum with decreased susceptibility to mefloquine can be selected in vitro or in vivo. Resistance of P. falciparum to mefloquine has been reported, in areas of multi-drug resistance in South East Asia. Increased incidences of resistance have also been reported in other parts of the world.<br/>Cross Resistance: Cross-resistance between mefloquine and halofantrine and cross-resistance between mefloquine and quinine have been observed in some regions. | lld:dailymed |
| dailymed-drugs:94 | dailymed-instance:clinicalP... | Pharmacodynamics:<br/>Mechanism of Action: The antithrombotic activity of fondaparinux sodium is the result of antithrombin III (ATIII)-mediated selective inhibition of Factor Xa. By selectively binding to ATIII, fondaparinux sodium potentiates (about 300 times) the innate neutralization of Factor Xa by ATIII. Neutralization of Factor Xa interrupts the blood coagulation cascade and thus inhibits thrombin formation and thrombus development. Fondaparinux sodium does not inactivate thrombin (activated Factor II) and has no known effect on platelet function. At the recommended dose, fondaparinux sodium does not affect fibrinolytic activity or bleeding time.<br/>Anti-Xa Activity: The pharmacodynamics/pharmacokinetics of fondaparinux sodium are derived from fondaparinux plasma concentrations quantified via anti-Factor Xa activity. Only fondaparinux can be used to calibrate the anti-Xa assay. (The international standards of heparin or LMWH are not appropriate for this use.) As a result, the activity of fondaparinux sodium is expressed as milligrams (mg) of the fondaparinux calibrator. The anti-Xa activity of the drug increases with increasing drug concentration, reaching maximum values in approximately 3 hours.<br/>Pharmacokinetics:<br/>Absorption: Fondaparinux sodium administered by subcutaneous injection is rapidly and completely absorbed (absolute bioavailability is 100%). Following a single subcutaneous dose of fondaparinux sodium 2.5 mg in young male subjects, Cof 0.34 mg/L is reached in approximately 2 hours. In patients undergoing treatment with fondaparinux sodium injection 2.5 mg, once daily, the peak steady-state plasma concentration is, on average, 0.39-0.50 mg/L and is reached approximately 3 hours post-dose. In these patients, the minimum steady-state plasma concentration is 0.14-0.19 mg/L. In patients with symptomatic deep vein thrombosis and pulmonary embolism undergoing treatment with fondaparinux sodium injection 5 mg (body weight<50 kg), 7.5 mg (body weight 50-100 kg) and 10 mg (body weight>100 kg) once daily, the body-weight-adjusted doses provide similar mean steady-state peaks and minimum plasma concentrations across all body weight categories. The mean peak steady-state plasma concentration is in the range of 1.20-1.26 mg/L. In these patients, the mean minimum steady-state plasma concentration is in the range of 0.46-0.62 mg/L.<br/>Distribution: In healthy adults, intravenously or subcutaneously administered fondaparinux sodium distributes mainly in blood and only to a minor extent in extravascular fluid as evidenced by steady state and non-steady state apparent volume of distribution of 7-11 L. Similar fondaparinux distribution occurs in patients undergoing elective hip surgery or hip fracture surgery. In vitro, fondaparinux sodium is highly (at least 94%) and specifically bound to antithrombin III (ATIII) and does not bind significantly to other plasma proteins (including platelet Factor 4 [PF4]) or red blood cells.<br/>Metabolism: In vivo metabolism of fondaparinux has not been investigated since the majority of the administered dose is eliminated unchanged in urine in individuals with normal kidney function.<br/>Elimination: In individuals with normal kidney function fondaparinux is eliminated in urine mainly as unchanged drug. In healthy individuals up to 75 years of age, up to 77% of a single subcutaneous or intravenous fondaparinux dose is eliminated in urine as unchanged drug in 72 hours. The elimination half-life is 17-21 hours.<br/>Special Populations:<br/>Renal Impairment: Fondaparinux elimination is prolonged in patients with renal impairment since the major route of elimination is urinary excretion of unchanged drug. In patients undergoing prophylaxis following elective hip surgery or hip fracture surgery, the total clearance of fondaparinux is approximately 25% lower in patients with mild renal impairment (creatinine clearance 50 to 80 mL/min), approximately 40% lower in patients with moderate renal impairment (creatinine clearance 30 to 50 mL/min), and approximately 55% lower in patients with severe renal impairment (<30 mL/min) compared to patients with normal renal function. A similar relationship between fondaparinux clearance and extent of renal impairment was observed in DVT treatment patients. (See CONTRAINDICATIONS and WARNINGS: Renal Impairment.)<br/>Hepatic Impairment: The pharmacokinetic properties of fondaparinux have not been studied in patients with hepatic impairment.<br/>Elderly Patients: Fondaparinux elimination is prolonged in patients older than 75 years. In studies evaluating fondaparinux sodium 2.5 mg prophylaxis in hip fracture surgery or elective hip surgery, the total clearance of fondaparinux was approximately 25% lower in patients older than 75 years as compared to patients younger than 65 years. A similar relationship between fondaparinux clearance and age was observed in DVT treatment patients.<br/>Patients Weighing Less Than 50 kg: Total clearance of fondaparinux sodium is decreased by approximately 30% in patients weighing less than 50 kg (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).<br/>Gender: The pharmacokinetic properties of fondaparinux sodium are not significantly affected by gender.<br/>Race: Pharmacokinetic differences due to race have not been studied prospectively. However, studies performed in Asian (Japanese) healthy subjects did not reveal a different pharmacokinetic profile compared to Caucasian healthy subjects. Similarly, no plasma clearance differences were observed between black and Caucasian patients undergoing orthopedic surgery.<br/>Drug Interactions: See PRECAUTIONS: Drug Interactions. | lld:dailymed |
| dailymed-drugs:95 | dailymed-instance:clinicalP... | The mechanism of action of Ridaura (auranofin) is not understood. In patients with adult rheumatoid arthritis, Ridaura may modify disease activity as manifested by synovitis and associated symptoms, and reflected by laboratory parameters such as ESR. There is no substantial evidence, however, that gold-containing compounds induce remission of rheumatoid arthritis. Pharmacokinetics: Pharmacokinetic studies were performed in rheumatoid arthritis patients, not in normal volunteers. Auranofin is rapidly metabolized and intact auranofin has never been detected in the blood. Thus, studies of the pharmacokinetics of auranofin have involved measurement of gold concentrations. Approximately 25% of the gold in auranofin is absorbed. The mean terminal plasma half-life of auranofin gold at steady state was 26 days (range 21 to 31 days; n=5). The mean terminal body half-life was 80 days (range 42 to 128; n=5). Approximately 60% of the absorbed gold (15% of the administered dose) from a single dose of auranofin is excreted in urine; the remainder is excreted in the feces. In clinical studies, steady state blood-gold concentrations are achieved in about three months. In patients on 6 mg auranofin/day, mean steady state blood-gold concentrations were 0.68��0.45 mcg/mL (n=63 patients). In blood, approximately 40% of auranofin gold is associated with red cells, and 60% associated with serum proteins. In contrast, 99% of injectable gold is associated with serum proteins. Mean blood-gold concentrations are proportional to dose; however, no correlation between blood-gold concentrations and safety or efficacy has been established. | lld:dailymed |
| dailymed-drugs:96 | dailymed-instance:clinicalP... | Mechanism of Action: Ipratropium bromide is an anticholinergic agent that inhibits vagally-mediated reflexes by antagonizing the action of acetylcholine at the cholinergic receptor. In humans, ipratropium bromide has anti-secretory properties and, when applied locally, inhibits secretions from the serous and seromucous glands lining the nasal mucosa. Ipratropium bromide is a quaternary amine that minimally crosses the nasal and gastrointestinal membrane and the blood-brain barrier, resulting in a reduction of the systemic anticholinergic effects (e.g., neurologic, ophthalmic, cardiovascular, and gastrointestinal effects) that are seen with tertiary anticholinergic amines.<br/>Pharmacokinetics:<br/>Absorption: Ipratropium bromide is poorly absorbed into the systemic circulation following oral administration (2 to 3%). Less than 20% of an 84 mcg per nostril dose was absorbed from the nasal mucosa of normal volunteers, induced-cold patients, or perennial rhinitis patients.<br/>Distribution: Ipratropium bromide is minimally bound (0 to 9% in vitro) to plasma albumin and��-acid glycoprotein. Its blood/plasma concentration ratio was estimated to be about 0.89. Studies in rats have shown that ipratropium bromide does not penetrate the blood-brain barrier.<br/>Metabolism: Ipratropium bromide is partially metabolized to ester hydrolysis products, tropic acid and tropane. These metabolites appear to be inactive based on in vitro receptor affinity studies using rat brain tissue homogenates.<br/>Elimination: After intravenous administration of 2 mg ipratropium bromide to 10 healthy volunteers, the terminal half-life of ipratropium was approximately 1.6 hours. The total body clearance and renal clearance were estimated to be 2,505 and 1,019 ml/min, respectively. The amount of the total dose excreted unchanged in the urine (Ae) within 24 hours was approximately one-half ofthe administered dose.<br/>Pediatrics: Following administration of 42 mcg of ipratropium bromide per nostril two or three times a day in perennial rhinitis patients 6 to 18 years old, the mean amounts of the total dose excreted unchanged in the urine (8.6 to 11.1%) were higher than those reported in adult volunteers or adult perennial rhinitis patients (3.7 to 5.6%). Plasma ipratropium concentrations were relatively low (ranging from undetectable up to 0.49 ng/ml). No correlation of the amount of the total dose excreted unchanged in the urine (Ae) with age or gender was observed in the pediatric population.<br/>Special Populations: Gender does not appear to influence the absorption or excretion of nasally administered ipratropium bromide. The pharmacokinetics of ipratropium bromide have not been studied in patients with hepatic or renal insufficiency or in the elderly.<br/>Drug-Drug Interaction: No specific pharmacokinetic studies were conducted to evaluate potential drug-drug interactions.<br/>Pharmacodynamics: In two single-dose trials (n=17), doses up to 336 mcg of ipratropium bromide did not significantly affect pupillary diameter, heart rate, or systolic/diastolic blood pressure. Similarly, in patients with induced-colds, Ipratropium Bromide Nasal Spray 0.06% (84 mcg/nostril four times a day), had no significant effects on pupillary diameter, heart rate or systolic/diastolic blood pressure. Two nasal provocation trials in perennial rhinitis patients (n=44) using ipratropium bromide nasal spray showed a dose dependent increase in inhibition of methacholine induced nasal secretion with an onset of action within 15 minutes (time of first observation). Controlled clinical trials demonstrated that intranasal fluorocarbon-propelled ipratropium bromide does not alter physiologic nasal functions (e.g., sense of smell, ciliary beat frequency, mucociliary clearance, or the air conditioning capacity of the nose).<br/>Clinical Trials: The clinical trials for Ipratropium Bromide Nasal Spray 0.03% were conducted in patients with nonallergic perennial rhinitis (NAPR) and in patients with allergic perennial rhinitis (APR). APR patients were those who experienced symptoms of nasal hypersecretion and nasal congestion or sneezing when exposed to specific perennial allergens (e.g., dust mites, molds) and were skin test positive to these allergens. NAPR patients were those who experienced symptoms of nasal hypersecretion and nasal congestion or sneezing throughout the year, but were skin test negative to common perennial allergens. In four controlled, four- and eight-week comparisons of Ipratropium Bromide Nasal Spray 0.03% (42 mcg per nostril, two or three times daily) with its vehicle, in patients with allergic or nonallergic perennial rhinitis, there was a statistically significant decrease in the severity and duration of rhinorrhea in the Ipratropium Bromide group throughout the entire study period. An effect was seen as early as the first day of therapy. There was no effect of Ipratropium Bromide Nasal Spray 0.03% on degree of nasal congestion, sneezing, or postnasal drip. The response to Ipratropium Bromide Nasal Spray 0.03% did not appear to be affected by the type of perennial rhinitis (NAPR or APR), age, or gender. No controlled clinical trials directly compared the efficacy of BID versus TID treatment. | lld:dailymed |
| dailymed-drugs:97 | dailymed-instance:clinicalP... | Bumetanide is a loop diuretic with a rapid onset and short duration of action. Pharmacological and clinical studies have shown that 1 mg bumetanide has a diuretic potency equivalent to approximately 40 mg furosemide. The major site of bumetanide action is the ascending limb of the loop of Henle. The mode of action has been determined through various clearance studies in both humans and experimental animals. Bumetanide inhibits sodium reabsorption in the ascending limb of the loop of Henle, as shown by marked reduction of free-water clearance (cH2O) during hydration and tubular free-water reabsorption (TcH2O) during hydropenia. Reabsorption of chloride in the ascending limb is also blocked by bumetanide, and bumetanide is somewhat more chloruretic than natriuretic. Potassium excretion is also increased by bumetanide, in a dose-related fashion. Bumetanide may have an additional action in the proximal tubule. Since phosphate reabsorption takes place largely in the proximal tubule, phosphaturia during bumetanide-induced diuresis is indicative of this additional action. This is further supported by the reduction in the renal clearance of bumetanide by probenecid, associated with diminution in the natriuretic response. This proximal tubular activity does not seem to be related to an inhibition of carbonic anhydrase. Bumetanide does not appear to have a noticeable action on the distal tubule. Bumetanide decreases uric acid excretion and increases serum uric acid. Following oral administration of bumetanide the onset of diuresis occurs in 30 to 60 minutes. Peak activity is reached between 1 and 2 hours. At usual doses (1 to 2 mg) diuresis is largely complete within 4 hours; with higher doses, the diuretic action lasts for 4 to 6 hours. Several pharmacokinetic studies have shown that bumetanide, administered orally or parenterally, is eliminated rapidly in humans, with a half-life of between 1 and 11���2 hours. Plasma protein-binding is in the range of 94% to 96%. Oral administration of carbon-14 labeled bumetanide to human volunteers revealed that 81% of the administered radioactivity was excreted in the urine, 45% of it as unchanged drug. Urinary and biliary metabolites identified in this study were formed by oxidation of the N-butyl side chain. Biliary excretion of bumetanide amounted to only 2% of the administered dose.<br/>Pediatric Pharmacology: Elimination of bumetanide appears to be considerably slower in neonatal patients compared with adults, possibly because of immature renal and hepatobiliary function in this population. Small pharmacokinetic studies of intravenous bumetanide in preterm and full term neonates with respiratory disorders have reported an apparent half-life of approximately 6 hours with a range up to 15 hours and a serum clearance ranging from 0.2 to 1.1 mL/min/kg. In a population of neonates receiving bumetanide for volume overload, mean serum clearance rates were 2.17 mL/min/kg in patients less than 2 months of age and 3.8 mL/min/kg in patients aged 2 to 6 months. Mean serum halflife of bumetanide was 2.5 hours and 1.5 hours in patients aged less than 2 months and those aged 2 to 6 months, respectively. Elimination half-life decreased considerably during the first month of life, from a mean of approximately 6 hours at birth to approximately 2.4 hours at 1 month of age. In preterm neonates, mean serum concentrations following a single 0.05 mg/kg dose ranged from 126 mcg/L at 1 hour to 57 mcg/L at 8 hours. In another study, mean serum concentrations following a single 0.05 mg/kg dose were 338 ng/mL at 30 minutes and 176 ng/mL after 4 hours. A single dose of 0.1 mg/kg produced mean serum levels of 314 ng/mL at 1 hour, and 195 ng/mL at 6 hours. Mean volume of distribution in neonates has been reported to range from 0.26 L/kg to 0.39 L/kg. The degree of protein binding of bumetanide in cord sera from healthy neonates was approximately 97%, suggesting the potential for bilirubin displacement. A study using pooled serafrom critically ill neonates found that bumetanide at concentrations of 0.5 to 50 mcg/mL, but not 0.25 mcg/mL, caused a linear increase in unbound bilirubin concentrations. In 56 infants aged 4 days to 6 months, bumetanide doses ranging from 0.005 mg/kg to 0.1 mg/kg were studied for pharmacodynamic effect. Peak bumetanide excretion rates increased linearly with increasing doses of drug. Maximal diuretic effect was observed at a bumetanide excretion rate of about 7 mcg/kg/hr, corresponding to doses of 0.035 to 0.040 mg/kg. Higher doses produced a higher bumetanide excretion rate but no increase in diuretic effect. Urine flow rate peaked during the first hour after drug administration in 80% of patients and by 3 hours in all patients.<br/>Geriatric Pharmacology: In a group of ten geriatric subjects between the ages of 65 and 73 years, total bumetanide clearance was significantly lower (1.8��0.3 mL/min���kg) compared with younger subjects (2.9��0.2 mL/min���kg) after a single oral bumetanide 0.5 mg dose. Maximum plasma concentrations were higher in geriatric subjects (16.9��1.8 ng/mL) compared with younger subjects (10.3��1.5 ng/mL). Urine flow rate and total excretion of sodium and potassium were increased less in the geriatric subjects compared with younger subjects, although potassium excretion and fractional sodium excretion were similar between the two age groups. Nonrenal clearance, bioavailability, and volume of distribution were not significantly different between the two groups. | lld:dailymed |
| dailymed-drugs:98 | dailymed-instance:clinicalP... | Although the precise mechanism of action of hydralazine is not fully understood, the major effects are on the cardiovascular system. Hydralazine apparently lowers blood pressure by exerting a peripheral vasodilating effect through a direct relaxation of vascular smooth muscle. Hydralazine, by altering cellular calcium metabolism, interferes with the calcium movements within the vascular smooth muscle that are responsible for initiating or maintaining the contractile state. The peripheral vasodilating effect of hydralazine results in decreased arterial blood pressure (diastolic more than systolic); decreased peripheral vascular resistance; and an increased heart rate, stroke volume, and cardiac output. The preferential dilatation of arterioles, as compared to veins, minimizes postural hypotension and promotes the increase in cardiac output. Hydralazine usually increases renin activity in plasma, presumably as a result of increased secretion of renin by the renal juxtaglomerular cells in response to reflex sympathetic discharge. This increase in renin activity leads to the production of angiotensin II, which then causes stimulation of aldosterone and consequent sodium reabsorption. Hydralazine also maintains or increases renal and cerebral blood flow. Hydralazine hydrochloride is rapidly absorbed after oral administration, and peak plasma levels are reached at 1-2 hours. Plasma levels of apparent hydralazine decline with a half-life of 3-7 hours. Binding to human plasma protein is 87%. Plasma levels of hydralazine vary widely among individuals. Hydralazine is subject to polymorphic acetylation; slow acetylators generally have higher plasma levelsof hydralazine and require lower doses to maintain control of blood pressure. Hydralazine undergoes extensive hepatic metabolism; it is excreted mainly in the form of metabolites in the urine. | lld:dailymed |
| dailymed-drugs:99 | dailymed-instance:clinicalP... | Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase Ainhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A. Corticosteroids are capable of producing a rise in intraocular pressure. | lld:dailymed |
| dailymed-drugs:669 | dailymed-instance:clinicalP... | Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase Ainhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A. Corticosteroids are capable of producing a rise in intraocular pressure. | lld:dailymed |
| dailymed-drugs:2235 | dailymed-instance:clinicalP... | Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase Ainhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A. Corticosteroids are capable of producing a rise in intraocular pressure. | lld:dailymed |
| dailymed-drugs:100 | dailymed-instance:clinicalP... | Mechanism of Action: Metformin is an antihyperglycemic agent which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.<br/>Pharmacokinetics:<br/>Absorption and Bioavailability: Two pharmacokinetic studies have been performed in healthy volunteers to evaluate the bioavailability of RIOMET in comparison with the commercially available metformin tablets under fasting and fed conditions (study 1 and study 2). A third pharmacokinetic study (study 3) assessed effects of food on absorption of RIOMET . The rate and extent of absorption of RIOMET was found to be comparable to that of Metformin tablets under fasting or fed conditions (see Table 1). The food-effect study (study 3) assessed the effects of a high fat/high calorie meal and a low fat/low calorie meal on the bioavailability of RIOMET in comparison with administration in the fasted state, in healthy volunteers. The extent of absorption was increased by 21% and 17% with the low fat/low calorie meal and the high fat/high calorie meal, respectively, compared with the administration in the fasted state. The rate and extent of absorption with high fat/high calorie and low fat/low calorie meal were similar. The mean twas 2.5 hours under fasting conditions as compared to 3.9 hours with both low fat/ low calorie meal and high fat/high calorie meals (see Table 2). Studies using single oral doses of metformin tablet formulations 500 mg to 1500 mg, and 850 mg to 2550 mg, indicate that there is a lack of dose proportionality with increasing doses, which is due to decreased absorption rather than an alteration in elimination.<br/>Distribution: The apparent volume of distribution (V/F) of metformin following single oral doses of a 850 mg tablet averaged 654��358 L. Metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. Metformin partitions into erythrocytes, most likely as a function of time. At usual clinical doses and dosing schedules of metformin, steady state plasma concentrations are reached within 24-48 hours and are generally<1��g/mL. During controlled clinical trials of metformin, maximum metformin plasma levels did not exceed 5��g/mL, even at maximum doses.<br/>Metabolism and Elimination: Intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. Renal clearance (see Table 3) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. Following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. In blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution.<br/>Special Populations: | lld:dailymed |
| dailymed-drugs:101 | dailymed-instance:clinicalP... | DDAVP contains as active substance desmopressin acetate, a synthetic analogue of the natural hormone arginine vasopressin. One mL (0.1 mg) of intranasal DDAVP has an antidiuretic activity of about 400 IU; 10 mcg of desmopressin acetate is equivalent to 40 IU.<br/>Human Pharmacokinetics: DDAVP is mainly excreted in the urine. A pharmacokinetic study conducted in healthy volunteers and patients with mild, moderate, and severe renal impairment (n=24, 6 subjects in each group) receiving single dose desmopressin acetate (2mcg) injection demonstrated a difference in DDAVP terminal half-life. Terminal half-life significantly increased from 3 hours in normal healthy patients to 9 hours in patients with severe renal impairment. | lld:dailymed |
| dailymed-drugs:102 | dailymed-instance:clinicalP... | Potassium Chloride in Lactated Ringer's and 5% Dextrose Injection, USP have value as a source of water, electrolytes, and calories. It is capable of inducing diuresis depending on the clinical condition of the patient. Potassium Chloride in Lactated Ringer's and 5% Dextrose Injection, USP produce a metabolic alkalinizing effect. Lactate ions are metabolized ultimately to carbon dioxide and water, which requires the consumption of hydrogen cations. | lld:dailymed |
| dailymed-drugs:104 | dailymed-instance:clinicalP... | Studies have shown that following intravenous administration of cefazolin to normal volunteers mean serum concentrations peaked at approximately 185 mcg/ml and were approximately 4 mcg/mL at 8 hours for a 1 gram dose. The serum half-life for cefazolin is approximately 1.8 hours following IV administration. In a study (using normal volunteers) of constant intravenous infusion with dosages of 3.5 mg/kg for 1 hour (approximately 250 mg) and 1.5 mg/kg the next 2 hours (approximately 100 mg), cefazolin produced a steady serum concentration at the third hour of approximately 28 mcg/mL. Studies in patients hospitalized with infections indicate that cefazolin produces mean peak serum concentrations approximately equivalent to those seen in normal volunteers. Bile concentrations in patients without obstructive biliary disease can reach or exceed serum concentrations by up to five times; however, in patients with obstructive biliary disease, bile concentrations of cefazolin are considerably lower than serum concentrations (<1 mcg/mL). In synovial fluid, the cefazolin concentration becomes comparable to that reached in serum at about 4 hours after drug administration. Studies of cord blood show prompt transfer of cefazolin across the placenta. Cefazolin is present in very low concentrations in the milk of nursing mothers. Cefazolin is excreted unchanged in the urine. In the first 6 hours approximately 60% of the drug is excreted in the urine and this increases to 70% to 80% within 24 hours. In patients undergoing peritoneal dialysis (2 l/hr, Cefazolin produced mean serum levels of approximately 10 and 30 mcg/mL after 24 hours' instillation of a dialyzing solution containing 50 mgi/l and 150 mg/l, respectively. Mean peak levels were 29 mcg/mL (range 13-44 mcg/ml) with 50 mg/l (three patients), and 72 mcg/mL (range 26 -142 mcg/mL) with 150 mg/I (six patients). Intraperitoneal administration of Cefazolin is usually well tolerated. Controlled studies on adult normal volunteers, receiving 1 gram 4 times a day for 10 days, monitoring CBC, AST (SGOT), ALT (SGPT), bilirubin, alkaline phosphatase, BUN, creatinine and urinalysis, indicated no clinically significant changes attributed to cefazolin.<br/>Microbiology: In vitro tests demonstrate that the bactericidal action of cephalosporins results from inhibition of cell wall synthesis. Cefazolin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:<br/>Aerobic Gram-positive microorganisms:: Staphylococcus aureus (including penicillinase-producing strains) Staphylococcus epidermidis Streptococcus pneumoniae Streptococcus pyogenes and other strains of Streptococci NOTE: Methicillin-resistant staphylococci are uniformly resistant to cefazolin. Many Enterococcus strains are resistant to cefazolin.<br/>Aerobic Gram-negative microorganisms:: Escherichia coli Haemophilus influenzae Klebsiella species Proteus mirabilis NOTE: Most strains of indole positive Proteus (Proteus vulgaris), Enterobacter cloacae, Morganella morganii and Providencia rettgeri are resistant. Serratia, Pseudomonas, Mima and Herellea species are almost uniformly resistant to cefazolin.<br/>Susceptibility Testing::<br/>Dilution Techniques:: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MiCs). These MlCs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MlCs should be determined using a standardized procedure. Standardized procedures are based on a dilution method(broth) or equivalent with standardized inoculum concentrations and standardized concentrations of cefazolin powder. The MlC values should be interpreted according to the following criteria: For Enterobacteriaceae and Staphylococcus spp. A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard cefazolin powder should provide the following MIC values:<br/>Diffusion Techniques:: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedurerequires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30-mcg cefazolin to test the susceptibility of microorganisms to cefazolin. Reports from the laboratory providing results of the standard single-disk susceptibility lest with a 30-mcg cefazolin disk should be interpreted according to the following criteria: For Enterobacteriaceae using the 30-mcg cefazolin disk For Staphylococcus spp. using the 30-mcg cefazolin or the 30-mcg cephalothin disks Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for cefazolin. As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30-mcg cefazolin disk should provide the following zone diameters in this laboratory test quality control strain: | lld:dailymed |
| dailymed-drugs:105 | dailymed-instance:clinicalP... | Pharmacodynamics: Diclofenac sodium is one of a series of phenylacetic acids that has demonstrated anti-inflammatory and analgesic properties in pharmacological studies. It is thought to inhibit the enzyme cyclooxygenase, which is essential in the biosynthesis of prostaglandins.<br/>Animal Studies: Prostaglandins have been shown in many animal models to be mediators of certain kinds of intraocular inflammation. In studies performed in animal eyes, prostaglandins have been shown to produce disruption of the blood-aqueous humor barrier, vasodilation, increased vascular permeability, leukocytosis, and increased intraocular pressure.<br/>Pharmacokinetics: Results from a bioavailability study established that plasma levels of diclofenac following ocular instillation of two drops of diclofenac sodium ophthalmic solution to each eye were below the limit of quantification (10 ng/mL) over a 4 hour period. This study suggests that limited, if any, systemic absorption occurs with diclofenac sodium ophthalmic solution.<br/>Clinical Trials:<br/>Postoperative Anti-Inflammatory Effects: In two double-masked, controlled, efficacy studies of postoperative inflammation, a total of 206 cataract patients were treated with diclofenac sodium ophthalmic solution and 103 patients were treated with vehicle placebo. Diclofenac sodium ophthalmic solution was favored over vehicle placebo over a 2-week period for the clinical assessments of inflammation as measured by anterior chamber cells and flare. In double-masked, controlled, studies of corneal refractive surgery (radial keratotomy (RK) and laser photorefractive keratectomy (PRK)) patients were treated with diclofenac sodium ophthalmic solution and/or vehicle placebo. The efficacy of diclofenac sodium ophthalmic solution given before and shortly after surgery was favored over vehicle placebo during the 6 hour period following surgery for the clinical assessments of pain and photophobia. Patients were permitted to use a hydrogel soft contact lens with diclofenac sodium ophthalmic solution for up to three days after PRK. | lld:dailymed |
| dailymed-drugs:106 | dailymed-instance:clinicalP... | Microbiology: Erythromycin inhibits protein synthesis without affecting nucleic acid synthesis. Erythromycin is usually active against the following organisms in vitro and in clinical infections: Streptococcus pyogenes (group A��-hemolytic), Alpha-hemolytic streptococci (viridans group); Staphylococcus aureus, including penicillinase-producing strains (methicillin-resistant staphylococci are uniformly resistant to erythromycin); Streptococcus pneumoniae; Mycoplasma pneumoniae (Eaton Agent, PPLO); Haemophilus influenzae (not all strains of this organism are susceptible at the erythromycin concentrations ordinarily achieved); Treponema pallidum; Corynebacterium diphtheriae; Neisseria gonorrhoeae; Chlamydia trachomatis. | lld:dailymed |
| dailymed-drugs:107 | dailymed-instance:clinicalP... | NOLVADEX is a nonsteroidal agent that has demonstrated potent antiestrogenic properties in animal test systems. The antiestrogenic effects may be related to its ability to compete with estrogen for binding sites in target tissues such as breast. Tamoxifen inhibits the induction of rat mammary carcinoma induced by dimethylbenzanthracene (DMBA) and causes the regression of already established DMBA-induced tumors. In this rat model, tamoxifen appears to exert its antitumor effects by binding the estrogen receptors. In cytosols derived from human breast adenocarcinomas, tamoxifen competes with estradiol for estrogen receptor protein.<br/>Absorption and Distribution:: Following a single oral dose of 20 mg tamoxifen, an average peak plasma concentration of 40 ng/mL (range 35 to 45 ng/mL) occurred approximately 5 hours after dosing. The decline in plasma concentrations of tamoxifen is biphasic with a terminal elimination half-life of about 5 to 7 days. The average peak plasma concentration of N-desmethyl tamoxifen is 15 ng/mL (range 10 to 20 ng/mL). Chronic administration of 10 mg tamoxifen given twice daily for 3 months to patients results in average steady-state plasma concentrations of 120 ng/mL (range 67-183 ng/mL) for tamoxifen and 336 ng/mL (range 148-654 ng/mL) for N-desmethyl tamoxifen. The average steady-state plasma concentrations of tamoxifen and N-desmethyl tamoxifen after administration of 20 mg tamoxifen once daily for 3 months are 122 ng/mL (range 71-183 ng/mL) and 353 ng/mL (range 152-706 ng/mL), respectively. After initiation of therapy, steady state concentrations for tamoxifen are achieved in about 4 weeks and steady-state concentrations for N-desmethyl tamoxifen are achieved in about 8 weeks, suggesting a half-life of approximately 14 days for this metabolite. In a steady-state, crossover study of 10 mg NOLVADEX tablets given twice a day vs. a 20 mg NOLVADEX tablet given once daily, the 20 mg NOLVADEX tablet was bioequivalent to the 10 mg NOLVADEXtablets.<br/>Metabolism:: Tamoxifen is extensively metabolized after oral administration. N-desmethyl tamoxifen is the major metabolite found in patients' plasma. The biological activity of N-desmethyl tamoxifen appears to be similar to that of tamoxifen. 4-Hydroxytamoxifen and a side chain primary alcohol derivative of tamoxifen have been identified as minor metabolites in plasma. Tamoxifen is a substrate of cytochrome P-450 3A, 2C9 and 2D6, and an inhibitor of P-glycoprotein.<br/>Excretion:: Studies in women receiving 20 mg ofC tamoxifen have shown that approximately 65% of the administered dose was excreted from the body over a period of 2 weeks with fecal excretion as the primary route of elimination. The drug is excreted mainly as polar conjugates, with unchanged drug and unconjugated metabolites accounting for less than 30% of the total fecal radioactivity.<br/>Special Populations:: The effects of age, gender and race on the pharmacokinetics of tamoxifen have not been determined. The effects of reduced liver function on the metabolism and pharmacokinetics of tamoxifen have not been determined.<br/>Pediatric Patients:: The pharmacokinetics of tamoxifen and N-desmethyl tamoxifen were characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 27 female pediatric patients aged 2 to 10 years enrolled in a study designed to evaluate the safety, efficacy, and pharmacokinetics of NOLVADEX in treating McCune-Albright Syndrome. Rich data from two tamoxifen citrate pharmacokinetic trials in which 59 postmenopausal women with breast cancer completed the studies were included in the analysis to determine the structuralpharmacokinetic model for tamoxifen. A one-compartment model provided the best fit to the data. In pediatric patients, an average steady state peak plasma concentration (C,) and AUC were of 187 ng/mL and 4110 ng hr/mL, respectively, and C,occurred approximately 8 hours after dosing. Clearance (CL/F) as body weight adjusted in female pediatric patients was approximately 2.3-fold higher than in female breast cancer patients. In the youngest cohort of female pediatric patients (2-6 year olds), CL/F was 2.6-fold higher; in the oldest cohort (7-10.9 year olds) CL/F was approximately 1.9-fold higher. Exposure to N-desmethyl tamoxifen was comparable between the pediatric and adult patients. The safety and efficacy of NOLVADEX for girls aged two to 10 years with McCune-Albright Syndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of NOLVADEX therapy in girls have not been established. In adults treated with NOLVADEX an increase in incidence of uterine malignancies, stroke and pulmonary embolism has been noted .<br/>Drug-Drug Interactions:: In vitro studies showed that erythromycin, cyclosporin, nifedipine and diltiazem competitively inhibited formation of N-desmethyl tamoxifen with apparent Kof 20, 1, 45 and 30��M, respectively. The clinical significance of these in vitro studies is unknown. Tamoxifen reduced the plasma concentration of letrozole by 37% when these drugs were co-administered. Rifampin, a cytochrome P-450 3A4 inducer reduced tamoxifen AUC and Cby 86% and 55%, respectively. Aminoglutethimide reduces tamoxifen and N-desmethyl tamoxifen plasma concentrations. Medroxyprogesterone reduces plasma concentrations of N-desmethyl, but not tamoxifen. In the anastrozole adjuvant trial, co-administration of anastrozole and NOLVADEX in breast cancer patients reduced anastrozole plasma concentration by 27% compared to those achieved with anastrozole alone; however, the coadministration did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen . NOLVADEX should not be co-administered with anastrozole.<br/>Clinical Studies:<br/>Metastatic Breast Cancer::<br/>Adjuvant Breast Cancer::<br/>Ductal Carcinoma in Situ:: NSABP B-24, a double-blind, randomized trial included women with ductal carcinoma in situ (DCIS). This trial compared the addition of NOLVADEX or placebo to treatment with lumpectomy and radiation therapy for women with DCIS. The primary objective was to determine whether 5 years of NOLVADEX therapy (20 mg/day) would reduce the incidence of invasive breast cancer in the ipsilateral (the same) or contralateral (the opposite) breast. In this trial 1,804 women were randomized to receive either NOLVADEX or placebo for 5 years: 902 women were randomized to NOLVADEX 10 mg tablets twice a day and 902 women were randomized to placebo. As of December 31, 1998, follow-up data were available for 1,798 women and the median duration of follow-up was 74 months. The NOLVADEX and placebo groups were well balanced for baseline demographic and prognostic factors. Over 80% of the tumors were less than or equal to 1 cm in their maximum dimension, were not palpable, and were detected by mammography alone. Over 60% of the study population was postmenopausal. In 16% of patients, the margin of the resected specimen was reported as being positive after surgery. Approximately half of the tumors were reported to contain comedo necrosis. For the primary endpoint, the incidence of invasive breast cancer was reduced by 43% among women assigned to NOLVADEX (44 cases - NOLVADEX, 74 cases - placebo; p=0.004; relative risk (RR)=0.57, 95% CI: 0.39-0.84). No data are available regarding the ER status of the invasive cancers. The stage distribution of the invasive cancers at diagnosis was similar to that reported annually in the SEER data base. Results are shown in Table 1. For each endpoint the following results are presented: the number of events and rate per 1,000 women per year for the placebo and NOLVADEX groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between NOLVADEX and placebo. Relative risks less than 1.0 indicate a benefit of NOLVADEX therapy. The limits of the confidence intervals can be used to assess the statisticalsignificance of the benefits of NOLVADEX therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit exists. Survival was similar in the placebo and NOLVADEX groups. At 5 years from study entry, survival was 97% for both groups.<br/>Reduction in Breast Cancer Incidence in High Risk Women:: The Breast Cancer Prevention Trial (BCPT, NSABP P-1) was a double-blind, randomized, placebo-controlled trial with a primary objective to determine whether 5 years of NOLVADEX therapy (20 mg/day) would reduce the incidence of invasive breast cancer in women at high risk for the disease . Secondary objectives included an evaluation ofthe incidence of ischemic heart disease; the effects on the incidence of bone fractures; and other events that might be associated with the use of NOLVADEX, including: endometrial cancer, pulmonary embolus, deep vein thrombosis, stroke, and cataract formation and surgery . The Gail Model was used to calculate predicted breast cancer risk for women who were less than 60 years of age and did not have lobular carcinoma in situ (LCIS). The following risk factors were used: age; number of first-degree female relatives with breast cancer; previous breast biopsies; presence or absence of atypical hyperplasia; nulliparity; age at first live birth; and age at menarche. A 5-year predicted risk of breast cancer of���1.67% was required for entry into the trial. In this trial, 13,388 women of at least 35 years of age were randomized to receive either NOLVADEX or placebo for five years. The median duration of treatment was 3.5 years. As of January 31, 1998, follow-up data is available for 13,114 women. Twenty-seven percent of women randomized to placebo (1,782) and 24% of women randomized to NOLVADEX (1,596) completed 5 years of therapy. The demographic characteristics of women on the trial with follow-up data are shown in Table 2. Results are shown in Table 3. After a median follow-up of 4.2 years, the incidence of invasive breast cancer was reduced by 44% among women assigned to NOLVADEX (86 cases-NOLVADEX, 156 cases-placebo; p<0.00001; relative risk (RR)=0.56, 95% CI: 0.43-0.72). A reduction in the incidence of breast cancer was seen in each prospectively specified age group (���49, 50-59,���60), in women with or without LCIS, and in each of the absolute risk levels specified in Table 3. A non-significant decrease in the incidence of ductal carcinoma in situ (DCIS) was seen (23-NOLVADEX, 35-placebo; RR=0.66; 95% CI: 0.39-1.11). There was no statistically significant difference in the number of myocardial infarctions, severe angina, or acute ischemic cardiac events between the two groups (61-NOLVADEX, 59-placebo; RR=1.04, 95% CI: 0.73-1.49). No overall difference in mortality (53 deaths in NOLVADEX group vs. 65 deaths in placebo group) was present. No difference in breast cancer-related mortality was observed (4 deaths in NOLVADEX group vs. 5 deaths in placebo group). Although there was a non-significant reduction in the number of hip fractures (9 on NOLVADEX, 20 on placebo) in the NOLVADEX group, the number of wrist fractures was similar in the two treatment groups (69 on NOLVADEX, 74 on placebo). A subgroup analysis of the P-1 trial, suggests a difference in effect in bone mineral density (BMD) related to menopausal status in patients receiving NOLVADEX. In postmenopausal women there was no evidence of bone loss of the lumbar spine and hip. Conversely, NOLVADEX was associated with significant bone loss of the lumbar spine and hip in premenopausal women. The risks of NOLVADEX therapy include endometrial cancer, DVT, PE, stroke, cataract formation and cataract surgery (See Table 3). In the NSABP P-1 trial, 33 cases of endometrial cancer were observed in the NOLVADEX group vs. 14 in the placebo group (RR=2.48, 95% CI: 1.27-4.92). Deep vein thrombosis was observed in 30 women receiving NOLVADEX vs. 19 in women receiving placebo (RR=1.59, 95% CI: 0.86-2.98). Eighteen cases of pulmonary embolism were observed in the NOLVADEX group vs. 6 in the placebo group (RR=3.01, 95% CI: 1.15-9.27). There were 34 strokes on the NOLVADEX arm and 24 on theplacebo arm (RR=1.42; 95% CI: 0.82-2.51). Cataract formation in women without cataracts at baseline was observed in 540 women taking NOLVADEX vs. 483 women receiving placebo (RR=1.13, 95% CI: 1.00-1.28). Cataract surgery (with or without cataracts at baseline) was performed in 201 women taking NOLVADEX vs. 129 women receiving placebo (RR=1.51, 95% CI: 1.21-1.89) . Table 3 summarizes the major outcomes of the NSABP P-1 trial. For each endpoint, the following results are presented: the number of events and rate per 1000 women per year for the placebo and NOLVADEX groups; and the relative risk (RR) and its associated 95% confidence interval (CI) between NOLVADEX and placebo. Relative risks less than 1.0 indicate a benefit of NOLVADEX therapy. The limits of the confidence intervals can be used to assess the statistical significance of the benefits or risks of NOLVADEX therapy. If the upper limit of the CI is less than 1.0, then a statistically significant benefit exists. For most participants, multiple risk factors would have been required for eligibility. This table considers risk factors individually, regardless of other co-existing risk factors, for women who developed breast cancer. The 5-year predicted absolute breast cancer risk accounts for multiple risk factors in an individual and should provide the best estimate of individual benefit . Table 4 describes the characteristics of the breast cancers in the NSABP P-1 trial and includes tumor size, nodal status, ER status. NOLVADEX decreased the incidence of small estrogen receptor positive tumors, but did not alter the incidence of estrogen receptor negative tumors or larger tumors. Interim results from 2 trials in addition to the NSABP P-1 trial examining the effects of tamoxifen in reducing breast cancer incidence have been reported. The first was the Italian Tamoxifen Prevention trial. In this trial women between the ages of 35 and 70, who had had a total hysterectomy, were randomized to receive 20 mg tamoxifen or matching placebo for 5 years. The primary endpoints were occurrence of, and death from, invasive breast cancer. Women without any specific risk factors for breast cancer were to be entered. Between 1992 and 1997, 5408 women were randomized. Hormone Replacement Therapy (HRT) was used in 14% of participants. The trial closed in 1997 due to the large number of dropouts during the first year of treatment (26%). After 46 months of follow-up there were 22 breast cancers in women on placebo and 19 in women on tamoxifen. Although no decrease in breast cancer incidence was observed, there was a trend for a reduction in breast cancer among women receiving protocol therapy for at least 1 year (19-placebo, 11- tamoxifen). The small numbers of participants along with the low level of risk in this otherwise healthy group precluded an adequate assessment of the effect of tamoxifen in reducing the incidence of breast cancer. The second trial, the Royal Marsden Trial (RMT) was reported as an interim analysis. The RMT was begun in 1986 as a feasibility study of whether larger scale trials could be mounted. The trial was subsequently extended to a pilot trial to accrue additional participants to further assess the safety of tamoxifen. Twenty-four hundred and seventy-one women were entered between 1986 and 1996; they were selected on the basis of a family history of breast cancer. HRT was usedin 40% of participants. In this trial, with a 70 month median follow-up, 34 and 36 breast cancers (8 noninvasive, 4 on each arm) were observed among women on tamoxifen and placebo, respectively. Patients in this trial were younger than those in the NSABP P-1 trial and may have been more likely to develop ER (-) tumors, which are unlikely to be reduced in number by tamoxifen therapy. Although women were selected on the basis of family history and were thought to have a high risk of breast cancer, few events occurred, reducing the statistical power of the study. These factors are potential reasons why the RMT may not have provided an adequate assessment of the effectiveness of tamoxifen in reducing the incidence of breast cancer. In these trials, an increased number of cases of deep vein thrombosis, pulmonary embolus, stroke, and endometrial cancer were observed on the tamoxifen arm compared to the placebo arm. The frequency of events was consistent with the safety data observed in the NSABP P-1 trial.<br/>McCune-Albright Syndrome:: A single, uncontrolled multicenter trial of NOLVADEX 20 mg once a day was conducted in a heterogenous group of girls with McCune-Albright Syndrome and precocious puberty manifested by physical signs of pubertal development, episodes of vaginal bleeding and/or advanced bone age (bone age of at least 12 months beyond chronological age). Twenty-eight female pediatric patients, aged 2 to 10 years, were treated for up to 12 months. Effect of treatment on frequency of vaginal bleeding, bone age advancement, and linear growth rate was assessed relative to prestudy baseline. NOLVADEX treatment was associated with a 50% reduction in frequency of vaginal bleeding episodes by patient or family report (mean annualized frequency of3.56 episodes at baseline and 1.73 episodes on-treatment). Among the patients who reported vaginal bleeding during the pre-study period, 62% (13 out of 21 patients) reported no bleeding for a 6-month period and 33% (7 out of 21 patients) reported no vaginal bleeding for the duration of the trial. Not all patients improved on treatment and a few patients not reporting vaginal bleeding in the 6 months prior to enrollment reported menses on treatment. NOLVADEX therapy was associated with a reduction in mean rate of increase of bone age. Individual responses with regard to bone age advancement were highly heterogeneous. Linear growth rate was reduced during the course of NOLVADEX treatment in a majority of patients (mean change of 1.68 cm/year relative to baseline; change from 7.47 cm/year at baseline to 5.79 cm/year on study). This change was not uniformly seen across all stages of bone maturity; all recorded response failures occurred in patients with bone ages less than 7 years at screening. Mean uterine volume increased after 6 months of treatment and doubled at the end of the one-year study. A causal relationship has not been established; however, as an increase in the incidence of endometrial adenocarcinoma and uterine sarcoma has been noted in adults treated with NOLVADEX , continued monitoring of McCune-Albright patients treated with NOLVADEX for long-term uterine effects is recommended. The safety and efficacy of NOLVADEX for girls aged two to 10 years with McCune-AlbrightSyndrome and precocious puberty have not been studied beyond one year of treatment. The long-term effects of NOLVADEX therapy in girls have not been established. | lld:dailymed |
| dailymed-drugs:108 | dailymed-instance:clinicalP... | Carvedilol is a racemic mixture in which nonselective��-adrenoreceptor blocking activity is present in the S(-) enantiomer and��-adrenergic blocking activity is present in both R(+) and S(-) enantiomers at equal potency. Carvedilol has no intrinsic sympathomimetic activity.<br/>Pharmacokinetics:<br/>Absorption: Carvedilol is rapidly and extensively absorbed following oral administration of immediate-release carvedilol tablets, with an absolute bioavailability of approximately 25% to 35% due to a significant degree of first-pass metabolism. COREG CR extended-release capsules have approximately 85% of the bioavailability of immediate-release carvedilol tablets. For corresponding dosages (see DOSAGE AND ADMINISTRATION), the exposure (area under the curve [AUC], C, trough concentration) of carvedilol as COREG CR extended-release capsules is equivalent to those of immediate-release carvedilol tablets when both are administered with food. The absorption of carvedilol from COREG CR is slower and more prolonged compared to the immediate-release carvedilol tablet with peak concentrations achieved approximately 5 hours after administration. Plasma concentrations of carvedilol increase in a dose-proportional manner over the dosage range of COREG CR 10 to 80 mg. Within-subject and between-subject variability for AUC and Cis similar for COREG CR and immediate-release carvedilol.<br/>Effect of Food: Administration of COREG CR with a high-fat meal resulted in increases (~20%) in AUC and Ccompared to COREG CR administered with a standard meal. Decreases in AUC (27%) and C(43%) were observed when COREG CR was administered in the fasted state compared to administration after a standard meal. COREG CR should be taken with food. In a study with adult subjects, sprinkling the contents of the COREG CR capsule on applesauce did not appear to have a significant effect on overall exposure (AUC) compared to administration of the intact capsule following a standard meal but did result in a decrease in C(18%).<br/>Distribution: Carvedilol is more than 98% bound to plasma proteins, primarily with albumin. The plasma-protein binding is independent of concentration over the therapeutic range. Carvedilol is a basic, lipophilic compound with a steady-state volume of distribution of approximately 115 L, indicating substantial distribution into extravascular tissues.<br/>Metabolism and Excretion: Carvedilol is extensively metabolized. Following oral administration of radiolabelled carvedilol to healthy volunteers, carvedilol accounted for only about 7% of the total radioactivity in plasma as measured by AUC. Less than 2% of the dose was excreted unchanged in the urine. Carvedilol is metabolized primarily by aromatic ring oxidation and glucuronidation. The oxidative metabolites are further metabolized by conjugation via glucuronidation and sulfation. The metabolites of carvedilol are excreted primarily viathe bile into the feces. Demethylation and hydroxylation at the phenol ring produce 3 active metabolites with��-receptor blocking activity. Based on preclinical studies, the 4'-hydroxyphenyl metabolite is approximately 13 times more potent than carvedilol for��-blockade. Compared to carvedilol, the 3 active metabolites exhibit weak vasodilating activity. Plasma concentrations of the active metabolites are about one-tenth of those observed for carvedilol and have pharmacokinetics similar to the parent. Carvedilol undergoes stereoselective first-pass metabolism with plasma levels of R(+)-carvedilol approximately 2 to 3 times higher than S(-)-carvedilol following oral administration of COREG CR in healthy subjects. Apparent clearance is 90 L/h and 213 L/h for R(+)- and S(-)-carvedilol, respectively. The primary P450 enzymes responsible for the metabolism of both R(+) and S(-)-carvedilol in human liver microsomes were CYP2D6 and CYP2C9 and to a lesser extent CYP3A4, 2C19, 1A2, and 2E1. CYP2D6 is thought to be the major enzyme in the 4'- and 5'-hydroxylation of carvedilol, with a potential contribution from 3A4. CYP2C9 is thought to be of primary importance in the O-methylation pathway of S(-)-carvedilol. Carvedilol is subject to the effects of genetic polymorphism with poor metabolizers of debrisoquin (a marker for cytochrome P450 2D6) exhibiting 2- to 3-fold higher plasma concentrations of R(+)-carvedilol compared to extensive metabolizers. In contrast, plasma levels of S(-)-carvedilol are increased only about 20% to 25% in poor metabolizers, indicating this enantiomer is metabolized to a lesser extent by cytochrome P450 2D6 than R(+)-carvedilol. The pharmacokinetics of carvedilol do not appear to be different in poor metabolizers of S-mephenytoin (patients deficient in cytochrome P450 2C19).<br/>Heart Failure: Following administration of immediate-release carvedilol tablets, steady-state plasma concentrations of carvedilol and its enantiomers increased proportionally over the dose range in patients with heart failure. Compared to healthy subjects, heart failure patients had increased mean AUC and Cvalues for carvedilol and its enantiomers, with up to 50% to 100% higher values observed in 6 patients with NYHA class IV heart failure. The mean apparent terminal elimination half-life for carvedilol was similar to that observed in healthy subjects. For corresponding dose levels (see DOSAGE AND ADMINISTRATION), the steady-state pharmacokinetics of carvedilol (AUC, C, trough concentrations) observed after administration of COREG CR to chronic heart failure patients (mild, moderate, and severe) were similar to those observed after administration of immediate-release carvedilol tablets.<br/>Hypertension: For corresponding dose levels (see DOSAGE AND ADMINISTRATION), the pharmacokinetics (AUC, C, and trough concentrations) observed with administration of COREG CR were equivalent (��20%) to those observed with immediate-release carvedilol tablets following repeat dosing in patients with essential hypertension.<br/>Pharmacokinetic Drug-Drug Interactions: Since carvedilol undergoes substantial oxidative metabolism, the metabolism and pharmacokinetics of carvedilol may be affected by induction or inhibition of cytochrome P450 enzymes. The following drug interaction studies were performed with immediate-release carvedilol tablets.<br/>Rifampin: In a pharmacokinetic study conducted in 8 healthy male subjects, rifampin (600 mg daily for 12 days) decreased the AUC and Cof carvedilol by about 70%.<br/>Cimetidine: In a pharmacokinetic study conducted in 10 healthy male subjects, cimetidine (1,000 mg/day) increased the steady-state AUC of carvedilol by 30% with no change in C.<br/>Glyburide: In 12 healthy subjects, combined administration of carvedilol (25 mg once daily) and a single dose of glyburide did not result in a clinically relevant pharmacokinetic interaction for either compound.<br/>Hydrochlorothiazide: A single oral dose of carvedilol 25 mg did not alter the pharmacokinetics of a single oral dose of hydrochlorothiazide 25 mg in 12 patients with hypertension. Likewise, hydrochlorothiazide had no effect on the pharmacokinetics of carvedilol.<br/>Digoxin: Following concomitant administration of carvedilol (25 mg once daily) and digoxin (0.25 mg once daily) for 14 days, steady-state AUC and trough concentrations of digoxin were increased by 14% and 16%, respectively, in 12 hypertensive patients (see PRECAUTIONS, Drug Interactions).<br/>Torsemide: In a study of 12 healthy subjects, combined oral administration of carvedilol 25 mg once daily and torsemide 5 mg once daily for 5 days did not result in any significant differences in their pharmacokinetics compared with administration of the drugs alone.<br/>Warfarin: Carvedilol (12.5 mg twice daily) did not have an effect on the steady-state prothrombin time ratios and did not alter the pharmacokinetics of R(+)- and S(-)-warfarin following concomitant administration with warfarin in 9 healthy volunteers.<br/>Special Populations:<br/>Elderly: Plasma levels of carvedilol average about 50% higher in the elderly compared to young subjects after administration of immediate-release carvedilol.<br/>Hepatic Impairment: No studies have been performed with COREG CR in patients with hepatic impairment. Compared to healthy subjects, patients with cirrhotic liver disease exhibit significantly higher concentrations of carvedilol (approximately 4- to 7-fold) following single-dose therapy with immediate-release carvedilol.<br/>Renal Insufficiency: No studies have been performed with COREG CR in patients with renal insufficiency. Although carvedilol is metabolized primarily by the liver, plasma concentrations of carvedilol have been reported to be increased in patients with renal impairment after dosing with immediate-release carvedilol. Based on mean AUC data, approximately 40% to 50% higher plasma concentrations of carvedilol were observed in hypertensive patients with moderate to severe renal impairment compared to a control group of hypertensive patients with normal renal function. However, the ranges of AUC values were similar for both groups. Changes in mean peak plasma levels were less pronounced, approximately 12% to 26% higher in patients with impaired renal function. Consistent with its high degree of plasma protein binding, carvedilol does not appear to be cleared significantly by hemodialysis.<br/>Pharmacodynamics:<br/>Heart Failure and Left Ventricular Dysfunction Following Myocardial Infarction: The basis for the beneficial effects of carvedilol in patients with heart failure and in patients with left ventricular dysfunction following an acute myocardial infarction is not known. The concentration-response relationship for��-blockade following administration of COREG CR is equivalent (��20%) to immediate-release carvedilol tablets.<br/>Hypertension: The mechanism by which��-blockade produces an antihypertensive effect has not been established. ��-adrenoreceptor blocking activity has been demonstrated in animal and human studies showing that carvedilol (1) reduces cardiac output in normal subjects; (2) reduces exercise- and/or isoproterenol-induced tachycardia; and (3) reduces reflex orthostatic tachycardia. Significant��-adrenoreceptor blocking effect is usually seen within 1 hour of drug administration. ��-adrenoreceptor blocking activity has been demonstrated in human and animal studies, showing that carvedilol (1) attenuates the pressor effects of phenylephrine; (2) causes vasodilation; and (3) reduces peripheral vascular resistance. These effects contribute to the reduction of blood pressure and usually are seen within 30 minutes of drug administration. Due to the��-receptor blocking activity of carvedilol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (1.8%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when immediate-release carvedilol is administered with food at the recommended starting dose and titration increments are closely followed (see DOSAGE AND ADMINISTRATION). In a randomized, double-blind, placebo-controlled trial, the��-blocking effect of COREG CR, as measured by heart rate response to submaximal bicycle ergometry, was shown to be equivalent to that observed with immediate-release carvedilol at steady state in adult patients with essential hypertension. In hypertensive patients with normal renal function, therapeutic doses of carvedilol decreased renal vascular resistance with no change in glomerular filtration rate or renal plasma flow. Changes in excretion of sodium, potassium, uric acid, and phosphorus in hypertensive patients with normal renal function were similar after carvedilol and placebo. Carvedilol has little effect on plasma catecholamines, plasma aldosterone, or electrolyte levels, but it does significantly reduce plasma renin activity when given for at least 4 weeks. It also increases levels of atrial natriuretic peptide. | lld:dailymed |
| dailymed-drugs:109 | dailymed-instance:clinicalP... | PHARMACODYNAMICS: Combination oral contraceptives (COCs) act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increases the difficulty of sperm entry into the uterus) and the endometrium (which reduces the likelihood of implantation). Drospirenone is a spironolactone analogue with antimineralocorticoid activity. Preclinical studies in animals and in vitro have shown that drospirenone has no androgenic, estrogenic, glucocorticoid, or antiglucocorticoid activity. Preclinical studies in animals have also shown that drospirenone has antiandrogenic activity.<br/>PHARMACOKINETICS:<br/>Absorption: The absolute bioavailability of drospirenone (DRSP) from a single entity tablet is about 76%. The absolute bioavailability of ethinyl estradiol (EE) is approximately 40% as a result of presystemic conjugation and first-pass metabolism. The absolute bioavailability of YAZ, which is a combination tablet of drospirenone and ethinyl estradiol stabilized by betadex as a clathrate (molecular inclusion complex), has not been evaluated. The bioavailability of EE is similar when dosed via a betadex clathrate formulation compared to when it is dosed as a free steroid. Serum concentrations of DRSP and EE reached peak levels within1c2 hours after administration of YAZ. The pharmacokinetics of DRSP are dose proportional following single doses ranging from 1���10 mg. Following daily dosing of YAZ, steady state DRSP concentrations were observed after 8 days. There was about 2 to 3 fold accumulation in serum Cmax and AUC (0���24h) values of DRSP following multiple dose administration of YAZ (see TABLE I ). For EE, steady-state conditions are reported during the second half of a treatment cycle. Following daily administration of YAZ serum Cmax and AUC (0���24h) values of EE accumulate by a factor of about 1.5 to 2.0 (see TABLE I ).<br/>Distribution: DRSP and EE serum levels decline in two phases. The apparent volume of distribution of DRSP is approximately 4 L/kg and that of EE is reported to be approximately 4���5 L/kg. DRSP does not bind to sex hormone binding globulin (SHBG) or corticosteroid binding globulin (CBG) but binds about 97% to other serum proteins. Multiple dosing over 3 cycles resulted in no change in the free fraction (as measured at trough levels). EE is reported to be highly but non-specifically bound to serum albumin (approximately 98.5 %) and induces an increase in the serum concentrations of both SHBG and CBG. EE induced effects on SHBG and CBG were not affected by variation of the DRSP dosage in the range of 2 to 3 mg.<br/>Metabolism: The two main metabolites of DRSP found in human plasma were identified to be the acid form of DRSP generated by opening of the lactone ring and the 4,5-dihydrodrospirenone-3-sulfate. These metabolites were shown not to be pharmacologically active. In in vitro studies with human liver microsomes, DRSP was metabolized only to a minor extent mainly by Cytochrome P450 3A4 (CYP3A4). EE has been reported to be subject to presystemic conjugation in both small bowel mucosa and the liver. Metabolism occurs primarily by aromatic hydroxylation but a wide variety of hydroxylated and methylated metabolites are formed. These are present as free metabolites and as conjugates with glucuronide and sulfate. CYP3A4 in the liver is responsible for the 2-hydroxylation which is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation and glucuronidation prior to urinary and fecal excretion.<br/>Excretion: DRSP serum levels are characterized by a terminal disposition phase half-life of approximately 30 hours after both single and multiple dose regimens. Excretion of DRSP was nearly complete after ten days and amounts excreted were slightly higher in feces compared to urine. DRSP was extensively metabolized and only trace amounts of unchanged DRSP were excreted in urine and feces. At least 20 different metabolites were observed in urine and feces. About 38���47% of the metabolites in urine were glucuronide and sulfate conjugates. In feces, about 17���20 % of the metabolites were excreted as glucuronides and sulfates. For EE the terminal disposition phase half-life has been reported to be approximately 24 hours. EE is not excreted unchanged. EE is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic circulation.<br/>Special Populations: | lld:dailymed |
| dailymed-drugs:110 | dailymed-instance:clinicalP... | Pharmacokinetics in Adults: The single- and multiple-dose pharmacokinetics of telbivudine were evaluated in healthy subjects and in patients with chronic hepatitis B. Telbivudine pharmacokinetics are similar between both populations.<br/>Absorption and Bioavailability: Following oral administration of telbivudine 600 mg once-daily in healthy subjects (n=12), steady state peak plasma concentration (C) was 3.69��1.25��g/mL (mean��SD) which occurred between 1 and 4 hours (median 2 hours), AUC was 26.1��7.2��g��h/mL (mean��SD), and trough plasma concentrations (C) were approximately 0.2-0.3��g/mL. Steady state was achieved after approximately 5 to 7 days of once-daily administration with ~1.5-fold accumulation, suggesting an effective half-life of ~15 hours.<br/>Effects of Food on Oral Absorption: Telbivudine absorption and exposure were unaffected when a single 600-mg dose was administered with a high-fat (~55 g), high-calorie (~950 kcal) meal. TYZEKA(telbivudine) may be taken with or without food.<br/>Distribution: In vitro binding of telbivudine to human plasma proteins is low (3.3%). After oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that telbivudine is widely distributed into tissues. Telbivudine was equally partitioned between plasma and blood cells.<br/>Metabolism and Elimination: No metabolites of telbivudine were detected following administration of [C]-telbivudine in humans. Telbivudine is not a substrate, or inhibitor of the cytochrome P450 (CYP450) enzyme system After reaching the peak concentration, plasma concentrations of telbivudine declined in a bi-exponential manner with a terminal elimination half-life (T) of 40 - 49 hours. Telbivudine is eliminated primarily by urinary excretion of unchanged drug. The renal clearance of telbivudine approaches normal glomerular filtration rate suggesting that passive diffusion is the main mechanism of excretion. Approximately 42% of the dose is recovered in the urine over 7 days following a single 600 mg oral dose of telbivudine. Because renal excretion is the predominant route of elimination, patients with moderate to severe renal dysfunction and those undergoing hemodialysis require a dose interval adjustment<br/>Cardiac Safety: In an in vitro hERG model, telbivudine was negative at concentrations up to 10,000��M. In a thorough QTc prolongation clinical study in healthy subjects, telbivudine had no effect on QT intervals or other electrocardiographic parameters after multiple daily doses up to 1800 mg.<br/>Special Populations: Gender: There are no significant gender-related differences in telbivudine pharmacokinetics. Race: There are no significant race-related differences in telbivudine pharmacokinetics. Pediatrics and Geriatrics: Pharmacokinetic studies have not been conducted in children or elderly subjects. Renal Impairment Single-dose pharmacokinetics of telbivudine have been evaluated in patients (without chronic hepatitis B) with various degrees of renal impairment (as assessed by creatinine clearance). Based on the results shown in Table 1, adjustment of the dose interval for TYZEKA is recommended in patients with creatinine clearance of<50 mL/min Renally Impaired Patients on Hemodialysis Hemodialysis (up to 4 hours) reduces systemic telbivudine exposure by approximately 23%. Following dose interval adjustment for creatinine clearance , no additional dose modification is necessary during routine hemodialysis. TYZEKA should be administered after hemodialysis. Hepatic Impairment The pharmacokinetics of telbivudine following a single 600-mg dose have been studied in patients (without chronic hepatitis B) with various degrees of hepatic impairment. There were no changes in telbivudine pharmacokinetics in hepatically impaired subjects compared to unimpaired subjects. Results of these studies indicate that no dosage adjustment is necessary for patients with hepatic impairment.<br/>Drug Interactions: Telbivudine is excreted mainly by passive diffusion so the potential for interactions between telbivudine and other drugs eliminated by renal excretion is low. However, because telbivudine is eliminated primarily by renal excretion, co-administration of telbivudine with drugs that alter renal function may alter plasma concentrations of telbivudine. Drug-drug interaction studies show that lamivudine, adefovir dipivoxil, cyclosporine and pegylated interferon-alfa 2a do not alter telbivudine pharmacokinetics. In addition, telbivudine does not alter the pharmacokinetics of lamivudine, adefovir dipivoxil, or cyclosporine. No definitive conclusion could be drawn regarding the effects of telbivudine on the pharmacokinetics of pegylated interferon-alfa 2a due to the high inter-individual variability of pegylated interferon-alfa 2a concentrations. At concentrations up to 12 times that in humans, telbivudine did not inhibit in vitro metabolism mediated by any of the following human hepatic microsomal cytochrome P450 (CYP) isoenzymes known to be involved in human medicinal product metabolism: 1A2, 2C9, 2C19, 2D26, 2E1, and 3A4. Based on the above results and the known elimination pathway of telbivudine, the potential for CYP450-mediated interactions involving telbivudine with other medicinal products is low. | lld:dailymed |
| dailymed-drugs:111 | dailymed-instance:clinicalP... | Pharmacodynamics: Cevimeline is a cholinergic agonist which binds to muscarinic receptors. Muscarinic agonists in sufficient dosage can increase secretion of exocrine glands, such as salivary and sweat glands and increase tone of the smooth muscle in the gastrointestinal and urinary tracts.<br/>Pharmacokinetics: Absorption: After administration of a single 30 mg capsule, cevimeline was rapidly absorbed with a mean time to peak concentration of 1.5 to 2 hours. No accumulation of active drug or its metabolites was observed following multiple dose administration. When administered with food, there is a decrease in the rate of absorption, with a fasting Tof 1.53 hours and a Tof 2.86 hours after a meal; the peak concentration is reduced by 17.3%. Single oral doses across the clinical dose range are dose proportional. Distribution: Cevimeline has a volume of distribution of approximately 6L/kg and is<20% bound to human plasma proteins. This suggests that cevimeline is extensively bound to tissues; however, the specific binding sites are unknown. Metabolism: Isozymes CYP2D6 and CYP3A3/4 are responsible for the metabolism of cevimeline. After 24 hours, 86.7% of the dose was recovered (16.0% unchanged, 44.5% as cis and trans-sulfoxide, 22.3% of the dose as glucuronic acid conjugate and 4% of the dose as N-oxide of cevimeline). Approximately 8% of the trans-sulfoxide metabolite is then converted into the corresponding glucuronic acid conjugate and eliminated. Cevimeline did not inhibit cytochrome P450 isozymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4. Excretion: The mean half-life of cevimeline is 5+/-1 hours. After 24 hours, 84% of a 30 mg dose of cevimeline was excreted in urine. After seven days, 97% of the dose was recovered in the urine and 0.5% was recovered in the feces. Special Populations: The effects of renal impairment, hepatic impairment, or ethnicity on the pharmacokinetics of cevimeline have not been investigated. | lld:dailymed |
| dailymed-drugs:112 | dailymed-instance:clinicalP... | Pharmacokinetics: Levofloxacin concentration in plasma was measured in 14 healthy adult volunteers during a 16-day course of treatment with IQUIXsolution. The dosing schedule was 1-2 drops per eye once in the morning on Days 1 and 16; 1-2 drops per eye every two hours Days 2 through 8; and 1-2 drops per eye every four hours Days 9 through 15. The mean levofloxacin concentration in plasma 1 hour postdose ranged from 3.13 ng/mL on Day 1 to 10.4 ng/mL on Day 16. Maximum mean levofloxacin concentrations increased from 3.22 ng/mL on Day 1 to 10.9 ng/mL on Day 16, which is more than 400 times lower than those reported after standard oral doses of levofloxacin.Levofloxacin concentration in tears was measured in 100 healthy adult volunteers at various time points following instillation of 2 drops of IQUIXsolution. Mean tear concentration measured 15 minutes after instillation was 757��g/mL.<br/>Microbiology: Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. The mechanism of action of levofloxacin and other fluoroquinolone antimicrobials involves the inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoisomerases), enzymes required for DNA replication, transcription, repair, and recombination.Levofloxacin has in vitro activity against a wide range of Gram-negative and Gram-positive microorganisms and is often bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.Fluoroquinolones, including levofloxacin, differ in chemical structure and mode of action from��-lactam antibiotics and aminoglycosides, and therefore may be active against bacteria resistant to��-lactam antibiotics and aminoglycosides. Additionally,��-lactam antibiotics and aminoglycosides may be active against bacteria resistant to levofloxacin.Resistance to levofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10to 10).Levofloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section: The following in vitro data are also available, but their clinical significance in ophthalmic infections is unknown. The safety and effectiveness of levofloxacin in treating ophthalmological infections due to these microorganisms have not been established in adequate and well-controlled trials.These organisms are considered susceptible when evaluated using systemic breakpoints. However, a correlation between the in vitro systemic breakpoint and ophthalmological efficacy has not been established. The list of organisms is provided as guidance only in assessing the potential treatment of corneal ulcer. Levofloxacin exhibits in vitro minimal inhibitory concentrations (MICs) of 2��g/mL or less (systemic susceptible breakpoint) against most (���90%) strains of the following ocular pathogens:<br/>Clinical Studies: In two randomized, double-masked, multicenter controlled clinical trials of 280 patients with positive cultures, subjects were dosed with IQUIX or ofloxacin 0.3% ophthalmic solution. Dosing occurred on Days 1 through 3 every two hours while awake and 4 and 6 hours after retiring. Dosing occurred on Day 4 through treatment completion 4 times daily while awake. Clinical cure was defined as complete re-epithelialization and no progression of the infiltrate for two consecutive visits. The IQUIX treated subjects had an approximately equal mean clinical cure rate of 80% (73% to 87%) compared to 84% (82% to 86%) for the subjects treated with ofloxacin 0.3% ophthalmic solution. | lld:dailymed |
| dailymed-drugs:113 | dailymed-instance:clinicalP... | Mechanism of Action:: Meloxicam is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of meloxicam, like that of other NSAIDs, may be related to prostaglandin synthetase (cyclo-oxygenase) inhibition.<br/>Pharmacokinetics::<br/>Absorption:: The absolute bioavailability of meloxicam capsules was 89% following a single oral dose of 30 mg compared with 30 mg IV bolus injection. Following single intravenous doses, dose-proportional pharmacokinetics were shown in the range of 5 mg to 60 mg. After multiple oral doses the pharmacokinetics of meloxicam capsules were dose-proportional over the range of 7.5 mg to 15 mg. Mean Cwas achieved within four to five hours after a 7.5 mg meloxicam tablet was taken under fasted conditions, indicating a prolonged drug absorption. With multiple dosing, steady state concentrations were reached by Day 5. A second meloxicam concentration peak occurs around 12 to 14 hours post-dose suggesting biliary recycling.<br/>Food and Antacid Effects:: Administration of meloxicam capsules following a high fat breakfast (75 g of fat) resulted in mean peak drug levels (i.e., C) being increased by approximately 22% while the extent of absorption (AUC) was unchanged. The time to maximum concentration (T) was achieved between 5 and 6 hours. No pharmacokinetic interaction was detected with concomitant administration of antacids. Based on these results, meloxicam can be administered without regard to timing of meals or concomitant administration of antacids.<br/>Distribution:: The mean volume of distribution (V) of meloxicam is approximately 10 L. Meloxicam is ~99.4% bound to human plasma proteins (primarily albumin) within the therapeutic dose range. The fraction of protein binding is independent of drug concentration, over the clinically relevant concentration range, but decreases to ~99% in patients with renal disease. Meloxicam penetration into human red blood cells, after oral dosing, is less than 10%. Following a radiolabeled dose, over 90% of the radioactivity detected in the plasma was present as unchanged meloxicam. Meloxicam concentrations in synovial fluid, after a single oral dose, range from 40% to 50% of those in plasma. The free fraction in synovial fluid is 2.5 times higher than in plasma, due to the lower albumin content in synovial fluid as compared to plasma. The significance of this penetration is unknown.<br/>Metabolism:: Meloxicam is almost completely metabolized to four pharmacologically inactive metabolites. The major metabolite, 5'-carboxy meloxicam (60% of dose), from P-450 mediated metabolism was formed by oxidation of an intermediate metabolite 5'-hydroxymethyl meloxicam which is also excreted to a lesser extent (9% of dose). In vitro studies indicate that cytochrome P-450 2C9 plays an important role in this metabolic pathway with a minor contribution of the CYP 3A4 isozyme. Patients' peroxidase activity is probably responsible for the other two metabolites which account for 16% and 4% of the administered dose, respectively.<br/>Excretion:: Meloxicam excretion is predominantly in the form of metabolites, and occurs to equal extents in the urine and feces. Only traces of the unchanged parent compound are excreted in the urine (0.2%) and feces (1.6%). The extent of the urinary excretion was confirmed for unlabeled multiple 7.5 mg doses: 0.5%, 6% and 13% of the dose were found in urine in the form of meloxicam, and the 5'-hydroxymethyl and 5'-carboxy metabolites, respectively. There is significant biliary and/or enteral secretion of the drug. This was demonstrated when oral administration of cholestyramine following a single IV dose of meloxicam decreased the AUC of meloxicam by 50%. The mean elimination half-life (t) ranges from 15 hours to 20 hours. The elimination half-life is constant across dose levels indicating linear metabolism within the therapeutic dose range. Plasma clearance ranges from 7 to 9 mL/min.<br/>Special Populations::<br/>Pediatric:: After single (0.25 mg/kg) dose administration and after achieving steady-state (0.375 mg/kg/day), there was a general trend of approximately 30% lower exposure in younger patients (2-6 years old) as compared to the older patients (7-16 years old). The older patients had meloxicam exposures similar (single dose) or slightly reduced (steadystate) to those in the adult patients, when using AUC values normalized to a dose of 0.25 mg/kg . The meloxicam mean (SD) elimination half-life was 15.2 (10.1) and 13.0 hours (3.0) for the 2-6 year old patients, and 7-16 year old patients, respectively. In a covariate analysis, utilizing population pharmacokinetics body-weight, but not age, was the single predictive covariate for differences in the meloxicam apparent oral plasma clearance. The body-weight normalized apparent oral clearance values were adequate predictors of meloxicam exposure in pediatric patients. The pharmacokinetics of meloxicam in pediatric patients under 2 years of age has not been investigated.<br/>Geriatric:: Elderly males ((65 years of age) exhibited meloxicam plasma concentrations and steady state pharmacokinetics similar to young males. Elderly females ((65 years of age) had a 47% higher AUCand 32% higher Cas compared to younger females ((55 years( of age) after body weight normalization. Despite the increased total concentrations in the elderly females, the adverse event profile was comparable for both elderly patient populations. A smaller free fraction was found in elderly female patients in comparison to elderly male patients.<br/>Gender:: Young females exhibited slightly lower plasma concentrations relative to young males. After single doses of 7.5 mg meloxicam, the mean elimination half-life was 19.5 hours for the female group as compared to 23.4 hours for the male group. At steady state, the data were similar (17.9 hours vs. 21.4 hours). This pharmacokinetic difference due to gender is likely to be of little clinical importance. There was linearity of pharmacokinetics and no appreciable difference in the Cor Tacross genders.<br/>Hepatic Insufficiency:: Following a single 15 mg dose of meloxicam there was no marked difference in plasma concentrations in subjects with mild (Child-Pugh Class I) and moderate (Child-Pugh Class II) hepatic impairment compared to healthy volunteers. Protein binding of meloxicam was not affected by hepatic insufficiency. No dose adjustment is necessary in mild to moderate hepatic insufficiency. Patients withsevere hepatic impairment (Child-Pugh Class III) have not been adequately studied.<br/>Renal Insufficiency:: Meloxicam pharmacokinetics have been investigated in subjects with different degrees of renal insufficiency. Total drug plasma concentrations decreased with the degree of renal impairment while free AUC values were similar. Total clearance of meloxicam increased in these patients probably due to the increase in free fraction leading to an increased metabolic clearance. There is no need for dose adjustment in patients with mild to moderate renal failure (CrCL>15 mL/min). Patients with severe renal insufficiency have not been adequately studied. The use of meloxicam in subjects with severe renal impairment is not recommended .<br/>Hemodialysis:: Following a single dose of meloxicam, the free Cplasma concentrations were higher in patients with renal failure on chronic hemodialysis (1% free fraction) in comparison to healthy volunteers (0.3% free fraction). Hemodialysis did not lower the total drug concentration in plasma; therefore, additional doses are not necessary after hemodialysis. Meloxicam is not dialyzable.<br/>CLINICAL TRIALS:<br/>Osteoarthritis and Rheumatoid Arthritis:: The use of meloxicam for the treatment of the signs and symptoms of osteoarthritis of the knee and hip was evaluated in a 12-week double-blind controlled trial. Meloxicam (3.75 mg, 7.5 mg and 15 mg daily) was compared to placebo. The four primary endpoints were investigator's global assessment, patient global assessment, patient pain assessment, and total WOMAC score (a self-administered questionnaire addressing pain, function and stiffness). Patients on meloxicam 7.5 mg daily and meloxicam 15 mg daily showed significant improvement in each of these endpoints compared with placebo. The use of meloxicam for the management of signs and symptoms of osteoarthritis was evaluated in six double-blind, active-controlled trials outside the U.S. ranging from 4 weeks to 6 months duration. In these trials, the efficacy of meloxicam, in doses of 7.5 mg/day and 15 mg/day, was comparable to piroxicam 20 mg/day and diclofenac SR 100 mg/day and consistent with the efficacy seen in the U.S. trial. The use of meloxicam for the treatment of the signs and symptoms of rheumatoid arthritis was evaluated in a 12-week double-blind, controlled multinational trial. Meloxicam (7.5 mg, 15 mg and 22.5 mg daily) was compared to placebo. The primary endpoint in this study was the ACR20 response rate, a composite measure of clinical, laboratory and functional measures of RA response. Patients receiving meloxicam 7.5 mg and 15 mg daily showed significant improvement in the primary endpoint compared with placebo. No incremental benefit was observed with the 22.5 mg dose compared to the 15 mg dose. Higher doses of meloxicam (22.5 mg and greater) have been associated with an increased risk of serious GI events; therefore the daily dose of meloxicam should not exceed 15 mg. | lld:dailymed |
| dailymed-drugs:114 | dailymed-instance:clinicalP... | Topical corticosteroids share anti-inflammatory, anti-pruritic and vasoconstrictive actions. The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man.<br/>Pharmacokinetics: The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. The topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses. Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. | lld:dailymed |
| dailymed-drugs:115 | dailymed-instance:clinicalP... | Mechanism of Action: Dihydroergotamine binds with high affinity to 5-HTand 5-HTreceptors. It also binds with high affinity to serotonin 5-HT, 5-HT, and 5-HTreceptors, noradrenaline��,��and��receptors, and dopamine Dand Dreceptors. The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effect at 5-HTreceptors. Two current theories have been proposed to explain the efficacy of 5-HTreceptor agonists in migraine. One theory suggests that activation of 5-HTreceptors located on intracranial blood vessels, including those on arterio-venous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache. The alternative hypothesis suggests that activation of 5-HTreceptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release. In addition, dihydroergotamine possesses oxytocic properties.<br/>Pharmacokinetics:<br/>Absorption: Absolute bioavailability for the subcutaneous and intramuscular route have not been determined, however, no difference was observed in dihydroergotamine bioavailability from intramuscular and subcutaneous doses. Dihydroergotamine mesylate is poorly bioavailable following oral administration.<br/>Distribution: Dihydroergotamine mesylate is 93% plasma protein bound. The apparent steady-state volume of distribution is approximately 800 liters.<br/>Metabolism: Four dihydroergotamine mesylate metabolites have been identified in human plasma following oral administration. The major metabolite, 8'-��-hydroxydihydroergotamine, exhibits affinity equivalent to its parent for adrenergic and 5-HT receptors and demonstrates equivalent potency in several venoconstrictor activity models, in vivo and in vitro. The other metabolites, i.e., dihydrolysergic acid, dihydrolysergic amide, and a metabolite formed by oxidative opening of the proline ring are of minor importance. Following nasal administration, total metabolites represent only 20% to 30% of plasma AUC. Quantitative pharmacokinetic characterization of the four metabolites has not been performed.<br/>Excretion: The major excretory route of dihydroergotamine is via the bile in the feces. The total body clearance is 1.5 L/min which reflects mainly hepatic clearance. Only 6% to 7% of unchanged dihydroergotamine is excreted in the urine after intramuscular injection. The renal clearance (0.1 L/min) is unaffected by the route of dihydroergotamine administration. The decline of plasma dihydroergotamine after intramuscular or intravenous administration is multi-exponential with a terminal half-life of about 9 hours.<br/>Subpopulations: No studies have been conducted on the effect of renal or hepatic impairment, gender, race, or ethnicity on dihydroergotamine pharmacokinetics. Dihydroergotamine mesylate injection is contraindicated in patients with severely impaired hepatic or renal function.<br/>Interactions: Pharmacokinetic interactions have been reported in patients treated orally with other ergot alkaloids (e.g., increased levels of ergtomine) and macrolide antibiotics, principally troleandomycin, presumably due to inhibition of cytochrome P450 3A metabolism of the alkaloids by troleandomycin. Dihydroergotamine has also been shown to be an inhibitor of cytochrome P450 3A catalyzed reactions and rare reports of ergotism have been obtained from patients treated with dihydroergotamine and macrolide antibiotics (e.g., troleandomycin, clarithromycin, crythromycin), and in patients treated with dihydroergotamine and protease inhibitors (e.g. ritonavir), presumably due to inhibition of cytochrome P450 3A metabolism of ergotamine . No pharmacokinectic interactions involving other cytochrome P450 isoenzymes are known. | lld:dailymed |
| dailymed-drugs:116 | dailymed-instance:clinicalP... | Cimetidine competitively inhibits the action of histamine at the histamine Hreceptors of the parietal cells and thus is a histamine H-receptor antagonist. Cimetidine is not an anticholinergic agent. Studies have shown that cimetidine inhibits both daytime and nocturnal basal gastric acid secretion. Cimetidine also inhibits gastric acid secretion stimulated by food, histamine, pentagastrin, caffeine and insulin.<br/>Antisecretory Activity:<br/>1) Acid Secretion:<br/>2) Pepsin: Oral cimetidine 300 mg reduced total pepsin output as a result of the decrease in volume of gastric juice.<br/>3) Intrinsic Factor: Intrinsic factor secretion was studied with betazole as a stimulant. Oral cimetidine 300 mg inhibited the rise in intrinsic factor concentration produced by betazole, but some intrinsic factor was secreted at all times.<br/>Other:<br/>Lower Esophageal Sphincter Pressure and Gastric Emptying: Cimetidine has no effect on lower esophageal sphincter (LES) pressure or the rate of gastric emptying.<br/>Pharmacokinetics: Cimetidine is rapidly absorbed after oral administration and peak levels occur in 45 to 90 minutes. The half-life of cimetidine is approximately 2 hours. Both oral and parenteral (I.V. or I.M.) administration provide comparable periods of therapeutically effective blood levels; blood concentrations remain above that required to provide 80% inhibition of basal gastric acid secretion for 4 to 5 hours following a dose of 300 mg. The principal route of excretion of cimetidine is the urine. Following parenteral administration, most of the drug is excreted as the parent compound; following oral administration, the drug is more extensively metabolized, the sulfoxide being the major metabolite. Following a single oral dose, 48% of the drug is recovered from the urine after 24 hours as the parent compound. Following IV or IM administration, approximately 75% of the drug is recovered from the urine after 24 hours as the parent compound. | lld:dailymed |
| dailymed-drugs:118 | dailymed-instance:clinicalP... | INDOCIN is a non-steroidal anti-inflammatory drug (NSAID) that exhibits antipyretic and analgesic properties. Its mode of action, like that of other anti-inflammatory drugs, is not known. However, its therapeutic action is not due to pituitary-adrenal stimulation. INDOCIN is a potent inhibitor of prostaglandin synthesis in vitro. Concentrations are reached during therapy which have been demonstrated to have an effect in vivo as well. Prostaglandins sensitize afferent nerves and potentiate the action of bradykinin in inducing pain in animal models. Moreover, prostaglandins are known to be among the mediators of inflammation. Since indomethacin is an inhibitor of prostaglandin synthesis, its mode of action may be due to a decrease of prostaglandinsin peripheral tissues. INDOCIN has been shown to be an effective anti-inflammatory agent, appropriate for long-term use in rheumatoid arthritis, ankylosing spondylitis, and osteoarthritis. INDOCIN affords relief of symptoms; it does not alter the progressive course of the underlying disease. INDOCIN suppresses inflammation in rheumatoid arthritis as demonstrated by relief of pain, and reduction of fever, swelling and tenderness. Improvement in patients treated with INDOCIN for rheumatoid arthritis has been demonstrated by a reduction in joint swelling, average number of joints involved, and morning stiffness; by increased mobility as demonstrated by a decrease in walking time; and by improved functional capability as demonstrated by an increase in grip strength. INDOCIN may enable the reduction of steroid dosage in patients receiving steroids for the more severe forms of rheumatoid arthritis. In such instances the steroid dosage should be reduced slowly and the patients followed very closely for any possible adverse effects. Indomethacin has been reported to diminish basal and COstimulated cerebral blood flow in healthy volunteers following acute oral and intravenous administration. In one study after one week of treatment with orally administered indomethacin, this effect on basal cerebral blood flow had disappeared. The clinical significance of this effect has not been established. Capsules INDOCIN have been found effective in relieving the pain, reducing the fever, swelling, redness, and tenderness of acute gouty arthritis . Following single oral doses of Capsules INDOCIN 25 mg or 50 mg, indomethacin is readily absorbed, attaining peak plasma concentrations of about 1 and 2 mcg/mL, respectively, at about 2 hours. Orally administered Capsules INDOCIN are virtually 100% bioavailable, with 90% of the dose absorbed within 4 hours. A single 50 mg dose of Oral Suspension INDOCIN was found to be bioequivalent to a 50 mg INDOCIN capsule when each was administered with food. Indomethacin is eliminated via renal excretion, metabolism, and biliary excretion. Indomethacin undergoes appreciable enterohepatic circulation. The mean half-life of indomethacin is estimated to be about 4.5 hours. With a typical therapeutic regimen of 25 or 50 mg t.i.d., the steady-state plasma concentrations of indomethacin are an average 1.4 times those following the first dose. Indomethacin exists in the plasma as the parent drug and its desmethyl, desbenzoyl, and desmethyldesbenzoyl metabolites, all in the unconjugated form. About 60 percent of an oral dosage is recovered in urine as drug and metabolites (26 percent as indomethacin and its glucuronide), and 33 percent is recovered in feces (1.5 percent as indomethacin). About 99% of indomethacin is bound to protein in plasma over the expected range of therapeutic plasma concentrations. Indomethacin has been found to cross the blood-brain barrier and the placenta. | lld:dailymed |
| dailymed-drugs:119 | dailymed-instance:clinicalP... | Following IM administration of a single 500 mg or 1 g dose of CLAFORAN to normal volunteers, mean peak serum concentrations of 11.7 and 20.5 mcg/mL respectively were attained within 30 minutes and declined with an elimination half-life of approximately 1 hour. There was a dose-dependent increase in serum levels after the IV administration of 500 mg, 1 g, and 2 g of CLAFORAN (38.9, 101.7, and 214.4 mcg/mL respectively) without alteration in the elimination half-life. There is no evidence of accumulation following repetitive IV infusion of 1 g doses every 6 hours for 14 days as there are no alterations of serum or renal clearance. About 60% of the administered dose was recovered from urine during the first 6 hours following the startof the infusion. Approximately 20���36% of an intravenously administered dose ofC-cefotaxime is excreted by the kidney as unchanged cefotaxime and 15���25% as the desacetyl derivative, the major metabolite. The desacetyl metabolite has been shown to contribute to the bactericidal activity. Two other urinary metabolites (Mand M) account for about 20���25%. They lack bactericidal activity. A single 50 mg/kg dose of CLAFORAN was administered as an intravenous infusion over a 10- to 15-minute period to 29 newborn infants grouped according to birth weight and age. The mean half-life of cefotaxime in infants with lower birth weights (���1500 grams), regardless of age, was longer (4.6 hours) than the mean half-life (3.4 hours) in infants whose birth weight was greater than 1500 grams. Mean serum clearance was also smaller in the lower birth weight infants. Although the differences in mean half-life values are statistically significant for weight, they are not clinically important. Therefore, dosage should be based solely on age. Additionally, no disulfiram-like reactions were reported in a study conducted in 22 healthy volunteers administered CLAFORAN and ethanol.<br/>Microbiology: The bactericidal activity of cefotaxime sodium results from inhibition of cell wall synthesis. Cefotaxime sodium has in vitro activity against a wide range of gram-positive and gram-negative organisms. Cefotaxime sodium has a high degree of stability in the presence of��-lactamases, both penicillinases and cephalosporinases, of gram-negative and gram-positive bacteria. Cefotaxime sodium has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.<br/>Aerobes, Gram-positive: Enterococcus spp.Staphylococcus aureus, including��-lactamase-positive and negative strainsStaphylococcus epidermidisStreptococcus pneumoniaeStreptococcus pyogenes (Group A beta-hemolytic streptococci)Streptococcus spp.<br/>Aerobes, Gram-negative: Acinetobacter spp.Citrobacter spp.Enterobacter spp.Escherichia coliHaemophilus influenzae (including ampicillin-resistant strains)Haemophilus parainfluenzaeKlebsiella spp. (including Klebsiella pneumoniae)Morganella morganiiNeisseria gonorrhoeae (including��-lactamase-positive and negative strains)Neisseria meningitidisProteus mirabilisProteus vulgarisProvidencia rettgeriProvidencia stuartiiSerratia marcescens NOTE: Many strains of the above organisms that are multiply resistant to other antibiotics, e.g. penicillins, cephalosporins, and aminoglycosides, are susceptible to cefotaxime sodium. Cefotaxime sodium is active against some strains of Pseudomonas aeruginosa.<br/>Anaerobes: Bacteroides spp., including some strains of Bacteroides fragilisClostridium spp. (Note: Most strains of Clostridium difficile are resistant.)Fusobacterium spp. (Including Fusobacterium nucleatum).Peptococcus spp.Peptostreptococcus spp. Cefotaxime sodium also demonstrates in vitro activity against the following microorganisms but the clinical significance is unknown. Cefotaxime sodium exhibits in vitro minimal inhibitory concentrations (MICs) of 8 mcg/mL or less against most (���90%) strains of the following microorganisms; however, the safety and effectiveness of cefotaxime sodium in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials:<br/>Aerobes, Gram-negative: Providencia spp.Salmonella spp. (including Salmonella typhi)Shigella spp. Cefotaxime sodium is highly stable in vitro to four of the five major classes of 5-lactamases described by Richmond et al., including type IIIa (TEM) which is produced by many gram-negative bacteria. The drug is also stable to��-lactamase (penicillinase) produced by staphylococci. In addition, cefotaxime sodium shows high affinity for penicillin-binding proteins in the cell wall, including PBP: Ib and III. Cefotaxime sodium and aminoglycosides have been shown to be synergistic in vitro against some strains of Pseudomonas aeruginosa but the clinical significance is unknown.<br/>Susceptibility Tests:<br/>Dilution techniques: Quantitative methods that are used to determine minimum inhibitory concentrations (MICs) provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized dilution method(broth or agar) or equivalent with cefotaxime sodium powder. The MIC values obtained should be interpreted according to the following criteria: A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal and if the microorganism is not fully susceptible to alternative clinically feasible drugs the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable, other therapy should be selected. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedure. Standard cefotaxime sodium powder should provide the following MIC values:<br/>Diffusion Techniques: Quantitative methods that require measurements of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedurerequires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcg cefotaxime sodium to test the susceptibility of microorganisms to cefotaxime sodium. Reports from the laboratory providing results of the standard single-disk susceptibility test using a 30 mcg cefotaxime sodium disk should be interpreted according to the following criteria: Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for cefotaxime sodium. As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30 mcg cefotaxime sodium disk should provide the following zone diameters in these laboratory test quality control strains:<br/>Anaerobic Techniques: For anaerobic bacteria, the susceptibility to cefotaxime sodium as MICs can be determined by standardized test methods.The MIC values obtained should be interpreted according to the following criteria: Interpretation is identical to that stated above for results using dilution techniques. As with other susceptibility techniques, the use of laboratory control microorganisms is required to control the technical aspects of the laboratory standardized procedures. Standardized cefotaxime sodium powder should provide the following MIC values: | lld:dailymed |
