Prescription Drugs

CLINICAL PHARMACOLOGY Mechanism Of Action Azithromycin is a macrolide antibacterial drug. [See Microbiology] Pharmacodynamics Cardiac Electrophysiology 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. Pharmacokinetics Zmax is an extended-release microsphere formulation. Based on data obtained from studies evaluating the pharmacokinetics of azithromycin in healthy adult subjects a higher peak serum concentration (Cmax) and greater systemic exposure (AUC 0-24) of azithromycin are achieved on the day of dosing following a single 2 g dose of Zmax versus 1.5 g of azithromycin tablets administered over 3 days (500 mg/day) or 5 days (500 mg on day 1, 250 mg/day on days 2-5) [Table 2]. Consequently, due to these different pharmacokinetic profiles, Zmax is not interchangeable with azithromycin tablet 3-day and 5-day dosing regimens. Table 2: Mean (SD) Pharmacokinetic Parameters for Azithromycin on Day 1 Following the Administration of a Single Dose of 2 g Zmax or 1.5 g of Azithromycin Tablets Given over 3 Days (500 mg/day) or 5 Days (500 mg on Day 1 and 250 mg on Days 2-5) to Healthy Adult Subjects Pharmacokinetic Parameter Azithromycin Regimen Zmax [N=4]† 3-day ‡ [N=12] 5-day‡ [N=12] Cmax (mcg/mL) 0.821 (0.281) 0.441 (0.223) 0.434 (0.202) Tmax§ (hr) 5.0 (2.0-8.0) 2.5 (1.0-4.0) 2.5 (1.0-6.0) AUC0-24 (mcg•hr/mL) 8.62 (2.34) 2.58 (0.84) 2.60 (0.71) AUC0-∞ (mcg•hr/mL) 20.0 (6.66) 17.4 (6.2) 14.9 (3.1) t½ (hr) 58.8 (6.91) 71.8 (14.7) 68.9 (13.8) * Zmax, 3-day and 5-day regimen parameters obtained from separate pharmacokinetic studies † N = 21 for AUC0-∞ and t½ ‡ Cmax, Tmax and AUC0-24 values for Day 1 only § Median (range) ¶Total AUC for the 1-day, 3-day and 5-day regimens SD = standard deviation Cmax = maximum serum concentration Tmax = time to Cmax AUC = area under concentration vs. time curve t½ = terminal serum half-life Absorption The bioavailability of Zmax relative to azithromycin immediate release (IR) (powder for oral suspension) was 83%. On average, peak serum concentrations were achieved approximately 2.5 hr later following Zmax administration and were lower by 57%, compared to 2 g azithromycin IR. Thus, single 2 g doses of Zmax and azithromycin IR are not bioequivalent and are not interchangeable. Effect of food on absorption: A high-fat meal increased the rate and extent of absorption of a 2 g dose of Zmax (115% increase in Cmax, and 23% increase in AUC0-72) compared to the fasted state. A standard meal also increased the rate of absorption (119% increase in Cmax) and with less effect on the extent of absorption (12% increase in AUC0-72) compared to administration of a 2 g Zmax dose in the fasted state. Effect of antacids: Following the administration of Zmax with an aluminum and magnesium hydroxide antacid, the rate and extent of azithromycin absorption were not altered. Distribution The serum protein binding of azithromycin is concentration dependent, decreasing from 51% at 0.02 mcg/mL to 7% at 2 mcg/mL. Following oral administration, azithromycin is widely distributed throughout the body with an apparent steady-state volume of distribution of 31.1 L/kg. Azithromycin concentrates in fibroblasts, epithelial cells, macrophages, and circulating neutrophils and monocytes. Higher azithromycin concentrations in tissues than in plasma or serum have been observed. White blood cell and lung exposure data in humans following a single 2 g dose of Zmax in adults are shown in Table 3. Following a 2 g single dose of Zmax, azithromycin achieved higher exposure (AUC0-120) in mononuclear leukocytes (MNL) and polymorphonuclear leukocytes (PMNL) than in serum. The azithromycin exposure (AUC0-72) in lung tissue and alveolar cells (AC) was approximately 100 times that in serum; and the exposure in epithelial lining fluid (ELF) was also higher (approximately 2-3 times) than in serum. The clinical significance of this distribution data is unknown. Table 3: Azithromycin Exposure Data in White Blood Cells and Lung Following a 2 g SingleDose of Zmax in Adults A single 2 g dose of Zmax WBC Cmax (mcg/mL) AUC0-24 (mcg•hr/mL) AU C0-120 (mcg• hr/mL) Ct=120† (mcg/mL) MNL‡ 116 (40.2) 1790 (540) 4710 (1100) 16.2 (5.51) PMNL‡ 146 (66.0) 2080 (650) 10000 (2690) 81.7 (23.3) LUNG Cmax (mcg/mL) AUC0-24 (mcg•hr/mL) AUC0-72 (mcg•hr/mL) ALVEOLAR CELL¶ 669 7028 20403 - ELF¶ 3.2 17.6 131 - Cmax (mcg/g) AUC0-24 (mcg•hr/g) AUC0-72 (mcg•hr/g) LUNG TISSUE¶ 37.9 505 1693 - Abbreviation: WBC: white blood cells; MNL: mononuclear leukocytes; PMNL: polymorphonuclear leukocytes; ELF: Epithelial lining fluid † Azithromycin concentration at 120 hr after the start of dosing ‡ Data are presented as mean (standard deviation) ¶Cmax and AUC were calculated based on composite profile (n = 4 subjects/time point/formulation). Following a regimen of 500 mg of azithromycin tablets 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. Metabolism In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed. Excretion Serum azithromycin concentrations following a single 2 g dose of Zmax declined in a polyphasic pattern with a terminal elimination half-life of 59 hr. The prolonged terminal half-life is thought to be due to a large apparent volume of distribution. 