AZITHROMYCIN- azithromycin_tablet, film coated

CLINICAL PHARMACOLOGY
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 0-72 max max With a regimen of 500 mg (two 250 mg capsules Azithromycin 250 mg tablets are bioequivalent to 250 mg capsules in the fasted state. Azithromycin 250 mg capsules are no longer commercially available. min max Pharmacokinetic Parameters (Mean) Total (n = 12) Day 1 Day 5 C max 0. 2 AUC 0-24 2. 05 Urinary Excret. 5 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 AUC 0-infinity Pharmacokinetic Parameter [mean (SD)] 3-Day Regimen 5-Day Regimen Day 1 Day 3 Day 1 Day 5 C max mcg/mL) 0. 06) Serum AUC 0-infinity (mcghr/mL) 17. 2) Total AUC for the entire 3-day and 5-day regimens 14. 1) Serum T 1/2 71. 9 hr Median azithromycin exposure (AUC 0-288 Two azithromycin 250 mg tablets are bioequivalent to a single 500 mg tablet. 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 C max When azithromycin suspension was administered with food to 28 adult healthy male subjects, C max The AUC of azithromycin was unaffected by co-administration of an antacid containing aluminum and magnesium hydroxide with azithromycin capsules; however, the C max 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. 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 decreasing pH. 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: Azithromycin Concentrations Following a 500 mg Dose (Two 250 mg Capsules) in Adults Azithromycin tissue concentrations were originally determined using 250 mg capsules. Tissue or Fluid Time After Dose (h) Tissue or Fluid Concentration (mcg/g or mcg/mL) Corresponding Plasma or Serum Level (mcg/mL) Tissue (Fluid) Plasma (Serum) Ratio Skin 72-96 0. 012 35 Lung 72-96 4. 012 >100 Sputum Sample was obtained 2 to 4 hours after the first dose. 64 2 Sputum Sample was obtained 10 to 12 hours after the first dose. 1 30 Tonsil Dosing regimen of two doses of 250 mg each, separated by 12 hours. 03 >100 Tonsil 180 0. 006 >100 Cervix Sample was obtained 19 hours after a single 500 mg dose. 04 70 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. In vitro in vivo Plasma concentrations of azithromycin following single 500 mg oral and i. 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. 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 C max 0-120 max 0-120 DOSAGE AND ADMINISTRATION The pharmacokinetics of azithromycin in subjects with hepatic impairment have not been established. There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended based on gender. 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. 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 max max 0-24 max max 0-24 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. 0 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. 0 kg or less) in the first study and 17 patients (weighing 41. 7 kg or less) in the second study received a total dose of 60 mg/kg. The following table shows pharmacokinetic data in the subset of pediatric patients who received a total dose of 60 mg/kg. Pharmacokinetic Parameter [mean (SD)] 3-Day Regimen (20 mg/kg x 3 days) 5-Day Regimen (12 mg/kg x 5 days) n 11 17 C max 1. 8) AUC 0-24 7. 9) The similarity of the overall exposure (AUC 0-infinity Single dose pharmacokinetics in pediatric patients given doses of 30 mg/kg have not been studied. (See DOSAGE AND ADMINISTRATION Drug interaction studies were performed with azithromycin and other drugs likely to be co-administered. 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. Co-administration 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 co-administered with azithromycin. Co-administration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the C max PRECAUTIONS: Drug Interactions Table 1. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin Co- Administered Drug Dose of Co- Administered Drug Dose of Azithromycin n Ratio (with/with- out azithromycin) of Co-adminis- tered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1. 00 Mean C max Mean AUC Atorvastatin 10 mg/day x 8 days 500 mg/day PO on days 6-8 12 0. 25) Carbamazepine 200 mg/day x 2 days, then 200 mg b. x 18 days 500 mg/day PO for days 16-18 7 0. 06) Cetirizine 20 mg/day x 11 days 500 mg PO on day 7, then 250 mg/ day on days 8-11 14 1. 13) Didanosine 200 mg PO b. x 21 days 1,200 mg/ day PO on days 8-21 6 1. 57) Efavirenz 400 mg/day x 7 days 600 mg PO on day 7 14 1. 04 -90% Confidence interval not reported 0. 95 Fluconazole 200 mg PO single dose 1,200 mg PO single dose 18 1. 05) Indinavir 800 mg t. x 5 days 1,200 mg PO on day 5 18 0. 00) Midazolam 15 mg PO on day 3 500 mg/day PO x 3 days 12 1. 56) Nelfinavir 750 mg t. x 11 days 1,200 mg PO on day 9 14 0. 93) Rifabutin 300 mg/day x 10 days 500 mg PO on day 1, then 250 mg/day on days 2-10 6 See footnote below NA Sildenafil 100 mg on days 1 and 4 500 mg/day PO x 3 days 12 1. 12) Theophylline 4 mg/kg IV on days 1, 11, 25 500 mg PO on day 7, 250 mg/day on days 8-11 10 1. 22) Theophylline 300 mg PO b. d x 15 days 500 mg PO on day 6, then 250 mg/ day on days 7-10 8 1. 31) Triazolam 0. 125 mg on day 2 500 mg PO on day 1, then 250 mg/day on day 2 12 1. 02 Trimethoprim/ Sulfamethoxazole 160 mg/ 800 mg/day PO x 7 days 1,200 mg PO on day 7 12 0. 03) Zidovudine 500 mg/day PO x 21 days 600 mg/day PO x 14 days 5 1. 70) Zidovudine 500 mg/day PO x 21 days 1,200 mg/day PO x 14 days 4 1. 43) NA - Not Available Mean rifabutin concentrations one-half day after the last dose of rifabutin were 60 ng/mL when co-administered with azithromycin and 71 ng/mL when co-administered with placebo. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs (See PRECAUTIONS: Drug Interactions Co- administered Drug Dose of Co- Administered Drug Dose of Azithromycin n Ratio (with/with- out Co-adminis- tered Drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1. 00 Mean C max Mean AUC Efavirenz 400 mg/day x 7 days 600 mg PO on day 7 14 1. 92 -90% Confidence interval not reported Fluconazole 200 mg PO single dose 1,200 mg PO single dose 18 0. 22) Nelfinavir 750 mg t. x 11 days 1,200 mg PO on day 9 14 2. 50) Rifabutin 300 mg/day x 10 days 500 mg PO on day 1, then 250 mg/day on days 2-10 6 See Footnote Below NA NA - Not Available Mean azithromycin concentrations one day after the last dose were 53 ng/mL when coadministered with 300 mg daily rifabutin and 49 ng/mL when coadministered with placebo. QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1000 mg) alone or in combination with azithromycin (500 mg, 1000 mg, and 1500 mg once daily). Co-administration of azithromycin increased the QTc interval in a dose- and concentration-dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively. Azithromycin binds to the 23S rRNA of the bacterial 50S ribosomal subunit. It blocks protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit. Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro In vivo The most frequently encountered mechanism of resistance to azithromycin is modification of the 23S rRNA at positions corresponding to A2058 and A2059 in the Escherichia coli in vitro INDICATIONS AND USAGE Staphylococcus aureus Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes Haemophilus ducreyi Haemophilus influenzae Moraxella catarrhalis Neisseria gonorrhoeae Chlamydophila pneumoniae Chlamydia trachomatis Mycoplasma pneumoniae The following in vitro but their clinical significance is unknown At least 90% of the following bacteria exhibit an in vitro Beta-hemolytic streptococci (Groups C, F, G) Viridans group streptococci Bordetella pertussis Peptostreptococcus Prevotella bivia Ureaplasma urealyticum Legionella pneumophila When available, the results of in vitro 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 1,2 Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure 2,3 Table 3. Susceptibility Test Interpretive Criteria for Azithromycin Susceptibility Test Result Interpretive Criteria Pathogen Minimum Inhibitory Concentrations (mcg /mL) Disk Diffusion (zone diameters in mm) S I R S I R Haemophilus influenzae Insufficient information is available to determine Intermediate or Resistant interpretive criteria The ability to correlate MIC values and plasma drug levels is difficult as azithromycin concentrates in macrophages and tissues (see CLINICAL PHARMACOLOGY <=4 en dash en dash >=12 en dash en dash Staphylococcus aureus <=2 4 >=8 >=18 14-17 <=13 Streptococci including S. pneumoniae <=0. 5 1 >=2 >=18 14-17 <=13 Susceptibility to azithromycin must be tested in ambient air. 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. Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test. Standard azithromycin powder should provide the following range of MIC values noted in Table 4. For the diffusion technique using the azithromycin 15 mcg disk, the criteria in Table 4 should be achieved. Acceptable Quality Control Ranges for Azithromycin QC Strain Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameters in mm) Haemophilus influenzae ATCC ATCC = American Type Culture Collection 1. 0 13-21 Staphylococcus aureus ATCC 29213 0. 0 -- Staphylococcus aureus ATCC 25923 -- 21-26 Streptococcus pneumoniae ATCC 49619 0. 25 19-25 Susceptibility to azithromycin must be tested in ambient air.
