Azithromycin (Tablet, Film Coated)

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Adults: Azithromycin tablets can be taken with or without food.<br/>Renal Insufficiency: No dosage adjustment is recommended for subjects with renal impairment (GFR���80 mL/min). The mean AUCwas similar in subjects with GFR 10 to 80 mL/min compared to subjects with normal renal function, whereas it increased 35% in subjects with GFR<10 mL/min compared to subjects with normal renal function. Caution should be exercised when azithromycin is administered to subjects with severe renal impairment.<br/>Hepatic Insufficiency: The pharmacokinetics of azithromycin in subjects with hepatic impairment have not been established. No dose adjustment recommendations can be made in patients with impaired hepatic function No dosage adjustment is recommended based on age or gender.<br/>Pediatric Patients: Azithromycin for oral suspension can be taken with or without food.<br/>Acute Otitis Media: The recommended dose of azithromycin for oral suspension for the treatment of pediatric patients with acute otitis media is 30 mg/kg given as a single dose or 10 mg/kg once daily for 3 days or 10 mg/kg as a single dose on the first day followed by 5 mg/kg/day on Days 2 through 5. (See chart below.)<br/>Acute Bacterial Sinusitis: The recommended dose of azithromycin for oral suspension for the treatment of pediatric patients with acute bacterial sinusitis is 10 mg/kg once daily for 3 days. (See chart below.)<br/>Community-Acquired Pneumonia: The recommended dose of azithromycin for oral suspension for the treatment of pediatric patients with community acquired pneumonia is 10 mg/kg as a single dose on the first day followed by 5 mg/kg on Days 2 through 5. (See chart below.) The safety of re-dosing azithromycin in pediatric patients who vomit after receiving 30 mg/kg as a single dose has not been established. In clinical studies involving 487 patients with acute otitis media given a single 30 mg/kg dose of azithromycin, eight patients who vomited within 30 minutes of dosing were re-dosed at the same total dose.<br/>Pharyngitis/Tonsillitis: The recommended dose of azithromycin for children with pharyngitis/tonsillitis is 12 mg/kg once daily for 5 days. (See chart below.)