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. Specific Populations Renal Insufficiency Azithromycin pharmacokinetics were investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1.0 g dose of azithromycin (4 × 250 mg capsules), the mean Cmax and AUC0-120 were 5.1% and 4.2% higher, respectively in subjects with GFR 10 to 80 mL/min compared to subjects with normal renal function (GFR > 80 mL/min). The mean Cmax and AUC0-120 were 61% and 35% higher, respectively in subjects with GFR < 10 mL/min compared to subjects with normal renal function. [See Use in Specific Populations, Renal Impairment] Hepatic Insufficiency The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established. Pediatric Patients The pharmacokinetics of azithromycin were characterized following a single 60 mg/kg dose of Zmax in pediatric patients aged 3 months to 16 years. Although there was high inter-patient variability in systemic exposure (AUC and Cmax) across the age groups studied, individual azithromycin AUC and Cmax values in pediatric patients were comparable to or higher than those following administration of 2 g Zmax in adults (Table 4). [See Use in Specific Populations] Table 4: Mean (SD) Pharmacokinetic Parameters for Azithromycin Following Administration of a Single Dose of Zmax (60 mg/kg, maximum dose of 2 g) to Pediatric Subjects Aged 3 Months to 16 Years Treatment Group Pharmacokinetic Parameters Cmax (mcg/mL) T* max (hr) AUC(0-24) (mcg•hr/mL ) AUC(0-∞) (mcg•hr/mL ) Group 1 (N = 6) [3 to 18 months] 0.74 (0.20) 3 (3-3) 6.29 (1.17) 14.1 (2.16) (n = 3) Group 2† (N = 6) [ > 18 to 36 months] 1.88†(0.50) 3 (3-3) 19.7f (5.35) 37.3 (12.9) (n = 5) Group 3 (N = 6) [ > 36 to 48 months] 1.23 (0.42) 3 (3-6) 12.9 (3.79) 22.4 (5.96) Group 4 (N = 6) [ > 48 months to 8 years] 1.13 (0.34) 3 (3-6) 13.0 (4.21) 22.2 (6.89) Group 5 (N = 6) [ > 8 to 12 years] 1.65 (0.38) 3 (3-6) 16.0 (4.99) 30.1 (10.7) Group 6 (N = 6) [ > 12 to 16 years] 0.98 (0.35) 3 (3-6) 11.0 (4.78) 21.3 (9.37) Pooled 1-6 (N = 36) [On an empty stomach] 1.27 (0.53) 3 (3-6) 13.1 (5.78) 25.2 (10.7) (n = 32) Group 7‡ (N = 7) [Fed; 18 months to 8 years] 1.41 (0.62) 3 (1.5-3.1) 7.43 (3.00) 18.9 (3.57) (n = 3) Empty stomach = dosed with Zmax at least 1 hr before or 2 hr after a meal (Groups I-VI) Fed = dosed with Zmax within 5 minutes of consuming an age-appropriate high-fat breakfast (Group VII) * Median (range) presented only for Tmax † High mean values were driven by 2 subjects with high exposure ‡ One subject vomited immediately after dosing and discontinued from the study Gender The impact of gender on the pharmacokinetics of azithromycin has not been evaluated for Zmax. However, previous studies have demonstrated no significant differences in the disposition of azithromycin between male and female subjects. Pharmacokinetic Interaction Studies A drug interaction study was performed with Zmax and antacids. All other drug interaction studies were performed with azithromycin immediate release (IR) formulations (capsules and tablets, doses ranging from 500 to 1200 mg) and other drugs likely to be co-administered. The effects of coadministration of azithromycin on the pharmacokinetics of other drugs are shown in Table 5 and the effects of other drugs on the pharmacokinetics of azithromycin are shown in Table 6. When used at therapeutic doses, azithromycin IR had a minimal effect on the pharmacokinetics of atorvastatin, carbamazepine, cetirizine, didanosine, efavirenz, fluconazole, indinavir, midazolam, nelfinavir, sildenafil, theophylline (intravenous and oral), triazolam, trimethoprim/sulfamethoxazole or zidovudine (Table 5). Although the drug interaction studies were not conducted with Zmax, similar modest effect as observed with IR formulation are expected since the total exposure to azithromycin is comparable for Zmax and other azithromycin IR regimens. Therefore, no dosage adjustment of drugs listed in Table 5 is recommended when co-administered with Zmax. Nelfinavir significantly increased the Cmax and AUC of azithromycin following co-administration with azithromycin IR 1200 mg (Table 6). However, no dose adjustment of azithromycin is recommended when Zmax is co-administered with nelfinavir. Pharmacokinetic and/or pharmacodynamic 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, pharmacokinetic and/or pharmacodynamic interactions with these drugs have been observed with other macrolide products. Until further data are developed, careful monitoring of patients is advised when azithromycin and these drugs are used concomitantly: digoxin, ergotamine or dihydroergotamine, cyclosporine, hexobarbital and phenytoin. Table 5: Drug Interactions: Pharmacokinetic Parameters of Co-administered Drugs in the Presence of Azithromycin Co-administered Drug Dose of Coadministered Drug Dose of Azithromycin* n Ratio (with/without Azithromycin) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Mean Cmax Mean AUC Atorvastatin 10 mg/day for 8 days 500 mg/day orally on days 6-8 12 0.83 (0.63 to 1.08) 1.01 (0.81 to 1.25) Carbamazepine 200 mg/day for 2 days, then 200 mg twice a day for 18 days 500 mg/day orally for days 16-18 7 0.97 (0.88 to 1.06) 0.96 (0.88 to 1.06) Cetirizine 20 mg/day for 11 days 500 mg orally on day 7, then 250 mg/day