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 0-72 max max With a regimen of 500 mg (two 250 mg capsules Azithromycin 250 mg tablets are bioequivalent to 250 mg capsules in the fasted state. Azithromycin 250 mg capsules are no longer commercially available. min max Pharmacokinetic Parameters (Mean) Total (n = 12) Day 1 Day 5 C max 0. 2 AUC 0-24 2. 05 Urinary Excret. 5 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 AUC 0-infinity Pharmacokinetic Parameter [mean (SD)] 3-Day Regimen 5-Day Regimen Day 1 Day 3 Day 1 Day 5 C max mcg/mL) 0. 06) Serum AUC 0-infinity (mcghr/mL) 17. 2) Total AUC for the entire 3-day and 5-day regimens 14. 1) Serum T 1/2 71. 9 hr Median azithromycin exposure (AUC 0-288 Two azithromycin 250 mg tablets are bioequivalent to a single 500 mg tablet. 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 C max When azithromycin suspension was administered with food to 28 adult healthy male subjects, C max The AUC of azithromycin was unaffected by co-administration of an antacid containing aluminum and magnesium hydroxide with azithromycin capsules; however, the C max 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. 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 decreasing pH. 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: Azithromycin Concentrations Following a 500 mg Dose (Two 250 mg Capsules) in Adults Azithromycin tissue concentrations were originally determined using 250 mg capsules. Tissue or Fluid Time After Dose (h) Tissue or Fluid Concentration (mcg/g or mcg/mL) Corresponding Plasma or Serum Level (mcg/mL) Tissue (Fluid) Plasma (Serum) Ratio Skin 72-96 0. 012 35 Lung 72-96 4. 012 >100 Sputum Sample was obtained 2 to 4 hours after the first dose. 64 2 Sputum Sample was obtained 10 to 12 hours after the first dose. 1 30 Tonsil Dosing regimen of two doses of 250 mg each, separated by 12 hours. 03 >100 Tonsil 180 0. 006 >100 Cervix Sample was obtained 19 hours after a single 500 mg dose. 04 70 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. In vitro in vivo Plasma concentrations of azithromycin following single 500 mg oral and i. 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. 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 C max 0-120 max 0-120 DOSAGE AND ADMINISTRATION The pharmacokinetics of azithromycin in subjects with hepatic impairment have not been established. There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended based on gender. 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. 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 max max 0-24 max max 0-24 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. 0 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. 0 kg or less) in the first study and 17 patients (weighing 41. 7 kg or less) in the second study received a total dose of 60 mg/kg. The following table shows pharmacokinetic data in the subset of pediatric patients who received a total dose of 60 mg/kg. Pharmacokinetic Parameter [mean (SD)] 3-Day Regimen (20 mg/kg x 3 days) 5-Day Regimen (12 mg/kg x 5 days) n 11 17 C max 1. 8) AUC 0-24 7. 9) The similarity of the overall exposure (AUC 0-infinity Single dose pharmacokinetics in pediatric patients given doses of 30 mg/kg have not been studied. (See DOSAGE AND ADMINISTRATION Drug interaction studies were performed with azithromycin and other drugs likely to be co-administered. 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. Co-administration 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 co-administered with azithromycin. Co-administration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the C max PRECAUTIONS: Drug Interactions Table 1. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin Co- Administered Drug Dose of Co- Administered Drug Dose of Azithromycin n Ratio (with/with- out azithromycin) of Co-adminis- tered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1. 00 Mean C max Mean AUC Atorvastatin 10 mg/day x 8 days 500 mg/day PO on days 6-8 12 0. 25) Carbamazepine 200 mg/day x 2 days, then 200 mg b. x 18 days 500 mg/day PO for days 16-18 7 0. 06) Cetirizine 20 mg/day x 11 days 500 mg PO on day 7, then 250 mg/ day on days 8-11 14 1. 13) Didanosine 200 mg PO b. x 21 days 1,200 mg/ day PO on days 8-21 6 1. 57) Efavirenz 400 mg/day x 7 days 600 mg PO on day 7 14 1. 04 -90% Confidence interval not reported 0. 95 Fluconazole 200 mg PO single dose 1,200 mg PO single dose 18 1. 05) Indinavir 800 mg t. x 5 days 1,200 mg PO on day 5 18 0. 00) Midazolam 15 mg PO on day 3 500 mg/day PO x 3 days 12 1. 56) Nelfinavir 750 mg t. x 11 days 1,200 mg PO on day 9 14 0. 93) Rifabutin 300 mg/day x 10 days 500 mg PO on day 1, then 250 mg/day on days 2-10 6 See footnote below NA Sildenafil 100 mg on days 1 and 4 500 mg/day PO x 3 days 12 1. 12) Theophylline 4 mg/kg IV on days 1, 11, 25 500 mg PO on day 7, 250 mg/day on days 8-11 10 1. 22) Theophylline 300 mg PO b. d x 15 days 500 mg PO on day 6, then 250 mg/ day on days 7-10 8 1. 31) Triazolam 0. 125 mg on day 2 500 mg PO on day 1, then 250 mg/day on day 2 12 1. 02 Trimethoprim/ Sulfamethoxazole 160 mg/ 800 mg/day PO x 7 days 1,200 mg PO on day 7 12 0. 03) Zidovudine 500 mg/day PO x 21 days 600 mg/day PO x 14 days 5 1. 70) Zidovudine 500 mg/day PO x 21 days 1,200 mg/day PO x 14 days 4 1. 43) NA - Not Available Mean rifabutin concentrations one-half day after the last dose of rifabutin were 60 ng/mL when co-administered with azithromycin and 71 ng/mL when co-administered with placebo. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs (See PRECAUTIONS: Drug Interactions Co- administered Drug Dose of Co- Administered Drug Dose of Azithromycin n Ratio (with/with- out Co-adminis- tered Drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1. 00 Mean C max Mean AUC Efavirenz 400 mg/day x 7 days 600 mg PO on day 7 14 1. 92 -90% Confidence interval not reported Fluconazole 200 mg PO single dose 1,200 mg PO single dose 18 0. 22) Nelfinavir 750 mg t. x 11 days 1,200 mg PO on day 9 14 2. 50) Rifabutin 300 mg/day x 10 days 500 mg PO on day 1, then 250 mg/day on days 2-10 6 See Footnote Below NA NA - Not Available Mean azithromycin concentrations one day after the last dose were 53 ng/mL when coadministered with 300 mg daily rifabutin and 49 ng/mL when coadministered with placebo.
Pharmacodynamics
QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1000 mg) alone or in combination with azithromycin (500 mg, 1000 mg, and 1500 mg once daily). Co-administration of azithromycin increased the QTc interval in a dose- and concentration-dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.
Microbiology
Azithromycin binds to the 23S rRNA of the bacterial 50S ribosomal subunit. It blocks protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit. Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro In vivo The most frequently encountered mechanism of resistance to azithromycin is modification of the 23S rRNA at positions corresponding to A2058 and A2059 in the Escherichia coli in vitro INDICATIONS AND USAGE Staphylococcus aureus Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes Haemophilus ducreyi Haemophilus influenzae Moraxella catarrhalis Neisseria gonorrhoeae Chlamydophila pneumoniae Chlamydia trachomatis Mycoplasma pneumoniae The following in vitro but their clinical significance is unknown At least 90% of the following bacteria exhibit an in vitro Beta-hemolytic streptococci (Groups C, F, G) Viridans group streptococci Bordetella pertussis Peptostreptococcus Prevotella bivia Ureaplasma urealyticum Legionella pneumophila When available, the results of in vitro 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 1,2 Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure 2,3 Table 3. Susceptibility Test Interpretive Criteria for Azithromycin Susceptibility Test Result Interpretive Criteria Pathogen Minimum Inhibitory Concentrations (mcg /mL) Disk Diffusion (zone diameters in mm) S I R S I R Haemophilus influenzae Insufficient information is available to determine Intermediate or Resistant interpretive criteria The ability to correlate MIC values and plasma drug levels is difficult as azithromycin concentrates in macrophages and tissues (see CLINICAL PHARMACOLOGY <=4 en dash en dash >=12 en dash en dash Staphylococcus aureus <=2 4 >=8 >=18 14-17 <=13 Streptococci including S. pneumoniae <=0. 5 1 >=2 >=18 14-17 <=13 Susceptibility to azithromycin must be tested in ambient air. 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. Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test. Standard azithromycin powder should provide the following range of MIC values noted in Table 4. For the diffusion technique using the azithromycin 15 mcg disk, the criteria in Table 4 should be achieved. Acceptable Quality Control Ranges for Azithromycin QC Strain Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameters in mm) Haemophilus influenzae ATCC ATCC = American Type Culture Collection 1. 0 13-21 Staphylococcus aureus ATCC 29213 0. 0 -- Staphylococcus aureus ATCC 25923 -- 21-26 Streptococcus pneumoniae ATCC 49619 0. 25 19-25 Susceptibility to azithromycin must be tested in ambient air.
ANIMAL TOXICOLOGY
Phospholipidosis (intracellular phospholipid accumulation) has been observed in some tissues of mice, rats, and dogs given multiple doses of azithromycin. It has been demonstrated in numerous organ systems (e.g., eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and pancreas) in dogs treated with azithromycin at doses which, expressed on the basis of mg/m 2 max max max max 2 2 2

INDICATIONS AND USAGE
Azithromycin tablets, USP are indicated for the treatment of patients with mild to moderate infections (pneumonia: see WARNINGS As recommended dosages, durations of therapy and applicable patient populations vary among these infections, please see DOSAGE AND ADMINISTRATION for specific dosing recommendations. Acute bacterial exacerbations of chronic obstructive pulmonary disease Haemophilus influenzae, Moraxella catarrhalis Streptococcus pneumoniae. Acute bacterial sinusitis Haemophilus influenzae, Moraxella catarrhalis Streptococcus pneumoniae. Community-acquired pneumonia Chlamydophilapneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae Streptococcus pneumoniae NOTE: Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors such as any of the following: patients with cystic fibrosis, patients with nosocomially acquired infections, patients with known or suspected bacteremia, patients requiring hospitalization, elderly or debilitated patients, or patients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia). Pharyngitis/tonsillitis Streptococcus pyogenes Streptococcus pyogenes Streptococcus pyogenes Uncomplicated skin and skin structure infections Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae. Urethritis and cervicitis Chlamydia trachomatis Neisseria gonorrhoeae. Genital ulcer disease Haemophilus ducreyi Azithromycin, at the recommended dose, should not be relied upon to treat syphilis. Antimicrobial agents used in high doses for short periods of time to treat non-gonococcal urethritis may mask or delay the symptoms of incubating syphilis. All patients with sexually-transmitted urethritis or cervicitis should have a serologic test for syphilis and appropriate cultures for gonorrhea performed at the time of diagnosis. Appropriate antimicrobial therapy and follow-up tests for these diseases should be initiated if infection is confirmed. Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to azithromycin. Therapy with azithromycin may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly. To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin and other antibacterial drugs, azithromycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy. (See PRECAUTIONS: Pediatric Use CLINICAL STUDIES IN PEDIATRIC PATIENTS Acute otitis media Haemophilus influenzae, Moraxella catarrhalis Streptococcus pneumoniae. DOSAGE AND ADMINISTRATION Community-acquired pneumonia Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae Streptococcus pneumoniae DOSAGE AND ADMINISTRATION NOTE: Azithromycin should not be used in pediatric patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors such as any of the following: patients with cystic fibrosis, patients with nosocomially acquired infections, patients with known or suspected bacteremia, patients requiring hospitalization, or patients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia). Pharyngitis/tonsillitis Streptococcus pyogenes DOSAGE AND ADMINISTRATION Streptococcus pyogenes Streptococcus pyogenes Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to azithromycin.