Pharmacokinetics: Following oral administration of a single 500 mg dose (two 250 mg tablets) to 36 fasted healthy male volunteers, the mean (SD) pharmacokinetic parameters were AUC= 4.3 (1.2) mcg���h/mL; C= 0.5(0.2) mcg/mL; T= 2.2 (0.9) hours. With a regimen of 500 mg (two 250 mg capsules) on day 1, followed by 250 mg daily (one 250 mg capsule) on days 2 through 5, the pharmacokinetic parameters of azithromycin in plasma in healthy young adults (18 to 40 years of age) are portrayed in the chart below. Cand Cremained essentially unchanged from day 2 through day 5 of therapy. In a two-way crossover study, 12 adult healthy volunteers (6 males, 6 females) received 1,500 mg of azithromycin administered in single daily doses over either 5 days (two 250 mg tablets on day 1, followed by one 250 mg tablet on days 2 to 5) or 3 days (500 mg per day for days 1 to 3). Due to limited serum samples on day 2 (3-day regimen) and days 2 to 4 (5-day regimen), the serum concentration-time profile of each subject was fit to a 3-compartment model and the AUCfor the fitted concentration profile was comparable between the 5-day and 3-day regimens. Median azithromycin exposure (AUC) in mononuclear (MN) and polymorphonuclear (PMN) leukocytes following either the 5-day or 3-day regimen was more than a 1,000-fold and 800-fold greater than in serum, respectively. Administration of the same total dose with either the 5-day or 3-day regimen may be expected to provide comparable concentrations of azithromycin within MN and PMN leukocytes. Two azithromycin 250 mg tablets are bioequivalent to a single 500 mg tablet.<br/>Absorption: The absolute bioavailability of azithromycin 250 mg capsules is 38%. In a two-way crossover study in which 12 healthy subjects received a single 500 mg dose of azithromycin (two 250 mg tablets) with or without a high fat meal, food was shown to increase Cby 23% but had no effect on AUC. When azithromycin suspension was administered with food to 28 adult healthy male subjects, Cincreased by 56% and AUC was unchanged. The AUC of azithromycin was unaffected by coadministration of an antacid containing aluminum and magnesium hydroxide with azithromycin capsules; however, the Cwas reduced by 24%. Administration of cimetidine (800 mg) two hours prior to azithromycin had no effect on azithromycin absorption.<br/>Distribution: The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 mcg/mL to 7% at 2 mcg/mL. Following oral administration, azithromycin is widely distributed throughout the body with an apparent steady-state volume of distribution of 31.1 L/kg. Greater azithromycin concentrations in tissues than in plasma or serum were observed. High tissue concentrations should not be interpreted to be quantitatively related to clinical efficacy. The antimicrobial activity of azithromycin is pH related and appears to be reduced with decreasingpH. However, the extensive distribution of drug to tissues may be relevant to clinical activity. Selected tissue (or fluid) concentration and tissue (or fluid) to plasma/serum concentration ratios are shown in the following table: The extensive tissue distribution was confirmed by examination of additional tissues and fluids (bone, ejaculum, prostate, ovary, uterus, salpinx, stomach, liver, and gallbladder). As there are no data from adequate and well controlled studies of azithromycin treatment of infections in these additional body sites, the clinical importance of these tissue concentration data is unknown. Following a regimen of 500 mg on the first day and 250 mg daily for 4 days, only very low concentrations were noted in cerebrospinal fluid (less than 0.01 mcg/mL) in the presence of non-inflamed meninges.<br/>Metabolism: In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed.<br/>Elimination: Plasma concentrations of azithromycin following single 500 mg oral and i.v. doses declined in a polyphasic pattern with a mean apparent plasma clearance of 630 mL/min and terminal elimination half-life of 68 hours. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues. Biliary excretion of azithromycin, predominantly as unchanged drug, is a major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine.<br/>Special Populations:<br/>Renal Insufficiency: Azithromycin pharmacokinetics were investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1,000 mg dose of azithromycin, mean Cand AUCincreased by 5.1% and 4.2%, respectively in subjects with mild to moderate renal impairment (GFR 10 to 80 mL/min) compared to subjects with normal renal function (GFR>80 mL/min). The mean Cand AUCincreased 61% and 35%, respectively in subjects with severe renal impairment (GFR<10 mL/min) compared to subjects with normal renal function (GFR>80 mL/min).<br/>Hepatic Insufficiency: The pharmacokinetics of azithromycin in subjects with hepatic impairment have not been established.<br/>Gender: There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended based on gender.<br/>Geriatric Patients: When studied in healthy elderly subjects aged 65 to 85 years, the pharmacokinetic parameters of azithromycin in elderly men were similar to those in young adults; however, in elderly women, although higher peak concentrations (increased by 30 to 50%) were observed, no significant accumulation occurred.<br/>Pediatric Patients: In two clinical studies, azithromycin for oral suspension was dosed at 10 mg/kg on day 1, followed by 5 mg/kg on days 2 through 5 to two groups of pediatric patients (aged 1 to 5 years and 5 to 15 years, respectively). The mean pharmacokinetic parameters on day 5 were C= 0.216 mcg/mL, T= 1.9 hours, and AUC= 1.822 mcg���hr/mL for the 1- to 5-year-old group and were C= 0.383 mcg/mL, T= 2.4 hours, and AUC= 3.109 mcg���hr/mL for the 5- to 15-year-old group. Two clinical studies were conducted in 68 pediatric patients aged 3 to 16 years to determine the pharmacokinetics and safety of azithromycin for oral suspension. Azithromycin was administered following a low-fat breakfast. The first study consisted of 35 pediatric patients treated with 20 mg/kg/day (maximum daily dose 500 mg) for 3 days of whom 34 patients were evaluated for pharmacokinetics. In the second study, 33 pediatric patients received doses of 12 mg/kg/day (maximum daily dose 500 mg) for 5 days of whom 31 patients were evaluated for pharmacokinetics. In both studies, azithromycin concentrations were determined over a 24 hour period following the last daily dose. Patients weighing above 25 kg in the 3-day study or 41.7 kg in the 5-day study received the maximum adult daily dose of 500 mg. Eleven patients (weighing 25 kg or less) in the first study and 17 patients (weighing 41.7 kg or less) in the second study received a total doseof 60 mg/kg. The following table shows pharmacokinetic data in the subset of pediatric patients who received a total dose of 60 mg/kg. The similarity of the overall exposure (AUC) between the 3-day and 5-day regimens in pediatric patients is unknown. Single dose pharmacokinetics in pediatric patients given doses of 30 mg/kg have not been studied.<br/>Drug-Drug Interactions: Drug interaction studies were performed with azithromycin and other drugs likely to be coadministered. The effects of coadministration of azithromycin on the pharmacokinetics of other drugs are shown in Table 1 and the effect of other drugs on the pharmacokinetics of azithromycin are shown in Table 2. Coadministration of azithromycin at therapeutic doses had a modest effect on the pharmacokinetics of the drugs listed in Table 1. No dosage adjustment of drugs listed in Table 1 is recommended when coadministered with azithromycin. Coadministration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the Cand AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2.<br/>Microbiology: Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms and, thus, interfering with microbial protein synthesis. Nucleic acid synthesis is not affected. Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. Using such methodology, the ratio of intracellular to extracellular concentration was>30 after one hour incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. Azithromycin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section. Aerobic and facultative gram-positive microorganisms: Staphylococcus aureusStreptococcus agalactiaeStreptococcus pneumoniaeStreptococcus pyogenes NOTE: Azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive strains. Most strains of Enterococcus faecalis and methicillin-resistant staphylococci are resistant to azithromycin. Aerobic and facultative gram-negative microorganisms: Haemophilus ducreyiHaemophilus influenzaeMoraxella catarrhalisNeisseria gonorrhoeae "Other" microorganisms: Chlamydia pneumoniaeChlamydia trachomatisMycoplasma pneumoniae Beta-lactamase production should have no effect on azithromycin activity. 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 breakpoints for azithromycin. However, the safety and effectiveness of azithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well controlled trials. Aerobic and facultative gram-positive microorganisms:Streptococci (Groups C, F, G)Viridans group streptococci Aerobic and facultative gram-negative microorganisms:Bordetella pertussisLegionella pneumophila Anaerobic microorganisms:Peptostreptococcus speciesPrevotella bivia "Other" microorganisms:Ureaplasma urealyticum<br/>Susceptibility Testing Methods: When available, the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals should be provided to the physician as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports may differ from susceptibility data obtained from outpatient use, but could aid the physician in selecting the most effective antimicrobial.<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 azithromycin powder. The MIC values should be interpreted according to criteria provided in Table 1.<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 15 mcg azithromycin to test the susceptibility of microorganisms to azithromycin. The disk diffusion interpretive criteria are provided in Table 1. No interpretive criteria have been established for testing Neisseria gonorrhoeae. This species is not usually tested. A report of "susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound 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 reaches the concentrations usually achievable; other therapy should be selected.<br/>Quality Control: Standardized susceptibility test procedures require the use of quality control microorganisms to control the technical aspects of the test procedures. Standard azithromycin powder should provide the following range of values noted in Table 2. Quality control microorganisms are specific strains of organisms with intrinsic biological properties. QC strains are very stable strains which will give a standard and repeatable susceptibility pattern. The specific strains used for microbiological quality control are not clinically significant.