on days 8-11 14 1.03 (0.93 to 1.14) 1.02 (0.92 to 1.13) Didanosine 200 mg orally twice a day for 21 days 1,200 mg/day orally on days 8-21 6 1.44 (0.85 to 2.43) 1.14 (0.83 to 1.57) Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.04† 0.95† Fluconazole 200 mg orally single dose 1,200 mg orally single dose 18 1.04 (0.98 to 1.11) 1.01 (0.97 to 1.05) Indinavir 800 mg three times a day for 5 days 1,200 mg orally on day 5 18 0.96 (0.86 to 1.08) 0.90 (0.81 to 1.00) Midazolam 15 mg orally on day 3 500 mg/day orally for 3 days 12 1.27 (0.89 to 1.81) 1.26 (1.01 to 1.56) Nelfinavir 750 mg three times a day for 11 days 1,200 mg orally on day 9 14 0.90 (0.81 to 1.01) 0.85 (0.78 to 0.93) Sildenafil 100 mg on days 1 and 4 500 mg/day orally for 3 days 12 1.16 (0.86 to 1.57) 0.92 (0.75 to 1.12) Theophylline 4 mg/kg IV on days 1, 11, 25 500 mg orally on day 7, then 250 mg/day on days 8-11 10 1.19 (1.02 to 1.40) 1.02 (0.86 to 1.22) Theophylline 300 mg orally twice a day for 15 days 500 mg orally on day 6, then 250 mg/day on days 7-10 8 1.09 (0.92 to 1.29) 1.08 (0.89 to 1.31) Triazolam 0.125 mg on day 2 500 mg orally on day 1, then 250 mg/day on day 2 12 1.06† 1.02† Trimethoprim/ Sulfamethoxazole 160 mg/800 mg/d ay orally for 7 days 1,200 mg orally on day 7 12 0.85 (0.75 to 0.97)/ 0.90 (0.78 to 1.03) 0.87 (0.80 to 0.95)/ 0.96 (0.88 to 1.03) Zidovudine 500 mg/day orally for 21 days 600 mg/day oraly for 14 days 5 1.12 (0.42 to 3.02) 0.94 (0.52 to 1.70) Zidovudine 500 mg/day orally for 21 days 1,200 mg/day orally for 14 days 4 1.31 (0.43 to 3.97) 1.30 (0.69 to 2.43) * Refers to azithromycin capsules and tablets unless specified † 90% confidence interval not reported Table 6: Drug Interactions: Pharmacokinetic Parameters of Azithromycin in the Presence of Coadministered Drugs Co-administered Drug Dose of Coadministered Drug Dose of Azithromycin* n Ratio (with/without co-administered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Mean Cmax Mean AUC Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.22 (1.04 to 1.42) 0.92† Fluconazole 200 mg orally single dose 1,200 mg orally single dose 18 0.82 (0.66 to 1.02) 1.07 (0.94 to 1.22) Nelfinavir 750 mg three times a day 11 days 1,200 mg orally on day 9 14 2.36 (1.77 to 3.15) 2.12 (1.80 to 2.50) Aluminum and Magnesium hydroxide 20 mL regular strength, single dose 2 g Zmax, single dose 39 0.99 (0.93 to 1.06) 0.99 (0.92 to 1.08) * Refers to azithromycin capsules and tablets unless specified † 90% confidence interval not reported Microbiology Mechanism Of Action Azithromycin binds to the 23S rRNA of the 50S ribosomal subunit and interferes with bacterial protein synthesis by impeding the assembly of the 50S ribosomal subunit. Resistance Azithromycin demonstrates cross resistance with erythromycin. The most frequently encountered mechanism of resistance to azithromycin is modification of the 23S rRNA target, most often by methylation. Ribosomal modifications can determine cross resistance to other macrolides, lincosamides and streptogramin B (MLSB phenotype). Azithromycin has been shown to be active against the following microorganisms, both in vitro and in clinical infections. [See INDICATIONS AND USAGE]. Gram-Positive Bacteria Streptococcus pneumoniae Gram-Negative Bacteria Haemophilus influenzae Moraxella catarrhalis “Other” Bacteria Chlamydophila pneumoniae Mycoplasma pneumoniae Susceptibility Testing Methods When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment. Dilution Techniques Quantitative methods are used to determine minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method1,3,4 (broth or agar). The MIC values should be interpreted according to criteria provided in Table 7. Diffusion Techniques Quantitative methods that require measurement of zone diameters can provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized method2,3,4. This procedure uses paper disk impregnated with 15 mcg azithromycin to test the susceptibility of bacteria to azithromycin. The disk diffusion interpretive criteria are provided in Table 7. Table 7: Susceptibility Interpretive Criteria for Azithromycin Pathogen Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameter in mm) S I R S I R Haemophilus influenzae* ≤ 4 - - ≥ 12 - - Moraxella catarrhalis* ≤ 0.25 - - ≥ 26 - - Streptococcus pneumoniae ≤ 0.5 1 ≥ 2 ≥ 18 14-17 ≤ 13 * Insufficient information is available to determine Intermediate or Resistant interpretive criteria A report of “Susceptible” (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration at the site of infection. A report of “Intermediate” (I) 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. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentrations usually achievable at the infection site; other therapy should be selected. Quality Control 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 individuals performing the test 1,2,3,4. Standard azithromycin powder should provide the following range of MIC values provided in Table 8. For the diffusion technique using the 15-mcg azithromycin disk the criteria provided in Table 8 should be achieved. Table 8: Acceptable Quality Control Ranges for Susceptibility Testing Quality Control Organism Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameters in mm) Haemophilus Influenzae ATCC 49247 1-4 13-21 Staphylococcus aureus ATCC 25923 Not Applicable 21-26 Staphylococcus aureus ATCC 29213 0.5-2 Not Applicable Streptococcus pneumoniae ATCC 49619 0.06-0.25 19-25 ATCC = American Type Culture Collection Animal Toxicology And/Or Pharmacology 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/or pancreas) in dogs treated with azithromycin at doses which, expressed on the basis of mg/m² , are approximately one-sixth the recommended adult dose, and in rats treated at doses approximately one-fourth the recommended adult dose. This effect has been shown to be reversible after cessation of azithromycin treatment. Based on the pharmacokinetic data, phospholipidosis has been seen in the rat (50 mg/kg/day dose) at the observed maximal plasma concentration of 1.3 mcg/mL (1.6 times the observed Cmax of 0.821 mcg/mL at the adult dose of 2 g.). Similarly, it has been shown in the dog (10 mg/kg/day dose) at the observed maximal serum concentration of 1 mcg/mL (1.2 times the observed Cmax of 0.821 mcg/mL at the adult dose of 2 g). Phospholipidosis was also observed in neonatal rats dosed for 18 days at 30 mg/kg/day, which is less than the pediatric dose of 60 mg/kgbased on the surface area. It was not observed in neonatal rats treated for 10 days at 40 mg/kg/day with mean maximal serum concentrations of 1.86 mcg/mL, approximately 1.5 times the Cmax of 1.27 mcg/mL at the pediatric dose. Phospholipidosis has been observed in neonatal dogs (10 mg/kg/day) at maximum mean whole blood concentrations of 3.54 mcg/mL, approximately 3 times the pediatric dose Cmax. The significance of the finding for animals and for humans is unknown. Clinical Studies Acute Bacterial Maxillary Sinusitis Adult subjects with a diagnosis of acute bacterial maxillary sinusitis were evaluated in a randomized, double-blind, multicenter study; a maxillary sinus tap was performed on all subjects at baseline. Clinical evaluations were conducted for all subjects at the TOC visit, 7 to 14 days post-treatment. Two hundred seventy (270) subjects were treated with a single 2 g oral dose of Zmax and 268 subjects were treated with levofloxacin, 500 mg orally once daily for 10 days. A subject was considered a cure if signs and symptoms related to the acute infection had resolved, or if clinical improvement was such that no additional antibiotics were deemed necessary. The clinical response for the primary population, Clinical Per Protocol Subjects, is presented below. Table 9: Clinical Response in Patients with Acute Bacterial Maxillary Sinusitis RESPONSE AT TOC ZMAX N = 255 LEVOFLOXACIN N = 254 CURE 241 (94.5%) 236 (92.9%) FAILURE 14 (5.5%) 18 (7.1%) Clinical response by pathogen in the Bacteriologic Per Protocol population is presented below. Table 10: Clinical Response by Pathogen in Patients with Acute Bacterial Maxillary Sinusitis Pathogen Zmax Levofloxacin N Cure N Cure S. pneumoniae 37 36 (97.3%) 39 36 (92.3%) H. influenzae 27 26 (96.3%) 30 30 (100.0%) M. catarrhalis 8 8 (100.0%) 11 10 (90.9%) Community-Acquired Pneumonia Adult subjects with a diagnosis of mild-to-moderate community-acquired pneumonia were evaluated in two, randomized, double-blind, multicenter studies. In both studies, clinical and microbiologic evaluations were conducted for all subjects at the Test of Cure (TOC) visit, 7 to 14 days posttreatment. In Trial 1, 247 subjects were treated with a single 2 g oral dose of Zmax and 252 subjects were treated with clarithromycin extended-release, 1 g orally once daily for 7 days. In Trial 2, 211 subjects were treated with a single 2.0 g oral dose of Zmax and 212 subjects were treated with levofloxacin, 500 mg orally once daily for 7 days. A patient was considered a cure if signs and symptoms related to the acute infection had resolved, or if clinical improvement was such that no additional antibiotics were deemed necessary; in addition, the chest x-ray performed at the TOC visit was to be either improved or stable. The clinical response at TOC for the primary population, Clinical Per Protocol Subjects, is presented in the table below. Table 11: Clinical Response at Test of Cure (TOC) in Patients with Community-Acquired Pneumonia Zmax vs. Clarithromycin extended-release Zmax N=202 Comparator N=209 Cure 187 (92.6%) 198 (94.7%) Failure 15 (7.4%) 11 (5.3%) Zmax vs. Levofloxacin N=174 N=189 Cure 156 (89.7%) 177 (93.7%) Failure 18 (10.3%) 12 (6.3%) Clinical response by pathogen in the Bacteriologic Per Protocol population, across both studies, is presented below: Table 12: Clinical Response by Pathogen in Patients with Community-Acquired Pneumonia Pathogen Zmax Comparators N Cure N Cure S. pneumoniae 33 28 (84.8%) 39 35 (89.7%) H. influenzae 30 28 (93.3%) 34 31 (91.2%) C. pneumoniae 40 37 (92.5%) 53 50 (94.3%) M. pneumoniae 33 30 (90.9%) 39 38 (97.4%) REFERENCES 1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard -Tenth Edition. CLSI document M07-A10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015. 2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-Fifth Informational Supplement. CLSI document M100-S25, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015. 3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015. 4. Clinical and Laboratory Standards Institute (CLSI). Methods for Antimicrobial Dilution and Disk Susceptibility Testing for Infrequently Isolated or Fastidious Bacteria: Approved Guidelines—Second Edition. CLSI document M45-A2, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2010.