| dailymed-drugs:120 | dailymed-instance:clinicalP... | Vinorelbine is a vinca alkaloid that interferes with microtubule assembly. The vinca alkaloids are structurally similar compounds comprised of 2 multiringed units, vindoline and catharanthine. Unlike other vinca alkaloids, the catharanthine unit is the site of structural modification for vinorelbine. The antitumor activity of vinorelbine is thought to be due primarily to inhibition of mitosis at metaphase through its interaction with tubulin. Like other vinca alkaloids, vinorelbine may also interfere with: 1) amino acid, cyclic AMP, and glutathione metabolism, 2) calmodulin- dependent Ca-transport ATPase activity, 3) cellular respiration, and 4) nucleic acid and lipid biosynthesis. In intact tectal plates from mouse embryos, vinorelbine, vincristine, and vinblastine inhibited mitotic microtubule formation at the same concentration (2��M), inducing a blockade of cells at metaphase. Vincristine produced depolymerization of axonal microtubules at 5��M, but vinblastine and vinorelbine did not have this effect until concentrations of 30��M and 40��M, respectively. These data suggest relative selectivity of vinorelbine for mitotic microtubules.<br/>Pharmacokinetics: The pharmacokinetics of vinorelbine were studied in 49 patients who received doses of 30 mg/min 4 clinical trials. Doses were administered by 15- to 20-minute constant-rate infusions. Following intravenous administration, vinorelbine concentration in plasma decays in a triphasic manner. The initial rapid decline primarily represents distribution of drug to peripheral compartments followed by metabolism and excretion of the drug during subsequent phases. The prolonged terminal phase is due to relatively slow efflux of vinorelbine from peripheral compartments. The terminal phase half-life averages 27.7 to 43.6 hours and the mean plasma clearance ranges from 0.97 to 1.26 L/hr/kg. Steady-state volume of distribution (V) values range from 25.4 to 40.1 L/kg. Vinorelbine demonstrated high binding to human platelets and lymphocytes. The free fraction was approximately 0.11 in pooled human plasma over a concentration range of 234 to 1,169 ng/mL. The binding to plasma constituents in cancer patients ranged from 79.6% to 91.2%. Vinorelbine binding was not altered in the presence of cisplatin, 5-fluorouracil, or doxorubicin. Vinorelbine undergoes substantial hepatic elimination in humans, with large amounts recovered in feces after intravenous administration to humans. Two metabolites of vinorelbine have been identified in human blood, plasma, and urine; vinorelbine N-oxide and deacetylvinorelbine. Deacetylvinorelbine has been demonstrated to be the primary metabolite of vinorelbine in humans, and has been shown to possess antitumor activity similar to vinorelbine. Therapeutic doses of Vinorelbine (30 mg/m) yield very small, if any, quantifiable levels of either metabolite in blood or urine. The metabolism of vinca alkaloids has been shown to be mediated by hepatic cytochrome P450 isoenzymes in the CYP3A subfamily. This metabolic pathway may be impaired in patients with hepatic dysfunction or who are taking concomitant potent inhibitors of these isoenzymes (see PRECAUTIONS). The effects of renal or hepatic dysfunction on the disposition of vinorelbine have not been assessed, but based on experience with other anticancer vinca alkaloids, dose adjustments are recommended for patients with impaired hepatic function (see DOSAGE AND ADMINISTRATION). The disposition of radiolabeled vinorelbine given intravenously was studied in a limited number of patients. Approximately 18% and 46% of the administered dose was recovered in the urine and in the feces, respectively. Incomplete recovery in humans is consistent with results in animals where recovery is incomplete, even after prolonged sampling times. A separate study of the urinary excretion of vinorelbine using specific chromatographic analytical methodology showed that 10.9%��0.7% of a 30-mg/mintravenous dose was excreted unchanged in the urine. The influence of age on the pharmacokinetics of vinorelbine was examined using data from 44 cancer patients (average age, 56.7��7.8 years; range, 41 to 74 years; with 12 patients���60 years and 6 patients���65 years) in 3 studies. CL (the mean plasma clearance), t(the terminal phase half-life), and V(the volume of distribution during terminal phase) were independent of age. A separate pharmacokinetic study was conducted in 10 elderly patients with metastatic breast cancer (age range, 66 to 81 years; 3 patients>75 years; normal liver function tests) receiving vinorelbine 30 mg/mintravenously. CL, V, and twere similar to those reported for younger adult patients in previous studies. No relationship between age, systemic exposure (AUC), and hematological toxicity was observed. The pharmacokinetics of vinorelbine are not influenced by the concurrent administration of cisplatin with Vinorelbine (see PRECAUTIONS: Drug Interactions).<br/>Clinical Trials: Data from 1 randomized clinical study (211 evaluable patients) with single-agent Vinorelbine and 2 randomized clinical trials (1,044 patients) using Vinorelbine combined with cisplatin support the use of Vinorelbine in patients with advanced nonsmall cell lung cancer NSCLC). Single-Agent Vinorelbine: Single-agent Vinorelbine was studied in a North American, randomized clinical trial in which patients with Stage IV NSCLC, no prior chemotherapy, and Karnofsky Performance Status���70 were treated with Vinorelbine (30 mg/m) weekly or 5-fluorouracil (5-FU) (425 mg/mIV bolus) plus leucovorin ( LV) (20 mg/mIV bolus) daily for 5 days every 4 weeks. A total of 211 patients were randomized at a 2:1 ratio to Vinorelbine (143) or 5-FU/LV (68). Vinorelbine showed improved survival time compared to 5-FU/LV. In an intent-to-treat analysis, the median survival time was 30 weeks versus 22 weeks for patients receiving Vinorelbine versus 5-FU/LV, respectively (P = 0.06). The 1-year survival rates were 24% (��4% SE) for Vinorelbine and 16% (��5% SE) for the 5-FU/LV group, using the Kaplan-Meier product-limit estimates. The median survival time with 5-FU/LV was similar to or slightly better than that usually observed in untreated patients with advanced NSCLC, suggesting that the difference was not related to some unknown detrimental effect of 5-FU/LV therapy. The response rates (all partial responses) for Vinorelbine and 5-FU/LV were 12% and 3%, respectively. Vinorelbine in Combination with Cisplatin: Vinorelbine plus Cisplatin versus Single-Agent Cisplatin: A Phase III open-label, randomized study was conducted which compared Vinorelbine (25 mg/m/week) plus cisplatin (100 mg/mevery 4 weeks) to single-agent cisplatin (100 mg/mevery 4 weeks) in patients with Stage IV or Stage IIIb NSCLC patients with malignant pleural effusion or multiple lesions in more than one lobe who were not previously treated with chemotherapy. Patients included in the study had a performance status of 0 or 1, and 34% had received prior surgery and/or radiotherapy. Characteristics of the 432 randomized patients are provided in Table 1. Two hundred and twelve patients received Vinorelbine plus cisplatin and 210 received single-agent cisplatin. The primary objective of this trial was to compare survival between the 2 treatment groups. Survival (Figure 1) for patients receiving Vinorelbine plus cisplatin was significantly better compared to the patients who received single-agent cisplatin. The results of this trial are summarized in Table 1. Vinorelbine plus Cisplatin versus Vindesine plus Cisplatin versus Single-Agent Vinorelbine:In a large European clinical trial, 612 patients with Stage III or IV NSCLC, no prior chemotherapy, and WHO Performance Status of 0, 1, or 2 were randomized to treatment with single-agent Vinorelbine (30 mg/m/week), Vinorelbine (30 mg/m/week) plus cisplatin (120 mg/mdays 1 and 29, then every 6 weeks), and vindesine (3 mg/m/week for 7 weeks, then every other week) plus cisplatin (120 mg/mdays 1 and 29, then every 6 weeks). Patient characteristics are provided in Table 1. Survival was longer in patients treated with Vinorelbine plus cisplatin compared to those treated with vindesine plus cisplatin (Figure 2). Study results are summarized in Table 1. Dose-Ranging Study: A dose-ranging study of Vinorelbine (20, 25, or 30 mg/m/week) plus cisplatin (120 mg/mdays 1 and 29, then every 6 weeks) in 32 patients with NSCLC demonstrated a median survival of 10.2 months. There were no responses at the lowest dose level; the response rate was 33% in the 21 patients treated at the 2 highest dose levels. Figure 1. Overall SurvivalVinorelbine/Cisplatin versus Single-Agent Cisplatin Figure 2. Overall SurvivalVinorelbine/Cisplatin versus Vindesine/Cisplatin versus Single-Agent Vinorelbine | lld:dailymed |
| dailymed-drugs:122 | dailymed-instance:clinicalP... | Pharmacodynamic Actions: Naltrexone is a pure opioid antagonist. It markedly attenuates or completely blocks, reversibly, the subjective effects of intravenously administered opioids. When co-administered with morphine, on a chronic basis, naltrexone blocks the physical dependence to morphine, heroin and other opioids. Naltrexone has few, if any, intrinsic actions besides its opioid blocking properties. However, it does produce some pupillary constriction, by an unknown mechanism. The administration of naltrexone is not associated with the development of tolerance or dependence. In subjects physically dependent on opioids, naltrexone will precipitate withdrawal symptomatology. Clinical studies indicate that 50 mg of naltrexone hydrochloride will block the pharmacologic effects of 25 mg of intravenously administered heroin for periods as long as 24 hours. Other data suggest that doubling the dose of naltrexone hydrochloride provides blockade for 48 hours, and tripling the dose of naltrexone hydrochloride provides blockade for about 72 hours. Naltrexone blocks the effects of opioids by competitive binding (i.e., analogous to competitive inhibition of enzymes) at opioid receptors. This makes the blockade produced potentially surmountable, but overcoming full naltrexone blockade by administration of very high doses of opiates has resulted in excessive symptoms of histamine release in experimental subjects. The mechanism of action of naltrexone in alcoholism is not understood; however, involvement of the endogenous opioid system is suggested by preclinical data. Naltrexone, an opioid receptor antagonist, competitively binds to such receptors and may block the effects of endogenous opioids. Opioid antagonists have been shown to reduce alcohol consumption by animals, and naltrexone has been shown to reduce alcohol consumption in clinical studies. Naltrexone is not aversive therapy and does not cause a disulfiram-like reaction either as a result of opiate use or ethanol ingestion. Pharmacokinetics: Naltrexone is a pure opioid receptor antagonist. Although well absorbed orally, naltrexone is subject to significant first pass metabolism with oral bioavailability estimates ranging from 5% to 40%. The activity of naltrexone is believed to be due to both parent and the 6-��-naltrexol metabolite. Both parent drug and metabolites are excreted primarily by the kidney (53% to 79% of the dose), however, urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose and fecal excretion is a minor elimination pathway. The mean elimination half-life (T-1/2) values for naltrexone and 6-��-naltrexol are 4 hours and 13 hours, respectively. Naltrexone and 6-��-naltrexol are dose proportional in terms of AUC and Cover the range of 50 to 200 mg and do not accumulate after 100 mg daily doses. Absorption: Following oral administration, naltrexone undergoes rapid and nearly complete absorption with approximately 96% of the dose absorbed from the gastrointestinal tract. Peak plasma levels of both naltrexone and 6-��-naltrexone occur within one hour of dosing. Distribution: The volume of distribution for naltrexone following intravenous administration is estimated to be 1350 liters. In vitro tests with human plasma show naltrexone to be 21% bound to plasma proteins over the therapeutic dose range. Metabolism: The systemic clearance (after intravenous administration) of naltrexone is ~3.5 L/min, which exceeds liver blood flow (~1.2 L/min). This suggests both that naltrexone is a highly extracted drug (>98% metabolized) and that extra-hepatic sites of drug metabolism exist. The major metabolite of naltrexone is 6-��-naltrexol. Two other minor metabolites are 2-hydroxy-3-methoxy-6-��-naltrexol and 2-hydroxy-3-methyl-naltrexone. Naltrexone and its metabolites are also conjugated to form additional metabolic products. Elimination: The renal clearance for naltrexone ranges from 30 to 127 mL/min and suggests that renal elimination is primarily by glomerular filtration. In comparison, the renal clearance for 6-��-naltrexol ranges from 230 to 369 mL/min, suggesting an additional renal tubular secretory mechanism. The urinary excretion of unchanged naltrexone accounts for less than 2% of an oral dose; urinary excretion of unchanged and conjugated 6-��-naltrexol accounts for 43% of an oral dose. The pharmacokinetic profile of naltrexone suggests that naltrexone and its metabolites may undergo enterohepatic recycling. Hepatic and Renal Impairment: Naltrexone appears to have extra-hepatic sites of drug metabolism and its major metabolite undergoes active tubular secretion (see Metabolism above). Adequate studies of naltrexone in patients with severe hepatic or renal impairment have not been conducted .<br/>Clinical Trials:: Alcoholism: The efficacy of naltrexone as an aid to the treatment of alcoholism was tested in placebo-controlled, outpatient, double blind trials. These studies used a dose of naltrexone hydrochloride 50 mg once daily for 12 weeks as an adjunct to social and psychotherapeutic methods when given under conditions that enhanced patient compliance. Patients with psychosis, dementia, and secondary psychiatric diagnoses were excluded from these studies. In one of these studies, 104 alcohol-dependent patients were randomized to receive either naltrexone hydrochloride 50 mg once daily or placebo. In this study, naltrexone proved superior to placebo in measures of drinking including abstention rates (51% vs. 23%), number of drinking days, and relapse (31% vs. 60%). In a second study with 82 alcohol-dependent patients, the group of patients receiving naltrexone were shown to have lower relapse rates (21% vs. 41%), less alcohol craving, and fewer drinking days compared with patients who received placebo, but these results depended on the specific analysis used. The clinical use of naltrexone as adjunctive pharmacotherapy for the treatment of alcoholism was also evaluated in a multicenter safety study. This study of 865 individuals with alcoholism included patients with comorbid psychiatric conditions, concomitant medications, polysubstance abuse and HIV disease. Results of this study demonstrated that the side effect profile of naltrexone appears to be similar in both alcoholic and opioid dependent populations, and that serious side effects are uncommon. In the clinical studies, treatment with naltrexone supported abstinence, prevented relapse and decreased alcohol consumption. In the uncontrolled study, the patterns of abstinence and relapse were similar to those observed in the controlled studies. Naltrexone was not uniformly helpful to all patients, and the expected effect of the drug is a modest improvement in the outcome of conventional treatment.<br/>Treatment of Opioid Addiction:: Naltrexone has been shown to produce complete blockade of the euphoric effects of opioids in both volunteer and addict populations. When administered by means that enforce compliance, it will produce an effective opioid blockade, but has not been shown to affect the use of cocaine or other non-opioid drugs of abuse. There are no data that demonstrate an unequivocally beneficial effect of naltrexone on rates of recidivism among detoxified, formerly opioid-dependent individuals who self-administer the drug. The failure of the drug in this setting appears to be due to poor medication compliance. The drug is reported to be of greatest use in good prognosis opioid addicts who take the drug as part of a comprehensive occupational rehabilitative program, behavioral contract, or other compliance-enhancing protocol. Naltrexone, unlike methadone or LAAM (levo-alpha-acetyl-methadol), does not reinforce medication compliance and is expected to have a therapeutic effect only when given under external conditions that support continued use of the medication.<br/>Individualization of Dosage:: DO NOT ATTEMPT TREATMENT WITH NALTREXONE UNLESS, IN THE MEDICAL JUDGEMENT OF THE PRESCRIBING PHYSICIAN, THERE IS NO REASONABLE POSSIBILITY OF OPIOID USE WITHIN THE PAST 7 to 10 DAYS. IF THERE IS ANY QUESTION OF OCCULT OPIOID DEPENDENCE, PERFORM A NALOXONE CHALLENGE TEST.<br/>Treatment of Alcoholism:: The placebo-controlled studies that demonstrated the efficacy of naltrexone as an adjunctive treatment of alcoholism used a dose regimen of naltrexone hydrochloride 50 mg once daily for up to 12 weeks. Other dose regimens or durations of therapy were not studied in these trials. Physicians are advised that 5% to 15% of patients taking naltrexone for alcoholism will complain of non-specific side effects, chiefly gastrointestinal upset. Prescribing physicians have tried using an initial 25 mg dose, splitting the daily dose, and adjusting the time of dosing with limited success. No dose or pattern of dosing has been shown to be more effective than any other in reducing these complaints for all patients.<br/>Treatment of Opioid Dependence:: Once the patient has been started on naltrexone hydrochloride, 50 mg once a day will produce adequate clinical blockade of the actions of parenterally administered opioids. As with many non-agonist treatments for addiction, naltrexone is of proven value only when given as part of a comprehensive plan of management that includes some measure to ensure the patient takes the medication. A flexible approach to a dosing regimen may be employed to enhance compliance. Thus, patients may receive 50 mg of naltrexone hydrochloride every weekday with a 100 mg dose on Saturday or patients may receive 100 mg every other day, or 150 mg every third day. Several of the clinical studies reported in the literature have employed the following dosing regimen: 100 mg on Monday, 100 mg on Wednesday, and 150 mg on Friday. This dosing schedule appeared to be acceptable to many naltrexone patients successfully maintaining their opioid-free state. Experience with the supervised administration of a number of potentially hepatotoxic agents suggests that supervised administration and single doses of naltrexone hydrochloride higher than 50 mg may have an associated increased risk of hepatocellular injury, even though three-times a week dosing has been well tolerated in the addict population and in initial clinical trials in alcoholism. Clinics using this approach should balance the possible risks against the probable benefits and may wish to maintain a higher index of suspicion for drug-associated hepatitis and ensure patients are advised of the need to report non-specific abdominal complaints . | lld:dailymed |
| dailymed-drugs:123 | dailymed-instance:clinicalP... | Mechanism of Action: The mechanism by which Totect���diminishes tissue damage resulting from the extravasation of anthracycline drugs is unknown. Some evidence suggests that dexrazoxane inhibits topoisomerase II reversibly.<br/>Pharmacokinetics/Pharmacodynamics: The pharmacokinetics of dexrazoxane following dosing of patients with anthracycline extravasation have not been studied. The pharmacokinetics of dexrazoxane have been studied in advanced cancer patients with normal renal and hepatic function. Generally, the pharmacokinetics of dexrazoxane can be adequately described by a two-compartment open model with first-order elimination. Dexrazoxane has been administered as a 15 minute infusion over a dose-range of 60 to 900 mg/mwith 60 mg/mof doxorubicin, and at a fixed dose of 500 mg/mwith 50 mg/mdoxorubicin. The disposition kinetics of dexrazoxane are dose-independent, as shown by linear relationship between the area under plasma concentration-time curves and administered doses ranging from 60 to 900 mg/m. The mean peak plasma concentration of dexrazoxane was 36.5��g/mL at the end of the 15 minute infusion of a 500 mg/mdose of dexrazoxane administered 15 to 30 minutes prior to the 50 mg/mdoxorubicin dose. The important pharmacokinetic parameters of dexrazoxane are summarized in the following table. Following a rapid distributive phase (~0.2 to 0.3 hours), dexrazoxane reaches post-distributive equilibrium within 2 to 4 hours. The estimated steady-state volume of distribution of dexrazoxane suggests its distribution primarily in the total body water (25 L/m). The mean systemic clearance and steady-state volume of distribution of dexrazoxane in two Asian female patients at 500 mg/mdexrazoxane along with 50 mg/mdoxorubicin were 15.15 L/h/mand 36.27 L/m, respectively, but their elimination half-life and renal clearance of dexrazoxane were similar to those of the ten Caucasian patients from the same study. Qualitative metabolism studies with dexrazoxane have confirmed the presence of unchanged drug, a diacid-diamide cleavage product, and two monoacid-monoamide ring products in the urine of animals and man. The metabolite levels were not measured in the pharmacokinetic studies. Urinary excretion plays an important role in the elimination of dexrazoxane. Forty-two percent of the 500 mg/mdose of dexrazoxane was excreted in the urine. Protein Binding: In vitro studies have shown that dexrazoxane is not bound to plasma proteins.<br/>Special Populations:: Pediatric: The pharmacokinetics of dexrazoxane have not been evaluated in pediatric patients. Gender: There are no clinically relevant differences in the pharmacokinetics of dexrazoxane between males and females. Renal insufficiency: The pharmacokinetics of dexrazoxane were assessed following a single 15 minute IV infusion of 150 mg/mof dexrazoxane in male and female subjects with varying degrees of renal dysfunction as determined by creatinine clearance (CL) based on a 24-hour urinary creatinine collection. Dexrazoxane clearance was reduced in subjects with renal dysfunction. Compared with controls, the mean AUCvalue was twofold greater in subjects with moderate (CL30-50 mL/min) to severe (CL<30 mL/min) renal dysfunction. Modeling demonstrated that equivalent exposure (AUC) could be achieved if dosing were reduced by 50% in subjects with creatinine clearance values<40 mL/min compared with control subjects (CL>80 mL/min) . Hepatic insufficiency: The pharmacokinetics of dexrazoxane have not been evaluated in patients with hepatic impairment. Drug Interactions: There were no significant changes in the pharmacokinetics of doxorubicin (50 mg/m) and its predominant metabolite, doxorubicinol, in the presence of dexrazoxane (500 mg/m) in a crossover study in cancer patients. | lld:dailymed |
| dailymed-drugs:124 | dailymed-instance:clinicalP... | Following IV doses of 750 mg and 1.5 g, serum concentrations were approximately 50 and 100 mcg/mL, respectively, at 15 minutes. Therapeutic serum concentrations of approximately 2 mcg/mL or more were maintained for 5.3 hours and 8 hours or more, respectively. There was no evidence of accumulation of cefuroxime in the serum following IV administration of 1.5 g doses every 8 hours to normal volunteers. The serum half-life after IV injection is approximately 80 minutes. Approximately 89% of a dose of cefuroxime is excreted by the kidneys over an 8 hour period, resulting in high urinary concentrations. Intravenous doses of 750 mg and 1.5 g produced urinary levels averaging 1,150 and 2,500 mcg/mL, respectively, during the first 8 hour period. The concomitant oral administration of probenecid with cefuroxime slows tubular secretion, decreases renal clearance by approximately 40%, increases the peak serum level by approximately 30%, and increases the serum half-life by approximately 30%. Cefuroxime is detectable in therapeutic concentrations in pleural fluid, joint fluid, bile, sputum, bone, cerebrospinal fluid (in patients with meningitis), and aqueous humor. Cefuroxime is detectable in therapeutic concentrations in cerebrospinal fluid (CSF) of adults and pediatric patients with meningitis. The following table shows the concentrations of cefuroxime achieved in cerebrospinal fluid during multiple dosing of patients with meningitis. Cefuroxime is approximately 50% bound to serum protein.<br/>Microbiology: Cefuroxime has in vitro activity against a wide range of gram-positive and gram-negative organisms, and it is highly stable in the presence of beta-lactamases of certain gram-negative bacteria. The bactericidal action of cefuroxime results from inhibition of cell-wall synthesis. Cefuroxime is usually active against the following organisms in vitro. Aerobes, Gram-positive:Staphylococcus aureusStaphylococcus epidermidisStreptococcus pneumoniae, andStreptococcus pyogenes (and other streptococci) NOTE: Most strains of enterococci, e.g., Enterococcus faecalis (formerly Streptococcus faecalis), are resistant to cefuroxime. Methicillin-resistant staphylococci and Listeria monocytogenes are resistant to cefuroxime. Aerobes, Gram-negative:Citrobacter spp.Enterobacter spp.Escherichia coliHaemophilus influenzae (including ampicillin-resistant strains)Haemophilus parainfluenzaeKlebsiella spp. (including Klebsiella pneumoniae)Moraxella (Branhamella) catarrhalis (including ampicillin- and cephalothin-resistant strains)Morganella morganii (formerly Proteus morganii)Neisseria gonorrhoeae (including penicillinase- and non-penicillinase-producing strains)Neisseria meningitidisProteus mirabilisProvidencia rettgeri (formerly Proteus rettgeri)Salmonella spp., and Shigella spp. NOTE: Some strains of Morganella morganii, Enterobacter cloacae, and Citrobacter spp. have been shown by in vitro tests to be resistant to cefuroxime and other cephalosporins. Pseudomonas and Campylobacter spp., Acinetobacter calcoaceticus, and most strains of Serratia spp. and Proteus vulgaris are resistant to most first- and second-generation cephalosporins. Anaerobes: Gram-positive and gram-negative cocci (including Peptococcus and Peptostreptococcus spp.), gram-positive bacilli (including Clostridium spp.), and gram-negative bacilli (including Bacteroides and Fusobacterium spp.). NOTE: Clostridium difficile and most strains of Bacteroides fragilis are resistant to cefuroxime.<br/>Susceptibility Tests: | lld:dailymed |
| dailymed-drugs:125 | dailymed-instance:clinicalP... | Isoproterenol acts directly on beta-adrenergic receptors and phenylephrine acts directly on alpha-adrenergic receptors. The beta-adrenergic effects stem from the release of cyclic AMP following activation of the enzyme adenyl cyclase. Alpha-adren��ergic effects probably result from inhibition of adenyl cyclase. Isoproterenol produces bronchodilatation, systemic vasodilation, mild hypotension, and tachycardia. Phenylephrine produces mild bronchodilatation, systemic vasoconstriction, mild hypertension, and bradycardia. These two drugs appear to act synergistically to allow the expression of each product's ability to relax bronchial smooth muscle. The vasoconstrictor effect of phenylephrine reduces bronchiolar blood flow thereby producing a decongestant effect, promotes retention of the drug in the bronchial mucosa, and blocks the tachycardia of isoproterenol. After oral inhalation of the combination, the pulmonary effects occur within a few minutes and persist up to three hours. Studies demonstrate that the ventilatory effects of isoproterenol��phenylephrine are superior to those obtained with the administration of isoproterenol alone. Because isoproterenol is a potent vasodilator that lowers blood pressure and acts upon the heart to increase cardiac output and pulse rate, its combination with phenylephrine results in a product with fewer cardiovascular effects. Studies have shown the absence of tachycardia and hypotension. Isoproterenol alone often lowers arterial blood oxygen (PO). Several studies have shown that the combination of isoproterenol and phenylephrine rarely produces a significant drop in arterial oxygen tension while usually producing an increase in POin asthmatic patients. Pharmacokinetics: The average half-life for isoproterenol admin��istered by aerosol was five minutes. A plasma concentration of 0.03 ng/ml was found within minutes following an inhalation dose of 500 mcg isoproterenol. Isoproterenol excretion following oral or inhalation administration is primarily renal. When given by inhalation, the major metabolite is the sulfate conjugate of the drug. When the drug is administered directly into the bronchial tree, it is inactivated by the enzyme catechol-o-methyl transferase, and the predominant metabolite is 3-o-methylisoproterenol sulfate. The explanation for this difference is supported by the observation that most (90%) of an aerosol dose is deposited in the mouth, swallowed, and converted to its sulfate conjugate in the gut wall, and to a lesser extent in the liver. The remaining isoproterenol is excreted as follows: 1% to 2% unchanged, 1% to 2% free methylated metabolite, and small amountsof metabolites in the bile. Plasma levels following inhalation of phenylephrine have not been reported. Following oral and intravenous administrations, the average half-life was about 2.5 hours. Phenylephrine is metabo��lized in the liver and intestine by the enzyme monoamine oxidase. About 80% of a dose is recovered in the urine, primarily as phenolic conjugates and m-hydroxymandelic acid. About 16% of a dose is excreted as unchanged drug following intravenous administration and, due to first pass metabolism, less than 3% is excreted unchanged following oral dosing. Recent studies in laboratory animals (minipigs, rodents, and dogs) recorded the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta agonists and methylxanthines were concomitantly administered. The significance of these findings when applied to human usage is currently unknown. | lld:dailymed |
| dailymed-drugs:126 | dailymed-instance:clinicalP... | MECHANISM OF ACTION: Nicardipine inhibits the transmembrane influx of calcium ions into cardiac muscle and smooth muscle without changing serum calcium concentrations. The contractile processes of cardiac muscle and vascular smooth muscle are dependent upon the movement of extracellular calcium ions into these cells through specific ion channels. The effects of nicardipine are more selective to vascular smooth muscle than cardiac muscle. In animal models, nicardipine produced relaxation of coronary vascular smooth muscle at drug levelswhich cause little or no negative inotropic effect.<br/>PHARMACOKINETICS AND METABOLISM: Following infusion, nicardipine plasma concentrations decline tri-exponentially, with a rapid early distribution phase (��-half-life of 2.7 minutes), an intermediate phase (��-half-life of 44.8 minutes), and a slow terminal phase (��-half-life of 14.4 hours) that can only be detected after long-term infusions. Total plasma clearance (Cl) is 0.4 L/hr���kg, and the apparent volume of distribution (V) using a non-compartment model is 8.3 L/kg. The pharmacokinetics of Cardene I.V. are linear over the dosage range of 0.5 to 40.0 mg/hr. Rapid dose-related increases in nicardipine plasma concentrations are seen during the first two hours after the start of an infusion of Cardene I.V. Plasma concentrations increase at a much slower rate after the first few hours, and approach steady state at 24 to 48 hours. On termination of the infusion, nicardipine concentrations decrease rapidly, with at least a 50% decrease during the first two hours post-infusion. The effects of nicardipine on blood pressure significantly correlate with plasma concentrations. Nicardipine is highly protein bound (>95%) in human plasma over a wide concentration range. Cardene I.V. has been shown to be rapidly and extensively metabolized by the liver. After coadministration of a radioactive intravenous dose of Cardene I.V. with an oral 30 mg dose given every 8 hours, 49% of the radioactivity was recovered in the urine and 43% in the feces within 96 hours. None of the dose was recovered as unchanged nicardipine. Nicardipine does not induce or inhibit its own metabolism and does not induce or inhibit hepatic microsomal enzymes. The steady-state pharmacokinetics of nicardipine are similar in elderly hypertensive patients (>65 years) and young healthy adults.<br/>HEMODYNAMICS: Cardene I.V. produces significant decreases in systemic vascular resistance. In a study of intra-arterially administered Cardene I.V., the degree of vasodilation and the resultant decrease in blood pressure were more prominent in hypertensive patients than in normotensive volunteers. Administration of Cardene I.V. to normotensive volunteers at dosages of 0.25 to 3.0 mg/hr for eight hours produced changes of<5 mmHg in systolic blood pressure and<3 mmHg in diastolic blood pressure. An increase in heart rate is a normal response to vasodilation and decrease in blood pressure; in some patients these increases in heart rate may be pronounced. In placebo-controlled trials, the mean increases in heart rate were 7��1 bpm in postoperative patients and 8��1 bpm in patients with severe hypertension at the end of the maintenance period. Hemodynamic studies following intravenous dosing in patients with coronary artery disease and normal or moderately abnormal left ventricular function have shown significant increases in ejection fraction and cardiac output with no significant change, or a small decrease, in left ventricular end-diastolic pressure (LVEDP). There is evidence that Cardene increases blood flow. Coronary dilatation induced by Cardene I.V. improves perfusion and aerobic metabolism in areas with chronic ischemia, resulting in reduced lactate production and augmented oxygen consumption. In patients with coronary artery disease, Cardene I.V., administered after beta-blockade, significantly improved systolic and diastolic left ventricular function. In congestive heart failure patients with impaired left ventricular function, Cardene I.V. increased cardiac output both at rest and during exercise. Decreases in left ventricular end-diastolic pressure were also observed. However, in some patients with severe left ventricular dysfunction, it may have a negative inotropic effect and could lead to worsened failure. ���Coronary steal���has not been observed during treatment with Cardene I.V. (Coronary steal is the detrimental redistribution of coronary blood flow in patients with coronary artery disease from underperfused areas toward better perfused areas.) Cardene I.V. has been shown to improve systolic shortening in both normal and hypokinetic segments of myocardial muscle. Radionuclide angiography has confirmed that wall motion remained improved during increased oxygen demand. (Occasional patients have developed increased angina upon receiving Cardene capsules. Whether this represents coronary steal in these patients, or is the result of increasedheart rate and decreased diastolic pressure, is not clear.) In patients with coronary artery disease, Cardene I.V. improves left ventricular diastolic distensibility during the early filling phase, probably due to a faster rate of myocardial relaxation in previously underperfused areas. There is little or no effect on normal myocardium, suggesting the improvement is mainly by indirect mechanisms such as afterload reduction and reduced ischemia. Cardene I.V. has no negative effect on myocardial relaxation at therapeutic doses. The clinical benefits of these properties have not yet been demonstrated.<br/>ELECTROPHYSIOLOGIC EFFECTS: In general, no detrimental effects on the cardiac conduction system have been seen with Cardene I.V. During acute electrophysiologic studies, it increased heart rate and prolonged the corrected QT interval to a minor degree. It did not affect sinus node recovery or SA conduction times. The PA, AH, and HV intervalsor the functional and effective refractory periods of the atrium were not prolonged. The relative and effective refractory periods of the His-Purkinje system were slightly shortened.<br/>HEPATIC FUNCTION: Because nicardipine is extensively metabolized by the liver, plasma concentrations are influenced by changes in hepatic function. In a clinical study with Cardene capsules in patients with severe liver disease, plasma concentrations were elevated and the half-life was prolonged (see���Precautions���). Similar results were obtained in patients with hepatic disease when Cardene I.V. (nicardipine hydrochloride) was administered for 24 hours at 0.6 mg/hr.<br/>RENAL FUNCTION: When Cardene I.V. was given to mild to moderate hypertensive patients with moderate degrees of renal impairment, significant reduction in glomerular filtration rate (GFR) and effective renal plasma flow (RPF) was observed. No significant differences in liver blood flow were observed in these patients. A significantly lower systemic clearance and higher area under the curve (AUC) were observed. When Cardene capsules (20 mg or 30 mg TID) were given to hypertensive patients with impaired renal function, mean plasma concentrations, AUC, and Cmax were approximately two-fold higher than in healthy controls. There is a transient increase in electrolyte excretion, including sodium (see���Precautions���). Acute bolus administration of Cardene I.V. (2.5 mg) in healthy volunteers decreased mean arterial pressure and renal vascular resistance; glomerular filtration rate (GFR), renal plasma flow (RPF), and the filtration fraction were unchanged. In healthy patients undergoing abdominal surgery, Cardene I.V. (10 mg over 20 minutes) increased GFR with no change in RPF when compared with placebo. In hypertensive type II diabetic patients with nephropathy, Cardene capsules (20 mg TID) did not change RPF and GFR, but reduced renal vascular resistance.<br/>PULMONARY FUNCTION: In two well-controlled studies of patients with obstructive airway disease treated with Cardene capsules, no evidence of increased bronchospasm was seen. In one of the studies, Cardene capsules improved forced expiratory volume 1 second (FEV) and forced vital capacity (FVC) in comparison with metoprolol. Adverse experiences reported in a limited number of patients with asthma, reactive airway disease, or obstructive airway disease are similar to all patients treated with Cardene capsules.<br/>EFFECTS IN HYPERTENSION: In patients with mild to moderate chronic stable essential hypertension, Cardene I.V. (0.5 to 4.0 mg/hr) produced dose-dependent decreases in blood pressure, although only the decreases at 4.0 mg/hr were statistically different from placebo. At the end of a 48-hour infusion at 4.0 mg/hr, the decreases were 26.0 mmHg (17%) in systolic blood pressure and 20.7 mmHg (20%) in diastolic blood pressure. In other settings (e.g., patients with severe or postoperative hypertension), Cardene I.V. (5 to 15 mg/hr) produced dose-dependent decreases in blood pressure. Higher infusion rates produced therapeutic responses more rapidly. The mean time to therapeutic response for severe hypertension, defined as diastolic blood pressure���95 mmHg or���25 mmHg decrease and systolic blood pressure���160 mmHg, was 77��5.2 minutes. The average maintenance dose was 8.0 mg/hr. The mean time to therapeutic response for postoperative hypertension, defined as���15% reduction in diastolic or systolic blood pressure, was 11.5��0.8 minutes. The average maintenance dose was 3.0 mg/hr. | lld:dailymed |
| dailymed-drugs:128 | dailymed-instance:clinicalP... | Studies in healthy volunteers show that in single high doses Ativan (lorazepam) has a tranquilizing action on the central nervous system with no appreciable effect on the respiratory or cardiovascular systems. Ativan (lorazepam) is readily absorbed with an absolute bioavailability of 90 percent. Peak concentrations in plasma occur approximately 2 hours following administration. The peak plasma level of lorazepam from a 2 mg dose is approximately 20 ng/mL. The mean half-life of unconjugated lorazepam in human plasma is about 12 hours and for its major metabolite, lorazepam glucuronide, about 18 hours. At clinically relevant concentrations, lorazepam is approximately 85% bound to plasma proteins. Ativan (lorazepam) is rapidly conjugated at its 3-hydroxy group into lorazepam glucuronide which is then excreted in the urine. Lorazepam glucuronide has no demonstrable CNS activity in animals. The plasma levels of lorazepam are proportional to the dose given. There is no evidence of accumulation of lorazepam on administration up to six months. Studies comparing young and elderly subjects have shown that advancing age does not have a significant effect on the pharmacokinetics of lorazepam. However, in one study involving single intravenous doses of 1.5 to 3 mg of Ativan Injection, mean total body clearance of lorazepam decreased by 20% in 15 elderly subjects of 60 to 84 years of age compared to that in 15 younger subjects of 19 to 38 years of age. | lld:dailymed |
| dailymed-drugs:129 | dailymed-instance:clinicalP... | Pharmacokinetics: In a multiple dose pharmacokinetic study that included 5 male patients with interdigital tinea pedis (range of diseased area, 42 - 140 cm; mean, 93 cm), ERTACZO Cream, 2%, was topically applied every 12 hours for a total of 13 doses to the diseased skin (0.5 grams sertaconazole nitrate per 100 cm). Sertaconazole concentrations in plasma measured by serial blood sampling for 72 hours after the thirteenth dose were below the limit of quantitation (2.5 ng/mL) of the analytical method used. Microbiology: Sertaconazole is an antifungal that belongs to the imidazole class of antifungals. While the exact mechanism of action of this class of antifungals is not known, it is believed that they act primarily by inhibiting the cytochrome P450-dependent synthesis of ergosterol. Ergosterol is a key component of the cell membrane of fungi, and lack of this component leads to fungal cell injury primarily byleakage of key constituents in the cytoplasm from the cell. ActivityIn Vivo: Sertaconazole nitrate has been shown to be active against isolates of the following microorganisms in clinical infections as described in the INDICATIONS AND USAGE section: Trichophyton rubrum Trichophyton mentagrophytes Epidermophyton floccosum | lld:dailymed |
| dailymed-drugs:131 | dailymed-instance:clinicalP... | When ketoconazole cream, 2% was applied dermally to intact or abraded skin of Beagle dogs for 28 consecutive days at a dose of 80 mg, there were no detectable plasma levels using an assay method having a lower detection limit of 2 ng/ml. After a single topical application to the chest, back and arms of normal volunteers, systemic absorption of ketoconazole was not detected at the 5 ng/ml level in blood over a 72-hour period. Two dermal irritancy studies, a human sensitization test, a phototoxicity study and a photoallergy study conducted in 38 male and 62 female volunteers showed no contact sensitization of the delayed hypersensitivity type, no irritation, no phototoxicity and no photoallergenic potential due to ketoconazole cream, 2%.<br/>Microbiology: Ketoconazole is a broad spectrum synthetic antifungal agent which inhibits the in vitro growth of the following common dermatophytes and yeasts by altering the permeability of the cell membrane: dermatophytes: Trichophyton rubrum, T. mentagrophytes, T. tonsurans, Microsporum canis, M. audouini, M. gypseum and Epidermophyton floccosum; yeasts: Candida albicans, Malassezia ovale (Pityrosporum ovale) and C. tropicalis; and the organism responsible for tinea versicolor, Malassezia furfur (Pityrosporum orbiculare). Only those organisms listed in the INDICATIONS AND USAGE Section have been proven to be clinically affected. Development of resistance to ketoconazole has not been reported.<br/>Mode of Action: In vitro studies suggest that ketoconazole impairs the synthesis of ergosterol, which is a vital component of fungal cell membranes. | lld:dailymed |
| dailymed-drugs:132 | dailymed-instance:clinicalP... | Visken (pindolol) is a non-selective beta-adrenergic antagonist (beta-blocker) which possesses intrinsic sympathomimetic activity (ISA) in therapeutic dosage ranges but does not possess quinidine-like membrane stabilizing activity. | lld:dailymed |
| dailymed-drugs:134 | dailymed-instance:clinicalP... | ZANTAC is a competitive, reversible inhibitor of the action of histamine at the histamine H-receptors, including receptors on the gastric cells. ZANTAC does not lower serum Ca++ in hypercalcemic states. ZANTAC is not an anticholinergic agent.<br/>Pharmacokinetics:<br/>Absorption: ZANTAC is 50% absorbed after oral administration, compared to an intravenous (IV) injection with mean peak levels of 440 to 545 ng/mL occurring 2 to 3 hours after a 150-mg dose. The syrup and EFFERdose formulations are bioequivalent to the tablets. Absorption is not significantly impaired by the administration of food or antacids. Propantheline slightly delays and increases peak blood levels of ZANTAC, probably by delaying gastric emptying and transit time. In one study, simultaneous administration of high-potency antacid (150 mmol) in fasting subjects has been reported to decrease the absorption of ZANTAC.<br/>Distribution: The volume of distribution is about 1.4 L/kg. Serum protein binding averages 15%.<br/>Metabolism: In humans, the N-oxide is the principal metabolite in the urine; however, this amounts to<4% of the dose. Other metabolites are the S-oxide (1%) and the desmethyl ranitidine (1%). The remainder of the administered dose is found in the stool. Studies in patients with hepatic dysfunction (compensated cirrhosis) indicate that there are minor, but clinically insignificant, alterations in ranitidine half-life, distribution, clearance, and bioavailability.<br/>Excretion: The principal route of excretion is the urine, with approximately 30% of the orally administered dose collected in the urine as unchanged drug in 24 hours. Renal clearance is about 410 mL/min, indicating active tubular excretion. The elimination half-life is 2.5 to 3 hours. Four patients with clinically significant renal function impairment (creatinine clearance 25 to 35 mL/min) administered 50 mg of ranitidine intravenously had an average plasma half-life of 4.8 hours, a ranitidine clearance of 29 mL/min, and a volume of distribution of 1.76 L/kg. In general, these parameters appear to be altered in proportion to creatinine clearance (see DOSAGE AND ADMINISTRATION).<br/>Geriatrics: The plasma half-life is prolonged and total clearance is reduced in the elderly population due to a decrease in renal function. The elimination half-life is 3 to 4 hours. Peak levels average 526 ng/mL following a 150-mg twice daily dose and occur in about 3 hours (see PRECAUTIONS: Geriatric Use and DOSAGE AND ADMINISTRATION: Dosage Adjustment for Patients With Impaired Renal Function).<br/>Pediatrics: There are no significant differences in the pharmacokinetic parameter values for ranitidine in pediatric patients (from 1 month up to 16 years of age) and healthy adults when correction is made for body weight. The average bioavailability of ranitidine given orally to pediatric patients is 48% which is comparable to the bioavailability of ranitidine in the adult population. All other pharmacokinetic parameter values (t, Vd, and CL) are similar to those observed with intravenous ranitidine use in pediatric patients. Estimates of Cand Tare displayed in Table 1. Plasma clearance measured in 2 neonatal patients (less than 1 month of age) was considerably lower (3 mL/min/kg) than children or adults and is likely due to reduced renal function observed in this population (see PRECAUTIONS: Pediatric Use and DOSAGE AND ADMINISTRATION: Pediatric Use).<br/>Pharmacodynamics: Serum concentrations necessary to inhibit 50% of stimulated gastric acid secretion are estimated to be 36 to 94 ng/mL. Following a single oral dose of 150 mg, serum concentrations of ZANTAC are in this range up to 12 hours. However, blood levels bear no consistent relationship to dose or degree of acid inhibition. In a pharmacodynamic comparison of the EFFERdose with the ZANTAC Tablets, during the first hour after administration, the EFFERdose tablet formulation gave a significantly higher intragastric pH, by approximately 1 pH unit, compared to the ZANTAC tablets.<br/>Antisecretory Activity:<br/>Other Pharmacologic Actions:<br/>Pediatrics: Oral doses of 6 to 10 mg/kg per day in 2 or 3 divided doses maintain gastric pH>4 throughout most of the dosing interval.<br/>Clinical Trials:<br/>Active Duodenal Ulcer: In a multicenter, double-blind, controlled, US study of endoscopically diagnosed duodenal ulcers, earlier healing was seen in the patients treated with ZANTAC as shown in Table 3. *All patients were permitted p.r.n. antacids for relief of pain. P<0.0001. In these studies, patients treated with ZANTAC reported a reduction in both daytime and nocturnal pain, and they also consumed less antacid than the placebo-treated patients. Foreign studies have shown that patients heal equally well with 150 mg b.i.d. and 300 mg h.s. (85% versus 84%, respectively) during a usual 4-week course of therapy. If patients require extended therapy of 8 weeks, the healing rate may be higher for 150 mg b.i.d. as compared to 300 mg h.s. (92% versus 87%, respectively). Studies have been limited to short-term treatment of acute duodenal ulcer. Patients whose ulcers healed during therapy had recurrences of ulcers at the usual rates.<br/>Maintenance Therapy in Duodenal Ulcer: Ranitidine has been found to be effective as maintenance therapy for patients following healing of acute duodenal ulcers. In 2 independent, double-blind, multicenter, controlled trials, the number of duodenal ulcers observed was significantly less in patients treated with ZANTAC (150 mg h.s.) than in patients treated with placebo over a 12-month period. % = Life table estimate. * = P<0.05 (ZANTAC versus comparator). RAN = ranitidine (ZANTAC). PLC = placebo. As with other H-antagonists, the factors responsible for the significant reduction in the prevalence of duodenal ulcers include prevention of recurrence of ulcers, more rapid healing of ulcers that may occur during maintenance therapy, or both.<br/>Gastric Ulcer: In a multicenter, double-blind, controlled, US study of endoscopically diagnosed gastric ulcers, earlier healing was seen in the patients treated with ZANTAC as shown in Table 6. *All patients were permitted p.r.n. antacids for relief of pain. P = 0.009. In this multicenter trial, significantly more patients treated with ZANTAC became pain free during therapy.<br/>Maintenance of Healing of Gastric Ulcers: In 2 multicenter, double-blind, randomized, placebo-controlled, 12-month trials conducted in patients whose gastric ulcers had been previously healed, ZANTAC 150 mg h.s. was significantly more effective than placebo in maintaining healing of gastric ulcers.<br/>Pathological Hypersecretory Conditions (such as Zollinger-Ellison syndrome): ZANTAC inhibits gastric acid secretion and reduces occurrence of diarrhea, anorexia, and pain in patients with pathological hypersecretion associated with Zollinger-Ellison syndrome, systemic mastocytosis, and other pathological hypersecretory conditions (e.g., postoperative, "short-gut" syndrome, idiopathic). Use of ZANTAC was followed by healing of ulcers in 8 of 19 (42%) patients who were intractable to previous therapy.<br/>Gastroesophageal Reflux Disease (GERD): In 2 multicenter, double-blind, placebo-controlled, 6-week trials performed in the United States and Europe, ZANTAC 150 mg b.i.d. was more effective than placebo for the relief of heartburn and other symptoms associated with GERD. Ranitidine-treated patients consumed significantly less antacid than did placebo-treated patients. The US trial indicated that ZANTAC 150 mg b.i.d. significantly reduced the frequency of heartburn attacks and severity of heartburn pain within 1 to 2 weeks after starting therapy. The improvement was maintained throughout the 6-week trial period. Moreover, patient response rates demonstrated that the effect on heartburn extends through both the day and night time periods. In 2 additional US multicenter, double-blind, placebo-controlled, 2-week trials, ZANTAC 150 mg b.i.d. was shown to provide relief of heartburn pain within 24 hours of initiating therapy and a reduction in the frequency of severity of heartburn. In these trials, ZANTAC EFFERdose Tablets were shown to provide heartburn relief within 45 minutes of dosing.<br/>Erosive Esophagitis: In 2 multicenter, double-blind, randomized, placebo-controlled, 12-week trials performed in the United States, ZANTAC 150 mg q.i.d. was significantly more effective than placebo in healing endoscopically diagnosed erosive esophagitis and in relieving associated heartburn. The erosive esophagitis healing rates were as follows: *All patients were permitted p.r.n. antacids for relief of pain. P<0.001 versus placebo. No additional benefit in healing of esophagitis or in relief of heartburn was seen with a ranitidine dose of 300 mg q.i.d.<br/>Maintenance of Healing of Erosive Esophagitis: In 2 multicenter, double-blind, randomized, placebo-controlled, 48-week trials conducted in patients whose erosive esophagitis had been previously healed, ZANTAC 150 mg b.i.d. was significantly more effective than placebo in maintaining healing of erosive esophagitis. | lld:dailymed |
| dailymed-drugs:135 | dailymed-instance:clinicalP... | Pharmacokinetics: PROTONIX Delayed-Release Tablets are prepared as enteric-coated tablet so that absorption of pantoprazole begins only after the tablet leaves the stomach. Peak serum concentration (C) and area under the serum concentration time curve (AUC) increase in a manner proportional to oral and intravenous doses from 10 mg to 80 mg. Pantoprazole does not accumulate and its pharmacokinetics are unaltered with multiple daily dosing. Following oral or intravenous administration, the serum concentration of pantoprazole declines biexponentially with a terminal elimination half-life of approximately one hour. In extensive metabolizers (see CLINICAL PHARMACOLOGY, Pharmacokinetics, Metabolism) with normal liver function receiving an oral dose of the enteric-coated 40 mg pantoprazole tablet, the peak concentration (C) is 2.5��g/mL, the time to reach the peak concentration (t) is 2.5 h and the total area under the plasma concentration versus time curve (AUC) is 4.8��g��hr/mL. When pantoprazole is given with food, its tis highly variable and may increase significantly. Following intravenous administration of pantoprazole to extensive metabolizers, its total clearance is 7.6-14.0 L/h and its apparent volume of distribution is 11.0���23.6 L. PROTONIX (pantoprazole sodium) For Delayed-Release Oral Suspension has been shown to be comparable to PROTONIX (pantoprazole sodium) Delayed-Release Tablets in suppressing pentagastrin-stimulated maximum acid output (MAO) in patients with gastroesophageal reflux disease (GERD) and a history of erosive esophagitis (EE) (see Clinical Pharmacology, Pharmacodynamics). PROTONIX For Delayed-Release Oral Suspension is bioequivalent when administered orally in applesauce or apple juice, or mixed in apple juice and administered through a nasogastric tube. The plasma pharmacokinetic parameters from a crossover study in healthy subjects are summarized in the table below. In this study, a single oral 40 mg dose of Protonix For Delayed-Release Oral Suspension was administered to healthy subjects (N = 22) as granules sprinkled over a teaspoonful of applesauce, as granules mixed with apple juice and, mixed with apple juice followed by administration through a nasogastric tube.<br/>Absorption: The absorption of pantoprazole is rapid, with a Cof 2.5��g/mL that occurs approximately 2.5 hours after administration of a single or multiple oral 40 mg doses of PROTONIX (pantoprazole sodium) Delayed-Release Tablets. Pantoprazole is well absorbed; it undergoes little first-pass metabolism resulting in an absolute bioavailability of approximately 77%. Pantoprazole absorption is not affected by concomitant administration of antacids. Administration of PROTONIX (pantoprazole sodium) Delayed-Release Tablets with food may delay its absorption up to 2 hours or longer; however, the Cand the extent of pantoprazole absorption (AUC) are not altered. Thus, PROTONIX (pantoprazole sodium) Delayed-release Tablets may be taken without regard to timing of meals. PROTONIX (pantoprazole sodium) For Delayed-Release Oral Suspension should be taken approximately 30 minutes before a meal.<br/>Distribution: The apparent volume of distribution of pantoprazole is approximately 11.0-23.6 L, distributing mainly in extracellular fluid. The serum protein binding of pantoprazole is about 98%, primarily to albumin.<br/>Metabolism: Pantoprazole is extensively metabolized in the liver through the cytochrome P450 (CYP) system. Pantoprazole metabolism is independent of the route of administration (intravenous or oral). The main metabolic pathway is demethylation, by CYP2C19, with subsequent sulfation; other metabolic pathways include oxidation by CYP3A4. There is no evidence that any of the pantoprazole metabolites have significant pharmacologic activity. CYP2C19 displays a known genetic polymorphism due to its deficiency in some sub-populations (eg, 3% of Caucasians and African-Americans and 17%-23% of Asians). Although these sub-populations of slow pantoprazole metabolizers have elimination half-life values of 3.5 to 10.0 hours, they still have minimal accumulation (���23%) with once daily dosing.<br/>Elimination: After a single oral or intravenous dose ofC-labeled pantoprazole to healthy, normal metabolizer volunteers, approximately 71% of the dose was excreted in the urine with 18% excreted in the feces through biliary excretion. There was no renal excretion of unchanged pantoprazole.<br/>Special Populations:<br/>Drug-Drug Interactions: Pantoprazole is metabolized mainly by CYP2C19 and to minor extents by CYPs 3A4, 2D6, and 2C9. In in vivo drug-drug interaction studies with CYP2C19 substrates (diazepam [also a CYP3A4 substrate] and phenytoin [also a CYP3A4 inducer]), nifedipine, midazolam, and clarithromycin (CYP3A4 substrates), metoprolol (a CYP2D6 substrate), diclofenac, naproxen and piroxicam (CYP2C9 substrates), and theophylline (a CYP1A2 substrate) in healthy subjects, the pharmacokinetics of pantoprazole were not significantly altered. It is, therefore, expected that other drugs metabolized by CYPs 2C19, 3A4, 2D6, 2C9, and 1A2 would not significantly affect the pharmacokinetics of pantoprazole. In vivo studies also suggest that pantoprazole doesnot significantly affect the kinetics of other drugs (cisapride, theophylline, diazepam [and its active metabolite, desmethyldiazepam], phenytoin, warfarin, metoprolol, nifedipine, carbamazepine, midazolam, clarithromycin, naproxen, piroxicam, and oral contraceptives [levonorgestrel/ethinyl estradiol]) metabolized by CYPs 2C19, 3A4, 2C9, 2D6, and 1A2. Therefore, it is expected that pantoprazole would not significantly affect the pharmacokinetics of other drugs metabolized by these isozymes. Dosage adjustment of such drugs is not necessary when they are coadministered with pantoprazole. In other in vivo studies, digoxin, ethanol, glyburide, antipyrine, caffeine, metronidazole, and amoxicillin had no clinically relevant interactions with pantoprazole. Although no significant drug-drug interactions have been observed in clinical studies, the potential for significant drug-drug interactions with more than once daily dosing with high doses of pantoprazole has not been studied in poor metabolizers or individuals who are hepatically impaired.<br/>Pharmacodynamics: PROTONIX (pantoprazole sodium) For Delayed-Release Oral Suspension has been shown to be comparable to PROTONIX (pantoprazole sodium) Delayed-Release Tablets in suppressing pentagastrin-stimulated MAO in patients (n = 49) with GERD and a history of EE. In this multicenter pharmacodynamic crossover study a 40 mg oral dose of Protonix For Delayed-Release Oral Suspension administered in a teaspoonful of applesauce was compared with a 40 mg oral dose of Protonix Delayed-Release Tablets after administration of each formulation once daily for 7 days. Both medications were administered thirty minutes before breakfast. Pentagastrin-stimulated (MAO) was assessed from hour 23 to 24 at steady state.<br/>Mechanism of Action: Pantoprazole is a proton pump inhibitor (PPI) that suppresses the final step in gastric acid production by covalently binding to the (H,K)-ATPase enzyme system at the secretory surface of the gastric parietal cell. This effect leads to inhibition of both basal and stimulated gastric acid secretion irrespective of the stimulus. The binding to the (H,K)-ATPase results in a duration of antisecretory effect that persists longer than 24 hours for all doses tested.<br/>Antisecretory Activity: Under maximal acid stimulatory conditions using pentagastrin, a dose-dependent decrease in gastric acid output occurs after a single dose of oral (20-80 mg) or a single dose of intravenous (20-120 mg) pantoprazole in healthy volunteers. Pantoprazole given once daily results in increasing inhibition of gastric acid secretion. Following the initial oral dose of 40 mg pantoprazole, a 51% mean inhibition was achieved by 2.5 hours. With once a day dosing for 7 days the mean inhibition was increased to 85%. Pantoprazole suppressed acid secretion in excess of 95% in half of the subjects. Acid secretion had returned to normal within a week after the last dose of pantoprazole; there was no evidence of rebound hypersecretion. In a series of dose-response studies pantoprazole, at oral doses ranging from 20 to 120 mg, caused dose-related increases in median basal gastric pH and in the percent of time gastric pH was>3 and>4. Treatment with 40 mg of pantoprazole produced optimal increases in gastric pH which were significantly greater than the 20-mg dose. Doses higher than 40 mg (60, 80, 120 mg) did not result in further significant increases in median gastric pH. The effects of pantoprazole on median pH from one double-blind crossover study are shown below.<br/>Serum Gastrin Effects: Fasting serum gastrin levels were assessed in two double-blind studies of the acute healing of erosive esophagitis (EE) in which 682 patients with gastroesophageal reflux disease (GERD) received 10, 20, or 40 mg of PROTONIX for up to 8 weeks. At 4 weeks of treatment there was an increase in mean gastrin levels of 7%, 35%, and 72% over pretreatment values in the 10, 20, and 40 mg treatment groups, respectively. A similar increasein serum gastrin levels was noted at the 8 week visit with mean increases of 3%, 26%, and 84% for the three pantoprazole dose groups. Median serum gastrin levels remained within normal limits during maintenance therapy with PROTONIX Delayed-Release Tablets. In long-term international studies involving over 800 patients, a 2- to 3-fold mean increase from the pretreatment fasting serum gastrin level was observed in the initial months of treatment with pantoprazole at doses of 40 mg per day during GERD maintenance studies and 40 mg or higher per day in patients with refractory GERD. Fasting serum gastrin levels generally remained at approximately 2 to 3 times baseline for up to 4 years of periodic follow-up in clinical trials. Following healing of gastric or duodenal ulcers with pantoprazole treatment, elevated gastrin levels return to normal by at least 3 months.<br/>Enterochromaffin-Like (ECL) Cell Effects: In 39 patients treated with oral pantoprazole 40 mg to 240 mg daily (majority receiving 40 mg to 80 mg) for up to 5 years, there was a moderate increase in ECL-cell density starting after the first year of use which appeared to plateau after 4 years. In a nonclinical study in Sprague-Dawley rats, lifetime exposure (24 months) to pantoprazole at doses of 0.5 to 200 mg/kg/day resulted in dose-related increases in gastric ECL-cell proliferation and gastric neuroendocrine (NE)-cell tumors. Gastric NE-cell tumors in rats may result from chronic elevation of serum gastrin concentrations. The high density of ECL cells in the rat stomach makes this species highly susceptible to the proliferative effects of elevated gastrin concentrations produced by proton pump inhibitors. However, there were no observed elevations in serum gastrin following the administration of pantoprazole at a dose of 0.5 mg/kg/day. In a separate study, a gastric NE-cell tumor without concomitant ECL-cell proliferative changes was observed in 1 female rat following 12 months of dosing with pantoprazole at 5 mg/kg/day and a 9 month off-dose recovery (see PRECAUTIONS, Carcinogenesis, Mutagenesis, Impairment of Fertility).<br/>Other Effects: No clinically relevant effects of pantoprazole on cardiovascular, respiratory, ophthalmic, or central nervous system function have been detected. In a clinical pharmacology study, pantoprazole 40 mg given once daily for 2 weeks had no effect on the levels of the following hormones: cortisol, testosterone, triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), thyronine-binding protein, parathyroid hormone, insulin, glucagon, renin, aldosterone, follicle-stimulating hormone, luteinizing hormone, prolactin, and growth hormone. In a 1-year study of GERD patients treated with pantoprazole 40 mg or 20 mg, there were no changes from baseline in overall levels of T3, T4, and TSH.<br/>Clinical Studies: PROTONIX Delayed-Release Tablets were used in the following clinical trials:<br/>Erosive Esophagitis (EE) Associated with Gastroesophageal Reflux Disease (GERD): A U.S. multicenter double-blind, placebo-controlled study of PROTONIX 10 mg, 20 mg, or 40 mg once daily was conducted in 603 patients with reflux symptoms and endoscopically diagnosed EE of grade 2 or above (Hetzel-Dent scale). In this study, approximately 25% of enrolled patients had severe EE of grade 3 and 10% hadgrade 4. The percentages of patients healed (per protocol, n = 541) in this study were as follows: In this study, all PROTONIX treatment groups had significantly greater healing rates than the placebo group. This was true regardless of H. pylori status for the 40-mg and 20-mg PROTONIX treatment groups. The 40-mg dose of PROTONIX resulted in healing rates significantly greater than those found with either the 20- or 10-mg dose. A significantly greater proportion of patients taking PROTONIX 40 mg experienced complete relief of daytime and nighttime heartburn and the absence of regurgitation starting from the first day of treatment compared with placebo. Patients taking PROTONIX consumed significantly fewer antacid tablets per day than those taking placebo. PROTONIX 40 mg and 20 mg once daily were also compared with nizatidine 150 mg twice daily in a U.S. multicenter, double-blind study of 243 patients with reflux symptoms and endoscopically diagnosed EE of grade 2 or above. The percentages of patients healed (per protocol, n = 212) were as follows: Once daily treatment with PROTONIX 40 mg or 20 mg resulted in significantly superior rates of healing at both 4 and 8 weeks compared with twice daily treatment with 150 mg of nizatidine. For the 40 mg treatment group, significantly greater healing rates compared to nizatidine were achieved regardless of the H. pylori status. A significantly greater proportion of the patients in the PROTONIX treatment groups experienced complete relief of nighttime heartburn and regurgitation starting on the first day and of daytime heartburn on the second day compared with those taking nizatidine 150 mg twice daily. Patients taking PROTONIX consumed significantly fewer antacid tablets per day than those taking nizatidine.<br/>Long-Term Maintenance of Healing of Erosive Esophagitis: Two independent, multicenter, randomized, double-blind, comparator-controlled trials of identical design were conducted in GERD patients with endoscopically-confirmed healed erosive esophagitis to demonstrate efficacy of PROTONIX in long-term maintenance of healing. The two U.S. studies enrolled 386 and 404 patients, respectively, to receive either 10 mg, 20 mg, or 40 mg of PROTONIX Delayed-Release Tablets once daily or 150 mg of ranitidine twice daily. As demonstrated in the tablebelow, PROTONIX 40 mg and 20 mg were significantly superior to ranitidine at every time point with respect to the maintenance of healing. In addition, PROTONIX 40 mg was superior to all other treatments studied. PROTONIX 40 mg was superior to ranitidine in reducing the number of daytime and nighttime heartburn episodes from the first through the twelfth month of treatment. PROTONIX 20 mg, administered once daily, was also effective in reducing episodes of daytime and nighttime heartburn in one trial.<br/>Pathological Hypersecretory Conditions Including Zollinger-Ellison Syndrome: In a multicenter, open-label trial of 35 patients with pathological hypersecretory conditions, such as Zollinger-Ellison syndrome with or without multiple endocrine neoplasia-type I, PROTONIX successfully controlled gastric acid secretion. Doses ranging from 80 mg daily to 240 mg daily maintained gastric acid output below 10 mEq/h in patients without prior acid-reducing surgery and below 5 mEq/h in patients with prior acid-reducing surgery. Doses were initially titrated to the individual patient needs, and adjusted in some patients based on the clinical response with time . PROTONIX was well tolerated at these dose levels for prolonged periods (greater than 2 years in some patients). | lld:dailymed |
| dailymed-drugs:136 | dailymed-instance:clinicalP... | Pharmacodynamics: CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereospecific receptors at several sites within the central nervous system. Their exact mechanism of action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis.<br/>Pharmacokinetics:<br/>Absorption: Following oral administration of alprazolam (immediate-release) tablets, alprazolam is readily absorbed. Peak concentrations in the plasma occur in one to two hours following administration. Plasma levels are proportional to the dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL were observed. Using a specific assay methodology, the mean plasma elimination half-life of alprazolam has been found to be about 11.2 hours (range: 6.3-26.9 hours) in healthy adults. The mean absolute bioavailability of alprazolam from alprazolam extended-release tablets is approximately 90%, and the relative bioavailability compared to alprazolam tablets is 100%. The bioavailability and pharmacokinetics of alprazolam following administration of alprazolam extended-release tablets are similar to that for alprazolam tablets, with the exception of a slower rate of absorption. The slower absorption rate results in a relatively constant concentration that is maintained between 5 and 11 hours after the dosing. The pharmacokinetics of alprazolam and two of its major active metabolites (4-hydroxyalprazolam and��-hydroxyalprazolam) are linear, and concentrations are proportional up to the recommended maximum daily dose of 10 mg given once daily. Multiple dose studies indicate that the metabolism and elimination of alprazolam are similar for the immediate-release and the extended-release products. Food has a significant influence on the bioavailability of alprazolam extended-release tablets. A high-fat meal given up to 2 hours before dosing with alprazolam extended-release tablets increased the mean Cby about 25%. The effect of this meal on Tdepended on the timing of the meal, with a reduction in Tby about 1/3 for subjects eating immediately before dosing and an increase in Tby about 1/3 for subjects eating 1 hour or more after dosing. The extent of exposure (AUC) and elimination half-life (t) were not affected by eating. There were significant differences in absorption rate for the alprazolam extended-release tablet, depending on the time of day administered, with the Cincreased by 30% and the Tdecreased by an hour following dosing at night, compared to morning dosing.<br/>Distribution: The apparent volume of distribution of alprazolam is similar for alprazolam extended-release tablets and alprazolam tablets. In vitro, alprazolam is bound (80%) to human serum protein. Serum albumin accounts for the majority of the binding.<br/>Metabolism: Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and��-hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. The pharmacokinetic parameters at steady-state for the two hydroxylated metabolites of alprazolam (4-hydroxyalprazolam and��-hydroxyalprazolam) were similar for alprazolam tablets and alprazolam extended-release tablets, indicating that the metabolism of alprazolam is not affected by absorption rate. The plasma concentrations of 4-hydroxyalprazolam and��-hydroxyalprazolam relative to unchanged alprazolam concentration after both alprazolam extended-release tablets and alprazolam tablets were always less than 10% and 4%, respectively. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and��-hydroxyalprazolam. Such low concentrations and the lesser potencies of 4-hydroxyalprazolam and��-hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.<br/>Elimination: Alprazolam and its metabolites are excreted primarily in the urine. The mean plasma elimination half-life of alprazolam following administration of alprazolam extended-release tablet ranges from 10.7-15.8 hours in healthy adults.<br/>Special Populations: While pharmacokinetic studies have not been performed in special populations with alprazolam extended-release tablets, the factors (such as age, gender, hepatic or renal impairment) that would affect the pharmacokinetics of alprazolam after the administration of alprazolam tablets would not be expected to be different with the administration of alprazolam extended-release tablets. Changes in the absorption, distribution, metabolism, and excretion of benzodiazepines have been reported in a variety of disease states including alcoholism, impaired hepatic function, and impaired renal function. Changes have also been demonstrated in geriatric patients. A mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects (range: 9.0-26.9 hours, n=16) compared to 11.0 hours (range: 6.3-15.8 hours, n=16) in healthy adult subjects. In patients with alcoholic liver disease the half-life of alprazolam ranged between 5.8 and 65.3 hours (mean: 19.7 hours, n=17) as compared to between 6.3 and 26.9 hours (mean=11.4 hours, n=17) in healthy subjects. In an obese group of subjects the half-life of alprazolam ranged between 9.9 and 40.4 hours (mean=21.8 hours, n=12) as compared to between 6.3 and 15.8 hours (mean=10.6 hours, n=12) in healthy subjects. Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes transplacental passage and that it is excreted in human milk. Race Maximal concentrations and half-life of alprazolam are approximately 15% and 25% higher in Asians compared to Caucasians. Pediatrics The pharmacokinetics of alprazolam after administration of the alprazolam extended-release tablet in pediatric patients have not been studied. Gender Gender has no effect on the pharmacokinetics of alprazolam. Cigarette Smoking Alprazolam concentrations may be reduced by up to 50% in smokers compared to non-smokers.<br/>Drug-Drug Interactions: Alprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most of the interactions that have been documented with alprazolam are with drugs that inhibit or induce CYP3A4. Compounds that are potent inhibitors of CYP3A would be expected to increase plasma alprazolam concentrations. Drug products that have been studied in vivo, along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.70 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold . CYP3A inducers would be expected to decrease alprazolam concentrations and this has been observed in vivo. The oral clearance of alprazolam (given in a 0.8 mg single dose) was increased from 0.90��0.21 mL/min/kg to 2.13��0.54 mL/min/kg and the elimination twas shortened (from 17.1��4.9 to 7.7��1.7 h) following administration of 300 mg/day carbamazepine for 10 days . However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000-1200 mg/day); the effect at usual carbamazepine doses is unknown. The ability of alprazolam to induce or inhibit human hepatic enzyme systems has not been determined. However, this is not a property of benzodiazepines in general. Further, alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally.<br/>CLINICAL EFFICACY TRIALS: The efficacy of alprazolam extended-release tablets in the treatment of panic disorder was established in two 6-week, placebo-controlled studies of alprazolam extended-release tablets in patients with panic disorder. In two 6-week, flexible-dose, placebo-controlled studies in patients meeting DSM-III criteria for panic disorder, patients were treated with alprazolam extended-release tablets in a dose range of 1 to 10 mg/day, on a once-a-day basis. The effectiveness of alprazolam extended-release tablets was assessed on the basis of changes in various measures of panic attack frequency, on various measures of the Clinical Global Impression, and on the Overall Phobia Scale. In all, there were seven primary efficacy measures in these studies, and alprazolam extended-release tablets were superior to placebo on all seven outcomes in both studies. The mean dose of alprazolam extended-release tablet at the last treatment visit was 4.2 mg/day in the first study and 4.6 mg/day in the second. In addition, there were two 8-week, fixed-dose, placebo-controlled studies of alprazolam extended-release tablets in patients with panic disorder, involving fixed alprazolam extended-release tablets doses of 4 and 6 mg/day, on a once-a-day basis, that did not show a benefit for either dose of alprazolam extended-release tablets. The longer-term efficacy of alprazolam extended-release tablets in panic disorder has not been systematically evaluated. Analyses of the relationship between treatment outcome and gender did not suggest any differential responsiveness on the basis of gender. | lld:dailymed |
| dailymed-drugs:137 | dailymed-instance:clinicalP... | Pharmacodynamics: The efficacy of paroxetine in the treatment of major depressive disorder, social anxiety disorder, obsessive compulsive disorder (OCD), panic disorder (PD), and generalized anxiety disorder (GAD) is presumed to be linked to potentiation of serotonergic activity in the central nervous system resulting from inhibition of neuronal reuptake of serotonin (5-hydroxy-tryptamine, 5-HT). Studies at clinically relevant doses in humans have demonstrated that paroxetine blocks the uptake of serotonin into humanplatelets. In vitro studies in animals also suggest that paroxetine is a potent and highly selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro radioligand binding studies indicate that paroxetine has little affinity for muscarinic, alpha-, alpha-, beta-adrenergic-, dopamine (D)-, 5-HT-, 5-HT-, and histamine (H)-receptors; antagonism of muscarinic, histaminergic, and alpha-adrenergic receptors has been associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. Because the relative potencies of paroxetine's major metabolites are at most 1/50 of the parent compound, they are essentially inactive.<br/>Pharmacokinetics: Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets of paroxetine daily for 30 days. Paroxetine is extensively metabolized and the metabolites are considered to be inactive. Nonlinearity in pharmacokinetics is observed with increasing doses. Paroxetine metabolism is mediatedin part by CYP2D6, and the metabolites are primarily excreted in the urine and to some extent in the feces. Pharmacokinetic behavior of paroxetine has not been evaluated in subjects who are deficient in CYP2D6 (poor metabolizers).<br/>Absorption and Distribution: Paroxetine is equally bioavailable from the oral suspension and tablet. Paroxetine hydrochloride is completely absorbed after oral dosing of a solution of the hydrochloride salt. In a study in which normal male subjects (n = 15) received 30 mg tablets daily for 30 days, steady-state paroxetine concentrations were achieved by approximately 10 days for most subjects, although it may take substantially longer in an occasional patient. At steady state, mean values of C, T,C, and T��were 61.7 ng/mL (CV 45%), 5.2 hr. (CV 10%), 30.7 ng/mL (CV 67%), and 21.0 hours (CV 32%), respectively. The steady-state Cand Cvalues were about 6 and 14 times what would be predicted from single-dose studies. Steady-state drug exposure based on AUCwas about 8 times greater than would have been predicted from single-dose data in these subjects. The excess accumulation is a consequence of the fact that 1 of the enzymes that metabolizes paroxetine is readily saturable. The effects of food on the bioavailability of paroxetine were studied in subjects administered a single dose with and without food. AUC was only slightly increased (6%) when drug was administered with food but the Cwas 29% greater, while the time to reach peak plasma concentration decreased from 6.4 hours post-dosing to 4.9 hours. Paroxetine distributes throughout the body, including the CNS, with only 1% remaining in the plasma. Approximately 95% and 93% of paroxetine is bound to plasma protein at 100 ng/mL and 400 ng/mL, respectively. Under clinical conditions, paroxetine concentrations would normally be less than 400 ng/mL. Paroxetine does not alter the in vitro protein binding of phenytoin or warfarin.<br/>Metabolism and Excretion: The mean elimination half-life is approximately 21 hours (CV 32%) after oral dosing of 30 mg tablets daily for 30 days of paroxetine hydrochloride. In steady-state dose proportionality studies involving elderly and nonelderly patients, at doses of 20 mg to 40 mg daily for the elderly and 20 mg to 50 mg daily for the nonelderly, some nonlinearity was observed in both populations, again reflecting a saturable metabolic pathway. In comparison toCvalues after 20 mg daily, values after 40 mg daily were only about 2 to 3 times greater than doubled. Paroxetine is extensively metabolized after oral administration. The principal metabolites are polar and conjugated products of oxidation and methylation, which are readily cleared. Conjugates with glucuronic acid and sulfate predominate, and major metabolites have been isolated and identified. Data indicate that the metabolites have no more than 1/50 the potency of the parent compound at inhibiting serotonin uptake. The metabolism of paroxetine is accomplished in part by CYP2D6. Saturation of this enzyme at clinical doses appears to account for the nonlinearity of paroxetine kinetics with increasing dose and increasing duration of treatment. The role of this enzyme in paroxetine metabolism also suggests potential drug-drug interactions (see PRECAUTIONS). Approximately 64% of a 30-mg oral solution dose of paroxetine was excreted in the urine with 2% as the parent compound and 62% as metabolites over a 10-day post-dosing period. About 36% was excreted in the feces (probably via the bile), mostly as metabolites and less than 1% as the parent compound over the 10-day post-dosing period.<br/>Other Clinical Pharmacology Information:<br/>Specific Populations:<br/>Clinical Trials:<br/>Major Depressive Disorder: The efficacy of paroxetine as a treatment for major depressive disorder has been established in 6 placebo-controlled studies of patients with major depressive disorder (aged 18 to 73). In these studies, paroxetine was shown to be significantly more effective than placebo in treating major depressive disorder by at least 2 of the following measures: Hamilton Depression Rating Scale (HDRS), the Hamilton depressed mood item, and the Clinical Global Impression (CGI)-Severity of Illness. Paroxetine was significantly better than placebo in improvement of the HDRS sub-factor scores, including the depressed mood item, sleep disturbance factor, and anxiety factor. A study of outpatients with major depressive disorder who had responded to paroxetine (HDRS total score<8) during an initial 8-week open-treatment phase and were then randomized to continuation on paroxetine or placebo for 1 year demonstrated a significantly lower relapse rate for patients taking paroxetine (15%) compared to those on placebo (39%). Effectiveness was similar for male and female patients.<br/>Obsessive Compulsive Disorder: The effectiveness of paroxetine in the treatment of obsessive compulsive disorder (OCD) was demonstrated in two 12-week multicenter placebo-controlled studies of adult outpatients (Studies 1 and 2). Patients in all studies had moderate to severe OCD (DSM-IIIR) with mean baseline ratings on the Yale Brown Obsessive Compulsive Scale (YBOCS) total score ranging from 23 to 26. Study 1, a dose-range finding study where patients were treated with fixed doses of 20, 40, or 60 mg of paroxetine/day demonstrated that daily doses of paroxetine 40 and 60 mg are effective in the treatment of OCD. Patients receiving doses of 40 and 60 mg paroxetine experienced a mean reduction of approximately 6 and 7 points, respectively, on the YBOCS total score which was significantly greater than the approximate 4-point reduction at 20 mg and a 3-point reduction in the placebo-treated patients. Study 2 was a flexible-dose study comparing paroxetine (20 to 60 mg daily) with clomipramine (25 to 250 mg daily). In this study, patients receiving paroxetine experienced a mean reduction of approximately 7 points on the YBOCS total score, which was significantly greater than the mean reduction of approximately 4 points in placebo-treated patients. The following table provides the outcome classification by treatment group on Global Improvement items of the Clinical Global Impression (CGI) scale for Study 1. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender. The long-term maintenance effects of paroxetine in OCD were demonstrated in a long-term extension to Study 1. Patients who were responders on paroxetine during the 3-month double-blind phase and a 6-month extension on open-label paroxetine (20 to 60 mg/day) were randomized to either paroxetine or placebo in a 6-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo.<br/>Panic Disorder: The effectiveness of paroxetine in the treatment of panic disorder was demonstrated in three 10- to 12-week multicenter, placebo-controlled studies of adult outpatients (Studies 1-3). Patients in all studies had panic disorder (DSM-IIIR), with or without agoraphobia. In these studies, paroxetine was shown to be significantly more effective than placebo in treating panic disorder by at least 2 out of 3 measures of panic attack frequency and on the Clinical Global Impression Severity of Illness score. Study 1 was a 10-week dose-range finding study; patients were treated with fixed paroxetine doses of 10, 20, or 40 mg/day or placebo. A significant difference from placebo was observed only for the 40 mg/day group. At endpoint, 76% of patients receiving paroxetine 40 mg/day were free of panic attacks, compared to 44% of placebo-treated patients. Study 2 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) and placebo. At endpoint, 51% of paroxetine patients were free of panic attacks compared to 32% of placebo-treated patients. Study 3 was a 12-week flexible-dose study comparing paroxetine (10 to 60 mg daily) to placebo in patients concurrently receiving standardized cognitive behavioral therapy. At endpoint, 33% of the paroxetine-treated patients showed a reduction to 0 or 1 panic attacks compared to 14% of placebo patients. In both Studies 2 and 3, the mean paroxetine dose for completers at endpoint was approximately 40 mg/day of paroxetine. Long-term maintenance effects of paroxetine in panic disorder were demonstrated in an extension to Study 1. Patients who were responders during the 10-week double-blind phase and during a 3-month double-blind extension phase were randomized to either paroxetine (10, 20, or 40 mg/day) or placebo in a 3-month double-blind relapse prevention phase. Patients randomized to paroxetine were significantly less likely to relapse than comparably treated patients who were randomized to placebo. Subgroup analyses did not indicate that there were any differences in treatment outcomes as a function of age or gender.<br/>Social Anxiety Disorder: The effectiveness of paroxetine in the treatment of social anxiety disorder was demonstrated in three 12-week, multicenter, placebo-controlled studies (Studies 1, 2, and 3) of adult outpatients with social anxiety disorder (DSM-IV). In these studies, the effectiveness of paroxetine compared to placebo was evaluated on the basis of (1) the proportion of responders, as defined by a Clinical Global Impression (CGI) Improvement score of 1 (very much improved) or 2 (much improved), and (2) change from baseline in the Liebowitz Social Anxiety Scale (LSAS). Studies 1 and 2 were flexible-dose studies comparing paroxetine (20 to 50 mg daily) and placebo. Paroxetine demonstrated statistically significant superiority over placebo on both the CGI Improvement responder criterion and the Liebowitz Social Anxiety Scale (LSAS). In Study 1, for patients who completed to week 12, 69% of paroxetine-treated patients compared to 29% of placebo-treated patients were CGI Improvement responders. In Study 2, CGI Improvement responders were 77% and 42% for the paroxetine- and placebo-treated patients, respectively. Study 3 was a 12-week study comparing fixed paroxetine doses of 20, 40, or 60 mg/day with placebo. Paroxetine 20 mg was demonstrated to be significantly superior to placebo on both the LSAS Total Score and the CGI Improvement responder criterion; there were trends for superiority over placebo for the 40 mg and 60 mg/day dose groups. There was no indication in this study of any additional benefit for doses higher than 20 mg/day. Subgroup analyses generally did not indicate differences in treatment outcomes as a function of age, race, or gender.<br/>Generalized Anxiety Disorder: The effectiveness of paroxetine in the treatment of Generalized Anxiety Disorder (GAD) was demonstrated in two 8-week, multicenter, placebo-controlled studies (Studies 1 and 2) of adult outpatients with Generalized Anxiety Disorder (DSM-IV). Study 1 was an 8-week study comparing fixed paroxetine doses of 20 mg or 40 mg/day with placebo. Doses of 20 mg or 40 mg of paroxetine were both demonstrated to be significantly superior to placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. There was not sufficient evidence in this study to suggest a greater benefit for the 40 mg/day dose compared to the 20 mg/day dose. Study 2 was a flexible-dose study comparing paroxetine (20 mg to 50 mg daily) and placebo. Paroxetine demonstrated statistically significant superiority over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score. A third study, also flexible-dose comparing paroxetine (20 mg to 50 mg daily), did not demonstrate statistically significant superiority of paroxetine over placebo on the Hamilton Rating Scale for Anxiety (HAM-A) total score, the primary outcome. Subgroup analyses did not indicate differences in treatment outcomes as a function of race or gender. There were insufficient elderly patients to conduct subgroup analyses on the basis of age. In a longer-term trial, 566 patients meeting DSM-IV criteria for Generalized Anxiety Disorder, who had responded during a single-blind, 8-week acute treatment phase with 20 to 50 mg/day of paroxetine, were randomized to continuation of paroxetine at their same dose, or to placebo, for up to 24 weeks of observation for relapse. Response during the single-blind phase was defined by having a decrease of���2 points compared to baseline on the CGI-Severity of Illness scale, to a score of���3. Relapse during the double-blind phase was defined as an increase of���2 points compared to baseline on the CGI-Severity of Illness scale to a score of���4, or withdrawal due to lack of efficacy. Patients receiving continued paroxetine experienced a significantly lower relapse rate over the subsequent 24 weeks compared to those receiving placebo. | lld:dailymed |
| dailymed-drugs:139 | dailymed-instance:clinicalP... | Polymyxin B sulfate has a bactericidal action against almost all gram-negative bacilli except the Proteus group. Polymyxins increase the permeability of bacterial cell wall membranes. All grampositive bacteria, fungi, and the gram-negative cocci, N gonorrhoeae and N meningitidis, are resistant. Susceptibility plate testing: If the Kirby-Bauer method of disc susceptibility testing is used, a 300-unit polymyxin B disc should give a zone of over 11 mm when tested against a polymyxin B susceptible bacterial strain. Polymyxin B sulfate is not absorbed from the normal alimentary tract. Since the drug loses 50 percent of its activity in the presence of serum, active blood levels are low. Repeated injections may give a cumulative effect. Levels tend to be higher in infants and children. The drug is excreted slowly by the kidneys. Tissue diffusion is poor and the drug does not pass the blood brain barrier into the cerebrospinal fluid. In therapeutic dosage, polymyxin B sulfate causes some nephrotoxicity with tubule damage to a slight degree. | lld:dailymed |
| dailymed-drugs:3771 | dailymed-instance:clinicalP... | Polymyxin B sulfate has a bactericidal action against almost all gram-negative bacilli except the Proteus group. Polymyxins increase the permeability of bacterial cell wall membranes. All grampositive bacteria, fungi, and the gram-negative cocci, N gonorrhoeae and N meningitidis, are resistant. Susceptibility plate testing: If the Kirby-Bauer method of disc susceptibility testing is used, a 300-unit polymyxin B disc should give a zone of over 11 mm when tested against a polymyxin B susceptible bacterial strain. Polymyxin B sulfate is not absorbed from the normal alimentary tract. Since the drug loses 50 percent of its activity in the presence of serum, active blood levels are low. Repeated injections may give a cumulative effect. Levels tend to be higher in infants and children. The drug is excreted slowly by the kidneys. Tissue diffusion is poor and the drug does not pass the blood brain barrier into the cerebrospinal fluid. In therapeutic dosage, polymyxin B sulfate causes some nephrotoxicity with tubule damage to a slight degree. | lld:dailymed |
| dailymed-drugs:140 | dailymed-instance:clinicalP... | Dextrose Injections USP provide calories and are a source of water for hydration. They are capable of inducing diuresis depending on the clinical condition of the patient. Dextrose is readily metabolized, may decrease losses of body protein and nitrogen, promotes glycogen deposition and decreases or prevents ketosis if sufficient doses are provided. Water is an essential constituent of all body tissues and accounts for approximately 70% of total body weight. Average normal adult daily requirements range from two to three liters (1.0 to 1.5 liters each for insensible water loss by perspiration and urine production). | lld:dailymed |
| dailymed-drugs:141 | dailymed-instance:clinicalP... | Fluphenazine hydrochloride has activity at all levels of the central nervous system, as well as on multiple organ systems. The mechanism whereby its therapeutic action is exerted is unknown. | lld:dailymed |
| dailymed-drugs:142 | dailymed-instance:clinicalP... | Pharmacokinetics: The cefaclor extended-release tablet formulation of cefaclor is pharmacokinetically different from the cefaclor immediate-release capsule formulation of cefaclor. (See Table 1.) No direct comparisons with the suspension formulation of cefaclor have been conducted; therefore, there are no data with which to compare the pharmacokinetic properties of the extended-release tablet formulation and the suspension formulation. Until further data are available, the pharmacokinetic equivalence of the extended-release tablet and the suspension formulations should NOT be assumed.<br/>Absorption and Metabolism: The extent of absorption (AUC) and the maximum plasma concentration (C) of cefaclor from cefaclor extended-release tablets are greater when the extended-release tablet is taken with food. [NOTE: The extent of absorption (AUC) of cefaclor from cefaclor immediate-release capsules is unaffected by food intake; however, when cefaclor immediate-release capsules are taken with food, the Cis decreased.] There is no evidence of metabolism of cefaclor in humans.<br/>Comparative Serum Pharmacokinetics: Serum pharmacokinetic parameters for cefaclor extended-release tablets and cefaclor immediate-release capsules are shown in the table below. (��1 standard deviation) NA = data not available No drug accumulation was noted when cefaclor extended-release tablets were given twice daily. The plasma half-life in healthy subjects is independent of dosage form and averages approximately 1 hour.<br/>Food Effect on Pharmacokinetics: When cefaclor extended-release tablets are taken with food, the AUC is 10% lower while the Cis 12% lower and occurs 1 hour later compared to cefaclor immediate-release capsules. In contrast, when cefaclor extended-release tablets are taken without food, the AUC is 23% lower while the Cis 67% lower and occurs 0.6 hours later, using an equivalent milligram dose of cefaclor immediate-release capsules as a reference. Therefore, cefaclor extended-release tablets should be taken with food.<br/>Special Populations:<br/>Renal Insufficiency: In patients with reduced renal function, the serum half-life of cefaclor is slightly prolonged. In those with complete absence of renal function, the plasma half-life of the intact molecule is 2.3 to 2.8 hours. Excretion pathways in patients with markedly impaired renal function have not been determined. Hemodialysis shortens the half-life by 25% to 30%.<br/>Geriatric Patients: In elderly subjects (over age 65) with normal serum creatinine values, higher peak plasma concentrations and AUCs have been observed. This is considered to be primarily a result of an age-related decrement in renal function, and has no apparent clinical significance. Therefore, dosage adjustment is not necessary in elderly subjects with normal serum creatinine values.<br/>Microbiology: Cefaclor has in vitro activity against a broad range of gram-positive and gram-negative bacteria. The bactericidal action of cefaclor results from inhibition of cell-wall synthesis. Cefaclor is stable in the presence of some bacterial��-lactamases; consequently, some��-lactamase-producing organisms may be susceptible to cefaclor. Cefaclor extended-release tablets have been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section: Gram-positive aerobes: Staphylococcus aureus Streptococcus pneumoniae Streptococcus pyogenes NOTE: Cefaclor is inactive against methicillin-resistant staphylococci. Gram-negative aerobes: Haemophilus influenzae (non-��-lactamase-producing strains only) Moraxella catarrhalis (including��-lactamase-producing strains) The following in vitro data are available, but their clinical significance is unknown. Cefaclor exhibits in vitro minimum inhibitory concentrations (MICs) of 8��g/mL or less (systemic susceptibility breakpoint) against most (���90%) strains of the following microorganisms; however, the safety and effectiveness of cefaclor extended-release tablets in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials. Gram-positive aerobes: Staphylococcus epidermidis Gram-negative aerobes: Haemophilus parainfluenzae Klebsiella pneumoniae Anaerobic bacteria: Peptococcus niger Peptostreptococci Propionibacterium acnes NOTE: Acinetobacter calcoaceticus, Enterobacter spp., Entercoccus spp., Morganella morganii, Proteus vulgaris, Providencia spp., Pseudomonas spp., and Serratia spp. are resistant to cefaclor.<br/>Susceptibility Testing:<br/>Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method(broth, agar, or microdilution) or equivalent with standardized inoculum concentrations and standardized amounts of cefaclor powder. The MIC values should be interpreted according to the following criteria: A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to beinhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard cefaclor powder should provide the following MIC values:<br/>Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedurerequires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30-��g cefaclor to test the susceptibility of microorganisms to cefaclor. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-��g cefaclor disk should be interpreted according to the following criteria: When testingH. Influenzae, the following interpretive criteria should be used: Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for cefaclor. As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30-��g cefaclor disk should provide the following zone diameters in these laboratory test quality control strains: | lld:dailymed |
| dailymed-drugs:144 | dailymed-instance:clinicalP... | Pharmacokinetics: Multiple dose ribavirin pharmacokinetic data are available for HCV patients who received ribavirin in combination with peginterferon alfa-2a. Following administration of 1200 mg/day with food for 12 weeks mean��SD (n=39; body weight>75 kg) AUCwas 25,361��7110 ng.hr/mL and Cwas 2748��818 ng/mL. The average time to reach Cwas 2 hours. Trough ribavirin plasma concentrations following 12 weeks of dosing with food were 1662��545 ng/mL in HCV infected patients who received 800 mg/day (n=89), and 2112��810 ng/mL in patients who received 1200 mg/day (n=75; body weight>75 kg). The terminal half-life of ribavirin following administration of a single oral dose of ribavirin tablet is about 120 to 170 hours. The total apparent clearance following administration of a single oral dose of ribavirin tablet is about 26 L/h. There is extensive accumulation of ribavirin after multiple dosing (twice daily) such that the Cat steady state was four-fold higher than that of a single dose. Effect of Food on Absorption of Ribavirin Bioavailability of a single oral dose of ribavirin was increased by co-administration with a high-fat meal. The absorption was slowed (Twas doubled) and the AUCand Cincreased by 42% and 66%, respectively, when ribavirin tablet was taken with a high-fat meal compared with fasting conditions . Elimination and Metabolism The contribution of renal and hepatic pathways to ribavirin elimination after administration of ribavirin tablet is not known. In vitro studies indicate that ribavirin is not a substrate of CYP450 enzymes.<br/>Special Populations: Race A pharmacokinetic study in 42 subjects demonstrated there is no clinically significant difference in ribavirin pharmacokinetics among Black (n=14), Hispanic (n=13) and Caucasian (n=15) subjects. Renal Dysfunction The pharmacokinetics of ribavirin following administration of ribavirin tablets have not been studied in patients with renal impairment and there are limited data from clinical trials on administration of ribavirin tablets in patients with creatinine clearance<50 mL/min. Therefore, patients with creatinine clearance<50 mL/min should not be treated with ribavirin tablets . Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of ribavirin following administration of ribavirin tablet has not been evaluated. The clinical trials of ribavirin tablets were restricted to patients with Child-Pugh class A disease. Pediatric Patients Pharmacokinetic evaluations in pediatric patients have not been performed. Elderly Patients Pharmacokinetic evaluations in elderly patients have not been performed. Gender Ribavirin pharmacokinetics, when corrected for weight, are similar in male and female patients.<br/>Drug Interactions: In vitro studies indicate that ribavirin does not inhibit CYP450 enzymes. Nucleoside Analogues In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. However, no pharmacokinetic (e.g., plasma concentrations or intracellular triphosphorylated active metabolite concentrations) or pharmacodynamic (e.g., loss of HIV/HCV virologic suppression) interaction was observed when ribavirin and lamivudine (n=18), stavudine (n=10), or zidovudine (n=6) were co-administered as part of a multi-drug regimen to HCV/HIV coinfected patients) see PRECAUTIONS: Drug Interactions). In vitro, didanosine or its active metabolite (dideoxyadenosine 5'-triphosphate) is increased when didanosine is co-administered with ribavirin, which could cause or worsen clinical toxicities . Drugs Metabolized by Cytochrome P450 There was no effect on the pharmacokinetics of representative drugs metabolized by CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4. Treatment with peginterferon alfa-2a once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25% increase in theophylline AUC . | lld:dailymed |
| dailymed-drugs:145 | dailymed-instance:clinicalP... | When administered intravenously, these solutions provide a source of water and electrolytes. Solutions which provide combinations of hypotonic or isotonic concentrations of sodium chloride are suitable for parenteral maintenance or replacement of water and electrolyte requirements. Isotonic concentrations of sodium chloride are suitable for parenteral replacement of chloride losses that exceed or equal the sodium loss. Hypotonic concentrations of sodium chloride are suited for parenteral maintenance of water requirements when only small quantities of salt are desired. A hypertonic concentrationof sodium chloride may be used to repair severe salt depletion syndrome. Sodium chloride in water dissociates to provide sodium (Na) and chloride (Cl) ions. Sodium (Na) is the principal cation of the extracellular fluid and plays a large part in the therapy of fluid and electrolyte disturbances. Chloride (Cl) has an integral role in buffering action when oxygen and carbon dioxide exchange occurs in the red blood cells. The distribution and excretion of sodium (Na) and chloride (Cl) are largely under the control of the kidney which maintains a balance between intake and output. Water is an essential constituent of all body tissues and accounts for approximately 70% of total body weight. Average normal adult daily requirements range from two to three liters (1.0 to 1.5 liters each for insensible water loss by perspiration and urine production). Water balance is maintained by various regulatory mechanisms. Water distribution depends primarily on the concentration of electrolytes in the body compartments and sodium (Na) plays a major role in maintaining physiologic equilibrium. | lld:dailymed |
| dailymed-drugs:146 | dailymed-instance:clinicalP... | Pharmacodynamics: Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).<br/>Pharmacokinetics:<br/>Absorption/Bioavailability: Equivalent oral doses of DEPAKOTE (divalproex sodium) products and DEPAKENE (valproic acid) capsules deliver equivalent quantities of valproate ion systemically. Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. However, it is possible that differences among the various valproate products in Tand Ccould be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorption of the tablet (increase in Tfrom 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in Tfrom 3.3 to 4.8 hours). While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown. Co-administration of oral valproate products with food and substitution among the various DEPAKOTE and DEPAKENE formulations should cause no clinical problems in the management of patients with epilepsy (see DOSAGE AND ADMINISTRATION). Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations.<br/>Distribution:<br/>Metabolism: Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial��-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine. The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear.<br/>Elimination: Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 mand 11 L/1.73 m, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 mand 92 L/1.73 m. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1000 mg. The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn.<br/>Special Populations:<br/>Plasma Levels and Clinical Effect: The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate cannot provide a reliable index of the bioactive valproate species. For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40��g/mL to 18.5% at 130��g/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases. | lld:dailymed |
| dailymed-drugs:148 | dailymed-instance:clinicalP... | Pharmacodynamics: The mechanism of action of citalopram hydrobromide as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro and in vivo studies in animals suggest that citalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake. Tolerance to the inhibition of 5-HT uptake is not induced by long-term (14 day) treatment of rats with citalopram. Citalopram is a racemic mixture (50/50), and the inhibition of 5-HT reuptake by citalopram is primarily due to the (S)-enantiomer. Citalopram has no or very low affinity for 5-HT, 5-HT, dopamine Dand D,��-,��-, and��-adrenergic, histamine H, gamma aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors. Antagonism of muscarinic, histaminergic and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of other psychotropic drugs.<br/>Pharmacokinetics: The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10 to 60 mg/day. Biotransformation of citalopram is mainly hepatic, with a mean terminal half-life of about 35 hours. With once daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be 2.5 times the plasma concentrations observed after a single dose. The tablet and oral solution dosage forms of citalopram hydrobromide are bioequivalent.<br/>Absorption and Distribution: Following a single oral dose (40 mg tablet) of citalopram, peak blood levels occur at about 4 hours. The absolute bioavailability of citalopram was about 80% relative to an intravenous dose, and absorption is not affected by food. The volume of distribution of citalopram is about 12 L/kg and the binding of citalopram (CT), demethylcitalopram (DCT) and didemethylcitalopram (DDCT) to human plasma proteins is about 80%.<br/>Metabolism and Elimination: Following intravenous administrations of citalopram, the fraction of drug recovered in the urine as citalopram and DCT was about 10% and 5%, respectively. The systemic clearance of citalopram was 330 mL/min, with approximately 20% of that due to renal clearance. Citalopram is metabolized to demethylcitalopram (DCT), didemethylcitalopram (DDCT), citalopram-N-oxide, and a deaminated propionic acid derivative. In humans, unchanged citalopram is the predominant compound in plasma. At steady state, the concentrations of citalopram's metabolites, DCT and DDCT, in plasma are approximately one-half and one-tenth, respectively, that of the parent drug. In vitro studies show that citalopram is at least 8 times more potent than its metabolites in the inhibition of serotonin reuptake, suggesting that the metabolites evaluated do not likely contribute significantly to the antidepressant actions of citalopram. In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of citalopram.<br/>Population Subgroups: Age - Citalopram pharmacokinetics in subjects���60 years of age were compared to younger subjects in two normal volunteer studies. In a single-dose study, citalopram AUC and half-life were increased in the elderly subjects by 30% and 50%, respectively, whereas in a multiple-dose study they were increased by 23% and 30%, respectively. 20 mg is the recommended dose for most elderly patients (see DOSAGE AND ADMINISTRATION). Gender - In three pharmacokinetic studies (total N=32), citalopram AUC in women was one and a half to two times that in men. This difference was not observed in five other pharmacokinetic studies (total N=114). In clinical studies, no differences in steady state serum citalopram levels were seen between men (N=237) and women (N=388). There were no gender differences in the pharmacokinetics of DCT and DDCT. No adjustment of dosage on the basis of gender is recommended. Reduced hepatic function - Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects. 20 mg is the recommended dose for most hepatically impaired patients (see DOSAGE AND ADMINISTRATION). Reduced renal function - In patients with mild to moderate renal function impairment, oral clearance of citalopram was reduced by 17% compared to normal subjects. No adjustment of dosage for such patients is recommended. No information is available about the pharmacokinetics of citalopram in patients with severely reduced renal function (creatinine clearance<20 mL/min).<br/>Drug-Drug Interactions: In vitro enzyme inhibition data did not reveal an inhibitory effect of citalopram on CYP3A4, -2C9, or -2E1, but did suggest that it is a weak inhibitor of CYP1A2, -2D6, and -2C19. Citalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. However, in vivo data to address this question are limited. Since CYP3A4 and 2C19 are the primary enzymes involved in the metabolism of citalopram, it is expected that potent inhibitors of 3A4 (e.g., ketoconazole, itraconazole, and macrolide antibiotics) and potent inhibitors of CYP2C19 (e.g., omeprazole) might decrease the clearance of citalopram. However, coadministration of citalopram and the potent 3A4 inhibitor ketoconazole did not significantly affect the pharmacokinetics of citalopram. Because citalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease citalopram clearance. Citalopram steady state levels were not significantly different in poor metabolizers and extensive 2D6 metabolizers after multiple-dose administration of citalopram, suggesting that coadministration, with citalopram, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on citalopram metabolism. See Drug Interactions under PRECAUTIONS for more detailed information on available drug interaction data.<br/>Clinical Efficacy Trials: The efficacy of citalopram as a treatment for depression was established in two placebo-controlled studies (of 4 to 6 weeks in duration) in adult outpatients (ages 18 to 66) meeting DSM-III or DSM-III-R criteria for major depression. Study 1, a 6-week trial in which patients received fixed citalopram doses of 10, 20, 40, and 60 mg/day, showed that citalopram at doses of 40 and 60 mg/day was effective as measured by the Hamilton Depression Rating Scale (HAMD) total score, the HAMD depressed mood item (Item 1), the Montgomery Asberg Depression Rating Scale, and the Clinical Global Impression (CGI) Severity scale. This study showed no clear effect of the 10 and 20 mg/day doses, and the 60 mg/day dose was not more effective than the 40 mg/day dose. In study 2, a 4-week, placebo-controlled trial in depressed patients, of whom 85% met criteria for melancholia, the initial dose was 20 mg/day, followed by titration to the maximum tolerated dose or a maximum dose of 80 mg/day. Patients treated withcitalopram showed significantly greater improvement than placebo patients on the HAMD total score, HAMD item 1, and the CGI Severity score. In three additional placebo-controlled depression trials, the difference in response to treatment between patients receiving citalopram and patients receiving placebo was not statistically significant, possibly due to high spontaneous response rate, smaller sample size, or, in the case of one study, too low a dose. In two long-term studies, depressed patients who had responded to citalopram during an initial 6 or 8 weeks of acute treatment (fixed doses of 20 or 40 mg/day in one study and flexible doses of 20 to 60 mg/day in the second study) were randomized to continuation of citalopram or to placebo. In both studies, patients receiving continued citalopram treatment experienced significantly lower relapse rates over the subsequent 6 months compared to those receiving placebo. In the fixed-dose study, the decreased rate of depression relapse was similar in patients receiving 20 or 40 mg/day of citalopram. Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.<br/>Comparison of Clinical Trial Results: Highly variable results have been seen in the clinical development of all antidepressant drugs. Furthermore, in those circumstances when the drugs have not been studied in the same controlled clinical trial(s), comparisons among the results of studies evaluating the effectiveness of different antidepressant drug products are inherently unreliable. Because conditions of testing (e.g., patient samples, investigators, doses of the treatments administered and compared, outcome measures, etc.) vary among trials, it is virtually impossible to distinguish a difference in drug effect from a difference due to one of the confounding factors just enumerated. | lld:dailymed |