Azithromycin tablets are contraindicated in patients with known hypersensitivity to azithromycin, erythromycin or any macrolide antibiotic.

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Azithromycin

In clinical trials, most of the reported side effects were mild to moderate in severity and were reversible upon discontinuation of the drug. Potentially serious side effects of angioedema and cholestatic jaundice were reported rarely. Approximately 0.7% of the patients (adults and pediatric patients) from the 5-day multiple-dose clinical trials discontinued azithromycin therapy because of treatment-related side effects. In adults given 500 mg/day for 3 days, the discontinuation rate due to treatment-related side effects was 0.6%. In clinical trials in pediatric patients given 30 mg/kg, either as a single dose or over 3 days, discontinuation from the trials due to treatment-related side effects was approximately 1%. Most of the side effects leading to discontinuation were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, or abdominal pain.<br/>Clinical:<br/>Adults:<br/>Pediatric Patients:<br/>Post-Marketing Experience: Adverse events reported with azithromycin during the post-marketing period in adult and/or pediatric patients for which a causal relationship may not be established include: Allergic: arthralgia, edema, urticaria and angioedema Cardiovascular: Arrhythmias including ventricular tachycardia and hypotension. There have been rare reports of QT prolongation and Torsades de pointes. Gastrointestinal: Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea rarely resulting in dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis and rare reports of tongue discoloration. General: asthenia, paresthesia, fatigue, malaise and anaphylaxis (rarely fatal) Genitourinary: interstitial nephritis and acute renal failure and vaginitis Hematopoietic: thrombocytopenia Liver/Biliary: Abnormal liver function including hepatitis and cholestatic jaundice, as well as rare cases of hepatic necrosis and hepatic failure, some of which have resulted in death. Nervous System: convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation and syncope Psychiatric: aggressive reaction and anxiety Skin/Appendages: Pruritus, rarely serious skin reactions including erythema multiforme, Stevens Johnson Syndrome and toxic epidermal necrolysis. Special Senses: Hearing disturbances including hearing loss, deafness and/or tinnitus and rare reports of taste perversion.<br/>Laboratory Abnormalities:<br/>Adults: Clinically significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows: with an incidence of greater than 1%: decreased hemoglobin, hematocrit, lymphocytes, neutrophils and blood glucose; elevated serum creatine phosphokinase, potassium, ALT, GGT, AST, BUN, creatinine, blood glucose, platelet count, lymphocytes, neutrophils and eosinophils; with an incidence of less than 1%: leukopenia, neutropenia, decreased sodium, potassium, platelet count; elevated monocytes, basophils, bicarbonate, serum alkaline phosphatase, bilirubin, LDH and phosphate. The majority of subjects with elevated serum creatinine also had abnormal values at baseline. When follow-up was provided, changes in laboratory tests appeared to be reversible. In multiple-dose clinical trials involving more than 5,000 patients, four patients discontinued therapy because of treatment-related liver enzyme abnormalities and one because of a renal function abnormality.<br/>Pediatric Patients:

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Azithromycin