CLINICAL PHARMACOLOGY Mechanism Of Action Azithromycin is a macrolide antibacterial drug. [see Microbiology] Pharmacodynamics Based on animal models of infection, the antibacterial activity of azithromycin appears to correlate with the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) for certain pathogens (S. pneumoniae and S. aureus). The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with azithromycin. Cardiac Electrophysiology 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 oral 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. Since the mean Cmax of azithromycin following a 500 mg IV dose given over 1 hr is higher than the mean Cmax of azithromycin following the administration of a 1500 mg oral dose, it is possible that QTc may be prolonged to a greater extent with IV azithromycin at close proximity to a one hour infusion of 500 mg. Pharmacokinetics In patients hospitalized with community-acquired pneumonia receiving single daily one-hour intravenous infusions for 2 to 5 days of 500 mg azithromycin at a concentration of 2 mg/mL, the mean Cmax ± S.D. achieved was 3.63 ± 1.60 mcg/mL, while the 24-hour trough level was 0.20 ± 0.15 mcg/mL, and the AUC was 9.60 ± 4.80 mcg·hr/mL. The mean Cmax, 24-hour trough and AUC24 values were 1.14 ± 0.14 mcg/mL, 0.18 ± 0.02 mcg/mL, and 8.03 ±0.86 mcg•hr/mL, respectively, in normal volunteers receiving a 3-hour intravenous infusion of 500 mg azithromycin at a concentration of 1 mg/mL. Similar pharmacokinetic values were obtained in patients hospitalized with community-acquired pneumonia who received the same 3-hour dosage regimen for 2–5 days. Infusion Concentration, Duration Time after starting the infusion (hr) 0.5 1 2 3 4 6 8 12 24 2 mg/mL, 1 hr* 2.98 ± 1.12 3.63 ± 1.73 0.60 ± 0.31 0.40 ± 0.23 0.33 ± 0.16 0.26 ± 0.14 0.27± 0.15 0.20 ± 0.12 0.20 ± 0.15 1 mg/mL, 3 hr† 0.91 ± 0.13 1.02 ± 0.11 1.14 ± 0.13 1.13 ± 0.16 0.32 ± 0.05 0.28 ± 0.04 0.27± 0.03 0.22 ± 0.02 0.18 ± 0.02 * 500 mg (2 mg/mL) for 2–5 days in community-acquired pneumonia patients. † 500 mg (1 mg/mL) for 5 days in healthy subjects. Comparison of the plasma pharmacokinetic parameters following the 1st and 5th daily doses of 500 mg intravenous azithromycin showed only an 8% increase in Cmax but a 61% increase in AUC24 reflecting a threefold rise in C24 trough levels. Following single-oral doses of 500 mg azithromycin (two 250 mg capsules) to 12 healthy volunteers, Cmax, trough level, and AUC24 were reported to be 0.41 mcg/mL, 0.05 mcg/mL, and 2.6 mcg·hr/mL, respectively. These oral values are approximately 38%, 83%, and 52% of the values observed following a single 500-mg I.V. 3-hour infusion (Cmax: 1.08 mcg/mL, trough: 0.06 mcg/mL, and AUC24: 5.0 mcg·hr/mL). Thus, plasma concentrations are higher following the intravenous regimen throughout the 24-hour interval. Distribution The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 mcg/mL to 7% at 2 mcg/mL. Tissue concentrations have not been obtained following intravenous infusions of azithromycin, but following oral administration in humans azithromycin has been shown to penetrate into tissues, including skin, lung, tonsil, and cervix. Tissue levels were determined following a single oral dose of 500 mg azithromycin in 7 gynecological patients. Approximately 17 hr after dosing, azithromycin concentrations were 2.7 mcg/g in ovarian tissue, 3.5 mcg/g in uterine tissue, and 3.3 mcg/g in salpinx. Following a regimen of 500 mg on the first day followed by 250 mg daily for 4 days, concentrations in the cerebrospinal fluid were less than 0.01 mcg/mL in the presence of non-inflamed meninges. Metabolism In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed. Elimination Plasma concentrations of azithromycin following single 500 mg oral and IV doses declined in a polyphasic pattern with a mean apparent plasma clearance of 630 mL/min and terminal elimination halflife of 68 hr. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues. In a multiple-dose study in 12 normal volunteers utilizing a 500 mg (1 mg/mL) one-hour intravenousdosage regimen for five days, the amount of administered azithromycin dose excreted in urine in 24 hr was about 11% after the 1st dose and 14% after the 5th dose. These values are greater than the reported 6% excreted unchanged in urine after oral administration of azithromycin. Biliary excretion is a major route of elimination for unchanged drug, following oral administration. Specific Populations Renal Insufficiency Azithromycin pharmacokinetics were investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1,000 mg dose of azithromycin, mean Cmax and AUC0-120 increased by 5.1% and 4.2%, respectively in subjects with mild to moderate renal impairment (GFR 10 to 80 mL/min) compared to subjects with normal renal function (GFR > 80 mL/min). The mean C and AUC increased 61% and 35%, respectively in subjects with severe renal impairment (GFR < 10 mL/min) compared