| dailymed-drugs:149 | dailymed-instance:clinicalP... | Absorption: Ciprofloxacin given as an oral tablet is rapidly and well absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability is approximately 70% with no substantial loss by first pass metabolism. Ciprofloxacin maximum serum concentrations and area under the curve are shown in the chart for the 250 mg to 1000 mg dose range. Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Mean concentrations 12 hours after dosing with 250, 500, or 750 mg are 0.1, 0.2, and 0.4��g/mL, respectively. The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Serum concentrations increase proportionately with doses up to 1000 mg. A 500 mg oral dose given every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by an intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours. A 750 mg oral dose given every 12 hours has been shown to produce an AUC at steady-state equivalent to that produced by an intravenous infusion of 400 mg given over 60 minutes every 8 hours. A 750 mg oral dose results in a Csimilar to that observed with a 400 mg I.V. dose. A 250 mg oral dose given every 12 hours produces an AUC equivalent to that produced by an infusion of 200 mg ciprofloxacin given every 12 hours.<br/>Distribution: The binding of ciprofloxacin to serum proteins is 20 to 40% which is not likely to be high enough to cause significant protein binding interactions with other drugs. After oral administration, ciprofloxacin is widely distributed throughout the body. Tissue concentrations often exceed serum concentrations in both men and women, particularly in genital tissue including the prostate. Ciprofloxacin is present in active form in the saliva, nasal and bronchial secretions, mucosa of the sinuses, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. Ciprofloxacin has also been detected in lung, skin, fat, muscle, cartilage, and bone. The drug diffuses into the cerebrospinal fluid (CSF); however, CSF concentrations are generally less than 10% of peak serum concentrations. Low levels of the drug have been detected in the aqueous and vitreous humors of the eye.<br/>Metabolism: Four metabolites have been identified in human urine which together account for approximately 15% of an oral dose. The metabolites have antimicrobial activity, but are less active than unchanged ciprofloxacin. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Coadministration of ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of the coadministered drug .<br/>Excretion: The serum elimination half-life in subjects with normal renal function is approximately 4 hours. Approximately 40 to 50% of an orally administered dose is excreted in the urine as unchanged drug. After a 250 mg oral dose, urine concentrations of ciprofloxacin usually exceed 200��g/mL during the first two hours and are approximately 30��g/mL at 8 to 12 hours after dosing. The urinary excretion of ciprofloxacin is virtually complete within 24 hours after dosing. The renal clearance of ciprofloxacin, which is approximately 300 mL/minute, exceeds the normal glomerular filtration rate of 120 mL/minute. Thus, active tubular secretion would seem to play a significant role in its elimination. Co-administration of probenecid with ciprofloxacin results in abouta 50% reduction in the ciprofloxacin renal clearance and a 50% increase in its concentration in the systemic circulation. Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after oral dosing, only a small amount of the dose administered is recovered from the bile as unchanged drug. An additional 1 to 2% of the dose is recovered from the bile in the form of metabolites. Approximately 20 to 35% of an oral dose is recovered from the feces within 5 days after dosing.This may arise from either biliary clearance or transintestinal elimination.<br/>Drug-drug Interactions: When ciprofloxacin tablets are given concomitantly with food, there is a delay in the absorption of the drug, resulting in peak concentrations that occur closer to 2 hours after dosing rather than 1 hour. The overall absorption of ciprofloxacin tablets, however, is not substantially affected. Concurrent administration of antacids containing magnesium hydroxide or aluminum hydroxide may reduce the bioavailability of ciprofloxacin by as much as 90%. The serum concentrations of ciprofloxacin and metronidazole were not altered when these two drugs were given concomitantly. Concomitant administration with tizanidine is contraindicated . Concomitant administration of ciprofloxacin with theophylline decreases the clearance of theophylline resulting in elevated serum theophylline levels and increased risk of a patient developing CNS or other adverse reactions. Ciprofloxacin also decreases caffeine clearance and inhibits the formation of paraxanthine after caffeine administration.<br/>Special Populations: Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (>65 years) as compared to young adults. Although the Cis increased 16-40%, the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant. In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged. Dosage adjustments may be required. In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. The kinetics of ciprofloxacin in patients with acute hepatic insufficiency, however, have not been fully elucidated. | lld:dailymed |
| dailymed-drugs:150 | dailymed-instance:clinicalP... | Dopamine exhibits an inotropic action on the myocardium, resulting in increased cardiac output. It causes less increase in myocardial oxygen consumption than isoproterenol and the effect of dopamine usually is not associated with tachyarrhythmia. Reported clinical studies have revealed that the drug usually increases systolic and pulse pressure without any or only a minor elevating effect on diastolic pressure. Total peripheral resistance at low and intermediate doses is usually unchanged. Blood flow to peripheral vascular beds may decrease while mesenteric blood flow is increased. The drug also has been reported to produce dilation of the renal vasculature which is accompanied by increases in glomerular filtration rate, renal blood flow and sodium excretion. Increased urinary output produced by dopamine is usually not associated with decreased urine osmolality. Solutions containing carbohydrate in the form of dextrose restore blood glucose levels and provide calories. Carbohydrate in the form of dextrose may aid in minimizing liver glycogen depletion and exerts a protein-sparing action. Dextrose injected parenterally undergoes oxidation to carbon dioxide and water. Water is an essential constituent of all body tissues and accounts for approximately 70% of total body weight. Average normal adult daily requirement ranges from two to three liters (1.0 to 1.5 liters each for insensible water loss due to perspiration and urine production). Water balance is maintained by various regulatory mechanisms. Water distribution depends primarily on the concentration of electrolytes and sodium (Na) plays a major role in maintaining physiologic equilibrium. The reported clearance rate of dopamine in critically ill infants and children has ranged from 46 to 168 mL/kg/min, with the higher values seen in the younger patients. The apparent volume of distribution in neonates is reported as 0.6 to 4 L/kg, leading to an elimination half-life of 5 to 11 minutes. | lld:dailymed |
| dailymed-drugs:151 | dailymed-instance:clinicalP... | Mean peak plasma levels of approximately 3.5��g/mL are reached within 1 to 2 hours, following oral administration of a single 200 mg dose taken with a meal. Subsequent plasma elimination is biphasic with a half-life of 2 hours during the first 10 hours and 8 hours thereafter. Following absorption from the gastrointestinal tract, NIZORAL (ketoconazole) is converted into several inactive metabolites. The major identified metabolic pathways are oxidation and degradation of the imidazole and piperazine rings, oxidative O-dealkylation and aromatic hydroxylation. About 13% of the dose is excreted in the urine, of which 2 to 4% is unchanged drug. The major route of excretion is through the bile into the intestinal tract. In vitro, the plasma protein binding is about 99% mainly to the albumin fraction. Only a negligible proportion of ketoconazole reaches the cerebral-spinal fluid. Ketoconazole is a weak dibasic agent and thus requires acidity for dissolution and absorption. NIZORAL Tablets are active against clinical infections with Blastomyces dermatitidis, Candida spp., Coccidioides immitis, Histoplasma capsulatum, Paracoccidioides brasiliensis, and Phialophora spp. NIZORAL Tablets are also active against Trichophyton spp., Epidermophyton spp., and Microsporum spp. Ketoconazole is also active in vitro against a variety of fungi and yeast. In animal models, activity has been demonstrated against Candida spp., Blastomyces dermatitidis, Histoplasma capsulatum, Malassezia furfur, Coccidioides immitis, and Cryptococcus neoformans.<br/>Mode of Action: In vitro studies suggest that ketoconazole impairs the synthesis of ergosterol, which is a vital component of fungal cell membranes. | lld:dailymed |
| dailymed-drugs:152 | dailymed-instance:clinicalP... | The mechanism of the antihypertensive effect of thiazides is unknown. Hydrochlorothiazide does not usually affect normal blood pressure. Hydrochlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic efficacy. Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. After oral use diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.<br/>Pharmacokinetics and Metabolism: Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. | lld:dailymed |
| dailymed-drugs:175 | dailymed-instance:clinicalP... | The mechanism of the antihypertensive effect of thiazides is unknown. Hydrochlorothiazide does not usually affect normal blood pressure. Hydrochlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic efficacy. Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. After oral use diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.<br/>Pharmacokinetics and Metabolism: Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. | lld:dailymed |
| dailymed-drugs:1900 | dailymed-instance:clinicalP... | The mechanism of the antihypertensive effect of thiazides is unknown. Hydrochlorothiazide does not usually affect normal blood pressure. Hydrochlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic efficacy. Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. After oral use diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.<br/>Pharmacokinetics and Metabolism: Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. | lld:dailymed |
| dailymed-drugs:3815 | dailymed-instance:clinicalP... | The mechanism of the antihypertensive effect of thiazides is unknown. Hydrochlorothiazide does not usually affect normal blood pressure. Hydrochlorothiazide affects the distal renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage all thiazides are approximately equal in their diuretic efficacy. Hydrochlorothiazide increases excretion of sodium and chloride in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. After oral use diuresis begins within 2 hours, peaks in about 4 hours and lasts about 6 to 12 hours.<br/>Pharmacokinetics and Metabolism: Hydrochlorothiazide is not metabolized but is eliminated rapidly by the kidney. When plasma levels have been followed for at least 24 hours, the plasma half-life has been observed to vary between 5.6 and 14.8 hours. At least 61 percent of the oral dose is eliminated unchanged within 24 hours. Hydrochlorothiazide crosses the placental but not the blood-brain barrier and is excreted in breast milk. | lld:dailymed |
| dailymed-drugs:153 | dailymed-instance:clinicalP... | Potassium is the major cation of body cells (160 mEq/liter of intracellular water) and is concerned with the maintenance of the body fluid composition and electrolyte balance. Potassium participates in carbohydrate utilization, protein synthesis, and is critical in the regulation of nerve conduction and muscle contraction, particularly in the heart. Chloride, the major extracellular anion, closely follows the metabolism of sodium, and changes in the acid-base of the body are reflected by changes in the chloride concentration. Normally about 80 to 90% of the potassium intake is excreted in the urine, the remainder in the stools and to a small extent, in the perspiration. The kidney does not conserve potassium well so that during fasting, or in patients on a potassium-free diet, potassium loss from the body continues resulting in potassium depletion. A deficiency of either potassium or chloride will lead to a deficit ofthe other. | lld:dailymed |
| dailymed-drugs:154 | dailymed-instance:clinicalP... | Aminosyn II (an amino acid injection) provides crystalline amino acids to promote protein synthesis and wound healing, and to reduce the rate of endogenous protein catabolism. Aminosyn II, given by central venous infusion in combination with concentrated dextrose, electrolytes, vitamins, trace metals, and ancillary fat supplements, constitutes total parenteral nutrition (TPN). Aminosyn II can also be administered by peripheral vein with dextrose and maintenance electrolytes. Intravenous fat emulsion may be substituted for part of the carbohydrate calories during either TPN or peripheral vein administration of Aminosyn II. | lld:dailymed |
| dailymed-drugs:155 | dailymed-instance:clinicalP... | Mechanism of Action: The mechanism by which gabapentin exerts its analgesic action is unknown, but in animal models of analgesia, gabapentin prevents allodynia (pain-related behavior in response to a normally innocuous stimulus) and hyperalgesia (exaggerated response to painful stimuli). In particular, gabapentin prevents pain-related responses in several models of neuropathic pain in rats or mice (e.g., spinal nerve ligation models, streptozocin-induced diabetes model, spinal cord injury model, acute herpes zoster infection model). Gabapentin also decreases pain-related responses after peripheral inflammation (carrageenan footpad test, late phase of formalin test). Gabapentin did not alter immediate pain-related behaviors (rat tail flick test, formalin footpad acute phase, acetic acid abdominal constriction test, footpad heat irradiation test). The relevance of these models to human pain is not known. The mechanism by which gabapentin exerts its anticonvulsant action is unknown, but in animal test systems designed to detect anticonvulsant activity, gabapentin prevents seizures as do other marketed anticonvulsants. Gabapentin exhibits antiseizure activity in mice and rats in both the maximal electroshock and pentylenetetrazole seizure models and other preclinical models (e.g., strains with genetic epilepsy, etc.). The relevance of these models to human epilepsy is not known. Gabapentin is structurally related to the neurotransmitter GABA (gamma-aminobutyric acid) but it does not modify GABAor GABAradioligand binding, it is not converted metabolically into GABA or a GABA agonist, and it is not an inhibitor of GABA uptake or degradation. Gabapentin was tested in radioligand binding assays at concentrations up to 100��M and did not exhibit affinity for a number of other common receptor sites, including benzodiazepine, glutamate, N-methyl-D-aspartate (NMDA), quisqualate, kainate, strychnine-insensitive or strychnine-sensitive glycine, alpha 1, alpha 2, or beta adrenergic, adenosine A1 or A2, cholinergic muscarinic or nicotinic, dopamine D1 or D2, histamine H1, serotonin S1 or S2, opiate mu, delta or kappa, cannabinoid 1, voltage-sensitive calcium channel sites labeled with nitrendipine or diltiazem,or at voltage-sensitive sodium channel sites labeled with batrachotoxinin A 20-alpha-benzoate. Furthermore, gabapentin did not alter the cellular uptake of dopamine, noradrenaline, or serotonin. In vitro studies with radiolabeled gabapentin have revealed a gabapentin binding site in areas of rat brain including neocortex and hippocampus. A high-affinity binding protein in animal brain tissue has been identified as an auxiliary subunit of voltage-activated calcium channels. However, functional correlates of gabapentin binding, if any, remain to be elucidated.<br/>Pharmacokinetics and Drug Metabolism: All pharmacological actions following gabapentin administration are due to the activity of the parent compound; gabapentin is not appreciably metabolized in humans. Oral Bioavailability: Gabapentin bioavailability is not dose proportional; i.e., as dose is increased, bioavailability decreases. Bioavailability of gabapentin is approximately 60%, 47%, 34%, 33%, and 27% following 900, 1200, 2400, 3600, and 4800 mg/day given in 3 divided doses, respectively. Food has only a slight effect on the rate and extent of absorption of gabapentin (14% increase in AUC and C). Distribution: Less than 3% of gabapentin circulates bound to plasma protein. The apparent volume of distribution of gabapentin after 150 mg intravenous administration is 58��6 L (Mean��SD). In patients with epilepsy, steady-state predose (C) concentrations of gabapentin in cerebrospinal fluid were approximately 20% of the corresponding plasma concentrations. Elimination: Gabapentin is eliminated from the systemic circulation by renal excretion as unchanged drug. Gabapentin is not appreciably metabolized in humans. Gabapentin elimination half-life is 5 to 7 hours and is unaltered by dose or following multiple dosing. Gabapentin elimination rate constant, plasma clearance, and renal clearance are directly proportional to creatinine clearance (see Special Populations: Patients With Renal Insufficiency, below). In elderly patients, and in patients with impaired renal function, gabapentin plasma clearance is reduced. Gabapentin can be removed from plasma by hemodialysis. Dosage adjustment in patients with compromised renal function or undergoing hemodialysis is recommended (see DOSAGE AND ADMINISTRATION, Table 5). Special Populations: Adult Patients With Renal Insufficiency: Subjects (N = 60) with renal insufficiency (mean creatinine clearance ranging from 13 to 114 mL/min) were administered single 400 mg oral doses of gabapentin. The mean gabapentin half-life ranged from about 6.5 hours (patients with creatinine clearance>60 mL/min) to 52 hours (creatinine clearance<30 mL/min) and gabapentin renal clearance from about 90 mL/min (>60 mL/min group) to about 10 mL/min (<30 mL/min). Mean plasma clearance (CL/F) decreased from approximately 190 mL/min to 20 mL/min. Dosage adjustment in adult patients with compromised renal function is necessary (see DOSAGE AND ADMINISTRATION). Pediatric patients with renal insufficiency have not been studied. Hemodialysis: In a study in adult anuric subjects (N = 11), the apparent elimination half-life of gabapentin on nondialysis days was about 132 hours; during dialysis the apparent half-life of gabapentin was reduced to 3.8 hours. Hemodialysis thus has a significant effect on gabapentin elimination in anuric subjects. Dosage adjustment in patients undergoing hemodialysis is necessary (see DOSAGE AND ADMINISTRATION). Hepatic Disease: Because gabapentin is not metabolized, no study was performed in patients with hepatic impairment. Age: The effect of age was studied in subjects 20 to 80 years of age. Apparent oral clearance (CL/F) of gabapentin decreased as age increased, from about 225 mL/min in those under 30 years of age to about 125 mL/min in those over 70 years of age. Renal clearance (CLr) and CLr adjusted for body surface area also declined with age; however, the decline in the renal clearance of gabapentin with age can largely be explained by the decline in renal function. Reduction of gabapentin dose may be required in patients who have age related compromised renal function. (see PRECAUTIONS, Geriatric Use, and DOSAGE AND ADMINISTRATION.) Pediatric: Gabapentin pharmacokinetics were determined in 48 pediatric subjects between the ages of 1 month and 12 years following a dose of approximately 10 mg/kg. Peak plasma concentrations were similar across the entire age group and occurred 2 to 3 hours postdose. In general, pediatric subjects between 1 month and<5 years of age achieved approximately 30% lower exposure (AUC) than that observed in those 5 years of age and older. Accordingly, oral clearance normalized per body weight was higher in the younger children. Apparent oral clearance of gabapentin was directly proportional to creatinine clearance. Gabapentin elimination half-life averaged 4.7 hours and was similar across the age groups studied. A population pharmacokinetic analysis was performed in 253 pediatric subjects between 1 month and 13 years of age. Patients received 10 to 65 mg/kg/day given TID. Apparent oral clearance (CL/F) was directly proportional to creatinine clearance and this relationship was similar following a single dose and at steady state. Higher oral clearance values were observed in children<5 years of age compared to those observed in children 5 years of age and older, when normalized per body weight. The clearance was highly variable in infants<1 year of age. The normalized CL/F values observed in pediatric patients 5 years of age and older were consistent with values observed in adults after a single dose. The oral volume of distribution normalized per body weight was constant across the age range. These pharmacokinetic data indicate that the effective daily dose in pediatric patients with epilepsy ages 3 and 4 years should be 40 mg/kg/day to achieve average plasma concentrations similar to those achieved in patients 5 years of age and older receiving gabapentin at 30 mg/kg/day. (see DOSAGE AND ADMINISTRATION). Gender: Although no formal study has been conducted to compare the pharmacokinetics of gabapentin in men and women, it appears that the pharmacokinetic parameters for males and females are similar and there are no significant gender differences. Race: Pharmacokinetic differences due to race have not been studied. Because gabapentin is primarily renally excreted and there are no important racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected.<br/>Clinical Studies:<br/>Postherpetic Neuralgia: Gabapentin was evaluated for the management of postherpetic neuralgia (PHN) in 2 randomized, double-blind, placebo-controlled, multicenter studies; N = 563 patients in the intent-to-treat (ITT) population (Table 1). Patients were enrolled if they continued to have pain for more than 3 months after healing of the herpes zoster skin rash. Given in 3 divided doses (TID) Each study included a 1-week baseline during which patients were screened for eligibility and a 7- or 8-week double-blind phase (3 or 4 weeks of titration and 4 weeks of fixed dose). Patients initiated treatment with titration to a maximum of 900 mg/day gabapentin over 3 days. Dosages were then to be titrated in 600 to 1200 mg/day increments at 3- to 7-day intervals to target dose over 3 to 4 weeks. In Study 1, patients were continued on lower doses if not able to achieve the target dose. During baseline and treatment, patients recorded their pain in a daily diary using an 11-point numeric pain rating scale ranging from 0 (no pain) to 10 (worst possible pain). A mean pain score during baseline of at least 4 was required for randomization (baseline mean pain score for Studies 1 and 2 combined was 6.4). Analyses were conducted using the ITT population (all randomized patients who received at least one dose of study medication). Both studies showed significant differences from placebo at all doses tested. A significant reduction in weekly mean pain scores was seen by Week 1 in both studies, and significant differences were maintained to the end of treatment. Comparable treatment effects were observed in all active treatment arms. Pharmacokinetic/pharmacodynamic modeling provided confirmatory evidence of efficacy across all doses. Figures 1and 2 show these changes for Studies 1 and 2. Figure 1. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 1 Figure 2. Weekly Mean Pain Scores (Observed Cases in ITT Population): Study 2 The proportion of responders (those patients reporting at least 50% improvement in endpoint pain score compared with baseline) was calculated for each study (Figure 3). Figure 3. Proportion of Responders (patients with���50% reduction in pain score) at Endpoint: Controlled PHN Studies<br/>Epilepsy: The effectiveness of gabapentin as adjunctive therapy (added to other antiepileptic drugs) was established in multicenter placebo-controlled, double-blind, parallel-group clinical trials in adult and pediatric patients (3 years and older) with refractory partial seizures. Evidence of effectiveness was obtained in three trials conducted in 705 patients (age 12 years and above) and one trial conducted in 247 pediatric patients (3 to 12 years of age). The patients enrolled had a history of at least 4 partial seizures per month in spite of receiving one or more antiepileptic drugs at therapeutic levels and were observed on their established antiepileptic drug regimen during a 12-week baseline period (6 weeks in the study of pediatric patients). In patients continuing to have at least 2 (or 4 in some studies) seizures per month, gabapentin or placebo was then added on to the existing therapy during a 12-week treatment period. Effectiveness was assessed primarily on the basis of the percent of patients with a 50% or greater reduction in seizure frequency from baseline to treatment (the���responder rate���) and a derived measure called response ratio, a measure of change defined as (T - B)/(T + B), where B is the patient's baseline seizure frequency and T is the patient's seizure frequency during treatment. Response ratio is distributed within the range -1 to +1. A zero value indicates no change while complete elimination of seizures would give a value of -1; increased seizure rates would give positive values. A response ratio of -0.33 corresponds to a 50% reduction in seizure frequency. The results given below are for all partial seizures in the intent-to-treat (all patients who received any doses of treatment) population in each study, unless otherwise indicated. One study compared gabapentin 1200 mg/day divided TID with placebo. Responder rate was 23% (14/61) in the gabapentin group and 9% (6/66) in the placebo group; the difference between groups was statistically significant. Response ratio was also better in the gabapentin group (-0.199) than in the placebo group (-0.044), a difference that also achieved statistical significance. A second study compared primarily 1200 mg/day divided TID gabapentin (N = 101) with placebo (N = 98). Additional smaller gabapentin dosage groups (600 mg/day, N = 53; 1800 mg/day, N = 54) were also studied for information regarding dose response. Responder rate was higher in the gabapentin 1200 mg/day group (16%) than in the placebo group (8%), but the difference was not statistically significant. The responder rate at 600 mg (17%) was also not significantly higher than in the placebo, but the responder rate in the 1800 mg group (26%) was statistically significantly superior to the placebo rate. Response ratio was better in the gabapentin 1200 mg/day group (-0.103) than in the placebo group (-0.022); but this difference was also not statistically significant (p = 0.224). A better response was seen in the gabapentin 600 mg/day group (-0.105) and 1800 mg/day group (-0.222) than in the 1200 mg/day group, with the 1800 mg/day group achieving statistical significance compared to the placebo group. A third study compared gabapentin 900 mg/day divided TID (N = 111) and placebo (N = 109). An additional gabapentin 1200 mg/day dosage group (N = 52) provided dose-response data. A statistically significant difference in responder rate was seen in the gabapentin 900 mg/day group (22%) compared to that in the placebo group (10%). Response ratio was also statistically significantly superior in the gabapentin 900 mg/day group (-0.119) compared to that in the placebo group (-0.027), as was response ratio in 1200 mg/day gabapentin (-0.184) compared to placebo. Analyses were also performed in each study to examine the effect of gabapentin on preventing secondarily generalized tonic-clonic seizures. Patients who experienced a secondarily generalized tonic-clonic seizure in either the baseline or in the treatment period in all three placebo-controlled studies were included in these analyses. There were several response ratio comparisons that showed a statistically significant advantage for gabapentin compared to placebo and favorable trends for almost all comparisons. Analysis of responder rate using combined data from all three studies and all doses (N = 162, gabapentin; N = 89, placebo) also showed a significant advantage for gabapentin over placebo in reducing the frequency of secondarily generalized tonic-clonic seizures. In two of the three controlled studies, more than one dose of gabapentin was used. Within each study the results did not show a consistently increased response to dose. However, looking across studies, a trend toward increasing efficacy with increasing dose is evident (see Figure 4). Figure 4. Responder Rate in Patients Receiving Gabapentin Expressed as a Difference from Placebo by Dose and Study: Adjunctive Therapy Studies in Patients���12 Years of Age With Partial Seizures In the figure, treatment effect magnitude, measured on the Y axis in terms of the difference in the proportion of gabapentin and placebo assigned patients attaining a 50% or greater reduction in seizure frequency from baseline, is plotted against the daily dose of gabapentin administered (X axis). Although no formal analysis by gender has been performed, estimates of response (Response Ratio) derived from clinical trials (398 men, 307 women) indicate no important gender differences exist. There was no consistent pattern indicating that age had any effect on the response to gabapentin. There were insufficient numbers of patients of races other than Caucasian to permit a comparison of efficacy among racial groups. A fourth study in pediatric patients age 3 to 12 years compared 25 to 35 mg/kg/day gabapentin (N = 118) with placebo (N = 127). For all partial seizures in the intent-to-treat population, the response ratio was statistically significantly better for the gabapentin group (-0.146) than for the placebo group (-0.079). For the same population, the responder rate for gabapentin (21%) was not significantly different from placebo (18%). A study in pediatric patients age 1 month to 3 years compared 40 mg/kg/day gabapentin (N = 38) with placebo (N = 38) in patients who were receiving at least one marketed antiepileptic drug and had at least one partial seizure during the screening period (within 2 weeks prior to baseline). Patients had up to 48 hours of baseline and up to 72 hours of double-blind video EEG monitoring to record and count the occurrence of seizures. There were no statistically significant differences between treatments in either the response ratio or responder rate. | lld:dailymed |
| dailymed-drugs:156 | dailymed-instance:clinicalP... | Phenytoin is an antiepileptic drug which can be useful in the treatment of epilepsy. The primary site of action appears to be the motor cortex where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, phenytoin tends to stabilize the threshold against hyperexcitability caused by excessive stimulation or environmental changes capable of reducing membrane sodium gradient. This includes the reduction of posttetanic potentiation at synapses. Loss of posttetanic potentiation prevents cortical seizure foci from detonating adjacent cortical areas. Phenytoin reduces the maximal activityof brain stem centers responsible for the tonic phase of tonic-clonic (grand-mal) seizures. The plasma half-life in man after oral administration of phenytoin averages 22 hours, with a range of 7 to 42 hours. Steady-state therapeutic levels are achieved at least 7 to 10 days (5-7 half-lives) after initiation of therapy with recommended doses of 300 mg/day. When serum level determinations are necessary, they should be obtained at least 5-7 half-lives after treatment initiation, dosage change, or addition or subtraction of another drug to the regimen so that equilibrium or steady-state will have been achieved. Trough levels provide information about clinically effective serum level range and confirm patient compliance and are obtained just prior to the patient's next scheduled dose. Peak levels indicate an individual's threshold for emergence of dose-related side effects and are obtained at the time of expected peak concentration. For phenytoin suspension peak levelsoccur 1��-3 hours after administration. Optimum control without clinical signs of toxicity occurs more often with serum levels between 10 and 20 mcg/mL, although some mild cases of tonic-clonic (grand-mal) epilepsy may be controlled with lower serum levels of phenytoin. In most patients maintained at a steady dosage, stable phenytoin serum levels are achieved. There may be wide interpatient variability in phenytoin serum levels with equivalent dosages. Patients with unusually low levels may be noncompliant or hypermetabolizers of phenytoin. Unusually high levels result from liver disease, congenital enzyme deficiency, or drug interactions which result in metabolic interference. The patient with large variations in phenytoin plasma levels, despite standard doses, presents a difficult clinical problem. Serum level determinations in such patients may be particularly helpful. As phenytoin is highly protein bound, free phenytoin levels may be altered in patients whose protein binding characteristics differ from normal. Most of the drug is excreted in the bile as inactive metabolites which are then reabsorbed from the intestinal tract and excreted in the urine. Urinary excretion of phenytoin and its metabolites occurs partly with glomerular filtration but, more importantly, by tubular secretion. Because phenytoin is hydroxylated in the liver by an enzyme system which is saturable at high plasma levels, small incremental doses may increase the half-life and produce very substantial increases in serum levels, when these are in the upper range. The steady-state level may be disproportionately increased, with resultant intoxication, from an increase in dosage of 10% or more. | lld:dailymed |
| dailymed-drugs:158 | dailymed-instance:clinicalP... | Labetalol combines both selective, competitive, alpha-adrenergic blocking and nonselective, competitive, beta-adrenergic blocking activity in a single substance. In man, the ratios of alpha- to beta-blockade have been estimated to be approximately 1:3 and 1:7 following oral and intravenous administration, respectively. Beta-agonist activity has been demonstrated in animals with minimal beta-agonist (ISA) activity detected. In animals, at doses greater than those required for alpha- or beta-adrenergic blockade, a membrane stabilizing effect has been demonstrated.<br/>Pharmacodynamics: The capacity of labetalol to block alpha receptors in man has been demonstrated by attenuation of the pressor effect of phenylephrine and by a significant reduction of the pressor response caused by immersing the hand in ice-cold water (���cold-pressor test���). Labetalol's beta-receptor blockade in man was demonstrated by a small decrease in the resting heart rate, attenuation of tachycardia produced by isoproterenol or exercise, and by attenuation of the reflex tachycardia to the hypotension produced by amyl nitrite. Beta-receptor blockade was demonstrated by inhibition of the isoproterenol-induced fall in diastolic blood pressure. Both the alpha- and beta-blocking actions of orally administered labetalol HCl contribute to a decrease in blood pressure in hypertensive patients. Labetalol consistently, in dose-related fashion, blunted increases in exercise-induced blood pressure and heart rate, and in their double product. The pulmonary circulation during exercise was not affected by labetalol HCl dosing. Single oral doses of labetalol HCl administered to patients with coronary artery disease had no significant effect on sinus rate, intraventricular conduction, or QRS duration. The atrioventricular (A-V) conduction time was modestly prolonged in two of seven patients. In another study, intravenous labetalol slightly prolonged A-V nodal conduction time and atrial effective refractory period with onlysmall changes in heart rate. The effects on A-V nodal refractoriness were inconsistent. Labetalol produces dose-related falls in blood pressure without reflex tachycardia and without significant reduction in heart rate, presumably through a mixture of its alpha-blocking and beta-blocking effects. Hemodynamic effects are variable, with small, nonsignificant changes in cardiac output seen in some studies but not others, and small decreases in total peripheral resistance. Elevated plasmarenins are reduced. Doses of labetalol HCl that controlled hypertension did not affect renal function in mildly to severely hypertensive patients with normal renal function. Due to the alpha-receptor blocking activity of labetalol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension can occur. During dosing with intravenous labetalol HCl, the contribution of the postural component should be considered when positioning patients for treatment, and patients should not be allowed to move to an erect position unmonitored until their ability to do so is established. In a clinical pharmacologic study in severe hypertensives, an initial 0.25 mg/kg injection of labetalol HCl administered to patients in the supine position decreased blood pressure by an average of 11/7 mmHg. Additional injections of 0.5 mg/kg at 15 minute intervals up to a total cumulative dose of 1.75 mg/kg of labetalol HCl caused further dose-related decreases in blood pressure. Some patients required cumulative doses of up to 3.25 mg/kg. The maximal effect of each dose level occurred within 5 minutes. Following discontinuation of intravenous treatment with labetalol HCl, the blood pressure rose gradually and progressively, approaching pretreatment baseline values within an average of 16 to 18 hours in the majority of patients. Similar results were obtained in the treatment of patients with severe hypertension who required urgent blood pressure reduction with an initial dose of 20 mg (which corresponds to 0.25 mg/kg for an 80 kg patient) followed by additional doses of either 40 or 80 mg at 10 minute intervals to achieve the desired effect, or up to a cumulative dose of 300 mg. Labetalol HCl administered as a continuous intravenous infusion, with a mean dose of 136 mg (27 to 300 mg) over a period of 2 to 3 hours (mean of 2 hours and 39 minutes), lowered the blood pressure by an average of 60/35 mmHg. Exacerbation of angina and, in some cases, myocardial infarction and ventricular dysrhythmias have been reported after abrupt discontinuation of therapy with beta-adrenergic blocking agents in patients with coronary artery disease. Abrupt withdrawal of these agents in patients without coronary artery disease has resulted in transient symptoms, including tremulousness, sweating, palpitation, headache, and malaise. Several mechanisms have been proposed to explain these phenomena, among them increased sensitivity to catecholamines because of increased numbers of beta receptors. Although beta-adrenergic receptor blockade is useful in the treatment of angina and hypertension, there are also situations in which sympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. Beta-adrenergic blockade may worsen A-V block by preventing the necessary facilitatingeffects of sympathetic activity on conduction. Beta-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm, and may also interfere with exogenous bronchodilators in such patients.<br/>Pharmacokinetics and Metabolism: Following intravenous infusion of labetalol, the elimination half-life is about 5.5 hours and the total body clearance is approximately 33 mL/min/kg. The plasma half-life of labetalol following oral administration is about 6 to 8 hours. In patients with decreased hepatic or renal function, the elimination half-life of labetalol is not altered; however, the relative bioavailability in hepatically impaired patients is increased due to decreased���first-pass���metabolism. The metabolism of labetalol is mainly through conjugation to glucuronide metabolites. These metabolites are present in plasma and are excreted in the urine and, via the bile, into the feces. Approximately 55% to 60% of a dose appears in the urine as conjugates or unchanged labetalol within the first24 hours of dosing. Labetalol has been shown to cross the placental barrier in humans. Only negligible amounts of the drug crossed the blood-brain barrier in animal studies. Labetalol is approximately 50% protein bound. Neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol from the general circulation (<1%). | lld:dailymed |
| dailymed-drugs:159 | dailymed-instance:clinicalP... | Pharmacodynamics:<br/>A. Benign Prostatic Hyperplasia (BPH): Benign prostatic hyperplasia (BPH) is a common cause of urinary outflow obstruction in aging males. Severe BPH may lead to urinary retention and renal damage. A static and a dynamic component contribute to the symptoms and reduced urinary flow rate associated with BPH. The static component is related to an increase in prostate size caused, in part, by a proliferation of smooth muscle cells in the prostatic stroma. However, the severity of BPH symptoms and the degree of urethral obstruction do not correlate well with the size of the prostate. The dynamic component of BPH is associated with an increase in smooth muscle tone in the prostate and bladder neck. The degree of tone in this area is mediated by the alphaadrenoceptor, which is present in high density in the prostatic stroma, prostatic capsule, and bladder neck. Blockade of the alphareceptor decreases urethral resistance and may relieve the obstruction and BPH symptoms. In the human prostate, doxazosin mesylate antagonizes phenylephrine (alphaagonist)-induced contractions, in vitro, and binds with high affinity to the alphaadrenoceptor. The receptor subtype is thought to be the predominant functional type in the prostate. Doxazosin mesylate acts within 1 to 2 weeks to decrease the severity of BPH symptoms and improve urinary flow rate. Since alphaadrenoceptors are of low density in the urinary bladder (apart from the bladder neck), doxazosin mesylate should maintain bladder contractility. The efficacy of doxazosin mesylate was evaluated extensively in over 900 patients with BPH in double-blind, placebo-controlled trials. Doxazosin mesylate treatment was superior to placebo in improving patient symptoms and urinary flow rate. Significant relief with doxazosin mesylate was seen as early as one week into the treatment regimen, with doxazosin mesylate treated patients (N = 173) showing a significant (p<0.01) increase in maximum flow rate of 0.8 mL/sec compared to a decrease of 0.5 mL/sec in the placebo group (N = 41). In long-term studies improvement was maintained for up to 2 years of treatment. In 66 to 71% of patients, improvements above baseline were seen in both symptoms and maximum urinary flow rate. In three placebo-controlled studies of 14 to 16 weeks duration obstructive symptoms (hesitation, intermittency, dribbling, weak urinary stream, incomplete emptying of the bladder) and irritative symptoms (nocturia, daytime frequency, urgency, burning) of BPH were evaluated at each visit by patient-assessed symptom questionnaires. The bothersomeness of symptoms was measured with a modified Boyarsky questionnaire. Symptom severity/frequency was assessed using a modified Boyarsky questionnaire or an AUA-based questionnaire. Uroflowmetric evaluations were performed at times of peak (2 to 6 hours post-dose) and/or trough (24 hours post-dose) plasma concentrations of doxazosin mesylate. The results from the three placebo-controlled studies (N = 609) showing significant efficacy with 4 mg and 8 mg doxazosin are summarized in TABLE 1. In all three studies, doxazosin mesylate resulted in statistically significant relief of obstructive and irritative symptoms compared to placebo. Statistically significant improvements of 2.3 to 3.3 mL/sec in maximum flow rate were seen with doxazosin mesylate in STUDIES 1 and 2, compared to 0.1 to 0.7 mL/sec with placebo. In one fixed dose study (STUDY 2) doxazosin mesylate therapy (4 to 8 mg, once daily) resulted in a significant and sustained improvement in maximum urinary flow rate of 2.3 to 3.3 mL/sec (TABLE 1) compared to placebo (0.1 mL/sec). In this study, the only study in which weekly evaluations were made, significant improvement with doxazosin mesylate vs. placebo was seen after one week. The proportion of patients who responded with a maximum flow rate improvement of���3 mL/sec was significantly larger with doxazosin mesylate (34 to 42%) than placebo (13 to 17%). A significantly greater improvement was also seen in average flow rate with doxazosin mesylate (1.6 mL/sec) than with placebo (0.2 mL/sec). The onset and time course of symptom relief and increased urinary flow from STUDY 1 are illustrated in Figure 1. In BPH patients (N = 450) treated for up to 2 years in open-label studies, doxazosin mesylate therapy resulted in significant improvement above baseline in urinary flow rates and BPH symptoms. The significant effects of doxazosin mesylate were maintained over the entire treatment period. Although blockade of alphaadrenoceptors also lowers blood pressure in hypertensive patients with increased peripheral vascular resistance, doxazosin mesylate treatment of normotensive men with BPH did not result in a clinically significant blood pressure lowering effect (TABLE 2). The proportion of normotensive patients with a sitting systolic blood pressure less than 90 mmHg and/or diastolic blood pressure less than 60 mmHg at any time during treatment with doxazosin mesylate 1 to 8 mg once daily was 6.7% with doxazosin and not significantly different (statistically) from that with placebo (5%).<br/>B. Hypertension: The mechanism of action of doxazosin mesylate is selective blockade of the alpha(postjunctional) subtype of adrenergic receptors. Studies in normal human subjects have shown that doxazosin competitively antagonized the pressor effects of phenylephrine (an alphaagonist) and the systolic pressor effect of norepinephrine. Doxazosin and prazosin have similar abilities to antagonize phenylephrine. The antihypertensive effect of doxazosin mesylate results from a decrease in systemic vascular resistance. The parent compound doxazosin is primarily responsible for the antihypertensive activity. The low plasma concentrations of known active and inactive metabolites of doxazosin (2-piperazinyl, 6��- and 7��-hydroxy and 6- and 7-O-desmethyl compounds) compared to parent drug indicate that the contribution of even the most potent compound (6��-hydroxy) to the antihypertensive effect of doxazosin in man is probably small. The 6��- and 7��-hydroxy metabolites have demonstrated antioxidant properties at concentrations of 5��M, in vitro. Administration of doxazosin mesylate results in a reduction in systemic vascular resistance. In patients with hypertension there is little change in cardiac output. Maximum reductions in blood pressure usually occur 2 to 6 hours after dosing and are associated with a small increase in standing heart rate. Like other alpha-adrenergic blocking agents, doxazosin has a greater effect on blood pressure and heart rate in the standing position. In a pooled analysis of placebo-controlled hypertension studies with about 300 hypertensive patients per treatment group, doxazosin, at doses of 1 to 16 mg given once daily, lowered blood pressure at 24 hours by about 10/8 mmHg compared to placebo in the standing position and about 9/5 mmHg in the supine position. Peak blood pressure effects (1 to 6 hours) were larger by about 50 to 75% (i.e., trough values were about 55 to 70% of peak effect), with the larger peak-trough differences seen in systolic pressures. There was no apparent difference in the blood pressure response of Caucasians and blacks or of patients above and below age 65. In these predominantly normocholesterolemic patients doxazosin produced small reductions in total serum cholesterol (2 to 3%), LDL cholesterol (4%), and a similarly small increase in HDL/total cholesterol ratio (4%). The clinical significance of these findings is uncertain. In the same patient population, patients receiving doxazosin mesylate gained a mean of 0.6 kg compared to a mean loss of 0.1 kg for placebo patients.<br/>Pharmacokinetics: After oral administration of therapeutic doses, peak plasma levels of doxazosin mesylate occur at about 2 to 3 hours. Bioavailability is approximately 65%, reflecting first pass metabolism of doxazosin by the liver. The effect of food on the pharmacokinetics of doxazosin mesylate was examined in a crossoverstudy with twelve hypertensive subjects. Reductions of 18% in mean maximum plasma concentration and 12% in the area under the concentration-time curve occurred when doxazosin mesylate was administered with food. Neither of these differences was statistically or clinically significant. Doxazosin mesylate is extensively metabolized in the liver, mainly by O-demethylation of the quinazoline nucleus or hydroxylation of the benzodioxan moiety. Although several active metabolites of doxazosin have been identified, the pharmacokinetics of these metabolites have not been characterized. In a study of two subjects administered radiolabelled doxazosin 2 mg orally and 1 mg intravenously on two separate occasions, approximately 63% of the dose was eliminated in the feces and 9% of the dose was found in the urine. On average only 4.8% of the dose was excreted as unchanged drug in the feces and only a trace of the total radioactivity in the urine was attributed to unchanged drug. At the plasma concentrations achieved by therapeutic doses approximately 98% of the circulating drug is bound to plasma proteins. Plasma elimination of doxazosin is biphasic, with a terminal elimination half-life of about 22 hours. Steady-state studies in hypertensive patients given doxazosin doses of 2 to 16 mg once daily showed linear kinetics and dose proportionality. In two studies, following the administration of 2 mg orally once daily, the mean accumulation ratios (steady-state AUC vs. first dose AUC) were 1.2 and 1.7. Enterohepatic recycling is suggested by secondary peaking of plasma doxazosin concentrations. In a crossover study in 24 normotensive subjects, the pharmacokinetics and safety of doxazosin were shown to be similar with morning and evening dosing regimens. The area under the curve after morning dosing was, however, 11% less than that after evening dosing and the time to peak concentration after evening dosing occurred significantly later than that after morning dosing (5.6 hr vs. 3.5 hr). The pharmacokinetics of doxazosin mesylate in young (<65 years) and elderly (���65 years) subjects were similar for plasma half-life values and oral clearance. Pharmacokinetic studies in elderly patients and patients with renal impairment have shown no significant alterations compared to younger patients with normal renal function. Administration of a single 2 mg dose to patients with cirrhosis (Child-Pugh Class A) showed a 40% increase in exposure to doxazosin. There are only limited data on the effects of drugs known to influence the hepatic metabolism of doxazosin [e.g., cimetidine (see PRECAUTIONS)]. As with any drug wholly metabolized by the liver, use of doxazosin mesylate in patients with altered liver function should be undertaken with caution. In two placebo-controlled studies, of normotensive and hypertensive BPH patients, in which doxazosin was administered in the morning and the titration interval was two weeks and one week, respectively, trough plasma concentrations of doxazosin mesylate were similar in the two populations. Linear kinetics and dose proportionality were observed. | lld:dailymed |
| dailymed-drugs:161 | dailymed-instance:clinicalP... | Pharmacodynamics: The mechanism of action of citalopram hydrobromide as an antidepressant is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro and in vivo studies in animals suggest that citalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine (NE) and dopamine (DA) neuronal reuptake. Tolerance to the inhibition of 5-HT uptake is not induced by long-term (14 day) treatment of rats with citalopram. Citalopram is a racemic mixture (50/50), and the inhibition of 5-HT reuptake by citalopram is primarily due to the (S)-enantiomer. Citalopram has no or very low affinity for 5-HT, 5-HT, dopamine Dand D,��1-,��2-, and��-adrenergic, histamine H, gamma aminobutyric acid (GABA), muscarinic cholinergic, and benzodiazepine receptors. Antagonism of muscarinic, histaminergic and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative and cardiovascular effects of other psychotropic drugs.<br/>Pharmacokine tics: The single- and multiple-dose pharmacokinetics of citalopram are linear and dose-proportional in a dose range of 10 mg/day to 60 mg/day. Biotransformation of citalopram is mainly hepatic, with a mean terminal half-life of about 35 hours. With once daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of citalopram in plasma, based on the half-life, is expected to be 2.5 times the plasma concentrations observed after a single dose.<br/>Absorption and Distribution: Following a single oral dose (40 mg tablet) of citalopram, peak blood levels occur at about 4 hours. The absolute bioavailability of citalopram was about 80% relative to an intravenous dose and absorption is not affected by food. The volume of distribution of citalopram is about 12 L/kg and the binding of citalopram (CT), demethylcitalopram (DCT) and didemethylcitalopram (DDCT) to human plasma proteins is about 80%.<br/>Metabolism and Elimination: Following intravenous administrations of citalopram, the fraction of drug recovered in the urine as citalopram and DCT was about 10% and 5%, respectively. The systemic clearance of citalopram was 330 mL/min, with approximately 20% of that due to renal clearance. Citalopram is metabolized to demethylcitalopram (DCT), didemethylcitalopram (DDCT), citalopram-N-oxide and a deaminated propionic acid derivative. In humans, unchanged citalopram is the predominant compound in plasma. At steady state, the concentrations of citalopram's metabolites, DCT and DDCT, in plasma are approximately one-half and one-tenth, respectively, that of the parent drug. In vitro studies show that citalopram is at least 8 times more potent than its metabolites in the inhibition of serotonin reuptake, suggesting that the metabolites evaluated do not likely contribute significantly to the antidepressant actions of citalopram. In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of citalopram.<br/>Population Subgroups:<br/>Drug-Drug Interactions: In vitro enzyme inhibition data did not reveal an inhibitory effect of citalopram on CYP3A4, -2C9, or -2E1, but did suggest that it is a weak inhibitor of CYP1A2, -2D6, and -2C19. Citalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. However, in vivo data to address this question are limited. Since CYP3A4 and 2C19 are the primary enzymes involved in the metabolism of citalopram, it is expected that potent inhibitors of 3A4 (e.g., ketoconazole, itraconazole, and macrolide antibiotics) and potent inhibitors of CYP2C19 (e.g., omeprazole) might decrease the clearance of citalopram. However, coadministration of citalopram and the potent 3A4 inhibitor ketoconazole did not significantly affect the pharmacokinetics of citalopram. Because citalopram is metabolized by multiple enzyme systems, inhibition of a single enzyme may not appreciably decrease citalopram clearance. Citalopram steady state levels were not significantly different in poor metabolizers and extensive 2D6 metabolizers after multiple-dose administration of citalopram hydrobromide, suggesting that coadministration, with citalopram hydrobromide, of a drug that inhibits CYP2D6, is unlikely to have clinically significant effects on citalopram metabolism. See Drug Interactions under PRECAUTIONS for more detailed information on available drug interaction data.<br/>Clinical Efficacy Trials: The efficacy of citalopram hydrobromide as a treatment for depression was established in two placebo-controlled studies (of 4 to 6 weeks in duration) in adult outpatients (ages 18 to 66) meeting DSM-III or DSM-III-R criteria for major depression. Study 1, a 6-week trial in which patients received fixed citalopram hydrobromide doses of 10 mg/day, 20 mg/day, 40 mg/day and 60 mg/day, showed that citalopram hydrobromide at doses of 40 mg/day and 60 mg/day was effective as measured by the Hamilton Depression Rating Scale (HAMD) total score, the HAMD depressed mood item (Item 1), the Montgomery Asberg Depression Rating Scale, and the Clinical Global Impression (CGI) Severity scale. This study showed no clear effect of the 10 mg/day and 20 mg/day doses, and the 60 mg/day dose was not more effective than the 40 mg/day dose. In study 2, a 4-week, placebo-controlled trial in depressed patients, of whom 85% met criteria for melancholia, the initial dose was 20 mg/day, followed by titration to the maximum tolerated dose or a maximum dose of 80 mg/day. Patients treated with citalopram hydrobromide showed significantly greater improvement than placebo patients on the HAMD total score, HAMD item 1, and the CGI Severity score. In three additional placebo-controlled depression trials, the difference in response to treatment between patients receiving citalopram hydrobromide and patients receiving placebo was not statistically significant, possibly due to high spontaneous response rate, smaller sample size, or, in the case of one study, too low a dose. In two long-term studies, depressed patients who had responded to citalopram hydrobromide during an initial 6 or 8 weeks of acute treatment (fixed doses of 20 mg/day or 40 mg/day in one study and flexible doses of 20 mg/day to 60 mg/day in the second study) were randomized to continuation of citalopram hydrobromide or to placebo. In both studies, patients receiving continued citalopram hydrobromide treatment experienced significantly lower relapse rates over the subsequent 6 months compared to those receiving placebo. In the fixed dose study, the decreased rate of depression relapse was similar in patients receiving 20 mg/day or 40 mg/day of citalopram hydrobromide. Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics.<br/>Comparison of Clinical Trial Results: Highly variable results have been seen in the clinical development of all antidepressant drugs. Furthermore in those circumstances when the drugs have not been studied in the same controlled clinical trial(s), comparisons among the results of studies evaluating the effectiveness of different antidepressant drug products are inherently unreliable. Because conditions of testing (e.g., patient samples, investigators, doses of the treatments administered and compared, outcome measures, etc.) vary among trials, it is virtually impossible to distinguish a difference in drug effect from a difference due to one of the confounding factors just enumerated. | lld:dailymed |
| dailymed-drugs:162 | dailymed-instance:clinicalP... | Corticoids suppress the inflammatory response to a variety of agents and they may delay healing. Since corticoids may inhibit the body's defense mechanism against infection, a concomitant antimicrobial drug may be used when this inhibition is considered to be clinically significant in a particular case. The anti-infective components in the combination are included to provide action against specific organisms susceptible to them. Polymyxin B sulfate, bacitracin zinc, and neomycin sulfate together are considered active against the following microorganisms: Staphylococcus aureus, streptococci, including Streptococcus pneumoniae, Escherichia coli, Haemophilus influenzae, Klebsiella-Enterobacter species, Neisseria species, and Pseudomonas aeruginosa. The product does not provide adequate coverage against Serratia marcescens. The relative potency of corticosteroids depends on the molecular structure, concentration, and release from the vehicle. | lld:dailymed |
| dailymed-drugs:163 | dailymed-instance:clinicalP... | Nystatin: Nystatin exerts its antifungal activity against a variety of pathogenic and nonpathogenic yeasts and fungi by binding to sterols in the cell membrane. The binding process renders the cell membrane incapable of functioning as a selective barrier. Nystatin provides specific anticandidal activity to Candida (Monilia) albicans and other Candida species, but is not active against bacteria, protozoa, trichomonads, or viruses. Nystatin is not absorbed from intact skin or mucous membranes.<br/>Triamcinolone Acetonide: Triamcinolone acetonide is primarily effective because of its anti-inflammatory, antipruritic and vasoconstrictive actions, characteristic of the topical corticosteroid class of drugs. The pharmacologic effects of the topical corticosteroids are well-known; however, the mechanisms of their dermatologic actions are unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man.<br/>Pharmacokinetics: The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings . Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids . Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.<br/>Nystatin and Triamcinolone Acetonide: During clinical studies of mild to severe manifestations of cutaneous candidiasis, patients treated with MYCOLOG II (Nystatin and Triamcinolone Acetonide Cream) showed a faster and more pronounced clearing of erythema and pruritus than patients treated with nystatin or triamcinolone acetonide alone. | lld:dailymed |
| dailymed-drugs:164 | dailymed-instance:clinicalP... | Pharmacokinetics: Levofloxacin concentration in plasma was measured in 15 healthy adult volunteers at various time points during a 15-day course of treatment with QUIXIN solution. The mean levofloxacin concentration in plasma 1 hour postdose, ranged from 0.86 ng/mL on Day 1 to 2.05 ng/mL on Day 15. The highest maximum mean levofloxacin concentration of 2.25 ng/mL was measured on Day 4 following 2 days of dosing every 2 hours for a total of 8 doses per day. Maximum mean levofloxacin concentrations increased from 0.94 ng/mL on Day 1 to 2.15 ng/mL on Day 15, which is more than 1,000 times lower than those reported after standard oral doses of levofloxacin. Levofloxacin concentration in tears was measured in 30 healthy adult volunteers at various time points following instillation of a single drop of QUIXIN solution. Mean levofloxacin concentrations in tears ranged from 34.9 to 221.1��g/mL during the 60-minute period following the single dose. The mean tear concentrations measured 4 and 6 hours postdose were 17.0 and 6.6��g/mL. The clinical significance of these concentrations is unknown.<br/>Microbiology: Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. The mechanism of action of levofloxacin and other fluoroquinolone antimicrobials involves the inhibition of bacterial topoisomerase IV and DNA gyrase (both of which are type II topoisomerases), enzymes required for DNA replication, transcription, repair, and recombination. Levofloxacin has in vitro activity against a wide range of Gram-negative and Gram-positive microorganisms and is often bactericidal at concentrations equal to or slightly greater than inhibitory concentrations. Fluoroquinolones, including levofloxacin, differ in chemical structure and mode of action from��-lactam antibiotics and aminoglycosides, and therefore may be active against bacteria resistant to��-lactam antibiotics and aminoglycosides. Additionally,��-lactam antibiotics and aminoglycosides may be active against bacteria resistant to levofloxacin. Resistance to levofloxacin due to spontaneous mutation in vitro is a rare occurrence (range: 10to 10). Levofloxacin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section:<br/>AEROBIC GRAM-POSITIVE MICROORGANISMS: Corynebacterium speciesStaphylococcus aureusStaphylococcus epidermidisStreptococcus pneumoniaeStreptococcus (Groups C/F)Streptococcus (Group G)Viridans group streptococci<br/>AEROBIC GRAM-NEGATIVE MICROORGANISMS: Acinetobacter lwoffiiHaemophilus influenzaeSerratia marcescens Efficacy for this organism was studied in fewer than 10 infections. The following in vitro data are also available, but their clinical significance in ophthalmic infections is unknown. The safety and effectiveness of levofloxacin in treating ophthalmological infections due to these microorganisms have not been established in adequate and well-controlled trials. These organisms are considered susceptible when evaluated using systemic breakpoints. However, a correlation between the in vitro systemic breakpoint and ophthalmological efficacy has not been established. The list of organisms is provided as guidance only in assessing the potential treatment of conjunctival infections. Levofloxacin exhibits in vitro minimal inhibitory concentrations (MICs) of 2��g/mL or less (systemic susceptible breakpoint) against most (���90%) strains of the following ocular pathogens.<br/>AEROBIC GRAM-POSITIVE MICROORGANISMS:<br/>AEROBIC GRAM-NEGATIVE MICROORGANISMS:<br/>Clinical Studies: In randomized, double-masked, multicenter controlled clinical trials where patients were dosed for 5 days, QUIXIN demonstrated clinical cures in 79% of patients treated for bacterial conjunctivitis on the final study visit day (day 6-10). Microbial outcomes for the same clinical trials demonstrated an eradication rate for presumed pathogens of 90%. | lld:dailymed |
| dailymed-drugs:165 | dailymed-instance:clinicalP... | Endogenous androgens are responsible for normal growth and development of the male sex organs and for maintenance of secondary sex characteristics. These effects include growth and maturation of the prostate, seminal vesicles, penis, and scrotum; development of male hair distribution, such as beard, pubic, chest, and axillary hair; laryngeal enlargement, vocal cord thickening, and alterations in body musculature and fat distribution. Drugs in this class also cause retention of nitrogen, sodium, potassium, and phosphorus, and decreased urinary excretion of calcium. Androgens have been reported to increase protein anabolism and decrease protein catabolism. Nitrogen balance is improved only when there is sufficient intake of calories and protein. Androgens are responsible for the growth spurt of adolescence and for eventual termination of linear growth, brought about by fusion of the epiphyseal growth centers. In children, exogenous androgens accelerate linear growth rates, but may cause disproportionate advancement in bone maturation. Use over long periods may result in fusion of the epiphyseal growth centers and termination of the growth process. Androgens have been reported to stimulate production of red blood cells by enhancing production of erythropoietic stimulation factor. During exogenous administration of androgens, endogenous testosterone release is inhibited through feedback inhibition of pituitary luteinizing hormone (LH). At large doses of exogenous androgens, spermatogenesis may also be suppressed through feedback inhibition of pituitary follicle stimulating hormone (FSH). Inactivation of testosterone occurs primarily in the liver. The half-life of fluoxymesterone after oral administration is approximately 9.2 hours. | lld:dailymed |
| dailymed-drugs:166 | dailymed-instance:clinicalP... | In animals, diazepam appears to act on parts of the limbic system, the thalamus and hypothalamus, and induces calming effects. Diazepam, unlike chlorpromazine and reserpine, has no demonstrable peripheral autonomic blocking action, nor does it produce extrapyramidal side effects; however, animals treated with diazepam do have a transient ataxia at higher doses. Diazepam was found to have transient cardiovascular depressor effects in dogs. Long-term experiments in rats revealed no disturbances of endocrine function. Injections into animals have produced localized irritation of tissue surrounding injection sites and some thickening of veins after intravenous use. | lld:dailymed |
| dailymed-drugs:655 | dailymed-instance:clinicalP... | In animals, diazepam appears to act on parts of the limbic system, the thalamus and hypothalamus, and induces calming effects. Diazepam, unlike chlorpromazine and reserpine, has no demonstrable peripheral autonomic blocking action, nor does it produce extrapyramidal side effects; however, animals treated with diazepam do have a transient ataxia at higher doses. Diazepam was found to have transient cardiovascular depressor effects in dogs. Long-term experiments in rats revealed no disturbances of endocrine function. Injections into animals have produced localized irritation of tissue surrounding injection sites and some thickening of veins after intravenous use. | lld:dailymed |
| dailymed-drugs:993 | dailymed-instance:clinicalP... | In animals, diazepam appears to act on parts of the limbic system, the thalamus and hypothalamus, and induces calming effects. Diazepam, unlike chlorpromazine and reserpine, has no demonstrable peripheral autonomic blocking action, nor does it produce extrapyramidal side effects; however, animals treated with diazepam do have a transient ataxia at higher doses. Diazepam was found to have transient cardiovascular depressor effects in dogs. Long-term experiments in rats revealed no disturbances of endocrine function. Injections into animals have produced localized irritation of tissue surrounding injection sites and some thickening of veins after intravenous use. | lld:dailymed |
| dailymed-drugs:1956 | dailymed-instance:clinicalP... | In animals, diazepam appears to act on parts of the limbic system, the thalamus and hypothalamus, and induces calming effects. Diazepam, unlike chlorpromazine and reserpine, has no demonstrable peripheral autonomic blocking action, nor does it produce extrapyramidal side effects; however, animals treated with diazepam do have a transient ataxia at higher doses. Diazepam was found to have transient cardiovascular depressor effects in dogs. Long-term experiments in rats revealed no disturbances of endocrine function. Injections into animals have produced localized irritation of tissue surrounding injection sites and some thickening of veins after intravenous use. | lld:dailymed |
| dailymed-drugs:167 | dailymed-instance:clinicalP... | Mechanism of Action: Benazepril and benazeprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. Hypertensive patients treated with benazepril alone for up to 52 weeks had elevations of serum potassium of up to 0.2 mEq/L. Similar patients treated with benazepril and hydrochlorothiazide for up to 24 weeks had no consistent changes in their serum potassium . Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. In animal studies, benazepril had no inhibitory effect on the vasopressor response to angiotensin II and did not interfere with the hemodynamic effects of the autonomic neurotransmitters acetylcholine, epinephrine, and norepinephrine. ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of benazepril remains to be elucidated. While the mechanism through which benazepril lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, benazepril has an antihypertensive effect even in patients with low-renin hypertension .<br/>Pharmacokinetics and Metabolism: Following oral administration of benazepril, peak plasma concentrations of benazepril are reached within 0.5 to 1.0 hours. The extent of absorption is at least 37% as determined by urinary recovery and is not significantly influenced by the presence of food in the GI tract. Cleavage of the ester group (primarily in the liver) converts benazepril to its active metabolite, benazeprilat. Peak plasma concentrations of benazeprilat are reached 1 to 2 hours after drug intake in the fasting state and 2 to 4 hours after drug intake in the nonfasting state. The serum protein binding of benazepril is about 96.7% and that of benazeprilat about 95.3%, as measured by equilibrium dialysis; on the basis of in vitro studies, the degree of protein binding should be unaffected by age, hepatic dysfunction, or concentration (over the concentration range of 0.24 to 23.6��mol/L). Benazepril is almost completely metabolized to benazeprilat, which has much greater ACE inhibitory activity than benazepril, and to the glucuronide conjugates of benazepril and benazeprilat. Only trace amounts of an administered dose of benazepril can be recovered in the urine as unchanged benazepril, while about 20% of the dose is excreted as benazeprilat, 4% as benazepril glucuronide, and 8% as benazeprilat glucuronide. The kinetics of benazepril are approximately dose-proportional within the dosage range of 10 to 80 mg. In adults, the effective half-life of accumulation of benazeprilat following multiple dosing of benazepril hydrochloride is 10 to 11 hours. Thus, steady-state concentrations of benazeprilat should be reached after 2 or 3 doses of benazepril hydrochloride given once daily. The effective half-life of accumulation of benazeprilat following multiple dosing of benazepril hydrochloride is 10 to 11 hours. Thus, steady-state concentrations of benazeprilat should be reached after 2 or 3 doses of benazepril hydrochloride given once daily. The kinetics did not change, and there was no significant accumulation during chronic administration (28 days) of once-daily doses between 5 mg and 20 mg. Accumulation ratios based on AUC and urinary recovery of benazeprilat were 1.19 and 1.27, respectively. Benazepril and benazeprilat are cleared predominantly by renal excretion in healthy subjects with normal renal function. Nonrenal (i.e., biliary) excretion accounts for approximately 11% to 12% of benazeprilat excretion in healthy subjects. In patients with renal failure, biliary clearance may compensate to an extent for deficient renal clearance. In patients with renal insufficiency, the disposition of benazepril and benazeprilat in patients with mild-to-moderate renal insufficiency (creatinine clearance>30 mL/min) is similar to that in patients with normal renal function. In patients with creatinine clearance���30 mL/min, peak benazeprilat levels and the initial (alpha phase) half-life increase, and time to steady state may be delayed . When dialysis was started 2 hours after ingestion of 10 mg of benazepril, approximately 6% of benazeprilat was removed in 4 hours of dialysis. The parent compound, benazepril, was not detected in the dialysate. In patients with hepatic insufficiency (due to cirrhosis), the pharmacokinetics of benazeprilat are essentially unaltered. The pharmacokinetics of benazepril and benazeprilat do not appear to be influenced by age. In pediatric patients, (N=45) hypertensive, age 6 to 16 years, given multiple daily doses of benazepril (0.1 to 0.5 mg/kg), the clearance of benazeprilat for children 6 to 12 years old was 0.35 L/hr/kg, more than twice that of healthy adults receiving a single dose of 10 mg (0.13 L/hr/kg). In adolescents, it was 0.17 L/hr/kg, 27% higher than that of healthy adults. The terminal elimination half-life of benazeprilat in pediatric patients was around 5 hours, one-third that observed in adults.<br/>Pharmacodynamics: Single and multiple doses of 10 mg or more of benazepril cause inhibition of plasma ACE activity by at least 80% to 90% for at least 24 hours after dosing. Pressor responses to exogenous angiotensin I were inhibited by 60% to 90% (up to 4 hours post-dose) at the 10 mg dose.<br/>Hypertension: Adult Administration of benazepril to patients with mild-to-moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted . In single-dose studies, benazepril lowered blood pressure within 1 hour, with peak reductions achieved 2 to 4 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In multiple-dose studies, once-daily doses of 20 to 80 mg decreased seated pressure (systolic/diastolic) 24 hours after dosing by about 6 to 12 /4 to 7 mmHg. The trough values represent reductions of about 50% of that seen at peak. Four dose-response studies using once-daily dosing were conducted in 470 mild-to-moderate hypertensive patients not using diuretics. The minimal effective once-daily dose of benazepril was 10 mg; but further falls in blood pressure, especially at morning trough, were seen with higher doses in the studied dosing range (10 to 80 mg). In studies comparing the same daily dose of benazepril given as a single morning dose or as a twice-daily dose, blood pressure reductions at the time of morning trough blood levels were greater with the divided regimen. During chronic therapy, the maximum reduction in blood pressure with any dose is generally achieved after 1 to 2 weeks. The antihypertensive effects of benazepril have continued during therapy for at least two years. Abrupt withdrawal of benazepril has not been associated with a rapid increase in blood pressure. In patients with mild-to-moderate hypertension, benazepril 10 to 20 mg was similar in effectiveness to captopril, hydrochlorothiazide, nifedipine SR, and propranolol. The antihypertensive effects of benazepril were not appreciably different in patients receiving high- or low-sodium diets. In hemodynamic studies in dogs, blood pressure reduction was accompanied by a reduction in peripheral arterial resistance, with an increase in cardiac output and renal blood flow and little or no change in heart rate. In normal human volunteers, single doses of benazepril caused an increase in renal blood flow buthad no effect on glomerular filtration rate. Use of benazepril in combination with thiazide diuretics gives a blood-pressure-lowering effect greater than that seen with either agent alone. By blocking the renin-angiotensin-aldosterone axis, administration of benazepril tends to reduce the potassium loss associated with the diuretic. Pediatric In a clinical study of 107 pediatric patients, 7 to 16 years of age, with either systolic or diastolic pressure above the 95th percentile, patients were given 0.1 or 0.2 mg/kg then titrated up to 0.3 or 0.6 mg/kg with a maximum dose of 40 mg once daily. After four weeks of treatment, the 85 patients whose blood pressure was reduced on therapy were then randomized to either placebo or benazepril and were followed up for an additional two weeks. At the end of two weeks, blood pressure (both systolic and diastolic) in children withdrawn to placebo rose by 4 to 6 mmHg more than in children on benazepril. Nodose-response was observed for the three doses. | lld:dailymed |
| dailymed-drugs:168 | dailymed-instance:clinicalP... | Methylphenidate is a racemic mixture comprised of the d- and l-threo enantiomers. The d-threo enantiomer is more pharmacologically active than the l-threo enantiomer. Methylphenidate HCl is a central nervous system (CNS) stimulant. The mode of therapeutic action in humans is not completely understood, but methylphenidate presumably activates the brain stem arousal system and cortex to produce its stimulant effect. Methylphenidate is thought to block the reuptake of norepinephrine and dopamine into the presynaptic neuron and increase the release of these monoamines into the extraneuronal space. There is neither specific evidence which clearly establishes the mechanism whereby Methylin produces its mental and behavioral effects in children, nor conclusive evidence regarding how these effects relate to the condition of the central nervous system.<br/>Pharmacokinetics:<br/>Absorption: Methylin Chewable Tablets are readily absorbed. Following oral administration of Methylin Chewable Tablets, peak plasma methylphenidate concentrations are achieved at about 1 to 2 hours. Methylin Chewable Tablets have been shown to be bioequivalent to Ritalin tablet. The mean Cfollowing a 20 mg dose is approximately 10 ng/mL.<br/>Metabolism and Excretion: In humans, methylphenidate is metabolized primarily via deesterification to alpha-phenyl-piperidine acetic acid (PPA, ritalinic acid). The metabolite has little or no pharmacologic activity. After oral dosing of radiolabeled methylphenidate in humans, about 90% of the radioactivity was recovered in urine. The main urinary metabolite was PPA, accounting for approximately 80% of the dose. The pharmacokinetics of the Methylin Chewable Tablets have been studied in healthy adult volunteers. The mean terminal half-life (t) of methylphenidate following administration of 20 mg Methylin Chewable Tablets (t= 3 hours) is comparable to the mean terminal tfollowing administration of Ritalin (methylphenidate hydrochloride immediate-release tablets) (t= 2.8 hours) in healthy adult volunteers.<br/>Special Populations:<br/>Renal Insufficiency: There is no experience with the use of Methylin Chewable Tablets in patients with renal insufficiency. After oral administration of radiolabeled methylphenidate in humans, methylphenidate was extensively metabolized and approximately 80% of the radioactivity was excreted in the urine in the form of ritalinic acid. Since renal clearance is not an important route of methylphenidate clearance, renal insufficiency is expected to have little effect on the pharmacokinetics of Methylin Chewable Tablets.<br/>Hepatic Insufficiency: There is no experience with the use of Methylin Chewable Tablets in patients with hepatic insufficiency. | lld:dailymed |
| dailymed-drugs:170 | dailymed-instance:clinicalP... | Actions: Glyburide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glyburide lowers blood glucose during long-term administration has not been clearly established. With chronic administration in Type II diabetic patients, the blood glucose lowering effect persists despite a gradual decline in the insulin secretory response to the drug. Extrapancreatic effects may be involved in the mechanism of action of oral sulfonylurea hypoglycemic drugs. The combination of glyburide and metformin may have a synergistic effect, since both agents act to improve glucose tolerance by different but complementary mechanisms. Some patients who are initially responsive to oral hypoglycemic drugs, including MICRONASE, may become unresponsive or poorly responsive over time. Alternatively, MICRONASE Tablets may be effective in some patients who have become unresponsive to one or more other sulfonylurea drugs. In addition to its blood glucose lowering actions, glyburide produces a mild diuresis by enhancement of renal free water clearance. Disulfiram-like reactions have very rarely been reported in patients treated with MICRONASE Tablets.<br/>Pharmacokinetics: Single dose studies with MICRONASE Tablets in normal subjects demonstrate significant absorption of glyburide within one hour, peak drug levels at about four hours, and low but detectable levels at twenty-four hours. Mean serum levels of glyburide, as reflected by areas under the serum concentration-time curve, increase in proportion to corresponding increases in dose. Multiple dose studies with MICRONASE in diabetic patients demonstrate drug level concentration-time curves similar to single dose studies, indicating no buildup of drug in tissue depots. The decrease of glyburide in the serum of normal healthy individuals is biphasic; the terminal half-lifeis about 10 hours. In single dose studies in fasting normal subjects, the degree and duration of blood glucose lowering is proportional to the dose administered and to the area under the drug level concentration-time curve. The blood glucose lowering effect persists for 24 hours following single morning doses in nonfasting diabetic patients. Under conditions of repeated administration in diabetic patients, however, there is no reliable correlation between blood drug levels and fasting blood glucose levels.A one year study of diabetic patients treated with MICRONASE showed no reliable correlation between administered dose and serum drug level. The major metabolite of glyburide is the 4-transhydroxy derivative. A second metabolite, the 3-cishydroxy derivative, also occurs. These metabolites probably contribute no significant hypoglycemic action in humans since they are only weakly active (1/400th and 1/40th as active, respectively, as glyburide) in rabbits. Glyburide is excreted as metabolites in the bile and urine, approximately 50% by each route. This dual excretory pathway is qualitatively different from that of other sulfonylureas, which are excreted primarily in the urine. Sulfonylurea drugs are extensively bound to serum proteins. Displacement from protein binding sites by other drugs may lead to enhanced hypoglycemic action. In vitro, the protein binding exhibited by glyburide is predominantly non-ionic, whereas that of other sulfonylureas (chlorpropamide, tolbutamide, tolazamide) is predominantly ionic. Acidic drugs such as phenylbutazone, warfarin, and salicylates displace the ionic-binding sulfonylureas from serum proteins to a far greater extent than the non-ionic binding glyburide. It has not been shown that this difference in protein binding will result in fewer drug-drug interactions with MICRONASE Tablets in clinical use. | lld:dailymed |
| dailymed-drugs:171 | dailymed-instance:clinicalP... | Mechanism of Action: Idarubicin hydrochloride is a DNA-intercalating analog of daunorubicin which has an inhibitory effect on nucleic acid synthesis and interacts with the enzyme topoisomerase II. The absence of a methoxy group at position 4 of the anthracycline structure gives the compound a high lipophilicity which results in an increased rate of cellular uptake compared with other anthracyclines.<br/>Pharmacokinetics:<br/>General Pharmacokinetics: Pharmacokinetic studies have been performed in adult leukemia patients with normal renal and hepatic function following intravenous administration of 10 to 12 mg/mof idarubicin daily for 3 to 4 days as a single agent or combined with cytarabine. The plasma concentrations of idarubicin are best described by a two or three compartment open model. The elimination rate of idarubicin from plasma is slow with an estimated mean terminal half-life of 22 hours (range, 4 to 48 hours) when used as a single agent and 20 hours (range, 7 to 38 hours) when used in combination with cytarabine. The elimination of the primary active metabolite, idarubicinol, is considerably slower than that of the parent drug with an estimated mean terminal half-life that exceeds 45 hours; hence, its plasma levels are sustained for a period greater than 8 days.<br/>Distribution: The disposition profile shows a rapid distributive phase with a very high volume of distribution presumably reflecting extensive tissue binding. Studies of cellular (nucleated blood and bone marrow cells) drug concentrations in leukemia patients have shown that peak cellular idarubicin concentrations are reached a few minutes after injection. Concentrations of idarubicin and idarubicinol in nucleated blood and bone marrow cells are more than a hundred times the plasma concentrations. Idarubicin disappearance rates in plasma and cells were comparable with a terminal half-life of about 15 hours. The terminal half-life of idarubicinol in cells was about 72 hours. The extent of drug and metabolite accumulation predicted in leukemia patients for Days 2 and 3 of dosing, based on the mean plasma levels and half-life obtained after the first dose, is 1.7- and 2.3-fold, respectively, and suggests no change in kinetics following a daily��3 regimen. The percentages of idarubicin and idarubicinol bound to human plasma proteins averaged 97% and 94%, respectively, at concentrations similar to maximum plasma levels obtained in the pharmacokinetic studies. The binding is concentration independent. The plasma clearance is twice the expected hepatic plasma flow indicating extensive extrahepatic metabolism.<br/>Metabolism: The primary active metabolite formed is idarubicinol. As idarubicinol has cytotoxic activity, it presumably contributes to the effects of idarubicin.<br/>Elimination: The drug is eliminated predominately by biliary and to a lesser extent by renal excretion, mostly in the form of idarubicinol.<br/>Pharmacokinetics in Special Populations:<br/>Pediatric Patients: Idarubicin studies in pediatric leukemia patients, at doses of 4.2 to 13.3 mg/m/day��3, suggest dose independent kinetics. There is no difference between the half-lives of the drug following daily��3 or weekly��3 administration. Cerebrospinal fluid (CSF) levels of idarubicin and idarubicinol were measured in pediatric leukemia patients treated intravenously. Idarubicin was detected in 2 of 21 CSF samples (0.14 and 1.57 ng/mL), while idarubicinol was detected in 20 of these 21 CSF samples obtained 18 to 30 hours after dosing (mean = 0.51 ng/mL; range, 0.22 to 1.05 ng/mL). The clinical relevance of these findings is unknown.<br/>Hepatic and Renal Impairment: The pharmacokinetics of idarubicin have not been evaluated in leukemia patients with hepatic impairment. It is expected that in patients with moderate or severe hepatic dysfunction, the metabolism of idarubicin may be impaired and lead to higher systemic drug levels. The disposition of idarubicin may be also affected by renal impairment. Therefore, a dose reduction should be considered in patients with hepatic and/or renal impairment .<br/>Drug-Drug Interactions: No formal drug interaction studies have been performed. | lld:dailymed |
| dailymed-drugs:172 | dailymed-instance:clinicalP... | Mode of Action: Combination oral contraceptives act by suppression of gonadotropins. Although the primary mechanism of this action is inhibition of ovulation, other alterations include changes in the cervical mucus (which increase the difficulty of sperm entry into the uterus) and the endometrium (which reduce the likelihood of implantation).<br/>Pharmacokinetics:<br/>Absorption: No specific investigation of the absolute bioavailability of LYBREL in humans has been conducted. However, literature indicates that levonorgestrel is rapidly and completely absorbed after oral administration (bioavailability about 100%) and is not subject to first-pass metabolism. Ethinyl estradiol is rapidly and almost completely absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the bioavailability of ethinyl estradiol is between 38% and 48%. A summary of the single dose and multiple dose levonorgestrel and ethinyl estradiol pharmacokinetic parameters for 18 women under fasting conditions is provided in Table 1. The plasma concentrations of levonorgestrel and ethinyl estradiol reached steady-state by approximately day 14. Levonorgestrel and ethinyl estradiol concentrations did not increase from days 14 to 28, but did increase from days 1 to 28. The mean plasma concentrations of levonorgestrel and ethinyl estradiol following single (day 1) and multiple (days 14 and 28) oral administrations of levonorgestrel 90 mcg in combination with ethinyl estradiol 20 mcg to 18 healthy women is provided in Figure 1. The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of LYBREL has not been evaluated.<br/>Distribution: Levonorgestrel in serum is primarily bound to sex hormone-binding globulin (SHBG). Ethinyl estradiol is about 97% bound to serum albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis.<br/>Metabolism: Levonorgestrel: The most important metabolic pathways are reduction of the��4-3-oxo group and hydroxylation at positions 2��, 1��, and 16��, followed by conjugation. Most of the circulating metabolites are sulfates of 3��, 5��-tetrahydro-levonorgestrel, while excretion occurs predominantly in the form of glucuronides. Some of the parent levonorgestrel also circulates as 17��-sulfate. Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users. Ethinyl estradiol: Cytochrome P450 enzymes (CYP3A4) in the liver are responsible for the 2���hydroxylation that is the major oxidative reaction. The 2-hydroxy metabolite is further transformed by methylation, sulfation, and glucuronidation prior to urinary and fecal excretion. Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of ethinyl estradiol 2-hydroxylation.<br/>Excretion: The terminal elimination half-life for levonorgestrel in LYBREL is about 36 hours. Levonorgestrel and its metabolites are excreted in the urine (40% to 68%) and in feces (16% to 48%). The terminal elimination half-life of ethinyl estradiol in LYBREL is about 21 hours. Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates and undergoes enterohepatic recirculation.<br/>Special Populations:<br/>Race: No formal studies on the effect of race on the pharmacokinetic parameters of LYBREL were conducted.<br/>Hepatic Insufficiency: No formal studies have evaluated the effect of hepatic disease on the disposition of LYBREL. However, steroid hormones may be poorly metabolized in patients with impaired liver function.<br/>Renal Insufficiency: No formal studies have evaluated the effect of renal disease on the disposition of LYBREL.<br/>Drug-Drug Interactions: See PRECAUTIONS section - Drug Interactions. | lld:dailymed |
| dailymed-drugs:173 | dailymed-instance:clinicalP... | Intravascular injection of a radiopaque diagnostic agent opacifies those vessels in the path of the flow of the contrast medium, permitting radiographic visualization of the internal structures of the human body until significant hemodilution occurs. At physiologic pH, the water-soluble contrast media are completely dissociated into a radiopaque anion and a solubilizing cation. While circulating in tissue fluids, the compound remains ionized. However, it is not metabolized but excreted unchanged in the urine, each diatrizoate molecule remaining "obligated" to its sodium or meglumine moiety. Following intravenous injection, the radiopaque diagnostic agents are immediately diluted in the circulating plasma. Equilibrium is reached with the extracellular compartment at about 10 minutes. Hence, the plasma concentration at 10 minutes is closely related to the dose corrected to body size. The pharmacokinetics of the intravenously administered radiopaque contrast media are usually best described by a two compartment model with a rapid alpha phase for drug distribution and a slow beta phase for drug elimination. In patients with normal renal function, the alpha and beta half-lives were respectively 30 minutes and 120 minutes for diatrizoate. But in patients with renal functional impairment, the elimination half-life for the beta phase can be prolonged up to several days. Injectable radiopaque diagnostic agents are excreted either through the liver or through the kidneys. These two excretory pathways are not mutually exclusive, but the main route of excretion seems to be governed by the affinity of the contrast medium for serum albumin. From 0% to 10% of diatrizoate sodium is bound to serum protein. Diatrizoate salts are excreted unchanged predominantly through the kidneys by glomerular filtration. The amount excreted by the kidney during any period of time is determined by the filtered load; i.e., the product of plasma contrast media concentration and glomerular filtration rate. The plasma concentration is dependent upon the dose administered and thebody size. The glomerular filtration rate varies with the body size, sex, age, circulatory dynamics, diuretic effect of the drug, and renal function. In patients with normal renal function the maximum urinary concentration of diatrizoate meglumine and diatrizoate sodium occurs within 10 minutes with 12 percent of the administered dose being excreted. The mean values of cumulative urinary excretion for diatrizoate meglumine and diatrizoate sodium expressed as percentage of administered dose are 38 percent at 60 minutes, 45 percent at 3 hours, and 94 to 100 percent at 24 hours. Urinary excretion of contrast media is delayed in infants younger than 1 month and in patients with urinary tract obstruction. The urinary iodine concentration is higher with the sodium salt of diatrizoic acid than with the meglumine salt. The liver and small intestine provide the major alternate route of excretion for diatrizoate. In patients free of severe renal disease, the fecal recovery is less than 2 percent of the administered dose. In patients with severe renal impairment the excretion of these contrast media through the gallbladder and into the small intestine sharply increases; up to 20 percent of the administered dose has been recovered in the feces in 48 hours. Saliva is a minor secretory pathway for injectable radiopaque diagnostic agents. In patients with normal renal function, minimal amounts of contrast media are secreted unchanged. However, in uremic patients small amounts of free iodides resulting from deiodination prior to administration or in vivo, have been detected in the saliva. Diatrizoate salts cross the placental barrier in humans by simple diffusion and appear to enter fetal tissue passively. No apparent harm to the fetus was observed when diatrizoate sodium and diatrizoate meglumine were injected intravenously 24 hours prior to delivery. However, abnormal neonatal opacification of the small intestine and colon were detected 4 to 6 days after delivery. Procedures including radiation involve a certain risk related to the exposure of the fetus. Injectable radiopaque diagnostic agents are excreted unchanged in human milk.<br/>Computed Tomography: HYPAQUE-76 enhances computed tomographic brain scanning through augmentation of radiographic efficiency. The degree of enhancement of visualization of tissue density is directly related to the iodine content in an administered dose; peak iodine blood levels occur immediately following rapid injection of the dose. These levels fall rapidly within five to ten minutes. This can be accounted for by the dilution in the vascular and extracellular fluid compartments which causes an initial sharp fall in plasma concentration. Equilibration with the extracellular compartments is reached in about ten minutes; thereafter, the fall becomes exponential. Maximum contrast enhancement frequently occurs after peak blood iodine levels are reached. The delay in maximum contrast enhancement can range from five to forty minutes, depending on the peak iodine levels achieved and the cell type of the lesion. This lag suggests that radiographic contrast enhancement is at least in part dependent on the accumulation of iodine within the lesion and outside the blood pool, although the mechanism by which this occurs is not clear. The radiographic enhancement of nontumoral lesions, such as arteriovenous malformations and aneurysms, is probably dependent on the iodine content of the circulating blood pool. In brain scanning, HYPAQUE-76, brand of diatrizoate meglumine and diatrizoate sodium injection, does not accumulate in normal brain tissue due to the presence of the blood-brain barrier. The increase in x-ray absorption in normal brain is due to the presence of contrast agent within the blood pool. A break in the blood-brain barrier such as occurs in malignant tumors of the brain allows the accumulation of the contrast medium within the interstitial tumor tissue. Adjacent normal brain tissue does not contain the contrast medium. In nonneural tissues (during computed tomography of the body), diatrizoate diffuses rapidly from the vascular into the extravascular space. Increase in x-ray absorption is related to blood flow, concentration of the contrast medium, and extraction of the contrast medium by interstitial tumor tissue since no barrier exists. Contrast enhancement is thus due to the relative differences in extravascular diffusion between normal and abnormal tissue, quite different from that in the brain. The pharmacokinetics of diatrizoate in both normal and abnormal tissue have been shown to be variable. Contrast enhancement appears to be greatest soon after administration of the contrast medium, and following intra-arterial rather than intravenous administration. The greatest enhancement can be detected by a series of consecutive two- to three-second scans performed just after injection (within 30 to 90 seconds), i.e., dynamic computed tomographic scanning.<br/>Effects of Steroid Therapy: The anti-inflammatory and antiedema effects in patients receiving steroid therapy have interfered with the expected distribution of CT tissue enhancement on the scan in certain diseases. | lld:dailymed |
| dailymed-drugs:174 | dailymed-instance:clinicalP... | In humans, uric acid is the final step in the catabolic pathway of purines. Rasburicase catalyzes enzymatic oxidation of uric acid into an inactive and soluble metabolite (allantoin). Rasburicase is only active at the end of the purine catabolic pathway. Pharmacokinetics of rasburicase were evaluated in two studies that enrolled patients with lymphoid leukemia (B and T cell), non-Hodgkin's lymphoma (including Burkitt's lymphoma) or acute myelogenous leukemia. ELITEK exposure, as measured by AUCand C, tended to increase linearly with doses over a limited dose range (0.15 to 0.20 mg/kg). The overall elimination half-life was 18 hours. No accumulation of rasburicase was observed between days 1 and 5 of dosing. ELITEK mean volume of distribution was 110 to 127 mL/kg in pediatric patients. There are insufficient data to characterize pharmacokinetics in adult patients. | lld:dailymed |
| dailymed-drugs:176 | dailymed-instance:clinicalP... | Pharmacokinetics: Disposition of metronidazole in the body is similar for both oral and intravenous dosage forms, with an average elimination half-life in healthy humans of 8 hours. The major route of elimination of metronidazole and its metabolites is via the urine (60% to 80% of the dose), with fecal excretion accounting for 6% to 15% of the dose. The metabolites that appear in the urine result primarily from side-chain oxidation [1-(��hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole and 2-methyl-5-nitroimidazole-1-yl-acetic acid] and glucuronide conjugation, with unchanged metronidazole accounting for approximately 20% of the total. Renal clearance of metronidazole is approximately 10 mL/ min/1.73m. Flagyl ER 750 mg tablets contain 750 mg of metronidazole in an extended release formulation which allows for once-daily dosing. The steady state pharmacokinetics were determined in 24 healthy adult female subjects with a mean��SD age of 28.8��8.8 years (range: 19���46).The pharmacokinetic parameters of metronidazole after administration of Flagyl ER 750 mg under fed and fasting conditions are summarized in the following table. Relative to the fasting state, the rate of metronidazole absorption from the extended release tablet is increased in the fed state resulting in alteration of the extended release characteristics. Decreased renal function does not alter the single-dose pharmacokinetics of metronidazole. However, plasma clearance of metronidazole is decreased in patients with decreased liver function.<br/>Microbiology: Metronidazole exerts an antimicrobial effect in an anaerobic environment by the following possible mechanism: Once metronidazole enters the organism, the drug is reduced by intra-cellular electron transport proteins. Because of this alteration to the metronidazole molecule, a concentration gradient is maintained which promotes the drug's intracellular transport. Presumably, free radicals are formed which, in turn, react with cellular components resulting in death of the microorganism. The following in vitro data are available, but their clinical significance is unknown: Metronidazole exhibits in vitro minimal inhibitory concentrations (MIC's) of 8��g/mL or less against most (���90%) strains of the following microorganisms; however, the safety and effectiveness of metronidazole in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials. Gram-positive anaerobes:Clostridium speciesEubacterium speciesPeptococcus nigerPeptostreptococcus species Gram-negative anaerobes:Bacteroides fragilis group (B. fragilis, B. distasonis, B. ovatus, B. thetaiotaomicron, B. vulgatus)Fusobacterium speciesPrevotella species (P. bivia, P. buccae, P. disiens)Porphyromonas species Protozoal parasites:Entamoeba histolyticaTrichomonas vaginalis Metronidazole has shown minimal to no activity against clinically relevant facultative anaerobes or obligate aerobes. Metronidazole has minimal activity against Lactobacillus spp and other aerobic microorganisms commonly isolated from the vaginal tract.<br/>Susceptibility Tests:<br/>Dilution techniques: Quantitative methods that are used to determine minimum inhibitory concentrations provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. For anaerobic bacteria, the susceptibility to metronidazole can be determined by the reference agar dilution method or by alternate standardized test methods.The MIC values obtained should be interpreted according to the following criteria: For protozoal parasites: Standardized tests do not exist for use in clinical microbiology laboratories. A report of "Susceptible" indicates that the pathogen is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in the blood. A report of "Intermediate" indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that usually achievable concentrations of the antimicrobial compound in the blood are unlikely to be inhibitory and other therapy should be selected. Standardized susceptibility test procedures require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. Standard metronidazole powder should provide the following MIC values: | lld:dailymed |