Treatment of pneumonia
In the treatment of pneumonia, azithromycin has only been shown to be safe and effective in the treatment of community-acquired pneumonia due to Chlamydia pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae Streptococcus pneumoniae
Genitourinary
Monilia, vaginitis and nephritis.
Nervous System
Dizziness, headache, vertigo and somnolence.
Community-Acquired Pneumonia
For the recommended dosage regimen of 10 mg/kg on Day 1 followed by 5 mg/kg on Days 2 to 5, the most frequent side effects attributed to treatment were diarrhea/loose stools, abdominal pain, vomiting, nausea and rash. The incidence is described in the table below: Dosage Regimen Diarrhea/ Loose stools, % Abdominal Pain, % Vomiting, % Nausea, % Rash, % 5-day 5.8% 1.9% 1.9% 1.9% 1.6%
Nervous System
Headache (otitis media dosage), hyperkinesia, dizziness, agitation, nervousness and insomnia.

Adults
Acute bacterial exacerbations of chronic obstructive pulmonary disease Haemophilus influenzae, Moraxella catarrhalis Streptococcus pneumoniae. Acute bacterial sinusitis Haemophilus influenzae, Moraxella catarrhalis Streptococcus pneumoniae. Community-acquired pneumonia Chlamydophilapneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae Streptococcus pneumoniae NOTE: Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors such as any of the following: patients with cystic fibrosis, patients with nosocomially acquired infections, patients with known or suspected bacteremia, patients requiring hospitalization, elderly or debilitated patients, or patients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia). Pharyngitis/tonsillitis Streptococcus pyogenes Streptococcus pyogenes Streptococcus pyogenes Uncomplicated skin and skin structure infections Staphylococcus aureus, Streptococcus pyogenes, Streptococcus agalactiae. Urethritis and cervicitis Chlamydia trachomatis Neisseria gonorrhoeae. Genital ulcer disease Haemophilus ducreyi Azithromycin, at the recommended dose, should not be relied upon to treat syphilis. Antimicrobial agents used in high doses for short periods of time to treat non-gonococcal urethritis may mask or delay the symptoms of incubating syphilis. All patients with sexually-transmitted urethritis or cervicitis should have a serologic test for syphilis and appropriate cultures for gonorrhea performed at the time of diagnosis. Appropriate antimicrobial therapy and follow-up tests for these diseases should be initiated if infection is confirmed. Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to azithromycin. Therapy with azithromycin may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly. To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin and other antibacterial drugs, azithromycin should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.
DOSAGE AND ADMINISTRATION
(See INDICATIONS AND USAGE CLINICAL PHARMACOLOGY Infection Recommended Dose/Duration of Therapy Community-acquired pneumonia (mild severity) Pharyngitis/tonsillitis (second line therapy) Skin/skin structure (uncomplicated) 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5. Acute bacterial exacerbations of chronic obstructive pulmonary disease (mild to moderate) 500 mg QD x 3 days OR 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5. Acute bacterial sinusitis 500 mg QD x 3 days Genital ulcer disease (chancroid) One single 1 gram dose Non-gonoccocal urethritis and cervicitis One single 1 gram dose Gonococcal urethritis and cervicitis One single 2 gram dose Azithromycin tablets can be taken with or without food. No dosage adjustment is recommended for subjects with renal impairment (GFR <=80 mL/min). The mean AUC 0-120 CLINICAL PHARMACOLOGY: Special Populations: Renal 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 (See CLINICAL PHARMACOLOGY: Special Populations: Hepatic Insufficiency No dosage adjustment is recommended based on age or gender. (See CLINICAL PHARMACOLOGY: Special Populations Azithromycin for oral suspension can be taken with or without food. 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. ) 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. ) 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. ) PEDIATRIC DOSAGE GUIDELINES FOR OTITIS MEDIA, ACUTE BACTERIAL SINUSITIS AND COMMUNITY-ACQUIRED PNEUMONIA (Age 6 months and above, see PRECAUTIONS: Pediatric Use OTITIS MEDIA AND COMMUNITY-ACQUIRED PNEUMONIA: (5-Day Regimen) Dosing Calculated on 10 mg/kg/day Day 1 and 5 mg/kg/day Days 2 to 5. Weight 100 mg/5 mL 200 mg/5 mL Total mL Per Treatment Course Total mg Per Treatment Course Kg Lbs. Day 1 Days 2-5 Day 1 Days 2-5 5 11 2. 5 mL (1/2 tsp) 1. 25 mL (1/4 tsp) 7. 5 mL 150 mg 10 22 5 mL (1 tsp) 2. 5 mL (1/2 tsp) 15 mL 300 mg 20 44 5 mL (1 tsp) 2. 5 mL (1/2 tsp) 15 mL 600 mg 30 66 7. 5 mL (1-1/2 tsp) 3. 75 mL (3/4 tsp) 22. 5 mL 900 mg 40 88 10 mL (2 tsp) 5 mL (1 tsp) 30 mL 1200 mg 50 and above 110 and above 12. 5 mL (2-1/2 tsp) 6. 25 mL (1-1/4 tsp) 37. 5 mL 1500 mg OTITIS MEDIA AND ACUTE BACTERIAL SINUSITIS: (3-Day Regimen) Dosing Calculated on 10 mg/kg/day Weight 100 mg/5 mL 200 mg/5 mL Total mL per Treatment Course Total mg per Treatment Course Kg Lbs. Day 1-3 Day 1-3 5 11 2. 5 mL (1/2 tsp) 7. 5 mL 150 mg 10 22 5 mL (1 tsp) 15 mL 300 mg 20 44 5 mL (1 tsp) 15 mL 600 mg 30 66 7. 5 mL (1-1/2 tsp) 22. 5 mL 900 mg 40 88 10 mL (2 tsp) 30 mL 1200 mg 50 and above 110 and above 12. 5 mL (2-1/2 tsp) 37. 5 mL 1500 mg OTITIS MEDIA: (1-Day Regimen) Dosing Calculated on 30 mg/kg as a single dose Weight 200 mg/5 mL Total mL per Treatment Course Total mg per Treatment Course Kg Lbs. Day 1 5 11 3. 75 mL (3/4 tsp) 3. 75 mL 150 mg 10 22 7. 5 mL (1-1/2 tsp) 7. 5 mL 300 mg 20 44 15 mL (3 tsp) 15 mL 600 mg 30 66 22. 5 mL (4-1/2 tsp) 22. 5 mL 900 mg 40 88 30 mL (6 tsp) 30 mL 1200 mg 50 and above 110 and above 37. 5 mL (7-1/2 tsp) 37. 5 mL 1500 mg 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. The recommended dose of azithromycin for children with pharyngitis/tonsillitis is 12 mg/kg once daily for 5 days. ) PEDIATRIC DOSAGE GUIDELINES FOR PHARYNGITIS/TONSILLITIS (Age 2 years and above, see PRECAUTIONS: Pediatric Use PHARYNGITIS/TONSILLITIS: (5-Day Regimen) Dosing Calculated on 12 mg/kg/day for 5 days. Weight 200 mg/5 mL Total mL per Treatment Course Total mg per Treatment Course Kg Lbs. Day 1-5 8 18 2. 5 mL (1/2 tsp) 12. 5 mL 500 mg 17 37 5 mL (1 tsp) 25 mL 1000 mg 25 55 7. 5 mL (1-1/2 tsp) 37. 5 mL 1500 mg 33 73 10 mL (2 tsp) 50 mL 2000 mg 40 88 12. 5 mL (2-1/2 tsp) 62. 5 mL 2500 mg.
Adults
Infection Recommended Dose/Duration of Therapy Community-acquired pneumonia (mild severity) Pharyngitis/tonsillitis (second line therapy) Skin/skin structure (uncomplicated) 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5. Acute bacterial exacerbations of chronic obstructive pulmonary disease (mild to moderate) 500 mg QD x 3 days OR 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5. Acute bacterial sinusitis 500 mg QD x 3 days Genital ulcer disease (chancroid) One single 1 gram dose Non-gonoccocal urethritis and cervicitis One single 1 gram dose Gonococcal urethritis and cervicitis One single 2 gram dose Azithromycin tablets can be taken with or without food. No dosage adjustment is recommended for subjects with renal impairment (GFR <=80 mL/min). The mean AUC 0-120 CLINICAL PHARMACOLOGY: Special Populations: Renal 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 (See CLINICAL PHARMACOLOGY: Special Populations: Hepatic Insufficiency No dosage adjustment is recommended based on age or gender. (See CLINICAL PHARMACOLOGY: Special Populations.