to subjects with normal renal function (GFR > 80 mL/min). Hepatic Insufficiency The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established. Gender There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended based on gender. Geriatric Patients Pharmacokinetic studies with intravenous azithromycin have not been performed in older volunteers. Pharmacokinetics of azithromycin following oral administration in older volunteers (65–85 years old) were similar to those in younger volunteers (18–40 years old) for the 5-day therapeutic regimen. [see Geriatric Use] Pediatric Patients Pharmacokinetic studies with intravenous azithromycin have not been performed in children. Drug-drug Interactions Drug interaction studies were performed with oral azithromycin and other drugs likely to be coadministered. The effects of co-administration of azithromycin on the pharmacokinetics of other drugs are shown in Table 1 and the effects 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 coadministered with azithromycin. Co-administration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the C and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2. [see DRUG INTERACTIONS] Table 1: Drug Interactions : Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin Co- administered Drug Dose of Coadministered Drug Dose of Azithromycin n Ratio (with/without azithromycin) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Mean Cmax Mean AUC Atorvastatin 10 mg/day for 8 days 500 mg/day orally on days 68 12 0.83 (0.63 to 1.08) 1.01 (0.81 to 1.25) Carbamazepine 200 mg/day for 2 days, then 200 mg twice a day for 18 days 500 mg/day orally for days 16-18 7 0.97 (0.88 to 1.06) 0.96 (0.88 to 1.06) Cetirizine 20 mg/day for 11 days 500 mg orally on day 7, then 250 mg/day on days 8-11 14 1.03 (0.93 to 1.14) 1.02 (0.92 to 1.13) Didanosine 200 mg orally twice a day for 21 days 1,200 mg/day orally on days 8-21 6 1.44 (0.85 to 2.43) 1.14 (0.83 to 1.57) Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.04* 0.95* Fluconazole 200 mg orally single dose 1,200 mg orally single dose 18 1.04 (0.98 to 1.11) 1.01 (0.97 to 1.05) Indinavir 800 mg three times a day for 5 days 1,200 mg orally on day 5 18 0.96 (0.86 to 1.08) 0.90 (0.81 to 1.00) Midazolam 15 mg orally on day 3 500 mg/day orally for 3 days 12 1.27 (0.89 to 1.81) 1.26 (1.01 to 1.56) Nelfinavir 750 mg three times a day for 11 days 1,200 mg orally on day 9 14 0.90 (0.81 to 1.01) 0.85 (0.78 to 0.93) Sildenafil 100 mg on days 1 and 4 500 mg/day orally for 3 days 12 1.16 (0.86 to 1.57) 0.92 (0.75 to 1.12) Theophylline 4 mg/kg IV on days 1, 11, 25 500 mg orally on day 7, 250 mg/day on days 8-11 10 1.19 (1.02 to 1.40) 1.02 (0.86 to 1.22) Theophylline 300 mg orally BID *15 days 500 mg orally on day 6, then 250 mg/day on days 7-10 8 1.09 (0.92 to 1.29) 1.08 (0.89 to 1.31) Triazolam 0.125 mg on day 2 500 mg orally on day 1, then 250 mg/day on day 2 12 1.06* 1.02* Trimethoprim/ Sulfamethoxazole 160 mg/800 mg/day orally for 7 days 1,200 mg orally on day 7 12 0.85 (0.75 to 0.97)/ 0.90 (0.78 to 1.03) 0.87 (0.80 to 0.95/ 0.96 (0.88 to 1.03) Zidovudine 500 mg/day orally for 21 days 600 mg/day orally for 14 days 5 1.12 (0.42 to 3.02) 0.94 (0.52 to 1.70) Zidovudine 500 mg/day orally for 21 days 1,200 mg/day orally for 14 days 4 1.31 (0.43 to 3.97) 1.30 (0.69 to 2.43) *-90% Confidence interval not reported Table 2: Drug Interactions : Pharmacokinetic Parameters for Azithromycin in the Presence of Coadministered Drugs. [see DRUG INTERACTIONS] Co-administered Drug Dose of Coadministered Drug Dose of Azithromycin n Ratio (with/without co-administered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Mean Cmax Mean AUC Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.22 (1.04 to 1.42) 0.92* Fluconazole 200 mg orally single dose 1,200 mg orally single dose 18 0.82 (0.66 to 1.02) 1.07 (0.94 to 1.22) Nelfinavir 750 mg three times a day for 11 days 1,200 mg orally on day 9 14 2.36 (1.77 to 3.15) 2.12 (1.80 to 2.50) *- 90% Confidence interval not reported Microbiology Mechanism Of Action Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms and, thus, interfering with microbial protein synthesis. Nucleic acid synthesis is not affected. Cross Resistance Azithromycin demonstrates cross-resistance with erythromycin-resistant Gram-positive isolates. Azithromycin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical infections as described in [see INDICATIONS AND USAGE]. Gram-positive Bacteria Staphylococcus aureus Streptococcus pneumoniae Gram-negative Bacteria Haemophilus influenzae Moraxella catarrhalis Neisseria gonorrhoeae Legionella pneumophila Other Bacteria Chlamydophila pneumoniae Chlamydia trachomatis Mycoplasma hominis Mycoplasma pneumoniae The following in vitro data are available, but their clinical significance is unknown. Azithromycin exhibits in vitro minimal inhibitory concentrations (MICs) of 2.0 mcg/mL or less against most ( ≥ 90%) isolates of the following bacteria; however, the safety and effectiveness of azithromycin in treating clinical infections due to these bacteria have not been established in adequate and well-controlled trials. Aerobic Gram-positive Bacteria Streptococci (Groups C, F, G) Viridans group streptococci