| dailymed-drugs:177 | dailymed-instance:clinicalP... | Mechanism of Action: The physiologic mechanism of erection of the penis involves release of nitric oxide (NO) in the corpus cavernosum during sexual stimulation. NO then activates the enzyme guanylate cyclase, which results in increased levels of cyclic guanosine monophosphate (cGMP), producing smooth muscle relaxation in the corpus cavernosum and allowing inflow of blood. Sildenafil has no direct relaxant effect on isolated human corpus cavernosum, but enhances the effect of nitric oxide (NO) by inhibiting phosphodiesterase type 5 (PDE5), which is responsible for degradation of cGMP in the corpus cavernosum. When sexual stimulation causes local release of NO, inhibition of PDE5 by sildenafil causes increased levels of cGMP in the corpus cavernosum, resulting in smooth muscle relaxation and inflow of blood to the corpus cavernosum. Sildenafil at recommended doses has no effect in the absence of sexual stimulation. Studies in vitro have shown that sildenafil is selective for PDE5. Its effect is more potent on PDE5 than on other known phosphodiesterases (10-fold for PDE6,>80-fold for PDE1,>700-fold for PDE2, PDE3, PDE4, PDE7, PDE8, PDE9, PDE10, and PDE11). The approximately 4,000-fold selectivity for PDE5 versus PDE3 is important because PDE3 is involved in control of cardiac contractility. Sildenafil is only about 10-fold as potent for PDE5 compared to PDE6, an enzyme found in the retina which is involved in the phototransduction pathway of the retina. This lower selectivity is thought to be the basis for abnormalities related to color vision observed with higher doses or plasma levels (see Pharmacodynamics). In addition to human corpus cavernosum smooth muscle, PDE5 is also found in lower concentrations in other tissues including platelets, vascular and visceral smooth muscle, and skeletal muscle. The inhibition of PDE5 in these tissues by sildenafil may be the basis for the enhanced platelet antiaggregatory activity of nitric oxide observed in vitro, an inhibition of platelet thrombus formation in vivo and peripheral arterial-venous dilatation in vivo.<br/>Pharmacokinetics and Metabolism: VIAGRA is rapidly absorbed after oral administration, with a mean absolute bioavailability of 41% (range 25���63%). Its pharmacokinetics are dose-proportional over the recommended dose range. It is eliminated predominantly by hepatic metabolism (mainly cytochrome P450 3A4) and is converted to an active metabolite with properties similar to the parent, sildenafil. The concomitant use of potent cytochrome P450 3A4 inhibitors (e.g., erythromycin, ketoconazole, itraconazole) as well as the nonspecific CYP inhibitor, cimetidine, is associated with increased plasma levels of sildenafil . Both sildenafil and the metabolite have terminal half lives of about 4 hours. Mean sildenafil plasma concentrations measured after the administration of a single oral dose of 100 mg to healthy male volunteers is depicted below:<br/>Absorption and Distribution: VIAGRA is rapidly absorbed. Maximum observed plasma concentrations are reached within 30 to 120 minutes (median 60 minutes) of oral dosing in the fasted state. When VIAGRA is taken with a high fat meal, the rate of absorption is reduced, with a mean delay in Tof 60 minutes and a mean reduction in Cof 29%. The mean steady state volume of distribution (Vss) for sildenafil is 105 L, indicating distribution into the tissues. Sildenafil and its major circulating N-desmethyl metabolite are both approximately 96% bound to plasma proteins. Protein binding is independent of total drug concentrations. Based upon measurements of sildenafil in semen of healthy volunteers 90 minutes after dosing, less than 0.001% of the administered dose may appear in the semen of patients.<br/>Metabolism and Excretion: Sildenafil is cleared predominantly by the CYP3A4 (major route) and CYP2C9 (minor route) hepatic microsomal isoenzymes. The major circulating metabolite results from N-desmethylation of sildenafil, and is itself further metabolized. This metabolite has a PDE selectivity profile similar to sildenafil and an in vitro potency for PDE5 approximately 50% of the parent drug. Plasma concentrations of this metabolite are approximately 40% of those seen for sildenafil, so that the metabolite accounts for about 20% of sildenafil's pharmacologic effects. After either oral or intravenous administration, sildenafil is excreted as metabolites predominantly in the feces (approximately 80% of administered oral dose) and to a lesser extent in the urine (approximately 13% of the administered oral dose). Similar values for pharmacokinetic parameters were seen in normal volunteers and in the patient population, using a population pharmacokinetic approach.<br/>Pharmacokinetics in Special Populations:<br/>Geriatrics: Healthy elderly volunteers (65 years or over) had a reduced clearance of sildenafil, resulting in approximately 84% and 107% higher plasma AUC values of sildenafil and its active N-desmethyl metabolite, respectively, compared to those seen in healthy younger volunteers (18���45 years). Due to age-differences in plasma protein binding, the corresponding increase in the AUC of free (unbound) sildenafil and its active N-desmethyl metabolite were 45% and 57%, respectively.<br/>Renal Insufficiency: In volunteers with mild (CLcr=50���80 mL/min) and moderate (CLcr=30���49 mL/min) renal impairment, the pharmacokinetics of a single oral dose of VIAGRA (50 mg) were not altered. In volunteers with severe (CLcr=<30 mL/min) renal impairment, sildenafil clearance was reduced, resulting in approximately doubling of AUC and Ccompared to age-matched volunteers with no renal impairment. In addition, N-desmethyl metabolite AUC and Cmax values significantly increased 200% and 79% respectively in subjects with severe renal impairment compared to subjects with normal renal function.<br/>Hepatic Insufficiency: In volunteers with hepatic cirrhosis (Child-Pugh A and B), sildenafil clearance was reduced, resulting in increases in AUC (85%) and C(47%) compared to age-matched volunteers with no hepatic impairment. The pharmacokinetics of sildenafil in patients with severely impaired hepatic function (Child Pugh class C) have not been studied. Therefore, age>65, hepatic impairment and severe renal impairment are associated with increased plasma levels of sildenafil. A starting oral dose of 25 mg should be considered in those patients .<br/>Pharmacodynamics:<br/>Effects of VIAGRA on Erectile Response: In eight double-blind, placebo-controlled crossover studies of patients with either organic or psychogenic erectile dysfunction, sexual stimulation resulted in improved erections, as assessed by an objective measurement of hardness and duration of erections (RigiScan), after VIAGRA administration compared with placebo. Most studies assessed the efficacy of VIAGRA approximately 60 minutes post dose. The erectile response, as assessed by RigiScan, generally increased with increasing sildenafil dose and plasma concentration. The time course of effect was examined in one study, showing an effect for up to 4 hours but the response was diminished compared to 2 hours.<br/>Effects of VIAGRA on Blood Pressure: Single oral doses of sildenafil (100 mg) administered to healthy volunteers produced decreases in sitting blood pressure (mean maximum decrease in systolic/diastolic blood pressure of 8.3/5.3 mmHg). The decrease in sitting blood pressure was most notable approximately 1���2 hours after dosing, and was not different than placebo at 8 hours. Similar effects on blood pressure were noted with 25 mg, 50 mg and 100 mg of VIAGRA, therefore the effects are not related to dose or plasma levels within this dosage range. Larger effects were recorded among patients receiving concomitant nitrates .<br/>Effects of VIAGRA on Cardiac Parameters: Single oral doses of sildenafil up to 100 mg produced no clinically relevant changes in the ECGs of normal male volunteers. Studies have produced relevant data on the effects of VIAGRA on cardiac output. In one small, open-label, uncontrolled, pilot study, eight patients with stable ischemic heart disease underwent Swan-Ganz catheterization. A total dose of 40 mg sildenafil was administered by four intravenous infusions. The results from this pilot study are shown in Table 1; the mean resting systolic and diastolic blood pressures decreased by 7% and 10% compared to baseline in these patients. Mean resting values for right atrial pressure, pulmonary artery pressure, pulmonary artery occluded pressure and cardiac outputdecreased by 28%, 28%, 20% and 7% respectively. Even though this total dosage produced plasma sildenafil concentrations which were approximately 2 to 5 times higher than the mean maximum plasma concentrations following a single oral dose of 100 mg in healthy male volunteers, the hemodynamic response to exercise was preserved in these patients. In a double-blind study, 144 patients with erectile dysfunction and chronic stable angina limited by exercise, not receiving chronic oral nitrates, were randomized to a single dose of placebo or VIAGRA 100 mg 1 hour prior to exercise testing. The primary endpoint was time to limiting angina in the evaluable cohort. The mean times (adjusted for baseline) to onset of limiting angina were 423.6 and 403.7 seconds for sildenafil (N=70) and placebo, respectively. These results demonstrated that the effect of VIAGRA on the primary endpoint was statistically non-inferior to placebo.<br/>Effects of VIAGRA on Vision: At single oral doses of 100 mg and 200 mg, transient dose-related impairment of color discrimination (blue/green) was detected using the Farnsworth-Munsell 100-hue test, with peak effects near the time of peak plasma levels. This finding is consistent with the inhibition of PDE6, which is involved in phototransduction in the retina. An evaluation of visual function at doses up to twice the maximum recommended dose revealed no effects of VIAGRA on visual acuity, intraocular pressure, or pupillometry.<br/>Clinical Studies: In clinical studies, VIAGRA was assessed for its effect on the ability of men with erectile dysfunction (ED) to engage in sexual activity and in many cases specifically on the ability to achieve and maintain an erection sufficient for satisfactory sexual activity. VIAGRA was evaluated primarily at doses of 25 mg, 50 mg and 100 mg in 21 randomized, double-blind, placebo-controlled trials of up to 6 months in duration, using a variety of study designs (fixed dose, titration, parallel, crossover). VIAGRA was administered to more than 3,000 patients aged 19 to 87 years, with ED of various etiologies (organic, psychogenic, mixed) with a mean duration of 5 years. VIAGRA demonstrated statistically significant improvement compared to placebo in all 21 studies. The studies that established benefit demonstrated improvements in success rates for sexual intercourse compared with placebo. The effectiveness of VIAGRA was evaluated in most studies using several assessment instruments. The primary measure in the principal studies was a sexual function questionnaire (the International Index of Erectile Function - IIEF) administered during a 4-week treatment-free run-in period, at baseline, at follow-up visits, and at the end of double-blind, placebo-controlled, at-home treatment. Two of the questions from the IIEF served as primary study endpoints; categorical responses were elicited to questions about (1) the ability to achieve erections sufficient for sexual intercourse and (2) the maintenance of erections after penetration. The patient addressed both questions at the final visit for the last 4 weeks of the study. The possible categorical responses to these questions were (0) no attempted intercourse, (1) never or almost never, (2) a few times, (3) sometimes, (4) most times, and (5) almost always or always. Also collected as part of the IIEF was information about other aspects of sexual function, including information on erectile function, orgasm, desire, satisfaction with intercourse, and overall sexual satisfaction. Sexual function data were also recorded by patients in a daily diary. In addition, patients were asked a global efficacy question and an optional partner questionnaire was administered. The effect on one of the major end points, maintenance of erections after penetration, is shown in Figure 3, for the pooled results of 5 fixed-dose, dose-response studies of greater than one month duration, showing response according to baseline function. Results with all doses have been pooled, but scores showed greater improvement at the 50 and 100 mg doses than at 25 mg. The pattern of responses was similar for the other principal question, the ability to achieve an erection sufficient for intercourse. The titration studies, in which most patients received 100 mg, showed similar results. Figure 3 shows that regardless of the baseline levels of function, subsequent function in patients treated with VIAGRA was better than that seen in patients treated with placebo. At the same time, on-treatment function was better in treated patients who were less impaired at baseline. The frequency of patients reporting improvement of erections in response to a global question in four of the randomized, double-blind, parallel, placebo-controlled fixed dose studies (1797 patients) of 12 to 24 weeks duration is shown in Figure 4. These patients had erectile dysfunction at baseline that was characterized by median categorical scores of 2 (a few times) on principal IIEF questions.Erectile dysfunction was attributed to organic (58%; generally not characterized, but including diabetes and excluding spinal cord injury), psychogenic (17%), or mixed (24%) etiologies. Sixty-three percent, 74%, and 82% of the patients on 25 mg, 50 mg and 100 mg of VIAGRA, respectively, reported an improvement in their erections, compared to 24% on placebo. In the titration studies (n=644) (with most patients eventually receiving 100 mg), results were similar. The patients in studies had varying degrees of ED. One-third to one-half of the subjects in these studies reported successful intercourse at least once during a 4-week, treatment-free run-in period. In many of the studies, of both fixed dose and titration designs, daily diaries were kept by patients. In these studies, involving about 1600 patients, analyses of patient diaries showed no effect of VIAGRA on rates of attempted intercourse (about 2 per week), but there was clear treatment-related improvement in sexual function: per patient weekly success rates averaged 1.3 on 50���100 mg of VIAGRA vs 0.4 on placebo; similarly, group mean success rates (total successes divided by total attempts) were about 66% on VIAGRA vs about 20% on placebo. During 3 to 6 months of double-blind treatment or longer-term (1 year), open-label studies, few patients withdrew from active treatment for any reason, including lack of effectiveness. At the end of the long-term study, 88% of patients reported that VIAGRA improved their erections. Men with untreated ED had relatively low baseline scores for all aspects of sexual function measured (again using a 5-point scale) in the IIEF. VIAGRA improved these aspects of sexual function: frequency, firmness and maintenance of erections; frequency of orgasm; frequency and level of desire; frequency, satisfaction and enjoyment of intercourse; and overall relationship satisfaction. One randomized, double-blind, flexible-dose, placebo-controlled study included only patients with erectile dysfunction attributed to complications of diabetes mellitus (n=268). As in the other titration studies, patients were started on 50 mg and allowed to adjust the dose up to 100 mg or down to 25 mg of VIAGRA; all patients, however, were receiving 50 mg or 100 mg at the end of the study. There were highly statistically significant improvements on the two principal IIEF questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) on VIAGRA compared to placebo. On a global improvement question, 57% of VIAGRA patients reported improved erections versus 10% on placebo. Diary data indicated that on VIAGRA, 48%of intercourse attempts were successful versus 12% on placebo. One randomized, double-blind, placebo-controlled, crossover, flexible-dose (up to 100 mg) study of patients with erectile dysfunction resulting from spinal cord injury (n=178) was conducted. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of VIAGRA.On a global improvement question, 83% of patients reported improved erections on VIAGRA versus 12% on placebo. Diary data indicated that on VIAGRA, 59% of attempts at sexual intercourse were successful compared to 13% on placebo. Across all trials, VIAGRA improved the erections of 43% of radical prostatectomy patients compared to 15% on placebo. Subgroup analyses of responses to a global improvement question in patients with psychogenic etiology in two fixed-dose studies (total n=179) and two titration studies (total n=149) showed 84% of VIAGRA patients reported improvement in erections compared with 26% of placebo. The changes from baseline in scoring on the two end point questions (frequency of successful penetration during sexual activity and maintenance of erections after penetration) were highly statistically significantly in favor of VIAGRA. Diary data in two of the studies (n=178) showed rates of successful intercourse per attempt of 70% for VIAGRA and 29% for placebo. A review of population subgroups demonstrated efficacy regardless of baseline severity, etiology, race and age. VIAGRA was effective in a broad range of ED patients, including those with a history of coronary artery disease, hypertension, other cardiac disease, peripheral vascular disease, diabetes mellitus, depression, coronary artery bypass graft (CABG), radical prostatectomy, transurethral resection of the prostate (TURP) and spinal cord injury, and in patients taking antidepressants/antipsychotics and antihypertensives/diuretics. Analysis of the safety database showed no apparent difference in the side effect profile in patients taking VIAGRA with and without antihypertensive medication. This analysis was performed retrospectively, and was not powered to detect any pre-specified difference in adverse reactions. | lld:dailymed |
| dailymed-drugs:178 | dailymed-instance:clinicalP... | Thyroid hormones enhance oxygen consumption by most tissues of the body and increase the basal metabolic rate and the metabolism of carbohydrates, lipids and proteins. In vitro studies indicate that Tincreases aerobic mitochondrial function, thereby increasing the rates of synthesis and utilization of myocardial high-energy phosphates. This, in turn, stimulates myosin ATPase and reduces tissue lactic acidosis. Thus, thyroid hormones exert a profound influence on virtually every organ system in the body and are of particular importance in the development of the central nervous system. While the source of levothyroxine (T) and some triiodothyronine (T) is via secretion from the thyroid gland, it is now well-established that approximately 80% of circulating Tarises predominantly by way of the extrathyroidal conversion of T. The membrane-bound enzyme responsible for this reaction is iodothyronine 5'-deiodinase. Activity of the enzyme is greatest in the liver and kidney. A second pathway of Tto Tconversion occurs via a PTU-insensitive 5'-deiodinase located primarily in the pituitary and central nervous system. The prohormone Tmust be converted to Tin the body before it can exert biological effects. During periods of illness or stress, this conversion is often inhibited and can be diverted to the inactive reverse T(rT) moiety. Therefore, correction of the hypothyroid condition in patients with myxedema coma is facilitated by the parenteral administration of triiodothyronine (T). Tis bound much less firmly to serum binding proteins and therefore penetrates into the cells much more rapidly than T. Also, the binding of Tto a nuclear thyroid hormone receptor seems to initiate most of the effects of thyroid hormone in tissues. Although most thyroid hormone analogs, both natural and synthetic, will bind to this protein, the affinity of Tfor this receptor is roughly 10-fold higher than that of T. Thus, Tis the biologically active thyroid hormone.<br/>Pharmacodynamics: The clinical features of myxedema coma include depression of the cardiovascular, respiratory, gastrointestinal and central nervous systems, impaired diuresis, and hypothermia. Administration of thyroid hormones reverses or attenuates these conditions. Thyroid hormones increase heart rate, ventricular contractility and cardiac output, as well as decrease total systemic vascular resistance. They also increase the rate and depth of respiration, motilityof the gastrointestinal tract, rapidity of cerebration, and vasodilatation. Thyroid hormones correcthypothermia by markedly increasing the basal metabolic rate, as well as the number and activity of mitochondria in almost all cells of the body.<br/>Pharmacokinetics: Since liothyronine sodium (T) is not firmly bound to serum protein, it is readily available to body tissues. Liothyronine sodium has a rapid cutoff of activity which permits quick dosage adjustment and facilitates control of the effects of overdosage, should they occur. The higher affinity of levothyroxine (T) as compared to triiodothyronine (T) for both thyroid-binding globulin and thyroid-binding prealbumin partially explains the higher serum levels and longer half-life of the former hormone. Both protein-bound hormones exist in reverse equilibrium with minute amounts of free hormone, the latter accounting for the metabolic activity. Tis deiodinated to T. A single dose of liothyronine sodium administered intravenously produces a detectable metabolic response in as little as two to four hours and a maximum therapeutic response within two days. However, no pharmacokinetic studies have been performed with intravenous liothyronine (T) in myxedema coma or precoma patients. | lld:dailymed |
| dailymed-drugs:179 | dailymed-instance:clinicalP... | Parkinson's disease is a progressive, neurodegenerative disorder of the extrapyramidal nervous system affecting the mobility and control of the skeletal muscular system. Its characteristic features include resting tremor, rigidity, and bradykinetic movements. Symptomatic treatments, such as levodopa therapies, may permit the patient better mobility.<br/>Mechanism of Action: Current evidence indicates that symptoms of Parkinson's disease are related to depletion of dopamine in the corpus striatum. Administration of dopamine is ineffective in the treatment of Parkinson's disease apparently because it does not cross the blood-brain barrier. However, levodopa, the metabolic precursor of dopamine, does cross the blood-brain barrier, and presumably is converted to dopamine in the brain. This is thought to be the mechanism wherebylevodopa relieves symptoms of Parkinson's disease.<br/>Pharmacodynamics: When levodopa is administered orally it is rapidly decarboxylated to dopamine in extracerebral tissues so that only a small portion of a given dose is transported unchanged to the central nervous system. For this reason, large doses of levodopa are required for adequate therapeutic effect and these may often be accompanied by nausea and other adverse reactions, some of which are attributable to dopamine formed in extracerebral tissues. The incidence of levodopa-induced nausea and vomiting is less when LODOSYN is used with levodopa than when levodopa is used without LODOSYN. In many patients this reduction in nausea and vomiting will permit more rapid dosage titration. Carbidopa inhibits decarboxylation of peripheral levodopa. Carbidopa has not been demonstrated to have any overt pharmacodynamic actions in the recommended doses. It does not appear to cross the blood-brain barrier readily and does not affect the metabolism of levodopa within the central nervous system at doses of carbidopa that are recommended for maximum effective inhibition of peripheral decarboxylation of levodopa. Since its decarboxylase-inhibiting activity is limited primarily to extracerebral tissues, administration of carbidopa with levodopa makes more levodopa available for transport to the brain. However, since levodopa and carbidopa compete with certain amino acids for transport across the gut wall, the absorption of levodopa and carbidopa may be impaired in some patients on a high protein diet.<br/>Pharmacokinetics: Carbidopa reduces the amount of levodopa required to produce a given response by about 75% and, when administered with levodopa, increases both plasma levels and the plasma half-life of levodopa, and decreases plasma and urinary dopamine and homovanillic acid. In clinical pharmacologic studies, simultaneous administration of separate tablets of carbidopa and levodopa produced greater urinary excretion of levodopa in proportion to the excretion of dopamine when compared to the two drugs administered at separate times. Supplemental pyridoxine (vitamin B) can be given to patients when they are receiving carbidopa and levodopa concomitantly or as SINEMET* CR (Carbidopa-Levodopa) Sustained-Release or SINEMET* (Carbidopa-Levodopa). Previous reports in the medical literature cautioned that high doses of vitamin Bshould not be taken by patients on levodopa therapy alone because exogenously administered pyridoxine would enhance the metabolism of levodopa to dopamine. The introduction of carbidopa to levodopa therapy, which inhibits the peripheral decarboxylation of levodopa to dopamine, counteracts the metabolic-enhancing effect of pyridoxine. Carbidopa is combined with levodopa in SINEMET (Carbidopa-Levodopa) and SINEMET CR (Carbidopa-Levodopa) Sustained-Release tablets. These combination tablets are available in three strengths for SINEMET: SINEMET 10-100 (Carbidopa-Levodopa), SINEMET 25-250 (Carbidopa-Levodopa) (1:10 ratio of carbidopa to levodopa) and SINEMET 25-100 (Carbidopa-Levodopa) (1:4 ratio of carbidopa to levodopa), and in two strengths for SINEMET CR: SINEMET CR 50-200 (Carbidopa-Levodopa) Sustained-Release and SINEMET CR 25-100 (Carbidopa-Levodopa) Sustained-Release (1:4 ratio of carbidopa to levodopa). Clinical trials show that these ratios of carbidopa and levodopa provide useful therapeutic effects in most patients. | lld:dailymed |
| dailymed-drugs:180 | dailymed-instance:clinicalP... | Topical corticosteroids share anti-inflammatory, anti-pruritic and vasoconstrictive actions. The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man. Pharmacokinetics: The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses. Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. | lld:dailymed |
| dailymed-drugs:182 | dailymed-instance:clinicalP... | Microbiology: Gentamicin sulfate is active in vitro against many strains of the following micro-organisms: Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes, Streptococcus pneumoniae, Enterobacter aerogenes, Escherichia coli, Haemophilus influenzae, Klebsiella pneumoniae, Neisseria gonorrhoeae, Pseudomonas aeruginosa, and Serratia marcescens. | lld:dailymed |
| dailymed-drugs:184 | dailymed-instance:clinicalP... | Metoprolol tartrate is a beta-adrenergic receptor blocking agent. In vitro and in vivo animal studies have shown that it has a preferential effect on betaadrenoreceptors, chiefly located in cardiac muscle. This preferential effect is not absolute, however, and at higher doses, metoprolol tartrate also inhibits betaadrenoreceptors, chiefly located in the bronchial and vascular musculature. Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia. Relative betaselectivity has been confirmed by the following: (1) In normal subjects, metoprolol tartrate is unable to reverse the beta-mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective (betaplus beta) beta blockers, which completely reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, metoprolol tartrate reduces FEVand FVC significantly less than a nonselective beta blocker, propranolol, at equivalent beta-receptor blocking doses. Metoprolol tartrate has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at doses much greater than required for beta blockade. Metoprolol tartrate crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration. Animal and human experiments indicate that metoprolol tartrate slows the sinus rate and decreases AV nodal conduction. In controlled clinical studies, metoprolol tartrate has been shown to be an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics, at dosages of 100���450 mg daily. In controlled, comparative, clinical studies, metoprolol tartrate has been shown to be as effective an antihypertensive agent as propranolol, methyldopa, and thiazide-type diuretics, and to be equally effective in supine and standing positions. The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression of renin activity. By blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial contraction, and in blood pressure, metoprolol tartrate reduces the oxygen requirements of the heart at any given level of effort, thus making it useful in the long-term management of angina pectoris. However, in patients with heart failure, beta-adrenergic blockade may increase oxygen requirements by increasing left ventricular fiber length and end-diastolic pressure. Although beta-adrenergic receptor blockade is useful in the treatment of angina and hypertension, there are situations in which sympathetic stimulation is vital. In patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. In the presence of AV block, beta blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients. In controlled clinical trials, metoprolol tartrate, administered two or four times daily, has been shown to be an effective antianginal agent, reducing the number of angina attacks and increasing exercise tolerance. The dosage used in these studies ranged from 100���400 mg daily. A controlled, comparative, clinical trial showed that metoprolol tartrate was indistinguishable from propranolol in the treatment of angina pectoris. In a large (1,395 patients randomized), double-blind, placebo-controlled clinical study, metoprolol tartrate was shown to reduce 3-month mortality by 36% in patients with suspected or definite myocardial infarction. Patients were randomized and treated as soon as possible after their arrival in the hospital, once their clinical condition had stabilized and their hemodynamic status had been carefully evaluated. Subjects were ineligible if they had hypotension, bradycardia, peripheral signs of shock, and/or more than minimal basal rales as signs of congestiveheart failure. Initial treatment consisted of intravenous followed by oral administration of metoprolol tartrate or placebo, given in a coronary care or comparable unit. Oral maintenance therapy with metoprolol tartrate or placebo was then continued for 3 months. After this double-blind period, all patients were given metoprolol tartrate and followed up to 1 year. The median delay from the onset of symptoms to the initiation of therapy was 8 hours in both the metoprolol tartrate- and placebo-treatment groups. Among patients treated with metoprolol tartrate, there were comparable reductions in 3-month mortality for those treated early (���8 hours) and those in whom treatment was started later. Significant reductions in the incidence of ventricular fibrillation and in chest pain following initial intravenous therapy were also observed with metoprolol tartrate and were independent of the interval between onset of symptoms and initiation of therapy. The precise mechanism of action of metoprolol tartrate in patients with suspected or definite myocardial infarction is not known. In this study, patients treated with metoprolol received the drug both very early (intravenously) and during a subsequent 3-month period, while placebo patients received no beta-blocker treatment for this period. The study thus was able to show a benefit from the overall metoprolol regimen but cannot separate the benefit of very early intravenous treatment from the benefitof later beta-blocker therapy. Nonetheless, because the overall regimen showed a clear beneficial effect on survival without evidence of an early adverse effect on survival, one acceptable dosage regimen is the precise regimen used in the trial. Because the specific benefit of very early treatment remains to be defined however, it is also reasonable to administer the drug orally to patients at a later time as is recommended for certain other beta blockers.<br/>Pharmacokinetics: In man, absorption of metoprolol tartrate is rapid and complete. Plasma levels following oral administration, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism. Plasma levels achieved are highly variable after oral administration. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R- and S-enantiomers. Less than 5% of an oral dose of metoprolol tartrate is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no clinical significance. The systemic availability and half-life of metoprolol tartrate in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. Consequently, no reduction in dosage is usually needed in patients with chronic renal failure. Metoprolol tartrate is extensively metabolized by the cytochrome P450 enzyme system in the liver. The oxidative metabolism of metoprolol tartrate is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolizers (PM) phenotype.Approximately 7% of Caucasians and less than 1% Asian are poor metabolizers. Poor CYP2D6 metabolizers exhibit several-fold higher plasma concentrations of metoprolol tartrate than extensive metabolizers with normal CYP2D6 activity. The elimination half-life of metoprolol is about 7.5 hours in poor metabolizers and 2.8 hours in extensive metabolizers. However, the CYP2D6 dependent metabolism of metoprolol tartrate seems to have little or no effect on safety or tolerability of the drug.None of the metabolites of metoprolol tartrate contribute significantly to its beta-blocking effect. Significant beta-blocking effect (as measured by reduction of exercise heart rate) occurs within 1 hour after oral administration, and its duration is dose-related. For example, a 50% reduction of the maximum registered effect after single oral doses of 20, 50, and 100 mg occurred at 3.3, 5.0, and 6.4 hours, respectively, in normal subjects. After repeated oral dosages of 100 mg twicedaily, a significant reduction in exercise systolic blood pressure was evident at 12 hours. Equivalent maximal beta-blocking effect is achieved with oral and intravenous doses in the ratio of approximately 2.5:1. There is a linear relationship between the log of plasma levels and reduction of exercise heart rate. However, antihypertensive activity does not appear to be related to plasma levels. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity to dose, selection of proper dosage requires individual titration. In several studies of patients with acute myocardial infarction, intravenous followed by oral administration of metoprolol tartrate caused a reduction in heart rate, systolic blood pressure, and cardiac output. Stroke volume, diastolic blood pressure, and pulmonary artery end diastolic pressure remained unchanged. In patients with angina pectoris, plasma concentration measured at 1 hour is linearly related to the oral dose within the range of 50���400 mg. Exercise heart rate and systolic blood pressure are reduced in relation to the logarithm of the oral dose of metoprolol. The increase in exercise capacity and the reduction in left ventricular ischemia are also significantly related to the logarithm of the oral dose. In elderly subjects with clinically normal renal and hepatic function, there are no significant differences in metoprolol tartrate pharmacokinetics compared to young subjects. | lld:dailymed |
| dailymed-drugs:186 | dailymed-instance:clinicalP... | Mechanism of Action: Amiodarone is generally considered a class III antiarrhythmic drug, but it possesses electrophysiologic characteristics of all four Vaughan Williams classes. Like class I drugs, amiodarone blocks sodium channels at rapid pacing frequencies, and like class II drugs, it exerts a noncompetitive antisympathetic action. One of its main effects, with prolonged administration, is to lengthen the cardiac action potential, a class III effect. The negative chronotropic effect of amiodarone in nodal tissues is similar to the effect of class IV drugs. In addition to blocking sodium channels, amiodarone blocks myocardial potassium channels, which contributes to slowing of conduction and prolongation of refractoriness. The antisympathetic action and the block of calcium and potassium channels are responsible for the negative dromotropic effects on the sinus node and for the slowing of conduction and prolongation of refractoriness in the atrioventricular (AV) node. Its vasodilatory action can decrease cardiac workload and consequently myocardial oxygen consumption. Amiodarone I.V. administration prolongs intranodal conduction (Atrial-His, AH) and refractoriness of the atrioventricular node (ERP AVN), but has little or no effect on sinus cycle length (SCL), refractoriness of the right atrium and right ventricle (ERP RA and ERP RV), repolarization (QTc), intraventricular conduction (QRS), and infranodal conduction (His-ventricular, HV). A comparisonof the electrophysiologic effects of amiodarone I.V. and oral amiodarone is shown in the table below. At higher doses (>10 mg/kg) of amiodarone I.V., prolongation of the ERP RV and modest prolongation of the QRS have been seen. These differences between oral and intravenous administration suggest that the initial acute effects of amiodarone I.V. may be predominantly focused on the AV node, causing an intranodal conduction delay and increased nodal refractoriness due to slow channel blockade (class IV activity) and noncompetitive adrenergic antagonism (class II activity).<br/>Pharmacokinetics and Metabolism: Amiodarone exhibits complex disposition characteristics after intravenous administration. Peak serum concentrations after single 5 mg/kg 15-minute intravenous infusions in healthy subjects range between 5 and 41 mg/L. Peak concentrations after 10-minute infusions of 150 mg amiodarone I.V. in patients with ventricular fibrillation (VF) or hemodynamically unstable ventricular tachycardia (VT) range between 7 and 26 mg/L. Due to rapid distribution, serum concentrations decline to 10% of peak values within 30 to 45 minutes after the end of the infusion. In clinical trials, after 48 hours of continued infusions (125, 500, or 1000 mg/day) plus supplemental (150 mg) infusions (for recurrent arrhythmias), amiodarone mean serum concentrations between 0.7 to 1.4 mg/L were observed (n = 260). N-desethylamiodarone (DEA) is the major active metabolite of amiodarone in humans. DEA serum concentrations above 0.05 mg/L are not usually seen until after several days of continuous infusion but with prolonged therapy reach approximately the same concentration as amiodarone. Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines. The highly variable systemic availability of oral amiodarone may be attributed potentially to large interindividual variability in CYP3A4 activity. Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable. Amiodarone and DEA cross the placenta and both appear in breast milk. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEA's precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular class III effects after oral amiodarone administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation. On the other hand (see Clinical Trials), after amiodarone I.V. administration, there is evidence of activity well before significant concentrations of DEA are attained. The following table summarizes the mean ranges of pharmacokinetic parameters of amiodarone reported in single dose I.V. (5 mg/kg over 15 min) studies of healthy subjects. Notes: Vand Vdenote the central and steady-state volumes of distribution from I.V. studies. ���������denotes not available. Desethylamiodarone clearance and volume involve an unknown biotransformation factor. The systemic availability of oral amiodarone in healthy subjects ranges between 33% and 65%. From in vitro studies, the protein binding of amiodarone is>96%. In clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients with VT and VF ranged between 220 and 440 mL/h/kg. Age, sex, renal disease, and hepatic disease (cirrhosis) do not have marked effects on the disposition of amiodarone or DEA. Renal impairment does not influence the pharmacokinetics of amiodarone. After a single dose of amiodarone I.V. in cirrhotic patients, significantly lower Cand average concentration values are seen for DEA, but mean amiodarone levels are unchanged. Normal subjects over 65 years of age show lower clearances (about 100 mL/hr/kg) than younger subjects (about 150 mL/hr/kg) and an increase in tfrom about 20 to 47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition tof DEA is prolonged. Although no dosage adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with oralamiodarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction. There is no established relationship between drug concentration and therapeutic response for short-term intravenous use. Steady-state amiodarone concentrations of 1 to 2.5 mg/L have been associated with antiarrhythmic effects and acceptable toxicity following chronic oral amiodarone therapy.<br/>Pharmacodynamics: Amiodarone I.V. has been reported to produce negative inotropic and vasodilatory effects in animals and humans. In clinical studies of patients with refractory VF or hemodynamically unstable VT, treatment-emergent, drug-related hypotension occurred in 288 of 1836 patients (16%) treated with amiodarone I.V. No correlations were seen between the baseline ejection fraction and the occurrence of clinically significant hypotension during infusion of amiodarone I.V.<br/>Clinical Trials: Apart from studies in patients with VT or VF, described below, there are two other studies of amiodarone showing an antiarrhythmic effect before significant levels of DEA could have accumulated. A placebo-controlled study of I.V. amiodarone (300 mg over 2 hours followed by 1200 mg/day) in post-coronary artery bypass graft patients with supraventricular and 2- to 3-consecutive-beat ventricular arrhythmias showed a reduction in arrhythmias from 12 hours on. A baseline-controlled study using a similar I.V. regimen in patients with recurrent, refractory VT/VF also showed rapid onset of antiarrhythmic activity; amiodarone therapy reduced episodes of VT by 85% compared to baseline. The acute effectiveness of amiodarone I.V. in suppressing recurrent VF or hemodynamically unstable VT is supported by two randomized, parallel, dose-response studies of approximately 300 patients each. In these studies, patients with at least two episodes of VF or hemodynamically unstable VT in the preceding 24 hours were randomly assigned to receive doses of approximately 125 or 1000 mg over the first 24 hours, an 8-fold difference. In one study, a middle dose of approximately 500 mg was evaluated. The dose regimen consisted of an initial rapid loading infusion, followed by a slower 6-hour loading infusion, and then an 18-hour maintenance infusion. The maintenance infusion was continued up to hour 48. Additional 10-minute infusions of 150 mg amiodarone I.V. were given for "breakthrough" VT/VF more frequently to the 125 mg dose group, thereby considerably reducing the planned 8-fold differences in total dose to 1.8- and 2.6-fold, respectively, in the two studies. The prospectively defined primary efficacy end point was the rate of VT/VF episodes per hour. For both studies, the median rate was 0.02 episodes per hour in patients receiving the high dose and 0.07 episodes per hour in patients receiving the low dose, or approximately 0.5 versus 1.7 episodes per day (p = 0.07, 2-sided, in both studies). In one study, the time to first episode of VT/VF was significantly prolonged (approximately 10 hours in patients receiving the low dose and 14 hours in patients receiving the high dose). In both studies, significantly fewer supplemental infusions were given to patients in the high-dose group. Mortality was not affected in these studies; at the end of double-blind therapy or after 48 hours, all patients were given open access to whatever treatment (including amiodarone I.V.) was deemed necessary. | lld:dailymed |
| dailymed-drugs:187 | dailymed-instance:clinicalP... | Intravenous Administration: After intravenous administration of a 300 or 600 mg dose of rifampin infused over 30 minutes to healthy male volunteers (n=12), mean peak plasma concentrations were 9.0��3.0 and 17.5��5.0 mcg/mL, respectively. Total body clearances after the 300 and 600 mg IV doses were 0.19��0.06 and 0.14��0.03 L/hr/kg, respectively. Volumes of distribution at steady state were 0.66��0.14 and 0.64��0.11 L/kg for the 300 and 600 mg IV doses, respectively. After intravenous administration of 300 or 600 mg doses, rifampin plasma concentrations in these volunteers remained detectable for 8 and 12 hours, respectively (see Table). Plasma concentrations after the 600 mg dose, which were disproportionately higher (up to 30% greater than expected) than those found after the 300 mg dose, indicated that the elimination of larger doses was not as rapid. After repeated once-a-day infusions (3 hr duration) of 600 mg in patients (n=5) for 7 days, concentrations of IV rifampin decreased from 5.81��3.38 mcg/mL 8 hours after the infusion on day 1 to 2.6��1.88 mcg/mL 8 hours after the infusion on day 7. Rifampin is widely distributed throughout the body. It is present in effective concentrations in many organs and body fluids, including cerebrospinal fluid. Rifampin is about 80% protein bound. Most of the unbound fraction is not ionized and therefore diffuses freely into tissues. Rifampin is rapidly eliminated in the bile and undergoes progressive enterohepatic circulation and deacetylation to the primary metabolite, 25-desacetyl-rifampin. This metabolite is microbiologically active. Less than 30% of the dose is excreted in the urine as rifampin or metabolites. Serum concentrations do not differ in patients with renal failure at a studied dose of 300 mg and, consequently, no dosage adjustment is required.<br/>Pediatrics: Intravenous Administration: In pediatric patients 0.25 to 12.8 years old (n=12), the mean peak serum concentration of rifampin at the end of a 30 minute infusion of approximately 300 mg/mwas 25.9��1.3 mcg/mL; individual peak concentrations 1 to 4 days after initiation of therapy ranged from 11.7 to 41.5 mcg/mL; individual peak concentrations 5 to 14 days after initiation of therapy were 13.6 to 37.4 mcg/mL. The individual serum half-life of rifampin changed from 1.04 to 3.81 hours early in therapy to 1.17 to 3.19 hours 5 to 14 days after therapy was initiated.<br/>Microbiology: Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. Rifampin at therapeutic levels has demonstrated bactericidal activity against both intracellular and extracellular Mycobacterium tuberculosis organisms. Organisms resistant to rifampin are likely to be resistant to other rifamycins. Rifampin has bactericidal activity against slow and intermittently growing M tuberculosis organisms. It also has significant activity against Neisseria meningitidis isolates . In the treatment of both tuberculosis and the meningococcal carrier state , the small number of resistant cells present within large populations of susceptible cells can rapidly become predominant. In addition, resistance to rifampin has been determined to occur as single-step mutations of the DNA-dependent RNA polymerase. Since resistance can emerge rapidly, appropriate susceptibility tests should be performed in the event of persistent positive cultures. Rifampin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. The following in vitro data are available, but their clinical significance is unknown. Rifampin exhibits in vitro activity against most strains of the following microorganisms; however, the safety and effectiveness of rifampin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials ��-lactamase production should have no effect on rifampin activity.<br/>Susceptibility Tests: Prior to initiation of therapy, appropriate specimens should be collected for identification of the infecting organism and in vitro susceptibility tests. In vitro testing for Mycobacterium tuberculosis isolates: Two standardized in vitro susceptibility methods are available for testing rifampin against M tuberculosis organisms. The agar proportion method (CDC or NCCLSM24-P) utilizes Middlebrook 7H10 medium impregnated with rifampin at a final concentration of 1 mcg/mL to determine drug resistance. After three weeks of incubation MICvalues are calculated by comparing the quantity of organisms growing in the medium containing drug to the control cultures. Mycobacterial growth in the presence of drug, of at least 1% of the growth in the control culture, indicates resistance. The radiometric broth method employs the BACTEC 460 machine to compare the growth index from untreated control cultures to cultures grown in the presence of 2 mcg/mL of rifampin. Strict adherence to the manufacturer's instructions for sample processing and data interpretation is required for this assay. Susceptibility test results obtained by the two different methods can only be compared if the appropriate rifampin concentration is used for each test method as indicated above. Both procedures require the use of M tuberculosis H37Rv ATCC 27294 as a control organism. The clinical relevance of in vitro susceptibility test results for mycobacterial species other than M tuberculosis using either the radiometric or the proportion method has not been determined. In vitro testing for Neisseria meningitidis isolates: Dilution Techniques: Quantitative methods that are used to determine minimum inhibitory concentrations provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized dilution method(broth, agar, or microdilution) or equivalent with rifampin powder. The MIC values obtained should be interpreted according to the following criteria for Neisseria meningitidis: A report of���susceptible���indicates that the pathogen is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in the blood. A report of���intermediate���indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where the maximum acceptable dose of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of���resistant���indicates that usually achievable concentrations of the antimicrobial compound in the blood are unlikely to be inhibitory and that other therapy should be selected. Measurement of MIC or minimum bactericidal concentrations (MBC) and achieved antimicrobial compound concentrations may be appropriate to guide therapy in some infections. (See CLINICAL PHARMACOLOGY section for further information on drug concentrations achieved in infected body sites and other pharmacokinetic properties of this antimicrobial drug product.) Standardized susceptibility test procedures require the use of laboratory control microorganisms. The use of these microorganisms does not imply clinical efficacy ; they are used to control the technical aspects of the laboratory procedures. Standard rifampin powder should give the following MIC values: Diffusion Techniques: Quantitative methods that require measurement of zone diameters provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedurethat has been recommended for use with disks to test the susceptibility of microorganisms to rifampin uses the 5 mcg rifampin disk. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for rifampin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5 mcg rifampin disk should be interpreted according to the following criteria for Neisseria meningitidis: Interpretation should be as stated above for results using dilution techniques. As with standard dilution techniques, diffusion methods require the use of laboratory control microorganisms. The use of these microorganisms does not imply clinical efficacy ; they are used to control the technical aspects of the laboratory procedures. The 5 mcg rifampin disk should provide the following zone diameters in these quality control strains: | lld:dailymed |
| dailymed-drugs:188 | dailymed-instance:clinicalP... | Mechanism of Action: The Isosorbide Mononitrate product is an oral extended-release formulation of ISMN, the major active metabolite of isosorbide dinitrate; most of the clinical activity of the dinitrate is attributable to the mononitrate. The principal pharmacological action of ISMN and all organic nitrates in general is relaxation of vascular smooth muscle, producing dilatation of peripheral arteries and veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end-diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, and systolic arterial pressure and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs. The relative importance of preload reduction, afterload reduction, and coronary dilatation remains undefined. Pharmacodynamics: Dosing regimens for most chronically used drugs are designed to provide plasma concentration's that are continuously greater than a minimally effective concentration. This strategy is inappropriate for organic nitrates. Several well-controlled clinical trials have used exercise testing to assess the antianginal efficacy of continuously delivered nitrates. In the large majority of these trials, active agents were indistinguishable from placebo after 24 hours (or less) of continuous therapy. Attempts to overcome tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates have been absent from the body for several hours has their antianginal efficacy been restored. Isosorbide Mononitrate Tablets during long-term use over 42 days dosed at 120 mg once daily continued to improve exercise performance at 4 hours and at 12 hours after dosing, but its effects (although better than placebo) are less than or, at best, equal to the effects of the first dose of 60 mg. Pharmacokinetics and Metabolism: After oral administration of ISMN as a solution or immediate-release tablets, maximum plasma concentrations of ISMN are achieved in 30 to 60 minutes, with an absolute bioavailability of approximately 100%. After intravenous administration, ISMN is distributed into total body water in about 9 minutes with a volume of distribution of approximately 0.6 to 0.7 L/kg. Isosorbide mononitrate is approximately 5% bound to human plasma proteins and is distributed into blood cells and saliva. Isosorbide mononitrate is primarily metabolized by the liver, but unlike oral isosorbide dinitrate, it is not subject to first-pass metabolism. Isosorbide mononitrate is cleared by denitration to isosorbide and glucuronidation as the mononitrate, with 96% of the administered dose excreted in the urine within 5 days and only about 1% eliminated in the feces. At least six different compounds have been detected in urine, with about 2% of the dose excreted as the unchanged drug and at least five metabolites. The metabolites are not pharmacologically active. Renal clearance accounts for only about 4% of total body clearance. The mean plasma elimination half-life of ISMN is approximately 5 hours. The disposition of ISMN in patients with various degrees of renal insufficiency, liver cirrhosis, or cardiac dysfunction was evaluated and found to be similar to that observed in healthy subjects. The elimination half-life of ISMN was not prolonged, and there was no drug accumulation in patients with chronic renal failure after multiple oral dosing. The pharmacokinetics and/or bioavailability of Isosorbide Mononitrate Extended-Release Tablets have been studied in both normal volunteers and patients following single- and multiple-dose administration. Data from these studies suggest that the pharmacokinetics of ISMN administered as Isosorbide Mononitrate Tablets are similar between normal healthy volunteers and patients with angina pectoris. In single- and multiple-dose studies, the pharmacokinetics of ISMN were dose proportional between 30 mg and 240 mg. In a multiple-dose study, the effect of age on the pharmacokinetic profile of Isosorbide Mononitrate 60 mg and 120 mg (2 x 60 mg) Tablets was evaluated in subjects���45 years. The results of that study indicate that there are no significant differences in any of the pharmacokinetic variables of ISMN between elderly (���65 years) and younger individuals (45-64 years) for the isosorbide mononitrate 60 mg dose. The administration of Isosorbide Mononitrate Tablets 120 mg (2 x 60 mg tablets every 24 hours for 7 days) produced a dose-proportional increase in Cand AUC, without changes in T,or the terminal half-life. The older group (65-74 years) showed 30% lower apparent oral clearance (Cl/F) following the higher dose, ie, 120 mg, compared to the younger group (45-64 years); CI/F was not different between the two groups following the 60-mg regimen. While CI/F was independent of dose in the younger group, the older group showed slightly lower CI/F following the 120 mg regimen compared to the 60 mg regimen. Differences between the two age groups, however, were not statistically significant. In the same study, females showed a slight (15%) reduction in clearance when the dose was increased. Females showed higher AUCs and Ccompared to males, but these differences were accounted for by differences in body weight between the two groups. When the data were analyzed using age as a variable, the results indicated that there were no significant differences in any of the pharmacokinetic variables of ISMN between older (���65 years) and younger individuals (45-64 years). The results of this study, however, should be viewed with caution due to the small numbers of subjects in each age subgroup and consequently the lack of sufficient statistical power. The following table summarizes key pharmacokinetic parameters of ISMN after single- and multiple-dose administration of ISMN as an oral solution or Isosorbide Mononitrate Tablets: Food Effects: The influence of food on the bioavailability of ISMN after single-dose administration of Isosorbide Mononitrate Tablets 60 mg was evaluated in three different studies involving either a���light���breakfast or a high-calorie, high-fat breakfast. Results of these studies indicate that concomitant food intake may decrease the rate (increase in T) but not the extent (AUC) of absorption of ISMN. | lld:dailymed |
| dailymed-drugs:190 | dailymed-instance:clinicalP... | Pharmacodynamics: The mechanism of action of fluoxetine in premenstrual dysphoric disorder (PMDD) is unknown, but is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in humans have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and�����adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of certain psychoactive drugs. Fluoxetine has little affinity for these receptors.<br/>Absorption, Distribution, Metabolism, and Excretion: Systemic bioavailability���In humans, following a single oral 40���mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption inconsequentially. Thus, fluoxetine may be administered with or without food. Protein binding���Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and�����glycoprotein. The interaction between fluoxetine and other highly protein���bound drugs has not been fully evaluated, but may be important . Enantiomers���Fluoxetine is a racemic mixture (50/50) of R���fluoxetine and S���fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S���fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state. Metabolism���Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S���norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R���or S���fluoxetine. R���norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney. Clinical issues related to metabolism/elimination���The complexity of the metabolism of fluoxetine has several consequences that may potentially affect fluoxetine's clinical use. Variability in metabolism���A subset (about 7%) of the population has reduced activity of the drug metabolizing enzyme cytochrome P450 2D6 (CYP2D6). Such individuals are referred to as���poor metabolizers���of drugs such as debrisoquin, dextromethorphan, and the tricyclic antidepressants (TCAs). In a study involving labeled and unlabeled enantiomers administered as a racemate, these individuals metabolized S���fluoxetine at a slower rate and thus achieved higher concentrations of S���fluoxetine. Consequently, concentrations of S���norfluoxetine at steady state were lower. The metabolism of R���fluoxetine in these poor metabolizers appears normal. When compared with normal metabolizers, the total sum at steady state of the plasma concentrations of the 4 active enantiomers was not significantly greater among poor metabolizers. Thus, the net pharmacodynamic activities were essentially the same. Alternative, nonsaturable pathways (non���2D6) also contribute to the metabolism of fluoxetine. This explains how fluoxetine achieves a steady���state concentration rather than increasing without limit. Because fluoxetine's metabolism, like that of a number of other compounds including TCAs and other SSRIs, involves the CYP2D6 system, concomitant therapy with drugs also metabolized by this enzyme system (such as the TCAs) may lead to drug interactions . Accumulation and slow elimination���The relatively slow elimination of fluoxetine (elimination half���life of 1 to 3 days after acute administration and 4 to 6 days after chronic administration) and its active metabolite, norfluoxetine (elimination half���life of 4 to 16 days after acute and chronic administration), leads to significant accumulation of these active species in chronic use and delayed attainment of steady state, even when a fixed dose is used. After 30 days of dosing at 40 mg/day, plasma concentrations of fluoxetine in the range of 91 to 302 ng/mL and norfluoxetine in the range of 72 to 258 ng/mL have been observed. Plasma concentrations of fluoxetine were higher than those predicted by single���dose studies, because fluoxetine's metabolism is not proportional to dose. Norfluoxetine, however, appears to have linear pharmacokinetics. Its mean terminal half���life after a single dose was 8.6 days and after multiple dosing was 9.3 days. Steady���state levels after prolonged dosing are similar to levels seen at 4 to 5 weeks. The long elimination half���lives of fluoxetine and norfluoxetine assure that, even when dosing is stopped, active drug substance will persist in the body for weeks (primarily depending on individual patient characteristics, previous dosing regimen, and length of previous therapy at discontinuation). This is of potential consequence when drug discontinuation is required or when drugs are prescribed that might interact with fluoxetine and norfluoxetine following the discontinuation of SARAFEM. Liver disease���As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half���life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used . Renal disease���In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months produced steady���state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients . | lld:dailymed |
| dailymed-drugs:191 | dailymed-instance:clinicalP... | 8% Hepatasol (Amino Acid) Injection provides a mixture of essential and nonessential amino acids with high concentrations of the branched chain amino acids isoleucine, leucine, and valine, and low concentrations of methionine and the aromatic amino acids phenylalanine and tryptophan, relative to general purpose amino acid injections, This amino acid composition has been specifically formulated to provide a well tolerated nitrogensource for nutritional support and therapy of patients with liver disease who have hepatic encephalopathy. The precise mechanisms which produce the therapeutic effects of this amino acid formulation are not known. The etiopathology of hepatic encephalopathy is also unknown and is thought to be of multifactorial origin. The rationale for this amino acid formulation is based on observations of plasma amino acid imbalances in patients with liver disease and on theories which postulate that these abnormal patterns are causally related to the development of hepatic encephalopathy. Clinical studies in patients with hepatic encephalopathy showed that the infusion of this amino acid formulation reversed the abnormal plasma amino acid pattern characterized by decreased levels of branched chain amino acids and elevated levels of aromatic amino acids and methionine. The trendtoward normalization of these amino acids was generally associated with an improvement in mental status and EEG patterns. This clinical response was observed in the majority of patients studied. Nitrogen balance was significantly improved and mortality reduced in these typically protein-intolerant patients who received substantial amounts of protein equivalent as this amino acid injection. When infused with hypertonic dextrose as a calorie source, supplemented with electrolytes, vitamins, and minerals, this amino acid formulation provides total parenteral nutrition in patients with liver disease, with the exception of essential fatty acids. Phosphate is a major intracellular anion which participates in providing energy for metabolism of substrates and contributes to significant metabolic and enzymatic reactions in all organs and tissues. It exerts a modifying influence on calcium levels, a buffering effect on acid-base equilibrium, and has a primary role in the renal excretion of hydrogen ions. It is thought that the acetate from lysine acetate and acetic acid, under the conditions of parenteral nutrition, does not impact net acid-base balance when renal and respiratory functions are normal. Clinical evidence seems to support this thinking; however, confirmatory experimental evidence is not available. The amounts of sodium and chloride present are not of clinical significance. | lld:dailymed |
| dailymed-drugs:192 | dailymed-instance:clinicalP... | Metoprolol tartrate is a beta-adrenergic receptor blocking agent. In vitro and in vivo animal studies have shown that it has a preferential effect on betaadrenoreceptors, chiefly located in cardiac muscle. This preferential effect is not absolute, however, and at higher doses, metoprolol tartrate also inhibits betaadrenoreceptors, chiefly located in the bronchial and vascular musculature. Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reductionof reflex orthostatic tachycardia. Relative betaselectivity has been confirmed by the following: (1) In normal subjects, metoprolol tartrate is unable to reverse the beta-mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective (betaplus beta) beta-blockers, which completely reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, metoprolol tartrate reduces FEVand FVC significantly less than a nonselective beta blocker, propranolol, at equivalent beta-receptor blocking doses. Metoprolol tartrate has no intrinsic sympathomimetic activity, and membrane-stabilizing activity is detectable only at doses much greater than required for beta blockade. Metoprolol tartrate crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration. Animal and human experiments indicate that metoprolol tartrate slows the sinus rate and decreases AV nodal conduction. In controlled clinical studies, metoprolol tartrate has been shown to be an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics, at dosages of 100 to 450 mg daily. In controlled, comparative, clinical studies, metoprolol tartrate has been shown to be as effective an antihypertensive agent as propranolol, methyldopa, and thiazide-type diuretics, and to be equallyeffective in supine and standing positions. The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression of renin activity. By blocking catecholamine-induced increases in heart rate, in velocity and extent of myocardial contraction, and in blood pressure, metoprolol tartrate reduces the oxygen requirements of the heart at any given level of effort, thus making it useful in the long-term management of angina pectoris. However, in patients with heart failure, beta-adrenergic blockade may increase oxygen requirements by increasing left ventricular fiber length and end-diastolic pressure. Although beta-adrenergic receptor blockade is useful in the treatment of angina and hypertension, there are situations in which sympathetic stimulation is vital. In patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. In the presence of AV block, beta blockade may prevent the necessary facilitating effect of sympathetic activity on conduction. Beta-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients. In controlled clinical trials, metoprolol tartrate, administered two or four times daily, has been shown to be an effective antianginal agent, reducing the number of angina attacks and increasing exercise tolerance. The dosage used in these studies ranged from 100 to 400 mg daily. A controlled, comparative, clinical trial showed that metoprolol tartrate was indistinguishable from propranolol in the treatment of angina pectoris. In a large (1,395 patients randomized), double-blind, placebo-controlled clinical study, metoprolol tartrate was shown to reduce 3-month mortality by 36% in patients with suspected or definite myocardial infarction. Patients were randomized and treated as soon as possible after their arrival in the hospital, once their clinical condition had stabilized and their hemodynamic status had been carefully evaluated. Subjects were ineligible if they had hypotension, bradycardia, peripheral signs of shock, and/or more than minimal basal rales as signs of congestive heart failure. Initial treatment consisted of intravenous followed by oral administration of metoprolol tartrate or placebo, given in a coronary care or comparable unit. Oral maintenance therapy with metoprolol tartrate or placebo was then continued for 3 months. After this double-blind period, all patients were given metoprolol tartrate and followed up to 1 year. The median delay from the onset of symptoms to the initiation of therapy was 8 hours in both the metoprolol tartrate- and placebo- treatment groups. Among patients treated with metoprolol tartrate, there were comparable reductions in 3-month mortality for those treated early (���8 hours) and those in whom treatment was started later. Significant reductions in the incidence of ventricular fibrillation and in chest pain following initial intravenous therapy were also observed with metoprolol tartrate and were independent of the interval between onset of symptoms and initiation of therapy. The precise mechanism of action of metoprolol tartrate in patients with suspected or definite myocardial infarction is not known. In this study, patients treated with metoprolol received the drug both very early (intravenously) and during a subsequent 3-month period, while placebo patients received no beta-blocker treatment for this period. The study thus was able to show a benefit from the overall metoprolol regimen but cannot separate the benefit of very early intravenous treatment from the benefit of later beta-blocker therapy. Nonetheless, because the overall regimen showed a clear beneficial effect on survival without evidence of an early adverse effect on survival, one acceptable dosage regimen is the precise regimen used in the trial. Because the specific benefit of very early treatment remains to be defined however, it is also reasonable to administer the drug orally to patients at a later time as is recommended for certain other beta-blockers.<br/>Pharmacokinetics: In man, absorption of metoprolol tartrate is rapid and complete. Plasma levels following oral administration, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism. Plasma levels achieved are highly variable after oral administration. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R- and S-enantiomers. Less than 5% of an oral dose of metoprolol tartrate is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no clinical significance. The systemic availability and half-life of metoprolol tartrate in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. Consequently, no reduction in dosage is usually needed in patients with chronic renal failure. Metoprolol tartrate is extensively metabolized by the cytochrome P450 enzyme system in the liver. The oxidative metabolism of metoprolol tartrate is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolizers (PM) phenotype. Approximately 7% of Caucasians and less than 1% Asian are poor metabolizers. Poor CYP2D6 metabolizers exhibit several-fold higher plasma concentrations of metoprolol tartrate than extensive metabolizers with normal CYP2D6 activity. The elimination half-life of metoprolol is about 7.5 hours in poor metabolizers and 2.8 hours in extensive metabolizers. However, the CYP2D6 dependent metabolism of metoprolol tartrate seems to have little or no effect on safety or tolerability of the drug. None of the metabolites of metoprolol tartrate contribute significantly to its beta-blocking effect. Significant beta-blocking effect (as measured by reduction of exercise heart rate) occurs within 1 hour after oral administration, and its duration is dose-related. For example, a 50% reduction of the maximum registered effect after single oral doses of 20, 50, and 100 mg occurred at 3.3, 5.0, and 6.4 hours, respectively, in normal subjects. After repeated oral dosages of 100 mg twice daily, a significant reduction in exercise systolic blood pressure was evident at 12 hours. Following intravenous administration of metoprolol tartrate, the urinary recovery of unchanged drug is approximately 10%. When the drug was infused over a 10-minute period, in normal volunteers, maximum beta blockade was achieved at approximately 20 minutes. Doses of 5 mg and 15 mg yielded a maximal reduction in exercise-induced heart rate of approximately 10% and 15%, respectively. The effect on exercise heart rate decreased linearly with time at the same rate for both doses, and disappeared at approximately 5 hours and 8 hours for the 5 mg and 15 mg doses, respectively. Equivalent maximal beta-blocking effect is achieved with oral and intravenous doses in the ratio of approximately 2.5:1. There is a linear relationship between the log of plasma levels and reduction of exercise heart rate. However, antihypertensive activity does not appear to be related to plasma levels. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity to dose, selection of proper dosage requires individual titration. In several studies of patients with acute myocardial infarction, intravenous followed by oral administration of metoprolol tartrate caused a reduction in heart rate, systolic blood pressure, and cardiac output. Stroke volume, diastolic blood pressure, and pulmonary artery end diastolic pressure remained unchanged. In patients with angina pectoris, plasma concentration measured at 1 hour is linearly related to the oral dose within the range of 50 to 400 mg. Exercise heart rate and systolic blood pressure are reduced in relation to the logarithm of the oral dose of metoprolol. The increase in exercise capacity and the reduction in left ventricular ischemia are also significantly related to the logarithm of the oral dose. In elderly subjects with clinically normal renal and hepatic function, there are no significant differences in metoprolol tartrate pharmacokinetics compared to young subjects. | lld:dailymed |
| dailymed-drugs:193 | dailymed-instance:clinicalP... | The in vivo synthesis of the major biologically active metabolites of vitamin D occurs in two steps. The first hydroxylation of ergocalciferol takes place in the liver (to 25-hydroxyvitamin D) and the second in the kidneys (to 1,25-dihydroxyvitamin D). Vitamin D metabolites promote the active absorption of calcium and phosphorus by the small intestine, thus elevating serum calcium and phosphate levels sufficiently to permit bone mineralization. Vitamin D metabolites also mobilize calcium and phosphate from bone and probably increase the reabsorption of calcium and perhaps also of phosphate by the renal tubules. There is a time lag of 10 to 24 hours between the administration of vitamin D and the initiation of its action in the body due to the necessity of synthesis of the active metabolites in the liver and kidneys. Parathyroid hormone is responsible for the regulation of this metabolism in the kidneys. | lld:dailymed |
| dailymed-drugs:194 | dailymed-instance:clinicalP... | The fibrinolysis-inhibitory effects of aminocaproic acid appear to be exerted principally via inhibition of plasminogen activators and to a lesser degree through antiplasmin activity. In adults, oral absorption appears to be a zero-order process with an absorption rate of 5.2 g/hr. The mean lag time in absorption is 10 minutes. After a single oral dose of 5 g, absorption was complete (F=1). Mean��SD peak plasma concentrations (164��28 mcg/mL) were reached within 1.2��0.45 hours. After oral administration, the apparent volume of distribution was estimated to be 23.1��6.6 L (mean��SD). Correspondingly, the volume of distribution after intravenous administration has been reported to be 30.0��8.2 L. After prolonged administration, aminocaproic acid has been found to distribute throughout extravascular and intravascular compartments of the body, penetrating human red blood cells as well as other tissue cells. Renal excretion is the primary route of elimination, whether aminocaproic acid is administered orally or intravenously. 65% of the dose is recovered in the urine as unchanged drug and 11% of the dose appears as the metabolite adipic acid. Renal clearance (116 mL/min) approximates endogenous creatinine clearance. The total body clearance is 169 mL/min. The terminal elimination halflife for aminocaproic acid is approximately 2 hours. | lld:dailymed |
| dailymed-drugs:195 | dailymed-instance:clinicalP... | 0.9% Sodium Chloride Irrigation USP is utilized for a variety of clinical indications such as sterile irrigation of body cavities, tissues or wounds, indwelling urethral catheters, surgical drainage tubes, and for washing, rinsing or soaking surgical dressings, instruments and laboratory specimens. It also servesas a diluent or vehicle for drugs used for irrigation or other pharmaceutical preparations. 0.9% Sodium Chloride Irrigation USP provides an isotonic saline irrigation identical in composition with 0.9% Sodium Chloride Injection USP (normal saline). Physiological irrigation solutions are considered generally compatible with living tissues and organs. Sodium, the major cation of the extracellular fluid, functions primarily in the control of water distribution, fluid balance, and osmotic pressure of body fluids. Sodium is also associated with chloride and bicarbonate in the regulation of the acid-base equilibrium of body fluid. Chloride, the major extracellular anion, closely follows the metabolism of sodium, and changes in the acid-base balance of the body are reflected by changes in the chloride concentration. | lld:dailymed |
| dailymed-drugs:196 | dailymed-instance:clinicalP... | General Pharmacology: Tositumomab binds specifically to the CD20 (human B-lymphocyte���restricted differentiation antigen, Bp 35 or B1) antigen. This antigen is a transmembrane phosphoprotein expressed on pre-B lymphocytes and at higher density on mature B lymphocytes (Ref. 2). The antigen is also expressed on>90% of B-cell non-Hodgkin's lymphomas (NHL) (Ref. 3). The recognition epitope for Tositumomab is found within the extracellular domain of the CD20 antigen. CD20 does not shed from the cell surface and does not internalize following antibody binding (Ref. 4).<br/>Mechanism of Action: Possible mechanisms of action of the BEXXAR therapeutic regimen include induction of apoptosis (Ref. 5), complement-dependent cytotoxicity (CDC) (Ref. 6), and antibody-dependent cellular cytotoxicity (ADCC) (Ref. 5) mediated by the antibody. Additionally, cell death is associated with ionizing radiation from the radioisotope.<br/>Pharmacokinetics/Pharmacodynamics: The phase 1 study of Iodine I 131 Tositumomab determined that a 475 mg predose of unlabeled antibody decreased splenic targeting and increased the terminal half-life of the radiolabeled antibody. The median blood clearance following administration of 485 mg of Tositumomab in 110 patients with NHL was 68.2 mg/hr (range: 30.2���260.8 mg/hr). Patients with high tumor burden, splenomegaly, or bone marrow involvement were noted to have a faster clearance, shorter terminal half-life, and larger volume of distribution. The total body clearance, as measured by total body gamma camera counts, was dependent on the same factors noted for blood clearance. Patient-specific dosing, based on total body clearance, provided a consistent radiation dose, despite variable pharmacokinetics, by allowing each patient's administered activity to be adjusted forindividual patient variables. The median total body effective half-life, as measured by total body gamma camera counts, in 980 patients with NHL was 67 hours (range: 28-115 hours). Elimination of Iodine-131 occurs by decay (see Table 2) and excretion in the urine. Urine was collected for 49 dosimetric doses. After 5 days, the whole body clearance was 67% of the injected dose. Ninety-eight percent of the clearance was accounted for in the urine. Administration of the BEXXAR therapeutic regimen results in sustained depletion of circulating CD20 positive cells. The impact of administration of the BEXXAR therapeutic regimen on circulating CD20 positive cells was assessed in two clinical studies, one conducted in chemotherapy na��ve patients and one in heavily pretreated patients. The assessment of circulating lymphocytes did not distinguish normal from malignant cells. Consequently, assessment of recovery of normal B cell function was not directly assessed. At seven weeks, the median number of circulating CD20 positive cells was zero (range: 0-490 cells/mm). Lymphocyte recovery began at approximately 12 weeks following treatment. Among patients who had CD20 positive cell counts recorded at baseline and at 6 months, 8 of 58 (14%) chemotherapy na��ve patients had CD20 positive cell counts below normal limits at six months and 6 of 19 (32%) heavily pretreated patients had CD20 positive cell counts below normal limits at six months. There was no consistent effect of the BEXXAR therapeutic regimen on post-treatment serum IgG, IgA, or IgM levels.<br/>Radiation Dosimetry: Estimations of radiation-absorbed doses for Iodine I 131 Tositumomab were performed using sequential whole body images and the MIRDOSE 3 software program. Patients with apparent thyroid, stomach, or intestinal imaging were selected for organ dosimetry analyses. The estimated radiation-absorbed doses to organs and marrow from a course of the BEXXAR therapeutic regimen are presented in Table 3. | lld:dailymed |
| dailymed-drugs:197 | dailymed-instance:clinicalP... | OSMITROL Injection (Mannitol Injection, USP) is one of the nonelectrolyte, obligatory, osmotic diuretics. It is freely filterable at the renal glomerulus, only poorly reabsorbed by the renal tubule, not secreted by the tubule, and is pharmacologically inert. Mannitol, when administered intravenously, exerts its osmotic effect as a solute of relatively small molecular size being largely confined to the extracellular space. Only relatively small amounts of the dose administered is metabolized. Mannitol is readily diffused through the glomerulus of the kidney over a wide range of normal and impaired kidney function. In this fashion, approximately 80% of a 100 gram dose of mannitol will appear in the urine in three hours with lesser amounts thereafter. Even at peak concentrations, mannitol will exhibit less than 10% of tubular reabsorption and is not secreted by tubular cells. Mannitol will hinder tubular reabsorption of water and enhance excretion of sodium and chloride by elevating the osmolarity of the glomerular filtrate. This increase in extracellular osmolarity effected by the intravenous administration of mannitol will induce the movement of intracellular water to the extracellular and vascular spaces. This action underlies the role of mannitol in reducing intracranial pressure, intracranial edema, and elevated intraocular pressure. | lld:dailymed |
| dailymed-drugs:198 | dailymed-instance:clinicalP... | Mechanism of Action: Fluticasone propionate is a synthetic, trifluorinated corticosteroid with anti-inflammatory activity. In vitro dose response studies on a cloned human glucocorticoid receptor system involving binding and gene expression afforded 50% responses at 1.25 and 0.17 nM concentrations, respectively. Fluticasone propionate was 3-fold to 5-fold more potent than dexamethasone in these assays. Data from the McKenzie vasoconstrictor assay in man also support its potent glucocorticoid activity. In preclinical studies, fluticasone propionate revealed progesterone-like activity similar to the natural hormone. However, the clinical significance of these findings in relation to the low plasma levels (see Pharmacokinetics) is not known. The precise mechanism through which fluticasone propionate affects allergic rhinitis symptoms is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (e.g., mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (e.g., histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation. In seven trials in adults, Fluticasone Propionate Nasal Spray has decreased nasal mucosal eosinophils in 66% (35% for placebo) of patients and basophils in 39% (28% for placebo) of patients. The direct relationship of these findings to long-term symptom relief is not known. Fluticasone Propionate Nasal Spray, like other corticosteroids, is an agent that does not have an immediate effect on allergic symptoms. A decrease in nasal symptoms has been noted in some patients 12 hours after initial treatment with Fluticasone Propionate Nasal Spray. Maximum benefit may not be reached for several days. Similarly, when corticosteroids are discontinued, symptoms may not return for several days.<br/>Pharmacokinetics:<br/>Absorption: The activity of Fluticasone Propionate Nasal Spray is due to the parent drug, fluticasone propionate. Indirect calculations indicate that fluticasone propionate delivered by the intranasal route has an absolute bioavailability averaging less than 2%. After intranasal treatment of patients with allergic rhinitis for 3 weeks, fluticasone propionate plasma concentrations were above the levelof detection (50 pg/mL) only when recommended doses were exceeded and then only in occasional samples at low plasma levels. Due to the low bioavailability by the intranasal route, the majority of the pharmacokinetic data was obtained via other routes of administration. Studies using oral dosing of radiolabeled drug have demonstrated that fluticasone propionate is highly extracted from plasma and absorption is low. Oral bioavailability is negligible, and the majority of the circulating radioactivity is dueto an inactive metabolite.<br/>Distribution: Following intravenous administration, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The volume of distribution averaged 4.2 L/kg. The percentage of fluticasone propionate bound to human plasma proteins averaged 91% with no obvious concentration relationship. Fluticasone propionate is weakly and reversibly bound to erythrocytes and freely equilibrates between erythrocytes and plasma. Fluticasone propionate is not significantly bound to human transcortin.<br/>Metabolism: The total blood clearance of fluticasone propionate is high (average, 1,093 mL/min), with renal clearance accounting for less than 0.02% of the total. The only circulating metabolite detected in man is the 17��-carboxylic acid derivative of fluticasone propionate, which is formed through the cytochrome P450 3A4 pathway. This inactive metabolite had less affinity (approximately 1/2,000) than the parent drug for the glucocorticoid receptor of human lung cytosol invitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man.<br/>Elimination: Following intravenous dosing, fluticasone propionate showed polyexponential kinetics and had a terminal elimination half-life of approximately 7.8 hours. Less than 5% of a radiolabeled oral dose was excreted in the urine as metabolites, with the remainder excreted in the feces as parent drug and metabolites.<br/>Special Populations: Fluticasone propionate nasal spray was not studied in any special populations, and no gender-specific pharmacokinetic data have been obtained.<br/>Drug Interactions: Fluticasone propionate is a substrate of cytochrome P450 3A4. Coadministration of fluticasone propionate and the highly potent cytochrome P450 3A4 inhibitor ritonavir is not recommended based upon a multiple-dose, crossover drug interaction study in 18 healthy subjects. Fluticasone propionate aqueous nasal spray (200 mcg once daily) was coadministered for 7 days with ritonavir (100 mg twice daily). Plasma fluticasone propionate concentrations following fluticasone propionate aqueous nasal spray alone were undetectable (<10 pg/mL) in most subjects, and when concentrations were detectable peak levels (Caveraged 11.9 pg/mL [range, 10.8 to 14.1 pg/mL] and AUCaveraged 8.43 pg���hr/mL [range 4.2 to 18.8 pg���hr/mL]). Fluticasone propionate Cand AUCincreased to 318 pg/mL (range, 110 to 648 pg/mL) and 3,102.6 pg���hr/mL (range, 1,207.1 to 5,662 pg���hr/mL), respectively, after coadministration of ritonavir with fluticasone propionate aqueous nasal spray. This significant increase in plasma fluticasone propionate exposure resulted in a significant decrease (86%) in plasma cortisol area under the plasma concentration versus time curve (AUC). Caution should be exercised when other potent cytochrome P450 3A4 inhibitors are coadministered with fluticasone propionate. In a drug interaction study, coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in increased fluticasone propionate exposure and reduced plasma cortisol AUC, but had no effect on urinary excretion of cortisol. In another multiple-dose drug interaction study, coadministration of orally inhaled fluticasone propionate (500 mcg twice daily) and erythromycin (333 mg 3 times daily) did not affect fluticasone propionate pharmacokinetics.<br/>Pharmacodynamics: In a trial to evaluate the potential systemic and topical effects of Fluticasone Propionate Nasal Spray on allergic rhinitis symptoms, the benefits of comparable drug blood levels produced by Fluticasone Propionate Nasal Spray and oral fluticasone propionate were compared. The doses used were 200 mcg of Fluticasone Propionate Nasal Spray, the nasal spray vehicle (plus oral placebo), and 5 and 10 mg of oral fluticasone propionate (plus nasal spray vehicle) per day for 14 days. Plasma levels were undetectable in the majority of patients after intranasal dosing, but present at low levels in the majority after oral dosing. Fluticasone Propionate Nasal Spray was significantly more effective in reducing symptoms of allergic rhinitis than either the oral fluticasone propionate or the nasal vehicle. This trial demonstrated that the therapeutic effect of Fluticasone Propionate Nasal Spray can be attributed to the topical effects of fluticasone propionate. In another trial, the potential systemic effects of Fluticasone Propionate Nasal Spray on the hypothalamic-pituitary-adrenal (HPA) axis were also studied in allergic patients. Fluticasone Propionate Nasal Spray given as 200 mcg once daily or 400 mcg twice daily was compared with placebo or oral prednisone 7.5 or 15 mg given in the morning. Fluticasone Propionate Nasal Spray at either dose for 4 weeks did not affect the adrenal response to 6-hour cosyntropin stimulation, while both doses of oral prednisone significantly reduced the response to cosyntropin.<br/>Clinical Trials: A total of 13 randomized, double-blind, parallel-group, multicenter, vehicle placebo-controlled clinical trials were conducted in the United States in adults and pediatric patients (4 years of age and older) to investigate regular use of Fluticasone Propionate Nasal Spray in patients with seasonal or perennial allergic rhinitis. The trials included 2,633 adults (1,439 men and 1,194 women) with a mean age of 37 (range, 18 to 79 years). A total of 440 adolescents (405 boys and 35 girls) mean age of 14 (range, 12 to 17 years), and 500 children (325 boys and 175 girls), mean age of 9 (range, 4 to 11 years) were also studied. The overall racial distribution was 89% white, 4% black, and 7% other. These trials evaluated the total nasal symptom scores (TNSS) that included rhinorrhea, nasal obstruction, sneezing, and nasal itching in known allergic patients who were treated for 2 to 24 weeks. Subjects treated with Fluticasone Propionate Nasal Spray exhibited significantly greater decreases in TNSS than vehicle placebo-treated patients. Nasal mucosal basophils and eosinophils were also reduced at the end of treatment in adult studies; however, the clinical significance of this decrease is not known. There were no significant differences between fluticasone propionate regimens whether administered as a single daily dose of 200 mcg (two 50 mcg sprays in each nostril) or as 100 mcg (one 50 mcg spray in each nostril) twice daily in six clinical trials. A clear dose response could not be identified in clinical trials. In one trial, 200 mcg/day was slightly more effective than 50 mcg/day during the first few days of treatment;thereafter, no difference was seen. In two randomized, double-blind, parallel-group, multicenter, vehicle-controlled, clinical trials of 14 days' duration in 401 adult and adolescent patients with allergic rhinitis, Fluticasone Propionate Nasal Spray 200 mcg once daily provided a statistically significant decrease in patient-rated sinus pain and pressure. Three randomized, double-blind, parallel, vehicle placebo-controlled trials were conducted in 1,191 patients to investigate regular use of Fluticasone Propionate Nasal Spray in patients with perennial nonallergic rhinitis. These trials evaluated the patient-rated TNSS (nasal obstruction, postnasal drip, rhinorrhea) in patients treated for 28 days of double-blind therapy and in 1 of the 3 trials for 6 months of open-label treatment. Two of these trials demonstrated that patients treated with Fluticasone Propionate Nasal Spray at a dose of 100 mcg twice daily exhibited statistically significant decreases in TNSS compared with patients treated with vehicle.<br/>Individualization of Dosage: Patients should use Fluticasone Propionate Nasal Spray at regular intervals for optimal effect. Adult patients may be started on a 200 mcg once daily regimen (two 50 mcg sprays in each nostril once daily). An alternative 200 mcg/day dosage regimen can be given as 100 mcg twice daily (one 50 mcg spray in each nostril twice daily). Individual patients will experience a variable time to onset and different degree of symptom relief. In four randomized, double-blind, vehicle placebo-controlled, parallel-group allergic rhinitis studies and two studies of patients in a outdoor���park���setting (park studies), a decrease in nasal symptoms in treated subjects compared to placebo was shown to occur as soon as 12 hours after treatment with a 200 mcg dose of Fluticasone Propionate Nasal Spray. Maximum effect may take several days. Regular-use patients who have responded may be able to be maintained (after 4 to 7 days) on 100 mcg/day (one spray in each nostril once daily). Pediatric patients (4 years of age and older) should be started with 100 mcg (one spray in each nostril once daily). Treatment with 200 mcg (two sprays in each nostril once daily or one spray in each nostril twice daily) should be reserved for pediatric patients not adequately responding to 100 mcg daily. Once adequate control is achieved, the dosage should be decreased to 100 mcg (one spray in each nostril) daily. Maximum total daily doses should not exceed two sprays in each nostril (total dose, 200 mcg/day). There is no evidence that exceeding the recommended dose is more effective. | lld:dailymed |
| dailymed-drugs:200 | dailymed-instance:clinicalP... | Mechanism of Action: Angiotensin II is formed from angiotensin I in a reaction catalyzed by angiotensin-converting enzyme (ACE, kininase II). Angiotensin II is the principal pressor agent of the renin-angiotensin system, with effects that include vasoconstriction, stimulation of synthesis and release of aldosterone, cardiac stimulation, and renal reabsorption of sodium. Valsartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by selectively blocking the binding of angiotensin II to the ATreceptor in many tissues, such as vascular smooth muscle and the adrenal gland. Its action is therefore independent of the pathways for angiotensin II synthesis. There is also an ATreceptor found in many tissues, but ATis not known to be associated with cardiovascular homeostasis. Valsartan has much greater affinity (about 20,000-fold) for the ATreceptor than for the ATreceptor. The primary metabolite of valsartan is essentially inactive with an affinity for the ATreceptor about one 200th that of valsartan itself. Blockade of the renin-angiotensin system with ACE inhibitors, which inhibit the biosynthesis of angiotensin II from angiotensin I, is widely used in the treatment of hypertension. ACE inhibitors also inhibit the degradation of bradykinin, a reaction also catalyzed by ACE. Because valsartan does not inhibit ACE (kininase II), it does not affect the response to bradykinin. Whether this difference has clinical relevance is not yet known. Valsartan does not bind to or block other hormone receptors orion channels known to be important in cardiovascular regulation. Blockade of the angiotensin II receptor inhibits the negative regulatory feedback of angiotensin II on renin secretion, but the resulting increased plasma renin activity and angiotensin II circulating levels do not overcome the effect of valsartan on blood pressure.<br/>Pharmacokinetics: Valsartan peak plasma concentration is reached 2 to 4 hours after dosing. Valsartan shows bi-exponential decay kinetics following intravenous administration, with an average elimination half-life of about 6 hours. Absolute bioavailability for the capsule formulation is about 25% (range 10%-35%). Food decreases the exposure (as measured by AUC) to valsartan by about 40% and peak plasma concentration (C) by about 50%. AUC and Cvalues of valsartan increase approximately linearly with increasing dose over the clinical dosing range. Valsartan does not accumulate appreciably in plasma following repeated administration.<br/>Metabolism and Elimination: Valsartan, when administered as an oral solution, is primarily recovered in feces (about 83% of dose) and urine (about 13% of dose). The recovery is mainly as unchanged drug, with only about 20% of dose recovered as metabolites. The primary metabolite, accounting for about 9% of dose, is valeryl 4-hydroxy valsartan. The enzyme(s) responsible for valsartan metabolism have not been identified but do not seem to be CYP 450 isozymes. Following intravenous administration, plasma clearance of valsartan is about 2 L/h and its renal clearance is 0.62 L/h (about 30% of total clearance).<br/>Distribution: The steady state volume of distribution of valsartan after intravenous administration is small (17 L), indicating that valsartan does not distribute into tissues extensively. Valsartan is highly bound to serum proteins (95%), mainly serum albumin.<br/>Special Populations: Pediatric: The pharmacokinetics of valsartan have not been investigated in patients<18 years of age. Geriatric: Exposure (measured by AUC) to valsartan is higher by 70% and the half-life is longer by 35% in the elderly than in the young. No dosage adjustment is necessary (see DOSAGE AND ADMINISTRATION). Gender: Pharmacokinetics of valsartan does not differ significantly between males and females. Renal Insufficiency: There is no apparent correlation between renal function (measured by creatinine clearance) and exposure (measured by AUC) to valsartan in patients with different degrees of renal impairment. Consequently, dose adjustment is not required in patients with mild-to-moderate renal dysfunction. No studies have been performed in patients with severe impairment of renal function (creatinineclearance<10 mL/min). Valsartan is not removed from the plasma by hemodialysis. In the case of severe renal disease, exercise care with dosing of valsartan (see DOSAGE AND ADMINISTRATION). Hepatic Insufficiency: On average, patients with mild-to-moderate chronic liver disease have twice the exposure (measured by AUC values) to valsartan of healthy volunteers (matched by age, sex and weight). In general, no dosage adjustment is needed in patients with mild-to-moderate liver disease. Care should be exercised in patients with liver disease (see DOSAGE AND ADMINISTRATION).<br/>Pharmacodynamics and Clinical Effects: Valsartan inhibits the pressor effect of angiotensin II infusions. An oral dose of 80 mg inhibits the pressor effect by about 80% at peak with approximately 30% inhibition persisting for 24 hours. No information on the effect of larger doses is available. Removal of the negative feedback of angiotensin II causes a 2- to 3-fold rise in plasma renin and consequent rise in angiotensin II plasma concentration in hypertensive patients. Minimal decreases in plasma aldosterone were observed after administration of valsartan; very little effect on serum potassium was observed. In multiple-dose studies in hypertensive patients with stable renal insufficiency and patients with renovascular hypertension, valsartan had no clinically significant effects on glomerular filtration rate, filtration fraction, creatinine clearance, or renal plasma flow. In multiple-dose studies in hypertensive patients, valsartan had no notable effects on total cholesterol, fasting triglycerides, fasting serum glucose, or uric acid. The antihypertensive effects of Diovan were demonstrated principally in 7 placebo-controlled, 4- to 12-week trials (one in patients over 65) of dosages from 10 to 320 mg/day in patients with baseline diastolic blood pressures of 95-115. The studies allowed comparison of once-daily and twice-daily regimens of 160 mg/day; comparison of peak and trough effects; comparison (in pooled data) of response by gender, age, and race; and evaluation of incremental effects of hydrochlorothiazide. Administration of valsartan to patients with essential hypertension results in a significant reduction of sitting, supine, and standing systolic and diastolic blood pressure, usually with little or no orthostatic change. In most patients, after administration of a single oral dose, onset of antihypertensive activity occurs at approximately 2 hours, and maximum reduction of blood pressure is achieved within 6 hours. The antihypertensive effect persists for 24 hours after dosing, but there is a decrease from peak effect at lower doses (40 mg) presumably reflecting loss of inhibition of angiotensin II. At higher doses, however (160 mg), there is little difference in peak and trough effect. During repeated dosing, the reduction in blood pressure with any dose is substantially present within 2 weeks, and maximal reduction is generally attained after 4 weeks. In long-term follow-up studies (without placebo control), the effect of valsartan appeared to be maintained for up to two years. The antihypertensive effect is independent of age, gender or race. The latter finding regarding race is based on pooled data and should be viewed with caution, because antihypertensive drugs that affect the renin-angiotensin system (that is, ACE inhibitors and angiotensin-II blockers) have generally been found to be less effective in low-renin hypertensives (frequently blacks) than in high-renin hypertensives (frequently whites). In pooled, randomized, controlled trials of Diovan that included a total of 140 blacks and 830 whites, valsartan and an ACE-inhibitor control were generally at least as effective in blacks as whites. The explanation for this difference from previous findings is unclear. Abrupt withdrawal of valsartan has not been associated with a rapid increase in blood pressure. The blood pressure lowering effect of valsartan and thiazide-type diuretics are approximately additive. The 7 studies of valsartan monotherapy included over 2000 patients randomized to various doses of valsartan and about 800 patients randomized to placebo. Doses below 80 mg were not consistently distinguished from those of placebo at trough, but doses of 80, 160 and 320 mg produced dose-related decreases in systolic and diastolic blood pressure, with the difference from placebo of approximately 6-9/3-5 mmHg at 80-160 mg and 9/6 mmHg at 320 mg. In a controlled trial the addition of HCTZ tovalsartan 80 mg resulted in additional lowering of systolic and diastolic blood pressure by approximately 6/3 and 12/5 mmHg for 12.5 and 25 mg of HCTZ, respectively, compared to valsartan 80 mg alone. Patients with an inadequate response to 80 mg once daily were titrated to either 160 mg once daily or 80 mg twice daily, which resulted in a comparable response in both groups. In controlled trials, the antihypertensive effect of once-daily valsartan 80 mg was similar to that of once-daily enalapril 20 mg or once-daily lisinopril 10 mg. There was essentially no change in heart rate in valsartan-treated patients in controlled trials. | lld:dailymed |
| dailymed-drugs:201 | dailymed-instance:clinicalP... | Ethosuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli. | lld:dailymed |
| dailymed-drugs:1916 | dailymed-instance:clinicalP... | Ethosuximide suppresses the paroxysmal three cycle per second spike and wave activity associated with lapses of consciousness which is common in absence (petit mal) seizures. The frequency of epileptiform attacks is reduced, apparently by depression of the motor cortex and elevation of the threshold of the central nervous system to convulsive stimuli. | lld:dailymed |