Hepatotoxicity
Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur.
ADVERSE REACTIONS
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. 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%. (See DOSAGE AND ADMINISTRATION CLINICAL STUDIES IN PEDIATRIC PATIENTS Overall, the most common treatment-related side effects in adult patients receiving multiple-dose regimens of azithromycin were related to the gastrointestinal system with diarrhea/loose stools (4 to 5%), nausea (3%) and abdominal pain (2 to 3%) being the most frequently reported. No other treatment-related side effects occurred in patients on the multiple-dose regimens of azithromycin with a frequency greater than 1%. Side effects that occurred with a frequency of 1% or less included the following: Palpitations, chest pain. Dyspepsia, flatulence, vomiting, melena and cholestatic jaundice. Monilia, vaginitis and nephritis. Dizziness, headache, vertigo and somnolence. Rash, pruritus, photosensitivity and angioedema. Overall, the most common side effects in patients receiving a single-dose regimen of 1 gram of azithromycin were related to the gastrointestinal system and were more frequently reported than in patients receiving the multiple-dose regimen. Side effects that occurred in patients on the single one-gram dosing regimen of azithromycin with a frequency of 1% or greater included diarrhea/loose stools (7%), nausea (5%), abdominal pain (5%), vomiting (2%), dyspepsia (1%) and vaginitis (1%). Overall, the most common side effects in patients receiving a single 2-gram dose of azithromycin were related to the gastrointestinal system. Side effects that occurred in patients in this study with a frequency of 1% or greater included nausea (18%), diarrhea/loose stools (14%), vomiting (7%), abdominal pain (7%), vaginitis (2%), dyspepsia (1%) and dizziness (1%). The majority of these complaints were mild in nature. The types of side effects in pediatric patients were comparable to those seen in adults, with different incidence rates for the dosage regimens recommended in pediatric patients. Acute Otitis Media: For the recommended total dosage regimen of 30 mg/kg, the most frequent side effects (>=1%) attributed to treatment were diarrhea, abdominal pain, vomiting, nausea and rash. (See DOSAGE AND ADMINISTRATION CLINICAL STUDIES: Pediatric Patients The incidence, based on dosing regimen, is described in the table below: Dosage Regimen Diarrhea, % Abdominal Pain, % Vomiting, % Nausea, % Rash, % 1-day 4. 4% For the recommended dosage regimen of 10 mg/kg on Day 1 followed by 5 mg/kg on Days 2 to 5, the most frequent side effects attributed to treatment were diarrhea/loose stools, abdominal pain, vomiting, nausea and rash. The incidence is described in the table below: Dosage Regimen Diarrhea/ Loose stools, % Abdominal Pain, % Vomiting, % Nausea, % Rash, % 5-day 5. 6% For the recommended dosage regimen of 12 mg/kg on Days 1 to 5, the most frequent side effects attributed to treatment were diarrhea, vomiting, abdominal pain, nausea and headache. The incidence is described in the table below: Dosage Regimen Diarrhea, % Abdominal Pain, % Vomiting, % Nausea, % Rash, % Headache, % 5-day 5. 1% With any of the treatment regimens, no other treatment-related side effects occurred in pediatric patients treated with azithromycin with a frequency greater than 1%. Side effects that occurred with a frequency of 1% or less included the following: Chest pain. Dyspepsia, constipation, anorexia, enteritis, flatulence, gastritis, jaundice, loose stools and oral moniliasis. Anemia and leukopenia. Headache (otitis media dosage), hyperkinesia, dizziness, agitation, nervousness and insomnia. Fever, face edema, fatigue, fungal infection, malaise and pain. Rash and allergic reaction. Cough increased, pharyngitis, pleural effusion and rhinitis. Eczema, fungal dermatitis, pruritus, sweating, urticaria and vesiculobullous rash. Conjunctivitis. 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: Arthralgia, edema, urticaria and angioedema. Arrhythmias including ventricular tachycardia and hypotension. There have been rare reports of QT prolongation and torsades de pointes. Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea rarely resulting in dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and rare reports of tongue discoloration. Asthenia, paresthesia, fatigue, malaise and anaphylaxis (rarely fatal). Interstitial nephritis and acute renal failure and vaginitis. Thrombocytopenia. Adverse reactions related to hepatic dysfunction have been reported in postmarketing experience with azithromycin. (See WARNINGS: Hepatotoxicity Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation and syncope. Aggressive reaction and anxiety. Pruritus, rarely serious skin reactions including erythema multiforme, Stevens Johnson Syndrome and toxic epidermal necrolysis. Hearing disturbances including hearing loss, deafness and/or tinnitus and reports of taste/smell perversion and/or loss. 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 5000 patients, four patients discontinued therapy because of treatment-related liver enzyme abnormalities and one because of a renal function abnormality. Laboratory data collected from comparative clinical trials employing two 3-day regimens (30 mg/kg or 60 mg/kg in divided doses over 3 days), or two 5-day regimens (30 mg/kg or 60 mg/kg in divided doses over 5 days) were similar for regimens of azithromycin and all comparators combined, with most clinically significant laboratory abnormalities occurring at incidences of 1 to 5%. Laboratory data for patients receiving 30 mg/kg as a single dose were collected in one single center trial. In that trial, an absolute neutrophil count between 500 to 1500 cells/mm 3 3 DOSAGE AND ADMINISTRATION In multiple-dose clinical trials involving approximately 4700 pediatric patients, no patients discontinued therapy because of treatment-related laboratory abnormalities.
Clinical
Overall, the most common treatment-related side effects in adult patients receiving multiple-dose regimens of azithromycin were related to the gastrointestinal system with diarrhea/loose stools (4 to 5%), nausea (3%) and abdominal pain (2 to 3%) being the most frequently reported. No other treatment-related side effects occurred in patients on the multiple-dose regimens of azithromycin with a frequency greater than 1%. Side effects that occurred with a frequency of 1% or less included the following: Palpitations, chest pain. Dyspepsia, flatulence, vomiting, melena and cholestatic jaundice. Monilia, vaginitis and nephritis. Dizziness, headache, vertigo and somnolence. Rash, pruritus, photosensitivity and angioedema. Overall, the most common side effects in patients receiving a single-dose regimen of 1 gram of azithromycin were related to the gastrointestinal system and were more frequently reported than in patients receiving the multiple-dose regimen. Side effects that occurred in patients on the single one-gram dosing regimen of azithromycin with a frequency of 1% or greater included diarrhea/loose stools (7%), nausea (5%), abdominal pain (5%), vomiting (2%), dyspepsia (1%) and vaginitis (1%). Overall, the most common side effects in patients receiving a single 2-gram dose of azithromycin were related to the gastrointestinal system. Side effects that occurred in patients in this study with a frequency of 1% or greater included nausea (18%), diarrhea/loose stools (14%), vomiting (7%), abdominal pain (7%), vaginitis (2%), dyspepsia (1%) and dizziness (1%). The majority of these complaints were mild in nature. The types of side effects in pediatric patients were comparable to those seen in adults, with different incidence rates for the dosage regimens recommended in pediatric patients. Acute Otitis Media: For the recommended total dosage regimen of 30 mg/kg, the most frequent side effects (>=1%) attributed to treatment were diarrhea, abdominal pain, vomiting, nausea and rash. (See DOSAGE AND ADMINISTRATION CLINICAL STUDIES: Pediatric Patients The incidence, based on dosing regimen, is described in the table below: Dosage Regimen Diarrhea, % Abdominal Pain, % Vomiting, % Nausea, % Rash, % 1-day 4. 4% For the recommended dosage regimen of 10 mg/kg on Day 1 followed by 5 mg/kg on Days 2 to 5, the most frequent side effects attributed to treatment were diarrhea/loose stools, abdominal pain, vomiting, nausea and rash. The incidence is described in the table below: Dosage Regimen Diarrhea/ Loose stools, % Abdominal Pain, % Vomiting, % Nausea, % Rash, % 5-day 5. 6% For the recommended dosage regimen of 12 mg/kg on Days 1 to 5, the most frequent side effects attributed to treatment were diarrhea, vomiting, abdominal pain, nausea and headache. The incidence is described in the table below: Dosage Regimen Diarrhea, % Abdominal Pain, % Vomiting, % Nausea, % Rash, % Headache, % 5-day 5. 1% With any of the treatment regimens, no other treatment-related side effects occurred in pediatric patients treated with azithromycin with a frequency greater than 1%. Side effects that occurred with a frequency of 1% or less included the following: Chest pain. Dyspepsia, constipation, anorexia, enteritis, flatulence, gastritis, jaundice, loose stools and oral moniliasis. Anemia and leukopenia. Headache (otitis media dosage), hyperkinesia, dizziness, agitation, nervousness and insomnia. Fever, face edema, fatigue, fungal infection, malaise and pain. Rash and allergic reaction. Cough increased, pharyngitis, pleural effusion and rhinitis. Eczema, fungal dermatitis, pruritus, sweating, urticaria and vesiculobullous rash. Conjunctivitis.
Cardiovascular
Palpitations, chest pain.
Gastrointestinal
Dyspepsia, flatulence, vomiting, melena and cholestatic jaundice.
Allergic
Rash, pruritus, photosensitivity and angioedema.
Pharyngitis/tonsillitis
For the recommended dosage regimen of 12 mg/kg on Days 1 to 5, the most frequent side effects attributed to treatment were diarrhea, vomiting, abdominal pain, nausea and headache. The incidence is described in the table below: Dosage Regimen Diarrhea, % Abdominal Pain, % Vomiting, % Nausea, % Rash, % Headache, % 5-day 5.4% 3.4% 5.6% 1.8% 0.7% 1.1% With any of the treatment regimens, no other treatment-related side effects occurred in pediatric patients treated with azithromycin with a frequency greater than 1%. Side effects that occurred with a frequency of 1% or less included the following:
Cardiovascular
Chest pain.