Gram-negative Bacteria Bordetella pertussis Anaerobic Bacteria Peptostreptococcus species Prevotella bivia Other Bacteria Ureaplasma urealyticum Susceptibility Testing Methods When available, clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antimicrobial products used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment. Dilution Techniques Quantitative methods are used to determine minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method1,2 (broth, and/or agar). The MIC values should be interpreted according to criteria provided in Table 3. Diffusion Techniques Quantitative methods that require measurement of zone diameters can provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size provides an estimate of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using standardized methods2,3. This procedure uses paper disk impregnated with 15 mcg azithromycin to test the susceptibility of bacteria to azithromycin. The disk diffusion interpretive criteria are provided in Table 3. Table 3: Susceptibility Interpretive Criteria for Azithromycin Pathogen Minimum Inhibitory Concentrations ( mcg/mL) Disk Diffusion (zone diameters in mm) S I R S I R Haemophilus influenzae.* ≤ 4 -- -- ≥ 12 -- -- Staphylococcus aureus ≤ 2 4 > 8 ≥ 18 14-17 ≤ 13 Streptococci including S. pneumoniae ≤ 0.5 1 > 2 ≥ 18 14-17 ≤ 13 *Insufficient information is available to determine Intermediate or Resistant interpretive criteria A report of “Susceptible” indicates that the pathogen is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentration at the infection site necessary to inhibit growth of the pathogen. 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. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected. Quality Control 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 individuals performing the test1,2,3. Standard azithromycin powder should provide the following range of MIC values provided in Table 4. For the diffusion technique using the 15-mcg azithromycin disk the criteria provided in Table 4 should be achieved. Table 4: Acceptable Quality Control Ranges for Susceptibility Testing Quality Control Organism Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameters in mm) Staphylococcus aureus ATCC 25923 Not Applicable 21-26 Staphylococcus aureus ATCC 29213 0.5-2 Not Applicable Haemophilus Influenzae ATCC 49247 1-4 13-21 Streptococcus pneumoniae ATCC 49619 0.06-0.25 19-25 ATCC = American Type Culture Collection The ability to correlate MIC values and plasma drug levels is difficult as azithromycin concentrates in macrophages and tissues. [see CLINICAL PHARMACOLOGY] Animal Toxicology And/Or Pharmacology Phospholipidosis (intracellular phospholipid accumulation) has been observed in some tissues of mice, rats, and dogs given multiple oral doses of azithromycin. It has been demonstrated in numerous organ systems (e.g., eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and/or pancreas) in dogs and rats treated with azithromycin at doses which, expressed on the basis of body surface area, are similar to or less than the highest recommended adult human dose. This effect has been shown to be reversible after cessation of azithromycin treatment. Based on the pharmacokinetic data, phospholipidosis has been seen in the rat (50 mg/kg/day dose) at the observed maximal plasma concentration of 1.3 mcg/mL (1.6 times the observed Cmax of 0.821 mcg /mL at the adult dose of 2 g.) Similarly, it has been shown in the dog (10 mg/kg/day dose) at the observed maximal serum concentration of 1 mcg /mL (1.2 times the observed Cmax of 0.821 mcg /mL at the adult dose of 2 g). Phospholipidosis was also observed in neonatal rats dosed for 18 days at 30 mg/kg/day, which is less than the pediatric dose of 60 mg/kg based on body surface area. It was not observed in neonatal rats treated for 10 days at 40 mg/kg/day with mean maximal serum concentrations of 1.86 mcg /ml, approximately 1.5 times the Cmax of 1.27 mcg/ml at the pediatric dose. Phospholipidosis has been observed in neonatal dogs (10 mg/kg/day) at maximum mean whole blood concentrations of 3.54 mcg /ml, approximately 3 times the pediatric dose Cmax. The significance of the findings for animals and for humans is unknown. Clinical Studies Community-Acquired Pneumonia In a controlled trial of community-acquired pneumonia performed in the U.S., azithromycin (500 mg as a single daily dose by the intravenous route for 2 to 5 days, followed by 500 mg/day by the oral route to complete 7 to 10 days therapy) was compared to cefuroxime (2250 mg/day in three divided doses by the intravenous route for 2 to 5 days followed by 1000 mg/day in two divided doses by the oral route to complete 7 to 10 days therapy), with or without erythromycin. For the 291 patients who were evaluable for clinical efficacy, the clinical outcome rates, i.e., cure, improved, and success (cure + improved) among the 277 patients seen at 10 to 14 days post-therapy were as follows: Clinical Outcome Azithromycin Comparator Cure 46% 44% Improved 32% 30% Success (Cure + Improved) 78% 74% In a separate, uncontrolled clinical and microbiological trial performed in the U.S., 94 patients with community-acquired pneumonia who received azithromycin in