| dailymed-drugs:202 | dailymed-instance:clinicalP... | The involvement of low-density lipoprotein cholesterol (LDL-C) in atherogenesis has been well-documented in clinical and pathological studies, as well as in many animal experiments. Epidemiological and clinical studies have established that high LDL-C and low high-density lipoprotein cholesterol (HDL-C) are both associated with coronary heart disease. However, the risk of developing coronary heart disease is continuous and graded over the range of cholesterol levels and many coronary events do occur in patients with total cholesterol (total-C) and LDL-C in the lower end of this range. Lovastatin has been shown to reduce both normal and elevated LDL-C concentrations. LDL is formed from very low-density lipoprotein (VLDL) and is catabolized predominantly by the high affinity LDL receptor. The mechanism of the LDL-lowering effect of lovastatin may involve both reduction of VLDL-C concentration, and induction of the LDL receptor, leading to reduced production and/or increased catabolism of LDL-C. Apolipoprotein B also falls substantially during treatment with lovastatin. Since each LDL particle contains one molecule of apolipoprotein B, and since little apolipoprotein B is found in other lipoproteins, this strongly suggests that lovastatin does not merely cause cholesterol to be lost from LDL, but also reduces the concentration of circulating LDL particles. In addition, lovastatin can produce increases of variable magnitude in HDL-C, and modestly reduces VLDL-C and plasma triglycerides (TG) (see TABLES I through III under Clinical Studies in Adults). The effects of lovastatin on Lp(a), fibrinogen, and certain other independent biochemical risk markers for coronary heart disease are unknown. Lovastatin is a specific inhibitor of HMG-CoA reductase, the enzyme which catalyzes the conversion of HMG-CoA to mevalonate. The conversion of HMG-CoA to mevalonate is an early step in the biosynthetic pathway for cholesterol.<br/>Pharmacokinetics: Lovastatin is a lactone which is readily hydrolyzed in vivo to the corresponding��-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Inhibition of HMG-CoA reductase is the basis for an assay in pharmacokinetic studies of the��-hydroxyacid metabolites (active inhibitors) and, following base hydrolysis, active plus latent inhibitors (total inhibitors) in plasma following administration of lovastatin. Following an oral dose ofC-labeled lovastatin in man, 10% of the dose was excreted in urine and 83% in feces. The latter represents absorbed drug equivalents excreted in bile, as well as any unabsorbed drug. Plasma concentrations of total radioactivity (lovastatin plusC-metabolites) peaked at 2 hours and declined rapidly to about 10% of peak by 24 hours postdose. Absorption of lovastatin, estimated relative to an intravenous reference dose, in each of four animal species tested, averaged about 30% of an oral dose. In animal studies, after oral dosing, lovastatin had high selectivity for the liver, where it achieved substantially higher concentrations than in non-target tissues. Lovastatin undergoes extensive first-pass extraction in the liver, its primary site of action,with subsequent excretion of drug equivalents in the bile. As a consequence of extensive hepatic extraction of lovastatin, the availability of drug to the general circulation is low and variable. In a single dose study in four hypercholesterolemic patients, it was estimated that less than 5% of an oral dose of lovastatin reaches the general circulation as active inhibitors. Following administration of lovastatin tablets the coefficient of variation, based on between-subject variability, was approximately 40% for the area under the curve (AUC) of total inhibitory activity in the general circulation. Both lovastatin and its��-hydroxyacid metabolite are highly bound (>95%) to human plasma proteins. Animal studies demonstrated that lovastatin crosses the blood-brain and placental barriers. The major active metabolites present in human plasma are the b-hydroxyacid of lovastatin, its 6'-hydroxy derivative, and two additional metabolites. Peak plasma concentrations of both active and total inhibitors were attained within 2 to 4 hours of dose administration. While the recommended therapeutic dose range is 10 to 80 mg/day, linearity of inhibitory activity in the general circulation was established by a single dose study employing lovastatin tablet dosages from 60 to as high as 120 mg. With a once-a-day dosing regimen, plasma concentrations of total inhibitors over a dosing interval achieved a steady state between the second and third days of therapy and were about 1.5 times those following a single dose. When lovastatin was given under fasting conditions, plasma concentrations of total inhibitors were on average about two-thirds those found when lovastatin was administered immediately after a standard test meal. In a study of patients with severe renal insufficiency (creatinine clearance 10 to 30 mL/min), the plasma concentrations of total inhibitors after a single dose of lovastatin were approximately two-fold higher than those in healthy volunteers. In a study including 16 elderly patients between 70 to 78 years of age who received lovastatin 80 mg/day, the mean plasma level of HMG-CoA reductase inhibitory activity was increased approximately 45% compared with 18 patients between 18 to 30 years of age (see PRECAUTIONS, Geriatric Use). Although the mechanism is not fully understood, cyclosporine has been shown to increase the AUC of HMG-CoA reductase inhibitors. The increase in AUC for lovastatin and lovastatin acid is presumably due, in part, to inhibition of CYP3A4. The risk of myopathy is increased by high levels of HMG-CoA reductase inhibitory activity in plasma. Potent inhibitors of CYP3A4 can raise the plasma levels of HMG-CoA reductase inhibitory activity and increase the risk of myopathy (see WARNINGS, Myopathy/Rhabdomyolysis and PRECAUTIONS, Drug Interactions). Lovastatin is a substrate for cytochrome P450 isoform 3A4 (CYP3A4) (see PRECAUTIONS, Drug Interactions). Grapefruit juice contains one or more components that inhibit CYP3A4 and can increase the plasma concentrations of drugs metabolized by CYP3A4. In one study**, 10 subjects consumed 200 mL of double-strength grapefruit juice (one can of frozen concentrate diluted with one rather than 3 cans of water) three times daily for 2 days and an additional 200 mL double-strength grapefruit juice together with and 30 and 90 minutes following a single dose of 80 mg lovastatin on the third day. This regimen of grapefruit juice resulted in a mean increase in the serum concentration of lovastatin and its��-hydroxyacid metabolite (as measured by the area under the concentration-time curve) of 15 fold and 5 fold, respectively [as measured using chemical assay���high performance liquid chromatography]. In a second study, 15 subjects consumed one 8 oz glass of single-strength grapefruit juice (one can of frozen concentrate diluted with 3 cans of water) with breakfast for 3 consecutive days and a single dose of 40 mg lovastatin in the evening of the third day.This regimen of grapefruit juice resulted in a mean increase in the plasma concentration (as measured by the area under the concentration-time curve) of active and total HMG-CoA reductase inhibitory activity [using an enzyme inhibition assay both before (for active inhibitors) and after (for total inhibitors) base hydrolysis] of 1.34 fold and 1.36 fold, respectively, and of lovastatin and its��-hydroxyacid metabolite [measured using a chemical assay - liquid chromatography/tandem mass spectrometry - different from that used in the first**study] of 1.94 fold and 1.57 fold, respectively. The effect of amounts of grapefruit juice between those used in these two studies on lovastatin pharmacokinetics has not been studied.<br/>Clinical Studies in Adults: Lovastatin has been shown to be highly effective in reducing total-C and LDL-C in heterozygous familial and non-familial forms of primary hypercholesterolemia and in mixed hyperlipidemia. A marked response was seen within 2 weeks, and the maximum therapeutic response occurred within 4 to 6 weeks. The response was maintained during continuation of therapy. Single daily doses given in the evening were more effective than the same dose given in the morning, perhaps because cholesterol is synthesized mainlyat night. In multicenter, double-blind studies in patients with familial or non-familial hypercholesterolemia, lovastatin, administered in doses ranging from 10 mg q.p.m. to 40 mg b.i.d., was compared to placebo. Lovastatin consistently and significantly decreased plasma total-C, LDL-C, total-C/HDL-C ratio and LDL-C/HDL-C ratio. In addition, lovastatin produced increases of variable magnitude in HDL-C, and modestly decreased VLDL-C and plasma TG (see TABLES I through III for dose response results). The results of a study in patients with primary hypercholesterolemia are presented in TABLE I. Lovastatin was compared to cholestyramine in a randomized open parallel study. The study was performed with patients with hypercholesterolemia who were at high risk of myocardial infarction. Summary results are presented in TABLE II. Lovastatin was studied in controlled trials in hypercholesterolemic patients with well-controlled non-insulin dependent diabetes mellitus with normal renal function. The effect of lovastatin on lipids and lipoproteins and the safety profile of lovastatin were similar to that demonstrated in studies in nondiabetics. Lovastatin had no clinically important effect on glycemic control or on the dose requirement of oral hypoglycemic agents.<br/>Expanded Clinical Evaluation of Lovastatin (EXCEL) Study: Lovastatin was compared to placebo in 8,245 patients with hypercholesterolemia (total-C 240 to 300 mg/dL [6.2 mmol/L to 7.6 mmol/L], LDL-C>160 mg/dL [4.1 mmol/L]) in the randomized, double-blind, parallel, 48 week EXCEL study. All changes in the lipid measurements (TABLE III) in lovastatin treated patients were dose-related and significantly different from placebo (p���0.001). These results were sustained throughout the study.<br/>Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS): The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a double-blind, randomized, placebo-controlled, primary prevention study, demonstrated that treatment with lovastatin decreased the rate of acute major coronary events (composite endpoint of myocardial infarction, unstable angina, and sudden cardiac death) compared with placebo during a median of 5.1 years of follow-up. Participants were middle-aged and elderly men (ages 45 to 73) and women (ages 55 to 73) without symptomatic cardiovascular disease with average to moderately elevated total-C and LDL-C, below average HDL-C, and who were at high risk based on elevated total-C/HDL-C. In addition to age, 63% of the participants had at least one other risk factor (baseline HDL-C<35 mg/dL, hypertension, family history, smoking and diabetes). AFCAPS/TexCAPS enrolled 6,605 participants (5,608 men, 997 women) based on the following lipid entry criteria: total-C range of 180 to 264 mg/dL, LDL-C range of 130 to 190 mg/dL, HDL-C of���45 mg/dL for men and���47 mg/dL for women, and TG of���400 mg/dL. Participants were treated with standard care, including diet, and either lovastatin 20 to 40 mg daily (n = 3,304) or placebo (n = 3,301). Approximately 50% of the participants treated with lovastatin were titrated to 40 mg daily when their LDL-C remained>110 mg/dL at the 20 mg starting dose. Lovastatin reduced the risk of a first acute major coronary event, the primary efficacy endpoint, by 37% (lovastatin 3.5%, placebo 5.5%; p<0.001; Figure 1). A first acute major coronary event was defined as myocardial infarction (54 participants on lovastatin, 94 on placebo) or unstable angina (54 vs. 80) or sudden cardiac death (8 vs. 9). Furthermore, among the secondary endpoints, lovastatin reduced the risk of unstable angina by 32% (1.8 vs. 2.6%; p = 0.023), of myocardial infarction by 40% (1.7 vs. 2.9%; p = 0.002), and of undergoing coronary revascularization procedures (e.g., coronary artery bypass grafting or percutaneous transluminal coronary angioplasty) by 33% (3.2 vs. 4.8%; p = 0.001). Trends in risk reduction associated with treatment with lovastatinwere consistent across men and women, smokers and non-smokers, hypertensives and non-hypertensives, and older and younger participants. Participants with���2 risk factors had risk reductions (RR) in both acute major coronary events (RR 43%) and coronary revascularization procedures (RR 37%). Because there were too few events among those participants with age as their only risk factor in this study, the effect of lovastatin on outcomes could not be adequately assessed in this subgroup.<br/>Atherosclerosis: In the Canadian Coronary Atherosclerosis Intervention Trial (CCAIT), the effect of therapy with lovastatin on coronary atherosclerosis was assessed by coronary angiography in hyperlipidemic patients. In the randomized, double-blind, controlled clinical trial, patients were treated with conventional measures (usually diet and 325 mg of aspirin every other day) and either lovastatin 20 to 80 mg daily or placebo. Angiograms were evaluated at baseline and at two years by computerized quantitative coronary angiography (QCA). Lovastatin significantly slowed the progression of lesions as measured by the mean change per patient in minimum lumen diameter (the primary endpoint) and percent diameter stenosis, and decreased the proportions of patients categorized with disease progression (33% vs. 50%) and with new lesions (16% vs. 32%). In a similarly designed trial, the Monitored Atherosclerosis Regression Study (MARS), patients were treated with diet and either lovastatin 80 mg daily or placebo. No statistically significant difference between lovastatin and placebo was seen for the primary endpoint (mean change per patient in percent diameter stenosis of all lesions), or for most secondary QCA endpoints. Visual assessment by angiographers who formed a consensus opinion of overall angiographic change (Global Change Score) was also a secondary endpoint. By this endpoint, significant slowing of disease was seen, with regression in 23% of patients treated with lovastatin compared to11% of placebo patients. In the Familial Atherosclerosis Treatment Study (FATS), either lovastatin or niacin in combination with a bile acid sequestrant for 2.5 years in hyperlipidemic subjects significantly reduced the frequency of progression and increased the frequency of regression of coronary atherosclerotic lesions by QCA compared to diet and, in some cases, low-dose resin. The effect of lovastatin on the progression of atherosclerosis in the coronary arteries has been corroborated by similar findings in another vasculature. In the Asymptomatic Carotid Artery Progression Study (ACAPS), the effect of therapy with lovastatin on carotid atherosclerosis was assessed by B-mode ultrasonography in hyperlipidemic patients with early carotid lesions and without known coronary heart disease at baseline. In this double-blind, controlled clinical trial, 919 patients were randomized in a 2 x 2 factorial design to placebo, lovastatin 10 to 40 mg daily and/or warfarin. Ultrasonograms of the carotid walls were used to determine the change per patient from baseline to three years in mean maximum intimal-medial thickness (IMT) of 12 measured segments. There was a significant regression of carotid lesions in patients receiving lovastatin alone compared to those receiving placebo alone (p = 0.001). The predictive value of changes in IMT for stroke has not yet been established. In thelovastatin group there was a significant reduction in the number of patients with major cardiovascular events relative to the placebo group (5 vs. 14) and a significant reduction in all-cause mortality (1 vs. 8).<br/>Eye: There was a high prevalence of baseline lenticular opacities in the patient population included in the early clinical trials with lovastatin. During these trials the appearance of new opacities was noted in both the lovastatin and placebo groups. There was no clinically significant change in visual acuity in the patients who had new opacities reported nor was any patient, including those with opacitiesnoted at baseline, discontinued from therapy because of a decrease in visual acuity. A three-year, double-blind, placebo-controlled study in hypercholesterolemic patients to assess the effect of lovastatin on the human lens demonstrated that there were no clinically or statistically significant differences between the lovastatin and placebo groups in the incidence, type or progression of lenticular opacities. There are no controlled clinical data assessing the lens available for treatment beyond three years.<br/>Clinical Studies in Adolescent Patients:<br/>Efficacy of Lovastatin in Adolescent Boys with Heterozygous Familial Hypercholesterolemia: In a double-blind, placebo-controlled study, 132 boys 10 to 17 years of age (mean age 12.7 yrs) with heterozygous familial hypercholesterolemia (heFH) were randomized to lovastatin (n = 67) or placebo (n = 65) for 48 weeks. Inclusion in the study required a baseline LDL-C level between 189 and 500 mg/dL and at least one parent with an LDL-C level>189 mg/dL. The mean baseline LDL-C value was 253.1 mg/dL (range: 171 to 379 mg/dL) in the lovastatin group compared to 248.2 mg/dL (range: 158.5 to 413.5 mg/dL) in the placebo group. The dosage of lovastatin (once daily in the evening) was 10 mg for the first 8 weeks, 20 mg for the second 8 weeks, and 40 mg thereafter. Lovastatin significantly decreased plasma levels of total-C, LDL-C, and apolipoprotein B (see TABLE IV). The mean achieved LDL-C value was 190.9 mg/dL (range: 108 to 336 mg/dL) in the lovastatin group compared to 244.8 mg/dL (range: 135 to 404 mg/dL) in the placebo group.<br/>Efficacy of Lovastatin in Post-Menarchal Girls with Heterozygous Familial Hypercholesterolemia: In a double-blind, placebo-controlled study, 54 girls 10 to 17 years of age who were at least 1 year post-menarche with heFH were randomized to lovastatin (n = 35) or placebo (n = 19) for 24 weeks. Inclusion in the study required a baseline LDL-C level of 160 to 400 mg/dL and a parental history of familial hypercholesterolemia. The mean baseline LDL-C value was 218.3 mg/dL (range: 136.3 to 363.7 mg/dL) in the lovastatin group compared to 198.8 mg/dL (range: 151.1 to 283.1 mg/dL) in the placebo group. The dosage of lovastatin (once daily in the evening) was 20 mg for the first 4 weeks, and 40 mg thereafter. Lovastatin significantly decreased plasma levels of total-C, LDL-C, and apolipoprotein B (see TABLE V). The mean achieved LDL-C value was 154.5 mg/dL (range: 82 to 286 mg/dL) in the lovastatin group compared to 203.5 mg/dL (range: 135 to 304 mg/dL) in the placebo group. The safety and efficacy of doses above 40 mg daily have not been studied in children. The long-term efficacy of lovastatin therapy in childhood to reduce morbidity and mortality in adulthood has not been established. | lld:dailymed |
| dailymed-drugs:203 | dailymed-instance:clinicalP... | Like other topical corticosteroids, fluticasone propionate has anti-inflammatory, antipruritic and vasoconstrictive properties. The mechanism of the anti-inflammatory activity of the topical steroids, in general, is unclear. However, corticosteroids are thought to act by the induction of phospholipase Ainhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor, arachidonic acid. Arachidonic acid is released from membrane phospholipidsby phospholipase A. Fluticasone propionate is lipophilic and has a strong affinity for the glucocorticoid receptor. It has weak affinity for the progesterone receptor, and virtually no affinity for the mineralocorticoid, estrogen, or androgen receptors. The therapeutic potency of glucocorticoids is related to the half-life of the glucocorticoid-receptor complex. The half-life of the fluticasone propionate-glucocorticoid receptor complex is approximately 10 hours. Studies performed with Fluticasone Propionate Cream, 0.05% indicate that it is in the medium range of potency as compared with other topical corticosteroids.<br/>Pharmacokinetics:: Absorption: The activity of Fluticasone Propionate Cream is due to the parent drug, fluticasone propionate. The extent of percutaneous absorption of topical corticosteroids is determined by many factors, including the vehicle and the integrity of the epidermal barrier. Occlusive dressing enhances penetration. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. In a human study of 12 healthy males receiving 12.5 g of 0.05% fluticasone propionate cream twice daily for 3 weeks, plasma levels were generally below the level of quantification (0.05 ng/mL). In another study of six healthy males administered 25 g of 0.05% fluticasone propionate cream under occlusion for 5 days, plasma levels of fluticasone ranged from 0.07 to 0.39 ng/mL. In an animal study using radiolabeled 0.05% fluticasone propionate cream and ointment preparations, rats received a topical dose of 1 g/kg for a 24 hour period. Total recovery of radioactivity was approximately 80% at the end of 7 days. The majority of the dose (73%) was recovered from the surface of the application site. Less than 1% of the dose was recovered in the skin at the application site. Approximately 5% of the dose was absorbed systemically through the skin. Absorption from the skin continued for the duration of the study (7 days), indicating a long retention time at the application site. Distribution: Following intravenous administration of 1 mg fluticasone propionate in healthy volunteers, the initial disposition phase for fluticasone propionate was rapid and consistent with its high lipid solubility and tissue binding. The apparent volume of distribution averaged 4.2 L/kg (range 2.3-16.7 L/kg). The percentage of fluticasone propionate bound to human plasma proteins averaged 91%. Fluticasone propionate is weakly and reversibly bound to erythrocytes. Fluticasone propionate is not significantly bound to human transcortin. Metabolism: No metabolites of fluticasone propionate were detected in an in vitro study of radiolabeled fluticasone propionate incubated in a human skin homogenate. The total blood clearance of systemically absorbed fluticasone propionate averages 1093 mL/min (range 618-1702 mL/min) after a 1 mg intravenous dose, with renal clearance accounting for less than 0.02% of the total. Fluticasone propionate is metabolized in the liver by cytochrome P450 3A4-mediated hydrolysis of the 5-fluoromethyl carbothioate grouping. This transformation occurs in 1 metabolic step to produce the inactive 17-��-carboxylic acid metabolite, the only known metabolite detected in man. This metabolite has approximately 2000 times less affinity than the parent drug for the glucocorticoid receptor of human lung cytosol in vitro and negligible pharmacological activity in animal studies. Other metabolites detected in vitro using cultured human hepatoma cells have not been detected in man. Excretion: Following intravenous dose of 1 mg in healthy volunteers, fluticasone propionate showed polyexponential kinetics and had an average terminal half-life of 7.2 hours (range 3.2-11.2 hours). | lld:dailymed |
| dailymed-drugs:204 | dailymed-instance:clinicalP... | Corticosteroids suppress the inflammatory response to a variety of agents and they probably delay or slow healing. Since corticosteroids may inhibit the body's defense mechanism against infection, a concomitant antibacterial drug may be used when this inhibition is considered to be clinically significant in a particular case. When a decision to administer both a corticosteroid and an antibacterial is made, the administration of such drugs in combination has the advantage of greater patient compliance and convenience, with the added assurance that the appropriate dosage of both drugs is administered. When both types of drugs are in the same formulation, compatibility of ingredients is assured and the correct volume of drug is delivered and retained. The relative potency of corticosteroids depends on the molecular structure, concentration and release from the vehicle. Microbiology: Sulfacetamide sodium exerts a bacteriostatic effect against susceptible bacteria by restricting the synthesis of folic acid required for growth through competition with p-aminobenzoic acid. Some strains of these bacteria may be resistant to sulfacetamide or resistant strains may emerge in vivo. The anti-infective component in these products is included to provide action against specific organisms susceptible to it. Sulfacetamide sodium is active in vitro against susceptible strains of the following microorganisms: Escherichia coli, Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus (viridans group), Haemophilus influenzae, Klebsiella species, and Enterobacter species. This product does not provide adequate coverage against: Neisseria species, Pseudomonas species, and Serratia marcescens . | lld:dailymed |
| dailymed-drugs:205 | dailymed-instance:clinicalP... | Mechanism of Action:<br/>Pharmacokinetics and Metabolism:<br/>Pharmacodynamics and Clinical Effects:<br/>Hypertension:<br/>Heart Failure:<br/>Acute Myocardial Infarction: | lld:dailymed |
| dailymed-drugs:206 | dailymed-instance:clinicalP... | Pharmacokinetics:Plasma concentrations of moxifloxacin were measured in healthy adult male and female subjects who received bilateral topical ocular doses of VIGAMOX' 3 times a day. The mean steady-state C(2.7 ng/mL) and estimated daily exposure AUC (45 ng��hr/mL) values were 1,600 and 1,000 times lower than the mean Cand AUC reported after therapeutic 400 mg oral doses of moxifloxacin. The plasma half-life of moxifloxacin was estimated to be 13 hours. Microbiology: Moxifloxacin is an 8-methoxy fluoroquinolone with a diazabicyclononyl ring at the C7 position. The antibacterial action of moxifloxacin results from inhibition of the topoisomerase II (DNA gyrase) and topoisomerase IV. DNA gyrase is an essential enzyme that is involved in the replication, transcription and repair of bacterial DNA. Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division. The mechanism of action for quinolones, including moxifloxacin, is different from that of macrolides, aminoglycosides, or tetracyclines. Therefore, moxifloxacin may be active against pathogens that are resistant to these antibiotics and these antibiotics may be active against pathogens that are resistant to moxifloxacin. There is no cross-resistance between moxifloxacin and the aforementioned classes of antibiotics. Cross resistance has been observed between systemic moxifloxacin and some other quinolones. In vitroresistance to moxifloxacin develops via multiple-step mutations. Resistance to moxifloxacin occurs in vitroat a general frequency of between 1.8 x 10to<1 x 10for Gram-positive bacteria. Moxifloxacin has been shown to be active against most strains of the following microorganisms, both in vitroand in clinical infections as described in the INDICATIONS AND USAGE section: Aerobic Gram-positive microorganisms: Corynebacteriumspecies* Micrococcus luteus* Staphylococcus aureus Staphylococcus epidermidis Staphylococcus haemolyticus Staphylococcus hominis Staphylococcus warneri* Streptococcus pneumoniae Streptococcusviridans group Aerobic Gram-negative microorganisms: Acinetobacter lwoffii* Haemophilus influenzae Haemophilus parainfluenzae* Other microorganisms: Chlamydia trachomatis *Efficacy for this organism was studied in fewer than 10 infections. The following in vitrodata are also available, but their clinical significance in ophthalmic infections is unknown.The safety and effectiveness of VIGAMOX' in treating ophthalmological infections due to these microorganisms have not been established in adequate and well-controlled trials. The following organisms are considered susceptible when evaluated using systemic breakpoints. However, a correlation between the in vitrosystemic breakpoint and ophthalmological efficacy has not been established. The list of organisms is provided as guidance only in assessing the potential treatment of conjunctival infections. Moxifloxacin exhibits in vitrominimal inhibitory concentrations (MICs) of 2��g/ml or less (systemic susceptible breakpoint) against most (���90%) of strains of the following ocular pathogens. Aerobic Gram-positive microorganisms: Listeria monocytogenes Staphylococcus saprophyticus Streptococcus agalactiae Streptococcus mitis Streptococcus pyogenes StreptococcusGroup C, G and F Aerobic Gram-negative microorganisms: Acinetobacter baumannii Acinetobacter calcoaceticus Citrobacter freundii Citrobacter koseri Enterobacter aerogenes Enterobacter cloacae Escherichia coli Klebsiella oxytoca Klebsiella pneumoniae Moraxella catarrhalis Morganella morganii Neisseria gonorrhoeae Proteus mirabilis Proteus vulgaris Pseudomonas stutzeri Anaerobic microorganisms: Clostridium perfringens Fusobacteriumspecies Prevotellaspecies Propionibacterium acnes Other microorganisms: Chlamydia pneumoniae Legionella pneumophila Mycobacterium avium Mycobacterium marinum Mycoplasma pneumoniae | lld:dailymed |
| dailymed-drugs:207 | dailymed-instance:clinicalP... | Electrophysiology/Mechanisms of Action: In animals, amiodarone is effective in the prevention or suppression of experimentally-induced arrhythmias. The antiarrhythmic effect of amiodarone may be due to at least two major properties: 1) a prolongation of the myocardial cell-action potential duration and refractory period and 2) noncompetitive��- and��-adrenergic inhibition. Amiodarone prolongs the duration of the action potential of all cardiac fibers while causing minimal reduction of dV/dt (maximal upstroke velocity of the action potential). The refractory period is prolonged in all cardiac tissues. Amiodarone increases the cardiac refractory period without influencing resting membrane potential, except in automatic cells where the slope of the prepotential is reduced, generally reducing automaticity. These electrophysiologic effects are reflected in a decreased sinus rate of 15 to 20%, increased PR and QT intervals of about 10%, the development of U-waves, and changes in T-wave contour. These changes should not require discontinuation of amiodarone as they are evidence of its pharmacological action, although amiodarone can cause marked sinus bradycardia or sinus arrest and heart block. Onrare occasions, QT prolongation has been associated with worsening of arrhythmia (see WARNINGS).<br/>Hemodynamics: In animal studies and after intravenous administration in man, amiodarone relaxes vascular smooth muscle, reduces peripheral vascular resistance (afterload), and slightly increases cardiac index. After oral dosing, however, amiodarone produces no significant change in left ventricular ejection fraction (LVEF), even in patients with depressed LVEF. After acute intravenous dosing in man, amiodarone may have a mild negative inotropic effect.<br/>Pharmacokinetics: Following oral administration in man, amiodarone is slowly and variably absorbed. The bioavailability of amiodarone is approximately 50%, but has varied between 35 and 65% in various studies. Maximum plasma concentrations are attained 3 to 7 hours after a single dose. Despite this, the onset of action may occur in 2 to 3 days, but more commonly takes 1 to 3 weeks, even with loading doses. Plasma concentrations with chronic dosing at 100 to 600 mg/day are approximately dose proportional, with a mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual variability. Food increases the rate and extent of absorption of amiodarone. The effects of food upon the bioavailability of amiodarone have been studied in 30 healthy subjects who received a single 600 mg dose immediately after consuming a high-fat meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (C) of amiodarone increased by 2.3 (range 1.7 to 3.6) and 3.8 (range 2.7 to 4.4) times, respectively, in the presence of food. Food also increased the rate of absorption of amiodarone, decreasing the time to peak plasma concentration (T) by 37%. The mean AUC and mean Cof desethylamiodarone increased by 55% (range 58 to 101%) and 32% (range 4 to 84%), respectively, but there was no change in the Tin the presence of food. Amiodarone has a very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen. One major metabolite of amiodarone, desethylamiodarone (DEA), has been identified in man; it accumulates to an even greater extent in almost all tissues. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEA's precise role and contribution to the antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular Class III effects after oral amiodarone administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation. Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines. Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable. In clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients with VT and VF ranged between 220 and 440 mL/hr/kg. Age, sex, renal disease, and hepatic disease (cirrhosis) do not have marked effects on the disposition of amiodarone or DEA. Renal impairment does not influence the pharmacokinetics of amiodarone. After a single dose of intravenous amiodarone in cirrhotic patients, significantly lower Cand average concentration values are seen for DEA, but mean amiodarone levels are unchanged. Normal subjects over 65 years of age show lower clearances (about 100 mL/hr/kg) than younger subjects (about 150 mL/hr/kg) and an increase in tfrom about 20 to 47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition tof DEA is prolonged. Although no dosage adjustment for patients with renal, hepatic, or cardiac abnormalities has been defined during chronic treatment with amiodarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction. Following single dose administration in 12 healthy subjects, amiodarone exhibited multi-compartmental pharmacokinetics with a mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In patients, following discontinuation of chronic oral therapy, amiodarone has been shown to have a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 10 days.A much slower terminal plasma-elimination phase shows a half-life of the parent compound ranging from 26 to 107 days, with a mean of approximately 53 days and most patients in the 40 to 55 day range. In the absence of a loading-dose period, steady-state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well-perfused tissue (the 2.5 to 10 day half-life phase), followed by a terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat. The considerable intersubject variation in both phases of elimination, as well as uncertainty as to what compartment is critical to drug effect, requires attention to individual responses once arrhythmia control is achieved with loading doses because the correct maintenance dose is determined, in part, by the elimination rates. Daily maintenance doses of amiodarone should be based on individual patient requirements (see DOSAGE AND ADMINISTRATION). Amiodarone and its metabolite have a limited transplacental transfer of approximately 10 to 50%. The parent drug and its metabolite have been detected in breast milk. Amiodarone is highly protein-bound (approximately 96%). Although electrophysiologic effects, such as prolongation of QT, can be seen within hours after a parenteral dose of amiodarone, effects on abnormal rhythms are not seen before 2 to 3 days and usually require 1 to 3 weeks, even when a loading dose is used. There may be a continued increase in effect for longer periods still. There is evidence that the time to effect is shorter when a loading-dose regimen is used. Consistent with the slow rate of elimination, antiarrhythmic effects persist for weeks or months after amiodarone is discontinued, but the time of recurrence is variable and unpredictable. In general, when the drug is resumed after recurrence of the arrhythmia, control is established relatively rapidly compared to the initial response, presumably because tissue stores were not wholly depleted at the time of recurrence.<br/>Pharmacodynamics: There is no well-established relationship of plasma concentration to effectiveness, but it does appear that concentrations much below 1 mg/L are often ineffective and that levels above 2.5 mg/L are generally not needed. Within individuals dose reductions and ensuing decreased plasma concentrations can result in loss of arrhythmia control. Plasma-concentration measurements can be used to identify patients whose levels are unusually low, and who might benefit from a dose increase, or unusually high, and who might have dosage reduction in the hope of minimizing side effects. Some observations have suggested a plasma concentration, dose, or dose/duration relationship for side effects such as pulmonary fibrosis, liver-enzyme elevations, corneal deposits and facial pigmentation, peripheral neuropathy, gastrointestinal and central nervous system effects.<br/>Monitoring Effectiveness: Predicting the effectiveness of any antiarrhythmic agent in long-term prevention of recurrent ventricular tachycardia and ventricular fibrillation is difficult and controversial, with highly qualified investigators recommending use of ambulatory monitoring, programmed electrical stimulation with various stimulation regimens, or a combination of these, to assess response. There is no present consensus on many aspects of how best to assess effectiveness, but there is a reasonable consensus on some aspects: Several predictors of success not based on PES have also been suggested, including complete elimination of all nonsustained ventricular tachycardia on ambulatory monitoring and very low premature ventricular-beat rates (less than 1 VPB/1,000 normal beats). While these issues remain unsettled for amiodarone, as for other agents, the prescriber of amiodarone should have access to (direct or through referral), and familiarity with, the full range of evaluatory procedures used in the care of patients with life-threatening arrhythmias. It is difficult to describe the effectiveness rates of amiodarone, as these depend on the specific arrhythmia treated, the success criteria used, the underlying cardiac disease of the patient, the number of drugs tried before resorting to amiodarone, the duration of follow-up, the dose of amiodarone, the use of additional antiarrhythmic agents, and many other factors. As amiodarone has been studied principally in patients with refractory life-threatening ventricular arrhythmias, in whom drug therapy must be selected on the basis of response and cannot be assigned arbitrarily, randomized comparisons with other agents or placebo have not been possible. Reports of series of treated patients with a history of cardiac arrest and mean follow-up of one year or more have given mortality (due to arrhythmia) rates that were highly variable, ranging from less than 5% to over 30%, with most series in the range of 10 to 15%. Overall arrhythmia-recurrence rates (fatal and nonfatal) also were highly variable (and, as noted above, depended on response to PES and other measures), and depend on whether patients who do not seem to respond initially are included. In mostcases, considering only patients who seemed to respond well enough to be placed on long-term treatment, recurrence rates have ranged from 20 to 40% in series with a mean follow-up of a year or more. | lld:dailymed |
| dailymed-drugs:209 | dailymed-instance:clinicalP... | Mechanism of Action: Flunisolide has demonstrated marked anti-inflammatory activity in classical test systems. It is a corticosteroid that is several hundred times more potent than cortisol in animal anti-inflammatory assays, and several hundred times more potent than dexamethasone in anti-inflammatory effect as determined by the McKenzie skin blanching test. The clinical significance of these findings is unknown. Airway inflammation in both large and small airways is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of anti-inflammatory effects, inhibiting both inflammatory cells and release of inflammatory mediators. It is presumed that these anti-inflammatory actions play an important role in the efficacy of flunisolide in controlling symptoms and improving lung function in asthma. Inhaled flunisolide probably acts topically at the site of deposition in the bronchial tree after inhalation.<br/>Pharmacokinetics:: All the data described below is based on studies conducted in subjects 18 to 51 years of age. Absorption: Flunisolide is rapidly absorbed after oral inhalation. Mean values for the time to maximum concentration, T, of flunisolide range from 0.09 to 0.17 hr after a single 320 mcg dose of AEROSPAN Inhalation Aerosol. The corresponding mean values for the maximum concentration, C, of flunisolide vary from 1.9 to 3.3 ng/mL. Oral bioavailability is less than 7%. Over the dose range of 80 mcg to 320 mcg of AEROSPAN Inhalation Aerosol, values for Cincrease proportionately with dose after single as well as multiple dose administration. Distribution: Flunisolide is extensively distributed in the body, with mean values for apparent volume of distribution ranging from 170 to 350 L after a single 320 mcg dose of AEROSPAN Inhalation Aerosol. Metabolism: Flunisolide is rapidly and extensively converted to 6��-OH flunisolide and to water-soluble conjugates during the first pass through the liver. Conversion to 6��-OH flunisolide, the only circulating metabolite detected in man, is thought to occur via the cytochrome P450 enzyme system, particularly the enzyme CYP3A4. 6��-OH flunisolide has a low corticosteroid potency (ten times less potent than cortisol and more than 200 times less potent than flunisolide). Maximum levels of 6��-OH flunisolide were 0.66 mcg/mL after a single 320 mcg dose of AEROSPAN Inhalation Aerosol, and 0.71 mcg/mL after multiple doses of AEROSPAN Inhalation Aerosol. Excretion: Urinary excretion of flunisolide is low. Less than 1% of the administered dose of flunisolide is recovered in urine after inhalation. The half-life values for 6��-OH flunisolide range from 3.1 to 5.1 hrs after administration of AEROSPAN Inhalation Aerosol in the dose range of 160 mcg to 320 mcg. Disposition and Elimination: Twice daily inhalation administration of flunisolide hemihydrate for up to 14 days did not result in appreciable accumulation of flunisolide. Upon multiple dosing with 160 mcg and 320 mcg, the Cvalues were 1.0 ng/mL and 2.1 ng/mL, respectively. The corresponding AUCvalues were 1.2 ng.hr/mL and 2.5 ng.hr/mL. Flunisolide is rapidly cleared from the body, independent of route of administration or dose administered. Flunisolide is not detectable in plasma twelve hours post-dose. After administration of 320 mcg of AEROSPAN Inhalation Aerosol the elimination half-life ranges from 1.3 to 1.7 hours. After a single 320 mcgdose, mean oral clearance values, not adjusted for bioavailability, range from 83 to 167 L/hr. Special Populations: There were no gender differences for flunisolide after single and multiple dose administration of the AEROSPAN Inhalation Aerosol. Formal pharmacokinetic studies using flunisolide were not carried out in any other special populations. Pharmacodynamics: Dose finding for AEROSPAN Inhalation Aerosol was based on comparability of systemic exposure to flunisolide CFC inhalation aerosol. The effect of flunisolide CFC inhalation aerosol and AEROSPAN Inhalation Aerosol on pharmacokinetics and 12-hour plasma cortisol levels was investigated in two studies. In both studies, the Cmax and AUC of flunisolide, 6��-OH flunisolide, and 12-hour plasma cortisol measurements were comparable for 1000 mcg of flunisolide CFC inhalation aerosol and 320 mcg of AEROSPAN Inhalation Aerosol. The first was a parallel arm study in 31 subjects. Pharmacokinetics and plasma cortisol levels were determined after single and multiple doses of flunisolide CFC inhalation aerosol 1000��g and AEROSPAN Inhalation Aerosol 160��g or 320��g administered twice daily for 13.5 days. At steady state, flunisolide mean peak plasma concentrations from flunisolide CFC inhalation aerosol 1000 mcg and AEROSPAN Inhalation Aerosol 320 mcg were found to be 2.6 ng/mL and 3.4 ng/mL, respectively. The corresponding mean AUC values for the 12-hr dosing interval were 5.7 ng.hr/mL and 4.7 ng.hr/mL, respectively. At steady state, the mean peak plasma concentrations of 6��-OH flunisolide from flunisolide CFC inhalation aerosol 1000 mcg and AEROSPAN Inhalation Aerosol 320 mcg were found to be 0.9 ng/mL and 0.3 ng/mL, respectively. The corresponding mean AUC values for the 12-hr dosing interval were 3.8 ng.hr/mL and 1.1 ng.hr/mL, respectively. The second was a crossover study in 11 subjects after single doses of flunisolide CFC inhalation aerosol 1000 mcg or AEROSPAN Inhalation Aerosol 320 mcg. The mean peak plasma concentrations of flunisolide from the flunisolide CFC inhalation aerosol 1000 mcg and AEROSPAN Inhalation Aerosol 320 mcg were found to be 2.5 ng/mL and 3.3 ng/mL, respectively. The corresponding mean AUC values were 5.1 ng.hr/mL and 5.8 ng.hr/mL, respectively. The mean peak plasma concentrations of 6��-OH flunisolide from flunisolide CFC inhalation aerosol 1000 mcg and AEROSPAN Inhalation Aerosol 320��g were found to be 0.8 ng/mL and 0.3 ng/mL, respectively. The corresponding mean AUC values were 3.8 ng.hr/mL and 2.3 ng.hr/mL, respectively. Controlled clinical studies with flunisolide CFC inhalation aerosol included over 500 treated asthma patients, among them 150 children aged 6 years and older. Open label studies of two years or more duration included more than 120 treated patients. No significant adrenal suppression attributed to flunisolide was seen in these studies. The potential effects of AEROSPAN Inhalation Aerosol and flunisolide CFC inhalation aerosol on the hypothalamic-pituitary-adrenal (HPA) axis were studied in 2 placebo- and active-controlled studies and 2 active-controlled, open label, long-term studies . In the placebo-controlled studies, the ability to increase cortisol production in response to stress was assessed by the 60 minute cosyntropin (ACTH) stimulation test. For adult and adolescent patients treated with AEROSPAN Inhalation Aerosol 80 mcg, 160 mcg, 320 mcg, or placebo twice daily for 12 weeks, 92%(22/24), 93% (26/28), 93% (26/28), and 92% (22/24) of patients, normal at baseline, respectively, continued to have a normal stimulated cortisol response (peak cortisol���18 mcg/dL and an increase in plasma cortisol���7 mcg/dL within 60 minutes after cosyntropin injection) at trial's end. All patients had peak cortisol levels���18mcg/dL. There was no significant suppression of 24 hour urinary cortisol, and 100% (96/96) of patients treated with AEROSPAN Inhalation Aerosol had normal morning serum cortisol levels at the end of study. For pediatric patients treated with the AEROSPAN Inhalation Aerosol, 80 mcg and 160 mcg or placebo twice daily for 12 weeks, 91% (31/34), 97% (28/29), and 89% (24/27) of patients, respectively, continued to have a normal stimulated cortisol response (as defined above) at trial's end. No suppression of 24-hour urinary cortisol was noted. In these studies, comparable results were obtained in patients treated with flunisolide CFC inhalation aerosol. In the active-controlled, open label, long-term studies, 99.4% (161/162) of adult and adolescent patients and 98.4% (126/128) pediatric patients treated with AEROSPAN Inhalation Aerosol had normal morning serum cortisol levels (���5 mcg/dL) after 12 or 52 weeks of treatment, respectively. For patients treated with AEROSPAN Inhalation Aerosol, 92.5% (99/107) continued to have a normal stimulated plasma cortisol response to cosyntropin at trial's end with all having peak cortisol levels���18mcg/dL. In these studies, no suppression of 24-hour urinary cortisol was noted, and comparable results were obtained in patients treated with flunisolide CFC inhalation aerosol. | lld:dailymed |
| dailymed-drugs:210 | dailymed-instance:clinicalP... | Mode of Action: Pentoxifylline and its metabolites improve the flow properties of blood by decreasing its viscosity. In patients with chronic peripheral arterial disease, this increases blood flow to the affected microcirculation and enhances tissue oxygenation. The precise mode of action of pentoxifylline and the sequence of events leading to clinical improvement are still to be defined. Pentoxifylline administration has been shown to produce dose related hemorrheologic effects, lowering blood viscosity, and improving erythrocyte flexibility. Leukocyte properties of hemorrheologic importance have been modified in animal and in vitro human studies. Pentoxifylline has been shown to increase leukocyte deformability and to inhibit neutrophil adhesion and activation. Tissue oxygen levels have been shown to be significantly increased by therapeutic doses of pentoxifylline in patients with peripheral arterial disease.<br/>Pharmacokinetics and Metabolism: After oral administration in aqueous solution pentoxifylline is almost completely absorbed. It undergoes a first-pass effect and the various metabolites appear in plasma very soon after dosing. Peak plasma levels of the parent compound and its metabolites are reached within 1 hour. The major metabolites are Metabolite 1 (1-[5-hydroxyhexyl]-3,7-di-methylxanthine) and Metabolite V (1-[3-carboxypropyl]-3,7-dimethylxanthine), and plasma levels of these metabolites are 5 and 8 times greater, respectively, than pentoxifylline. Following oral administration of aqueous solutions containing 100 to 400 mg of pentoxifylline, the pharmacokinetics of the parent compound and Metabolite 1 are dose-related and not proportional (non-linear), with half-life and area under the blood-level time curve (AUC) increasing with dose. The elimination kinetics of Metabolite V are not dose-dependent. The apparent plasma half-life of pentoxifylline varies from 0.4 to 0.8 hours and the apparent plasma half-lives of its metabolites vary from 1 to 1.6 hours. There is no evidence of accumulation or enzyme induction (Cytochrome P450) following multiple oral doses. Excretion is almost totally urinary; the main biotransformation product is Metabolite V. Essentially no parent drug is found in the urine. Despite large variations in plasma levels of parent compound and its metabolites, the urinary recovery of Metabolite V is consistent and shows dose proportionality. Less than 4% of the administered dose is recovered in feces. Food intake shortly before dosing delays absorption of an immediate release dosage form but does not affect total absorption. The pharmacokinetics and metabolism of pentoxifylline have not been studied in patients with renal and/or hepatic dysfunction, but AUC was increased and elimination rate decreased in an older population (60 to 68years) compared to younger individuals (22 to 30 years). After administration of a 400 mg pentoxifylline extended-release tablet, plasma levels of the parent compound and its metabolites reach their maximum within 2 to 4 hours and remain constant over an extended period of time. Coadministration of pentoxifylline extended-release tablets with meals resulted in an increase in mean Cand AUC by about 28% and 13% for pentoxifylline, respectively. Cfor Metabolite 1 also increased by about 20%. The controlled release of pentoxifylline from the tablet eliminates peaks and troughs in plasma levels for improved gastrointestinal tolerance. | lld:dailymed |
| dailymed-drugs:211 | dailymed-instance:clinicalP... | Tenoretic: Atenolol and chlorthalidone have been used singly and concomitantly for the treatment of hypertension. The antihypertensive effects of these agents are additive, and studies have shown that there is no interference with bioavailability when these agents are given together in the single combination tablet. Therefore, this combination provides a convenient formulation for the concomitant administration of these two entities. In patients with more severe hypertension, TENORETIC may be administered with other antihypertensives such as vasodilators.<br/>Atenolol: Atenolol is a beta-selective (cardioselective) beta-adrenergic receptor blocking agent without membrane stabilizing or intrinsic sympathomimetic (partial agonist) activities. This preferential effect is not absolute, however, and at higher doses, atenolol inhibits beta-adrenoreceptors, chiefly located in the bronchial and vascular musculature. | lld:dailymed |
| dailymed-drugs:212 | dailymed-instance:clinicalP... | Carbinoxamine maleate is an antihistamine with anticholinergic (drying) and sedative properties. Antihistamines appear to compete with histamine for receptor sites on effector cells. The pharmacological effects of carbinoxamine maleate after oral absorption have been shown to last approximately 4 hours. Interactions of carbinoxamine maleate with food or with other drugs and the possibility of cardiac conduction effects on the QT interval have not been studied. | lld:dailymed |
| dailymed-drugs:213 | dailymed-instance:clinicalP... | Pharmacokinetics: Following a single bilateral 4-drop (total dose = 0.28 mL, 0.84 mg ciprofloxacin, 0.28 mg dexamethasone) topical otic dose of CIPRODEX' Otic to pediatric patients after tympanostomy tube insertion, measurable plasma concentrations of ciprofloxacin and dexamethasone were observed at 6 hours following administration in 2 of 9 patients and 5 of 9 patients, respectively. Mean��SD peak plasma concentrations of ciprofloxacin were 1.39��0.880 ng/mL (n=9). Peak plasma concentrations ranged from 0.543 ng/mL to 3.45 ng/mL and were on average approximately 0.1% of peak plasma concentrations achieved with an oral dose of 250-mg. Peak plasma concentrations of ciprofloxacin were observed within 15 minutes to 2 hours post dose application. Mean��SD peak plasma concentrations of dexamethasone were 1.14��1.54 ng/mL (n=9). Peak plasma concentrations ranged from 0.135 ng/mL to 5.10 ng/mL and were on average approximately 14% of peak concentrations reported in the literature following an oral 0.5-mg tablet dose. Peak plasma concentrations of dexamethasone were observed within 15 minutes to 2 hours post dose application. Dexamethasone has been added to aid in the resolution of the inflammatory response accompanying bacterial infection (such as otorrhea in pediatric patients with AOM with tympanostomy tubes).<br/>Microbiology: Ciprofloxacin has in vitro activity against a wide range of gram-positive and gram-negative microorganisms. The bactericidal action of ciprofloxacin results from interference with the enzyme, DNA gyrase, which is needed for the synthesis of bacterial DNA. Cross-resistance has been observed between ciprofloxacin and other fluoroquinolones. There is generally no cross-resistance between ciprofloxacin and other classes of antibacterial agents such as beta-lactams or aminoglycosides. Ciprofloxacin has been shown to be active against most isolates of the following microorganisms, both in vitro and clinically in otic infections as described in the INDICATIONS AND USAGE section. Aerobic and facultative gram-positive microorganismsStaphylococcus aureusStreptococcus pneumoniae Aerobic and facultative gram-negative microorganismsHaemophilus influenzaeMoraxella catarrhalisPseudomonas aeruginosa | lld:dailymed |
| dailymed-drugs:214 | dailymed-instance:clinicalP... | Introduction: Wilson's disease (hepatolenticular degeneration) is an autosomal inherited metabolic defect resulting in an inability to maintain a near-zero balance of copper. Excess copper accumulates possibly because the liver lacks the mechanism to excrete free copper into the bile. Hepatocytes store excess copper but when their capacity is exceeded copper is released into the blood and is taken up into extrahepatic sites. This condition is treated with a low copper diet and the use of chelating agents that bind copper to facilitate its excretion from the body.<br/>Clinical Summary: Forty-one patients (18 male and 23 female) between the ages of 6 and 54 with a diagnosis of Wilson's disease and who were intolerant of d-penicillamine were treated in two separate studies with trientine hydrochloride. The dosage varied from 450 to 2400 mg per day. The average dosage required to achieve an optimal clinical response varied between 1000 mg and 2000 mg per day. The mean duration of trientine hydrochloride therapy was 48.7 months (range 2-164 months). Thirty-four of the 41 patients improved, 4 had no change in clinical global response, 2 were lost to follow-up and one showed deterioration in clinical condition. One of the patients who improved while on therapy with trientine hydrochloride experienced a recurrence of the symptoms of systemic lupus erythematosus which had appeared originally during therapy with penicillamine. Therapy with trientine hydrochloride was discontinued. No other adverse reactions, except iron deficiency, were noted among any of these 41 patients. One investigator treated 13 patients with trientine hydrochloride following their development of intolerance to d-penicillamine. Retrospectively, he compared these patients to an additional group of 12 patients with Wilson's disease who were both tolerant of and controlled with d-penicillamine therapy, but who failed to continue any copper chelation therapy. The mean age at onset of disease of the latter group was 12 years as compared to 21 years for the former group. The trientine hydrochloride group received d-penicillamine for an average of 4 years as compared to an average of 10 years for the non-treated group. Various laboratory parameters showed changes in favor of the patients treated with trientine hydrochloride. Free and total serum copper, SGOT, and serum bilirubin all showed mean increases over baseline in the untreated group which were significantly larger than with the patients treated with trientine hydrochloride. In the 13 patients treated with trientine hydrochloride, previous symptoms and signs relating to d-penicillamine intolerance disappeared in 8 patients, improved in 4 patients, and remained unchanged in one patient. The neurological status in the trientine hydrochloride group was unchanged or improved over baseline, whereas in the untreated group, 6 patients remained unchanged and 6 worsened. Kayser-Fleischer rings improved significantly during trientine hydrochloride treatment. The clinical outcome of the two groups also differed markedly. Of the 13 patients on therapy with trientine hydrochloride (mean duration of therapy 4.1 years; range 1 to 13 years), all were alive at the data cutoff date, and in the non-treated group (mean years with no therapy 2.7 years; range 3 months to 9 years), 9 of the 12 died of hepatic disease.<br/>Chelating Properties:<br/>Preclinical Studies: Studies in animals have shown that trientine hydrochloride has cupriuretic activities in both normal and copper-loaded rats. In general, the effects of trientine hydrochloride on urinary copper excretion are similar to those of equimolar doses of penicillamine, although in one study they were significantly smaller.<br/>Human Studies: Renal clearance studies were carried out with penicillamine and trientine hydrochloride on separate occasions in selected patients treated with penicillamine for at least one year. Six-hour excretion rates of copper were determined off treatment and after a single dose of 500 mg of penicillamine or 1.2 g of trientine hydrochloride. The mean urinary excretion rates of copper were as follows: In patients not previously treated with chelating agents, a similar comparison was made: These results demonstrate that SYPRINE is effective as a cupriuretic agent in patients with Wilson's disease although on a molar basis it appears to be less potent or less effective than penicillamine. Evidence from a radio-labelled copper study indicates that the different cupriuretic effect between thesetwo drugs could be due to a difference in selectivity of the drugs for different copper pools within the body.<br/>Pharmacokinetics: Data on the pharmacokinetics of trientine hydrochloride are not available. Dosage adjustment recommendations are based upon clinical use of the drug . | lld:dailymed |
| dailymed-drugs:216 | dailymed-instance:clinicalP... | Lactulose is poorly absorbed from the gastrointestinal tract, and no enzyme capable of hydrolysis of this disaccharide is present in human gastrointestinal tissue. As a result, oral doses of lactulose solution reach the colon virtually unchanged. In the colon, lactulose is broken down primarily to lactic acid, and also to small amounts of formic and acetic acids, by the action of colonic bacteria, which results in an increase in osmotic pressure and slight acidification of the colonic contents. This in turn causes an increase in stool water content and softens the stool. Since lactulose does not exert its effect until it reaches the colon, and since transit time through the colon may be slow, 24 to 48 hours may be required to produce the desired bowel movement. Lactulose solution given orally to man and experimental animals resulted in only small amounts reaching the blood. Urinary excretion has been determined to be 3% or less and is essentially complete within 24 hours. | lld:dailymed |
| dailymed-drugs:217 | dailymed-instance:clinicalP... | Naphazoline constricts the vascular system of the conjunctiva. It is presumed that this effect is due to direct stimulation action of the drug upon the alpha adrenergic receptors in the arterioles of the conjunctiva resulting in decreased conjunctival congestion. Naphalozine belongs to the imidazoline class of sympathomimetics. | lld:dailymed |
| dailymed-drugs:219 | dailymed-instance:clinicalP... | Pharmacokinetics: Multiple dose ribavirin pharmacokinetic data are available for HCV patients who received ribavirin in combination with peginterferon alfa-2a. Following administration of 1200 mg/day with food for 12 weeks mean��SD (n=39; body weight>75 kg) AUCwas 25,361��7110 ng��hr/mL and Cwas 2748��818 ng/mL. The average time to reach Cwas 2 hours. Trough ribavirin plasma concentrations following 12 weeks of dosing with food were 1662��545 ng/mL in HCV infected patients who received 800 mg/day (n=89), and 2112��810 ng/mL in patients who received 1200 mg/day (n=75; body weight>75 kg). The terminal half-life of ribavirin following administration of a single oral dose of ribavirin is about 120 to 170 hours. The total apparent clearance following administration of a single oral dose of ribavirin is about 26 L/h. There is extensive accumulation of ribavirin after multiple dosing (twice daily) such that the Cat steady state was four-fold higher than that of a single dose.<br/>Effect of Food on Absorption of Ribavirin: Bioavailability of a single oral dose of ribavirin was increased by co-administration with a high-fat meal. The absorption was slowed (Twas doubled) and the AUCand Cincreased by 42% and 66%, respectively, when ribavirin was taken with a high-fat meal compared with fasting conditions .<br/>Elimination and Metabolism: The contribution of renal and hepatic pathways to ribavirin elimination after administration of ribavirin is not known. In vitro studies indicate that ribavirin is not a substrate of CYP450 enzymes.<br/>Special Populations:<br/>Race: A pharmacokinetic study in 42 subjects demonstrated there is no clinically significant difference in ribavirin pharmacokinetics among Black (n=14), Hispanic (n=13) and Caucasian (n=15) subjects.<br/>Renal Dysfunction: The pharmacokinetics of ribavirin following administration of ribavirin have not been studied in patients with renal impairment and there are limited data from clinical trials on administration of ribavirin in patients with creatinine clearance<50 mL/min. Therefore, patients with creatinine clearance<50 mL/min should not be treated with ribavirin .<br/>Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of ribavirin following administration of ribavirin has not been evaluated. The clinical trials of ribavirin were restricted to patients with Child-Pugh class A disease.<br/>Pediatric Patients: Pharmacokinetic evaluations in pediatric patients have not been performed.<br/>Elderly Patients: Pharmacokinetic evaluations in elderly patients have not been performed.<br/>Gender: Ribavirin pharmacokinetics, when corrected for weight, are similar in male and female patients.<br/>Drug Interactions: In vitro studies indicate that ribavirin does not inhibit CYP450 enzymes.<br/>Nucleoside Analogues: In vitro data indicate ribavirin reduces phosphorylation of lamivudine, stavudine, and zidovudine. In vitro, didanosine or its active metabolite (dideoxyadenosine 5'���triphosphate) is increased when didanosine is co-administered with ribavirin, which could cause or worsen clinical toxicities .<br/>Drugs Metabolized by Cytochrome P450: There was no effect on the pharmacokinetics of representative drugs metabolized by CYP 2C9, CYP 2C19, CYP 2D6 or CYP 3A4. Treatment with peginterferon alfa-2a once weekly for 4 weeks in healthy subjects was associated with an inhibition of P450 1A2 and a 25% increase in theophylline AUC . | lld:dailymed |
| dailymed-drugs:220 | dailymed-instance:clinicalP... | Pharmacodynamics: Oxaprozin is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic properties in animal models. The mechanism of action of oxaprozin, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition. Pharmacokinetics (see Table 1) Absorption: Oxaprozin is 95% absorbed after oral administration. Food may reduce the rate of absorption of oxaprozin, but the extent of absorption is unchanged. Antacids do not significantly affect the extent and rate of oxaprozin absorption. Distribution: In dose proportionality studies utilizing 600, 1200 and 1800 mg doses, the pharmacokinetics of oxaprozin in healthy subjects demonstrated nonlinear kinetics of both the total and unbound drug in opposite directions, i.e., dose exposure related increase in the clearance of total drug and decrease in the clearance of unbound drug. Decreased clearance of the unbound drug was related predominantly to a decrease in the volume of distribution and not an increase in the half life. This phenomenon is considered to have minimal impact on drug accumulation upon multiple dosing. The apparent volume of distribution (Vd/F) of total oxaprozin is approximately 11-17 L/70 kg. Oxaprozin is 99% bound to plasma proteins, primarily to albumin. At therapeutic drug concentrations, the plasma protein binding of oxaprozin is saturable, resulting in a higher proportion of the free drug as the total drug concentration is increased. With increases in single doses or following repetitive once-daily dosing, the apparent volume of distribution and clearance of total drug increased, while that of unbound drug decreased due to the effects of nonlinear protein binding. Oxaprozin penetrates into synovial tissues of rheumatoid arthritis patients with oxaprozin concentrations 2-fold and 3-fold greater than in plasma and synovial fluid, respectively. Oxaprozin is expected to be excreted in human milk based on its physical-chemical properties, however, the amount of oxaprozin excreted in breast milk has not been evaluated. Metabolism: Several oxaprozin metabolites have been identified in human urine or feces. Oxaprozin is primarily metabolized by the liver, by both microsomal oxidation (65%) and glucuronic acid conjugation (35%). Ester and ether glucuronide are the major conjugated metabolites of oxaprozin. On chronic dosing, metabolites do not accumulate in the plasma of patients with normal renal function. Concentrations of the metabolites in plasma are very low. Oxaprozin's metabolites do not have significant pharmacologic activity. The major ester and ether glucuronide conjugated metabolites have been evaluated along with oxaprozin in receptor binding studies and in vivo animal models and have demonstrated no activity. A small amount (<5%) of active phenolic metabolites are produced, but the contribution to overall activity is limited. Excretion: Approximately 5% of the oxaprozin dose is excreted unchanged in the urine. Sixty-five percent (65%) of the dose is excreted in the urine and 35% in the feces as metabolite. Biliary excretion of unchanged oxaprozin is a minor pathway, and enterohepatic recycling of oxaprozin is insignificant. Upon chronic dosing the accumulation half-life is approximately 22 hours. The elimination half-life is approximately twice the accumulation half-life due to increased binding and decreased clearance at lower concentrations.<br/>Special populations: Pediatric patients: A population pharmacokinetic study indicated no clinically important age dependent changes in the apparent clearance of unbound oxaprozin between adult rheumatoid arthritis patients (N = 40) and juvenile rheumatoid arthritis (JRA) patients (����6 years, N = 44) when adjustments were made for differences in body weight between these patient groups. The extent of protein binding of oxaprozin at various therapeutic total plasma concentrations was also similar between the adult and pediatric patient groups. Pharmacokinetic model-based estimates of daily exposure (AUC0-24) to unbound oxaprozin in JRA patients relative to adult rheumatoid arthritis patients suggest dose to body weight range relationships as shown in Table 2. No pharmacokinetic data are available for pediatric patients under 6 years of age. (see PRECAUTIONS: Pediatric use). Model-based nomogram derived from unbound oxaprozin steady-state drug plasma concentrations of JRA patients weighing 22.1���42.7 kg or���45.0 kg administered oxaprozin 600 mg or 1200 mg QD for 14 days, respectively. Geriatric: As with any NSAID, caution should be exercised in treating the elderly (65 years and older). No dosage adjustment is necessary in the elderly for pharmacokinetics reasons, although many elderly may need a reduced dose due to low body weight or disorders associated with aging. A multiple dose study comparing the pharmacokinetics of oxaprozin (1200 mg QD) in 20 young (21-44 years) adults and 20 elderly (64-83 years) adults, did not show any statistically significant differences between age groups. Race: Pharmacokinetics differences due to race have not been identified. Hepatic insufficiency: Approximately 95% of oxaprozin is metabolized by the liver. However, patients with well compensated cirrhosis do not require reduced doses of oxaprozin as compared to patients with normal hepatic function. Nevertheless, caution should be observed in patients with severe hepatic dysfunction. Cardiac failure: Well-compensated cardiac failure does not affect the plasma protein binding or the pharmacokinetics of oxaprozin. Renal insufficiency: The pharmacokinetics of oxaprozin have been investigated in patients with renal insufficiency. Oxaprozin's renal clearance decreased proportionally with creatinine clearance (CrCl), but since only about 5% of oxaprozin dose is excreted unchanged in the urine, the decrease in total body clearance becomes clinically important only in those subjects with highly decreased CrCl. Oxaprozin is not significantly removed from the blood in patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis (CAPD) due to its high protein binding. Oxaprozin plasma protein binding may decrease in patients with severe renal deficiency. Dosage adjustment may be necessary in patients with renal insufficiency (see Precautions: Renal effects). CLINICAL STUDIES Rheumatoid Arthritis Oxaprozin was evaluated for managing the signs and symptoms of rheumatoid arthritis in placebo and active controlled clinical trials in a total of 646 patients. Oxaprozin was given in single or divided daily doses of 600 to 1800 mg/day and was found to be comparable to 2600 to 3900 mg/day of aspirin. At these doses there was a trend (over all trials) for oxaprozin to be more effective and cause fewer gastrointestinal side effects than aspirin. Oxaprozin was given as a once-a-day dose of 1200 mg in most of the clinical trials, but larger doses (up to 26 mg/kg or 1800 mg/day) were used in selected patients. In some patients, oxaprozin may be better tolerated in divided doses. Due to its long half-life, several days of oxaprozin therapy were needed for the drug to reach its full effect (see DOSAGE AND ADMINISTRATION: Individualization of dosage). Osteoarthritis Oxaprozin was evaluated for the management of the signs and symptoms of osteoarthritis in a total of 616 patients in active controlled clinical trials against aspirin (N=464), piroxicam (N=102), and other NSAIDs. Oxaprozin was given both in variable (600 to 1200 mg/day) and in fixed (1200 mg/day) dosing schedules in either single or divided doses. In these trials, oxaprozin was found to be comparable to 2600 to 3200 mg/day doses of aspirin or 20 mg/day doses of piroxicam. Oxaprozin waseffective both in once-daily and in divided dosing schedules. In controlled clinical trials several days of oxaprozin therapy were needed for the drug to reach its full effects (see DOSAGE AND ADMINISTRATION: Individualization of dosage). | lld:dailymed |
| dailymed-drugs:221 | dailymed-instance:clinicalP... | Endogenous estrogens are largely responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than its metabolites, estrone and estriol, at the receptor level. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 mcg of estradiol daily, depending on the phase of the menstrual cycle. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone and the sulfate conjugated form, estrone sulfate, are the most abundant circulating estrogens in postmenopausal women. Estrogens act through binding to nuclear receptors in estrogen-responsive tissues. To date, two estrogen receptors have been identified. These vary in proportion from tissue to tissue. Circulating estrogens modulate the pituitary secretion of the gonadotropins, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) through a negative feedback mechanism. Estrogens act to reduce the elevated levels of these hormones seen in postmenopausal women. Progestin compounds enhance cellular differentiation and generally oppose the actions of estrogens by decreasing estrogen receptor levels, increasing local metabolism of estrogens to less active metabolites, or inducing gene products that blunt cellular responses to estrogen. Progestins exert their effects in target cells by binding to specific progesterone receptors that interact with progesterone response elements in target genes. Progesterone receptors have been identified in the female reproductive tract, breast, pituitary, hypothalamus, and central nervous system. Progestins produce similar endometrial changes to those of the naturally occurring hormone progesterone. | lld:dailymed |
| dailymed-drugs:222 | dailymed-instance:clinicalP... | OPHTHETIC ophthalmic solution is a rapidly-acting topical anesthetic, with induced anesthesia lasting approximately 10-20 minutes. | lld:dailymed |
| dailymed-drugs:223 | dailymed-instance:clinicalP... | Sucralfate is only minimally absorbed from the gastrointestinal tract. The small amounts of the sulfated disaccharide that are absorbed are excreted primarily in the urine. Although the mechanism of sucralfate's ability to accelerate healing of duodenal ulcers remains to be fully defined, it is known that it exerts its effect through a local, rather than systemic, action. The following observations also appear pertinent: These observations suggest that sucralfate's antiulcer activity is the result of formation of an ulcer-adherent complex that covers the ulcer site and protects it against further attack by acid, pepsin, and bile salts. There are approximately 14 to 16 mEq of acid-neutralizing capacity per 1-g dose of sucralfate. | lld:dailymed |
| dailymed-drugs:225 | dailymed-instance:clinicalP... | Mechanism of Action: Ramipril and ramiprilat inhibit angiotensin-converting enzyme (ACE) in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor substance, angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE results in decreased plasma angiotensin II, which leads to decreased vasopressor activity and to decreased aldosterone secretion. The latter decrease may result in a small increase of serum potassium. In hypertensive patients with normal renal function treated with ALTACE alone for up to 56 weeks, approximately 4% of patients during the trial had an abnormally high serum potassium and an increase from baseline greater than 0.75 mEq/L, and none of the patients had an abnormally low potassium and a decrease from baseline greater than 0.75 mEq/L. In the same study, approximately 2% of patients treated with ALTACE and hydrochlorothiazide for up to 56 weeks had abnormally high potassium values and an increase from baseline of0.75 mEq/L or greater, and approximately 2% had abnormally low values and decreases from baseline of 0.75 mEq/L or greater. Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity. The effect of ramipril on hypertension appears to result at least in part from inhibition of both tissue and circulating ACE activity, thereby reducing angiotensin II formation in tissue and plasma. ACE is identical to kininase, an enzyme that degrades bradykinin. Whether increased levels of bradykinin, a potent vasodepressor peptide, play a role in the therapeutic effects of ALTACE remains to be elucidated. While the mechanism through which ALTACE lowers blood pressure is believed to be primarily suppression of the renin-angiotensin-aldosterone system, ALTACE has an antihypertensive effect even in patients with low-renin hypertension. Although ALTACE was antihypertensive in all races studied, black hypertensive patients (usually a low-renin hypertensive population) had a smaller average response to monotherapy than non-black patients.<br/>Pharmacokinetics and Metabolism: Following oral administration of ALTACE, peak plasma concentrations of ramipril are reached within one hour. The extent of absorption is at least 50���60% and is not significantly influenced by the presence of food in the GI tract, although the rate of absorption is reduced. In a trial in which subjects received ALTACE capsules or the contents of identical capsules dissolved in water, dissolved in apple juice, or suspended in apple sauce, serum ramiprilat levels were essentially unrelated to the use or nonuse of the concomitant liquid or food. Cleavage of the ester group (primarily in the liver) converts ramipril to its active diacid metabolite, ramiprilat. Peak plasma concentrations of ramiprilat are reached 2���4 hours after drug intake. The serum protein binding of ramipril is about 73% and that of ramiprilat about 56%; in vitro, these percentages are independent of concentration over the range of 0.01 to 10��g/ml. Ramipril is almost completely metabolized to ramiprilat, which has about 6 times the ACE inhibitory activity of ramipril, and to the diketopiperazine ester, the diketopiperazine acid, and the glucuronides of ramipril and ramiprilat, all of which are inactive. After oral administration of ramipril, about 60% of the parent drug and its metabolites is eliminated in the urine, and about 40% is found in the feces. Drug recovered in the feces may represent both biliary excretion of metabolites and/or unabsorbed drug, however the proportion of a dose eliminated by the bile has not been determined. Less than 2% of the administered dose is recovered in urine as unchanged ramipril. Blood concentrations of ramipril and ramiprilat increase with increased dose, but are not strictly dose-proportional. The 24-hour AUC for ramiprilat, however, is dose-proportional over the 2.5���20 mg dose range. The absolute bioavailabilities of ramipril and ramiprilat were 28% and 44%, respectively, when 5 mg of oral ramipril was compared with the same dose of ramipril given intravenously. Plasma concentrations of ramiprilat decline in a triphasic manner (initial rapid decline, apparent elimination phase, terminal elimination phase). The initial rapid decline, which represents distribution of the drug into a large peripheral compartment and subsequent binding to both plasma and tissue ACE, has a half-life of 2���4 hours. Because of its potent binding to ACE and slow dissociation from the enzyme, ramiprilat shows two elimination phases. The apparent elimination phase corresponds to the clearance of free ramiprilat and has a half-life of 9���18 hours. The terminal elimination phase has a prolonged half-life (>50 hours) and probably represents the binding/dissociation kinetics of the ramiprilat/ACE complex. It does not contribute to the accumulation of the drug. After multiple daily doses of ramipril 5���10 mg, the half-life of ramiprilat concentrations within the therapeutic range was 13���17 hours. After once-daily dosing, steady-state plasma concentrations of ramiprilat are reached by the fourth dose. Steady-state concentrations of ramiprilat are somewhat higher than those seen after the first dose of ALTACE, especially at low doses (2.5 mg), but the difference is clinically insignificant. In patients with creatinine clearance less than 40 ml/min/1.73m, peak levels of ramiprilat are approximately doubled, and trough levels may be as much as quintupled. In multiple-dose regimens, the total exposure to ramiprilat (AUC) in these patients is 3���4 times as large as it is in patients with normal renal function who receive similar doses. The urinary excretion of ramipril, ramiprilat, and their metabolites is reduced in patients with impaired renal function. Compared to normal subjects, patients with creatinine clearance less than 40 ml/min/1.73mhad higher peak and trough ramiprilat levels and slightly longer times to peak concentrations. In patients with impaired liver function, the metabolism of ramipril to ramiprilat appears to be slowed, possibly because of diminished activity of hepatic esterases, and plasma ramipril levels in these patients are increased about 3-fold. Peak concentrations of ramiprilat in these patients, however, are not different from those seen in subjects with normal hepatic function, and the effect of a given dose on plasma ACE activity does not vary with hepatic function.<br/>Pharmacodynamics: Single doses of ramipril of 2.5���20 mg produce approximately 60���80% inhibition of ACE activity 4 hours after dosing with approximately 40���60% inhibition after 24 hours. Multiple oral doses of ramipril of 2.0 mg or more cause plasma ACE activity to fall by more than 90% 4 hours after dosing, with over 80% inhibition of ACE activity remaining 24 hours after dosing. The more prolonged effect of even small multiple doses presumably reflects saturation of ACE binding sites by ramiprilat and relatively slow release from those sites.<br/>Pharmacodynamics and Clinical Effects:<br/>Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes: The Heart Outcomes Prevention Evaluation study (HOPE study) was a large, multi-center, randomized, placebo controlled, 2x2 factorial design, double-blind study conducted in 9,541 patients (4,645 on ALTACE) who were 55 years or older and considered at high risk of developing a major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that was accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria). Patients were either normotensive or under treatment with other antihypertensive agents. Patients were excluded if they had clinical heart failure or were known to have a low ejection fraction (<0.40). This study was designed to examine the long-term (mean of five years) effects of ALTACE (10 mg orally once a day) on the combined endpoint of myocardial infarction, stroke or death from cardiovascular causes. The HOPE study results showed that ALTACE (10 mg/day) significantly reduced the rate of myocardial infarction, stroke or death from cardiovascular causes (651/4645 vs. 826/4652, relative risk 0.78), as well as the rates of the 3 components of the combined endpoint. This effect was evident after about one year of treatment. Ramipril was effective in different demographic subgroups, (i.e., gender, age), subgroups defined by underlying disease (e.g., cardiovascular disease, hypertension), and subgroups defined by concomitant medication. There were insufficient data to determine whether or not ramipril was equally effective in ethnic subgroups. This study was designed with a prespecified substudy in diabetics with at least one other cardiovascular risk factor. Effects of ramipril on the combined endpoint and its components were similar in diabetics (n=3,577) to those in the overall study population. The benefits of Altace were observed among patients who were taking aspirin or other anti-platelet agents, beta-blockers, and lipid-lowering agents as well as diuretics and calcium channel blockers.<br/>Hypertension: Administration of ALTACE to patients with mild to moderate hypertension results in a reduction of both supine and standing blood pressure to about the same extent with no compensatory tachycardia. Symptomatic postural hypotension is infrequent, although it can occur in patients who are salt- and/or volume-depleted. Use of ALTACE in combination with thiazide diuretics gives a blood pressure lowering effect greater than that seen with either agent alone. In single-dose studies, doses of 5���20 mg of ALTACE lowered blood pressure within 1���2 hours, with peak reductions achieved 3���6 hours after dosing. The antihypertensive effect of a single dose persisted for 24 hours. In longer term (4���12 weeks) controlled studies, once-daily doses of 2.5���10 mg were similar in their effect, lowering supine or standing systolic and diastolic blood pressures 24 hours after dosing by about 6/4 mm Hg more than placebo. In comparisons of peak vs. trough effect, the trough effect represented about 50���60% of the peak response. In a titration study comparing divided (bid) vs. qd treatment, the divided regimen was superior, indicating that for some patients the antihypertensive effect with once-daily dosing is not adequately maintained. In most trials, the antihypertensive effect of ALTACE increased during the first several weeks of repeated measurements. The antihypertensive effect of ALTACE has been shown to continue during long-term therapy for at least 2 years. Abrupt withdrawal of ALTACE has not resulted in a rapid increase in blood pressure. ALTACE has been compared with other ACE inhibitors, beta-blockers, and thiazide diuretics. It was approximately as effective as other ACE inhibitors and as atenolol. In both caucasians and blacks, hydrochlorothiazide (25 or 50 mg) was significantly more effective than ramipril. Except for thiazides, no formal interaction studies of ramipril with other antihypertensive agents have been carried out. Limited experience in controlled and uncontrolled trials combining ramipril with a calcium channel blocker, a loop diuretic, or triple therapy (beta-blocker, vasodilator, and a diuretic) indicate no unusual drug-drug interactions. Other ACE inhibitors have had less than additive effects with beta adrenergic blockers, presumably because both drugs lower blood pressure by inhibiting parts of the renin-angiotensin system. ALTACE was less effective in blacks than in caucasians. The effectiveness of ALTACE was not influenced by age, sex, or weight. In a baseline controlled study of 10 patients with mild essential hypertension, blood pressure reduction was accompanied by a 15% increase in renal blood flow. In healthy volunteers, glomerular filtration rate was unchanged.<br/>Heart Failure Post Myocardial Infarction: ALTACE was studied in the Acute Infarction Ramipril Efficacy (AIRE) trial. This was a multinational (mainly European) 161-center, 2006-patient, double-blind, randomized, parallel-group study comparing ALTACE to placebo in stable patients, 2���9 days after an acute myocardial infarction (MI), who had shown clinical signs of congestive heart failure (CHF) at any time after the MI. Patients in severe (NYHA class IV) heart failure, patients with unstable angina, patients with heart failure of congenital or valvular etiology, and patients with contraindications to ACE inhibitors were all excluded. The majority of patients had received thrombolytic therapy at the time of the index infarction, and the average time between infarction and initiation of treatment was 5 days. Patients randomized to ramipril treatment were given an initial dose of 2.5 mg twice daily. If the initial regimen caused undue hypotension, the dose was reduced to 1.25 mg, but in either event doses were titrated upward (as tolerated) to a target regimen (achieved in 77% of patients randomized to ramipril) of 5 mg twicedaily. Patients were then followed for an average of 15 months (range 6���46). The use of ALTACE was associated with a 27% reduction (p=0.002), in the risk of death from any cause; about 90% of the deaths that occurred were cardiovascular, mainly sudden death. The risks of progression to severe heart failure and of CHF-related hospitalization were also reduced, by 23% (p=0.017) and 26% (p=0.011), respectively. The benefits of ALTACE therapy were seen in both genders, and they werenot affected by the exact timing of the initiation of therapy, but older patients may have had a greater benefit than those under 65. The benefits were seen in patients on, and not on, various concomitant medications; at the time of randomization these included aspirin (about 80% of patients), diuretics (about 60%), organic nitrates (about 55%), beta-blockers (about 20%), calcium channel blockers (about 15%), and digoxin (about 12%). | lld:dailymed |
| dailymed-drugs:227 | dailymed-instance:clinicalP... | General: Immediately after completion of a 15-minute intravenous infusion of Ampicillin and Sulbactam for Injection, peak serum concentrations of ampicillin and sulbactam are attained. Ampicillin serum levels are similar to those produced by the administration of equivalent amounts of ampicillin alone. Peak ampicillin serum levels ranging from 109 to 150 mcg/mL are attained after administration of 2000 mg of ampicillin plus 1000 mg sulbactam and 40 to 71 mcg/mL after administration of 1000 mg ampicillin plus 500 mg sulbactam. The corresponding mean peak serum levels for sulbactam range from 48 to 88 mcg/mL and 21 to 40 mcg/mL, respectively. After an intramuscular injection of 1000 mg ampicillin plus 500 mg sulbactam, peak ampicillin serum levels ranging from 8 to 37mcg/mL and peak sulbactam serum levels ranging from 6 to 24 mcg/mL are attained. The mean serum half-life of both drugs is approximately 1 hour in healthy volunteers. Approximately 75 to 85% of both ampicillin and sulbactam are excreted unchanged in the urine during the first 8 hours after administration of Ampicillin and Sulbactam for Injection to individuals with normal renal function. Somewhat higher and more prolonged serum levels of ampicillin and sulbactam can be achieved with the concurrent administration of probenecid. In patients with impaired renal function the elimination kinetics of ampicillin and sulbactam are similarly affected, hence the ratio of one to the other will remain constant whatever the renal function. The dose of Ampicillin and Sulbactam for Injection in such patients should be administered less frequently in accordance with the usual practice for ampicillin (see DOSAGE AND ADMINISTRATION). Ampicillin has been found to be approximately 28% reversibly bound to human serum protein and sulbactam approximately 38% reversibly bound. The following average levels of ampicillin and sulbactam were measured in the tissues and fluids listed: Penetration of both ampicillin and sulbactam into cerebrospinal fluid in the presence of inflamed meninges has been demonstrated after IV administration of Ampicillin and Sulbactam for Injection. The pharmacokinetics of ampicillin and sulbactam in pediatric patients receiving ampicillin and sulbactam are similar to those observed in adults. Immediately after a 15-minute infusion of 50 to 75 mg ampicillin and sulbactam/kg body weight, peak serum and plasma concentrations of 82 to 446 mcg ampicillin/mL and 44 to 203 mcg sulbactam/mL were obtained. Mean half-life values were approximately 1 hour.<br/>Microbiology: Ampicillin is similar to benzyl penicillin in its bactericidal action against susceptible organisms during the stage of active multiplication. It acts through the inhibition of cell wall mucopeptide biosynthesis. Ampicillin has a broad spectrum of bactericidal activity against many gram-positive and gram-negative aerobic and anaerobic bacteria. (Ampicillin is, however, degraded by beta-lactamases and therefore the spectrum of activity does not normally include organisms which produce these enzymes.) A wide range of beta-lactamases found in microorganisms resistant to penicillins and cephalosporins have been shown in biochemical studies with cell free bacterial systems to be irreversibly inhibited by sulbactam. Although sulbactam alone possesses little useful antibacterial activity except against the Neisseriaciae, whole organism studies have shown that sulbactam restores ampicillin activity against beta-lactamase producing strains. In particular, sulbactam has good inhibitory activity against the clinically important plasmid mediated beta-lactamases most frequently responsible for transferred drug resistance. Sulbactam has no effect on the activity of ampicillin against ampicillin susceptible strains. The presence of sulbactam in the injection formulation effectively extends the antibiotic spectrum of ampicillin to include many bacteria normally resistant to it and to other beta-lactam antibiotics. Thus, ampicillin and sulbactam possesses the properties of a broad-spectrum antibiotic and a beta-lactamase inhibitor. Whilein vitro studies have demonstrated the susceptibility of most strains of the following organisms, clinical efficacy for infections other than those included in the indications section has not been documented.<br/>Gram-Positive Bacteria: Staphylococcus aureus (beta-lactamase and non-beta-lactamase producing), Staphylococcus epidermidis (beta-lactamase and non-beta-lactamase producing), Staphylococcus saprophyticus(beta-lactamase and non-beta-lactamase producing), Streptococcus faecalis(Enterococcus),Streptococcus pneumoniae(formerly D. pneumoniae),Streptococcus pyogenes, Streptococcus viridans.<br/>Gram-Negative Bacteria: Hemophilus influenzae (beta-lactamase and non-beta-lactamase producing), Moraxella (Branhamella) catarrhalis (beta-lactamase and non-beta-lactamase producing), Escherichia coli(beta-lactamase and non-beta-lactamase producing), Klebsiella species (all known strains are beta-lactamase producing), Proteus mirabilis (beta-lactamase and non-beta-lactamase producing), Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Morganella morganii,and Neisseria gonorrhoeae (beta-lactamase and non-beta-lactamase producing).<br/>Anaerobes: Clostridium species, Peptococcus species, Peptostreptococcus species, Bacteroides species, including B.fragilis.<br/>Susceptibility Testing:<br/>Diffusion Technique: For the Kirby-Bauer method of susceptibility testing, a 20 mcg (10 mcg ampicillin + 10 mcg sulbactam) diffusion disk should be used. The method is one outlined in the NCCLS publication M2-A4.With this procedure, a report from the laboratory of "Susceptible" indicates that the infecting organism is likely to respond to ampicillin/sulbactam therapy and a report of "Resistant" indicates that the infecting organism is not likely to respond to therapy. An "Intermediate" susceptibility report suggests that the infecting organism would be susceptible to Ampicillin and Sulbactam for Injection if a higher dosage is used or if the infection is confined to tissues or fluids (e.g., urine) in which high antibiotic levels are attained.<br/>Dilution Techniques: Broth or agar dilution methods may be used to determine the minimal inhibitory concentration (MIC) value for susceptibility of bacterial isolates to ampicillin/sulbactam. The method used is one outlined in the NCCLS publication M7-A2.Tubes should be inoculated to contain 10to 10organisms/mL or plates "spotted" with 10organisms. The recommended dilution method employs a constant ampicillin/sulbactam ratio of 2:1 in all tubes with increasing concentrations of ampicillin. MICs are reported in terms of ampicillin concentration in the presence of sulbactam at a constant 2 parts ampicillin to 1 part sulbactam. | lld:dailymed |
| dailymed-drugs:228 | dailymed-instance:clinicalP... | Central Nervous System: Oxycodone is a semisynthetic pure opioid agonist whose principal therapeutic action is analgesia. Other pharmacological effects of oxycodone include anxiolysis, euphoria and feelings of relaxation. These effects are mediated by receptors (notably��and��) in the central nervous system for endogenous opioid-like compounds such as endorphins and enkephalins. Oxycodone produces respiratory depression through direct activity at respiratory centers in the brain stem and depresses the cough reflex by direct effect on the center of the medulla. Acetaminophen is a non-opiate, non-salicylate analgesic and antipyretic. The site and mechanism for the analgesic effect of acetaminophen has not been determined. The antipyretic effect of acetaminophen is accomplished through the inhibition of endogenous pyrogen action on the hypothalamic heat-regulating centers.<br/>Gastrointestinal Tract and Other Smooth Muscle: Oxycodone reduces motility by increasing smooth muscle tone in the stomach and duodenum. In the small intestine, digestion of food is delayed by decreases in propulsive contractions. Other opioid effects include contraction of biliary tract smooth muscle, spasm of the Sphincter of Oddi, increased ureteral and bladder sphincter tone, and a reduction in uterine tone.<br/>Cardiovascular System: Oxycodone may produce a release of histamine and may be associated with orthostatic hypotension, and other symptoms, such as pruritus, flushing, red eyes, and sweating.<br/>Pharmacokinetics:<br/>Absorption and Distribution: The mean absolute oral bioavailability of oxycodone in cancer patients was reported to be about 87%. Oxycodone has been shown to be 45% bound to human plasma proteins in vitro. The volume of distribution after intravenous administration is 211.9��186.6 L. Absorption of acetaminophen is rapid and almost complete from the GI tract after oral administration. With overdosage, absorption is complete in 4 hours. Acetaminophen is relatively uniformly distributed throughout most body fluids. Binding of the drug to plasma proteins is variable; only 20% to 50% may be bound at the concentrations encountered during acute intoxication.<br/>Metabolism and Elimination: A high portion of oxycodone is N-dealkylated to noroxycodone during first-pass metabolism. Oxymorphone, is formed by the O-demethylation of oxycodone. The metabolism of oxycodone to oxymorphone is catalyzed by CYP2D6. Free and conjugated noroxycodone, free and conjugated oxycodone, and oxymorphone are excreted in human urine following a single oral dose of oxycodone. Approximately 8% to 14% of the dose is excreted as free oxycodone over 24 hours after administration. Followinga single, oral dose of oxycodone, the mean��SD elimination half-life is 3.51��1.43 hours. Acetaminophen is metabolized in the liver via cytochrome P450 microsomal enzyme. About 80���85% of the acetaminophen in the body is conjugated principally with glucuronic acid and to a lesser extent with sulfuric acid and cysteine. After hepatic conjugation, 90 to 100% of the drug is recovered in the urine within the first day. About 4% of acetaminophen is metabolized via cytochrome P450 oxidase to a toxic metabolite which is further detoxified by conjugation with glutathione, present in a fixed amount. It is believed that the toxic metabolite NAPQI (N acetyl-p-benzoquinoneimine, N-acetylimidoquinone) is responsible for liver necrosis. High doses of acetaminophen may deplete the glutathione stores so that inactivation of the toxic metabolite is decreased. At high doses, the capacity of metabolic pathways for conjugation with glucuronic acid and sulfuric acid may be exceeded, resulting in increased metabolism of acetaminophen by alternate pathways. | lld:dailymed |
| dailymed-drugs:229 | dailymed-instance:clinicalP... | 5% Dextrose in Ringer's Injection provides electrolytes and calories and is a source of water for hydration. It is capable of inducing diuresis depending on the clinical condition of the patient. Sodium, the major cation of the extracellular fluid, functions primarily in the control of water distribution, fluid balance, and osmotic pressure of body fluids. Sodium is also associated with chloride and bicarbonate in the regulation of the acid-base equilibrium of body fluid. Potassium, the principal cation of intracellular fluid, participates in carbohydrate utilization and protein synthesis, and is critical in the regulation of nerve conduction and muscle contraction, particularly in the heart. Chloride, the major extracellular anion, closely follows the metabolism of sodium, and changes in the acid-base balance of the body are reflected by changes in the chloride concentration. Calcium, an important cation, provides the framework of bones and teeth in the form of calcium phosphate and calcium carbonate. In the ionized form, calcium is essential for the functional mechanism of the clotting of blood, normal cardiac function, and regulation of neuromuscular irritability. Dextrose provides a source of calories. Dextrose is readily metabolized, may decrease losses of body protein and nitrogen, promotes glycogen deposition and decreases or prevents ketosis if sufficient doses are provided. | lld:dailymed |
| dailymed-drugs:230 | dailymed-instance:clinicalP... | The systemic sulfonamides are bacteriostatic agents having a similar spectrum of activity. Sulfonamides competitively inhibit bacterial synthesis of folic acid (pteroylglutamic acid) from aminobenzoic acid. Resistant strains are capable of utilizing folic acid precursors or preformed folic acid. Sulfonamides exist in the blood in 3 forms - free, conjugated (acetylated and possibly others), and protein bound. The free form is considered to be the therapeutically active one. Sulfadiazine given orally is readily absorbed from the gastrointestinal tract. After a single 2 g oral dose, a peak of 6.04 mg/100 mL is reached in 4 hours; of this, 4.65 mg/100 mL is free drug. When a dose of 100 mg/kg of body weight is given initially and followed by 50 mg/kg every 6 hours, blood levels of free sulfadiazine are about 7 mg/100mL. Protein binding is 38 to 48%. Sulfadiazine diffuses into the cerebrospinal fluid; free drug reaches 32 to 65% of blood levels and total drug 40 to 60%. Sulfadiazine is excreted largely in the urine, where concentrations are 10 to 25 times greater than serum levels. Approximately 10% of a single oral dose is excreted in the first 6 hours, 50% within 24 hours, and 60 to 85% in 48 to 72 hours. Of the amount excreted in the urine, 15% to 40% is in the acetyl form. | lld:dailymed |
| dailymed-drugs:232 | dailymed-instance:clinicalP... | When administered intravenously as a vehicle for drugs, sterile water for injection provides a source of water for parenteral fluid replenishment after sufficient solute is introduced to achieve an osmolarity of 112 mOsmol or more per liter. Water is an essential constituent of all body tissues and accounts for approximately 70% of total body weight. Average normal adult daily requirement ranges from two to three liters (1.0 to 1.5 liters each for insensible water loss by perspiration and urine production). Water balance is maintained by various regulatory mechanisms. Water distribution depends primarily on the concentration of electrolytes in the body compartments and sodium (Na) plays a major role in maintaining physiologic equilibrium. | lld:dailymed |
| dailymed-drugs:1940 | dailymed-instance:clinicalP... | When administered intravenously as a vehicle for drugs, sterile water for injection provides a source of water for parenteral fluid replenishment after sufficient solute is introduced to achieve an osmolarity of 112 mOsmol or more per liter. Water is an essential constituent of all body tissues and accounts for approximately 70% of total body weight. Average normal adult daily requirement ranges from two to three liters (1.0 to 1.5 liters each for insensible water loss by perspiration and urine production). Water balance is maintained by various regulatory mechanisms. Water distribution depends primarily on the concentration of electrolytes in the body compartments and sodium (Na) plays a major role in maintaining physiologic equilibrium. | lld:dailymed |
| dailymed-drugs:233 | dailymed-instance:clinicalP... | Following administration of 100 mg twice daily for three consecutive days, plasma levels of mebendazole and its primary metabolite, the 2-amine, do not exceed 0.03��g/mL and 0.09��g/mL, respectively. All metabolites are devoid of anthelmintic activity. In man, approximately 2% of administered mebendazole is excreted in urine and the remainder in the feces as unchanged drug or a primary metabolite.<br/>Mode of Action: Mebendazole inhibits the formation of the worms' microtubules and causes the worms' glucose depletion. | lld:dailymed |