Gastrointestinal
Dyspepsia, constipation, anorexia, enteritis, flatulence, gastritis, jaundice, loose stools and oral moniliasis.
Allergic
Rash and allergic reaction.
Respiratory
Cough increased, pharyngitis, pleural effusion and rhinitis.
Skin and Appendages
Eczema, fungal dermatitis, pruritus, sweating, urticaria and vesiculobullous rash.
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: Arthralgia, edema, urticaria and angioedema. Arrhythmias including ventricular tachycardia and hypotension. There have been rare reports of QT prolongation and torsades de pointes. Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea rarely resulting in dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and rare reports of tongue discoloration. Asthenia, paresthesia, fatigue, malaise and anaphylaxis (rarely fatal). Interstitial nephritis and acute renal failure and vaginitis. Thrombocytopenia. Adverse reactions related to hepatic dysfunction have been reported in postmarketing experience with azithromycin. (See WARNINGS: Hepatotoxicity Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation and syncope. Aggressive reaction and anxiety. Pruritus, rarely serious skin reactions including erythema multiforme, Stevens Johnson Syndrome and toxic epidermal necrolysis. Hearing disturbances including hearing loss, deafness and/or tinnitus and reports of taste/smell perversion and/or loss.
Laboratory Abnormalities
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 5000 patients, four patients discontinued therapy because of treatment-related liver enzyme abnormalities and one because of a renal function abnormality. Laboratory data collected from comparative clinical trials employing two 3-day regimens (30 mg/kg or 60 mg/kg in divided doses over 3 days), or two 5-day regimens (30 mg/kg or 60 mg/kg in divided doses over 5 days) were similar for regimens of azithromycin and all comparators combined, with most clinically significant laboratory abnormalities occurring at incidences of 1 to 5%. Laboratory data for patients receiving 30 mg/kg as a single dose were collected in one single center trial. In that trial, an absolute neutrophil count between 500 to 1500 cells/mm 3 3 DOSAGE AND ADMINISTRATION In multiple-dose clinical trials involving approximately 4700 pediatric patients, no patients discontinued therapy because of treatment-related laboratory abnormalities.

CONTRAINDICATIONS
Azithromycin tablets are contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide antibiotic. Azithromycin tablets are contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.
Hypersensitivity
Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Stevens Johnson Syndrome and toxic epidermal necrolysis have been reported rarely in patients on azithromycin therapy. Although rare, fatalities have been reported. (See CONTRAINDICATIONS recurred soon thereafter in some patients without further azithromycin exposure. If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.

Pediatric Patients
(See PRECAUTIONS: Pediatric Use CLINICAL STUDIES IN PEDIATRIC PATIENTS Acute otitis media Haemophilus influenzae, Moraxella catarrhalis Streptococcus pneumoniae. DOSAGE AND ADMINISTRATION Community-acquired pneumonia Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae Streptococcus pneumoniae DOSAGE AND ADMINISTRATION NOTE: Azithromycin should not be used in pediatric patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors such as any of the following: patients with cystic fibrosis, patients with nosocomially acquired infections, patients with known or suspected bacteremia, patients requiring hospitalization, or patients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia). Pharyngitis/tonsillitis Streptococcus pyogenes DOSAGE AND ADMINISTRATION Streptococcus pyogenes Streptococcus pyogenes Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to azithromycin. Therapy with azithromycin may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly.
Pregnancy
Reproduction studies have been performed in rats and mice at doses up to moderately maternally toxic dose concentrations (i.e., 200 mg/kg/day). These doses, based on a mg/m 2
Nursing Mothers
It is not known whether azithromycin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when azithromycin is administered to a nursing woman.
Pediatric Use
(See CLINICAL PHARMACOLOGY INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION (total dosage regimen: 30 mg/kg, DOSAGE AND ADMINISTRATION (dosage regimen: 10 mg/kg on Days 1 to 3): (dosage regimen: 10 mg/kg on Day 1 followed by 5 mg/kg on Days 2 to 5): Chlamydophila pneumoniae Mycoplasma pneumoniae Haemophilus influenzae Streptococcus pneumoniae (dosage regimen: 12 mg/kg on Days 1 to 5): Studies evaluating the use of repeated courses of therapy have not been conducted. CLINICAL PHARMACOLOGY ANIMAL TOXICOLOGY.
Geriatric Use
Pharmacokinetic parameters in older volunteers (65 to 85 years old) were similar to those in younger volunteers (18 to 40 years old) for the 5-day therapeutic regimen. Dosage adjustment does not appear to be necessary for older patients with normal renal and hepatic function receiving treatment with this dosage regimen. (See CLINICAL PHARMACOLOGY In multiple-dose clinical trials of oral azithromycin, 9% of patients were at least 65 years of age (458/4949) and 3% of patients (144/4949) were at least 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients may be more susceptible to development of torsades de pointes WARNINGS Azithromycin tablets 250 mg contain 0.21 mg of sodium per tablet. Azithromycin tablets 500 mg contain 0.41 mg of sodium per tablet.
Special Senses
Conjunctivitis.
Pediatric Patients
Azithromycin for oral suspension can be taken with or without food. 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. ) 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. ) 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. ) PEDIATRIC DOSAGE GUIDELINES FOR OTITIS MEDIA, ACUTE BACTERIAL SINUSITIS AND COMMUNITY-ACQUIRED PNEUMONIA (Age 6 months and above, see PRECAUTIONS: Pediatric Use OTITIS MEDIA AND COMMUNITY-ACQUIRED PNEUMONIA: (5-Day Regimen) Dosing Calculated on 10 mg/kg/day Day 1 and 5 mg/kg/day Days 2 to 5. Weight 100 mg/5 mL 200 mg/5 mL Total mL Per Treatment Course Total mg Per Treatment Course Kg Lbs. Day 1 Days 2-5 Day 1 Days 2-5 5 11 2. 5 mL (1/2 tsp) 1. 25 mL (1/4 tsp) 7. 5 mL 150 mg 10 22 5 mL (1 tsp) 2. 5 mL (1/2 tsp) 15 mL 300 mg 20 44 5 mL (1 tsp) 2. 5 mL (1/2 tsp) 15 mL 600 mg 30 66 7. 5 mL (1-1/2 tsp) 3. 75 mL (3/4 tsp) 22. 5 mL 900 mg 40 88 10 mL (2 tsp) 5 mL (1 tsp) 30 mL 1200 mg 50 and above 110 and above 12. 5 mL (2-1/2 tsp) 6. 25 mL (1-1/4 tsp) 37. 5 mL 1500 mg OTITIS MEDIA AND ACUTE BACTERIAL SINUSITIS: (3-Day Regimen) Dosing Calculated on 10 mg/kg/day Weight 100 mg/5 mL 200 mg/5 mL Total mL per Treatment Course Total mg per Treatment Course Kg Lbs. Day 1-3 Day 1-3 5 11 2. 5 mL (1/2 tsp) 7. 5 mL 150 mg 10 22 5 mL (1 tsp) 15 mL 300 mg 20 44 5 mL (1 tsp) 15 mL 600 mg 30 66 7. 5 mL (1-1/2 tsp) 22. 5 mL 900 mg 40 88 10 mL (2 tsp) 30 mL 1200 mg 50 and above 110 and above 12. 5 mL (2-1/2 tsp) 37. 5 mL 1500 mg OTITIS MEDIA: (1-Day Regimen) Dosing Calculated on 30 mg/kg as a single dose Weight 200 mg/5 mL Total mL per Treatment Course Total mg per Treatment Course Kg Lbs. Day 1 5 11 3. 75 mL (3/4 tsp) 3. 75 mL 150 mg 10 22 7. 5 mL (1-1/2 tsp) 7. 5 mL 300 mg 20 44 15 mL (3 tsp) 15 mL 600 mg 30 66 22. 5 mL (4-1/2 tsp) 22. 5 mL 900 mg 40 88 30 mL (6 tsp) 30 mL 1200 mg 50 and above 110 and above 37. 5 mL (7-1/2 tsp) 37. 5 mL 1500 mg 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. The recommended dose of azithromycin for children with pharyngitis/tonsillitis is 12 mg/kg once daily for 5 days. ) PEDIATRIC DOSAGE GUIDELINES FOR PHARYNGITIS/TONSILLITIS (Age 2 years and above, see PRECAUTIONS: Pediatric Use PHARYNGITIS/TONSILLITIS: (5-Day Regimen) Dosing Calculated on 12 mg/kg/day for 5 days. Weight 200 mg/5 mL Total mL per Treatment Course Total mg per Treatment Course Kg Lbs. Day 1-5 8 18 2. 5 mL (1/2 tsp) 12. 5 mL 500 mg 17 37 5 mL (1 tsp) 25 mL 1000 mg 25 55 7. 5 mL (1-1/2 tsp) 37. 5 mL 1500 mg 33 73 10 mL (2 tsp) 50 mL 2000 mg 40 88 12. 5 mL (2-1/2 tsp) 62. 5 mL 2500 mg.
