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Pharmacokinetics:
Please refer to the package insert for ProstaScint or Zevalin for this information on the final drug product.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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:
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.
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.
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.
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'.
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.
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.
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).
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:
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.
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.
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.
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.
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.
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.
Pharmacokinetics and Metabolism:
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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:
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.
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.
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.
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.
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.
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.
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.
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:
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:
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.
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.
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.
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:
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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.
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:
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.
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.
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.
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.
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.
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).
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).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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:
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.
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.
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:
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.
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.
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.
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.
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:
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.
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.
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.
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.
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.
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.
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.
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.
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:
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
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 .
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.
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:
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.
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.
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.
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
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.
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.
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.
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).
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.
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.
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.
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.
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).
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.
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:
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 .
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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%).
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.
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.
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.
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.
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%.
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.
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.
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.
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.
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.
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.
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.
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.
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 pati