| dailymed-drugs:234 | dailymed-instance:clinicalP... | Electrophysiology/Mechanisms of Action: In animals, amiodarone hydrochloride is effective in the prevention or suppression of experimentally induced arrhythmias. The antiarrhythmic effect of amiodarone may be due to at least two major properties: 1) a prolongation of the myocardial cell-action potential duration and refractory period and 2) noncompetitive��- and��-adrenergic inhibition. Amiodarone prolongs the duration of the action potential of all cardiac fibers while causing minimal reduction of dV/dt (maximal upstroke velocity of the action potential). The refractory period is prolonged in all cardiac tissues. Amiodarone increases the cardiac refractory period without influencing resting membrane potential, except in automatic cells where the slope of the prepotential is reduced, generally reducing automaticity. These electrophysiologic effects are reflected in a decreased sinus rate of 15% to 20%, increased PR and QT intervals of about 10%, the development of U-waves, and changes in T-wave contour. These changes should not require discontinuation of amiodarone as they are evidence of its pharmacological action, although amiodarone can cause marked sinus bradycardia or sinus arrest and heart block. On rare occasions, QT prolongation has been associated with worsening of arrhythmia .<br/>Hemodynamics: In animal studies and after intravenous administration in man, amiodarone relaxes vascular smooth muscle, reduces peripheral vascular resistance (afterload) and slightly increases cardiac index. After oral dosing, however, amiodarone produces no significant change in left ventricular ejection fraction (LVEF), even in patients withdepressed LVEF. After acute intravenous dosing in man, amiodarone may have a mild negative inotropic effect.<br/>Pharmacokinetics: Following oral administration in man, amiodarone is slowly and variably absorbed. The bioavailability of amiodarone is approximately 50%, but has varied between 35% and 65% in various studies. Maximum plasma concentrations are attained 3 to 7 hours after a single dose. Despite this, the onset of action may occur in 2 to 3 days, but more commonly takes 1 to 3 weeks, even with loading doses. Plasma concentrations with chronic dosing at 100 mg/day to 600 mg/day are approximately dose proportional, with a mean 0.5 mg/L increase for each 100 mg/day. These means, however, include considerable individual variability. Food increases the rate and extent of absorption of amiodarone. The effects of food upon the bioavailability of amiodarone have been studied in 30 healthy subjects who received a single 600-mg dose immediately after consuming a high-fat meal and following an overnight fast. The area under the plasma concentration-time curve (AUC) and the peak plasma concentration (C) of amiodarone increased by 2.3 (range 1.7 to 3.6) and 3.8 (range 2.7 to 4.4) times, respectively, in the presence of food. Food also increased the rate of absorption of amiodarone, decreasing the time to peak plasma concentration (T) by 37%. The mean AUC and mean Cof desethylamiodarone increased by 55% (range 58% to 101%) and 32% (range 4% to 84%), respectively, but there was no change in the Tin the presence of food. Amiodarone has a very large but variable volume of distribution, averaging about 60 L/kg, because of extensive accumulation in various sites, especially adipose tissue and highly perfused organs, such as the liver, lung, and spleen. One major metabolite of amiodarone, desethylamiodarone (DEA), has been identified in man; it accumulates to an even greater extent in almost all tissues. No data are available on the activity of DEA in humans, but in animals, it has significant electrophysiologic and antiarrhythmic effects generally similar to amiodarone itself. DEA's precise role and contribution tothe antiarrhythmic activity of oral amiodarone are not certain. The development of maximal ventricular Class lll effects after oral amiodarone administration in humans correlates more closely with DEA accumulation over time than with amiodarone accumulation. Amiodarone is metabolized to desethylamiodarone by the cytochrome P450 (CYP450) enzyme group, specifically cytochrome P450 3A4 (CYP3A4) and CYP2C8. The CYP3A4 isoenzyme is present in both the liver and intestines. Amiodarone is eliminated primarily by hepatic metabolism and biliary excretion and there is negligible excretion of amiodarone or DEA in urine. Neither amiodarone nor DEA is dialyzable. In clinical studies of 2 to 7 days, clearance of amiodarone after intravenous administration in patients with VT and VF ranged between 220 mL/hr/kg and 440 mL/hr/kg. Age, sex, renal disease and hepatic disease (cirrhosis) do not have marked effects on the disposition of amiodarone or DEA. Renal impairment does not influence the pharmacokinetics of amiodarone. After a single dose of intravenous amiodarone in cirrhotic patients, significantly lower Cand average concentration values are seen for DEA, but mean amiodarone levels are unchanged. Normal subjects over 65 years of age show lower clearances (about 100 mL/hr/kg) than younger subjects (about 150 mL/hr/kg) and an increase in tfrom about 20 to 47 days. In patients with severe left ventricular dysfunction, the pharmacokinetics of amiodarone are not significantly altered but the terminal disposition tof DEA is prolonged. Although no dosage adjustment for patients with renal, hepatic or cardiac abnormalities has been defined during chronic treatment with amiodarone, close clinical monitoring is prudent for elderly patients and those with severe left ventricular dysfunction. Following single dose administration in 12 healthy subjects, amiodarone exhibited multi-compartmental pharmacokinetics with a mean apparent plasma terminal elimination half-life of 58 days (range 15 to 142 days) for amiodarone and 36 days (range 14 to 75 days) for the active metabolite (DEA). In patients, following discontinuation of chronic oral therapy, amiodarone has been shown to have a biphasic elimination with an initial one-half reduction of plasma levels after 2.5 to 10 days. A much slower terminal plasma-elimination phase shows a half-life of the parent compound ranging from 26 to 107 days, with a mean of approximately 53 days and most patients in the 40- to 55-day range. In the absence of a loading-dose period, steady-state plasma concentrations, at constant oral dosing, would therefore be reached between 130 and 535 days, with an average of 265 days. For the metabolite, the mean plasma-elimination half-life was approximately 61 days. These data probably reflect an initial elimination of drug from well-perfused tissue (the 2.5- to 10-day half-life phase), followed by a terminal phase representing extremely slow elimination from poorly perfused tissue compartments such as fat. The considerable intersubject variation in both phases of elimination, as well as uncertainty as to what compartment is critical to drug effect, requires attention to individual responses once arrhythmia control is achieved with loading doses because the correct maintenance dose is determined, in part, by the elimination rates. Daily maintenance doses of amiodarone should be based on individual patient requirements . Amiodarone and its metabolite have a limited transplacental transfer of approximately 10% to 50%. The parent drug and its metabolite have been detected in breast milk. Amiodarone is highly protein-bound (approximately 96%). Although electrophysiologic effects, such as prolongation of QTc, can be seen within hours after a parenteral dose of amiodarone hydrochloride, effects on abnormal rhythms are not seen before 2 to 3 days and usually require 1 to 3 weeks, even when a loading dose is used. There may be a continued increase in effect for longer periods still. There is evidence that the time to effect is shorter when a loading-dose regimen is used. Consistent with the slow rate of elimination, antiarrhythmic effects persist for weeks or months after amiodarone hydrochloride is discontinued, but the time of recurrence is variable and unpredictable. In general, when the drug is resumed after recurrence of the arrhythmia, control is established relatively rapidly compared to the initial response, presumably because tissue stores were not wholly depleted at the time of recurrence.<br/>Pharmacodynamics: There is no well-established relationship of plasma concentration to effectiveness, but it does appear that concentrations much below 1 mg/L are often ineffective and that levels above 2.5 mg/L are generally not needed. Within individuals dose reductions and ensuing decreased plasma concentrations can result in loss of arrhythmia control. Plasma-concentration measurements can be used to identify patients whose levels are unusually low, and who might benefit from a dose increase, or unusually high and who might have dosage reduction in the hope of minimizing side effects. Some observations have suggested a plasma concentration, dose or dose/duration relationship for side effects such as pulmonary fibrosis, liver-enzyme elevations, corneal deposits and facial pigmentation, peripheral neuropathy, gastrointestinal and central nervous system effects.<br/>Monitoring Effectiveness: Predicting the effectiveness of any antiarrhythmic agent in long-term prevention of recurrent ventricular tachycardia and ventricular fibrillation is difficult and controversial, with highly qualified investigators recommending use of ambulatory monitoring, programmed electrical stimulation with various stimulation regimens or a combination of these, to assess response. There is no present consensus on many aspects of how best to assess effectiveness, but there is a reasonable consensus on some aspects: Several predictors of success not based on PES have also been suggested, including complete elimination of all nonsustained ventricular tachycardia on ambulatory monitoring and very low premature ventricular-beat rates (less than 1 VPB/1,000 normal beats). While these issues remain unsettled for amiodarone, as for other agents, the prescriber of amiodarone should have access to (direct or through referral) and familiarity with, the full range of evaluatory procedures used in the care of patients with life-threatening arrhythmias. It is difficult to describe the effectiveness rates of amiodarone, as these depend on the specific arrhythmia treated, the success criteria used, the underlying cardiac disease of the patient, the number of drugs tried before resorting to amiodarone hydrochloride, the duration of follow-up, the dose of amiodarone hydrochloride, the use of additional antiarrhythmic agents, and many other factors. As amiodarone has been studied principally in patients with refractory life-threatening ventricular arrhythmias, in whom drug therapy must be selected on the basis of response and cannot be assigned arbitrarily, randomized comparisons with other agents or placebo have not been possible. Reports of series of treated patients with a history of cardiac arrest and mean follow-up of one year or more have given mortality (due to arrhythmia) rates that were highly variable, ranging fromless than 5% to over 30%, with most series in the range of 10% to 15%. Overall arrhythmia-recurrence rates (fatal and nonfatal) also were highly variable (and, as noted above, depended on response to PES and other measures) and depend on whether patients who do not seem to respond initially are included. In most cases, considering only patients who seemed to respond well enough to be placed on long-term treatment, recurrence rates have ranged from 20% to 40% in series with a mean follow-up of a year or more. | lld:dailymed |
| dailymed-drugs:235 | dailymed-instance:clinicalP... | Mechanism of action: Cyclosporine is an immunosuppressive agent when administered systemically. In patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca, cyclosporine emulsion is thought to act as a partial immunomodulator. The exact mechanism of action is not known.<br/>Pharmacokinetics: Blood cyclosporin A concentrations were measured using a specific high pressure liquid chromatography-mass spectrometry assay. Blood concentrations of cyclosporine, in all the samples collected, after topical administration of RESTASIS 0.05%, BID, in humans for up to 12 months, were below the quantitation limit of 0.1 ng/mL. There was no detectable drug accumulation in blood during 12 months of treatment with RESTASIS ophthalmic emulsion.<br/>Clinical Evaluations: Four multicenter, randomized, adequate and well-controlled clinical studies were performed in approximately 1200 patients with moderate to severe keratoconjunctivitis sicca. RESTASIS demonstrated statistically significant increases in Schirmer wetting of 10 mm versus vehicle at six months in patients whose tear production was presumed to be suppressed due to ocular inflammation. This effect was seen in approximately 15% of RESTASIS ophthalmic emulsion treated patients versus approximately 5% of vehicle treated patients. Increased tear production was not seen in patients currently taking topical anti-inflammatory drugs or using punctal plugs. No increase in bacterial or fungal ocular infections was reported following administration of RESTASIS. | lld:dailymed |
| dailymed-drugs:237 | dailymed-instance:clinicalP... | Estrogen drug products act by regulating the transcription of a limited number of genes. Estrogens diffuse throughout cell membranes, distribute themselves throughout the cell, and bind to and activate the nuclear estrogen receptor, a DNA-binding protein which is found in estrogen-responsive tissues. The activated estrogen receptor binds to specific DNA sequences, or hormone-response elements, which enhance the transcription of adjacent genes and in turn lead to the observed effects. Estrogen receptors have been identified in tissues of the reproductive tract, breast, pituitary, hypothalamus, liver, and bone of women. Estrogens are important in the development and maintenance of the female reproductive system and secondary sex characteristics. By a direct action, they cause growth and development of the uterus, fallopian tubes, and vagina. With other hormones, such as pituitary hormones and progesterone, they cause enlargement of the breasts through promotion of ductal growth, stromal development, and the accretion of fat. Estrogens are intricately involved with other hormones, especially progesterone, in the processes of the ovulatory menstrual cycle and pregnancy, and affect the release of pituitary gonadotropins. They also contribute to the shaping of the skeleton, maintenance of tone and elasticity of urogenital structures, changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its termination, and pigmentation of the nipples and genitals. Estrogens occur naturally in several forms. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. This is converted primarily to estrone, which circulates in roughly equal proportion to estradiol, and to small amounts of estriol. Aftermenopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone - especially in its sulfate ester form - is the most abundant circulating estrogen in postmenopausal women. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than estrone or estriol at the receptor. Estrogens used in therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. When applied for a local action, absorption is usually sufficient to cause systemic effects. When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks. Administered estrogens and their esters are handled within the body essentially the same as the endogenous hormones. Metabolic conversion of the estrogens occurs primarily in the liver (first pass effect), but also at local target tissue sites. Complex metabolic processes result in a dynamic equilibrium of circulating conjugated and unconjugated estrogenic forms which are continually interconverted, especially between estrone and estradiol and between esterified and unesterified forms. Although naturally-occurring estrogens circulate in the blood largely bound to sex hormone-binding globulin and albumin, only unbound estrogens enter target tissue cells. A significant proportion of the circulating estrogen exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogenic species. A certain proportion of the estrogen is excreted into the bile and then reabsorbed from the intestine. During this enterohepatic recirculation, estrogens aredesulfated and resulfated and undergo degradation through conversion to less active estrogens (estriol and other estrogens), oxidation to nonestrogenic substances (catecholestrogens, which interact with catecholamine metabolism, especially in the central nervous system), and conjugation with glucuronic acids (which are then rapidly excreted in the urine). When given orally, naturally-occurring estrogens and their esters are extensively metabolized (first pass effect) and circulate primarily as estrone sulfate, with smaller amounts of other conjugated and unconjugated estrogenic species. This results in limited oral potency. By contrast synthetic estrogens such as ethinyl estradiol and the nonsteroidal estrogens, are degraded very slowly in the liver and other tissues, which results in their high intrinsic potency. Estrogen drug products administered by non-oral routes are not subject to first-pass metabolism, but also undergo significant hepatic uptake, metabolism, and enterohepatic recycling. | lld:dailymed |
| dailymed-drugs:238 | dailymed-instance:clinicalP... | When administered intravenously, this solution provides a source of water and carbohydrate. Solutions containing carbohydrate in the form of dextrose restore blood glucose levels and provide calories. Carbohydrate in the form of dextrose may aid in minimizing liver glycogen depletion and exerts a protein-sparing action. Dextrose injected parenterally undergoes oxidation to carbon dioxide and water. Water is an essential constituent of all body tissues and accounts for approximately 70% of total body weight. Average normal adult daily requirements range from two to three liters (1.0 to 1.5 liters each for insensible water loss by perspiration and urine production). Water balance is maintained by various regulatory mechanisms. Water distribution depends primarily on the concentration of electrolytes in the body compartments and sodium (Na) plays a major role in maintaining physiologic equilibrium. | lld:dailymed |
| dailymed-drugs:239 | dailymed-instance:clinicalP... | Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their potent anti-inflammatory effects in disorders of many organ systems. Glucocorticoids cause profound and varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli. | lld:dailymed |
| dailymed-drugs:240 | dailymed-instance:clinicalP... | Labetalol combines both selective, competitive alpha-adrenergic blocking and nonselective, competitive beta-adrenergic blocking activity in a single substance. In man, the ratios of alpha- to beta-blockade have been estimated to be approximately 1:3 and 1:7 following oral and intravenous administration, respectively. Beta-agonist activity has been demonstrated in animals with minimal beta-agonist (ISA) activity detected. In animals, at doses greater than those required for alpha- or beta-adrenergic blockade, a membrane-stabilizing effect has been demonstrated.<br/>Pharmacodynamics: The capacity of labetalol to block alpha receptors in man has been demonstrated by attenuation of the pressor effect of phenylephrine and by a significant reduction of the pressor response caused by immersing the hand in ice-cold water (���cold pressor test���). Labetalol's beta-receptor blockade in man was demonstrated by a small decrease in the resting heart rate, attenuation of tachycardia produced by isoproterenol or exercise, and by attenuation of the reflex tachycardia to the hypotension produced by amyl nitrite. Beta-receptor blockade was demonstrated by inhibition of the isoproterenol-induced fall in diastolic blood pressure. Both the alpha- and beta-blocking actions of orally administered labetalol HCl contribute to a decrease in blood pressure in hypertensive patients. Labetalol consistently, in dose-related fashion, blunted increases in exercise-induced blood pressure and heart rate, and in their double product. The pulmonary circulation during exercise was not affected by labetalol HCl dosing. Single oral doses of labetalol HCl administered in patients with coronary artery disease had no significant effect on sinus rate, intraventricular conduction, or QRS duration. The AV conduction time was modestly prolonged in 2 of 7 patients. In another study, intravenous labetalol slightly prolonged AV nodal conduction time and atrial effective refractory period with only small changes in heart rate. The effects on AV nodal refractoriness were inconsistent. Labetalol produces dose-related falls in blood pressure without reflex tachycardia and without significant reduction in heart rate, presumably through a mixture of its alpha-blocking and beta-blocking effects. Hemodynamic effects are variable with small nonsignificant changes in cardiac output seen in some studies but not others, and small decreases in total peripheral resistance. Elevated plasma renins are reduced. Doses of Labetalol HCl that controlled hypertension did not affect renal function in mild to severe hypertensive patients with normal renal function. Due to the alpha-receptor blocking activity of labetalol, blood pressure is lowered more in the standing than in the supine position, and symptoms of postural hypotension (2%), including rare instances of syncope, can occur. Following oral administration, when postural hypotension has occurred, it has been transient and is uncommon when the recommended starting dose and titration increments are closely followed . Symptomatic postural hypotension is most likely to occur 2 to 4 hours after a dose, especially following the use of large initial doses or upon large changes in dose. The peak effects of single oral doses of labetalol HCl occur within 2 to 4 hours. The duration of effect depends upon dose, lasting at least 8 hours following single oral doses of 100 mg and more than 12 hours following single oral doses of 300 mg. The maximum, steady-state blood pressure response upon oral, twice-a-day dosing occurs within 24 to 72 hours. The antihypertensive effect of labetalol has a linear correlation with the logarithm of labetalol plasma concentration, and there is also a linear correlation between the reduction in exercise-induced tachycardia occurring at 2 hours after oral administration of labetalol HCl and the logarithm of the plasma concentration. About 70% of the maximum beta-blocking effect is present for 5 hours after the administration of a single oral dose of 400 mg, with suggestion that about 40% remains at 8 hours. The anti-anginal efficacy of labetalol has not been studied. In 37 patients with hypertension and coronary artery disease, labetalol did not increase the incidence or severity of angina attacks. Exacerbation of angina and, in some cases, myocardial infarction and ventricular dysrhythmias have been reported after abrupt discontinuation of therapy with beta-adrenergic blocking agents in patients with coronary artery disease. Abrupt withdrawal of these agents in patients without coronary artery disease has resulted in transient symptoms, including tremulousness, sweating, palpitation, headache, and malaise. Several mechanisms have been proposed to explain these phenomena, among them increased sensitivity to catecholamines because of increased numbers of beta receptors. Although beta-adrenergic receptor blockade is useful in the treatment of angina and hypertension, there are also situations in which sympathetic stimulation is vital. For example, in patients with severely damaged hearts, adequate ventricular function may depend on sympathetic drive. Beta-adrenergic blockade may worsen AV block by preventing the necessary facilitating effects of sympathetic activity on conduction. Beta-adrenergic blockade results in passive bronchial constriction by interfering with endogenous adrenergic bronchodilator activity in patients subject to bronchospasm and may also interfere with exogenous bronchodilators in such patients.<br/>Pharmacokinetics and Metabolism: Labetalol is completely absorbed from the gastrointestinal tract with peak plasma levels occurring 1 to 2 hours after oral administration. The relative bioavailability of labetalol HCl tablets compared to an oral solution is 100%. The absolute bioavailability (fraction of drug reaching systemic circulation) of labetalol when compared to an intravenous infusion is 25%; this is due to extensive���first-pass���metabolism. Despite���first-pass���metabolism there is a linear relationship between oral doses of 100 to 3000 mg and peak plasma levels. The absolute bioavailability of labetalol is increased when administered with food. The plasma half-life of labetalol following oral administration is about 6 to 8 hours. Steady-state plasma levels of labetalol during repetitive dosing are reached by about the third day of dosing. In patients with decreased hepatic or renal function, the elimination half-life of labetalol is not altered; however, the relative bioavailability in hepatically impaired patients is increased due to decreased���firstpass���metabolism. The metabolism of labetalol is mainly through conjugation to glucuronide metabolites. These metabolites are present in plasma and are excreted in the urine and, via the bile, into the feces. Approximately 55% to 60% of a dose appears in the urine as conjugates or unchanged labetalol within the first 24 hours of dosing. Labetalol has been shown to cross the placental barrier in humans. Only negligible amounts of the drug crossed the blood-brain barrier in animal studies. Labetalol is approximately 50% protein bound. Neither hemodialysis nor peritoneal dialysis removes a significant amount of labetalol from the general circulation (<1%). | lld:dailymed |
| dailymed-drugs:241 | dailymed-instance:clinicalP... | Mechanism of Action: Dihydroergotamine binds with high affinity to 5-HTand 5-HTreceptors. It also binds with high affinity to serotonin 5-HT, 5-HT, and 5-HTreceptors, noradrenaline��,��and��receptors, and dopamine Dand Dreceptors. The therapeutic activity of dihydroergotamine in migraine is generally attributed to the agonist effect at 5-HTreceptors. Two current theories have been proposed to explain the efficacy of 5-HTreceptor agonists in migraine. One theory suggests that activation of 5-HTreceptors located on intracranial blood vessels, including those on arterio-venous anastomoses, leads to vasoconstriction, which correlates with the relief of migraine headache. The alternative hypothesis suggests that activation of 5-HTreceptors on sensory nerve endings of the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release. In addition, dihydroergotamine possesses oxytocic properties.<br/>Pharmacokinetics:<br/>Absorption: Absolute bioavailability for the subcutaneous and intramuscular route have not been determined, however, no difference was observed in dihydroergotamine bioavailability from intramuscular and subcutaneous doses. Dihydroergotamine mesylate is poorly bioavailable following oral administration.<br/>Distribution: Dihydroergotamine mesylate is 93% plasma protein bound. The apparent steady-state volume of distribution is approximately 800 liters.<br/>Metabolism: Four dihydroergotamine mesylate metabolites have been identified in human plasma following oral administration. The major metabolite, 8'-��-hydroxydihydroergotamine, exhibits affinity equivalent to its parent for adrenergic and 5-HT receptors and demonstrates equivalent potency in several venoconstrictor activity models, in vivo and in vitro. The other metabolites, i.e., dihydrolysergic acid, dihydrolysergic amide, and a metabolite formed by oxidative opening of the proline ring are of minor importance. Following nasal administration, total metabolites represent only 20%-30% of plasma AUC. Quantitative pharmacokinetic characterization of the four metabolites has not been performed.<br/>Excretion: The major excretory route of dihydroergotamine is via the bile in the feces. The total body clearance is 1.5 L/min which reflects mainly hepatic clearance. Only 6%-7% of unchanged dihydroergotamine is excreted in the urine after intramuscular injection. The renal clearance (0.1 L/min) is unaffected by the route of dihydroergotamine administration. The decline of plasma dihydroergotamine after intramuscular or intravenous administration is multi-exponential with a terminal half-life of about 9 hours.<br/>Subpopulations: No studies have been conducted on the effect of renal or hepatic impairment, gender, race, or ethnicity on dihydroergotamine pharmacokinetics. Dihydroergotamine Mesylate Injection, USP is contraindicated in patients with severely impaired hepatic or renal function.<br/>Interactions: Pharmacokinetic interactions have been reported in patients treated orally with other ergot alkaloids (e.g., increased levels of ergotamine) and macrolide antibiotics, principally troleandomycin, presumably due to inhibition of cytochrome P450 3A metabolism of the alkaloids by troleandomycin. Dihydroergotamine has also been shown to be an inhibitor of cytochrome P450 3A catalyzed reactions and rare reports of ergotism have been obtained from patients treated with dihydroergotamine and macrolide antibiotics (e.g., troleandomycin, clarithromycin, erythromycin), and in patients treated with dihydroergotamine and protease inhibitors (e.g. ritonavir), presumably due to inhibition of cytochrome P450 3A metabolism of ergotamine . No pharmacokinetic interactions involving other cytochrome P450 isoenzymes are known. | lld:dailymed |
| dailymed-drugs:242 | dailymed-instance:clinicalP... | Pharmacokinetics:<br/>Elderly:<br/>Hepatic Impairment:<br/>Clinical Studies:<br/>Surveillance Program: | lld:dailymed |
| dailymed-drugs:243 | dailymed-instance:clinicalP... | Mechanism of Action: Many breast cancers have estrogen receptors and growth of these tumors can be stimulated by estrogen. In postmenopausal women, the principal source of circulating estrogen (primarily estradiol) is conversion of adrenally-generated androstenedione to estrone by aromatase in peripheral tissues, such as adipose tissue, with further conversion of estrone to estradiol. Many breast cancers also contain aromatase; the importance of tumor-generated estrogens is uncertain. Treatment of breast cancer has included efforts to decrease estrogen levels, by ovariectomy premenopausally and by use of anti-estrogens and progestational agents both pre- and post-menopausally; and these interventions lead to decreased tumor mass or delayed progression of tumor growth in some women. Anastrozole is a potent and selective non-steroidal aromatase inhibitor. It significantly lowers serum estradiol concentrations and has no detectable effect on formation of adrenal corticosteroids or aldosterone.<br/>Pharmacokinetics: Inhibition of aromatase activity is primarily due to anastrozole, the parent drug. Studies with radiolabeled drug have demonstrated that orally administered anastrozole is well absorbed into the systemic circulation with 83 to 85% of the radiolabel recovered in urine and feces. Food does not affect the extent of absorption. Elimination of anastrozole is primarily via hepatic metabolism (approximately 85%) and to a lesser extent, renal excretion (approximately 11%), and anastrozole has a mean terminal elimination half-life of approximately 50 hours in postmenopausal women. The major circulating metabolite of anastrozole, triazole, lacks pharmacologic activity. The pharmacokinetic parameters are similar in patients and in healthy postmenopausal volunteers. The pharmacokinetics of anastrozole are linear over the dose range of 1 to 20 mg and do not change with repeated dosing. Consistent with the approximately 2-day terminal elimination half-life, plasma concentrations approach steady-state levels at about 7 days of once daily dosing and steady-state levels are approximately three- to four-fold higher than levels observed after a single dose of ARIMIDEX. Anastrozole is 40% bound to plasma proteins in the therapeutic range.<br/>Metabolism and Excretion: Studies in postmenopausal women demonstrated that anastrozole is extensively metabolized with about 10% of the dose excreted in the urine as unchanged drug within 72 hours of dosing, and the remainder (about 60% of the dose) is excreted in urine as metabolites. Metabolism of anastrozole occurs by N-dealkylation, hydroxylation and glucuronidation. Three metabolites of anastrozole have been identified in human plasma and urine. The known metabolites are triazole, a glucuronide conjugate of hydroxy-anastrozole, and a glucuronide of anastrozole itself. Several minor (less than 5% of the radioactive dose) metabolites have not been identified. Because renal elimination is not a significant pathway of elimination, total body clearance of anastrozole is unchanged even in severe (creatinine clearance less than 30 mL/min/1.73m) renal impairment, dosing adjustment in patients with renal dysfunction is not necessary (see Special Populations and DOSAGE AND ADMINISTRATION sections). Dosage adjustment is also unnecessary in patients with stable hepatic cirrhosis (see Special Populations and DOSAGE AND ADMINISTRATION sections).<br/>Special Populations:<br/>Geriatric: Anastrozole pharmacokinetics have been investigated in postmenopausal female volunteers and patients with breast cancer. No age related effects were seen over the range<50 to>80 years.<br/>Race: Estradiol and estrone sulfate levels were similar between Japanese and Caucasian postmenopausal women who received 1 mg of anastrozole daily for 16 days. Anastrozole mean steady-state minimum plasma concentrations in Caucasian and Japanese postmenopausal women were 25.7 and 30.4 ng/mL, respectively.<br/>Renal Insufficiency: Anastrozole pharmacokinetics have been investigated in subjects with renal insufficiency. Anastrozole renal clearance decreased proportionally with creatinine clearance and was approximately 50% lower in volunteers with severe renal impairment (creatinine clearance<30 mL/min/1.73m) compared to controls. Since only about 10% of anastrozole is excreted unchanged in the urine, the reduction in renal clearance did not influence the total body clearance (See DOSAGE AND ADMINISTRATION).<br/>Hepatic Insufficiency: Hepatic metabolism accounts for approximately 85% of anastrozole elimination. Anastrozole pharmacokinetics have been investigated in subjects with hepatic cirrhosis related to alcohol abuse. The apparent oral clearance (CL/F) of anastrozole was approximately 30% lower in subjects with stable hepatic cirrhosis than in control subjects with normal liver function. However, plasma anastrozole concentrations in the subjects with hepatic cirrhosis were within the range of concentrations seen in normal subjects across all clinical trials (see DOSAGE AND ADMINISTRATION), so that no dosage adjustment is needed.<br/>Drug-Drug Interactions: Anastrozole inhibited reactions catalyzed by cytochrome P450 1A2, 2C8/9, and 3A4 in vitro with Ki values which were approximately 30 times higher than the mean steady-state Cvalues observed following a 1 mg daily dose. Anastrozole had no inhibitory effect on reactions catalyzed by cytochrome P450 2A6 or 2D6 in vitro. Administration of a single 30 mg/kg or multiple 10 mg/kg doses of anastrozole to healthy subjects had no effect on the clearance of antipyrine or urinary recovery of antipyrine metabolites. Based on these in vitro and in vivo results, it is unlikely that co-administration of ARIMIDEX 1 mg with other drugs will resultin clinically significant inhibition of cytochrome P450 mediated metabolism. In a study conducted in 16 male volunteers, anastrozole did not alter the pharmacokinetics as measured by Cand AUC, and anticoagulant activity as measured by prothrombin time, activated partial thromboplastine time, and thrombin time of both R- and S-warfarin. Co-administration of anastrozole and tamoxifen in breast cancer patients reduced anastrozole plasma concentration by 27% compared to those achieved with anastrozole alone; however, the coadministration did not affect the pharmacokinetics of tamoxifen or N-desmethyltamoxifen (see PRECAUTIONS -Drug Interactions).<br/>Pharmacodynamics:<br/>Effect on Estradiol: Mean serum concentrations of estradiol were evaluated in multiple daily dosing trials with 0.5, 1, 3, 5, and 10 mg of ARIMIDEX in postmenopausal women with advanced breast cancer. Clinically significant suppression of serum estradiol was seen with all doses. Doses of 1 mg and higher resulted in suppression of mean serum concentrations of estradiol to the lower limit of detection (3.7 pmol/L). The recommended daily dose, ARIMIDEX 1 mg, reduced estradiol by approximately 70% within 24 hours and by approximately 80% after 14 days of daily dosing. Suppression of serum estradiol was maintained for up to 6 days after cessation of daily dosing with ARIMIDEX 1 mg. The effect of ARIMIDEX on estradiol levels in premenopausal women has not been studied. Because aromatization of adrenal androgens is not a significant source of estradiol in premenopausal women (women with functioning ovaries as evidenced by menstruation and/or premenopausal LH, FSH and estradiol levels), ARIMIDEX would not be expected to lower estradiol levels in premenopausal women.<br/>Effect on Corticosteroids: In multiple daily dosing trials with 3, 5, and 10 mg, the selectivity of anastrozole was assessed by examining effects on corticosteroid synthesis. For all doses, anastrozole did not affect cortisol or aldosterone secretion at baseline or in response to ACTH. No glucocorticoid or mineralocorticoid replacement therapy is necessary with anastrozole.<br/>Other Endocrine Effects: In multiple daily dosing trials with 5 and 10 mg, thyroid stimulating hormone (TSH) was measured; there was no increase in TSH during the administration of ARIMIDEX. ARIMIDEX does not possess direct progestogenic, androgenic, or estrogenic activity in animals, but does perturb the circulating levels of progesterone, androgens, and estrogens.<br/>Clinical Studies:<br/>Adjuvant Treatment of Breast Cancer in Postmenopausal Women: A multicenter, double-blind trial (ATAC) randomized 9,366 postmenopausal women with operable breast cancer to adjuvant treatment with ARIMIDEX 1 mg daily, tamoxifen 20 mg daily, or a combination of the two treatments for five years or until recurrence of the disease. The primary endpoint of the trial was disease-free survival (ie, time to occurrence of a distant or local recurrence, or contralateral breast cancer or death from any cause). Secondary endpoints of the trial included distant disease-free survival, the incidence of contralateral breast cancer and overall survival. At a median follow-up of 33 months, the combination of ARIMIDEX and tamoxifen did not demonstrate any efficacy benefit when compared with tamoxifen in all patients as well as in the hormone receptor positive subpopulation. This treatment arm was discontinued from the trial. Demographic and other baseline characteristics were similar among the three treatment groups (see Table 1). Patients in the two monotherapy arms of the ATAC trial were treated for a median of 60 months (5 years) and followed for a median of 68 months. Disease-free survival in the intent-to-treat population was statistically significantly improved [Hazard Ratio (HR) = 0.87, 95% CI: 0.78, 0.97, p=0.0127 in the ARIMIDEX arm compared to the tamoxifen arm. In the hormone receptor-positive subpopulation representing about 84% of the trial patients, disease-free survival was also statistically significantly improved (HR =0.83, 95% CI: 0.73, 0.94, p=0.0049) in the ARIMIDEX arm compared to the tamoxifen arm. The survival data with 68 months follow-up is presented in Table 3. In the group of patients who had previous adjuvant chemotherapy (N=698 for ARIMIDEX and N=647 for tamoxifen), the hazard ratio for disease-free survival was 0.91 (95% CI: 0.73 to 1.13) in the Arimidex arm compared to the tamoxifen arm. For patients who were 65 years of age and older (N=1413 for ARIMIDEX and N=1410 for tamoxifen), the hazard ratio for disease-free survival was 0.93 (95% CI: 0.80 to1.08) in the Arimidex arm compared to the tamoxifen arm. The frequency of individual events in the intent-to-treat population and the hormone receptor-positive subpopulation are described in Table 2. A summary of the study efficacy results is provided in Table 3.<br/>First Line Therapy in Postmenopausal Women with Advanced Breast Cancer: Two double-blind, well-controlled clinical studies of similar design (0030, a North American study and 0027, a predominately European study) were conducted to assess the efficacy of ARIMIDEX compared with tamoxifen as first-line therapy for hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer in postmenopausal women. A total of 1021 patients betweenthe ages of 30 and 92 years old were randomized to receive trial treatment. Patients were randomized to receive 1 mg of ARIMIDEX once daily or 20 mg of tamoxifen once daily. The primary end points for both trials were time to tumor progression, objective tumor response rate, and safety. Demographics and other baseline characteristics, including patients who had measurable and no measurable disease, patients who were given previous adjuvant therapy, the site of metastatic disease and ethnic origin were similar for the two treatment groups for both trials. The following table summarizes the hormone receptor status at entry for all randomized patients in trials 0030 and 0027. For the primary endpoints, trial 0030 showed ARIMIDEX was at least as effective as tamoxifen for objective tumor response rate. ARIMIDEX had a statistically significant advantage over tamoxifen (p=0.006) for time to tumor progression (see Table 5 and Figure 3). Trial 0027 showed ARIMIDEX was at least as effective as tamoxifen for objective tumor response rate and time to tumor progression (See Table 5 and Figure 4). Table 5 below summarizes the results of trial 0030 and trial 0027 for the primary efficacy endpoints. Results from the secondary endpoints of time to treatment failure, duration of tumor response, and duration of clinical benefit were supportive of the results of the primary efficacy endpoints. There were too few deaths occurring across treatment groups of both trials to draw conclusions on overall survival differences.<br/>Second Line Therapy in Postmenopausal Women with Advanced Breast Cancer who had Disease Progression following Tamoxifen Therapy: Anastrozole was studied in two well-controlled clinical trials (0004, a North American study; 0005, a predominately European study) in postmenopausal women with advanced breast cancer who had disease progression following tamoxifen therapy for either advanced or early breast cancer. Some of the patients had also received previous cytotoxic treatment. Most patients were ER-positive; a smaller fraction were ER-unknown or ER-negative; the ER-negative patients were eligible only if they had had a positive response to tamoxifen. Eligible patients with measurable and non-measurable disease were randomized to receive either a single daily dose of 1 mg or 10 mg of ARIMIDEX or megestrol acetate 40 mg four times a day. The studies were double-blinded with respect to ARIMIDEX. Time to progression and objective response (only patients with measurable disease could be considered partial responders) rates were the primary efficacy variables. Objective response rates were calculated based on the Union Internationale Contre le Cancer (UICC) criteria. The rate of prolonged (more than 24 weeks) stable disease, the rate of progression, and survival were also calculated. Both trials included over 375 patients; demographics and other baseline characteristics were similar for the three treatment groups in each trial. Patients in the 0005 trial had responded better to prior tamoxifen treatment. Of the patients entered who had prior tamoxifen therapy for advanced disease (58% in Trial 0004; 57% in Trial 0005), 18% of these patients in Trial 0004 and 42% in Trial 0005 were reported by the primary investigator to have responded. In Trial 0004, 81% of patients were ER-positive, 13% were ER-unknown, and 6% were ER-negative. In Trial 0005, 58% of patients were ER-positive, 37% were ER-unknown, and 5% were ER-negative. In Trial 0004, 62% of patients had measurable disease compared to 79% in Trial 0005. The sites of metastatic disease were similar among treatment groups for each trial. On average, 40% of the patients had soft tissue metastases; 60% had bone metastases; and 40% had visceral (15% liver) metastases. As shown in the table below, similar results were observed among treatment groups and between the two trials. None of the within-trial differences were statistically significant. More than 1/3 of the patients in each treatment group in both studies had either an objective response or stabilization of their disease for greater than 24 weeks. Among the 263 patients who received ARIMIDEX 1 mg, there were 11 complete responders and 22 partial responders. In patients who had an objective response, more than 80% were still responding at 6 months from randomization and more than 45% were still responding at 12 months from randomization. When data from the two controlled trials are pooled, the objective response rates and median times to progression and death were similar for patients randomized to ARIMIDEX 1 mg and megestrol acetate. There is, in this data, no indication that ARIMIDEX 10 mg is superior to ARIMIDEX 1 mg. Objective response rates and median times to progression and death for ARIMIDEX 1 mg were similar to megestrol acetate for women over or under 65. There were too few non-white patients studied to draw conclusions about racial differences in response. | lld:dailymed |
| dailymed-drugs:244 | dailymed-instance:clinicalP... | Mechanism of Action:The mechanism of the effects of cilostazol on the symptoms of intermittent claudication is not fully understood. Cilostazol and several of its metabolites are cyclic AMP (cAMP) phosphodiesterase III inhibitors (PDE III inhibitors), inhibiting phosphodiesterase activity and suppressing cAMP degradation with a resultant increase in cAMP in platelet and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively. Cilostazol reversibly inhibits platelet aggregation induced by a variety of stimuli, including thrombin, ADP, collagen, arachidonic acid, epinephrine, and shear stress. Effects on circulating plasma lipids have been examined in patients taking cilostazol. After 12 weeks, as compared to placebo, cilostazol 100 mg b.i.d. produced a reduction in triglycerides of 29.3 mg/dL (15%) and an increase in HDL-cholesterol of 4.0 mg/dL (���10%). Cardiovascular Effects:Cilostazol affects both vascular beds and cardiovascular function. It produces non-homogeneous dilation of vascular beds, with greater dilation in femoral beds than in vertebral, carotid, or superior mesenteric arteries. Renal arteries were not responsive to the effects of cilostazol. In dogs or cynomolgous monkeys, cilostazol increased heart rate, myocardial contractile force, and coronary blood flow as well as ventricular automaticity, as would be expected for a PDE III inhibitor. Left ventricular contractility was increased at doses required to inhibit platelet aggregation. A-V conduction was accelerated. In humans, heart rate increased in a dose-proportional manner by a mean of 5.1 and 7.4 beats per minute in patients treated with 50 and 100 mg b.i.d., respectively. In 264 patients evaluated with Holter monitors, numerically more cilostazol-treated patients had increases in ventricular premature beats and non-sustained ventricular tachycardia events than did placebo-treated patients; the increases were not dose-related. Pharmacokinetics:Cilostazol is absorbed after oral administration. A high fat meal increases absorption, with an approximately 90% increase in Cand a 25% increase in AUC. Absolute bioavailability is not known. Cilostazol is extensively metabolized by hepatic cytochrome P-450 enzymes, mainly 3A4, and, to a lesser extent, 2C19, with metabolites largely excreted in urine. Two metabolites are active, with one metabolite appearing to account for at least 50% of the pharmacologic (PDE III inhibition) activity after administration of cilostazol. Pharmacokinetics are approximately dose proportional. Cilostazol and its active metabolites have apparent elimination half-lives of about 11-13 hours. Cilostazol and its active metabolites accumulate about 2-fold with chronic administration and reach steady state blood levels within a few days. The pharmacokinetics of cilostazol and its two major active metabolites were similar in healthy normal subjects and patients with intermittent claudication due to peripheral arterial disease (PAD). The mean��SEM plasma concentration-time profile at steady state after multiple dosing of cilostazol 100 mg b.i.d. is shown below:<br/>Distribution:: Metabolism and Excretion:Cilostazol is eliminated predominately by metabolism and subsequent urinary excretion of metabolites. Based on in vitro studies, the primary isoenzymes involved in cilostazol's metabolism are CYP3A4 and, to a lesser extent, CYP2C19. The enzyme responsible for metabolism of 3,4-dehydro-cilostazol, the most active of the metabolites, is unknown. Following oral administration of 100 mg radiolabeled cilostazol, 56% of the total analytes in plasma was cilostazol, 15% was 3,4-dehydro-cilostazol (4-7 times as active as cilostazol), and 4% was 4��-trans-hydroxy-cilostazol (one fifth as active as cilostazol). The primary route of elimination was via the urine (74%), with the remainder excreted in feces (20%). No measurable amount of unchanged cilostazol was excreted in the urine, and less than 2% of the dose was excreted as 3,4-dehydro-cilostazol. About 30% of the dose was excreted in urine as 4��-trans-hydroxy-cilostazol. The remainder was excreted as other metabolites, none of which exceeded 5%. There was no evidence of induction of hepatic microenzymes.<br/>Special Populations:: Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions:Cilostazol could have pharmacodynamic interactions with other inhibitors of platelet function and pharmacokinetic interactions because of effects of other drugs on its metabolism by CYP3A4 or CYP2C19. A reduced dose of cilostazol should be considered when taken concomitantly with CYP3A4 or CYP2C19 inhibitors. Cilostazol does not appear to inhibit CYP3A4 (see Pharmacokinetic and Pharmacodynamic Drug-Drug Interactions, Lovastatin).<br/>CLINICAL EFFICACY:: The ability of cilostazol to improve walking distance in patients with stable intermittent claudication was studied in eight large, randomized, placebo-controlled, double-blind trials of 12 to 24 weeks' duration using dosages of 50 mg b.i.d. (n=303), 100 mg b.i.d. (n=998), and placebo (n=973). Efficacy was determined primarily by the change in maximal walking distance from baseline (compared to change on placebo) on one of several standardized exercise treadmill tests. Compared to patients treated with placebo, patients treated with cilostazol 50 or 100 mg b.i.d. experienced statistically significant improvements in walking distances both for the distance before the onset of claudication pain and the distance before exercise-limiting symptoms supervened (maximal walking distance). The effect of cilostazol on walking distance was seen as early as the first on-therapy observation point of two or four weeks. The following figure depicts the percent mean improvement in maximal walking distance at study end for each of the eight studies. Across the eight clinical trials, the range of improvement in maximal walking distance in patients treated with cilostazol 100 mg b.i.d., expressed as the percent mean change from baseline, was 28% to 100%. The corresponding changes in the placebo group were���10% to 41%. The Walking Impairment Questionnaire, which was administered in six of the eight clinical trials, assesses the impact of a therapeutic intervention on walking ability. In a pooled analysis of the six trials, patients treated with either cilostazol 100 mg b.i.d. or 50 mg b.i.d. reported improvements in their walking speed and walking distance as compared to placebo. Improvements in walking performance were seen in the various subpopulations evaluated, including those defined by gender, smoking status, diabetes mellitus, duration of peripheral artery disease, age, and concomitant use of beta blockers or of calcium channel blockers. Cilostazol has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers, or gangrene. Its long-term effects on limb preservation and hospitalization have not been evaluated. | lld:dailymed |
| dailymed-drugs:245 | dailymed-instance:clinicalP... | Aminosyn-RF 5.2%, Sulfite-Free, (an amino acid injection���renal formula) is a mixture of amino acids specifically designed for patients with acute renal failure who are unable to eat. The use of these essential amino acids in the management of the uremic patient is based on the minimal requirements for each of the eight amino acids essential in adult nutrition established by Rose. In renal failure nonspecific nitrogen such as urea, glycine, or ammonium chloride, are broken down in the intestine. The ammonia formed is absorbed into the portal system and incorporated by the liver into nonessential amino acids, provided requirements for essential amino acids are being met. By this metabolic route, urea nitrogen contributes to protein synthesis when the proper combination of essential amino acids, sufficient calories and other required nutrients are administered. Thus, the administration of essential amino acids to uremic patients, particularly those who are protein-deficient, results in the utilization of retained urea in protein synthesis, and may be followed by a drop in BUN and resolution of many of the symptoms associated with azotemia. Aminosyn-RF 5.2% contains histidine, an amino acid considered essential for infant growth, and identified as an essential amino acid for uremic patients. In patients with potentially reversible acute renal failure who cannot eat, maintenance of adequate nutrition may assist in reducing morbidity. | lld:dailymed |
| dailymed-drugs:246 | dailymed-instance:clinicalP... | Hydroxyzine hydrochloride is unrelated chemically to the phenothiazines, reserpine, meprobamate, or the benzodiazepines. Hydroxyzine is not a cortical depressant, but its action may be due to a suppression of activity in certain key regions of the subcortical area of the central nervous system. Primary skeletal muscle relaxation has been demonstrated experimentally. Bronchodilator activity, and antihistaminic and analgesic effects havebeen demonstrated experimentally and confirmed clinically. An antiemetic effect, both by the apomorphine test and the veriloid test, has been demonstrated. Pharmacological and clinical studies indicate that hydroxyzine in therapeutic dosage does not increase gastric secretion or acidity and in most cases has mild antisecretory activity. Hydroxyzine is rapidly absorbed from the gastrointestinal tract and its clinical effects are usually noted within 15 to 30 minutes after oral administration. | lld:dailymed |
| dailymed-drugs:248 | dailymed-instance:clinicalP... | Flumazenil, an imidazobenzodiazepine derivative, antagonizes the actions of benzodiazepines on the central nervous system. Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA/benzodiazepine receptor complex. Flumazenil is a weak partial agonist in some animal models of activity, but has little or no agonist activity in man. Flumazenil does not antagonize the central nervous system effects of drugs affecting GABA-ergic neurons by means other than the benzodiazepine receptor (including ethanol, barbiturates, or general anesthetics) and does not reverse the effects of opioids. In animals pretreated with high doses of benzodiazepines over several weeks, flumazenil elicited symptoms of benzodiazepine withdrawal, including seizures. A similar effect was seen in adult human subjects.<br/>Pharmacodynamics: Intravenous flumazenil has been shown to antagonize sedation, impairment of recall, psychomotor impairment and ventilatory depression produced by benzodiazepines in healthy human volunteers. The duration and degree of reversal of sedative benzodiazepine effects are related to the dose and plasma concentrations of flumazenil as shown in the following data from a study in normal volunteers. Generally, doses of approximately 0.1 mg to 0.2 mg (corresponding to peak plasma levels of 3 to 6 ng/mL) produce partial antagonism, whereas higher doses of 0.4 to 1 mg (peak plasma levels of 12 to 28 ng/mL) usually produce complete antagonism in patients who have received the usual sedating doses of benzodiazepines. The onset of reversal is usually evident within 1 to 2 minutes after the injection is completed. Eighty percent response will be reached within 3 minutes, with the peak effect occurring at 6 to 10 minutes. The duration and degree of reversal are related to the plasma concentration of the sedating benzodiazepine as well as the dose of flumazenil given. In healthy volunteers, flumazenil did not alter intraocular pressure when given alone and reversed the decrease in intraocular pressure seen after administration of midazolam.<br/>Pharmacokinetics: After IV administration, plasma concentrations of flumazenil follow a two-exponential decay model. The pharmacokinetics of flumazenil are dose-proportional up to 100 mg.<br/>Distribution: Flumazenil is extensively distributed in the extravascular space with an initial distribution half-life of 4 to 11 minutes and a terminal half-life of 40 to 80 minutes. Peak concentrations of flumazenil are proportional to dose, with an apparent initial volume of distribution of 0.5 L/kg. The volume of distribution at steady-state is 0.9 to 1.1 L/kg. Flumazenil is a weak lipophilic base. Protein binding is approximately 50% and the drug shows no preferential partitioning into red blood cells. Albumin accounts for two thirds of plasma protein binding.<br/>Metabolism: Flumazenil is completely (99%) metabolized. Very little unchanged flumazenil (<1%) is found in the urine. The major metabolites of flumazenil identified in urine are the de-ethylated free acid and its glucuronide conjugate. In preclinical studies there was no evidence of pharmacologic activity exhibited by the de-ethylated free acid.<br/>Elimination: Elimination of radiolabeled drug is essentially complete within 72 hours, with 90% to 95% of the radioactivity appearing in urine and 5% to 10% in the feces. Clearance of flumazenil occurs primarily by hepatic metabolism and is dependent on hepatic blood flow. In pharmacokinetic studies of normal volunteers, total clearance ranged from 0.8 to 1.0 L/hr/kg. Pharmacokinetic parameters following a 5 minute infusion of a total of 1 mg of flumazenil mean (coefficient of variation, range):<br/>Food Effects: Ingestion of food during an intravenous infusion of the drug results in a 50% increase in clearance, most likely due to the increased hepatic blood flow that accompanies a meal.<br/>Special Populations:<br/>The Elderly: The pharmacokinetics of flumazenil are not significantly altered in the elderly.<br/>Gender: The pharmacokinetics of flumazenil are not different in male and female subjects.<br/>Renal Failure (creatinine clearance<10 mL/min) and Hemodialysis: The pharmacokinetics of flumazenil are not significantly affected.<br/>Patients With Liver Dysfunction: For patients with moderate liver dysfunction, their mean total clearance is decreased to 40% to 60% and in patients with severe liver dysfunction, it is decreased to 25% of normal value, compared with age-matched healthy subjects. This results in a prolongation of the half-life to 1.3 hours in patients with moderate hepatic impairment and 2.4 hours in severely impaired patients. Caution should be exercised with initial and/or repeated dosing to patients with liver disease.<br/>Drug-Drug Interaction: The pharmacokinetic profile of flumazenil is unaltered in the presence of benzodiazepine agonists and the kinetic profiles of those benzodiazepines studied (i.e., diazepam, flunitrazepam, lormetazepam, and midazolam) are unaltered by flumazenil. During the 4 hour steady-state and post infusion of ethanol, there were no pharmacokinetic interactions on ethanol mean plasma levels as compared to placebo when flumazenil doses were given intravenously (at 2.5 hours and 6 hours) nor were interactions of ethanol on the flumazenil elimination half-life found.<br/>Pharmacokinetics in Pediatric Patients: The pharmacokinetics of flumazenil have been evaluated in 29 pediatric patients ranging in age from 1 to 17 years who had undergone minor surgical procedures. The average doses administered were 0.53 mg (0.044 mg/kg) in patients aged 1 to 5 years, 0.63 mg (0.020 mg/kg) in patients aged 6 to 12 years, and 0.8 mg (0.014 mg/kg) in patients aged 13 to 17 years. Compared to adults, the elimination half-life in pediatric patients was more variable, averaging 40 minutes (range: 20 to 75 minutes). Clearance and volume of distribution, normalized for body weight, were in the same range as those seen in adults, although more variability was seen in the pediatric patients.<br/>CLINICAL TRIALS: Flumazenil has been administered in adults to reverse the effects of benzodiazepines in conscious sedation, general anesthesia, and the management of suspected benzodiazepine overdose. Limited information from uncontrolled studies in pediatric patients is available regarding the use of flumazenil to reverse the effects ofbenzodiazepines in conscious sedation only.<br/>Conscious Sedation in Adults: Flumazenil was studied in four trials in 970 patients who received an average of 30 mg diazepam or 10 mg midazolam for sedation (with or without a narcotic) in conjunction with both inpatient and outpatient diagnostic or surgical procedures. Flumazenil was effective in reversing the sedating and psychomotor effects of the benzodiazepine; however, amnesia was less completely and less consistently reversed. In these studies, flumazenil was administered as an initial dose of 0.4 mg IV (two doses of 0.2 mg) with additional 0.2 mg doses as needed to achieve complete awakening, up to a maximum total dose of 1 mg. Seventy-eight percent of patients receiving flumazenil responded by becoming completely alert. Of those patients, approximately half responded to doses of 0.4 mg to 0.6 mg, while the other half responded to doses of 0.8 mg to 1 mg. Adverse effects were infrequent in patients who received 1 mg of flumazenil or less, although injection site pain, agitation, and anxiety did occur. Reversal of sedation was not associated with any increase in the frequency of inadequate analgesia or increase in narcotic demand in these studies. While most patients remained alert throughout the 3 hour postprocedure observation period,resedation was observed to occur in 3% to 9% of the patients, and was most common in patients who had received high doses of benzodiazepines .<br/>General Anesthesia in Adults: Flumazenil was studied in four trials in 644 patients who received midazolam as an induction and/or maintenance agent in both balanced and inhalational anesthesia. Midazolam was generally administered in doses ranging from 5 mg to 80 mg, alone and/or in conjunction with muscle relaxants, nitrous oxide, regional or local anesthetics, narcotics and/or inhalational anesthetics. Flumazenil was given as an initial dose of 0.2 mg IV, with additional 0.2 mg doses as needed to reach a complete response, up to a maximum total dose of 1 mg. These doses were effective in reversing sedation and restoring psychomotor function, but did not completelyrestore memory as tested by picture recall. Flumazenil was not as effective in the reversal of sedation in patients who had received multiple anesthetic agents in addition to benzodiazepines. Eighty-one percent of patients sedated with midazolam responded to flumazenil by becoming completely alert or just slightly drowsy. Of those patients, 36% responded to doses of 0.4 mg to 0.6 mg, while 64% responded to doses of 0.8 mg to 1 mg. Resedation in patients who responded to flumazenil occurred in 10% to 15% of patients studied and was more common with larger doses of midazolam (>20 mg), long procedures (>60 minutes) and use of neuromuscular blocking agents .<br/>Management of Suspected Benzodiazepine Overdose in Adults: Flumazenil was studied in two trials in 497 patients who were presumed to have taken an overdose of a benzodiazepine, either alone or in combination with a variety of other agents. In these trials, 299 patients were proven to have taken a benzodiazepine as part of the overdose, and 80% of the 148 who received flumazenil responded by an improvement in level of consciousness. Of the patients who responded to flumazenil, 75% responded to a total dose of 1 mg to 3 mg. Reversal of sedation was associated with an increased frequency of symptoms of CNS excitation. Of the patients treated with flumazenil, 1% to 3% were treated for agitation or anxiety. Serious side effects were uncommon, but six seizures were observed in 446 patients treated with flumazenil in these studies. Four of these 6 patients had ingested a large dose of cyclic antidepressants, which increased the risk of seizures .<br/>INDIVIDUALIZATION OF DOSAGE:<br/>General Principles: The serious adverse effects of flumazenil are related to the reversal of benzodiazepine effects. Using more than the minimally effective dose of flumazenil is tolerated by most patients but may complicate the management of patients who are physically dependent on benzodiazepines or patients who are depending on benzodiazepines for therapeutic effect (such as suppression of seizures in cyclic antidepressant overdose). In high-risk patients, it is important to administer the smallest amount of flumazenil that is effective. The 1-minute wait between individual doses in the dose-titration recommended for general clinical populations may be too short for high-risk patients. This is because it takes 6 to 10 minutes for any single dose offlumazenil to reach full effects. Practitioners should slow the rate of administration of flumazenil administered to high-risk patients as recommended below.<br/>Anesthesia and Conscious Sedation in Adult Patients: Flumazenil is well tolerated at the recommended doses in individuals who have no tolerance to (or dependence on) benzodiazepines. The recommended doses and titration rates in anesthesia and conscious sedation (0.2 mg to 1 mg given at 0.2 mg/min) are well tolerated in patients receiving the drug for reversal of a single benzodiazepine exposure in most clinical settings . The major risk will be resedation because the duration of effect of a long-acting (or large dose of a short-acting) benzodiazepine may exceed that of flumazenil. Resedation may be treated by giving a repeat dose at no less than 20 minute intervals. For repeat treatment, no more than 1 mg (at 0.2 mg/min doses) should be given at any one time and no more than 3 mg should be given in any one hour.<br/>Benzodiazepine Overdose in Adult Patients: The risk of confusion, agitation, emotional lability, and perceptual distortion with the doses recommended in patients with benzodiazepine overdose (3 mg to 5 mg administered as 0.5 mg/min) may be greater than that expected with lower doses and slower administration. The recommended doses represent a compromise between a desirable slow awakening and the need for prompt response and a persistent effect in the overdose situation. If circumstances permit, the physician may elect to use the 0.2 mg/minute titration rate to slowly awaken the patient over 5 to 10 minutes, which may help to reduce signs and symptoms on emergence. Flumazenil has no effect in cases where benzodiazepines are not responsible for sedation. Once doses of 3 mg to 5 mg have been reached without clinical response, additional flumazenil is likely to have no effect.<br/>Patients Tolerant to Benzodiazepines: Flumazenil may cause benzodiazepine withdrawal symptoms in individuals who have been taking benzodiazepines long enough to have some degree of tolerance. Patients who had been taking benzodiazepines prior to entry into the flumazenil trials, who were given flumazenil in doses over 1 mg, experienced withdrawal-like events 2 to 5 times more frequently than patients who received less than 1 mg. In patients who may have tolerance to benzodiazepines, as indicated by clinical history or by the need for larger than usual doses of benzodiazepines, slower titration rates of 0.1 mg/min and lower total doses may help reduce the frequency of emergent confusion and agitation. In such cases, special care must be taken to monitor the patients for resedation because of the lower doses of flumazenil used.<br/>Patients Physically Dependent on Benzodiazepines: Flumazenil is known to precipitate withdrawal seizures in patients who are physically dependent on benzodiazepines, even if such dependence was established in a relatively few days of high-dose sedation in Intensive Care Unit (ICU) environments. The risk of either seizures or resedation in such cases is high and patients have experienced seizures before regaining consciousness. Flumazenil should be used in such settings with extreme caution, since the use of flumazenil inthis situation has not been studied and no information as to dose and rate of titration is available. Flumazenil should be used in such patients only if the potential benefits of using the drug outweigh the risks of precipitated seizures. Physicians are directed to the scientific literature for the most current information in this area. | lld:dailymed |
| dailymed-drugs:249 | dailymed-instance:clinicalP... | Naturally occurring glucocorticoids (hydrocortisone), which also have salt-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs are primarily used for their potent anti-inflammatory effects in disorders of many organ systems. Prednisolone is a synthetic adrenocortical steroid drug with predominantly glucocorticoid properties. Some of these properties reproduce the physiological actions of endogenous glucocorticosteroids, but others do not necessarily reflect any of the adrenal hormones' normal functions; they are seen only after administration of large therapeutic doses of the drug. The pharmacological effects of prednisolone which are due to its glucocorticoid properties include: promotion of gluconeogenesis; increased deposition of glycogen in the liver; inhibition of the utilization of glucose; anti-insulin activity; increased catabolism of protein; increased lipolysis; stimulation of fat synthesis and storage; increased glomerular filtration rate and resulting increase in urinary excretion of urate (creatinine excretion remains unchanged); and increased calcium excretion. Depressed production of eosinophils and lymphocytes occurs, but erythropoiesis and production of polymorphonuclear leukocytes are stimulated. Inflammatory processes (edema, fibrin deposition, capillary dilatation, migration of leukocytes and phagocytosis) and the later stages of wound healing (capillary proliferation, deposition of collagen, cicatrization) are inhibited. Prednisolone can stimulate secretion of various components of gastric juice. Suppression of the production of corticotropin may lead to suppression of endogenous corticosteroids. Prednisolone has slight mineralocorticoid activity, whereby entry of sodium into cells and loss of intracellular potassium is stimulated. This is particularly evident in the kidney, where rapid ion exchange leads to sodium retention and hypertension. Prednisolone is rapidly and well absorbed from the gastrointestinal tract following oral administration. Prednisolone sodium phosphate oral solution produces a 14% higher peak plasma level of prednisolone which occurs 20% faster than that seen with tablets. Prednisolone is 70���90% protein-bound in the plasma and it is eliminated from the plasma with a half-life of 2 to 4 hours. It is metabolized mainly in the liver and excreted in the urine as sulfate and glucuronide conjugates. The systemic availability, metabolism and elimination of prednisolone after administration of single weight-based doses (0.8 mg/kg) of intravenous (IV) prednisolone and oral prednisone were reported in a small study of 19 young (23 to 34 years) and 12 elderly (65 to 89 years) subjects. Results showed that the systemic availability of total and unbound prednisolone, as well as interconversion between prednisolone and prednisone were independent of age. The mean unbound fraction of prednisolone was higher, and the steady-state volume of distribution (Vss) of unbound prednisolone was reduced in elderly patients. Plasma prednisolone concentrations were higher in elderly subjects, and the higher AUCs of total and unbound prednisolone were most likely reflective of an impaired metabolic clearance, evidenced by reduced fractional urinary clearance of 6��-hydroxyprednisolone. Despite these findings of higher total and unbound prednisolone concentrations, elderly subjects had higher AUCs of cortisol, suggesting that the elderly population is less sensitive to suppression of endogenous cortisol or their capacity for hepatic inactivation of cortisol is diminished. | lld:dailymed |
| dailymed-drugs:250 | dailymed-instance:clinicalP... | Mechanisms of Action: Disopyramide Phosphate is a Type 1 antiarrhythmic drug (ie, similar to procainamide and quinidine). In animal studies, Disopyramide Phosphate decreases the rate of diastolic depolarization (phase 4) in cells with augmented automaticity, decreases the upstroke velocity (phase 0) and increases the action potential duration of normal cardiac cells, decreases the disparity in refractoriness between infarcted and adjacent normally perfused myocardium, and has no effect on alpha- or beta-adrenergic receptors.<br/>Electrophysiology: In man, Disopyramide Phosphate at therapeutic plasma levels shortens the sinus node recovery time, lengthens the effective refractory period of the atrium, and has a minimal effect on the effective refractory period of the AV node. Little effect has been shown on AV-nodal and His-Purkinje conduction times or QRS duration. However, prolongation of conduction in accessory pathways occurs.<br/>Hemodynamics: At recommended oral doses, Disopyramide Phosphate rarely produces significant alterations of blood pressure in patients without congestive heart failure (see WARNINGS). With intravenous Disopyramide Phosphate, either increases in systolic/diastolic or decreases in systolic blood pressure have been reported, depending on the infusion rate and the patient population. Intravenous Disopyramide Phosphate may cause cardiac depression with an approximate mean 10% reduction of cardiac output, which is more pronounced in patients with cardiac dysfunction.<br/>Anticholinergic Activity: The in vitro anticholinergic activity of Disopyramide Phosphate is approximately 0.06% that of atropine; however, the usual dose for Disopyramide Phosphate is 150 mg every 6 hours compared to 0.4 to 0.6 mg for atropine (see WARNINGS and ADVERSE REACTIONS for anticholinergic side effects).<br/>Pharmacokinetics: Following oral administration of Disopyramide Phosphate, disopyramide phosphate is rapidly and almost completely absorbed, and peak plasma levels are usually attained within 2 hours. The usual therapeutic plasma levels of disopyramide base are 2 to 4 mcg/mL, and at these concentrations protein binding varies from 50% to 65%. Because of concentration-dependent protein binding, it is difficult to predict the concentration of the free drug when total drug is measured. The mean plasma half-life of disopyramide in healthy humans is 6.7 hours (range of 4 to 10 hours). In six patients with impaired renal function (creatinine clearance less than 40 mL/min), disopyramide half-life values were 8 to 18 hours. After the oral administration of 200 mg of disopyramide to 10 cardiac patients with borderline to moderate heart failure, the time to peak serum concentration of 2.3��1.5 hours (mean��SD) was increased, and the mean peak serum concentration of 4.8��1.6 mcg/mL was higher than in healthy volunteers. After intravenous administration in these same patients, the mean elimination half-life was 9.7��4.2 hours (range in healthy volunteers of 4.4 to 7.8 hours). In a second study of the oral administration of disopyramide to 7 patients with heart disease, including left ventricular dysfunction, the mean plasma half-life was slightly prolonged to 7.8��1.9 hours (range of 5 to 9.5 hours). In healthy men, about 50% of a given dose of disopyramide is excreted in the urine as the unchanged drug, about 20% as the mono-N-dealkylated metabolite, and 10% as the other metabolites. The plasma concentration of the major metabolite is approximately one tenth that of disopyramide. Altering the urinary pH in man does not affect the plasma half-life of disopyramide.<br/>Drug Interactions: Effects of other drugs on disopyramide pharmacokinetics: In vitro metabolic studies indicated that disopyramide is metabolized by cytochrome P450 3A4 and that inhibitors of this enzyme may result in elevation of plasma levels of disopyramide. Although specific drug interaction studies have not been done, cases of life-threatening interactions have been reported for disopyramide when given with clarithromycin and erythromycin. | lld:dailymed |
| dailymed-drugs:251 | dailymed-instance:clinicalP... | Animal Studies: Prostaglandins have been shown in many animal models to be mediators of certain kinds of intraocular inflammation. In studies performed in animal eyes, prostaglandins have been shown to produce disruption of the blood-aqueous humor barrier, vasodilation, increased vascular permeability, leukocytosis, and increased intraocular pressure.<br/>Pharmacodynamics: Diclofenac sodium is one of a series of phenylacetic acids that have demonstrated anti-inflammatory and analgesic properties in pharmacological studies. It is thought to inhibit the enzyme cyclooxygenase, which is essential in the biosynthesis of prostaglandins.<br/>Pharmacokinetics: Results from a bioavailability study of another formulation of diclofenac sodium ophthalmic solution established that plasma levels of diclofenac following ocular instillation of two drops of diclofenac sodium ophthalmic solution, 0.1% to each eye were below the limit of quantitation (10 ng/mL) over a 4-hour period. This study suggests that limited, if any, systemic absorption occurs with diclofenac sodium ophthalmic solution, 0.1%.<br/>Clinical Trials:<br/>Postoperative Anti-Inflammatory Effects: In a clinical therapeutic equivalence study, Diclofenac Sodium Ophthalmic Solution, 0.1%, was found to be therapeutically equivalent to VOLTAREN OPHTHALMIC' (diclofenac sodium ophthalmic solution) [CIBA VISION OPHTHALMICS'] in the treatment of signs and symptoms of inflammation resulting from cataract surgery. | lld:dailymed |
| dailymed-drugs:252 | dailymed-instance:clinicalP... | Pharmacokinetics and Metabolism: After intramuscular injection of quinidine gluconate, peak serum levels of quinidine are achieved in a little less than two hours. This time to peak levels is identical to the time measured when quinidine salts are administered orally. The volume of distribution of quinidine is typically 2���3 L/kg in healthy young adults, but this may be reduced to as little as 0.5 L/kg in patients with congestive heart failure, or increased to 3���5 L/kg in patients with cirrhosis of the liver. At concentrations of 2���5 mg/L (6.5���16.2��mol/L), the fraction of quinidine bound to plasma proteins (mainly to�����acid glycoprotein and to albumin) is 80���88% in adults and older children, but it is lower in pregnant women, and in infants and neonates it may be as low as 50���70%. Because�����acid glycoprotein levels are increased in response to stress, serum levels of total quinidine may be greatly increased in settings such as acute myocardial infarction, even though the serum content of unbound (active) drug may remain normal. Protein binding is also increased in chronic renal failure, but binding abruptly descends toward or below normal when heparin is administered for hemodialysis. Quinidine clearance typically proceeds at 3���5 mL/min/kg in adults, but clearance in pediatric patients may be twice or three times as rapid. The elimination half���life is about 6���8 hours in adults and 3���4 hours in pediatric patients. Quinidine clearance is unaffected by hepatic cirrhosis, so the increased volume of distribution seen in cirrhosis leads to a proportionate increase in the elimination half���life. Most quinidine is eliminated hepatically via the action of cytochrome P450IIIA4; there are several different hydroxylated metabolites, and some of these have antiarrhythmic activity. The most important of quinidine's metabolites is 3���hydroxy���quinidine (3HQ), serum levels of which can approach those of quinidine in patients receiving conventional doses of quinidine gluconate. The volume of distribution of 3HQ appears to be larger than that of quinidine, and the elimination half���life of 3HQ is about 12 hours. As measured by antiarrhythmic effects in animals, by QTprolongation in human volunteers, or by various in vitro techniques, 3HQ has at least half the antiarrhythmic activity of the parent compound, so it may be responsible for a substantial fraction of the effect of quinidine gluconate in chronic use. When the urine pH is less than 7, about 20% of administered quinidine appears unchanged in the urine, but this fraction drops to as little as 5% when the urine is more alkaline. Renal clearance involves both glomerular filtration and active tubular secretion, moderated by (pH���dependent) tubular reabsorption. The net renal clearance is about 1 mL/min/kg in healthy adults. When renal function is taken into account, quinidine clearance is apparently independent of patient age. Assays of serum quinidine levels are widely available, but the results of modern assays may not be consistent with results cited in the older medical literature. The serum levels of quinidine cited in this package insert are those derived from specific assays, using either benzene extraction or (preferably) reverse���phase high���pressure liquid chromatography. In matched samples, older assays might unpredictably have given results that were as much as two or three times higher. A typical "therapeutic" concentration range is 2���6 mg/L (6.2���18.5��mol/L).<br/>Mechanisms of Action: In patients with malaria, quinidine acts primarily as an intraerythrocytic schizonticide, with little effect upon sporozoites or upon pre���erythrocytic parasites. Quinidine is gametocidal to Plasmodium vivax and P. malariae , but not to P. falciparum. In cardiac muscle and in Purkinje fibers, quinidine depresses the rapid inward depolarizing sodium current, thereby slowing phase���0 depolarization and reducing the amplitude of the action potential without affecting the resting potential. In normal Purkinje fibers, it reduces the slope of phase���4 depolarization, shifting the threshold voltage upward toward zero. The result is slowed conduction and reduced automaticity in all parts of the heart, with increase of the effective refractory period relative to the duration of the action potential in the atria, ventricles, and Purkinje tissues. Quinidine also raises the fibrillation thresholds of the atria and ventricles, and it raises the ventricular defibrillation threshold as well.Quinidine's actions fall into class Ia in the Vaughan���Williams classification. By slowing conduction and prolonging the effective refractory period, quinidine can interrupt or prevent reentrant arrhythmias and arrhythmias due to increased automaticity, including atrial flutter, atrial fibrillation, and paroxysmal supraventricular tachycardia. In patients with the sick sinus syndrome, quinidine can cause marked sinus node depression and bradycardia. In most patients, however, use of quinidine is associated with an increase in sinus rate. Quinidine prolongs the QT interval in a dose���related fashion. This may lead to increased ventricular automaticity and polymorphic ventricular tachycardias, including torsades de pointes (see Warnings). In addition, quinidine has anticholinergic activity, it has negative inotropic activity, and it acts peripherally as an�����adrenergic antagonist (that is, as a vasodilator). | lld:dailymed |
| dailymed-drugs:253 | dailymed-instance:clinicalP... | Phentolamine mesylate produces an alpha-adrenergic block of relatively short duration. It also has direct, but less marked, positive inotropic and chronotropic effects on cardiac muscle and vasodilator effects on vascular smooth muscle. Phentolamine has a half-life in the blood of 19 minutes following intravenous administration. Approximately 13% of a single intravenous dose appears in the urine as unchanged drug. | lld:dailymed |
| dailymed-drugs:254 | dailymed-instance:clinicalP... | Flurbiprofen sodium is one of a series of phenylalkanoic acids that have shown analgesic antipyretic, and antiinflammatory activity in animal inflammatory diseases. Its mechanism of action is believed to be through inhibition of the cyclo-oxygenase enzyme that is essential in the biosynthesis of prostaglandins. Prostaglandins have been shown in many animal models to be mediators of certain kinds of intraocular inflammation. In studies performed on animal eyes, prostaglandins have been shown to produce disruption of the blood-aqueous humor barrier, vasodilatation, increased vascular permeability, leukocytosis, and increased intraocular pressure. Prostaglandins also appear to play a role in the miotic response produced during ocular surgery by constricting the iris sphincter independently of cholinergic mechanisms. In clinical studies, flurbiprofen sodium ophthalmic solution has been shown to inhibit the miosis induced during the course of cataract surgery. Results from clinical studies indicate that flurbiprofen sodium has no significant effect upon intraocular pressure. | lld:dailymed |
| dailymed-drugs:255 | dailymed-instance:clinicalP... | Topical corticosteroids share anti-inflammatory, anti-pruritic and vasoconstrictive actions. The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man.<br/>Pharmacokinetics: The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses . Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. | lld:dailymed |
| dailymed-drugs:1880 | dailymed-instance:clinicalP... | Topical corticosteroids share anti-inflammatory, anti-pruritic and vasoconstrictive actions. The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man.<br/>Pharmacokinetics: The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses . Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. | lld:dailymed |
| dailymed-drugs:3060 | dailymed-instance:clinicalP... | Topical corticosteroids share anti-inflammatory, anti-pruritic and vasoconstrictive actions. The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man.<br/>Pharmacokinetics: The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses . Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. | lld:dailymed |
| dailymed-drugs:3396 | dailymed-instance:clinicalP... | Topical corticosteroids share anti-inflammatory, anti-pruritic and vasoconstrictive actions. The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man.<br/>Pharmacokinetics: The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses . Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. | lld:dailymed |
| dailymed-drugs:3746 | dailymed-instance:clinicalP... | Topical corticosteroids share anti-inflammatory, anti-pruritic and vasoconstrictive actions. The mechanism of anti-inflammatory activity of the topical corticosteroids is unclear. Various laboratory methods, including vasoconstrictor assays, are used to compare and predict potencies and/or clinical efficacies of the topical corticosteroids. There is some evidence to suggest that a recognizable correlation exists between vasoconstrictor potency and therapeutic efficacy in man.<br/>Pharmacokinetics: The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressings. Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption. Occlusive dressings substantially increase the percutaneous absorption of topical corticosteroids. Thus, occlusive dressings may be a valuable therapeutic adjunct for treatment of resistant dermatoses . Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systemically administered corticosteroids. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile. | lld:dailymed |
| dailymed-drugs:256 | dailymed-instance:clinicalP... | Probenecid is a uricosuric and renal tubular blocking agent. It inhibits the tubular reabsorption of urate, thus increasing the urinary excretion of uric acid and decreasing serum urate levels. Effective uricosuria reduces the miscible urate pool, retards urate deposition, and promotes resorption of urate deposits. Probenecid inhibits the tubular secretion of penicillin and usually increases penicillin plasma levels by any route the antibiotic is given. A 2-fold to 4-fold elevation has been demonstrated for various penicillins. Probenecid also has been reported to inhibit the renal transport of many other compounds including aminohippuric acid (PAH), aminosalicylic acid (PAS), indomethacin, sodium iodomethamate and related iodinated organic acids, 17-ketosteroids, pantothenic acid, phenolsulfonphthalein (PSP), sulfonamides, and sulfonylureas. See also Drug Interactions. Probenecid decreases both hepatic and renal excretion of sulfobromophthalein (BSP). The tubular reabsorption of phosphorus is inhibited in hypoparathyroid but not in euparathyroid individuals. Probenecid does not influence plasma concentrations of salicylates, nor the excretion of streptomycin, chloramphenicol, chlortetracycline, oxytetracycline, or neomycin. | lld:dailymed |
| dailymed-drugs:257 | dailymed-instance:clinicalP... | The principal pharmacological action of isosorbide dinitrate is relaxation of vascular smooth muscle and consequent dilatation of peripheral arteries and veins, especially the latter. Dilatation of the veins promotes peripheral pooling of blood and decreases venous return to the heart, thereby reducing left ventricular end���diastolic pressure and pulmonary capillary wedge pressure (preload). Arteriolar relaxation reduces systemic vascular resistance, systolic arterial pressure, and mean arterial pressure (afterload). Dilatation of the coronary arteries also occurs. The relative importance of preload reduction, afterload reduction, and coronary dilatation remains undefined. Dosing regimens for most chronically used drugs are designed to provide plasma concentrations that are continuously greater than a minimally effective concentration. This strategy is inappropriate for organic nitrates. Several well-controlled clinical trials have used exercise testing to assess the anti-anginal efficacy of continuously-delivered nitrates. In the large majority of these trials, active agents were no more effective than placebo after 24 hours (or less) of continuous therapy. Attemptsto overcome nitrate tolerance by dose escalation, even to doses far in excess of those used acutely, have consistently failed. Only after nitrates have been absent from the body for several hours has their anti-anginal efficacy been restored.<br/>Pharmacokinetics: The kinetics of absorption of isosorbide dinitrate has not been well studied. Studies of immediate-release formulations of ISDN have found highly variable bioavailability (10% to 90%) with extensive first-pass metabolism in the liver. Most such studies have observed progressive increases in bioavailability during chronic therapy; it is not known whether similar increases in bioavailability appear during the course of chronic therapy with Isosorbide Dinitrate Extended-release Tablets. Once absorbed, the volume of distribution of isosorbide dinitrate is 2 to 4 L/kg, and this volume is cleared at the rate of 2 to 4 L/min, so ISDN's half-life in serum is about an hour. Since the clearance exceeds hepatic blood flow, considerable extrahepatic metabolism must also occur. Clearance is effected primarily by denitration to the 2-mononitrate (15 to 25%) and the 5-mononitrate (75 to 85%). Both metabolites have biological activity, especially the 5-mononitrate. With an overall half-life of about 5 hours, the 5-mononitrate is cleared from the serum by denitration to isosorbide, glucuronidation to the 5-mononitrate glucuronide, and denitration/hydration to sorbitol. The 2-mononitrate has been less well studied, but it appears to participate in the same metabolic pathways, with a half-life of about 2 hours. The daily dose-free interval sufficient to avoid tolerance to ISDN has not been well defined. Studies of nitroglycerin (an organic nitrate with a very short half-life) have shown that daily dose-free intervals of 10 to 12 hours are usually sufficient to minimize tolerance. Daily dose-free intervals that have succeeded in avoiding tolerance during trials of moderate doses (e.g., 30 mg) of immediate-release ISDN have generally been somewhat longer (at least 14 hours), but this is consistent with the longer half-lives of ISDN and its active metabolites. A dose-free interval sufficient to avoid tolerance with Isosorbide Dinitrate Extended-release Tablets has not been demonstrated. Clinical trials using Isosorbide Dinitrate Extended-release Tablets in a regimen designed to avoid tolerance have not been conducted, but in a multiple-dose study of another controlled-release isosorbide dinitrate product, 40 mg capsules were administered at 0800 and 1400 hours. After two weeks of this regimen, the controlled-release isosorbide dinitrate product was statistically indistinguishable from placebo. For the formulation of controlled-release isosorbide dinitrate that was tested, the necessary dose-free interval must therefore be greater than 18 hours; the necessary interval for Isosorbide Dinitrate Extended-release Tablets remains unknown. Few well-controlled clinical trials of organic nitrates have been designed to detect rebound or withdrawal effects. In one such trial, however, subjects receiving nitroglycerin had less exercise tolerance at the end of the daily dose-free interval than the parallel group receiving placebo. The incidence, magnitude, and clinical significance of similar phenomena in patients receiving ISDN have not been studied.<br/>Clinical Trials: In clinical trials, immediate-release oral isosorbide dinitrate has been administered in a variety of regimens, with total daily doses ranging from 30 mg to 480 mg. Controlled trials of single doses of controlled-release isosorbide dinitrate have demonstrated effective reductions in exercise-related angina for up to 8 hours. Anti-anginal activity is present about 1 hour after dosing. Adequate multiple-dose trials of Isosorbide Dinitrate Extended-release Tablets have not been reported. Most controlled trials of multiple-dose immediate-release oral ISDN taken every 12 hours (or more frequently) for several weeks have shown statistically significant anti-anginal efficacy for only 2 hours after dosing. Once-daily regimens, and regimens with one daily dose-free interval of at least 14 hours (e.g., a regimen providing doses at 0800, 1400 and 1800 hours), have shown efficacy after the first dose of each day that was similar to that shown in the single-dose studies cited above. The efficacy of subsequent doses has not been demonstrated. From large, well-controlled studies of other nitrates, it is reasonable to believe that the maximal achievable daily duration of anti-anginal effect from isosorbide dinitrate is about 12 hours. No dosing regimen for Isosorbide Dinitrate Extended-release Tablets has, however, ever actually been shown to achieve this duration of effect. | lld:dailymed |
| dailymed-drugs:258 | dailymed-instance:clinicalP... | Pharmacodynamics: The mechanism of action of sertraline is presumed to be linked to its inhibition of CNS neuronal uptake of serotonin (5HT). Studies at clinically relevant doses in man have demonstrated that sertraline blocks the uptake of serotonin into human platelets. In vitro studies in animals also suggest that sertraline is a potent and selective inhibitor of neuronal serotonin reuptake and has only very weak effects on norepinephrine and dopamine neuronal reuptake. In vitro studies have shown that sertraline has no significant affinity for adrenergic (alpha, alpha, beta), cholinergic, GABA, dopaminergic, histaminergic, serotonergic (5HT, 5HT, 5HT), or benzodiazepine receptors; antagonism of such receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects for other psychotropic drugs. The chronic administration of sertraline was found in animals to downregulate brain norepinephrine receptors, as has been observed with other drugs effective in the treatment of major depressive disorder. Sertraline does not inhibit monoamine oxidase.<br/>Pharmacokinetics:<br/>Systemic Bioavailability���: In man, following oral once-daily dosing over the range of 50 to 200 mg for 14 days, mean peak plasma concentrations (C) of sertraline occurred between 4.5 to 8.4 hours post-dosing. The average terminal elimination half-life of plasma sertraline is about 26 hours. Based on this pharmacokinetic parameter, steady-state sertraline plasma levels should be achieved after approximately one week of once-daily dosing. Linear dose-proportional pharmacokinetics were demonstrated in a single dose study in which the Cand area under the plasma concentration time curve (AUC) of sertraline were proportional to dose over a range of 50 to 200 mg. Consistent with the terminal elimination half-life, there is an approximately two-fold accumulation, compared to a single dose, of sertraline with repeated dosing over a 50 to 200 mg dose range. The single dose bioavailability of sertraline tablets is approximately equal to an equivalent dose of solution. In a relative bioavailability study comparing the pharmacokinetics of 100 mg sertraline as the oral solution to a 100 mg sertraline tablet in 16 healthy adults, the solution to tablet ratio of geometric mean AUC and Cvalues were 114.8% and 120.6%, respectively. 90% confidence intervals (CI) were within the range of 80-125% with the exception of the upper 90% CI limit for Cwhich was 126.5%. The effects of food on the bioavailability of the sertraline tablet and oral concentrate were studied in subjects administered a single dose with and without food. For the tablet, AUC was slightly increased when drug was administered with food but the Cwas 25% greater, while the time to reach peak plasma concentration (T) decreased from 8 hours post-dosing to 5.5 hours. For the oral concentrate, Twas slightly prolonged from 5.9 hours to 7.0 hours with food.<br/>Metabolism-: Sertraline undergoes extensive first pass metabolism. The principal initial pathway of metabolism for sertraline is N-demethylation. N-desmethylsertraline has a plasma terminal elimination half-life of 62 to 104 hours. Both in vitro biochemical and in vivo pharmacological testing have shown N-desmethylsertraline to be substantially less active than sertraline. Both sertraline and N-desmethylsertraline undergo oxidative deamination and subsequent reduction, hydroxylation, and glucuronide conjugation. In a study of radiolabeled sertraline involving two healthy male subjects, sertraline accounted for less than 5% of the plasma radioactivity. About 40-45% of the administered radioactivity was recovered in urine in 9 days. Unchanged sertraline was not detectable in the urine. For the same period, about 40-45% of the administered radioactivity was accounted for in feces, including 12-14% unchanged sertraline. Desmethylsertraline exhibits time-related, dose dependent increases in AUC (0-24 hour), Cand C, with about a 5-9 fold increase in these pharmacokinetic parameters between day 1 and day 14.<br/>Protein Binding-: In vitro protein binding studies performed with radiolabeledH-sertraline showed that sertraline is highly bound to serum proteins (98%) in the range of 20 to 500 ng/mL. However, at up to 300 and 200 ng/mL concentrations, respectively, sertraline and N-desmethylsertraline did not alter the plasma protein binding of two other highly protein bound drugs, viz., warfarin and propranolol .<br/>Pediatric Pharmacokinetics-: Sertraline pharmacokinetics were evaluated in a group of 61 pediatric patients (29 aged 6 to 12 years, 32 aged 13 to 17 years). Patients included both males (N=28) and females (N=33). During 42 days of chronic sertraline dosing, sertraline was titrated up to 200 mg/day and maintained at that dose for a minimum of 11 days. On the final day of sertraline 200 mg/day, the 6-12 year old group exhibited a mean sertraline AUC (0-24 hr) of 3107 ng-hr/mL, mean Cof 165 ng/mL, and mean half-life of 26.2 hr. The 13-17 year old group exhibited a mean sertraline AUC (0-24 hr) of 2296 ng-hr/mL, mean Cof 123 ng/mL, and mean half-life of 27.8 hr. Higher plasma levels in the 6-12 year old group were largely attributable to patients with lower body weights. No gender associated differences were observed. By comparison, a group of 22 separately studied adults between 18 and 45 years of age (11 male,11 female) received 30 days of 200 mg/day sertraline and exhibited a mean sertraline AUC (0-24 hr) of 2570 ng-hr/mL, mean Cof 142 ng/mL, and mean half-life of 27.2 hr. Relative to the adults, both the 6-12 year olds and the 13-17 year olds showed about 22% lower AUC (0-24 hr) and Cvalues when plasma concentration was adjusted for weight. These data suggest that pediatric patients metabolize sertraline with slightly greater efficiency than adults. Nevertheless, lower doses may be advisable for pediatric patients given their lower body weights, especially in very young patients, in order to avoid excessive plasma levels .<br/>Age-: Sertraline plasma clearance in a group of 16 (8 male, 8 female) elderly patients treated for 14 days at a dose of 100 mg/day was approximately 40% lower than in a similarly studied group of younger (25 to 32 y.o.) individuals. Steady-state, therefore, should be achieved after 2 to 3 weeks in older patients. The same study showed a decreased clearance of desmethylsertraline in older males, but not in older females.<br/>Liver Disease-: As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of sertraline. In patients with chronic mild liver impairment (N=10, 8 patients with Child-Pugh scores of 5-6 and 2 patients with Child-Pugh scores of 7-8) who received 50 mg sertraline per day maintained for 21 days, sertraline clearance was reduced, resulting in approximately 3-fold greater exposure compared to age-matched volunteers with no hepatic impairment (N=10). The exposure to desmethylsertraline was approximately 2-fold greater compared to age-matched volunteers with no hepatic impairment. There were no significant differences in plasma protein binding observed between the two groups. The effects of sertraline in patients with moderate and severe hepatic impairment have not been studied. The results suggest that the use of sertraline in patients with liver disease must be approached with caution. If sertraline is administered to patients with liver impairment, a lower or less frequent dose should be used .<br/>Renal Disease-: Sertraline is extensively metabolized and excretion of unchanged drug in urine is a minor route of elimination. In volunteers with mild to moderate (CL=30-60 mL/min), moderate to severe (CL=10-29 mL/min) or severe (receiving hemodialysis) renal impairment (N=10 each group), the pharmacokinetics and protein binding of 200 mg sertraline per day maintained for 21 days were not altered compared to age-matched volunteers (N=12) with no renal impairment. Thus sertraline multiple dose pharmacokinetics appear to be unaffected by renal impairment .<br/>Clinical Trials:<br/>Major Depressive Disorder-: The efficacy of sertraline hydrochloride tablets as a treatment for major depressive disorder was established in two placebo-controlled studies in adult outpatients meeting DSM-III criteria for major depressive disorder. Study 1 was an 8-week study with flexible dosing of sertraline hydrochloride tablets in a range of 50 to 200 mg/day; the mean dose for completers was 145 mg/day. Study 2 was a 6-week fixed-dose study, including sertraline hydrochloride tablets doses of 50, 100, and 200 mg/day. Overall, these studies demonstrated sertraline hydrochloride tablets to be superior to placebo on the Hamilton Depression Rating Scale and the Clinical Global Impression Severity and Improvement scales. Study 2 was not readily interpretable regarding a dose response relationship for effectiveness. Study 3 involved depressed outpatients who had responded by the end of an initial 8-week open treatment phase on sertraline hydrochloride tablets 50-200 mg/day. These patients (N=295) were randomized to continuation for 44 weeks on double-blind sertraline hydrochloride tablets 50-200 mg/day or placebo. A statistically significantly lower relapse rate was observed for patients taking sertraline hydrochloride tablets compared to those on placebo. The mean dose for completers was 70 mg/day. Analyses for gender effects on outcome did not suggest any differential responsiveness on the basis of sex. | lld:dailymed |
| dailymed-drugs:259 | dailymed-instance:clinicalP... | Following intravascular injection, CONRAY is rapidly transported through the circulatory system to the kidneys and is excreted unchanged in the urine by glomerular filtration. The pharmacokinetics of intravascularly administered radiopaque contrast media are usually best described by a two compartment model with a rapid alpha phase for drug distribution and a slower beta phase for drug elimination. In patients with normal renal function, the alpha and beta half-lives of CONRAY were approximately 10 and 90 minutes, respectively. Angiography may be performed following intravascular injection which will permit visualization until significant hemodilution occurs. Renal accumulation is sufficiently rapid that maximum radiographic density in the calyces and pelves occurs, in most instances, about 3-8 minutes after injection. In patients with impaired renal function, diagnostic opacification frequently is achieved only after prolonged periods. Injectable iodinated contrast agents are excreted either through the kidneys or through the liver. These two excretory pathways are not mutually exclusive, but the main route of excretion seems to be related to the affinity of the contrast medium for serum albumin. Iothalamate salts are poorly bound to serum albumin, and are excreted mainly through the kidneys. The liver and small intestine provide the major alternate route of excretion. In patients with severe renal impairment, the excretion of this contrast medium through the gallbladder and into the small intestine sharply increases. Iothalamate salts cross the placental barrier in humans and are excreted unchanged in human milk. The biliary system, pancreatic duct or joint spaces may be visualized by the direct injection of contrast medium into the region to be studied.<br/>CT Scanning of the Head: When used for contrast enhancement in computed tomographic brain scanning, the degree of enhancement is directly related to the amount of iodine administered. Rapid injection of the entire dose yields peak blood iodine concentrations immediately following the injection, which fall rapidly over the next five to ten minutes. This can be accounted for by the dilution in the vascular and extracellular fluid compartments which causes an initial sharp fallin plasma concentration. Equilibration with the extracellular compartments is reached by about ten minutes; thereafter, the fall becomes exponential. Maximum contrast enhancement frequently occurs after peak blood iodine levels are reached. The delay in maximum contrast enhancement can range from five to forty minutes, depending on the peak iodine levels achieved and the cell type of the lesion. This lag suggests that the contrast enhancement of the image is at least in part dependent on the accumulation ofiodine within the lesion and outside the blood pool. In brain scanning, the contrast medium (CONRAY) does not accumulate in normal brain tissue due to the presence of the���blood brain barrier.���The increase in x-ray absorption in the normal brain is due to the presence of the contrast agent within the blood pool. A break in the blood brain barrier, such as occurs in malignant tumors of the brain, allows accumulation of contrast medium within the interstitial tumor tissue; adjacent normal brain tissue does not contain the contrast medium. The image enhancement of non-tumoral lesions, such as arteriovenous malformations and aneurysms, is dependent on the iodine content of the circulating blood pool. When used for cranial computerized angiotomography, rapid bolus injection and/or infusion combined with rapid CT scanning will provide clear delineation of the cerebral vessels.<br/>CT Scanning of the Body: In non-neural tissues (during CT of the body), CONRAY diffuses rapidly from the vascular to the extra-vascular space. Increase in x-ray absorption is related to blood flow, concentration of the contrast medium and extraction of the contrast medium by interstitial tissue, since no barrier exists; contrast enhancement is thus due to the relative differences in extra-vascular diffusion between normal and abnormal tissue, a situation quite different than that in the brain. The pharmacokinetics of CONRAY in normal and abnormal tissues has been shown to be variable. Enhancement of CT with CONRAY may be of benefit in establishing diagnoses of certain lesions in some sites with greater assurance than is possible with unenhanced CT and in supplying additional features of the lesions. In other cases, the contrast medium may allow visualization of lesions not seen with CT alone or may help to define suspicious lesions seen with unenhanced CT. Contrast enhancement appears to be greatest within the 30-90 seconds after bolus administration of the contrast agent, and after intra-arterial, rather than intravenous, administration. Therefore, the use of a continuous scanning technique (a series of 2-3 second scans beginning at the injection���dynamic CT scanning) may improve enhancement and diagnostic assessment of tumors and other lesions, such as an abscess, occasionally revealing more extensive disease. A cyst, or similar non-vascularized lesion, may be distinguished from vascularized solid lesions by comparing enhanced and unenhanced scans; non-vascularized lesions show no change in CT number, whereas vascularized lesions would show an increase. The latter might bebenign, malignant or normal, but it is unlikely that it would be a cyst, hematoma, or other non-vascularized lesion. Because unenhanced scanning may provide adequate information in the individual patient, the decision to employ contrast enhancement, which is associated with additional risk and increased exposure, should be based upon a careful evaluation of clinical, other radiological, and unenhanced CT findings. | lld:dailymed |
| dailymed-drugs:260 | dailymed-instance:clinicalP... | Tetracyclines are readily absorbed and are bound to plasma proteins in varying degree. They are concentrated by the liver in the bile and excreted in the urine and feces at high concentrations and in a biologically active form. Doxycycline is virtually completely absorbed after oral administration. Following a 200 mg dose, normal adult volunteers averaged peak serum levels of 2.6 mcg/mL of doxycycline at 2 hours decreasing to 1.45 mcg/mL at 24 hours. Excretion of doxycycline by the kidney is about 40%/72 hours in individuals with normal function (creatinine clearance about 75 mL/min). This percentage excretion may fall as low as 1-5%/72 hours in individuals with severe renal insufficiency (creatinine clearance below 10 mL/min). Studies have shown no significant difference in serum half-life of doxycycline (range 18-22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter serum half-life. Results of animal studies indicate that tetracyclines cross the placenta and are found in fetal tissues.<br/>Microbiology: The tetracyclines are primarily bacteriostatic and are thought to exert their antimicrobial effect by the inhibition of protein synthesis. The tetracyclines, including doxycycline, have a similar antimicrobial spectrum of activity against a wide range of gram-positive and gram-negative organisms. Cross-resistance of these organisms to tetracycline is common. Gram-Negative Bacteria Neisseria gonorrhoeaeCalymmatobacterium granulomatisHaemophilus ducreyiHaemophilus influenzaeYersinia pestis (formerly Pasturella pestis)Francisella tularensis (formerly Pasteurella tularensis)Vibrio cholerae (formerly Vibrio comma)Bartonella bacilliformisBrucella species Because many strains of the following groups of gram-negative microorganisms have been shown to be resistant to tetracyclines, culture and susceptibility testing are recommended: Escherichia coliKlebsiella speciesEnterobacter aerogenesShigella speciesAcinetobacter species (formerly Mima species and Herellea species)Bacteroides species Gram-Positive Bacteria Because many strains of the following groups of gram-positive microorganisms have been shown to be resistant to tetracycline, culture and susceptibility testing are recommended. Up to 44 percent of strains of Streptococcus pyogenes and 74 percent of Streptococcus faecalis have been found to be resistant to tetracycline drugs. Therefore, tetracycline should not be used for streptococcal disease unless the organism has been demonstrated to be susceptible. Streptococcus pyogenesStreptococcus pneumoniaeEnterococcus group (Streptococcus faecalis and Streptococcus faecium)Alpha-hemolytic streptococci (viridans group) Other Microorganisms RickettsiaeChlamydia psittaciChlamydia trachomatisMycoplasma pneumoniaeUreaplasma urealyticumBorrelia recurrentisTreponema pallidumTreponema pertenueClostridium speciesFusobacterium fusiformeActinomyces speciesBacillus anthracisPropionibacterium acnesEntamoeba speciesBalantidium coliPlasmodium falciparum Doxycycline has been found to be active against the asexual erythrocytic forms of Plasmodium falciparum but not against the gametocytes of P. falciparum. The precise mechanism of action of the drug is not known.<br/>Susceptibility Tests: Diffusion Techniques: Quantitative methods that require measurement of zone diameters give the most precise estimate of the susceptibility of bacteria to antimicrobial agents. One such standard procedurethat has been recommended for use with disks to test susceptibility of organisms to doxycycline uses the 30 mcg tetracycline-class disk or the 30 mcg doxycycline disk. Interpretation involves the correlation of the diameter obtained in the disk test with the minimum inhibitory concentration (MIC) for tetracycline or doxycycline, respectively. Reports from the laboratory giving results of the standard single-disk susceptibility test with a 30 mcg tetracycline-class disk or the 30 mcg doxycycline disk should be interpreted according to the following criteria: A report of���Susceptible���indicates that the pathogen is likely to be inhibited by generally achievable blood levels. A report of���Intermediate���suggests that the organism would be susceptible if high dosage is used or if the infection is confined to tissues and fluids in which high antimicrobial levels are attained. A report of���Resistant���indicates that achievable concentrations are unlikely to be inhibitory, and other therapy should be selected. Standardized procedures require the use of laboratory control organisms. The 30 mcg tetracycline-class disk or the 30 mcg doxycycline disk should give the following zone diameters: Dilution Techniques: Use a standardized dilution method(broth, agar, microdilution) or equivalent with tetracycline powder. The MIC values obtained should be interpreted according to the following criteria: As with standard diffusion techniques, dilution methods require the use of laboratory control organisms. Standard tetracycline powder should provide the following MIC values: | lld:dailymed |