Pediatric Patients
From the perspective of evaluating pediatric clinical trials, Days 11-14 were considered on-therapy evaluations because of the extended half-life of azithromycin. Day 11-14 data are provided for clinical guidance. Day 24-32 evaluations were considered the primary test of cure endpoint. In a double-blind, controlled clinical study of acute otitis media performed in the United States, azithromycin (10 mg/kg on Day 1 followed by 5 mg/kg on Days 2-5) was compared to amoxicillin/clavulanate potassium (4:1). For the 553 patients who were evaluated for clinical efficacy, the clinical success rate (i. , cure plus improvement) at the Day 11 visit was 88% for azithromycin and 88% for the control agent. For the 521 patients who were evaluated at the Day 30 visit, the clinical success rate was 73% for azithromycin and 71% for the control agent. In the safety analysis of the above study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 9% with azithromycin and 31% with the control agent. The most common side effects were diarrhea/loose stools (4% azithromycin vs. 20% control), vomiting (2% azithromycin vs. 7% control), and abdominal pain (2% azithromycin vs. 5% control). In a non-comparative clinical and microbiologic trial performed in the United States, where significant rates of beta-lactamase producing organisms (35%) were found, 131 patients were evaluable for clinical efficacy. The combined clinical success rate (i. , cure and improvement) at the Day 11 visit was 84% for azithromycin. For the 122 patients who were evaluated at the Day 30 visit, the clinical success rate was 70% for azithromycin. Microbiologic determinations were made at the pre-treatment visit. Microbiology was not reassessed at later visits. The following presumptive bacterial/clinical cure outcomes (i. , clinical success) were obtained from the evaluable group: Presumed Bacteriologic Eradication Day 11 Azithromycin Day 30 Azithromycin S. pneumoniae 61/74 (82%) 40/56 (71%) H. influenzae 43/54 (80%) 30/47 (64%) M. catarrhalis 28/35 (80%) 19/26 (73%) S. pyogenes 11/11 (100%) 7/7 Overall 177/217 (82%) 97/137 (73%) In the safety analysis of this study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 9%. The most common side effect was diarrhea (4%). In another controlled comparative clinical and microbiologic study of otitis media performed in the United States, azithromycin was compared to amoxicillin/clavulanate potassium (4:1). This study utilized two of the same investigators as Protocol 2 (above), and these two investigators enrolled 90% of the patients in Protocol 3. For this reason, Protocol 3 was not considered to be an independent study. Significant rates of beta-lactamase producing organisms (20%) were found. Ninety-two (92) patients were evaluable for clinical and microbiologic efficacy. , cure and improvement) of those patients with a baseline pathogen at the Day 11 visit was 88% for azithromycin vs. 100% for control; at the Day 30 visit, the clinical success rate was 82% for azithromycin vs. 80% for control. At the Day 11 and Day 30 visits, the following presumptive bacterial/clinical cure outcomes (i. , clinical success) were obtained from the evaluable group: Presumed Bacteriologic Eradication Day 11 Day 30 Azithromycin Control Azithromycin Control S. pneumoniae 25/29 (86%) 26/26 (100%) 22/28 (79%) 18/22 (82%) H. influenzae 9/11 (82%) 9/9 8/10 (80%) 6/8 M. catarrhalis 7/7 5/5 5/5 2/3 S. pyogenes 2/2 5/5 2/2 4/4 Overall 43/49 (88%) 45/45 (100%) 37/45 (82%) 30/37 (81%) In the safety analysis of the above study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 4% with azithromycin and 31% with the control agent. The most common side effect was diarrhea/loose stools (2% azithromycin vs. 29% control). In a double-blind, controlled, randomized clinical study of acute otitis media in pediatric patients from 6 months to 12 years of age, azithromycin (10 mg/kg per day for 3 days) was compared to amoxicillin/clavulanate potassium (7:1) in divided doses q12h for 10 days. Each patient received active drug and placebo matched for the comparator. For the 366 patients who were evaluated for clinical efficacy at the Day 12 visit, the clinical success rate (i. , cure plus improvement) was 83% for azithromycin and 88% for the control agent. For the 362 patients who were evaluated at the Day 24-28 visit, the clinical success rate was 74% for azithromycin and 69% for the control agent. In the safety analysis of the above study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 10. 6% with azithromycin and 20. 0% with the control agent. The most common side effects were diarrhea/loose stools (5. 9% azithromycin vs. 6% control), vomiting (2. 1% azithromycin vs. 1% control), and rash (0. 0% azithromycin vs. 3% control). A double blind, controlled, randomized trial was performed at nine clinical centers. Pediatric patients from 6 months to 12 years of age were randomized 1:1 to treatment with either azithromycin (given at 30 mg/kg as a single dose on Day 1) or amoxicillin/clavulanate potassium (7:1), divided q12h for 10 days. Each child received active drug, and placebo matched for the comparator. Clinical response (Cure, Improvement, Failure) was evaluated at End of Therapy (Day 12-16) and Test of Cure (Day 28-32). Safety was evaluated throughout the trial for all treated subjects. For the 321 subjects who were evaluated at End of Treatment, the clinical success rate (cure plus improvement) was 87% for azithromycin, and 88% for the comparator. For the 305 subjects who were evaluated at Test of Cure, the clinical success rate was 75% for both azithromycin and the comparator. In the safety analysis, the incidence of treatment-related adverse events, primarily gastrointestinal, was 16. 8% with azithromycin, and 22. 5% with the comparator. The most common side effects were diarrhea (6. 4% with azithromycin vs. 7% with the comparator), vomiting (4% with each agent), rash (1. 7% with azithromycin vs. 2% with the comparator) and nausea (1. 2% with the comparator). In a non-comparative clinical and microbiological trial, 248 patients from 6 months to 12 years of age with documented acute otitis media were dosed with a single oral dose of azithromycin (30 mg/kg on Day 1). For the 240 patients who were evaluable for clinical modified Intent-to-Treat (MITT) analysis, the clinical success rate (i. , cure plus improvement) at Day 10 was 89% and for the 242 patients evaluable at Day 24-28, the clinical success rate (cure) was 85%. Presumed Bacteriologic Eradication Day 10 S. pneumoniae 70/76 (92%) 67/76 (88%) H. influenzae 30/42 (71%) 28/44 (64%) M. catarrhalis 10/10 (100%) 10/10 (100%) Overall 110/128 (86%) 105/130 (81%) In the safety analysis of this study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all the subjects treated was 12. The most common side effects were vomiting (5. 6%), diarrhea (3. 2%), and abdominal pain (1. In three double-blind controlled studies, conducted in the United States, azithromycin (12 mg/kg once a day for 5 days) was compared to penicillin V (250 mg three times a day for 10 days) in the treatment of pharyngitis due to documented Group A beta-hemolytic streptococci (GABHS or S. pyogenes Three U. Streptococcal Pharyngitis Studies Azithromycin vs. Penicillin V EFFICACY RESULTS Day 14 Day 30 Bacteriologic Eradication: Clinical Success (Cure plus improvement): Approximately 1% of azithromycin-susceptible S. pyogenes The incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 18% on azithromycin and 13% on penicillin. The most common side effects were diarrhea/loose stools (6% azithromycin vs. 2% penicillin), vomiting (6% azithromycin vs. 4% penicillin), and abdominal pain (3% azithromycin vs. 1% penicillin).
Adult Patients
In a randomized, double-blind controlled clinical trial of acute exacerbation of chronic bronchitis (AECB), azithromycin (500 mg once daily for 3 days) was compared with clarithromycin (500 mg twice daily for 10 days). The primary endpoint of this trial was the clinical cure rate at Day 21 to 24. For the 304 patients analyzed in the modified intent to treat analysis at the Day 21 to 24 visit, the clinical cure rate for 3 days of azithromycin was 85% (125/147) compared to 82% (129/157) for 10 days of clarithromycin. The following outcomes were the clinical cure rates at the Day 21 to 24 visit for the bacteriologically evaluable patients by pathogen: Pathogen Azithromycin (3 Days) Clarithromycin (10 Days) S. pneumoniae 29/32 (91%) 21/27 (78%) H. influenzae 12/14 (86%) 14/16 (88%) M. catarrhalis 11/12 (92%) 12/15 (80%) In the safety analysis of this study, the incidence of treatment-related adverse events, primarily gastrointestinal, were comparable between treatment arms (25% with azithromycin and 29% with clarithromycin). The most common side effects were diarrhea, nausea and abdominal pain with comparable incidence rates for each symptom of 5 to 9% between the two treatment arms. (See ADVERSE REACTIONS In a randomized, double-blind, double-dummy controlled clinical trial of acute bacterial sinusitis, azithromycin (500 mg once daily for 3 days) was compared with amoxicillin/clavulanate (500/125 mg t. for 10 days). Clinical response assessments were made at Day 10 and Day 28. The primary endpoint of this trial was prospectively defined as the clinical cure rate at Day 28. For the 594 patients analyzed in the modified intent to treat analysis at the Day 10 visit, the clinical cure rate for 3 days of azithromycin was 88% (268/303) compared to 85% (248/291) for 10 days of amoxicillin/clavulanate. For the 586 patients analyzed in the modified intent to treat analysis at the Day 28 visit, the clinical cure rate for 3 days of azithromycin was 71. 5% (213/298) compared to 71. 5% (206/288), with a 97. 5% confidence interval of -8. 3, for 10 days of amoxicillin/clavulanate. In the safety analysis of this study, the overall incidence of treatment-related adverse events, primarily gastrointestinal, was lower in the azithromycin treatment arm (31%) than in the amoxicillin/clavulanate arm (51%). The most common side effects were diarrhea (17% in the azithromycin arm vs. 32% in the amoxicillin/clavulanate arm), and nausea (7% in the azithromycin arm vs. 12% in the amoxicillin/clavulanate arm). (See ADVERSE REACTIONS In an open label, noncomparative study requiring baseline transantral sinus punctures the following outcomes were the clinical success rates at the Day 7 and Day 28 visits for the modified intent to treat patients administered 500 mg of azithromycin once daily for 3 days with the following pathogens: Azithromycin (500 mg per day for 3 Days) Pathogen Day 7 Day 28 S. pneumoniae 23/26 (88%) 21/25 (84%) H. influenzae 28/32 (87%) 24/32 (75%) M. catarrhalis 14/15 (93%) 13/15 (87%) The overall incidence of treatment-related adverse events in the noncomparative study was 21% in modified intent to treat patients treated with azithromycin at 500 mg once daily for 3 days with the most common side effects being diarrhea (9%), abdominal pain (4%) and nausea (3%). (See ADVERSE REACTIONS.