| dailymed-drugs:262 | dailymed-instance:clinicalP... | Sulfamethoxazole and trimethoprim is rapidly absorbed following oral administration. Both sulfamethoxazole and trimethoprim exist in the blood as unbound, protein-bound and metabolized forms; sulfamethoxazole also exists as the conjugated form. The metabolism of sulfamethoxazole occurs predominately by N-acetylation, although the glucuronide conjugate has been identified. The principal metabolites of trimethoprim are the 1- and 3-oxides and the 3'- and 4'-hydroxy derivatives. The free forms of sulfamethoxazole and trimethoprim are considered to be the therapeutically active forms. Approximately 70% of sulfamethoxazole and 44% of trimethoprim are bound to plasma proteins. The presence of 10 mg percent sulfamethoxazole in plasma decreases the protein binding of trimethoprim by an insignificant degree; trimethoprim does not influence the protein binding of sulfamethoxazole. Peak blood levels for the individual components occur 1 to 4 hours after oral administration. The mean serum half-lives of sulfamethoxazole and trimethoprim are 10 and 8 to 10 hours, respectively. However, patients with severely impaired renal function exhibit an increase in the half-lives of both components, requiring dosage regimen adjustment . Detectable amounts of sulfamethoxazole and trimethoprim are present in the blood 24 hours after drug administration. During administration of 800 mg sulfamethoxazole and 160 mg trimethoprim b.i.d., the mean steady-state plasma concentration of trimethoprimwas 1.72��g/mL. The steady-state mean plasma levels of free and total sulfamethoxazole were 57.4��g/mL and 68.0��g/mL, respectively. These steady-state levels were achieved after three days of drug administration.Excretion of sulfamethoxazole and trimethoprim is primarily by the kidneys through both glomerular filtration and tubular secretion. Urine concentrations of both sulfamethoxazole and trimethoprim are considerably higher than are the concentrations in the blood. The average percentage of the dose recovered in urine from 0 to 72 hours after a single oral dose of sulfamethoxazole and trimethoprim is 84.5% for total sulfonamide and 66.8% for free trimethoprim. Thirty percent of the total sulfonamide is excreted as free sulfamethoxazole, with the remaining as N-acetylated metabolite.When administered together as sulfamethoxazole and trimethoprim, neither sulfamethoxazole nor trimethoprim affects the urinary excretion pattern of the other. Both sulfamethoxazole and trimethoprim distribute to sputum, vaginal fluid and middle ear fluid; trimethoprim also distributes to bronchial secretion, and both pass the placental barrier and are excreted in human milk.<br/>Geriatric Pharmacokinetics: The pharmacokinetics of sulfamethoxazole 800 mg and trimethoprim 160 mg were studied in 6 geriatric subjects (mean age: 78.6 years) and 6 young healthy subjects (mean age: 29.3 years) using a non-US approved formulation. Pharmacokinetic values for sulfamethoxazole in geriatric subjects were similar to those observed in young adult subjects. The mean renal clearance of trimethoprim was significantly lower in geriatric subjects compared with young adult subjects (19 mL/h/kg vs. 55 mL/h/kg). However, after normalizing by body weight, the apparent total body clearance of trimethoprim was on average 19% lower in geriatric subjects compared with young adult subjects.<br/>Microbiology: Sulfamethoxazole inhibits bacterial synthesis of dihydrofolic acid by competing with para-aminobenzoic acid (PABA). Trimethoprim blocks the production of tetrahydrofolic acid from dihydrofolic acid by binding to and reversibly inhibiting the required enzyme, dihydrofolate reductase. Thus, sulfamethoxazole and trimethoprim blocks two consecutive steps in the biosynthesis of nucleic acids and proteins essential to many bacteria. In vitro studies have shown that bacterial resistance develops more slowly with both sulfamethoxazole and trimethoprim in combination than with either sulfamethoxazole or trimethoprim alone. Sulfamethoxazole and trimethoprim have been shown to be active against most strains of the following microorganisms, both In vitro and in clinical infections as described in the INDICATIONS AND USAGE section.<br/>Aerobic Gram-Positive Microorganisms: Streptococcus pneumoniae<br/>Aerobic Gram-Negative Microorganisms: Escherichia coli (including susceptible enterotoxigenic strains implicated in traveler's diarrhea) Klebsiella species Enterobacter species Haemophilus influenzae Morganella morganii Proteus mirabilis Proteus vulgaris Shigella flexneri Shigella sonnei<br/>Other Organisms: Pneumocystis carinii<br/>Susceptibility Testing Methods:<br/>Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method(broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of sulfamethoxazole/trimethoprim powder. The MIC values should be interpreted according to the following criteria: A report of���Susceptible���indicated that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of���Intermediate���indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of���Resistant���indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.<br/>Quality Control: Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard sulfamethoxazole/trimethoprim powder should provide the following range of values:<br/>Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedurerequires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 1.25/23.75��g of sulfamethoxazole/trimethoprim to test the susceptibility of microorganisms to sulfamethoxazole/trimethoprim. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 1.25/23.75��g of sulfamethoxazole/trimethoprim disk should be interpreted according to the following criteria: Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for sulfamethoxazole/trimethoprim.<br/>Quality Control: As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 1.25/23.75��g sulfamethoxazole/trimethoprim disk* should provide the following zone diameters in these laboratory test quality control strains: *Mueller-Hinton agar should be checked for excessive levels of thymidine or thymine. To determine whether Mueller-Hinton medium has sufficiently low levels of thymidine and thymine, an Enterococcus faecalis (ATCC 29212 or ATCC 33186) may be tested with sulfamethoxazole/trimethoprim disks. A zone of inhibition���20 mm that is essentially free of fine colonies indicates a sufficiently low level of thymidine and thymine. | lld:dailymed |
| dailymed-drugs:263 | dailymed-instance:clinicalP... | Mechanism of Action: Salmeterol is a long-acting beta-adrenergic agonist. In vitro studies and in vivo pharmacologic studies demonstrate that salmeterol is selective for beta-adrenoceptors compared with isoproterenol, which has approximately equal agonist activity on beta- and beta-adrenoceptors. In vitro studies show salmeterol to be at least 50 times more selective for beta-adrenoceptors than albuterol. Although beta-adrenoceptors are the predominant adrenergic receptors in bronchial smooth muscle and beta-adrenoceptors are the predominant receptors in the heart, there are also beta-adrenoceptors in the human heart comprising 10% to 50% of the total beta-adrenoceptors. The precise function of these receptors has not been established, but they raise the possibility that even highly selective beta-agonists may have cardiac effects. The pharmacologic effects of beta-adrenoceptor agonist drugs, including salmeterol, are at least in part attributable to stimulation of intracellular adenyl cyclase, the enzyme that catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3���,5���-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels cause relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. In vitro tests show that salmeterol is a potent and long-lasting inhibitor of the release of mast cell mediators, such as histamine, leukotrienes, and prostaglandin D, from human lung. Salmeterol inhibits histamine-induced plasma protein extravasation and inhibits platelet-activating factor-induced eosinophil accumulation in the lungs of guinea pigs when administered by the inhaled route. In humans, single doses of salmeterol administered via inhalation aerosol attenuate allergen-induced bronchial hyper-responsiveness.<br/>Pharmacokinetics: Salmeterol xinafoate, an ionic salt, dissociates in solution so that the salmeterol and 1-hydroxy-2-naphthoic acid (xinafoate) moieties are absorbed, distributed, metabolized, and eliminated independently. Salmeterol acts locally in the lung; therefore, plasma levels do not predict therapeutic effect.<br/>Absorption: Because of the small therapeutic dose, systemic levels of salmeterol are low or undetectable after inhalation of recommended doses (50 mcg of salmeterol inhalation powder twice daily). Following chronic administration of an inhaled dose of 50 mcg of salmeterol inhalation powder twice daily, salmeterol was detected in plasma within 5 to 45 minutes in 7 patients with asthma; plasma concentrations were very low, with mean peak concentrations of 167 pg/mL at 20 minutes and no accumulation with repeated doses.<br/>Distribution: The percentage of salmeterol bound to human plasma proteins averages 96% in vitro over the concentration range of 8 to 7,722 ng of salmeterol base per milliliter, much higher concentrations than those achieved following therapeutic doses of salmeterol.<br/>Metabolism: Salmeterol base is extensively metabolized by hydroxylation, with subsequent elimination predominantly in the feces. No significant amount of unchanged salmeterol base has been detected in either urine or feces. An in vitro study using human liver microsomes showed that salmeterol is extensively metabolized to��-hydroxysalmeterol (aliphatic oxidation) by cytochrome P450 3A4 (CYP3A4). Ketoconazole, a strong inhibitor of CYP3A4, essentially completely inhibited the formation of��-hydroxysalmeterol in vitro.<br/>Elimination: In 2 healthy subjects who received 1 mg of radiolabeled salmeterol (as salmeterol xinafoate) orally, approximately 25% and 60% of the radiolabeled salmeterol was eliminated in urine and feces, respectively, over a period of 7 days. The terminal elimination half-life was about 5.5 hours (1 volunteer only). The xinafoate moiety has no apparent pharmacologic activity. The xinafoate moiety is highly protein bound (>99%) and has a long elimination half-life of 11 days.<br/>Special Populations: The pharmacokinetics of salmeterol base has not been studied in elderly patients nor in patients with hepatic or renal impairment. Since salmeterol is predominantly cleared by hepatic metabolism, liver function impairment may lead to accumulation of salmeterol in plasma. Therefore, patients with hepatic disease should be closely monitored.<br/>Drug Interactions: Salmeterol is a substrate of CYP3A4.<br/>Pharmacodynamics: Inhaled salmeterol, like other beta-adrenergic agonist drugs, can in some patients produce dose-related cardiovascular effects and effects on blood glucose and/or serum potassium (see PRECAUTIONS: General). The cardiovascular effects (heart rate, blood pressure) associated with salmeterol inhalation aerosol occur with similar frequency, and are of similar type and severity, as those noted following albuterol administration. The effects of rising doses of salmeterol and standard inhaled doses of albuterol were studied in volunteers and in patients with asthma. Salmeterol doses up to 84 mcg administered as inhalation aerosol resulted in heart rate increases of 3 to 16 beats/min, about the same as albuterol dosed at 180 mcg by inhalation aerosol (4 to 10 beats/min). Adolescent and adult patients receiving 50-mcg doses of salmeterol inhalation powder (N = 60) underwent continuous electrocardiographic monitoring during two 12-hour periods after the first dose and after 1 month of therapy, and no clinically significant dysrhythmias were noted. Also, pediatric patients receiving 50-mcg doses of salmeterol inhalation powder (N = 67) underwent continuous electrocardiographic monitoring during two 12-hour periods after the first dose and after 3 months of therapy, and no clinically significant dysrhythmias were noted. In 24-week clinical studies in patients with chronic obstructive pulmonary disease (COPD), the incidence of clinically significant abnormalities on the predose electrocardiograms (ECGs) at Weeks 12 and 24 in patients who received salmeterol 50 mcg was not different compared with placebo. No effect of treatment with salmeterol 50 mcg was observed on pulse rate and systolic and diastolic blood pressure in a subset of patients with COPD who underwent 12-hour serial vital sign measurements after the first dose (N = 91) and after 12 weeks of therapy (N = 74). Median changes from baseline in pulse rate and systolic and diastolic blood pressure were similar for patients receiving either salmeterol or placebo (see ADVERSE REACTIONS). Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines are administered concurrently. The clinical significance of these findings is unknown. | lld:dailymed |
| dailymed-drugs:264 | dailymed-instance:clinicalP... | NASONEX Nasal Spray, 50 mcg is a corticosteroid demonstrating anti-inflammatory properties. The precise mechanism of corticosteroid action on allergic rhinitis is not known. Corticosteroids have been shown to have a wide range of effects on multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (eg, histamine, eicosanoids, leukotrienes, and cytokines) involved in inflammation. In two clinical studies utilizing nasal antigen challenge, NASONEX Nasal Spray, 50 mcg decreased some markers of the early- and late-phase allergic response. These observations included decreases (vs placebo) in histamine and eosinophil cationic protein levels, and reductions (vs baseline) in eosinophils, neutrophils, and epithelial cell adhesion proteins. The clinical significance of these findings is not known. The effect of NASONEX Nasal Spray, 50 mcg on nasal mucosa following 12 months of treatment was examined in 46 patients with allergic rhinitis. There was no evidence of atrophy and there was a marked reduction in intraepithelial eosinophilia and inflammatory cell infiltration (eg, eosinophils, lymphocytes, monocytes, neutrophils, and plasma cells).<br/>Pharmacokinetics:<br/>Absorption: Mometasone furoate monohydrate administered as a nasal spray is virtually undetectable in plasma from adult and pediatric subjects despite the use of a sensitive assay with a lower quantitation limit (LOQ) of 50 pcg/mL.<br/>Distribution: The in vitro protein binding for mometasone furoate was reported to be 98% to 99% in concentration range of 5 to 500 ng/mL.<br/>Metabolism: Studies have shown that any portion of a mometasone furoate dose which is swallowed and absorbed undergoes extensive metabolism to multiple metabolites. There are no major metabolites detectable in plasma. Upon in vitro incubation, one of the minor metabolites formed is 6��-hydroxy-mometasone furoate. In human liver microsomes, the formation of the metabolite is regulated by cytochrome P-450 3A4 (CYP3A4).<br/>Elimination: Following intravenous administration, the effective plasma elimination half-life of mometasone furoate is 5.8 hours. Any absorbed drug is excreted as metabolites mostly via the bile, and to a limited extent, into the urine.<br/>Special Populations: The effects of renal impairment, hepatic impairment, age, or gender on mometasone furoate pharmacokinetics have not been adequately investigated.<br/>Pharmacodynamics: Four clinical pharmacology studies have been conducted in humans to assess the effect of NASONEX Nasal Spray, 50 mcg at various doses on adrenal function. In one study, daily doses of 200 and 400 mcg of NASONEX Nasal Spray, 50 mcg and 10 mg of prednisone were compared to placebo in 64 patients with allergic rhinitis. Adrenal function before and after 36 consecutive days of treatment was assessed by measuring plasma cortisol levels following a 6-hour Cortrosyn (ACTH) infusion and by measuring 24-hour urinary-free cortisol levels. NASONEX Nasal Spray, 50 mcg, at both the 200- and 400-mcg dose, was not associated with a statistically significant decrease in mean plasma cortisol levels post-Cortrosyn infusion or a statistically significant decrease in the 24-hour urinary-free cortisol levels compared to placebo. A statistically significant decrease in the mean plasma cortisol levels post-Cortrosyn infusion and 24-hour urinary-free cortisol levels was detected in the prednisone treatment group compared to placebo. A second study assessed adrenal response to NASONEX Nasal Spray, 50 mcg (400 and 1600 mcg/day), prednisone (10 mg/day), and placebo, administered for 29 days in 48 male volunteers. The 24-hour plasma cortisol area under the curve (AUC), during and after an 8-hour Cortrosyn infusion and 24-hour urinary-free cortisol levels were determined at baseline and after 29 days of treatment. No statistically significant differences of adrenal function were observed with NASONEX Nasal Spray, 50 mcg compared to placebo. A third study evaluated single, rising doses of NASONEX Nasal Spray, 50 mcg (1000, 2000, and 4000 mcg/day), orally administered mometasone furoate (2000, 4000, and 8000 mcg/day), orally administered dexamethasone (200, 400, and 800 mcg/day), and placebo (administered at the end of each series of doses) in 24 male volunteers. Dose administrations were separated by at least 72 hours. Determination of serial plasma cortisol levels at 8 AM and for the 24-hour period following each treatment were used to calculate the plasma cortisol area under the curve (AUC). In addition, 24-hour urinary-free cortisol levels were collected prior to initial treatment administration and during the period immediately following each dose. No statistically significant decreases in the plasma cortisol AUC, 8 AM cortisol levels, or 24-hour urinary-free cortisol levels were observed in volunteers treated with either NASONEX Nasal Spray, 50 mcg or oral mometasone, as compared with placebo treatment. Conversely, nearly all volunteers treated with the three doses of dexamethasone demonstrated abnormal 8 AM cortisol levels (defined as a cortisol level<10 mcg/dL), reduced 24-hour plasma AUC values, and decreased 24-hour urinary-free cortisol levels, as compared to placebo treatment. In a fourth study, adrenal function was assessed in 213 patients with nasal polyps before and after 4 months of treatment with either NASONEX Nasal Spray, 50 mcg, (200 mcg once or twice daily) or placebo by measuring 24-hour urinary-free cortisol levels. NASONEX Nasal Spray, 50 mcg, at both doses (200 and 400 mcg/day), was not associated with statistically significant decreases in the 24-hour urinary-free cortisol levels compared to placebo. Three clinical pharmacology studies have been conducted in pediatric patients to assess the effect of mometasone furoate nasal spray on the adrenal function at daily doses of 50, 100, and 200 mcg vs placebo. In one study, adrenal function before and after 7 consecutive days of treatment was assessed in 48 pediatric patients with allergic rhinitis (ages 6 to11 years) by measuring morning plasma cortisol and 24-hour urinary-free cortisol levels. Mometasone furoate nasal spray, at all three doses, was not associated with a statistically significant decrease in mean plasma cortisol levels or a statistically significant decrease in the 24-hour urinary-free cortisol levels compared to placebo. In the second study, adrenal function before and after 14 consecutive days of treatment was assessed in 48 pediatric patients (ages 3 to 5 years) with allergic rhinitis by measuring plasma cortisol levels following a 30-minute Cortrosyn infusion. Mometasone furoate nasal spray, 50 mcg, at all three doses (50, 100, and 200 mcg/day), was not associated with a statistically significant decrease in mean plasma cortisol levels post-Cortrosyn infusion compared to placebo. All patients had a normal response to Cortrosyn. In the third study, adrenal function before and after up to 42 consecutive days of once-daily treatment was assessed in 52 patients with allergic rhinitis (ages 2 to5 years), 28 of whom received mometasone furoate nasal spray, 50 mcg per nostril (total daily dose 100 mcg), by measuring morning plasma cortisol and 24-hour urinary-free cortisol levels. Mometasone furoate nasal spray was not associated with a statistically significant decrease in mean plasma cortisol levels or a statistically significant decrease in the 24-hour urinary-free cortisol levels compared to placebo.<br/>Clinical Studies:<br/>Allergic Rhinitis: The efficacy and safety of NASONEX Nasal Spray, 50 mcg in the prophylaxis and treatment of seasonal allergic rhinitis and the treatment of perennial allergic rhinitis have been evaluated in 18 controlled trials, and one uncontrolled clinical trial, in approximately 3000 adults (ages 17 to 85 years) and adolescents (ages 12 to 16 years). This included 1757 males and 1453 females, including a total of 283 adolescents (182 boys and 101 girls) with seasonal allergic or perennial allergic rhinitis, treated with NASONEX Nasal Spray, 50 mcg at doses ranging from 50 to 800 mcg/day. The majority of patients were treated with 200 mcg/day. These trials evaluated the total nasal symptom scores that included stuffiness, rhinorrhea, itching, and sneezing. Patients treated with NASONEX Nasal Spray, 50 mcg, 200 mcg/day had a significant decrease in total nasal symptom scores compared to placebo-treated patients. No additional benefit was observed for mometasone furoate doses greater than 200 mcg/day. A total of 350 patients have been treated with NASONEX Nasal Spray, 50 mcg for 1 year or longer. The efficacy and safety of NASONEX Nasal Spray, 50 mcg in the treatment of seasonal allergic and perennial allergic rhinitis in pediatric patients (ages 3 to 11 years) have been evaluated in four controlled trials. This included approximately 990 pediatric patients ages 3 to 11 years (606 males and 384 females) with seasonal allergic or perennial allergic rhinitis treated with mometasone furoate nasal spray at doses ranging from 25 to 200 mcg/day. Pediatric patients treated with NASONEX Nasal Spray, 50 mcg (100 mcg total daily dose, 374 patients) had a significant decrease in total nasal symptom (congestion, rhinorrhea, itching, and sneezing) scores, compared to placebo-treated patients. No additional benefit was observed for the 200-mcg mometasone furoate total daily dose in pediatric patients (ages 3 to 11 years). A total of 163 pediatric patients have been treated for 1 year. In patients with seasonal allergic rhinitis, NASONEX Nasal Spray, 50 mcg, demonstrated improvement in nasal symptoms (vs placebo) within 11 hours after the first dose based on one single-dose, parallel-group study of patients in an outdoor "park" setting (park study) and one environmental exposure unit (EEU) study, and within 2 days in two randomized, double-blind, placebo-controlled, parallel-group seasonal allergic rhinitis studies. Maximum benefit is usually achieved within 1 to 2 weeks after initiation of dosing. Prophylaxis of seasonal allergic rhinitis for patients 12 years of age and older with NASONEX Nasal Spray, 50 mcg, given at a dose of 200 mcg/day, was evaluated in two clinical studies in 284 patients. These studies were designed such that patients received 4 weeks of prophylaxis with NASONEX Nasal Spray, 50 mcg prior to the anticipated onset of the pollen season; however, some patients received only 2 to 3 weeks of prophylaxis. Patients receiving 2 to 4 weeks of prophylaxis with NASONEX Nasal Spray, 50 mcg demonstrated a statisticallysignificantly smaller mean increase in total nasal symptom scores with onset of the pollen season as compared to placebo patients.<br/>Nasal Polyps: Two studies were performed to evaluate the efficacy and safety of NASONEX Nasal Spray in the treatment of nasal polyps. These studies involved 664 patients with nasal polyps, 441 of whom received NASONEX Nasal Spray. These studies were randomized, double-blind, placebo-controlled, parallel group, multicenter studies in patients 18 to 86 years of age with bilateral nasal polyps. Patients were randomized to receive NASONEX Nasal Spray 200 mcg once daily, 200 mcg twice daily or placebo for a period of 4 months. The co-primary efficacy endpoints were 1) change from baseline in nasal congestion/obstruction averaged over the first month of treatment; and 2) change from baseline to last assessment in bilateral polyp grade during the entire 4 months of treatment as assessed by endoscopy. Efficacy was demonstrated in both studies at a dose of 200 mcg twice daily and in one study at a dose of 200 mcg once a day (see table below). There were no clinically relevant differences in the effectiveness of NASONEX Nasal Spray, 50 mcg, in the studies evaluating treatment of nasal polyps across subgroups of patients defined by gender, age, or race. | lld:dailymed |
| dailymed-drugs:265 | dailymed-instance:clinicalP... | Pharmacokinetics The pharmacokinetics of acyclovir after oral administration have been evaluated in healthy volunteers and in immunocompromised patients with herpes simplex or varicella-zoster virus infection. Acyclovir pharmacokinetic parameters are summarised in Table 1. *Bioavailability decreases with increasing dose. In one multiple-dose, cross-over study in healthy subjects (n=23), it was shown that increases in plasma acyclovir concentrations were less than dose proportional with increasing dose, as shown in Table 2. The decrease in bioavailability is a function of the dose and not the dosage form. There was no effect of food on the absorption of acyclovir (n=6); therefore, Acyclovir Capsules and Tablets may be administered with or without food. The only known urinary metabolite is 9-[(carboxymethoxy)methyl]guanine. | lld:dailymed |
| dailymed-drugs:266 | dailymed-instance:clinicalP... | Pharmacodynamics: CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereospecific receptors at several sites within the central nervous system. Their exact mechanism of action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis.<br/>Pharmacokinetics:<br/>Absorption: Following oral administration of Alprazolam (immediate-release) tablets, alprazolam is readily absorbed. Peak concentrations in the plasma occur in one to two hours following administration. Plasma levels are proportional to the dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL were observed. Using a specific assay methodology, the mean plasma elimination half-life of alprazolam has been found to be about 11.2 hours (range: 6.3���26.9 hours) in healthy adults. The mean absolute bioavailability of alprazolam from Alprazolam XR tablets is approximately 90%, and the relative bioavailability compared to Alprazolam tablets is 100%. The bioavailability and pharmacokinetics of alprazolam following administration of Alprazolam XR tablets are similar to that for Alprazolam tablets, with the exception of a slower rate of absorption. The slower absorption rate results in a relatively constant concentration that is maintained between 5 and 11 hours after the dosing. The pharmacokinetics of alprazolam and two of its major active metabolites (4-hydroxyalprazolam and��-hydroxyalprazolam) are linear, and concentrations are proportional up to the recommended maximum daily dose of 10 mg given once daily. Multiple dose studies indicate that the metabolism and elimination of alprazolam are similar for the immediate-release and the extended-release products. Food has a significant influence on the bioavailability of Alprazolam XR tablets. A high-fat meal given up to 2 hours before dosing with Alprazolam XR tablets increased the mean Cby about 25%. The effect of this meal on Tdepended on the timing of the meal, with a reduction in Tby about 1/3 for subjects eating immediately before dosing and an increase in Tby about 1/3 for subjects eating 1 hour or more after dosing. The extent of exposure (AUC) and elimination half-life (t) were not affected by eating. There were significant differences in absorption rate for the Alprazolam XR tablet, depending on the time of day administered, with the Cincreased by 30% and the Tdecreased by an hour following dosing at night, compared to morning dosing.<br/>Distribution: The apparent volume of distribution of alprazolam is similar for Alprazolam XR and Alprazolam tablets. In vitro, alprazolam is bound (80%) to human serum protein. Serum albumin accounts for the majority of the binding.<br/>Metabolism: Alprazolam is extensively metabolized in humans, primarily by cytochrome P450 3A4 (CYP3A4), to two major metabolites in the plasma: 4-hydroxyalprazolam and��-hydroxyalprazolam. A benzophenone derived from alprazolam is also found in humans. Their half-lives appear to be similar to that of alprazolam. The pharmacokinetic parameters at steady-state for the two hydroxylated metabolites of alprazolam (4-hydroxyalprazolam and��-hydroxyalprazolam) were similar for Alprazolam and Alprazolam XR tablets, indicating that the metabolism of alprazolam is not affected by absorption rate. The plasma concentrations of 4-hydroxyalprazolam and��-hydroxyalprazolam relative to unchanged alprazolam concentration after both Alprazolam XR and Alprazolam tablets were always less than 10% and 4%, respectively. The reported relative potencies in benzodiazepine receptor binding experiments and in animal models of induced seizure inhibition are 0.20 and 0.66, respectively, for 4-hydroxyalprazolam and��-hydroxyalprazolam. Such low concentrations and the lesser potencies of 4-hydroxyalprazolam and��-hydroxyalprazolam suggest that they are unlikely to contribute much to the pharmacological effects of alprazolam. The benzophenone metabolite is essentially inactive.<br/>Elimination: Alprazolam and its metabolites are excreted primarily in the urine. The mean plasma elimination half-life of alprazolam following administration of Alprazolam XR tablet ranges from 10.7���15.8 hours in healthy adults.<br/>Special Populations: While pharmacokinetic studies have not been performed in special populations with Alprazolam XR tablets, the factors (such as age, gender, hepatic or renal impairment) that would affect the pharmacokinetics of alprazolam after the administration of Alprazolam tablets would not be expected to be different with the administration of Alprazolam XR tablets. Changes in the absorption, distribution, metabolism, and excretion of benzodiazepines have been reported in a variety of disease states including alcoholism, impaired hepatic function, and impaired renal function. Changes have also been demonstrated in geriatric patients. A mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects (range: 9.0���26.9 hours, n=16) compared to 11.0 hours (range: 6.3-15.8 hours, n=16) in healthy adult subjects. In patients with alcoholic liver disease the half-life of alprazolam ranged between 5.8 and 65.3 hours (mean: 19.7 hours, n=17) as compared to between 6.3 and 26.9 hours (mean=11.4 hours, n=17) in healthy subjects. In an obese group of subjects the half-life of alprazolam ranged between 9.9 and 40.4 hours (mean=21.8 hours, n=12) as compared to between 6.3 and 15.8 hours (mean=10.6 hours, n=12) in healthy subjects. Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes transplacental passage and that it is excreted in human milk.<br/>Drug-Drug Interactions: Alprazolam is primarily eliminated by metabolism via cytochrome P450 3A (CYP3A). Most of the interactions that have been documented with alprazolam are with drugs that inhibit or induce CYP3A4. Compounds that are potent inhibitors of CYP3A would be expected to increase plasma alprazolam concentrations. Drug products that have been studied in vivo, along with their effect on increasing alprazolam AUC, are as follows: ketoconazole, 3.98 fold; itraconazole, 2.70 fold; nefazodone, 1.98 fold; fluvoxamine, 1.96 fold; and erythromycin, 1.61 fold . CYP3A inducers would be expected to decrease alprazolam concentrations and this has been observed in vivo. The oral clearance of alprazolam (given in a 0.8 mg single dose) was increased from 0.90��0.21 mL/min/kg to 2.13��0.54 mL/min/kg and the elimination twas shortened (from 17.1��4.9 to 7.7��1.7 h) following administration of 300 mg/day carbamazepine for 10 days . However, the carbamazepine dose used in this study was fairly low compared to the recommended doses (1000���1200 mg/day); the effect at usual carbamazepine doses is unknown. The ability of alprazolam to induce or inhibit human hepatic enzyme systems has not been determined. However, this is not a property of benzodiazepines in general. Further, alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally. | lld:dailymed |
| dailymed-drugs:267 | dailymed-instance:clinicalP... | Each nitrofurantoin monohydrate/macrocrystals capsule contains two forms of nitrofurantoin. Twenty-five percent is macrocrystalline nitrofurantoin, which has slower dissolution and absorption than nitrofurantoin monohydrate. The remaining 75% is nitrofurantoin monohydrate contained in a powder blend which, upon exposure to gastric and intestinal fluids, forms a gel matrix that releases nitrofurantoin over time. Based on urinary pharmacokinetic data, the extent and rate of urinary excretion of nitrofurantoin from the 100 mg nitrofurantoin monohydrate/macrocrystals capsule are similar to those of the 50 mg or 100 mg nitrofurantoin macrocrystals capsule. Approximately 20 to 25% of a single dose of nitrofurantoin is recovered from the urine unchanged over 24 hours. Plasma nitrofurantoin concentrations after a single oral dose of the 100 mg nitrofurantoin monohydrate/macrocrystals capsule are low, with peak levels usually less than 1 mcg/mL. Nitrofurantoin is highly soluble in urine, to which it may impart a brown color. When nitrofurantoin monohydrate/macrocrystals is administered with food, the bioavailability of nitrofurantoin is increased by approximately 40%.<br/>Microbiology: Nitrofurantoin is bactericidal in urine at therapeutic doses. The mechanism of the antimicrobial action of nitrofurantoin is unusual among antibacterials. Nitrofurantoin is reduced by bacterial flavoproteins to reactive intermediates which inactivate or alter bacterial ribosomal proteins and other macromolecules. As a result of such inactivations, the vital biochemical processes of protein synthesis, aerobic energy metabolism, DNA synthesis, RNA synthesis, and cell wall synthesis are inhibited. The broad-based nature of this mode of action may explain the lack of acquired bacterial resistance to nitrofurantoin, as the necessary multiple and simultaneous mutations of the target macromolecules would likely be lethal to the bacteria. Development of resistance to nitrofurantoin has not been a significant problem since its introduction in 1953. Cross-resistance with antibiotics and sulfonamides has not been observed, and transferable resistance is, at most, a very rare phenomenon. Nitrofurantoin, in the form of nitrofurantoin monohydrate/macrocrystals, has been shown to be active against most strains of the following bacteria both in vitro and in clinical infections: Gram-Positive AerobesStaphylococcus saprophyticus Gram-Negative AerobesEscherichia coli Nitrofurantoin also demonstrates in vitro activity against the following microorganisms, although the clinical significance of these data with respect to treatment with nitrofurantoin monohydrate/macrocrystals is unknown: Gram-Positive AerobesCoagulase-negative staphylococci(including Staphylococcus epidermidis)Enterococcus faecalisStaphylococcus aureusStreptococcus agalactiaeGroup D streptococciViridans group streptococci Gram-Negative AerobesCitrobacter amalonaticusCitrobacter diversusCitrobacter freundiiKlebsiella oxytocaKlebsiella ozaenae Nitrofurantoin is not active against most strains of Proteus species or Serratia species. It has no activity against Pseudomonas species. Antagonism has been demonstrated in vitro between nitrofurantoin and quinolone antimicrobials. The clinical significance of this finding is unknown.<br/>Susceptibility Tests:<br/>Dilution Techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MIC's). These MIC's provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MIC's should be determined using a standardized procedure. Standardized procedures are based on a dilution method(broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of nitrofurantoin powder. The MIC values should be interpreted according to the following criteria: A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the urine reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the urine reaches the concentrations usually achievable; other therapy should be selected. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard nitrofurantoin powder should provide the following MIC values:<br/>Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedurerequires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 300��g nitrofurantoin to test the susceptibility of microorganisms to nitrofurantoin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 300��g nitrofurantoin disk should be interpreted according to the following criteria: Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for nitrofurantoin. As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 300��g nitrofurantoin disk should provide the following zone diameters in these laboratory test quality control strains: | lld:dailymed |
| dailymed-drugs:268 | dailymed-instance:clinicalP... | Milrinone is a positive inotrope and vasodilator, with little chronotropic activity different in structure and mode of action from either the digitalis glycosides or catecholamines. Milrinone, at relevant inotropic and vasorelaxant concentrations, is a selective inhibitor of peak III cAMP phosphodiesterase isozyme in cardiac and vascular muscle. This inhibitory action is consistent with cAMP mediated increases in intracellular ionized calcium and contractile force in cardiac muscle, as well as with cAMP dependent contractile protein phosphorylation and relaxation in vascular muscle. Additional experimental evidence also indicates that milrinone is not a beta-adrenergic agonist nor does it inhibit sodium-potassium adenosine triphosphatase activity as dothe digitalis glycosides. Clinical studies in patients with congestive heart failure have shown that milrinone produces dose-related and plasma drug concentration-related increases in the maximum rate of increase of left ventricular pressure. Studies in normal subjects have shown that milrinone produces increases in the slope of the left ventricular pressure-dimension relationship, indicating a direct inotropic effect of the drug. Milrinone also produces dose-related and plasma concentration-related increases in forearm blood flow in patients with congestive heart failure, indicating a direct arterial vasodilator activity of the drug. Both the inotropic and vasodilatory effects have been observed over the therapeutic range of plasma milrinone concentrations of 100 ng/mL to 300 ng/mL. In addition to increasing myocardial contractility, milrinone improves diastolic function as evidenced by improvements in left ventricular diastolic relaxation. The acute administration of intravenous milrinone has also been evaluated in clinical trials in excess of 1600 patients with chronic heart failure, heart failure associated with cardiac surgery, and heart failure associated with myocardial infarction. The total number of deaths, either on therapy or shortly thereafter (24 hours) was 15, less than 0.9%, few of which were thought to be drug-related.<br/>Pharmacokinetics: Following intravenous injections of 12.5 mcg/kg to 125 mcg/kg to congestive heart failure patients, milrinone had a volume of distribution of 0.38 liters/kg, a mean terminal elimination half-life of 2.3 hours, and a clearance of 0.13 liters/kg/hr. Following intravenous infusions of 0.2 mcg/kg/min to 0.7 mcg/kg/min to congestive heart failure patients, the drug had a volume of distribution of about 0.45 liters/kg, a mean terminal elimination half-life of 2.4 hours, and a clearance of 0.14 liters/kg/hr. These pharmacokinetic parameters were not dose-dependent, and the area under the plasma concentration versus time curve following injections was significantly dose-dependent. Milrinone has been shown (by equilibrium dialysis) to be approximately 70% bound to human plasma protein. The primary route of excretion of milrinone in man is via the urine. The major urinary excretions of orally administered milrinone in man are milrinone (83%) and its 0-glucuronide metabolite (12%). Elimination in normal subjects via the urine is rapid, with approximately 60% recovered within the first two hours following dosing and approximately 90% recovered within the first eight hours following dosing. The mean renal clearance of milrinone is approximately 0.3 liters/min, indicative of active secretion.<br/>Pharmacodynamics: In patients with heart failure due to depressed myocardial function, milrinone produced a prompt dose and plasma concentration related increase in cardiac output and decreases in pulmonary capillary wedge pressure and vascular resistance, which were accompanied by mild-to-moderate increases in heart rate. Additionally, there is no increased effect on myocardial oxygen consumption. In uncontrolled studies, hemodynamic improvement during intravenous therapy with milrinone was accompanied by clinical symptomatic improvement, but the ability of milrinone to relieve symptoms has not been evaluated in controlled clinical trials. The great majority of patients experience improvements in hemodynamic function within 5 to 15 minutes of initiation of therapy. In studies in congestive heart failure patients, milrinone when administered as a loading injection followed by a maintenance infusion produced significant mean initial increases in cardiac index of 25 percent, 38 percent, and 42 percent at dose regimens of 37.5 mcg/kg/0.375 mcg/kg/min, 50 mcg/kg/0.5mcg/kg/min, and 75 mcg/kg/0.75 mcg/kg/min, respectively. Over the same range of loading injections and maintenance infusions, pulmonary capillary wedge pressure significantly decreased by 20 percent, 23 percent, and 36 percent, respectively, while systemic vascular resistance significantly decreased by 17 percent, 21 percent, and 37 percent. Mean arterial pressure fell by up to 5 percent at the two lower dose regimens, but by 17 percent at the highest dose. Patients evaluated for 48 hours maintained improvements in hemodynamic function, with no evidence of diminished response (tachyphylaxis). A smaller number of patients have received infusions of milrinone for periods up to 72 hours without evidence of tachyphylaxis. The duration of therapy should depend upon patient responsiveness. Milrinone has a favorable inotropic effect in fully digitalized patients without causing signs of glycoside toxicity. Theoretically, in cases of atrial flutter/fibrillation, it is possible that milrinone may increase ventricular response rate because of its slight enhancement of AV node conduction. In these cases, digitalis should be considered prior to the institution of therapy with milrinone. Improvement in left ventricular function in patients with ischemic heart disease has been observed. The improvement has occurred without inducing symptoms or electrocardiographic signs of myocardial ischemia. The steady-state plasma milrinone concentrations after approximately 6 to 12 hours of unchanging maintenance infusion of 0.5 mcg/kg/min are approximately 200 ng/mL. Near maximum favorable effects of milrinone on cardiac output and pulmonary capillary wedge pressure are seen at plasma milrinone concentrations in the 150 ng/mL to 250 ng/mL range. | lld:dailymed |
| dailymed-drugs:269 | dailymed-instance:clinicalP... | Mechanism of Action ULTRAM ER is a centrally acting synthetic opioid analgesic. Although its mode of action is not completely understood, from animal tests, at least two complementary mechanisms appear applicable: binding of parent and M1 metabolite to��-opioid receptors and weak inhibition of reuptake of norepinephrine and serotonin. Opioid activity is due to both low affinity binding of the parent compound and higher affinity binding of the O-demethylated metabolite M1 to��-opioid receptors. In animal models, M1 is up to 6 times more potent than tramadol in producing analgesia and 200 times more potent in��-opioid binding. Tramadol-induced analgesia is only partially antagonized by the opiate antagonist naloxone in several animal tests. The relative contribution of both tramadol and M1 to human analgesia is dependent upon the plasma concentrations of each compound. Tramadol has been shown to inhibit reuptake of norepinephrine and serotonin in vitro, as have some other opioid analgesics. These mechanisms may contribute independently to the overall analgesic profile of tramadol. The relationship between exposure of tramadol and M1 and efficacy has not been evaluated in the ULTRAM ER clinical studies. Apart from analgesia, tramadol administration may produce a constellation of symptoms (including dizziness, somnolence, nausea, constipation, sweating and pruritus) similar to that of other opioids. In contrast to morphine, tramadol has not been shown to cause histamine release. At therapeutic doses, tramadol has no effect on heart rate, left-ventricular function or cardiac index. Orthostatic hypotension has been observed.<br/>Pharmacokinetics: The analgesic activity of tramadol is due to both parent drug and the M1 metabolite. ULTRAM ER is administered as a racemate and both the [-] and [+] forms of both tramadol and M1 are detected in the circulation. The pharmacokinetics of ULTRAM ER are approximately dose-proportional over a 100-400 mg dose range in healthy subjects. The observed tramadol AUC values for the 400-mg dose were 26% higher than predicted based on the AUC values for the 200-mg dose. The clinical significance of this finding has not been studied and is not known. Absorption In healthy subjects, the bioavailability of a ULTRAM ER 200 mg tablet relative to a 50 mg every six hours dosing regimen of the immediate-release dosage form (ULTRAM) was approximately 85-90%. Consistent with the extended-release nature of the formulation, there is a lag time in drug absorption following ULTRAM ER administration. The mean peak plasma concentrations of tramadol and M1 after administration of ULTRAM ER tablets to healthy volunteers are attained at about 12 h and 15 h, respectively, after dosing (see Table 1 and Figure 2). Following administration of the ULTRAM ER, steady-state plasma concentrations of both tramadol and M1 are achieved within four days with once daily dosing. The mean (%CV) pharmacokinetic parameter values for ULTRAM ER 200 mg administered once daily and tramadol HCl immediate-release (ULTRAM) 50 mg administered every six hours are provided in Table 1. Figure 2: Mean Steady-State Tramadol (a) and M1 (b) Plasma Concentrations on Day 8 Post Dose after Administration of 200 mg ULTRAM ER Once-Daily and 50 mg ULTRAM Every 6 Hours. Food Effects After a single dose administration of 200 mg ULTRAM ER tablet with a high fat meal, the Cand AUCof tramadol decreased 28% and 16%, respectively, compared to fasting conditions. Mean Twas increased by 3 hr (from 14 hr under fasting conditions to 17 hr under fed conditions). While ULTRAM ER may be taken without regard to food, it is recommended that it be taken in a consistent manner. Distribution The volume of distribution of tramadol was 2.6 and 2.9 liters/kg in male and female subjects, respectively, following a 100-mg intravenous dose. The binding of tramadol to human plasma proteins is approximately 20% and binding also appears to be independent of concentration up to 10��g/mL. Saturation of plasma protein binding occurs only at concentrations outside the clinically relevant range. Metabolism Tramadol is extensively metabolized after oral administration. The major metabolic pathways appear to be N���(mediated by CYP3A4 and CYP2B6) and O���(mediated by CYP2D6) demethylation and glucuronidation or sulfation in the liver. One metabolite (O-desmethyl tramadol, denoted M1) is pharmacologically active in animal models. Formation of M1 is dependent on CYP2D6 and as such is subject to inhibition, which may affect the therapeutic response . Elimination Tramadol is eliminated primarily through metabolism by the liver and the metabolites are eliminated primarily by the kidneys. Approximately 30% of the dose is excreted in the urine as unchanged drug, whereas 60% of the dose is excreted as metabolites. The remainder is excreted either as unidentified or as unextractable metabolites. The mean terminal plasma elimination half-lives of racemic tramadol and racemic M1 after administration of ULTRAM ER are approximately 7.9 and 8.8 hours, respectively.<br/>Special Populations: Renal Impaired renal function results in a decreased rate and extent of excretion of tramadol and its active metabolite, M1. The pharmacokinetics of tramadol were studied in patients with mild or moderate renal impairment after receiving multiple doses of ULTRAM ER 100 mg. There is no consistent trend observed for tramadol exposure related to renal function in patients with mild (CLcr: 50-80 mL/min) or moderate (CLcr: 30-50 mL/min) renal impairment in comparison to patients with normal renal function. However, exposure of M1 increased 20-40% with increased severity of the renal impairment (from normal to mild and moderate). ULTRAM ER has not been studied in patients with severe renal impairment (CLcr<30 mL/min). The limited availability of dose strengths of ULTRAM ER does not permit the dosing flexibility required for safe use in patients with severe renal impairment. Therefore, ULTRAM ER should not be used in patients with severe renal impairment . The total amount of tramadol and M1 removed during a 4-hour dialysis period is less than 7% of the administered dose. Hepatic Pharmacokinetics of tramadol was studied in patients with mild or moderate hepatic impairment after receiving multiple doses of ULTRAM ER 100 mg. The exposure of (+)- and (-)-tramadol was similar in mild and moderate hepatic impairment patients in comparison to patients with normal hepatic function. However, exposure of (+)- and (-)-M1 decreased ~50% with increased severity of the hepatic impairment (from normalto mild and moderate). The pharmacokinetics of tramadol after the administration of ULTRAM ER has not been studied in patients with severe hepatic impairment. After the administration of tramadol immediate-release tablets to patients with advanced cirrhosis of the liver, tramadol area under the plasma concentration time curve was larger and the tramadol and M1 half-lives were longer than subjects with normal hepatic function. The limited availability of dose strengths of ULTRAM ER does not permit the dosingflexibility required for safe use in patients with severe hepatic impairment. Therefore, ULTRAM ER should not be used in patients with severe hepatic impairment . Geriatric The effect of age on the absorption of tramadol from ULTRAM ER in patients over the age of 65 years has not been studied and is unknown . Gender Based on pooled multiple-dose pharmacokinetics studies for ULTRAM ER in 166 healthy subjects (111 males and 55 females), the dose-normalized AUC values for tramadol were somewhat higher in females than in males. There was a considerable degree of overlap in values between male and female groups. Dosage adjustment based on gender is not recommended.<br/>Drug Interactions: The formation of the active metabolite, M1, is mediated by CYP2D6. Approximately 7% of the population has reduced activity of the CYP2D6 isoenzyme of cytochrome P-450. Based on a population PK analysis of Phase I studies with immediate-release tablets in healthy subjects, concentrations of tramadol were approximately 20% higher in "poor metabolizers" versus "extensive metabolizers," while M1 concentrations were40% lower. In vitro drug interaction studies in human liver microsomes indicate that inhibitors of CYP2D6 (fluoxetine, norfluoxetine, amitriptyline, and quinidine) inhibit the metabolism of tramadol to various degrees, suggesting that concomitant administration of these compounds could result in increases in tramadol concentrations and decreased concentrations of M1. The full pharmacological impact of these alterations in terms of either efficacy or safety is unknown. Tramadol is also metabolized by CYP3A4. Administration of CYP3A4 inhibitors, such as ketoconazole and erythromycin, or inducers, such as rifampin and St. John's Wort, with ULTRAM ER may affect the metabolism of tramadol leading to altered tramadol exposure . Quinidine Tramadol is metabolized to M1 by CYP2D6. A study was conducted to examine the effect of quinidine, a selective inhibitor of CYP2D6, on the pharmacokinetics of tramadol by administering 200 mg quinidine two hours before the administration of ULTRAM ER 100 mg. The results demonstrated that the exposure of tramadol increased 50-60% and the exposure of M1 decreased 50-60% . In vitro drug interaction studies in human liver microsomes indicate that tramadol has no effect on quinidine metabolism. Carbamazepine Carbamazepine, a CYP3A4 inducer, increases tramadol metabolism. Patients taking carbamazepine may have a significantly reduced analgesic effect of tramadol. Because of the seizure risk associated with tramadol, concomitant administration of ULTRAM ER and carbamazepine is not recommended . Cimetidine Concomitant administration of tramadol immediate-release tablets with cimetidine does not result in clinically significant changes in tramadol pharmacokinetics. No alteration of the ULTRAM ER dosage regimen with cimetidine is recommended. | lld:dailymed |
| dailymed-drugs:270 | dailymed-instance:clinicalP... | Bethanechol chloride acts principally by producing the effects of stimulation of the parasympathetic nervous system. It increases the tone of the detrusor urinae muscle, usually producing a contraction sufficiently strong to initiate micturition and empty the bladder. It stimulates gastric motility, increases gastric tone and often restores impaired rhythmic peristalsis. Stimulation of the parasympathetic nervous system releases acetylcholine at the nerve endings. When spontaneous stimulation is reduced and therapeutic intervention is required, acetylcholine can be given, but it is rapidly hydrolyzed by cholinesterase and its effects are transient. Bethanechol chloride is not destroyed by cholinesterase and its effects are more prolonged than those of acetylcholine. Effects on the Gl and urinary tracts sometimes appear within 30 minutes after oral administration of bethanechol chloride, but more often 60 to 90 minutes are required to reach maximum effectiveness. Following oral administration, the usual duration of action of bethanechol is one hour, although large doses (300 to 400 mg) have been reported to produce effects for up to six hours. Subcutaneous injection produces a more intense action on bladder muscle than does oral administration of the drug. Because of the selective action of bethanechol, nicotinic symptoms of cholinergic stimulation are usually absent or minimal when orally or subcutaneously administered in therapeutic doses, while muscarinic effects are prominent. Muscarinic effects usually occur within 5 to 15 minutes after subcutaneous injection, reach a maximum in 15 to 30 minutes, and disappear withintwo hours. Doses that stimulate micturition and defecation and increase peristalsis do not ordinarily stimulate ganglia or voluntary muscles. Therapeutic test doses in normal human subjects have little effect on heart rate, blood pressure or peripheral circulation. Bethanechol chloride does not cross the blood-brain barrier because of its charged quaternary amine moiety. The metabolic rate and mode of excretion of the drug have not been elucidated. A clinical study (Diokno, A.C.; Lapides, J.; Urol 10: 23-24, July 1977) was conducted on the relative effectiveness of oral and subcutaneous doses of bethanechol chloride on the stretch response of bladder muscle in patients with urinary retention. Results showed that 5 mg of the drug given subcutaneously stimulated a response that was more rapid in onset and of larger magnitude than an oral dose of 50 mg, 100 mg, or 200 mg. All the oral doses, however, had a longer duration of effect than the subcutaneous dose. Althoughthe 50 mg oral dose caused little change in intravesical pressure in this study, this dose has been found in other studies to be clinically effective in the rehabilitation of patients with decompensated bladders. | lld:dailymed |
| dailymed-drugs:271 | dailymed-instance:clinicalP... | In humans, the natural supply of vitamin D depends mainly on exposure to the ultraviolet rays of the sun for conversion of 7-dehydrocholesterol to vitamin D(cholecalciferol) in the skin. Calcipotriene is a synthetic analog of vitamin D. Clinical studies with radiolabelled ointment indicate that approximately 6% (��3%, SD) of the applied dose of calcipotriene is absorbed systemically when the ointment is applied topically to psoriasis plaques or 5% (��2.6%, SD) when applied to normal skin, and much of the absorbed active is converted to inactive metabolites within 24 hours of application. Vitamin D and its metabolites are transported in the blood, bound to specific plasma proteins. The active form of the vitamin, 1,25-dihydroxy vitamin D(calcitriol), is known to be recycled via the liver and excreted in the bile. Calcipotriene metabolism following systemic uptake is rapid, and occurs via a similar pathway to the natural hormone. The primary metabolites are much less potent than the parent compound. There is evidence that maternal 1,25-dihydroxy vitamin D(calcitriol) may enter the fetal circulation, but it is not known whether it is excreted in human milk. The systemic disposition of calcipotriene is expected to be similar to that of the naturally occurring vitamin. | lld:dailymed |
| dailymed-drugs:272 | dailymed-instance:clinicalP... | CNS agents of the 1,4 benzodiazepine class presumably exert their effects by binding at stereo specific receptors at several sites within the central nervous system. Their exact mechanism of action is unknown. Clinically, all benzodiazepines cause a dose-related central nervous system depressant activity varying from mild impairment of task performance to hypnosis. Following oral administration, alprazolam is readily absorbed. Peak concentrations in the plasma occur in one to two hours following administration. Plasma levels are proportionate to the dose given; over the dose range of 0.5 to 3.0 mg, peak levels of 8.0 to 37 ng/mL were observed. Using a specific assaymethodology, the mean plasma elimination half-life of alprazolam has been found to be about 11.2 hours (range: 6.3���26.9 hours) in healthy adults. The predominant metabolites are��-hydroxy-alprazolam and a benzophenone derived from alprazolam. The biological activity of��-hydroxy-alprazolam is approximately one-half that of alprazolam. The benzophenone metabolite is essentially inactive. Plasma levels of these metabolites are extremely low, thus precluding precise pharmacokinetic description. However, their half-lives appear to be of the same order of magnitude as that of alprazolam. Alprazolam and its metabolites are excreted primarily in the urine. The ability of alprazolam to induce human hepatic enzyme systems has not yet been determined. However, this is not a property of benzodiazepines in general. Further, alprazolam did not affect the prothrombin or plasma warfarin levels in male volunteers administered sodium warfarin orally. In vitro , alprazolam is bound (80 percent) to human serum protein. Changes in the absorption, distribution, metabolism and excretion of benzodiazepines have been reported in a variety of disease states including alcoholism, impaired hepatic function and impaired renal function. Changes have also been demonstrated in geriatric patients. A mean half-life of alprazolam of 16.3 hours has been observed in healthy elderly subjects (range: 9.0���26.9 hours, n=16) compared to 11.0 hours (range: 6.3���15.8 hours, n = 16 ) in healthy adult subjects . In patients with alcoholic liver disease the half-life of alprazolam ranged between 5.8 and 65.3 hours (mean: 19.7 hours, n=17) as compared to between 6.3 and 26.9 hours (mean=11.4 hours, n=17) in healthy subjects. In an obese group of subjects the half-life of alprazolam ranged between 9.9 and 40.4 hours (mean=21.8 hours, n=12) as compared to between 6.3 and 15.8 hours (mean=10.6 hours, n=12) in healthy subjects. Because of its similarity to other benzodiazepines, it is assumed that alprazolam undergoes transplacental passage and that it is excreted in human milk. | lld:dailymed |
| dailymed-drugs:273 | dailymed-instance:clinicalP... | General: In vitro and in vivo preclinical and clinical testing have demonstrated that Nutropin AQ is therapeutically equivalent to pituitary-derived human GH (hGH). Pediatric patients who lack adequate endogenous GH secretion, patients with chronic renal insufficiency, and patients with Turner syndrome that were treated with Nutropin AQ or Nutropin [somatropin (rDNA origin) for injection] resulted in an increase in growth rate and anincrease in insulin���like growth factor-I (IGF-I) levels similar to that seen with pituitary���derived hGH. Actions that have been demonstrated for Nutropin AQ, somatropin, somatrem, and/or pituitary-derived hGH include:<br/>Tissue Growth:<br/>Protein Metabolism: Linear growth is facilitated in part by GH���stimulated protein synthesis. This is reflected by nitrogen retention as demonstrated by a decline in urinary nitrogen excretion and blood urea nitrogen during GH therapy.<br/>Carbohydrate Metabolism: GH is a modulator of carbohydrate metabolism. For example, patients with inadequate secretion of GH sometimes experience fasting hypoglycemia that is improved by treatment with GH. GH therapy may decrease insulin sensitivity. Untreated patients with chronic renal insufficiency and Turner syndrome have an increased incidence of glucose intolerance. Administration of hGH to adults or children resulted in increases in serum fasting and postprandial insulin levels, more commonly in overweight or obese individuals. In addition, mean fasting and postprandial glucose and hemoglobin Alevels remained in the normal range.<br/>Lipid Metabolism: In GH���deficient patients, administration of GH resulted in lipid mobilization, reduction in body fat stores, increased plasma fatty acids, and decreased plasma cholesterol levels.<br/>Mineral Metabolism: The retention of total body potassium in response to GH administration apparently results from cellular growth. Serum levels of inorganic phosphorus may increase slightly in patients with inadequate secretion of endogenous GH, chronic renal insufficiency, or patients with Turner syndrome during GH therapy due to metabolic activity associated with bone growth as well as increased tubular reabsorption of phosphate by the kidney. Serum calcium is not significantly altered in these patients. Sodium retention also occurs. Adults with childhood���onset GH deficiency show low bone mineral density (BMD). GH therapy results in increases in serum alkaline phosphatase.<br/>Connective Tissue Metabolism: GH stimulates the synthesis of chondroitin sulfate and collagen as well as the urinary excretion of hydroxyproline.<br/>Pharmacokinetics:<br/>Subcutaneous Absorption: The absolute bioavailability of recombinant human growth hormone (rhGH) after subcutaneous administration in healthy adult males has been determined to be 81��20%. The mean terminal tafter subcutaneous administration is significantly longer than that seen after intravenous administration (2.1��0.43 hours vs. 19.5��3.1 minutes) indicating that the subcutaneous absorption of the compound is slow and rate���limiting.<br/>Distribution: Animal studies with rhGH showed that GH localizes to highly perfused organs, particularly the liver and kidney. The volume of distribution at steady state for rhGH in healthy adult males is about 50 mL/kg body weight, approximating the serum volume.<br/>Metabolism: Both the liver and kidney have been shown to be important metabolizing organs for GH. Animal studies suggest that the kidney is the dominant organ of clearance. GH is filtered at the glomerulus and reabsorbed in the proximal tubules. It is then cleaved within renal cells into its constituent amino acids, which return to the systemic circulation.<br/>Elimination: The mean terminal tafter intravenous administration of rhGH in healthy adult males is estimated to be 19.5��3.1 minutes. Clearance of rhGH after intravenous administration in healthy adults and children is reported to be in the range of 116���174 mL/hr/kg.<br/>Bioequivalence of Formulations: Nutropin AQ has been determined to be bioequivalent to Nutropin based on the statistical evaluation of AUC and C.<br/>SPECIAL POPULATIONS: | lld:dailymed |
| dailymed-drugs:274 | dailymed-instance:clinicalP... | Human Pharmacology:: Studies have shown that following intravenous administration of cefazolin to normal volunteers, mean serum concentrations peaked at approximately 185 mcg/mL and were approximately 4 mcg/mL at 8 hours for a 1-gram dose. The serum half-life for cefazolin is approximately 1.8 hours following IV administration. In a study (using normal volunteers) of constant intravenous infusion with dosages of 3.5 mg/kg for 1 hour (approximately 250 mg) and 1.5 mg/kg the next 2 hours (approximately 100 mg), cefazolin produced a steady serum level at the third hour of approximately 28 mcg/mL. Studies in patients hospitalized with infections indicate that cefazolin produces mean peak serum levels approximately equivalent to those seen in normal volunteers. Bile levels in patients without obstructive biliary disease can reach or exceed serum levels by up to 5 times; however, in patients with obstructive biliary disease, bile levels of cefazolin are considerably lower than serum levels (<1.0 mcg/mL). In synovial fluid, the cefazolin level becomes comparable to that reached in serum at about 4 hours after drug administration. Studies of cord blood show prompt transfer of cefazolin across the placenta. Cefazolin is present in very low concentrations in the milk of nursing mothers. Cefazolin is excreted unchanged in the urine. In the first 6 hours approximately 60% of the drug is excreted in the urine and this increases to 70% to 80% within 24 hours. In patients undergoing peritoneal dialysis (2 L/hr.), cefazolin produced mean serum levels of approximately 10 and 30 mcg/mL after 24 hours instillation of a dialyzing solution containing 50 mg/L and 150 mg/L respectively. Mean peak levels were 29 mcg/mL (range 13-44 mcg/mL) with 50 mg/L (three patients), and 72 mcg/mL (range 26 to 142 mcg/mL) with 150 mg/L (6 patients). Intraperitoneal administration of cefazolin is usually well tolerated. Controlled studies on adult normal volunteers, receiving 1 gram 4 times a day for 10 days, monitoring CBC, SGOT, SGPT, bilirubin, alkaline phosphatase, BUN, creatinine, and urinalysis, indicated no clinically significant changes attributed to cefazolin.<br/>Microbiology:: In vitro tests demonstrate that the bactericidal action of cephalosporins results from inhibition of cell wall synthesis. Cefazolin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in INDICATIONS AND USAGE.<br/>Gram-Positive Aerobes:: Staphylococcus aureus (including��-lactamase-producing strains) Staphylococcus epidermidis Streptococcus pyogenes, Streptococcus agalactiae, and other strains of streptococci Streptococcus pneumoniae Methicillin-resistant staphylococci are uniformly resistant to cefazolin, and many strains of enterococci are resistant.<br/>Gram-Negative Aerobes:: Escherichia coli Proteus mirabilis Most strains of indole positive Proteus (Proteus vulgaris), Enterobacter spp., Morganella morganii, Providencia rettgeri, Serratia spp. and Pseudomonas spp. are resistant to cefazolin. | lld:dailymed |
| dailymed-drugs:275 | dailymed-instance:clinicalP... | Microbiology:<br/>Mechanism of Action: Ritonavir is a peptidomimetic inhibitor of both the HIV-1 and HIV-2 proteases. Inhibition of HIV protease renders the enzyme incapable of processing the gag-pol polyprotein precursor which leads to production of non-infectious immature HIV particles.<br/>Antiviral Activity In Vitro: The activity of ritonavir was assessed in vitro in acutely infected lymphoblastoid cell lines and in peripheral blood lymphocytes. The concentration of drug that inhibits 50% (EC) of viral replication ranged from 3.8 to 153 nM depending upon the HIV-1 isolate and the cells employed. The average ECfor low passage clinical isolates was 22 nM (n = 13). In MTcells, ritonavir demonstrated additive effects against HIV-1 in combination with either zidovudine (ZDV) or didanosine (ddI). Studies which measured cytotoxicity of ritonavir on several cell lines showed that>20��M was required to inhibit cellular growth by 50% resulting in an in vitro therapeutic index of at least 1000.<br/>Resistance: HIV-1 isolates with reduced susceptibility to ritonavir have been selected in vitro. Genotypic analysis of these isolates showed mutations in the HIV protease gene at amino acid positions 84 (Ile to Val), 82 (Val to Phe), 71 (Ala to Val), and 46 (Met to Ile). Phenotypic (n = 18) and genotypic (n = 44) changes in HIV isolates from selected patients treated with ritonavir were monitored in phase I/II trials over a period of 3 to 32 weeks. Mutations associated with the HIV viral protease in isolates obtained from 41 patients appeared to occur in a stepwise and ordered fashion; in sequence, these mutations were position 82 (Val toAla/Phe), 54 (Ile to Val), 71 (Ala to Val/Thr), and 36 (Ile to Leu), followed by combinations of mutations at an additional 5 specific amino acid positions. Of 18 patients for whom both phenotypic and genotypic analysis were performed on free virus isolated from plasma, 12 showed reduced susceptibility to ritonavir in vitro. All 18 patients possessed one or more mutations in the viral protease gene. The 82 mutation appeared to be necessary but not sufficient to confer phenotypic resistance. Phenotypic resistance was defined as a���5-fold decrease in viral sensitivity in vitro from baseline. The clinical relevance of phenotypic and genotypic changes associated with ritonavir therapy has not been established.<br/>Cross-Resistance to Other Antiretrovirals: Among protease inhibitors variable cross-resistance has been recognized. Serial HIV isolates obtained from six patients during ritonavir therapy showed a decrease in ritonavir susceptibility in vitro but did not demonstrate a concordant decrease in susceptibility to saquinavir in vitro when compared to matched baseline isolates. However, isolates from two of these patients demonstrated decreased susceptibility to indinavir in vitro (8-fold). Isolates from 5 patients were also tested for cross-resistance to amprenavir and nelfinavir; isolates from 2 patients had a decreasein susceptibility to nelfinavir (12- to 14-fold), and none to amprenavir. Cross-resistance between ritonavir and reverse transcriptase inhibitors is unlikely because of the different enzyme targets involved. One ZDV-resistant HIV isolate tested in vitro retained full susceptibility to ritonavir.<br/>Pharmacokinetics: The pharmacokinetics of ritonavir have been studied in healthy volunteers and HIV-infected patients (CD���50 cells/��L). See Table 1 for ritonavir pharmacokinetic characteristics.<br/>Absorption: The absolute bioavailability of ritonavir has not been determined. After a 600 mg dose of oral solution, peak concentrations of ritonavir were achieved approximately 2 hours and 4 hours after dosing under fasting and non-fasting (514 KCal; 9% fat, 12% protein, and 79% carbohydrate) conditions, respectively.<br/>Effect of Food on Oral Absorption: When the oral solution was given under non-fasting conditions, peak ritonavir concentrations decreased 23% and the extent of absorption decreased 7% relative to fasting conditions. Dilution of the oral solution, within one hour of administration, with 240 mL of chocolate milk, Advera or Ensure did not significantly affect the extent and rate of ritonavir absorption. After a single 600 mg dose under non-fasting conditions, in two separate studies, the soft gelatin capsule (n = 57) and oral solution (n = 18) formulations yielded mean��SD areas under the plasma concentration-time curve (AUCs) of 121.7��53.8 and 129.0��39.3��g���h/mL, respectively. Relative to fasting conditions, the extent of absorption of ritonavir from the soft gelatin capsule formulation was 13% higher when administered with a meal (615 KCal; 14.5% fat, 9% protein, and 76% carbohydrate).<br/>Metabolism: Nearly all of the plasma radioactivity after a single oral 600 mg dose ofC-ritonavir oral solution (n = 5) was attributed to unchanged ritonavir. Five ritonavir metabolites have been identified in human urine and feces. The isopropylthiazole oxidation metabolite (M-2) is the major metabolite and has antiviral activity similar to that of parent drug; however, the concentrations of this metabolite in plasma are low. In vitro studies utilizing human liver microsomes have demonstrated that cytochrome P450 3A (CYP3A) is the major isoform involved in ritonavir metabolism, although CYP2D6 also contributes to the formation of M-2.<br/>Elimination: In a study of five subjects receiving a 600 mg dose ofC-ritonavir oral solution, 11.3��2.8% of the dose was excreted into the urine, with 3.5��1.8% of the dose excreted as unchanged parent drug. In that study, 86.4��2.9% of the dose was excreted in the feces with 33.8��10.8% of the dose excreted as unchanged parent drug. Upon multiple dosing, ritonavir accumulation is less than predicted from a single dose possibly due to a time and dose-related increase in clearance.<br/>Effects on Electrocardiogram: QTcF interval was evaluated in a randomized, placebo and active (moxifloxacin 400 mg once-daily) controlled crossover study in 45 healthy adults, with 10 measurements over 12 hours on Day 3. The maximum mean (95% upper confidence bound) time-matched difference in QTcF from placebo after baseline correction was 5.5 (7.6) milliseconds (msec) for 400 mg twice-daily ritonavir. Ritonavir 400 mg twice dailyresulted in Day 3 ritonavir exposure that was approximately 1.5 fold higher than observed with ritonavir 600 mg twice-daily dose at steady state. PR interval prolongation was also noted in subjects receiving ritonavir in the same study on Day 3. The maximum mean (95% confidence interval) difference from placebo in the PR interval after baseline correction was 22 (25) msec for 400 mg twice-daily ritonavir. See PRECAUTIONS���PR Interval Prolongation.<br/>Special Populations: | lld:dailymed |
| dailymed-drugs:276 | dailymed-instance:clinicalP... | Absorption: Following 60-minute intravenous infusions of 200 mg and 400 mg ciprofloxacin to normal volunteers, the mean maximum serum concentrations achieved were 2.1 and 4.6 mcg/mL, respectively; the concentrations at 12 hours were 0.1 and 0.2 mcg/mL, respectively. The pharmacokinetics of ciprofloxacin are linear over the dose range of 200 to 400 mg administered intravenously. Comparison of the pharmacokinetic parameters following the 1st and 5th I.V. dose on a q 12 h regimen indicates no evidence of drug accumulation. The absolute bioavailability of oral ciprofloxacin is within a range of 70���80% with no substantial loss by first pass metabolism. An intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 12 hours has been shown to produce an area under the serum concentration time curve (AUC) equivalent to that produced by a 500-mg oral dose given every 12 hours. An intravenous infusion of 400 mg ciprofloxacin given over 60 minutes every 8 hours has been shown to produce an AUC at steady-state equivalent to that produced by a 750-mg oral dose given every 12 hours. A 400-mg I.V. dose results in a Csimilar to that observed with a 750-mg oral dose. An infusion of 200 mg ciprofloxacin given every 12 hours produces an AUC equivalent to that produced by a 250-mg oral dose given every 12 hours.<br/>Distribution: After intravenous administration, ciprofloxacin is present in saliva, nasal and bronchial secretions, sputum, skin blister fluid, lymph, peritoneal fluid, bile, and prostatic secretions. It has also been detected in the lung, skin, fat, muscle, cartilage, and bone. Although the drug diffuses into cerebrospinal fluid (CSF), CSF concentrations are generally less than 10% of peak serum concentrations. Levels of the drug in the aqueous and vitreous chambers of the eye are lower than in serum.<br/>Metabolism: After I.V. administration, three metabolites of ciprofloxacin have been identified in human urine which together account for approximately 10% of the intravenous dose. The binding of ciprofloxacin to serum proteins is 20 to 40%. Ciprofloxacin is an inhibitor of human cytochrome P450 1A2 (CYP1A2) mediated metabolism. Coadministration of ciprofloxacin with other drugs primarily metabolized by CYP1A2 results in increased plasma concentrations of these drugs and could lead to clinically significant adverse events of coadministered drug .<br/>Excretion: The serum elimination half-life is approximately 5���6 hours and the total clearance is around 35 L/hr. After intravenous administration, approximately 50% to 70% of the dose is excreted in the urine as unchanged drug. Following a 200-mg I.V. dose, concentrations in the urine usually exceed 200 mcg/mL 0���2 hours after dosing and are generally greater than 15 mcg/mL 8���12 hours after dosing. Following a 400-mg I.V. dose, urine concentrations generally exceed 400 mcg/mL 0���2 hours after dosing and are usually greater than 30 mcg/mL 8���12 hours after dosing. The renal clearance is approximately 22 L/hr. The urinary excretion of ciprofloxacin is virtually complete by 24 hours after dosing. Although bile concentrations of ciprofloxacin are several fold higher than serum concentrations after intravenous dosing, only a small amount of the administered dose (<1%) is recovered from the bile as unchanged drug. Approximately 15% of an I.V. dose is recovered from the feces within 5 days after dosing.<br/>Special Populations: Pharmacokinetic studies of the oral (single dose) and intravenous (single and multiple dose) forms of ciprofloxacin indicate that plasma concentrations of ciprofloxacin are higher in elderly subjects (>65 years) as compared to young adults. Although the Cis increased 16���40%, the increase in mean AUC is approximately 30%, and can be at least partially attributed to decreased renal clearance in the elderly. Elimination half-life is only slightly (~20%) prolonged in the elderly. These differences are not considered clinically significant. In patients with reduced renal function, the half-life of ciprofloxacin is slightly prolonged and dosage adjustments may be required. In preliminary studies in patients with stable chronic liver cirrhosis, no significant changes in ciprofloxacin pharmacokinetics have been observed. However, the kinetics of ciprofloxacin in patients with acute hepatic insufficiency have not been fully elucidated. Following a single oral dose of 10 mg/kg ciprofloxacin suspension to 16 children ranging in age from 4 months to 7 years, the mean Cwas 2.4 mcg/mL (range: 1.5���3.4 mcg/mL) and the mean AUC was 9.2 mcg*h/mL (range: 5.8���14.9 mcg*h/mL). There was no apparent age-dependence, and no notable increase in Cor AUC upon multiple dosing (10 mg/kg TID). In children with severe sepsis who were given intravenous ciprofloxacin (10 mg/kg as a 1-hour infusion), the mean Cwas 6.1 mcg/mL (range: 4.6���8.3 mcg/mL) in 10 children less than 1 year of age; and 7.2 mcg/mL (range: 4.7���11.8 mcg/mL) in 10 children between 1 and 5 years of age. The AUC values were 17.4 mcg*h/mL (range: 11.8���32.0 mcg*h/mL) and 16.5 mcg*h/mL (range: 11.0���23.8 mcg*h/mL) in the respective age groups. These values are within the range reported for adults at therapeutic doses. Based on population pharmacokinetic analysis of pediatric patients with various infections, the predicted mean half-life in children is approximately 4���5 hours and the bioavailability of the oral suspension is approximately 60%.<br/>Drug-drug Interactions: Concomitant administration with tizanidine is contraindicated . The potential for pharmacokinetic drug interactions between ciprofloxacin and theophylline, caffeine, cyclosporins, phenytoin, sulfonylurea glyburide, metronidazole, warfarin, probenecid, and piperacillin sodium has been evaluated. | lld:dailymed |
| dailymed-drugs:277 | dailymed-instance:clinicalP... | Pharmacodynamics: The mechanism of antidepressant action of escitalopram, the S-enantiomer of racemic citalopram, is presumed to be linked to potentiation of serotonergic activity in the central nervous system (CNS) resulting from its inhibition of CNS neuronal reuptake of serotonin (5-HT). In vitro and in vivo studies in animals suggest that escitalopram is a highly selective serotonin reuptake inhibitor (SSRI) with minimal effects on norepinephrine and dopamine neuronal reuptake. Escitalopram is at least 100-fold more potent than the R-enantiomer with respect to inhibition of 5-HT reuptake and inhibition of 5-HT neuronal firing rate. Tolerance to a model of antidepressant effect in rats was not induced by long-term (up to 5 weeks) treatment with escitalopram. Escitalopram has no or very low affinity for serotonergic (5-HT) or other receptors including alpha- and beta-adrenergic, dopamine (D), histamine (H), muscarinic (M), and benzodiazepine receptors. Escitalopram also does not bind to, or has low affinity for, various ion channels including Na, K, Cl, and Cachannels. Antagonism of muscarinic, histaminergic, and adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular side effects of other psychotropic drugs.<br/>Pharmacokinetics: The single- and multiple-dose pharmacokinetics of escitalopram are linear and dose-proportional in a dose range of 10 to 30 mg/day. Biotransformation of escitalopram is mainly hepatic, with a mean terminal half-life of about 27-32 hours. With once-daily dosing, steady state plasma concentrations are achieved within approximately one week. At steady state, the extent of accumulation of escitalopram in plasma in young healthy subjects was 2.2-2.5 times the plasma concentrations observed after a single dose. The tablet and the oral solution dosage forms of escitalopram oxalate are bioequivalent.<br/>Absorption and Distribution: Following a single oral dose (20 mg tablet or solution) of escitalopram, peak blood levels occur at about 5 hours. Absorption of escitalopram is not affected by food. The absolute bioavailability of citalopram is about 80% relative to an intravenous dose, and the volume of distribution of citalopram is about 12 L/kg. Data specific on escitalopram are unavailable. The binding of escitalopram to human plasma proteins is approximately 56%.<br/>Metabolism and Elimination: Following oral administrations of escitalopram, the fraction of drug recovered in the urine as escitalopram and S-demethylcitalopram (S-DCT) is about 8% and 10%, respectively. The oral clearance of escitalopram is 600 mL/min, with approximately 7% of that due to renal clearance. Escitalopram is metabolized to S-DCT and S-didemethylcitalopram (S-DDCT). In humans, unchanged escitalopram is the predominant compound in plasma. At steady state, the concentration of the escitalopram metabolite S-DCT in plasma is approximately one-third that of escitalopram. The level of S-DDCT was not detectable in most subjects. In vitro studies show that escitalopram is at least 7 and 27 times more potent than S-DCT and S-DDCT, respectively, in the inhibition of serotonin reuptake, suggesting that the metabolites of escitalopram do not contribute significantly to the antidepressant actions of escitalopram. S-DCT and S-DDCT also have no or very low affinity for serotonergic (5-HT) or other receptors including alpha- and beta-adrenergic, dopamine (D), histamine (H), muscarinic (M), and benzodiazepine receptors. S-DCT and S-DDCT also do not bind to various ion channels including Na, K, Cl, and Cachannels. In vitro studies using human liver microsomes indicated that CYP3A4 and CYP2C19 are the primary isozymes involved in the N-demethylation of escitalopram.<br/>Population Subgroups: Age - Escitalopram pharmacokinetics in subjects���65 years of age were compared to younger subjects in a single-dose and a multiple-dose study. Escitalopram AUC and half-life were increased by approximately 50% in elderly subjects, and Cwas unchanged. 10 mg is the recommended dose for elderly patients . Gender - In a multiple-dose study of escitalopram (10 mg/day for 3 weeks) in 18 male (9 elderly and 9 young) and 18 female (9 elderly and 9 young) subjects, there were no differences in AUC, C, and half-life between the male and female subjects. No adjustment of dosage on the basis of gender is needed. Reduced hepatic function - Citalopram oral clearance was reduced by 37% and half-life was doubled in patients with reduced hepatic function compared to normal subjects. 10 mg is the recommended dose of escitalopram for most hepatically impaired patients . Reduced renal function - In patients with mild to moderate renal function impairment, oral clearance of citalopram was reduced by 17% compared to normal subjects. No adjustment of dosage for such patients is recommended. No information is available about the pharmacokinetics of escitalopram in patients with severely reduced renal function (creatinine clearance<20 mL/min).<br/>Drug-Drug Interactions: In vitro enzyme inhibition data did not reveal an inhibitory effect of escitalopram on CYP3A4, -1A2, -2C9, -2C19, and -2E1. Based on in vitro data, escitalopram would be expected to have little inhibitory effect on in vivo metabolism mediated by these cytochromes. While in vivo data to address this question are limited, results from drug interaction studies suggest that escitalopram, at a dose of 20 mg, has no 3A4 inhibitory effect and a modest 2D6 inhibitory effect. See Drug Interactions under PRECAUTIONS for more detailed information on available drug interaction data.<br/>Clinical Efficacy Trials:<br/>Major Depressive Disorder: The efficacy of Lexapro as a treatment for major depressive disorder was established in three, 8-week, placebo-controlled studies conducted in outpatients between 18 and 65 years of age who met DSM-IV criteria for major depressive disorder. The primary outcome in all three studies was change from baseline to endpoint in the Montgomery Asberg Depression Rating Scale (MADRS). A fixed-dose study compared 10 mg/day Lexapro and 20 mg/day Lexapro to placebo and 40 mg/day citalopram. The 10 mg/day and 20 mg/day Lexapro treatment groups showed significantly greater mean improvement compared to placebo on the MADRS. The 10 mg and 20 mg Lexapro groups were similar on this outcome measure. In a second fixed-dose study of 10 mg/day Lexapro and placebo, the 10 mg/day Lexapro treatment group showed significantly greater mean improvement compared to placebo on the MADRS. In a flexible-dose study, comparing Lexapro, titrated between 10 and 20 mg/day, to placebo and citalopram, titrated between 20 and 40 mg/day, the Lexapro treatment group showed significantly greater mean improvement compared to placebo on the MADRS. Analyses of the relationship between treatment outcome and age, gender, and race did not suggest any differential responsiveness on the basis of these patient characteristics. In a longer-term trial, 274 patients meeting (DSM-IV) criteria for major depressive disorder, who had responded during an initial 8-week, open-label treatment phase with Lexapro 10 or 20 mg/day, were randomized to continuation of Lexapro at their same dose, or to placebo, for up to 36 weeks of observation for relapse. Response during the open-label phase was defined by having a decrease of the MADRS total score to���12. Relapse during the double-blind phase was defined as an increase of the MADRS total score to���22, or discontinuation due to insufficient clinical response. Patients receiving continued Lexapro experienced a significantly longer time to relapse over the subsequent 36 weeks compared to those receiving placebo.<br/>Generalized Anxiety Disorder: The efficacy of Lexapro in the treatment of Generalized Anxiety Disorder (GAD) was demonstrated in three, 8-week, multicenter, flexible-dose, placebo-controlled studies that compared Lexapro 10-20 mg/day to placebo in outpatients between 18 and 80 years of age who met DSM-IV criteria for GAD. In all three studies, Lexapro showed significantly greater mean improvement compared to placebo on the Hamilton Anxiety Scale (HAM-A). There were too few patients in differing ethnic and age groups to adequately assess whether or not Lexapro has differential effects in these groups. There was no difference in response to Lexapro between men and women. | lld:dailymed |
| dailymed-drugs:278 | dailymed-instance:clinicalP... | Amoxicillin is stable in the presence of gastric acid and is rapidly absorbed after oral administration. The effect of food on the absorption of amoxicillin from the tablets and suspension has been partially investigated. The 400 mg and 875 mg formulations have been studied only when administered at the start of a light meal. However, foodeffect studies have not been performed with the 200 mg and 500 mg formulations. Amoxicillin diffuses readily into most body tissues and fluids, with the exception of brain and spinal fluid, except when meninges are inflamed. The half-life of amoxicillin is 61.3 minutes. Most of the amoxicillin is excreted unchanged in the urine; its excretion can be delayed by concurrent administration of probenecid. In blood serum, amoxicillin is approximately 20% protein-bound. Orally administered doses of 250 mg and 500 mg of amoxicillin capsules result in average peak blood levels 1 to 2 hours after administration in the range of 3.5 mcg/mL to 5 mcg/mL and 5.5 mcg/mL to 7.5 mcg/mL, respectively. Mean amoxicillin pharmacokinetic parameters from an open, two-part, single-dose crossover bioequivalence study in 27 adults comparing 875 mg of Amoxicillin tablets with 875 mg of amoxicillin and clavulanate potassium showed that the 875 mg tablet of amoxicillin produces an AUCof 35.4��8.1 mcg���hr/mL and a Cof 13.8��4.1 mcg/mL. Dosing was at the start of a light meal following an overnight fast. Oral administration of single doses of amoxicillin 400 mg chewable tablets and 400 mg/5 mL suspension to 24 adult volunteers yielded the following pharmacokinetic data: Orally administered doses of amoxicillin suspension, 125 mg/5 mL and 250 mg/5 mL, result in average peak blood levels 1 to 2 hours after administration in the range of 1.5 mcg/mL to 3 mcg/mL and 3.5 mcg/mL to 5 mcg/ mL, respectively. Detectable serum levels are observed up to 8 hours after an orally administered dose of amoxicillin. Following a 1 gram dose and utilizing a special skin window technique to determine levels of the antibiotic, it was noted that therapeutic levels were found in the interstitial fluid. Approximately 60% of an orally administered doseof amoxicillin is excreted in the urine within 6 to 8 hours.<br/>Microbiology: Amoxicillin is similar to ampicillin in its bactericidal action against susceptible organisms during the stage of active multiplication. It acts through the inhibition of biosynthesis of cell wall mucopeptide. Amoxicillin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Aerobic Gram-Positive Microorganisms: Enterococcus faecalisStaphylococcus spp.(��-lactamase-negative strains only)Streptococcus pneumoniaeStreptococcus spp. (��- and��-hemolytic strains only) Aerobic Gram-Negative Microorganisms: Escherichia coli (��-lactamase-negative strains only)Haemophilus influenzae (��-lactamase-negative strains only)Neisseria gonorrhoeae (��-lactamase-negative strains only)Proteus mirabilis (��-lactamase-negative strains only) Helicobacter: Helicobacter pylori<br/>Susceptibility Tests:<br/>Dilution Techniques: Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method(broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of ampicillin powder. Ampicillin is sometimes used to predict susceptibility of S. pneumoniae to amoxicillin; however, some intermediate strains have been shown to be susceptible to amoxicillin. Therefore, S. pneumoniae susceptibility should be tested using amoxicillin powder. The MIC values should be interpreted according to the following criteria: For Gram-Positive Aerobes:Enterococcus Staphylococcus Streptococcus (except S. pneumoniae) S. pneumoniaefrom non-meningitis sources.(Amoxicillin powder should be used to determine susceptibility.) NOTE: These interpretive criteria are based on the recommended doses for respiratory tract infections. For Gram-Negative Aerobes: Enterobacteriaceae H. influenzae A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone, which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard ampicillin powder should provide the following MIC values: Using amoxicillin to determine susceptibility:<br/>Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedurerequires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10 mcg ampicillin to test the susceptibility of microorganisms, except S. pneumoniae, to amoxicillin. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for ampicillin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10 mcg ampicillin disk should be interpreted according to the following criteria: For Gram-Positive Aerobes:Enterococcus Staphylococcus ��-hemolytic streptococci NOTE: For streptococci (other than��-hemolytic streptococci and S. pneumoniae), an ampicillin MIC should be determined. S. pneumoniae S. pneumoniae should be tested using a 1 mcg oxacillin disk. Isolates with oxacillin zone sizes of���20 mm are susceptible to amoxicillin. An amoxicillin MIC should be determined on isolates of S. pneumoniae with oxacillin zone sizes of���19 mm. For Gram-Negative Aerobes: Enterobacteriaceae H. influenzae Interpretation should be as stated above for results using dilution techniques. As with standard dilution techniques, disk diffusion susceptibility test procedures require the use of laboratory control microorganisms. The 10 mcg ampicillin disk should provide the following zone diameters in these laboratory test quality control strains: Using 1 mcg oxacillin disk:<br/>Susceptibility Testing for Helicobacter pylori: In vitro susceptibility testing methods and diagnostic products currently available for determining minimum inhibitory concentrations (MICs) and zone sizes have not been standardized, validated, or approved for testing H. pylori microorganisms. Culture and susceptibility testing should be obtained in patients who fail triple therapy. If clarithromycin resistance is found, a nonclarithromycin-containing regimen should be used. | lld:dailymed |
| dailymed-drugs:279 | dailymed-instance:clinicalP... | After oral administration, cycloserine is readily absorbed from the gastrointestinal tract, with peak blood levels occurring in 4 to 8 hours. Blood levels of 25 to 30��g/mL can generally be maintained with the usual dosage of 250 mg twice a day, although the relationship of plasma levels to dosage is not always consistent. Concentrations in the cerebrospinal fluid, pleural fluid, fetal blood, and mother's milk approach those found in the serum. Detectable amounts are found in ascitic fluid, bile, sputum, amniotic fluid, and lung and lymph tissues. Approximately 65% of a single dose of cycloserine can be recovered in the urine within 72 hours after oral administration. The remaining 35% is apparently metabolized to unknown substances. The maximum excretion rate occurs 2 to 6 hours after administration, with 50% of the drug eliminated in 12 hours.<br/>Microbiology: Cycloserine inhibits cell���wall synthesis in susceptible strains of gram���positive and gram���negative bacteria and in Mycobacterium tuberculosis.<br/>Susceptibility Tests: Cycloserine clinical laboratory standard powder is available for both direct and indirect methodsof determining the susceptibility of strains of mycobacteria. Cycloserine MICs for susceptible strains are 25��g/mL or lower. | lld:dailymed |
| dailymed-drugs:280 | dailymed-instance:clinicalP... | Mechanism of Action: When taken orally, ticlopidine hydrochloride causes a time and dose-dependent inhibition of both platelet aggregation and release of platelet granule constituents, as well as a prolongation of bleeding time. The intact drug has no significant in vitro activity at the concentrations attained in vivo; and, although analysis of urine and plasma indicates at least twenty metabolites, no metabolite which accounts for the activity of ticlopidine has been isolated. Ticlopidine hydrochloride, after oral ingestion, interferes with platelet membrane function by inhibiting ADP-induced plateletfibrinogen binding and subsequent platelet-platelet interactions. The effect on platelet function is irreversible for the life of the platelet, as shown both by persistent inhibition of fibrinogen binding after washing platelets ex vivo and by inhibition of platelet aggregation after resuspension of platelets in buffered medium.<br/>Pharmacokinetics and Metabolism: After oral administration of a single 250 mg dose, ticlopidine hydrochloride is rapidly absorbed, with peak plasma levels occurring at approximately 2 hours after dosing, and is extensively metabolized. Absorption is greater than 80%. Administration after meals results in a 20% increase in the AUC of ticlopidine. Ticlopidine hydrochloride displays non-linear pharmacokinetics and clearance decreases markedly on repeated dosing. In older volunteers the apparent half-life of ticlopidine after a single 250 mg dose is about 12.6 hours; with repeat dosing at 250 mg bid, the terminal elimination half-life rises to 4 to 5 days and steady-state levels of ticlopidine hydrochloride in plasma are obtained after approximately 14 to 21 days. Ticlopidine hydrochloride binds reversibly (98%) to plasma proteins, mainly to serum albumin and lipoproteins. The binding to albumin and lipoproteins is nonsaturable over a wide concentration range. Ticlopidine also binds to alpha-1 acid glycoprotein. At concentrations attained with the recommended dose, only 15% or less ticlopidine in plasma is bound to this protein. Ticlopidine hydrochloride is metabolized extensively by the liver; only trace amounts of intact drug are detected in the urine. Following an oral dose of radioactive ticlopidine hydrochloride administered in solution, 60% of the radioactivity is recovered in the urine and 23% in the feces. Approximately 1/3 of the dose excreted in the feces is intact ticlopidine hydrochloride, possibly excreted in the bile. Ticlopidine hydrochloride is a minor component in plasma (5%) after a single dose, but at steady state is the major component (15%). Approximately 40% to 50% of the radioactive metabolites circulating in plasma are covalently bound to plasma proteins, probably by acylation. Clearance of ticlopidine decreases with age. Steady state trough values in elderly patients (mean age 70 years) are about twice those in younger volunteer populations.<br/>HEPATICALLY IMPAIRED PATIENTS: The effect of decreased hepatic function on the pharmacokinetics of ticlopidine hydrochloride was studied in 17 patients with advanced cirrhosis. The average plasma concentration of ticlopidine in these subjects was slightly higher than that seen in older subjects in a separate trial (See CONTRAINDICATIONS).<br/>RENALLY IMPAIRED PATIENTS: Patients with mildly (Ccr 50 to 80 mL/min) or moderately (Ccr 20 to 50 mL/min) impaired renal function were compared to normal subjects (Ccr 80 to 150 mL/min) in a study of the pharmacokinetic and platelet pharmacodynamic effects of ticlopidine hydrochloride (250 mg bid) for 11 days. Concentrations of unchanged ticlopidine hydrochloride were measured after a single 250 mg dose and after the final 250 mg dose on Day 11. AUC values of ticlopidine increased by 28% and 60% in mild and moderately impaired patients, respectively, and plasma clearance decreased by 37% and 52%, respectively, but there were no statistically significant differences in ADP-induced platelet aggregation. In this small study (26 patients) bleeding times showed significant prolongation only in the moderately impaired patients.<br/>Pharmacodynamics: In healthy volunteers over the age of 50, substantial inhibition (over 50%) of ADP-induced platelet aggregation is detected within 4 days after administration of ticlopidine hydrochloride 250 mg bid, and maximum platelet aggregation inhibition (60% to 70%) is achieved after 8 to 11 days. Lower doses cause less, and more delayed, platelet aggregation inhibition, while doses above 250 mg bid give little additional effect on platelet aggregation, but an increased rate of adverse effects. The dose of 250 mg bid is the only dose that has been evaluated in controlled clinical trials. After discontinuation of ticlopidine hydrochloride, bleeding time and other platelet function tests return to normal within two weeks in the majority of patients. At the recommended therapeutic dose (250 mg bid), ticlopidine hydrochloride has no known significant pharmacological actions in man other than inhibition of platelet function and prolongation of the bleeding time. | lld:dailymed |
| dailymed-drugs:281 | dailymed-instance:clinicalP... | Mechanism of Action The mechanism of action of trimethobenzamide hydrochloride as determined in animals is obscure, but may involve the chemoreceptor trigger zone (CTZ), an area in the medulla oblongata through which emetic impulses are conveyed to the vomiting center; direct impulses to the vomiting center apparently are not similarly inhibited. In dogs pretreated with trimethobenzamide hydrochloride, the emetic response to apomorphine is inhibited, while little or no protection is afforded against emesis induced by intragastric copper sulfate. PHARMACOKINETICS The pharmacokinetics of trimethobenzamide have been studied in healthy adult subjects. Following administration of 200 mg (100 mg/mL) trimethobenzamide I.M. injection, the time to reach maximum plasma concentration (T) was about half an hour, about 15 minutes longer for trimethobenzamide 300 mg oral capsule than an I.M. injection. A single dose of trimethobenzamide 300 mg oral capsule provided a plasma concentration profile of trimethobenzamide similar to trimethobenzamide 200 mg I.M. The relative bioavailability of the capsule formulation compared tothe solution is 100%. The mean elimination half-life of trimethobenzamide is 7 to 9 hours. Special Populations Gender Systemic exposure to trimethobenzamide was similar between men (N=40) and women (N=28). Race Pharmacokinetics appeared to be similar for Caucasians (N=53) and African Americans (N=12). | lld:dailymed |
| dailymed-drugs:282 | dailymed-instance:clinicalP... | Mechanism of Action: Quinapril is deesterified to the principal metabolite, quinaprilat, which is an inhibitor of ACE activity in human subjects and animals. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I to the vasoconstrictor, angiotensin II. The effect of quinapril in hypertension appears to result primarily from the inhibition of circulating and tissue ACE activity, thereby reducing angiotensin II formation. Quinapril inhibits the elevation in blood pressure caused by intravenously administered angiotensin I, but has no effect on the pressor response to angiotensin II, norepinephrine or epinephrine. Angiotensin II also stimulates the secretion of aldosterone from the adrenal cortex, thereby facilitating renalsodium and fluid reabsorption. Reduced aldosterone secretion by quinapril may result in a small increase in serum potassium. In controlled hypertension trials, treatment with quinapril alone resulted in mean increases in potassium of 0.07 mmol/L . Removal of angiotensin II negative feedback on renin secretion leads to increased plasma renin activity (PRA). While the principal mechanism of antihypertensive effect is thought to be through the renin-angiotensin-aldosterone system, quinapril exerts antihypertensive actions even in patients with low renin hypertension. Quinapril was an effective antihypertensive in all races studied, although it was somewhat less effective in blacks (usually a predominantly low renin group) than in nonblacks. ACE is identical to kininase II, an enzyme that degrades bradykinin, a potent peptide vasodilator; whether increased levels of bradykinin play a role in the therapeutic effect of quinapril remains to be elucidated.<br/>Pharmacokinetics and Metabolism: Following oral administration, peak plasma quinapril concentrations are observed within one hour. Based on recovery of quinapril and its metabolites in urine, the extent of absorption is at least 60%. The rate and extent of quinapril absorption are diminished moderately (approximately 25 to 30%) when quinapril is administered during a high-fat meal. Following absorption, quinapril is deesterified to its major active metabolite, quinaprilat (about 38% of oral dose), and to other minor inactive metabolites. Following multiple oral dosing of quinapril, there is an effective accumulation half-life of quinaprilat of approximately 3 hours, and peak plasma quinaprilat concentrations are observed approximately 2 hours post-dose. Quinaprilat is eliminated primarily by renal excretion, up to 96% of an IV dose, and has an elimination half-life in plasma of approximately 2 hours and a prolonged terminal phase with a half-life of 25 hours. The pharmacokinetics of quinapril and quinaprilat are linear over a single-dose range of 5 to 80 mg doses and 40 to 160 mg in multiple daily doses. Approximately 97% of either quinapril or quinaprilat circulating in plasma is bound to proteins. In patients with renal insufficiency, the elimination half-life of quinaprilat increases as creatinine clearance decreases. There is a linear correlation between plasma quinaprilat clearance and creatinine clearance. In patients with end-stage renal disease, chronic hemodialysis or continuous ambulatory peritoneal dialysis has little effect on the elimination of quinapril and quinaprilat. Elimination of quinaprilat may be reduced in elderly patients (���65 years) and in those with heart failure; this reduction is attributable to decrease in renal function . Quinaprilat concentrations are reduced in patients with alcoholic cirrhosis due to impaired deesterification of quinapril. Studies in rats indicate that quinapril and its metabolites do not cross the blood-brain barrier.<br/>Pharmacodynamics and Clinical Effects:<br/>Hypertension: Single doses of 20 mg of quinapril tablets USP provide over 80% inhibition of plasma ACE for 24 hours. Inhibition of the pressor response to angiotensin I is shorter-lived, with a 20 mg dose giving 75% inhibition for about 4 hours, 50% inhibition for about 8 hours, and 20% inhibition at 24 hours. With chronic dosing, however, there is substantial inhibition of angiotensin II levels at 24 hours by doses of 20 to 80 mg. Administration of 10 to 80 mg of quinapril tablets USP to patients with mild to severe hypertension results in a reduction of sitting and standing blood pressure to about the same extent with minimal effect on heart rate. Symptomatic postural hypotension is infrequent although it can occur in patients who are salt-and/or volume-depleted . Antihypertensive activity commences within 1 hour with peak effects usually achieved by 2 to 4 hours after dosing. During chronic therapy, most of the blood pressure lowering effect of a given dose is obtained in 1 to 2 weeks. In multiple-dose studies, 10 to 80 mg per day in single or divided doses lowered systolic and diastolic blood pressure throughout the dosing interval, with a trough effect of about 5-11/3-7 mm Hg. The trough effect represents about 50% of the peak effect. While the dose-response relationship is relatively flat, doses of 40 to 80 mg were somewhat more effective at trough than 10 to 20 mg, and twice daily dosing tended to give a somewhat lower trough blood pressure than once daily dosing with the same total dose. The antihypertensive effect of quinapril continues during long-term therapy, with no evidence of loss of effectiveness. Hemodynamic assessments in patients with hypertension indicate that blood pressure reduction produced by quinapril is accompanied by a reduction in total peripheral resistance and renal vascular resistance with little or no change in heart rate, cardiac index, renal blood flow, glomerular filtration rate, or filtration fraction. Use of quinapril with a thiazide diuretic gives a blood-pressure lowering effect greater than that seen with either agent alone. In patients with hypertension, quinapril tablets USP 10 to 40 mg were similar in effectiveness to captopril, enalapril, propranolol, and thiazide diuretics. Therapeutic effects appear to be the same for elderly (���65 years of age) and younger adult patients given the same daily dosages, with no increase in adverse events in elderly patients.<br/>INDICATIONS AND USAGE:<br/>Hypertension: Quinapril tablets USP are indicated for the treatment of hypertension. It may be used alone or in combination with thiazide diuretics. In using quinapril tablets USP, consideration should be given to the fact that another angiotensin-converting enzyme inhibitor, captopril, has caused agranulocytosis, particularly in patients with renal impairment or collagen vascular disease. Available data are insufficient to show that quinapril tablets USP do not have a similar risk (see WARNINGS).<br/>Angiodema in black patients: Black patients receiving ACE inhibitor monotherapy have been reported to have a higher incidence of angioedema compared to non-blacks. It should also be noted that in controlled clinical trials ACE inhibitors have an effect on blood pressure that is less in black patients than in non-blacks. | lld:dailymed |
| dailymed-drugs:283 | dailymed-instance:clinicalP... | Lindane exerts its parasiticidal action by being directly absorbed into the parasites and their ova. Feldmann and Maibachreported approximately 10% absorption of a lindane acetone solution applied to the forearm of human subjects and left in place for 24 hours. This vehicle was different from the approved product and the percutaneous penetration of lindane is dependent on the vehicle. Therefore, the clinical significance of these observations is unknown. Dale, et alreported a blood level of 290 ng/mL associated with convulsions following the accidental ingestion of a lindane-containing product. Ginsburgfound a mean peak blood level of 28 ng/mL 6 hours after total body application of Lindane Lotion to scabietic infants and children. The half-life in blood was determined to be 18 hours. Data available in the literature suggest that lindane has a rapid distribution phase followed by a longer��-elimination phase. There are no clinical dose ranging studies for Lindane Shampoo. | lld:dailymed |
| dailymed-drugs:284 | dailymed-instance:clinicalP... | Mechanism of Action: Naratriptan binds with high affinity to 5-HTand 5-HTreceptors and has no significant affinity or pharmacological activity at 5-HTreceptor subtypes or at adrenergic��,��, or��; dopaminergic Dor D; muscarinic; or benzodiazepine receptors. The therapeutic activity of naratriptan in migraine is generally attributed to its agonist activity at 5-HTreceptors. Two current theories have been proposed to explain the efficacy of 5-HTreceptor agonists in migraine. One theory suggests that activation of 5-HTreceptors located on intracranial blood vessels, including those on the arteriovenous anastomoses, leads to vasoconstriction, which is correlated with the relief of migraine headache. The other hypothesis suggests that activation of 5-HTreceptors on sensory nerve endings in the trigeminal system results in the inhibition of pro-inflammatory neuropeptide release. In the anesthetized dog, naratriptan has been shown to reduce the carotid arterial blood flow with little or no effect on arterial blood pressure or total peripheral resistance. While the effect on blood flow was selective for the carotid arterial bed, increases in vascular resistance of up to 30% were seen in the coronary arterial bed. Naratriptan has also been shown to inhibit trigeminal nerve activity in rat and cat. In 10 human subjects with suspected coronary artery disease (CAD) undergoing coronary artery catheterization, there was a 1% to 10% reduction in coronary artery diameter following subcutaneous injection of 1.5 mg of naratriptan.<br/>Pharmacokinetics: Naratriptan tablets are well absorbed, with about 70% oral bioavailability. Following administration of a 2.5-mg tablet orally, the peak concentrations are obtained in 2 to 3 hours. After administration of 1- or 2.5-mg tablets, the Cis somewhat (about 50%) higher in women (not corrected for milligram-per-kilogram dose) than in men. During a migraine attack, absorption was slower, with a Tof 3 to 4 hours. Food does not affect the pharmacokinetics of naratriptan. Naratriptan displays linear kinetics over the therapeutic dose range. The steady-state volume of distribution of naratriptan is 170 L. Plasma protein binding is 28% to 31% over the concentration range of 50 to 1,000 ng/mL. Naratriptan is predominantly eliminated in urine, with 50% of the dose recovered unchanged and 30% as metabolites in urine. In vitro, naratriptan is metabolized by a wide range of cytochrome P450 isoenzymes into a number of inactive metabolites. The mean elimination half-life of naratriptan is 6 hours. The systemic clearance of naratriptan is 6.6 mL/min/kg. The renal clearance (220 mL/min) exceeds glomerular filtration rate, indicating active tubular secretion. Repeat administration of naratriptan tablets does not result in drug accumulation.<br/>Special Populations:<br/>Age: A small decrease in clearance (approximately 26%) was observed in healthy elderly subjects (65 to 77 years) compared to younger patients, resulting in slightly higher exposure (see PRECAUTIONS).<br/>Race: The effect of race on the pharmacokinetics of naratriptan has not been examined.<br/>Renal Impairment: Clearance of naratriptan was reduced by 50% in patients with moderate renal impairment (creatinine clearance, 18 to 39 mL/min) compared to the normal group. Decrease in clearances resulted in an increase of mean half-life from 6 hours (healthy) to 11 hours (range, 7 to 20 hours). The mean Cincreased by approximately 40%. The effects of severe renal impairment (creatinine clearance,���15 mL/min) on the pharmacokinetics of naratriptan has not been assessed (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).<br/>Hepatic Impairment: Clearance of naratriptan was decreased by 30% in patients with moderate hepatic impairment (Child-Pugh grade A or B). This resulted in an approximately 40% increase in the half-life (range, 8 to 16 hours). The effects of severe hepatic impairment (Child-Pugh grade C) on the pharmacokinetics of naratriptan have not been assessed (see CONTRAINDICATIONS and DOSAGE AND ADMINISTRATION).<br/>Drug Interactions: In normal volunteers, coadministration of single doses of naratriptan tablets and alcohol did not result in substantial modification of naratriptan pharmacokinetic parameters. From population pharmacokinetic analyses, coadministration of naratriptan and fluoxetine, beta-blockers, or tricyclic antidepressants did not affect the clearance of naratriptan. Naratriptan does not inhibit monoamine oxidase (MAO) enzymes and is a poor inhibitor of P450; metabolic interactions between naratriptan and drugs metabolized by P450 or MAO are therefore unlikely.<br/>Oral Contraceptives: Oral contraceptives reduced clearance by 32% and volume of distribution by 22%, resulting in slightly higher concentrations of naratriptan. Hormone replacement therapy had no effect on pharmacokinetics in older female patients. Smoking increased the clearance of naratriptan by 30%. | lld:dailymed |
| dailymed-drugs:286 | dailymed-instance:clinicalP... | When injected intravenously, sincalide produces a substantial reduction in gallbladder size by causing this organ to contract. The evacuation of bile that results is similar to that which occurs physiologically in response to endogenous cholecystokinin. The intravenous (bolus) administration of sincalide causes a prompt contraction of the gallbladder that becomes maximal in 5 to 15 minutes, as compared with the stimulus of a fatty meal which causes a progressive contraction that becomes maximal after approximately 40 minutes. Generally, a 40 percent reduction in radiographic area of the gallbladder is considered satisfactory contraction, although some patients will show area reduction of 60 to 70 percent. Like cholecystokinin, sincalide stimulates pancreatic secretion; concurrent administration with secretin increases both the volume of pancreatic secretion and the out-put of bicarbonate and protein (enzymes) by the gland. This combined effect of secretin and sincalide permits the assessment of specific pancreatic function through measurement and analysis of the duodenal aspirate. The parameters usually determined are: volume of the secretion; bicarbonate concentration; and amylase content (which parallels thecontent of trypsin and total protein). Both cholecystokinin and sincalide stimulate intestinal motility, and may cause pyloric contraction which retards gastric emptying. | lld:dailymed |
| dailymed-drugs:287 | dailymed-instance:clinicalP... | Pharmacokinetic testing in 12 volunteers demonstrated that a single 30 mg dose of a capsule, tablet or suspension will result in an equivalent extent of absorption. For the capsule and tablet, peak plasma levels averaged 450 mg/mL and were observed to occur about 3 hours after dosing. The mean elimination half-life for oxazepam was approximately 8.2 hours (range 5.7 to 10.9 hours). This product has a single, major inactive metabolite in man, a glucuronide excreted in urine. Age (<80 years old) does not appear to have a clinically significant effect on oxazepam kinetics. A statistically significant increase in elimination half-life in the very elderly (>80 years of age) as compared to younger subjects has been reported, due to a 30% increase in volume of distribution, as well as a 50% reduction in unbound clearance of oxazepam in the very elderly. . | lld:dailymed |
| dailymed-drugs:288 | dailymed-instance:clinicalP... | The mechanism of DESYREL's antidepressant action in man is not fully understood. In animals, DESYREL selectively inhibits serotonin uptake by brain synaptosomes and potentiates the behavioral changes induced by the serotonin precursor, 5-hydroxytryptophan. Cardiac conduction effects of DESYREL in the anesthetized dog are qualitatively dissimilar and quantitatively less pronounced than those seen with tricyclic antidepressants. DESYREL is not a monoamine oxidase inhibitor and, unlike amphetamine-type drugs, does not stimulate the central nervous system.<br/>Pharmacokinetics:<br/>Absorption: In humans, DESYREL is well absorbed after oral administration without selective localization in any tissue. When DESYREL is taken shortly after ingestion of food, there may be an increase in the amount of drug absorbed, a decrease in maximum concentration and a lengthening in the time to maximum concentration. Peak plasma levels occur approximately one hour after dosing when DESYREL is taken on an empty stomach or two hours after dosing when taken with food.<br/>Metabolism: In vitro studies in human liver microsomes show that trazodone is metabolized to an active metabolite, m-chlorophenylpiperazine (mCPP) by cytochrome P450 3A4 (CYP3A4). Other metabolic pathways that may be involved in metabolism of trazodone have not been well characterized.<br/>Elimination: In some patients DESYREL may accumulate in the plasma.<br/>Drug-Drug Interactions: See also PRECAUTIONS: Drug Interactions. In vitro drug metabolism studies reveal that trazodone is a substrate of the cytochrome P450 3A4 (CYP3A4) enzyme and trazodone metabolism can be inhibited by the CYP3A4 inhibitors ketoconazole, ritonavir, and indinavir. The effect of short-term administration of ritonavir (200 mg twice daily, 4 doses) on the pharmacokinetics of a single dose of trazodone (50 mg) has been studied in 10 healthy subjects. The Cof trazodone increased by 34%, the AUC increased 2.4-fold, the half-life increased by 2.2-fold, and the clearance decreased by 52%. Adverse effects including nausea, hypotension, and syncope were observed when ritonavir and trazodone were co-administered. Carbamazepine induces CYP3A4. Following co-administration of carbamazepine 400 mg/day with trazodone 100 mg to 300 mg daily, carbamazepine reduced plasma concentrations of trazodone (as well as mCPP) by 76 and 60%, respectively, compared to pre-carbamazepine values. For those patients who responded to DESYREL, one-third of the inpatients and one-half of the outpatients had a significant therapeutic response by the end of the first week of treatment. Three-fourths of all responders demonstrated a significant therapeutic effect by the end of the second week. One-fourth of responders required 2���4 weeks for a significant therapeutic response. | lld:dailymed |
| dailymed-drugs:289 | dailymed-instance:clinicalP... | Pharmacodynamics: The antidepressant, antiobsessive compulsive, and antibulimic actions of fluoxetine are presumed to be linked to its inhibition of CNS neuronal uptake of serotonin. Studies at clinically relevant doses in man have demonstrated that fluoxetine blocks the uptake of serotonin into human platelets. Studies in animals also suggest that fluoxetine is a much more potent uptake inhibitor of serotonin than of norepinephrine. Antagonism of muscarinic, histaminergic, and��-adrenergic receptors has been hypothesized to be associated with various anticholinergic, sedative, and cardiovascular effects of classical tricyclic antidepressant (TCA) drugs. Fluoxetine binds to these and other membrane receptors from brain tissue much less potently in vitro than do the tricyclic drugs.<br/>Absorption, Distribution, Metabolism, and Excretion:<br/>Systemic bioavailability: In man, following a single oral 40-mg dose, peak plasma concentrations of fluoxetine from 15 to 55 ng/mL are observed after 6 to 8 hours. The capsule, tablet, and oral solution dosage forms of fluoxetine are bioequivalent. Food does not appear to affect the systemic bioavailability of fluoxetine, although it may delay its absorption by 1 to 2 hours, which is probably not clinically significant. Thus, fluoxetine may be administered with or without food.<br/>Protein binding: Over the concentration range from 200 to 1000 ng/mL, approximately 94.5% of fluoxetine is bound in vitro to human serum proteins, including albumin and��-glycoprotein. The interaction between fluoxetine and other highly protein-bound drugs has not been fully evaluated, but may be important .<br/>Enantiomers: Fluoxetine is a racemic mixture (50/50) of R-fluoxetine and S-fluoxetine enantiomers. In animal models, both enantiomers are specific and potent serotonin uptake inhibitors with essentially equivalent pharmacologic activity. The S-fluoxetine enantiomer is eliminated more slowly and is the predominant enantiomer present in plasma at steady state.<br/>Metabolism: Fluoxetine is extensively metabolized in the liver to norfluoxetine and a number of other unidentified metabolites. The only identified active metabolite, norfluoxetine, is formed by demethylation of fluoxetine. In animal models, S-norfluoxetine is a potent and selective inhibitor of serotonin uptake and has activity essentially equivalent to R- or S-fluoxetine. R-norfluoxetine is significantly less potent than the parent drug in the inhibition of serotonin uptake. The primary route of elimination appears to be hepatic metabolism to inactive metabolites excreted by the kidney.<br/>Clinical issues related to metabolism/elimination: The complexity of the metabolism of fluoxetine has several consequences that may potentially affect fluoxetine's clinical use.<br/>Liver disease: As might be predicted from its primary site of metabolism, liver impairment can affect the elimination of fluoxetine. The elimination half-life of fluoxetine was prolonged in a study of cirrhotic patients, with a mean of 7.6 days compared with the range of 2 to 3 days seen in subjects without liver disease; norfluoxetine elimination was also delayed, with a mean duration of 12 days for cirrhotic patients compared with the range of 7 to 9 days in normal subjects. This suggests that the use of fluoxetine in patients with liver disease must be approached with caution. If fluoxetine is administered to patients with liver disease, a lower or less frequent dose should be used .<br/>Renal disease: In depressed patients on dialysis (N=12), fluoxetine administered as 20 mg once daily for 2 months produced steady-state fluoxetine and norfluoxetine plasma concentrations comparable with those seen in patients with normal renal function. While the possibility exists that renally excreted metabolites of fluoxetine may accumulate to higher levels in patients with severe renal dysfunction, use of a lower or less frequent dose is not routinely necessary in renally impaired patients .<br/>Age: | lld:dailymed |
| dailymed-drugs:290 | dailymed-instance:clinicalP... | Biologically inactive clindamycin phosphate is rapidly converted to active clindamycin. By the end of short-term intravenous infusion, peak serum levels of active clindamycin are reached. Biologically inactive clindamycin phosphate disappears rapidly from the serum; the average elimination half-life is 6 minutes; however, the serum elimination half-life of active clindamycin is about 3 hours in adults and 2��hours in pediatric patients. After intramuscular injection of clindamycin phosphate, peak levels of active clindamycin are reached within 3 hours in adults and 1 hour in pediatric patients. Serum level curves may be constructed from I.V. peak serum levels as given in Table 1 by application of elimination half-lives listed above. Serum levels of clindamycin can be maintained above the in vitro minimum inhibitory concentrations for most indicated organisms by administration of clindamycin phosphate every 8 to 12 hours in adults and every 6 to 8 hours in pediatric patients, or by continuous intravenous infusion. An equilibrium state is reached by the third dose. The elimination half-life of clindamycin is increased slightly in patients with markedly reduced renal or hepatic function. Hemodialysis and peritoneal dialysis are not effective in removing clindamycin from the serum. Dosage schedules need not be modified in the presence of mild or moderate renal or hepatic disease. No significant levels of clindamycin are attained in the cerebrospinal fluid, even in the presence of inflamed meninges. Pharmacokinetic studies in elderly volunteers (61 to 79 years) and younger adults (18 to 39 years) indicate that age alone does not alter clindamycin pharmacokinetics (clearance, elimination half-life, volume of distribution, and area under the serum concentration-time curve) after I.V. administration of clindamycin phosphate. After oral administration of clindamycin hydrochloride, elimination half-life is increased to approximately 4 hours (range 3.4 to 5.1 h) in the elderly compared to 3.2 hours (range 2.1 to 4.2 h) in younger adults. The extent of absorption, however, is not different between the age groups and no dosage alteration is necessary for the elderly with normal hepatic function and normal (age-adjusted) renal function. Serum assays for active clindamycin require an inhibitor to prevent in vitro hydrolysis of clindamycin phosphate. Microbiology: Although clindamycin phosphate is inactive in vitro, rapid in vivo hydrolysis converts this compound to the antibacterially active clindamycin. Clindamycin has been shown to have in vitro activity against isolates of the following organisms: Clostridia: Clostridia are more resistant than most anaerobes to clindamycin. Most Clostridium perfringens are susceptible, but other species, e.g., Clostridium sporogenes and Clostridium tertium are frequently resistant to clindamycin. Susceptibility testing should be done. Cross resistance has been demonstrated between clindamycin and lincomycin. Antagonism has been demonstrated between clindamycin and erythromycin. In Vitro Susceptibility Testing: Disk diffusion technique-Quantitative methods that require measurement of zone diameters give the most precise estimates of antibiotic susceptibility. One such procedurehas been recommended for use with disks to test susceptibility to clindamycin. Reports from a laboratory using the standardized single-disk susceptibility testwith a 2 mcg clindamycin disk should be interpreted according to the following criteria: Susceptible organisms produce zones of 17 mm or greater, indicating that the tested organism is likely to respond to therapy. Organisms of intermediate susceptibility produce zones of 15-16 mm, indicating that the tested organism would be susceptible if a high dosage is used or if the infection is confined to tissues and fluids (e.g., urine), in which high antibiotic levels are attained. Resistant organisms produce zones of 14 mm or less, indicating that other therapy should be selected. Standardized procedures require the use of control organisms. The 2 mcg clindamycin disk should give a zone diameter between 24 and 30 mm for S. aureus ATCC 25923. Dilution techniques���A bacterial isolate may be considered susceptible if the minimum inhibitory concentration (MIC) for clindamycin is not more than 1.6 mcg/mL. Organisms are considered moderately susceptible if the MIC is greater than 1.6 mcg/mL and less than or equal to 4.8 mcg/mL. Organisms are considered resistant if the MIC is greater than 4.8 mcg per mL. The range of MIC's for the control strains are as follows: S. aureus ATCC 29213, 0.06 to 0.25 mcg/mL. E. faecalis ATCC 29212, 4 to 16 mcg/mL. For anaerobic bacteria the minimum inhibitory concentration (MIC) of clindamycin can be determined by agar dilution and broth dilution (including microdilution) techniques. If MICs are not determined routinely, the disk broth method is recommended for routine use. The KIRBY-BAUER DISK DIFFUSION METHOD AND ITS INTERPRETIVE STANDARDS ARE NOT RECOMMENDED FOR ANAEROBES. | lld:dailymed |
| dailymed-drugs:291 | dailymed-instance:clinicalP... | Naproxen is a nonsteroidal anti-inflammatory drug (NSAID), with analgesic and antipyretic properties. As with other NSAIDs, its mode of action is not fully understood; however, its ability to inhibit prostaglandin synthesis may be involved in the anti-inflammatory effect.<br/>Pharmacokinetics: Although naproxen itself is well absorbed, the sodium salt form is more rapidly absorbed resulting in higher peak plasma levels for a given dose. Approximately 30% of the total naproxen sodium dose in naproxen sodium extended-release tablets is present in the dosage form as an immediate release component. The remaining naproxen sodium is in the form of a sustained-release matrix. After oral administration, plasma levels of naproxen are detected within 30 minutes of dosing, with peak plasma levels occurring approximately 5 hours after dosing. The observed terminal elimination half-life of naproxen from both immediate release naproxen sodium and naproxen sodium extended-release tablets is approximately 15 hours. Steady state levels of naproxen are achieved in 3 days and the degree of naproxen accumulation in the blood is consistent with this.<br/>Absorption: Naproxen itself is rapidly and completely absorbed from the GI tract with an in vivo bioavailability of 95%. Based on the pharmacokinetic profile, the absorption phase of naproxen sodium extended-release tablets occurs in the first 4-6 hours after administration. This coincides with dissolution of the immediate-release component in the stomach, the transit of the sustained release matrix through the small intestine and into the proximal large intestine. The absorption rate from the sustained release component of naproxen sodium extended-release tablets is slower than that for conventional naproxen sodium tablets. It is this prolongation of drug absorption processes which maintains plasma levels and allows for once daily dosing.<br/>Distribution: Naproxen has a volume of distribution of 0.16 L/kg. At therapeutic levels naproxen is greater than 99% albumin-bound. At doses of naproxen greater than 500 mg/day there is a less than proportional increase in plasma levels due to an increase in clearance caused by saturation of plasma protein binding at higher doses. However the concentration of unbound naproxen continues to increase proportionally to dose. Naproxen sodium extended-release tablets exhibit similar dose proportional characteristics.<br/>Metabolism: Naproxen is extensively metabolized to 6-0-desmethyl naproxen and both parent and metabolites do not induce metabolizing enzymes.<br/>Elimination: The elimination half-life of naproxen sodium extended-release tablets and conventional naproxen is approximately 15 hours. Steady state conditions are attained after 2-3 doses of naproxen sodium extended-release tablets. Most of the drug is excreted in the urine, primarily as unchanged naproxen (less than 1%), 6-0-desmethyl naproxen (less than 1%) and their glucuronide or other conjugates (66-92%). A small amount (<5%) of the drug is excreted in the feces. The rate of excretion has been found to coincide closely with the rate of clearance from the plasma. In patients with renal failure metabolites may accumulate.<br/>Special Populations: | lld:dailymed |
| dailymed-drugs:292 | dailymed-instance:clinicalP... | Estrogen drug products act by regulating the transcription of a limited number of genes. Estrogens diffuse through cell membranes, distribute themselves throughout the cell, and bind to and activate the nuclear estrogen receptor, a DNA-binding protein which is found in estrogen-responsive tissues. The activated estrogen receptor binds to specific DNA sequences, or hormone-response elements, which enhance the transcription of adjacent genes and in turn lead to the observed effects. Estrogen receptors have been identified intissues of the reproductive tract, breast, pituitary, hypothalamus, liver, and bone of women. Estrogens are important in the development and maintenance of the female reproductive system and secondary sex characteristics. By a direct action, they cause growth and development of the uterus, fallopian tubes, and vagina. With other hormones, such as pituitary hormones and progesterone, they cause enlargement of the breasts through promotion of ductal growth, stromal development, and theaccretion of fat. Estrogens are intricately involved with other hormones, especially progesterone, in the processes of the ovulatory menstrual cycle and pregnancy, and affect the release of pituitary gonadotropins. They also contribute to the shaping of the skeleton, maintenance of tone and elasticity of urogenital structures, changes in the epiphyses of the long bones that allow for the pubertal growth spurt and its termination, and pigmentation of the nipples and genitals. Estrogens occur naturally in several forms. The primary source of estrogen in normally cycling adult women is the ovarian follicle, which secretes 70 to 500 micrograms of estradiol daily, depending on the phase of the menstrual cycle. This is converted primarily to estrone, which circulates in roughly equal proportion to estradiol, and to small amounts of estriol. After menopause, most endogenous estrogen is produced by conversion of androstenedione, secreted by the adrenal cortex, to estrone by peripheral tissues. Thus, estrone���especially in its sulfate ester form���is the most abundant circulating estrogen in postmenopausal women. Although circulating estrogens exist in a dynamic equilibrium of metabolic interconversions, estradiol is the principal intracellular human estrogen and is substantially more potent than estrone or estriol at the receptor. Estrogens used in therapy are well absorbed through the skin, mucous membranes, and gastrointestinal tract. When applied for a local action, absorption is usually sufficient to cause systemic effects. When conjugated with aryl and alkyl groups for parenteral administration, the rate of absorption of oily preparations is slowed with a prolonged duration of action, such that a single intramuscular injection of estradiol valerate or estradiol cypionate is absorbed over several weeks. Administered estrogens and their esters are handled within the body essentially the same as the endogenous hormones. Metabolic conversion of estrogens occurs primarily in the liver (first pass effect), but also at local target tissue sites. Complex metabolic processes result in a dynamic equilibrium of circulating conjugated and unconjugated estrogenic forms which are continually interconverted, especially between estrone and estradiol and between esterified and unesterified forms. Although naturally-occurring estrogens circulate in the blood largely bound to sex hormone-binding globulin and albumin, only unbound estrogens enter target tissue cells. A significant proportion of the circulating estrogen exists as sulfate conjugates, especially estrone sulfate, which serves as a circulating reservoir for the formation of more active estrogenic species. A certain proportion of the estrogen is excreted into the bile and then reabsorbed from the intestine. During this enterohepatic recirculation, estrogens are desulfated and resulfated and undergo degradation through conversion to less active estrogens (estriol and other estrogens), oxidation to nonestrogenic substances (catecholestrogens, which interact with catecholamine metabolism, especially in the central nervous system), and conjugation with glucuronic acids (which are then rapidly excreted in the urine). When given orally, naturally-occurring estrogens and their esters are extensively metabolized (first pass effect) and circulate primarily as estrone sulfate, with smaller amounts of other conjugated and unconjugated estrogenic species. This results in limited oral potency. By contrast, synthetic estrogens, such as ethinyl estradiol and the nonsteroidal estrogens, are degraded very slowly in the liver and other tissues, which results in their high intrinsic potency. Estrogen drug products administered by non-oral routes are not subject to first-pass metabolism, but also undergo significant hepatic uptake, metabolism, and enterohepatic recycling. | lld:dailymed |
| dailymed-drugs:293 | dailymed-instance:clinicalP... | The pharmacokinetic data were derived from the capsule formulation; however, bioequivalence has been demonstrated for the oral solution, capsule, tablet, and suspension formulations under fasting conditions. Following oral administration of cefprozil to fasting subjects, approximately 95% of the dose was absorbed. The average plasma half-life in normal subjects was 1.3 hours, while the steady-state volume of distribution was estimated to be 0.23 L/kg. The total body clearance and renal clearance rates were approximately 3 mL/min/kg and 2.3 mL/min/kg, respectively. Average peak plasma concentrations after administration of 250 mg, 500 mg, or 1 g doses of cefprozil to fasting subjects were approximately 6.1, 10.5, and 18.3 mcg/mL, respectively, and were obtained within 1.5 hours after dosing. Urinary recovery accounted for approximately 60% of the administered dose. (See Table.) During the first 4 hour period after drug administration, the average urine concentrations following 250 mg, 500 mg, and 1 g doses were approximately 700 mcg/mL, 1000 mcg/mL, and 2900 mcg/mL, respectively. Administration of cefprozil with food did not affect the extent of absorption (AUC) or the peak plasma concentration (C) of cefprozil. However, there was an increase of 0.25 to 0.75 hours in the time to maximum plasma concentration of cefprozil (T). The bioavailability of the capsule formulation of cefprozil was not affected when administered 5 minutes following an antacid. Plasma protein binding is approximately 36% and is independent of concentration in the range of 2 mcg/mL to 20 mcg/mL. There was no evidence of accumulation of cefprozil in the plasma in individuals with normal renal function following multiple oral doses of up to 1000 mg every 8 hours for 10 days. In patients with reduced renal function, the plasma half-life may be prolonged up to 5.2 hours depending on the degree of the renal dysfunction. In patients with complete absence of renal function, the plasma half-life of cefprozil has been shown to be as long as 5.9 hours. The half-life is shortened during hemodialysis. Excretion pathways in patients with markedly impaired renal function have not been determined. In patients with impaired hepatic function, the half-life increases to approximately 2 hours. The magnitude of the changes does not warrant a dosage adjustment for patients with impaired hepatic function. Healthy geriatric volunteers (���65 years old) who received a single 1 g dose of cefprozil had 35% to 60% higher AUC and 40% lower renal clearance values compared with healthy adult volunteers 20 to 40 years of age. The average AUC in young and elderly female subjects was approximately 15% to 20% higher than in young and elderly male subjects. The magnitude of these age- and gender-related changes in the pharmacokinetics of cefprozil is not sufficient to necessitate dosage adjustments. Adequate data on CSF levels of cefprozil are not available. Comparable pharmacokinetic parameters of cefprozil are observed between pediatric patients (6 months to 12 years) and adults following oral administration of selected matched doses. The maximum concentrations are achieved at 1 to 2 hours after dosing. The plasma elimination half-life is approximately 1.5 hours. In general, the observed plasma concentrations of cefprozil in pediatric patients at the 7.5, 15, and 30 mg/kg doses are similar to those observed within the same time frame in normal adult subjects at the 250, 500, and 1000 mg doses, respectively. The comparative plasma concentrations of cefprozil in pediatric patients and adult subjects at the equivalent dose level are presented in the table below.<br/>Microbiology:: Cefprozil has in vitro activity against a broad range of gram-positive and gram-negative bacteria. The bactericidal action of cefprozil results from inhibition of cell-wall synthesis. Cefprozil has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.<br/>Aerobic Gram-Positive Microorganisms:: Staphylococcus aureus (including��-lactamase-producing strains) NOTE: Cefprozil is inactive against methicillin-resistant staphylococci. Streptococcus pneumoniae Streptococcus pyogenes<br/>Aerobic Gram-Negative Microorganisms:: Haemophilus influenzae (including��-lactamase-producing strains) Moraxella (Branhamella) catarrhalis (including��-lactamase-producing strains) The following in vitro data are available; however, their clinical significance is unknown. Cefprozil exhibits in vitro minimum inhibitory concentrations (MICs) of 8 mcg/mL or less against most (���90%) strains of the following microorganisms; however, the safety and effectiveness of cefprozil in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.<br/>Aerobic Gram-Positive Microorganisms:: Enterococcus durans Enterococcus faecalis Listeria monocytogenes Staphylococcus epidermidis Staphylococcus saprophyticus Staphylococcus warneri Streptococcus agalactiae Streptococci (Groups C, D, F, and G) viridans group Streptococci NOTE: Cefprozil is inactive against Enterococcus faecium .<br/>Aerobic Gram-Negative Microorganisms:: Citrobacter diversus Escherichia coli Klebsiella pneumoniae Neisseria gonorrhoeae (including��-lactamase-producing strains) Proteus mirabilis Salmonella spp. Shigella spp . Vibrio spp. NOTE: Cefprozil is inactive against most strains of Acinetobacter, Enterobacter, Morganella morganii, Proteus vulgaris, Providencia, Pseudomonas, and Serratia.<br/>Anaerobic Microorganisms:: Prevotella (Bacteroides) melaninogenicus Clostridium difficile Clostridium perfringens Fusobacterium spp. Peptostreptococcus spp. Propionibacterium acnes NOTE: Most strains of the Bacteroides fragilis group are resistant to cefprozil.<br/>Susceptibility Tests:: Dilution Techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method(broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of cefprozil powder. The MIC values should be interpreted according to the following criteria: A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where high dosage of drug can be used. This category also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected. Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard cefprozil powder should provide the following MIC values: Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedurerequires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcg cefprozil to test the susceptibility of microorganisms to cefprozil. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 mcg cefprozil disk should be interpreted according to the following criteria: Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for cefprozil. As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 30 mcg cefprozil disk should provide the following zone diameters in these laboratory test quality control strains. | lld:dailymed |
| dailymed-drugs:294 | dailymed-instance:clinicalP... | Following intravaginal administration of terconazole in humans, absorption ranged from 5-8 % in three hysterectomized subjects and 12-16 % in two non-hysterectomized subjects with tubal ligations. Following oral (30 mg) administration ofC-labelled terconazole, the harmonic half-life of elimination from the blood for the parent terconazole was 6.9 hours (range 4.0-11.3). Terconazole is extensively metabolized; the plasma AUC for terconazole compared to the AUC for total radioactivity was 0.6 %. Total radioactivity was eliminated from the blood with a harmonic half-life of 52.2 hours (range 44-60). Excretion of radioactivity wasboth by renal (32-56 %) and fecal (47-52 %) routes. In vitro, terconazole is highly protein bound (94.9 %) and the degree of binding is independent of drug concentration. Photosensitivity reactions were observed in some normal volunteers following repeated dermal application of terconazole 2.0% and 0.8% creams under conditions of filtered artificial ultraviolet light. Photosensitivity reactions have not been observed in U.S. and foreign clinical trials in patients who were treated with terconazole vaginal cream 0.4%. Microbiology: Terconazole exhibits fungicidal activity in vitro against Candida albicans. Antifungal activity has also been demonstrated against other fungi. The MIC values of terconazole against most Lactobacillus spp. typically found in the human vagina were���128 mcg/mL; therefore these beneficial bacteria are not affected by drug treatment. The exact pharmacologic mode of action of terconazole is uncertain; however, it may exert its antifungal activity by the disruption of normal fungal cell membrane permeability. No resistance to terconazole has developed during successive passages of C. albicans. | lld:dailymed |
| dailymed-drugs:295 | dailymed-instance:clinicalP... | Lopressor: Lopressor is a beta-adrenergic receptor blocking agent. In vitro and in vivo animal studies have shown that it has a preferential effect on betaadrenoreceptors, chiefly located in cardiac muscle. This preferential effect is not absolute, however, and at higher doses, Lopressor also inhibits betaadrenoreceptors, chiefly located in the bronchial and vascular musculature. Clinical pharmacology studies have confirmed the beta-blocking activity of metoprolol in man, as shown by (1) reduction in heart rate and cardiac output at rest and upon exercise, (2) reduction of systolic blood pressure upon exercise, (3) inhibition of isoproterenol-induced tachycardia, and (4) reduction of reflex orthostatic tachycardia. Relative betaselectivity has been confirmed by the following: (1) In normal subjects, Lopressor is unable to reverse the beta-mediated vasodilating effects of epinephrine. This contrasts with the effect of nonselective (betaplus beta) beta blockers, which completely reverse the vasodilating effects of epinephrine. (2) In asthmatic patients, Lopressor reduces FEVand FVC significantly less than a nonselective beta blocker, propranolol at equivalent beta-receptor blocking doses. Lopressor has no intrinsic sympathomimetic activity and only weak membrane-stabilizing activity. Lopressor crosses the blood-brain barrier and has been reported in the CSF in a concentration 78% of the simultaneous plasma concentration. Animal and human experiments indicate that Lopressor slows the sinus rate and decreases AV nodal conduction. In controlled clinical studies, Lopressor has been shown to be an effective antihypertensive agent when used alone or as concomitant therapy with thiazide-type diuretics, at dosages of 100-450 mg daily. In controlled, comparative, clinical studies, Lopressor has been shown to be as effective an antihypertensive agent as propranolol, methyldopa, and thiazide-type diuretics, and to be equally effective in supine and standing positions. The mechanism of the antihypertensive effects of beta-blocking agents has not been elucidated. However, several possible mechanisms have been proposed: (1) competitive antagonism of catecholamines at peripheral (especially cardiac) adrenergic neuron sites, leading to decreased cardiac output; (2) a central effect leading to reduced sympathetic outflow to the periphery; and (3) suppression of renin activity.<br/>Pharmacokinetics: In man, absorption of Lopressor is rapid and complete. Plasma levels following oral administration, however, approximate 50% of levels following intravenous administration, indicating about 50% first-pass metabolism. Plasma levels achieved are highly variable after oral administration. Only a small fraction of the drug (about 12%) is bound to human serum albumin. Metoprolol is a racemic mixture of R- and S-enantiomers. Less than 5% of an oral dose of Lopressor is recovered unchanged in the urine; the rest is excreted by the kidneys as metabolites that appear to have no clinical significance. The systemic availability and half-life of Lopressor in patients with renal failure do not differ to a clinically significant degree from those in normal subjects. Consequently, no reduction in dosage is usually needed in patients with chronic renal failure. In elderly subjects with clinically normal renal function, there are no significant differences in Lopressor pharmacokinetics compared to young subjects. Lopressor is extensively metabolized by the cytochrome P450 enzyme system in the liver. The oxidative metabolism of Lopressor is under genetic control with a major contribution of the polymorphic cytochrome P450 isoform 2D6 (CYP2D6). There are marked ethnic differences in the prevalence of the poor metabolizers (PM) phenotype. Approximately 7% of Caucasians and less than 1% Asian are poor metabolizers. Poor CYP2D6 metabolizers exhibit several-fold higher plasma concentrations of Lopressor than extensive metabolizers with normal CYP2D6 activity. The elimination half-life of metoprolol is about 7.5 hours in poor metabolizers and 2.8 hours in extensive metabolizers. However, the CYP2D6 dependent metabolism of Lopressor seems to have little or no effect on safety or tolerability of the drug. None of the metabolites of Lopressor contribute significantly to its beta-blocking effect.<br/>Pharmacodynamics: Significant beta-blocking effect (as measured by reduction of exercise heart rate) occurs within 1 hour after oral administration, and its duration is dose-related. For example, a 50% reduction of the maximum registered effect after single oral doses of 20, 50, and 100 mg occurred at 3.3, 5.0, and 6.4 hours, respectively, in normal subjects. After repeated oral dosages of 100 mg twice daily, a significant reduction in exercise systolic blood pressure was evident at 12 hours. There is a linear relationship between the log of plasma levels and reduction of exercise heart rate. However, antihypertensive activity does not appear to be related to plasma levels. Because of variable plasma levels attained with a given dose and lack of a consistent relationship of antihypertensive activity to dose, selection of proper dosage requires individual titration.<br/>Hydrochlorothiazide: Thiazides affect the renal tubular mechanism of electrolyte reabsorption. At maximal therapeutic dosage, all thiazides are approximately equal in their diuretic potency. Thiazides increase excretion of sodium and chloride in approximately equivalent amounts. Natriuresis causes a secondary loss of potassium. The mechanism of the antihypertensive effect of thiazides is unknown. Thiazides do not affect normal blood pressure.<br/>Pharmacokinetics: Hydrochlorothiazide is rapidly absorbed, as indicated by peak plasma concentrations 1-2.5 hours after oral administration. Plasma levels of the drug are proportional to dose; the concentration in whole blood is 1.6-1.8 times higher than in plasma. Thiazides are eliminated rapidly by the kidney. After oral administration of 25- to 100-mg doses, 72-97% of the dose is excreted in the urine, indicating dose-independent absorption. Hydrochlorothiazide is eliminated from plasma in a biphasic fashion with a terminal half-life of 10-17 hours. Plasma protein binding is 67.9%. Plasma clearance is 15.9-30.0 L/hr; volume of distribution is 3.6-7.8 L/kg. Gastrointestinal absorption of hydrochlorothiazide is enhanced when administered with food. Absorption is decreased in patients with congestive heart failure, and the pharmacokinetics are considerably different in these patients.<br/>Pharmacodynamics: The onset of action of thiazides occurs in 2 hours and the peak effect at about 4 hours. The action persists for approximately 6-12 hours. | lld:dailymed |
| dailymed-drugs:296 | dailymed-instance:clinicalP... | In isolated nerve-muscle preparation, Dantrium has been shown to produce relaxation by affecting the contractile response of the skeletal muscle at a site beyond the myoneural junction, directly on the muscle itself. In skeletal muscle, Dantrium dissociates the excitation-contraction coupling, probably by interfering with the release of Cafrom the sarcoplasmic reticulum. This effect appears to be more pronounced in fast muscle fibers as compared to slow ones, but generally affects both. A central nervous system effect occurs, with drowsiness, dizziness, and generalized weakness occasionally present. Although Dantrium does not appear to directly affect the CNS, the extent of its indirect effect is unknown. The absorption of Dantrium after oral administration in humans is incomplete and slow but consistent, and dose-related blood levels are obtained. The duration and intensity of skeletal muscle relaxation is related to the dosage and blood levels. The mean biologic half-life of Dantrium in adults is 8.7 hours after a 100-mg dose. Specific metabolic pathways in the degradation and elimination of Dantrium in human subjects have been established. Metabolic patterns are similar in adults and pediatric patients. In addition to the parent compound, dantrolene, which is found in measurable amounts in blood and urine, the major metabolites noted in body fluids are the 5-hydroxy analog and the acetamido analog. Since Dantrium is probably metabolized by hepatic microsomal enzymes, enhancement of its metabolism by other drugs is possible. However, neither phenobarbital nor diazepam appears to affect Dantrium metabolism. Clinical experience in the management of fulminant human malignant hyperthermia, as well as experiments conducted in malignant hyperthermia susceptible swine, have revealed that the administration of intravenous dantrolene, combined with indicated supportive measures, is effective in reversing the hypermetabolic process of malignant hyperthermia. Known differences between human and swine malignant hyperthermia are minor. The prophylactic administration of oral or intravenous dantrolene to malignant hyperthermia susceptible swine will attenuate or prevent the development of signs of malignant hyperthermia in a manner dependent upon the dosage of dantrolene administered and the intensity of the malignant hyperthermia triggering stimulus. Limited clinical experience with the administration of oral dantrolene to patients judged malignant hyperthermia susceptible, when combined with clinical experience in the use of intravenous dantrolene for the treatment of malignant hyperthermia and data derived from the above cited animal model experiments, suggests that oral dantrolene will also attenuate or prevent the development of signs of human malignant hyperthermia, provided that currently accepted practices in the management of such patientsare adhered to ; intravenous dantrolene should also be available for use should the signs of malignant hyperthermia appear. | lld:dailymed |
| dailymed-drugs:297 | dailymed-instance:clinicalP... | Mechanism of Action: Fexofenadine hydrochloride, the major active metabolite of terfenadine, is an antihistamine with selective peripheral H-receptor antagonist activity. Fexofenadine hydrochloride inhibited antigen-induced bronchospasm in sensitized guinea pigs and histamine release from peritoneal mast cells in rats. In laboratory animals, no anticholinergic or alpha-adrenergic-receptor blocking effects were observed. Moreover, no sedative or other central nervous system effects were observed. Radiolabeled tissue distribution studies in rats indicated that fexofenadine does not cross the blood-brain barrier. Pseudoephedrine hydrochloride is an orally active sympathomimetic amine and exerts a decongestant action on the nasal mucosa. Pseudoephedrine hydrochloride is recognized as an effective agent for the relief of nasal congestion due to allergic rhinitis. Pseudoephedrine produces peripheral effects similar to those of ephedrine and central effects similar to, but less intense than, amphetamines. It has the potential for excitatory side effects. At the recommended oral dose, it has little or no pressor effect in normotensive adults.<br/>Pharmacokinetics: The pharmacokinetics of fexofenadine hydrochloride in subjects with seasonal allergic rhinitis were similar to those in healthy volunteers.<br/>Absorption: The pharmacokinetics of fexofenadine hydrochloride and pseudoephedrine hydrochloride when administered separately have been well characterized. Fexofenadine pharmacokinetics were linear for oral doses of fexofenadine hydrochloride up to a total daily dose of 240 mg (120 mg twice daily). Peak fexofenadine plasma concentrations were similar between adolescent (12���16 years of age) and adult subjects. The bioavailability of fexofenadine hydrochloride and pseudoephedrine hydrochloride from ALLEGRA-D 12 HOUR Extended-Release Tablets is similar to that achieved with separate administration of the components. Coadministration of fexofenadine and pseudoephedrine does not significantly affect the bioavailability of either component. Fexofenadine hydrochloride was rapidly absorbed following single-dose administration of the 60 mg fexofenadine hydrochloride/120 mg pseudoephedrine hydrochloride tablet with median time to mean maximum fexofenadine plasma concentration of 191 ng/mL occurring 2 hours post-dose. Pseudoephedrine hydrochloride produced a mean single-dose pseudoephedrine peak plasma concentration of 206 ng/mL which occurred 6 hours post-dose. Following multiple dosing to steady-state, a fexofenadine peak concentration of 255 ng/mL was observed 2 hours post-dose. Following multiple dosing to steady-state, a pseudoephedrine peak concentration of 411 ng/mL was observed 5 hours post-dose. The administration of ALLEGRA-D 12 HOUR with a high fat meal decreased the bioavailability of fexofenadine by approximately 50% (AUC 42% and Cmax 46%). Time to maximum concentration (T) was delayed by 50%. The rate or extent of pseudoephedrine absorption was not affected by food. Therefore, ALLEGRA-D 12 HOUR should be taken on an empty stomach with water .<br/>Distribution: Fexofenadine is 60% to 70% bound to plasma proteins, primarily albumin and��-acid glycoprotein. The protein binding of pseudoephedrine in humans is not known. Pseudoephedrine hydrochloride is extensively distributed into extravascular sites (apparent volume of distribution between 2.6 and 3.5 L/kg).<br/>Metabolism: Approximately 5% of the total dose of fexofenadine hydrochloride and less than 1% of the total oral dose of pseudoephedrine hydrochloride were eliminated by hepatic metabolism.<br/>Elimination: The mean elimination half-life of fexofenadine was 14.4 hours following administration of 60 mg fexofenadine hydrochloride, twice daily, to steady-state in healthy volunteers. Human mass balance studies documented a recovery of approximately 80% and 11% of the [C] fexofenadine hydrochloride dose in the feces and urine, respectively. Because the absolute bioavailability of fexofenadine hydrochloride has not been established, it is unknown if the fecal component is primarily unabsorbed drug or the result of biliary excretion. Pseudoephedrine has been shown to have a mean elimination half-life of 4���6 hours which is dependent on urine pH. The elimination half-life is decreased at urine pH lower than 6 and may be increased at urine pH higher than 8.<br/>Special Populations: Pharmacokinetics in special populations (for renal, hepatic impairment, and age), obtained after a single dose of 80 mg fexofenadine hydrochloride, were compared to those from healthy subjects in a separate study of similar design.<br/>Pharmacodynamics:<br/>Wheal and Flare: Human histamine skin wheal and flare studies following single and twice daily doses of 20 mg and 40 mg fexofenadine hydrochloride demonstrated that the drug exhibits an antihistamine effect by 1 hour, achieves maximum effect at 2���3 hours, and an effect is still seen at 12 hours. There was no evidence of tolerance to these effects after 28 days of dosing. The clinical significance of these observations is unknown.<br/>Effects on QT: In dogs (30 mg/kg orally twice daily for 5 days) and rabbits (10 mg/kg intravenously over 1 hour), fexofenadine hydrochloride did not prolong QTat plasma concentrations that were at least 17 and 38 times, respectively, the therapeutic plasma concentrations in man (based on a 60 mg twicedaily fexofenadine hydrochloride dose). No effect was observed on calcium channel current, delayed Kchannel current, or action potential duration in guinea pig myocytes, Nacurrent in rat neonatal myocytes, or on the delayed rectifier Kchannel cloned from human heart at concentrations up to 1��10M of fexofenadine. This concentration was at least 21 times the therapeutic plasma concentration in man (based on a 60 mg twice daily fexofenadine hydrochloride dose). No statistically significant increase in mean QTinterval compared to placebo was observed in 714 subjects with seasonal allergic rhinitis given fexofenadine hydrochloride capsules in doses of 60 mg to 240 mg twice daily for 2 weeks or in 40 healthy volunteers given fexofenadine hydrochloride as an oral solution at doses up to 400 mg twice daily for 6 days. A 1-year study designed to evaluate safety and tolerability of 240 mg of fexofenadine hydrochloride (n=240) compared to placebo (n=237) in healthy volunteers, did not reveal a statistically significant increase in the mean QTinterval for the fexofenadine hydrochloride treated group when evaluated pretreatment and after 1, 2, 3, 6, 9, and 12 months of treatment. Administration of the 60 mg fexofenadine hydrochloride/120 mg pseudoephedrine hydrochloride combination tablet for approximately 2 weeks to 213 subjects with seasonal allergic rhinitis demonstrated no statistically significant increase in the mean QTinterval compared to fexofenadine hydrochloride administered alone (60 mg twice daily, n=215), or compared to pseudoephedrine hydrochloride (120 mg twice daily, n=215) administered alone.<br/>Clinical Studies: In a 2-week, multicenter, randomized, double-blind, active-controlled trial in subjects 12���65 years of age with seasonal allergic rhinitis due to ragweed allergy (n=651), the 60 mg fexofenadine hydrochloride/120 mg pseudoephedrine hydrochloride combination tablet administered twice daily significantly reduced the intensity of sneezing, rhinorrhea, itchy nose/palate/throat, itchy/watery/red eyes, and nasal congestion. In three, 2-week, multicenter, randomized, double-blind, placebo-controlled trials in subjects 12���68 years of age with seasonal allergic rhinitis (n=1634), fexofenadine hydrochloride 60 mg twice daily significantly reduced total symptom scores (the sum of the individual scores for sneezing, rhinorrhea, itchy nose/palate/throat, itchy/watery/red eyes) compared to placebo. Statistically significant reductions in symptom scores were observed following the first 60 mg dose, with the effect maintained throughout the 12-hour interval. In general, there was no additional reduction in total symptom scores with higher doses of fexofenadine hydrochloride up to 240 mg twice daily. Although the number of subjects in some of the subgroups was small, there were no significant differences in the effect of fexofenadine hydrochloride across subgroups of subjects defined bygender, age, and race. Onset of action for reduction in total symptom scores, excluding nasal congestion, was observed at 60 minutes compared to placebo following a single 60 mg fexofenadine hydrochloride dose administered to subjects with seasonal allergic rhinitis who were exposed to ragweed pollen in an environmental exposure unit. | lld:dailymed |
| dailymed-drugs:298 | dailymed-instance:clinicalP... | Mechanism of Action: The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. In animal models designed to detect anticonvulsant activity, lamotrigine was effective in preventing seizure spread in the maximum electroshock (MES) and pentylenetetrazol (scMet) tests, and prevented seizures in the visually and electrically evoked after-discharge (EEAD) tests for antiepileptic activity. Lamotrigine also displayed inhibitory properties in the kindling model in rats both during kindling development and in the fully kindled state. The relevance of these models to human epilepsy, however, is not known. One proposed mechanism of action of lamotrigine, the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate). The mechanisms by which lamotrigine exerts its therapeutic action in Bipolar Disorder have not been established.<br/>Pharmacological Properties: Although the relevance for human use is unknown, the following data characterize the performance of lamotrigine in receptor binding assays. Lamotrigine had a weak inhibitory effect on the serotonin 5-HTreceptor (IC= 18��M). It does not exhibit high affinity binding (IC>100��M) to the following neurotransmitter receptors: adenosine Aand A; adrenergic��,��, and��; dopamine Dand D;��-aminobutyric acid (GABA) A and B; histamine H; kappa opioid; muscarinic acetylcholine; and serotonin 5-HT. Studies have failed to detect an effect of lamotrigine on dihydropyridine-sensitive calcium channels. It had weak effects at sigma opioid receptors (IC= 145��M). Lamotrigine did not inhibit the uptake of norepinephrine, dopamine, or serotonin (IC>200��M) when tested in rat synaptosomes and/or human platelets in vitro.<br/>Effect of Lamotrigine on N-Methyl d-Aspartate-Receptor Mediated Activity: Lamotrigine did not inhibit N-methyl d-aspartate (NMDA)-induced depolarizations in rat cortical slices or NMDA-induced cyclic GMP formation in immature rat cerebellum, nor did lamotrigine displace compounds that are either competitive or noncompetitive ligands at this glutamate receptor complex (CNQX, CGS, TCHP). The ICfor lamotrigine effects on NMDA-induced currents (in the presence of 3��M of glycine) in cultured hippocampal neurons exceeded 100��M.<br/>Folate Metabolism: In vitro,lamotrigine was shown to be an inhibitor of dihydrofolate reductase, the enzyme that catalyzes the reduction of dihydrofolate to tetrahydrofolate. Inhibition of this enzyme may interfere with the biosynthesis of nucleic acids and proteins. When oral daily doses of lamotrigine were given to pregnant rats during organogenesis, fetal, placental, and maternal folate concentrations were reduced. Significantly reduced concentrations of folate are associated with teratogenesis (see PRECAUTIONS, Pregnancy). Folate concentrations were also reduced in male rats given repeated oral doses of lamotrigine. Reduced concentrations were partially returned to normal when supplemented with folinic acid.<br/>Accumulation in Kidneys: Lamotrigine was found to accumulate in the kidney of the male rat, causing chronic progressive nephrosis, necrosis, and mineralization. These findings are attributed to��-2 microglobulin, a species- and sex-specific protein that has not been detected in humans or other animal species.<br/>Melanin Binding: Lamotrigine binds to melanin-containing tissues, e.g., in the eye and pigmented skin. It has been found in the uveal tract up to 52 weeks after a single dose in rodents.<br/>Cardiovascular: In dogs, lamotrigine is extensively metabolized to a 2-N-methyl metabolite. This metabolite causes dose-dependent prolongations of the PR interval, widening of the QRS complex, and, at higher doses, complete AV conduction block. Similar cardiovascular effects are not anticipated in humans because only trace amounts of the 2-N-methyl metabolite (<0.6% of lamotrigine dose) have been found in human urine (see Drug Disposition). However, it is conceivable that plasma concentrations of this metabolite could be increased in patients with a reduced capacity to glucuronidate lamotrigine (e.g., in patients with liver disease).<br/>Pharmacokinetics and Drug Metabolism: The pharmacokinetics of lamotrigine have been studied in patients with epilepsy, healthy young and elderly volunteers, and volunteers with chronic renal failure. Lamotrigine pharmacokinetic parameters for adult and pediatric patients and healthy normal volunteers are summarized in Tables 1 and 2.<br/>Absorption: Lamotrigine is rapidly and completely absorbed after oral administration with negligible first-pass metabolism (absolute bioavailability is 98%). The bioavailability is not affected by food. Peak plasma concentrations occur anywhere from 1.4 to 4.8 hours following drug administration.<br/>Distribution: Estimates of the mean apparent volume of distribution (Vd/F) of lamotrigine following oral administration ranged from 0.9 to 1.3 L/kg. Vd/F is independent of dose and is similar following single and multiple doses in both patients with epilepsy and in healthy volunteers.<br/>Protein Binding: Data from in vitro studies indicate that lamotrigine is approximately 55% bound to human plasma proteins at plasma lamotrigine concentrations from 1 to 10 mcg/mL (10 mcg/mL is 4 to 6 times the trough plasma concentration observed in the controlled efficacy trials). Because lamotrigine is not highly bound to plasma proteins, clinically significant interactions with other drugs through competition for protein binding sites are unlikely. The binding of lamotrigine toplasma proteins did not change in the presence of therapeutic concentrations of phenytoin, phenobarbital, or valproate. Lamotrigine did not displace other AEDs (carbamazepine, phenytoin, phenobarbital) from protein binding sites.<br/>Drug Disposition: Lamotrigine is metabolized predominantly by glucuronic acid conjugation; the major metabolite is an inactive 2-N-glucuronide conjugate. After oral administration of 240 mg ofC-lamotrigine (15��Ci) to 6 healthy volunteers, 94% was recovered in the urine and 2% was recovered in the feces. The radioactivity in the urine consisted of unchanged lamotrigine (10%), the 2-N-glucuronide (76%), a 5-N-glucurodine (10%), a 2-N-methyl metabolite (0.14%), and other unidentified minor metabolites (4%).<br/>Drug Interactions: The apparent clearance of lamotrigine is affected by the coadministration of certain medications. Because lamotrigine is metabolized predominantly by glucuronic acid conjugation, drugs that induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine. Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the apparent clearance of lamotrigine (see DOSAGE AND ADMINISTRATION and PRECAUTIONS, Drug Interactions). Most clinical experience is derived from patients taking these AEDs. Estrogen-containing oral contraceptives and rifampin have also been shown to increase the apparent clearance of lamotrigine (see PRECAUTIONS, Drug Interactions). Valproate decreases the apparent clearance of lamotrigine (i.e., more than doubles the elimination half-life of lamotrigine), whether given with or without carbamazepine, phenytoin, phenobarbital, or primidone. Accordingly, if lamotrigine is to be administered to a patient receiving valproate, lamotrigine must be given at a reduced dosage, no more than half the dose used in patients not receiving valproate, even in the presence of drugs that increase the apparent clearance of lamotrigine (see DOSAGE AND ADMINISTRATION and PRECAUTIONS, Drug Interactions). The following drugs were shown not to increase the apparent clearance of lamotrigine: felbamate, gabapentin, levetiracetam, oxcarbazepine, pregabalin, and topiramate. Zonisamide does not appear to change the pharmacokinetic profile of lamotrigine (see PRECAUTIONS, Drug Interactions). In vitro inhibition experiments indicated that the formation of the primary metabolite of lamotrigine, the 2-N-glucuronide, was not significantly affected by co-incubation with clozapine, fluoxetine, phenelzine, risperidone, sertraline, or trazodone, and was minimally affected by co-incubation with amitriptyline, bupropion, clonazepam, haloperidol, or lorazepam. In addition, bufuralol metabolism data from human liver microsomes suggested that lamotrigine does not inhibit the metabolism of drugs eliminated predominantly by CYP2D6. Lamotrigine has no effects on the pharmacokinetics of lithium (see PRECAUTIONS, Drug Interactions). The pharmacokinetics of lamotrigine were not changed by coadministration of bupropion (see PRECAUTIONS, Drug Interactions). Coadministration of olanzapine did not have a clinically relevant effect on lamotrigine pharmacokinetics (see PRECAUTIONS, Drug Interactions).<br/>Enzyme Induction: The effects of lamotrigine on the induction of specific families of mixed-function oxidase isozymes have not been systematically evaluated. Following multiple administrations (150 mg twice daily) to normal volunteers taking no other medications, lamotrigine induced its own metabolism, resulting in a 25% decrease in tand a 37% increase in Cl/F at steady state compared to values obtained in the same volunteers following a single dose. Evidence gathered from other sources suggests that self-induction by lamotrigine may not occur when lamotrigine is given as adjunctive therapy in patients receiving carbamazepine, phenytoin, phenobarbital, primidone, or rifampin.<br/>Dose Proportionality: In healthy volunteers not receiving any other medications and given single doses, the plasma concentrations of lamotrigine increased in direct proportion to the dose administered over the range of 50 to 400 mg. In 2 small studies (n = 7 and 8) of patients with epilepsy who were maintained on other AEDs, there also was a linear relationship between dose and lamotrigine plasma concentrations at steady state following doses of 50 to 350 mg twice daily.<br/>Elimination: (See Table 1.)<br/>Special Populations:<br/>Patients With Renal Insufficiency: Twelve volunteers with chronic renal failure (mean creatinine clearance = 13 mL/min; range = 6 to 23) and another 6 individuals undergoing hemodialysis were each given a single 100 mg dose of lamotrigine. The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure), 13.0 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared to 26.2 hours in healthy volunteers. On average, approximately 20% (range = 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated by hemodialysis during a 4 hour session.<br/>Hepatic Disease: The pharmacokinetics of lamotrigine following a single 100 mg dose of lamotrigine were evaluated in 24 subjects with mild, moderate, and severe hepatic dysfunction (Child-Pugh Classification system) and compared with 12 subjects without hepatic impairment. The patients with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5). The mean apparent clearance of lamotrigine in patients with mild (n = 12), moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment was 0.30��0.09, 0.24��0.1, 0.21��0.04, and 0.15��0.09 mL/min/kg, respectively, as compared to 0.37��0.1 mL/min/kg in the healthy controls. Mean half-life of lamotrigine in patients with mild, moderate, severe without ascites, and severe with ascites liver impairment was 46��20, 72��44, 67��11, and 100��48 hours, respectively, as compared to 33��7 hours in healthy controls (for dosing guidelines, see DOSAGE AND ADMINISTRATION, Patients With Hepatic Impairment).<br/>Age:<br/>Gender: The clearance of lamotrigine is not affected by gender. However, during dose escalation of lamotrigine in one clinical trial in patients with epilepsy on a stable dose of valproate (n = 77), mean trough lamotrigine concentrations, unadjusted for weight, were 24% to 45% higher (0.3 to 1.7 mcg/mL) in females than in males.<br/>Race: The apparent oral clearance of lamotrigine was 25% lower in non-Caucasians than Caucasians. | lld:dailymed |
| dailymed-drugs:299 | dailymed-instance:clinicalP... | Droperidol produces marked tranquilization and sedation. It allays apprehension and provides a state of mental detachment and indifference while maintaining a state of reflex alertness. Droperidol produces an antiemetic effect as evidenced by the antagonism of apomorphine in dogs. It lowers the incidence of nausea and vomiting during surgical procedures and provides antiemetic protection in the postoperative period. Droperidol potentiates other CNS depressants. It produces mild alpha-adrenergic blockade, peripheral vascular dilatation and reduction of the pressor effect of epinephrine. It can produce hypotension and decreased peripheral vascular resistance and may decrease pulmonary arterial pressure (particularly if it is abnormally high). It may reduce the incidence of epinephrine-induced arrhythmiasbut it does not prevent other cardiac arrhythmias. The onset of action of single intramuscular and intravenous doses is from three to ten minutes following administration, although the peak effect may not be apparent for up to thirty minutes. The duration of the tranquilizing and sedative effects generally is two to four hours, although alteration of alertness may persist for as long as twelve hours. | lld:dailymed |
| dailymed-drugs:300 | dailymed-instance:clinicalP... | Glucocorticoids, naturally occurring and synthetic, are adrenocortical steroids that are readily absorbed from the gastrointestinal tract. Glucocorticoids cause varied metabolic effects. In addition, they modify the body's immune responses to diverse stimuli. Naturally occurring glucocorticoids (hydrocortisone and cortisone), which also have sodium-retaining properties, are used as replacement therapy in adrenocortical deficiency states. Their synthetic analogs including dexamethasone are primarily used for their anti-inflammatory effects in disorders of many organ systems. At equipotent anti-inflammatory doses, dexamethasone almost completely lacks the sodium-retaining property of hydrocortisone and closely related derivatives of hydrocortisone. | lld:dailymed |
| dailymed-drugs:301 | dailymed-instance:clinicalP... | Alcohol and Dextrose Injections USP are an intravenous source of calories. In the average adult, pure ethyl alcohol is metabolized at a rate of 10 to 20 mL per hour. Sedative effects of alcohol occur if the rate of infusion exceeds the rate of metabolism. Dextrose (D-glucose) can be infused at a maximum rate of approximately 0.5 to 0.85 g/kg of body weight/hr without producing significant glycosuria. Thus, the maximum rate that alcohol can be infused without producing sedative effects is well below the maximum rate of utilization of dextrose. Alcohol is metabolized, mostly in the liver, to acetaldehyde or acetate. The rate of oxidation is a linear function of time. Starvation lowers the rate of metabolism and insulin increases the rate. | lld:dailymed |
| dailymed-drugs:302 | dailymed-instance:clinicalP... | Clemastine fumarate is an antihistamine with anticholinergic (drying) and sedative side effects. Antihistamines appear to compete with histamine for cell receptor sites on effector cells. The inherently long duration of antihistaminic effects of clemastine fumarate has been demonstrated in wheal and flare studies. In normal human subjects who received histamine injections over a 24-hour period, the antihistaminic activity of clemastine reached a peak at 5-7 hours, persisted for 10-12 hours and, in some cases, for as long as 24 hours. Pharmacokinetic studies in man utilizingH andC labeled compound demonstrates that: clemastine is rapidly and nearly completely absorbed from the gastrointestinal tract, peak plasma concentrations are attained in 2-4 hours, and urinary excretion is the major mode of elimination. | lld:dailymed |
| dailymed-drugs:304 | dailymed-instance:clinicalP... | Pharmacodynamics:<br/>Mechanism of Action: Alosetron is a potent and selective 5-HTreceptor antagonist. 5-HTreceptors are ligand-gated cation channels that are extensively distributed on enteric neurons in the human gastrointestinal tract, as well as other peripheral and central locations. Activation of these channels and the resulting neuronal depolarization affect the regulation of visceral pain, colonic transit and gastrointestinal secretions, processes that relate to the pathophysiology of irritable bowel syndrome (IBS). 5-HTreceptor antagonists such as alosetron inhibit activation of non-selective cation channels which results in the modulation of the enteric nervous system. The cause of IBS is unknown. IBS is characterized by visceral hypersensitivity and hyperactivity of the gastrointestinal tract, which lead to abnormal sensations of pain and motor activity. Following distention of the rectum, IBS patients exhibit pain and discomfort at lower volumes than healthy volunteers. Following such distention, alosetron reduced pain and exaggerated motor responses, possibly due to blockade of 5-HTreceptors. In healthy volunteers and IBS patients, alosetron (2 mg orally, twice daily for 8 days) increased colonic transit time without affecting orocecal transit time. In healthy volunteers, alosetron also increased basal jejunal water and sodium absorption after a single 4-mg dose. In IBS patients, multiple oral dosages of alosetron (4 mg twice daily for 6.5 days) significantly increased colonic compliance. Single oral doses of alosetron administered to healthy men produced a dose-dependent reduction in the flare response seen after intradermal injection of serotonin. Urinary 6-��-hydroxycortisol excretion decreased by 52% in elderly subjects after 27.5 days of alosetron 2 mg orally twice daily. This decrease was not statistically significant. In another study utilizing alosetron 1 mg orally twice daily for 4 days, there was a significant decrease in urinary 6-��-hydroxycortisol excretion. However, there was no change in the ratio of 6-��-hydroxycortisol to cortisol, indicating a possible decrease in cortisol production. The clinical significance of these findings is unknown.<br/>Pharmacokinetics: The pharmacokinetics of alosetron have been studied after single oral doses ranging from 0.05 to 16 mg in healthy men. The pharmacokinetics of alosetron have also been evaluated in healthy women and men and in patients with IBS after repeated oral dosages ranging from 1 mg twice daily to 8 mg twice daily.<br/>Absorption: Alosetron is rapidly absorbed after oral administration with a mean absolute bioavailability of approximately 50% to 60% (approximate range 30% to>90%). After administration of radiolabeled alosetron, only 1% of the dose was recovered in the feces as unchanged drug. Following oral administration of a 1-mg alosetron dose to young men, a peak plasma concentration of approximately 5 ng/mL occurs at 1 hour. In young women, the mean peak plasma concentration is approximately 9 ng/mL, with a similar time to peak.<br/>Food Effects: Alosetron absorption is decreased by approximately 25% by co-administration with food, with a mean delay in time to peak concentration of 15 minutes (see DOSAGE AND ADMINISTRATION: Usual Dosage in Adults).<br/>Distribution: Alosetron demonstrates a volume of distribution of approximately 65 to 95 L. Plasma protein binding is 82% over a concentration range of 20 to 4,000 ng/mL.<br/>Metabolism and Elimination: Plasma concentrations of alosetron increase proportionately with increasing single oral doses up to 8 mg and more than proportionately at a single oral dose of 16 mg. Twice-daily oral dosing of alosetron does not result in accumulation. The terminal elimination half-life of alosetron is approximately 1.5 hours (plasma clearance is approximately 600 mL/min). Population pharmacokinetic analysis in IBS patients confirmed that alosetron clearance is minimally influenced by doses up to 8 mg. Renal elimination of unchanged alosetron accounts for only 6% of the dose. Renal clearance is approximately 94 mL/min. Alosetron is extensively metabolized in humans. The biological activity of the metabolites is unknown. A mass balance study was performed utilizing an orally administered dose of unlabeled andC-labeled alosetron. On a molar basis, alosetron metabolites reached additive peak plasma concentrations 9-fold greater than alosetron, and the additive metabolite AUCs were 13-fold greater than the alosetron AUC. Plasma radioactivity declined with a half-life 2-fold longer than that of alosetron, indicating the presence of circulating metabolites. Approximately 73% of the radiolabeled dose was recovered in urine with another 24% of the dose recovered in feces. Only 7% of the dose was recovered as unchanged drug. At least 13 metabolites have been detected in urine. The predominant product in urine was a 6-hydroxy metabolite (15% of the dose). This metabolite was secondarily metabolized to a glucuronidethat was also present in urine (14% of the dose). Smaller amounts of the 6-hydroxy metabolite and the 6-O-glucuronide also appear to be present in feces. A bis-oxidized dicarbonyl accounted for 14% of the dose, and its monocarbonyl precursor accounted for another 4% in urine and 6% in feces. No other urinary metabolite accounted for more than 4% of the dose. Glucuronide or sulfate conjugates of unchanged alosetron were not detected in urine. In studies of Japanese men, an N-desmethyl metabolite was found circulating in plasma in all subjects and accounted for up to 30% of the dose in 1 subject when alosetron was administered with food. The clinical significance of this finding is unknown. Alosetron is metabolized by human microsomal cytochrome P450 (CYP), shown in vitro to involve enzymes 2C9 (30%), 3A4 (18%), and 1A2 (10%). Non-CYP-mediated Phase I metabolic conversion also contributes to an extent of about 11%. However, in vivo data suggest that CYP1A2 plays a more prominent role in alosetron metabolism, based on correlation of alosetron clearance with in vivo CYP1A2 activity measured by probe substrate, increased clearance induced by smoking, and inhibition of clearance by fluvoxamine (see CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions).<br/>Population Subgroups:<br/>Age: In some studies in healthy men or women, plasma concentrations were elevated by approximately 40% in individuals 65 years and older compared to young adults (see WARNINGS). However, this effect was not consistently observed in men.<br/>Gender: Plasma concentrations are 30% to 50% lower and less variable in men compared to women given the same oral dose. Population pharmacokinetic analysis in IBS patients confirmed that alosetron concentrations were influenced by gender (27% lower in men).<br/>Reduced Hepatic Function: A single 1-mg oral dose of alosetron was administered to 1 female and 5 male patients with moderate hepatic impairment (Child-Pugh score of 7 to 9) and to 1 female and 2 male patients with severe hepatic impairment (Child-Pugh score of>9). In comparison with historical data from healthy subjects, patients with severe hepatic impairment displayed higher systemic exposure to alosetron. The female with severe hepatic impairment displayed approximately 14-fold higher exposure, while the female with moderate hepatic impairment displayed approximately 1.6-fold higher exposure, than healthy females. Due to the small number of subjects and high intersubject variability in the pharmacokinetic findings, no definitive quantitative conclusions can be made. However, due to the greater exposure to alosetron in the female with severe hepatic impairment, alosetron should not be used in females with severe hepatic impairment (see CONTRAINDICATIONS, PRECAUTIONS: Hepatic Insufficiency, and DOSAGE AND ADMINISTRATION: Patients With Hepatic Impairment).<br/>Reduced Renal Function: Renal impairment (creatinine clearance 4 to 56 mL/min) has no effect on the renal elimination of alosetron due to the minor contribution of this pathway to elimination. The effect of renal impairment on metabolite kinetics and the effect of end-stage renal disease have not been assessed (see DOSAGE AND ADMINISTRATION: Patients With Renal Impairment).<br/>Drug Interactions: See CONTRAINDICATIONS and PRECAUTIONS: Drug Interactions. | lld:dailymed |
| dailymed-drugs:305 | dailymed-instance:clinicalP... | Isolyte S pH 7.4 provides electrolytes and is a source of water for hydration. It is capable of inducing diuresis depending on the clinical condition of the patient. Sodium, the major cation of the extracellular fluid, functions primarily in the control of water distribution, fluid balance, and osmotic pressure of body fluids. Sodium is also associated with chloride and bicarbonate in the regulation of the acid-base equilibrium of body fluid. Potassium, the principal cation of intracellular fluid, participates in carbohydrate utilization and protein synthesis, and is critical in the regulation of nerve conduction and muscle contraction, particularly in the heart. Chloride, the major extracellular anion, closely follows the metabolism of sodium, and changes in the acid-base balance of the body are reflected by changes in the chloride concentration. Phosphate is a major intracellular anion which participates in providing energy for metabolism of substrates and contributes to significant metabolic and enzymatic reactions in almost all organs and tissues. It exerts a modifying influence on calcium levels, a buffering effect on acid-base equilibrium and has a primary role in the renal excretion of hydrogen ions. Magnesium, a principal cation of soft tissue, is primarily involved in enzyme activity associated with the metabolism of carbohydrates and protein. Magnesium is also involved in neuromuscular irritability. Gluconate and acetate are organic ions which are hydrogen ion acceptors and contribute bicarbonate during their metabolism to carbon dioxide and water, and serve as alkalinizing agents. | lld:dailymed |
| dailymed-drugs:306 | dailymed-instance:clinicalP... | Procainamide (PA) increases the effective refractory period of the atria, and to a lesser extent the bundle of His-Purkinje system and ventricles of the heart. It reduces impulse conduction velocity in the atria, His-Purkinje fibers, and ventricular muscle, but has variable effects on the atrioventricular (A-V) node, a direct slowing action and a weaker vagolytic effect which may speed A-V conduction slightly. Myocardial excitability is reduced in the atria. Purkinje fibers, papillary muscles, and ventricles by an increase in the threshold for excitation, combined with inhibition of ectopicpacemaker activity by retardation of the slow phase of diastolic depolarization, thus decreasing automaticity especially in ectopic sites. Contractility of the undamaged heart is usually not affected by therapeutic concentrations, although slight reduction of cardiac output may occur, and may be significant in the presence of myocardial damage. Therapeutic levels of PA may exert vagolytic effects and produce slight acceleration of heart rate, while high or toxic concentrations may prolong A-V conduction time or induce A-V block, or even cause abnormal automaticity and spontaneous firing, by unknown mechanisms. The electrocardiogram may reflect these effects by showing slight sinus tachycardia (due to the anticholinergic action) and widened QRS complexes and, less regularly, prolonged Q-T and P-R intervals (due to longer systole and slower conduction), as well as some decrease in QRS and T wave amplitude. These direct effects of PA on electrical activity, conduction, responsiveness, excitability and automaticity are characteristic of a Group 1A antiarrhythmic agent, the prototype for which is quinidine; PA effects are very similar. However, PA has weaker vagal blocking action than does quinidine, does not induce alpha-adrenergic blockade, and is less depressing to cardiac contractility. Ingested PA is resistant to digestive hydrolysis, and the drug is well absorbed from the entire small intestinal surface, but individual patients vary in their completeness of absorption of PA. Following oral administration q6h, procainamide hydrochloride extended-release tablets achieve a mean steady state of procainamide (as well as procainamide plus N-acetyl procainamide) serum concentrations approximately equivalent to those from a comparable dose of an immediate-release (conventional) dosage form given q3h. Procainamide hydrochloride extended-release tablets result in a significantly later time to peak plasma concentration when compared to immediate-release dosage forms. About 15to 20 percent of PA is reversibly bound to plasma proteins, and considerable amounts are more slowly and reversibly bound to tissues of the heart, liver, lung, and kidney. The apparent volume of distribution eventually reaches about 2 liters per kilogram body weight with a half-time of approximately five minutes. While PA has been shown in the dog to cross the blood-brain barrier, it did not concentrate in the brain at levels higher than in plasma. PA crosses the placenta. Plasma esterases are far less active in hydrolysis of PA than of procaine. The half-time for elimination of PA is three to four hours in patients with normal renal function, but reduced creatinine clearance and advancing age each prolong the half-time of elimination of PA. A significant fraction of the circulating PA may be metabolized in hepatocytes to N-acetyl procainamide (NAPA), ranging from 16 to 21 percent of an administered dose in���slow acetylators���to 24 to 33 percent in���fast-acetylators���. Since NAPA also has significant antiarrhythmic activity and somewhat slower renal clearance than PA, both hepatic acetylation rate capability and renal function, as well as age, have significant effects on the effective biologic half-time of therapeutic action of administered PA and the NAPA derivative. Trace amounts may be excreted in the urine as free and conjugated p-aminobenzoic acid, 30 to 60 percent as unchanged PA, and 6 to 52 percent as the NAPA derivative. Both PA and NAPA are eliminated by active tubular secretion as well as by glomerular filtration. Action of PA on the central nervous system is not prominent, but high plasma concentrations may cause tremors. While therapeutic plasma levels for PA have been reported to be 3 to 10��g/mL, certain patients such as those with sustained ventricular tachycardia, may need higher levels for adequate control. This may justify the increased risk of toxicity . Where programmed ventricular stimulation has been used to evaluate efficacy of PA in preventing recurrent ventricular tachyarrhythmias, higher plasma levels (mean, 13.6��g/mL) of PA were found necessary for adequate control. | lld:dailymed |
| dailymed-drugs:309 | dailymed-instance:clinicalP... | The mechanism of action of doxepin is not definitely known. It is not a central nervous system stimulant nor a monoamine oxidase inhibitor. The current hypothesis is that the clinical effects are due, at least in part, to influences on the adrenergic activity at the synapses so that deactivation of norepinephrine by reuptake into the nerve terminals is prevented. Animal studies suggest that doxepin does not appreciably antagonize the antihypertensive action of guanethidine. In animal studies anticholinergic, antiserotonin and antihistamine effects on smooth muscle have been demonstrated. At higher than usual clinical doses norepinephrine response was potentiated in animals. This effect was not demonstrated in humans. At clinical dosages up to 150 mg per day, doxepin can be given to man concomitantly with guanethidine and related compounds without blocking the antihypertensive effect. At dosages above 150 mg per day blocking of the antihypertensive effect of these compounds has been reported. Doxepin is virtually devoid of euphoria as a side effect. Characteristic of this type of compound, doxepin has not been demonstrated to produce the physical tolerance or psychological dependence associated with addictive compounds. | lld:dailymed |
| dailymed-drugs:310 | dailymed-instance:clinicalP... | Within 1 to 2 hours after oral administration, isoniazid produces peak blood levels which decline to 50 percent or less within 6 hours. It diffuses readily into all body fluids (cerebrospinal, pleural, and ascitic fluids), tissues, organs, and excreta (saliva, sputum, and feces). The drug also passes through the placental barrier and into milk in concentrations comparable to those in the plasma. From 50 to 70 percent of a dose of isoniazid is excreted in the urine in 24 hours. Isoniazid is metabolized primarily by acetylation and dehydrazination. The rate of acetylation is genetically determined. Approximately 50 percent of Blacks and Caucasians are "slow inactivators" and the rest are "rapid inactivators"; the majority of Eskimos and Orientals are "rapid inactivators." The rate of acetylation does not significantly alter the effectiveness of isoniazid. However, slow acetylation may lead to higher blood levels of the drug and, thus, to an increase in toxic reactions. Pyridoxine (vitamin B) deficiency is sometimes observed in adults with high doses of isoniazid and is considered probably due to its competition with pyridoxal phosphate for the enzyme apotryptophanase.<br/>Mechanism of Action: Isoniazid inhibits the synthesis of mycoloic acids, an essential component of the bacterial cell wall. At therapeutic levels isoniazid is bacteriocidal against actively growing intracellular and extracellular Mycobacterium tuberculosis organisms. Isoniazid resistant Mycobacterium tuberculosis bacilli develop rapidly when isoniazid monotherapy is administered.<br/>Microbiology: Two standardized in vitro susceptibility methods are available for testing isoniazid against Mycobacterium tuberculosis organisms. The agar proportion method (CDC or NCCLS M24-P) utilizes middlebrook 7H10 medium impregnated with isoniazid at two final concentrations, 0.2 and 1.0 mcg/mL. MIC, values are calculated by comparing the quantity of organisms growing in the medium containing drug to the control cultures. Mycobacterial growth in the presence of drug���1% of the control indicates resistance. The radiometric broth method employs the BACTEC 460 machine to compare the growth index from untreated control cultures to cultures grown in the presence of 0.2 and 1.0 mcg/mL of isoniazid. Strict adherence to the manufacturer's instructions for sample processing and data interpretation is required for this assay. Mycobacterium tuberculosis isolates with an MIC���0.2 mcg/mL are considered to be susceptible to isoniazid. Susceptibility test results obtained by the two different methods discussed above cannot be compared unless equivalent drug concentrations are evaluated. The clinical relevance of in vitro susceptibility for mycobacterium species other than M. tuberculosis using either the BACTEC or the proportion method has not been determined. | lld:dailymed |
| dailymed-drugs:312 | dailymed-instance:clinicalP... | When administered intravenously, solutions containing carbohydrate in the form of dextrose restore blood glucose levels and provide calories. Carbohydrate in the form of dextrose may aid in minimizing liver glycogen depletion and exerts a protein sparing action. Dextrose injection undergoes oxidation to carbon dioxide and water. Water is an essential constituent of all body tissues and accounts for approximately 70% of total body weight. Average normal adult daily requirement ranges from two to three liters (1.0 to 1.5 liters each for insensible water loss by perspiration and urine production, respectively). Water balance is maintained by various regulatory mechanisms. Water distribution depends primarily on the concentration of electrolytes in the body compartments, and sodium (Na) plays a major role in maintaining physiologic equilibrium. | lld:dailymed |
| dailymed-drugs:313 | dailymed-instance:clinicalP... | Pharmacodynamics: Cataflam (diclofenac potassium immediate-release tablets) is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of action of Cataflam, like that of other NSAIDs, is not completely understood but may be related to prostaglandin synthetase inhibition.<br/>Pharmacokinetics:<br/>Absorption: Diclofenac is 100% absorbed after oral administration compared to IV administration as measured by urine recovery.However, due to first-pass metabolism, only about 50% of the absorbed dose is systemically available(see Table 1). In some fasting volunteers, measurable plasma levels are observed within 10 minutes of dosing with Cataflam. Peak plasma levels are achieved approximately 1 hour in fasting normal volunteers, with a range of .33 to 2 hours. Food has no significant effect on the extent of diclofenac absorption. However, there is usually a delay in the onset of absorption and a reduction in peak plasma levels of approximately 30%.<br/>Distribution: The apparent volume of distribution (V/F) of diclofenac potassium is 1.3 L/kg. Diclofenac is more than 99% bound to human serum proteins, primarily to albumin. Serum protein binding is constant over the concentration range (0.15-105��g/mL) achieved with recommended doses. Diclofenac diffuses into and out of the synovial fluid. Diffusion into the joint occurs when plasma levels are higher than those in the synovial fluid, after which the process reverses and synovial fluid levels are higher than plasma levels. It is not known whether diffusion into the joint plays a role in the effectiveness of diclofenac.<br/>Metabolism: Five diclofenac metabolites have been identified in human plasma and urine. The metabolites include 4'-hydroxy-, 5-hydroxy-, 3'-hydroxy-, 4',5-dihydroxy- and 3'-hydroxy-4'-methoxy diclofenac. In patients with renal dysfunction, peak concentrations of metabolites 4'-hydroxy- and 5-hydroxy-diclofenac were approximately 50% and 4% of the parent compound after single oral dosing compared to 27% and 1% in normal healthy subjects. However, diclofenac metabolites undergo further glucuronidation and sulfation followed by biliary excretion. One diclofenac metabolite 4'-hydroxy-diclofenac has very weak pharmacologic activity.<br/>Excretion: Diclofenac is eliminated through metabolism and subsequent urinary and biliary excretion of the glucuronide and the sulfate conjugates of the metabolites.Little or no free unchanged diclofenac is excreted in the urine. Approximately 65% of the dose is excreted in the urine and approximately 35% in the bile as conjugates of unchanged diclofenac plus metabolites.Because renal elimination is not a significant pathway of elimination for unchanged diclofenac, dosing adjustment in patients with mild to moderate renal dysfunction is not necessary. The terminal half-life of unchanged diclofenac is approximately 2 hours.<br/>Special Populations:<br/>Pediatric:: The pharmacokinetics of Cataflam has not been investigated in pediatric patients.<br/>Race:: Pharmacokinetic differences due to race have not been identified.<br/>Hepatic Insufficiency:: Hepatic metabolism accounts for almost 100% of Cataflam elimination, so patients with hepatic disease may require reduced doses of Cataflam compared to patients with normal hepatic function.<br/>Renal Insufficiency:: Diclofenac pharmacokinetics has been investigated in subjects with renal insufficiency. No differences in the pharmacokinetics of diclofenac have been detected in studies of patients with renal impairment. In patients with renal impairment (inulin clearance 60-90, 30-60, and<30 mL/min; N=6 in each group), AUC values and elimination rate were comparable to those in healthy subjects. | lld:dailymed |
| dailymed-drugs:315 | dailymed-instance:clinicalP... | Mechanism of Action: Mercaptopurine (6-MP) competes with hypoxanthine and guanine for the enzyme hypoxanthineguanine phosphoribosyltransferase (HGPRTase) and is itself converted to thioinosinic acid (TIMP). This intracellular nucleotide inhibits several reactions involving inosinic acid (IMP), including the conversion of IMP to xanthylic acid (XMP) and the conversion of IMP to adenylic acid (AMP) via adenylosuccinate (SAMP). In addition, 6-methylthioinosinate (MTIMP) is formed by the methylation of TIMP.Both TIMP and MTIMP have been reported to inhibit glutamine-5-phosphoribosylpyrophosphate amidotransferase, the first enzyme unique to the de novo pathway for purine ribonucleotide synthesis. Experiments indicate that radiolabeled mercaptopurine may be recovered from the DNA in the form of deoxythioguanosine. Some mercaptopurine is converted to nucleotide derivatives of 6-thioguanine (6-TG) by the sequential actions of inosinate (IMP) dehydrogenase and xanthylate (XMP) aminase, converting TIMP to thioguanylic acid (TGMP). Animal tumors that are resistant to mercaptopurine often have lost the ability to convert mercaptopurine to TIMP. However, it is clear that resistance to mercaptopurine may be acquired by other means as well, particularly in human leukemias. It is not known exactly which of any one or more of the biochemical effects of mercaptopurine and its metabolites are directly or predominantly responsible for cell death.<br/>Pharmacokinetics: Clinical studies have shown that the absorption of an oral dose of mercaptopurine in humans is incomplete and variable, averaging approximately 50% of the administered dose. The factors influencing absorption are unknown. Intravenous administration of an investigational preparation of mercaptopurine revealed a plasma half-disappearance time of 21 minutes in pediatric patients and 47 minutes in adults. The volume of distribution usually exceeded that of the total body water. Following the oral administration ofS-6-mercaptopurine in one subject, a total of 46% of the dose could be accounted for in the urine (as parent drug and metabolites) in the first 24 hours. There is negligible entry of mercaptopurine into cerebrospinal fluid. Plasma protein binding averages 19% over the concentration range 10 to 50 mcg/mL (a concentration only achieved by intravenous administration of mercaptopurine at doses exceeding 5 to 10 mg/kg). A reduction in mercaptopurine dosage is required if patients are receiving both mercaptopurine and allopurinol .<br/>Metabolism and Genetic Polymorphism: Variability in mercaptopurine metabolism is one of the major causes of interindividual differences in systemic exposure to the drug and its active metabolites. Mercaptopurine activation occurs via hypoxanthineguanine phosphoribosyl transferase (HGPRT) and several enzymes to form 6-thioguanine nucleotides (6-TGNs). The cytotoxicity of mercaptopurine is due, in part, to the incorporation of 6-TGN into DNA. Mercaptopurine is inactivated via two major pathways. One is thiol methylation, which is catalyzed by the polymorphic enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-6-MP. TPMT activity is highly variable in patients because of a genetic polymorphism in the TPMT gene. For Caucasians and African Americans, approximately 0.3% (1:300) of patients have two non-functional alleles (homozygous-deficient) of the TPMT gene and have little or no detectable enzyme activity. Approximately 10% of patients have one TPMT non-functional allele (heterozygous) leading to low or intermediate TPMT activity and 90% of individuals have normal TPMT activity with two functional alleles. Homozygous-deficient patients (two non-functional alleles), if given usual doses of mercaptopurine, accumulate excessive cellular concentrations of active thioguanine nucleotides predisposing them to mercaptopurine toxicity . Heterozygous patients with low or intermediate TPMT activity accumulate higher concentrations of active thioguanine nucleotides than people with normal TPMT activity and are more likely to experience mercaptopurine toxicity . TPMT genotyping or phenotyping (red blood cell TPMT activity) can identify patients who are homozygous deficient or have low or intermediate TPMT activity . Another inactivation pathway is oxidation, which is catalyzed by xanthine oxidase (XO) and forms 6-thiouric acid. Xanthine oxidase is inhibited by ZYLOPRIM(allopurinol). Concomitant use of allopurinol with mercaptopurine decreases the catabolism of mercaptopurine and its active metabolites leading to mercaptopurine toxicity. A reduction in mercaptopurine dosage is therefore required if patients are receiving both mercaptopurine and allopurinol . After oral administration ofS-6-mercaptopurine, urine contains intact mercaptopurine, thiouric acid (formed by direct oxidation by xanthine oxidase, probably via 6-mercapto-8-hydroxypurine), and a number of 6-methylated thiopurines. | lld:dailymed |
| dailymed-drugs:319 | dailymed-instance:clinicalP... | Streptozocin inhibits DNA synthesis in bacterial and mammalian cells. In bacterial cells, a specific interaction with cytosine moieties leads to degradation of DNA. The biochemical mechanism leading to mammalian cell death has not been definitely established; streptozocin inhibits cell proliferation at a considerably lower level than that needed to inhibit precursor incorporation into DNA or to inhibit several of the enzymes involved in DNA synthesis. Although streptozocin inhibits the progression of cells into mitosis, no specific phase of the cell cycle is particularly sensitive to its lethal effects. Streptozocin is active in the L1210 leukemic mouse over a fairly wide range of parenteral dosage schedules. In experiments in many animal species, streptozocin induced a diabetes that resembles human hyperglycemic nonketotic diabetes mellitus. This phenomenon, which has been extensively studied, appears to be mediated through a lowering of beta cell nicotinamide adenine dinucleotide (NAD) and consequent histopathologic alteration of pancreatic islet beta cells. The metabolism and the chemical dissociation of streptozocin that occurs under physiologic conditions has not been extensively studied. When administered intravenously to a variety of experimental animals, streptozocin disappears from the blood very rapidly. In all species tested, it was found to concentrate in the liver and kidney. As much as 20% of the drug (or metabolites containing an N-nitrosourea group) is metabolized and/or excreted by the kidney. Metabolic products have not yet been identified. | lld:dailymed |
| dailymed-drugs:320 | dailymed-instance:clinicalP... | Doxycycline is primarily bacteriostatic and thought to exert its antimicrobial effect by the inhibition of protein synthesis. Doxycycline is active against a wide range of gram-positive and gram-negative organisms. The drugs in the tetracycline class have closely similar antimicrobial spectra, and cross resistance among them is common. Microorganisms may be considered susceptible to doxycycline (likely to respond to doxycycline therapy) if the minimum inhibitory concentration (M.I.C.) is not more than 4 mcg/mL. Microorganisms may be considered intermediate (harboring partial resistance) if the M.I.C. is 4 to 12.5 mcg/mL and resistant (not likely to respond to therapy) if the M.I.C. is greater than 12.5 mcg/mL. Susceptibility Plate Testing: If the Kirby-Bauer method of disc susceptibility is used, a 30 mcg doxycycline disc should give a zone of at least 16 mm when tested against a doxycycline-susceptible strain. A tetracycline disc may be used to determine microbial susceptibility. If the Kirby-Bauer method of disc susceptibility is used, a 30 mcg tetracycline disc should givea zone of at least 19 mm when tested against a tetracycline-susceptible bacterial strain. Tetracyclines are readily absorbed and are bound to plasma proteins in varying degree. They are concentrated by the liver in the bile, and excreted in the urine and feces at high concentrations and in a biologically active form. Following a 100 mg single dose administered in a concentration of 0.4 mg/mL in a one-hour infusion, normal adult volunteers average a peak of 2.5 mcg/mL, while 200 mg of a concentration of 0.4 mg/mL administered over two hours average a peak of 3.6 mcg/mL. Excretion of doxycycline by the kidney is about 40 percent/72 hours in individuals with normal function (creatinine clearance about 75 mL/min). This percentage excretion may fall as low as 1 to 5 percent/72 hours in individuals with severe renal insufficiency (creatinine clearance below 10 mL/min). Studies have shown no significant difference in serum half-life of doxycycline (range 18 to 22 hours) in individuals with normal and severely impaired renal function. Hemodialysis does not alter this serum half-life of doxycycline. | lld:dailymed |
| dailymed-drugs:322 | dailymed-instance:clinicalP... | Chlorthalidone is an oral diuretic with prolonged action (48���72 hours) and low toxicity. The major portion of the drug is excreted unchanged by the kidneys. The diuretic effect of the drug occurs in approximately 2.6 hours and continues for up to 72 hours. The mean half-life following a 50 to 200 mg dose is 40 hours. In the first order of absorption, the elimination half-life is 53 hours following a 50 mg dose, and 60 hours following a 100 mg dose. Approximately 75 percent of the drug is bound to plasma proteins, 58 percent of the drug being bound to albumin. This is caused by an increased affinity of the drug to erythrocyte carbonic anhydrase. Nonrenal routes of elimination have yet to be clarified. Data are not available regarding percentage of dose as unchanged drug and metabolites, concentration of the drug in body fluids, degree of uptake by a particular organ or in the fetus, or passage across the blood-brain barrier. The drug produces copious diuresis with greatly increased excretion of sodium and chloride. At maximal therapeutic dosage, chlorthalidone is approximately equal in its diuretic effect to comparable maximal therapeutic doses of benzothiadiazine diuretics. The site of action appears to be the cortical diluting segment of the ascending limb of Henle's loop of the nephron. | lld:dailymed |