Drug Interactions
Co-administration of nelfinavir at steady-state with a single oral dose of azithromycin resulted in increased azithromycin serum concentrations. Although a dose adjustment of azithromycin is not recommended when administered in combination with nelfinavir, close monitoring for known side effects of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. (See ADVERSE REACTIONS Although, in a study of 22 healthy men, a 5-day course of azithromycin did not affect the prothrombin time from a subsequently administered dose of warfarin, spontaneous post-marketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly. Drug interaction studies were performed with azithromycin and other drugs likely to be co-administered. (See CLINICAL PHARMACOLOGY: Drug-Drug Interactions Interactions with the drugs listed below have not been reported in clinical trials with azithromycin; however, no specific drug interaction studies have been performed to evaluate potential drug-drug interaction. Nonetheless, they have been observed with macrolide products. Until further data are developed regarding drug interactions when azithromycin and these drugs are used concomitantly, careful monitoring of patients is advised:
Laboratory Test Interactions
There are no reported laboratory test interactions.

WARNINGS
Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Stevens Johnson Syndrome and toxic epidermal necrolysis have been reported rarely in patients on azithromycin therapy. Although rare, fatalities have been reported. (See CONTRAINDICATIONS recurred soon thereafter in some patients without further azithromycin exposure. If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued. Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur. In the treatment of pneumonia, azithromycin has only been shown to be safe and effective in the treatment of community-acquired pneumonia due to Chlamydia pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae Streptococcus pneumoniae Clostridium difficile C. difficile C. difficile If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes torsades de pointes torsades de pointes Elderly patients may be more susceptible to drug-associated effects on the QT interval.
Carcinogenesis,Mutagenesis, Impairment of Fertility
Long-term studies in animals have not been performed to evaluate carcinogenic potential. Azithromycin has shown no mutagenic potential in standard laboratory tests: mouse lymphoma assay, human lymphocyte clastogenic assay, and mouse bone marrow clastogenic assay. No evidence of impaired fertility due to azithromycin was found.
Hematologic and Lymphatic
Anemia and leukopenia.
CLINICAL STUDIES
(See INDICATIONS AND USAGE Pediatric Use From the perspective of evaluating pediatric clinical trials, Days 11-14 were considered on-therapy evaluations because of the extended half-life of azithromycin. Day 11-14 data are provided for clinical guidance. Day 24-32 evaluations were considered the primary test of cure endpoint. In a double-blind, controlled clinical study of acute otitis media performed in the United States, azithromycin (10 mg/kg on Day 1 followed by 5 mg/kg on Days 2-5) was compared to amoxicillin/clavulanate potassium (4:1). For the 553 patients who were evaluated for clinical efficacy, the clinical success rate (i. , cure plus improvement) at the Day 11 visit was 88% for azithromycin and 88% for the control agent. For the 521 patients who were evaluated at the Day 30 visit, the clinical success rate was 73% for azithromycin and 71% for the control agent. In the safety analysis of the above study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 9% with azithromycin and 31% with the control agent. The most common side effects were diarrhea/loose stools (4% azithromycin vs. 20% control), vomiting (2% azithromycin vs. 7% control), and abdominal pain (2% azithromycin vs. 5% control). In a non-comparative clinical and microbiologic trial performed in the United States, where significant rates of beta-lactamase producing organisms (35%) were found, 131 patients were evaluable for clinical efficacy. The combined clinical success rate (i. , cure and improvement) at the Day 11 visit was 84% for azithromycin. For the 122 patients who were evaluated at the Day 30 visit, the clinical success rate was 70% for azithromycin. Microbiologic determinations were made at the pre-treatment visit. Microbiology was not reassessed at later visits. The following presumptive bacterial/clinical cure outcomes (i. , clinical success) were obtained from the evaluable group: Presumed Bacteriologic Eradication Day 11 Azithromycin Day 30 Azithromycin S. pneumoniae 61/74 (82%) 40/56 (71%) H. influenzae 43/54 (80%) 30/47 (64%) M. catarrhalis 28/35 (80%) 19/26 (73%) S. pyogenes 11/11 (100%) 7/7 Overall 177/217 (82%) 97/137 (73%) In the safety analysis of this study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 9%. The most common side effect was diarrhea (4%). In another controlled comparative clinical and microbiologic study of otitis media performed in the United States, azithromycin was compared to amoxicillin/clavulanate potassium (4:1). This study utilized two of the same investigators as Protocol 2 (above), and these two investigators enrolled 90% of the patients in Protocol 3. For this reason, Protocol 3 was not considered to be an independent study. Significant rates of beta-lactamase producing organisms (20%) were found. Ninety-two (92) patients were evaluable for clinical and microbiologic efficacy. , cure and improvement) of those patients with a baseline pathogen at the Day 11 visit was 88% for azithromycin vs. 100% for control; at the Day 30 visit, the clinical success rate was 82% for azithromycin vs. 80% for control. At the Day 11 and Day 30 visits, the following presumptive bacterial/clinical cure outcomes (i. , clinical success) were obtained from the evaluable group: Presumed Bacteriologic Eradication Day 11 Day 30 Azithromycin Control Azithromycin Control S. pneumoniae 25/29 (86%) 26/26 (100%) 22/28 (79%) 18/22 (82%) H. influenzae 9/11 (82%) 9/9 8/10 (80%) 6/8 M. catarrhalis 7/7 5/5 5/5 2/3 S. pyogenes 2/2 5/5 2/2 4/4 Overall 43/49 (88%) 45/45 (100%) 37/45 (82%) 30/37 (81%) In the safety analysis of the above study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 4% with azithromycin and 31% with the control agent. The most common side effect was diarrhea/loose stools (2% azithromycin vs. 29% control). In a double-blind, controlled, randomized clinical study of acute otitis media in pediatric patients from 6 months to 12 years of age, azithromycin (10 mg/kg per day for 3 days) was compared to amoxicillin/clavulanate potassium (7:1) in divided doses q12h for 10 days. Each patient received active drug and placebo matched for the comparator. For the 366 patients who were evaluated for clinical efficacy at the Day 12 visit, the clinical success rate (i. , cure plus improvement) was 83% for azithromycin and 88% for the control agent. For the 362 patients who were evaluated at the Day 24-28 visit, the clinical success rate was 74% for azithromycin and 69% for the control agent. In the safety analysis of the above study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 10. 6% with azithromycin and 20. 0% with the control agent. The most common side effects were diarrhea/loose stools (5. 9% azithromycin vs. 6% control), vomiting (2. 1% azithromycin vs. 1% control), and rash (0. 0% azithromycin vs. 3% control). A double blind, controlled, randomized trial was performed at nine clinical centers. Pediatric patients from 6 months to 12 years of age were randomized 1:1 to treatment with either azithromycin (given at 30 mg/kg as a single dose on Day 1) or amoxicillin/clavulanate potassium (7:1), divided q12h for 10 days. Each child received active drug, and placebo matched for the comparator. Clinical response (Cure, Improvement, Failure) was evaluated at End of Therapy (Day 12-16) and Test of Cure (Day 28-32). Safety was evaluated throughout the trial for all treated subjects. For the 321 subjects who were evaluated at End of Treatment, the clinical success rate (cure plus improvement) was 87% for azithromycin, and 88% for the comparator. For the 305 subjects who were evaluated at Test of Cure, the clinical success rate was 75% for both azithromycin and the comparator. In the safety analysis, the incidence of treatment-related adverse events, primarily gastrointestinal, was 16. 8% with azithromycin, and 22. 5% with the comparator. The most common side effects were diarrhea (6. 4% with azithromycin vs. 7% with the comparator), vomiting (4% with each agent), rash (1. 7% with azithromycin vs. 2% with the comparator) and nausea (1. 2% with the comparator). In a non-comparative clinical and microbiological trial, 248 patients from 6 months to 12 years of age with documented acute otitis media were dosed with a single oral dose of azithromycin (30 mg/kg on Day 1). For the 240 patients who were evaluable for clinical modified Intent-to-Treat (MITT) analysis, the clinical success rate (i. , cure plus improvement) at Day 10 was 89% and for the 242 patients evaluable at Day 24-28, the clinical success rate (cure) was 85%. Presumed Bacteriologic Eradication Day 10 S. pneumoniae 70/76 (92%) 67/76 (88%) H. influenzae 30/42 (71%) 28/44 (64%) M. catarrhalis 10/10 (100%) 10/10 (100%) Overall 110/128 (86%) 105/130 (81%) In the safety analysis of this study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all the subjects treated was 12. The most common side effects were vomiting (5. 6%), diarrhea (3. 2%), and abdominal pain (1. In three double-blind controlled studies, conducted in the United States, azithromycin (12 mg/kg once a day for 5 days) was compared to penicillin V (250 mg three times a day for 10 days) in the treatment of pharyngitis due to documented Group A beta-hemolytic streptococci (GABHS or S. pyogenes Three U. Streptococcal Pharyngitis Studies Azithromycin vs. Penicillin V EFFICACY RESULTS Day 14 Day 30 Bacteriologic Eradication: Clinical Success (Cure plus improvement): Approximately 1% of azithromycin-susceptible S. pyogenes The incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 18% on azithromycin and 13% on penicillin. The most common side effects were diarrhea/loose stools (6% azithromycin vs. 2% penicillin), vomiting (6% azithromycin vs. 4% penicillin), and abdominal pain (3% azithromycin vs. 1% penicillin). In a randomized, double-blind controlled clinical trial of acute exacerbation of chronic bronchitis (AECB), azithromycin (500 mg once daily for 3 days) was compared with clarithromycin (500 mg twice daily for 10 days). The primary endpoint of this trial was the clinical cure rate at Day 21 to 24. For the 304 patients analyzed in the modified intent to treat analysis at the Day 21 to 24 visit, the clinical cure rate for 3 days of azithromycin was 85% (125/147) compared to 82% (129/157) for 10 days of clarithromycin. The following outcomes were the clinical cure rates at the Day 21 to 24 visit for the bacteriologically evaluable patients by pathogen: Pathogen Azithromycin (3 Days) Clarithromycin (10 Days) S. pneumoniae 29/32 (91%) 21/27 (78%) H. influenzae 12/14 (86%) 14/16 (88%) M. catarrhalis 11/12 (92%) 12/15 (80%) In the safety analysis of this study, the incidence of treatment-related adverse events, primarily gastrointestinal, were comparable between treatment arms (25% with azithromycin and 29% with clarithromycin). The most common side effects were diarrhea, nausea and abdominal pain with comparable incidence rates for each symptom of 5 to 9% between the two treatment arms. (See ADVERSE REACTIONS In a randomized, double-blind, double-dummy controlled clinical trial of acute bacterial sinusitis, azithromycin (500 mg once daily for 3 days) was compared with amoxicillin/clavulanate (500/125 mg t. for 10 days). Clinical response assessments were made at Day 10 and Day 28. The primary endpoint of this trial was prospectively defined as the clinical cure rate at Day 28. For the 594 patients analyzed in the modified intent to treat analysis at the Day 10 visit, the clinical cure rate for 3 days of azithromycin was 88% (268/303) compared to 85% (248/291) for 10 days of amoxicillin/clavulanate. For the 586 patients analyzed in the modified intent to treat analysis at the Day 28 visit, the clinical cure rate for 3 days of azithromycin was 71. 5% (213/298) compared to 71. 5% (206/288), with a 97. 5% confidence interval of -8. 3, for 10 days of amoxicillin/clavulanate. In the safety analysis of this study, the overall incidence of treatment-related adverse events, primarily gastrointestinal, was lower in the azithromycin treatment arm (31%) than in the amoxicillin/clavulanate arm (51%). The most common side effects were diarrhea (17% in the azithromycin arm vs. 32% in the amoxicillin/clavulanate arm), and nausea (7% in the azithromycin arm vs. 12% in the amoxicillin/clavulanate arm). (See ADVERSE REACTIONS In an open label, noncomparative study requiring baseline transantral sinus punctures the following outcomes were the clinical success rates at the Day 7 and Day 28 visits for the modified intent to treat patients administered 500 mg of azithromycin once daily for 3 days with the following pathogens: Azithromycin (500 mg per day for 3 Days) Pathogen Day 7 Day 28 S. pneumoniae 23/26 (88%) 21/25 (84%) H. influenzae 28/32 (87%) 24/32 (75%) M. catarrhalis 14/15 (93%) 13/15 (87%) The overall incidence of treatment-related adverse events in the noncomparative study was 21% in modified intent to treat patients treated with azithromycin at 500 mg once daily for 3 days with the most common side effects being diarrhea (9%), abdominal pain (4%) and nausea (3%). (See ADVERSE REACTIONS.
Protocol 1
In a double-blind, controlled clinical study of acute otitis media performed in the United States, azithromycin (10 mg/kg on Day 1 followed by 5 mg/kg on Days 2-5) was compared to amoxicillin/clavulanate potassium (4:1). For the 553 patients who were evaluated for clinical efficacy, the clinical success rate (i.e., cure plus improvement) at the Day 11 visit was 88% for azithromycin and 88% for the control agent. For the 521 patients who were evaluated at the Day 30 visit, the clinical success rate was 73% for azithromycin and 71% for the control agent. In the safety analysis of the above study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 9% with azithromycin and 31% with the control agent. The most common side effects were diarrhea/loose stools (4% azithromycin vs. 20% control), vomiting (2% azithromycin vs. 7% control), and abdominal pain (2% azithromycin vs. 5% control).
Protocol 2
In a non-comparative clinical and microbiologic trial performed in the United States, where significant rates of beta-lactamase producing organisms (35%) were found, 131 patients were evaluable for clinical efficacy. The combined clinical success rate (i.e., cure and improvement) at the Day 11 visit was 84% for azithromycin. For the 122 patients who were evaluated at the Day 30 visit, the clinical success rate was 70% for azithromycin. Microbiologic determinations were made at the pre-treatment visit. Microbiology was not reassessed at later visits. The following presumptive bacterial/clinical cure outcomes (i.e., clinical success) were obtained from the evaluable group: Presumed Bacteriologic Eradication Day 11 Azithromycin Day 30 Azithromycin S. pneumoniae 61/74 (82%) 40/56 (71%) H. influenzae 43/54 (80%) 30/47 (64%) M. catarrhalis 28/35 (80%) 19/26 (73%) S. pyogenes 11/11 (100%) 7/7 Overall 177/217 (82%) 97/137 (73%) In the safety analysis of this study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 9%. The most common side effect was diarrhea (4%).
Protocol 3
In another controlled comparative clinical and microbiologic study of otitis media performed in the United States, azithromycin was compared to amoxicillin/clavulanate potassium (4:1). This study utilized two of the same investigators as Protocol 2 (above), and these two investigators enrolled 90% of the patients in Protocol 3. For this reason, Protocol 3 was not considered to be an independent study. Significant rates of beta-lactamase producing organisms (20%) were found. Ninety-two (92) patients were evaluable for clinical and microbiologic efficacy. The combined clinical success rate (i.e., cure and improvement) of those patients with a baseline pathogen at the Day 11 visit was 88% for azithromycin vs. 100% for control; at the Day 30 visit, the clinical success rate was 82% for azithromycin vs. 80% for control. Microbiologic determinations were made at the pre-treatment visit. Microbiology was not reassessed at later visits. At the Day 11 and Day 30 visits, the following presumptive bacterial/clinical cure outcomes (i.e., clinical success) were obtained from the evaluable group: Presumed Bacteriologic Eradication Day 11 Day 30 Azithromycin Control Azithromycin Control S. pneumoniae 25/29 (86%) 26/26 (100%) 22/28 (79%) 18/22 (82%) H. influenzae 9/11 (82%) 9/9 8/10 (80%) 6/8 M. catarrhalis 7/7 5/5 5/5 2/3 S. pyogenes 2/2 5/5 2/2 4/4 Overall 43/49 (88%) 45/45 (100%) 37/45 (82%) 30/37 (81%) In the safety analysis of the above study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 4% with azithromycin and 31% with the control agent. The most common side effect was diarrhea/loose stools (2% azithromycin vs. 29% control).
Protocol 4
In a double-blind, controlled, randomized clinical study of acute otitis media in pediatric patients from 6 months to 12 years of age, azithromycin (10 mg/kg per day for 3 days) was compared to amoxicillin/clavulanate potassium (7:1) in divided doses q12h for 10 days. Each patient received active drug and placebo matched for the comparator. For the 366 patients who were evaluated for clinical efficacy at the Day 12 visit, the clinical success rate (i.e., cure plus improvement) was 83% for azithromycin and 88% for the control agent. For the 362 patients who were evaluated at the Day 24-28 visit, the clinical success rate was 74% for azithromycin and 69% for the control agent. In the safety analysis of the above study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all patients treated was 10.6% with azithromycin and 20.0% with the control agent. The most common side effects were diarrhea/loose stools (5.9% azithromycin vs. 14.6% control), vomiting (2.1% azithromycin vs. 1.1% control), and rash (0.0% azithromycin vs. 4.3% control).
Protocol 5
A double blind, controlled, randomized trial was performed at nine clinical centers. Pediatric patients from 6 months to 12 years of age were randomized 1:1 to treatment with either azithromycin (given at 30 mg/kg as a single dose on Day 1) or amoxicillin/clavulanate potassium (7:1), divided q12h for 10 days. Each child received active drug, and placebo matched for the comparator. Clinical response (Cure, Improvement, Failure) was evaluated at End of Therapy (Day 12-16) and Test of Cure (Day 28-32). Safety was evaluated throughout the trial for all treated subjects. For the 321 subjects who were evaluated at End of Treatment, the clinical success rate (cure plus improvement) was 87% for azithromycin, and 88% for the comparator. For the 305 subjects who were evaluated at Test of Cure, the clinical success rate was 75% for both azithromycin and the comparator. In the safety analysis, the incidence of treatment-related adverse events, primarily gastrointestinal, was 16.8% with azithromycin, and 22.5% with the comparator. The most common side effects were diarrhea (6.4% with azithromycin vs. 12.7% with the comparator), vomiting (4% with each agent), rash (1.7% with azithromycin vs. 5.2% with the comparator) and nausea (1.7% with azithromycin vs. 1.2% with the comparator).
Protocol 6
In a non-comparative clinical and microbiological trial, 248 patients from 6 months to 12 years of age with documented acute otitis media were dosed with a single oral dose of azithromycin (30 mg/kg on Day 1). For the 240 patients who were evaluable for clinical modified Intent-to-Treat (MITT) analysis, the clinical success rate (i.e., cure plus improvement) at Day 10 was 89% and for the 242 patients evaluable at Day 24-28, the clinical success rate (cure) was 85%. Presumed Bacteriologic Eradication Day 10 S. pneumoniae 70/76 (92%) 67/76 (88%) H. influenzae 30/42 (71%) 28/44 (64%) M. catarrhalis 10/10 (100%) 10/10 (100%) Overall 110/128 (86%) 105/130 (81%) In the safety analysis of this study, the incidence of treatment-related adverse events, primarily gastrointestinal, in all the subjects treated was 12.1%. The most common side effects were vomiting (5.6%), diarrhea (3.2%), and abdominal pain (1.6%).

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