the same regimen were evaluable for clinical efficacy. The clinical outcome rates, i.e., cure, improved, and success (cure + improved) among the 84 patients seen at 10 to 14 days post-therapy were as follows: Clinical Outcome Azithromycin Cure 60% Improved 29% Success (Cure + Improved) 89% Microbiological determinations in both trials were made at the pre-treatment visit and, where applicable, were reassessed at later visits. Serological testing was done on baseline and final visit specimens. The following combined presumptive bacteriological eradication rates were obtained from the evaluable groups: Combined Bacteriological Eradication Rates for Azithromycin: (at last completed visit) Azithromycin S. pneumonia 64/67 (96%)* H. influenzae 41/43 (95%) M. catarrhalis 9/10 (90%) S. aureus 9/10 (90%) *Nineteen of twenty-four patients (79%) with positive blood cultures for S. pneumoniae were cured (intent-to-treat analysis) with eradication of the pathogen. The presumed bacteriological outcomes at 10 to 14 days post-therapy for patients treated with azithromycin with evidence (serology and/or culture) of atypical pathogens for both trials were as follows: Evidence of Infection Total Cure Improved Cure + Improved Mycoplasma pneumoniae 18 11 (61%) 5 (28%) 16 (89%) Chlumyuiu pneumoniae 34 15 (44%) 13 (38%) 28 (82%) Legionella pneumophila 16 5 (31%) 8 (50%) 13 (81%) REFERENCES 1. Clinical and Laboratory Standards Institute (CLSI) Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically: Approved Standard-Ninth Edition. CLSI Document M07-A9. CLSI, 950 West Valley Rd., Suite 2500, Wayne, PA 19087, 2012. 2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement, CLSI document M100-S23. CLSI document M100-S23, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013. 3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.

CLINICAL PHARMACOLOGY Mechanism Of Action Azithromycin is a macrolide antibacterial drug. [see Microbiology] Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. Using such methodology, the ratio of intracellular to extracellular concentration was > 30 after one hr of incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. Pharmacodynamics Based on animal models of infection, the antibacterial activity of azithromycin appears to correlate with the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) for certain pathogens (S. pneumoniae and S. aureus). The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with azithromycin. Cardiac Electrophysiology 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 oral azithromycin (500 mg, 1000 mg, and 1500 mg once daily). Coadministration 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. Pharmacokinetics The pharmacokinetic parameters of azithromycin in plasma after dosing as per labeled recommendations in healthy young adults and asymptomatic HIV-positive adults (age 18-40 years old) are portrayed in the following chart: MEAN (CV%) PK PARAMETER DOSE/DOSAGE FORM (serum, except as indicated) Subjects Day No. Cmax (mcg/mL) Tmax (hr) C24 (mcg/mL) AUC (mcg•hr/mL) T½ (hr) Urinary Excretion (% of dose) 500 mg/250 mg capsule 12 1 0.41 2.5 0.05 2.6a - 4.5 and 250 mg on Days 2-5 12 5 0.24 3.2 0.05 2.1a - 6.5 1200 mg/600 mg tablets 12 1 0.66 2.5 0.074 6.8b 40 - %CV (62%) (79%) (49%) (64%) (33%) 600 mg tablet/day 7 1 0.33 2.0 0.039 2.4a %CV 25% (50%) (36%) (19%) 7 22 0.55 2.1 0.14 5.8a 84.5 - %CV (18%) (52%) (26%) (25%) - 600 mg tablet/day (leukocytes) 7 22 252 10.9 146 4763a 82.8 - %CV (49%) (28%) (33%) (42%) - - aAUC0-24; b0-last. With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2-5, Cmin and Cmax remained essentially unchanged from Day 2 through Day 5 of therapy. However, without a loading dose, azithromycin Cmin levels required 5 to 7 days to reach steady state. In asymptomatic HIV-positive adult subjects receiving 600 mg ZITHROMAX tablets once daily for 22 days, steady state azithromycin serum levels were achieved by Day 15 of dosing. The high values in adults for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 mL/min) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues. Absorption The 1 gram single-dose packet is bioequivalent to four 250 mg azithromycin capsule When the oral suspension of azithromycin was administered with food, the Cmax increased by 46% and the AUC by 14%. The absolute bioavailability of two 600 mg tablets was 34% (CV=56%). Administration of two 600 mg tablets with food increased Cmax by 31% (CV=43%) while the extent of absorption (AUC) was unchanged (mean ratio of AUCs=1.00; CV=55%). Distribution The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 μg/mL to 7% at 2 μg/mL. The antibacterial 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. Azithromycin has been shown to penetrate into tissues in humans, including skin, lung, tonsil, and cervix. 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 oral administration of a single 1200 mg dose (two 600 mg tablets), the mean maximum concentration in peripheral leukocytes was 140 μg/mL. Concentration remained above 32 μg/mL, for approximately 60 hr. The mean half-lives for 6 males and 6 females were 34 hr and 57 hr, respectively. Leukocyte-to-plasma Cmax ratios for males and females were 258 (±77%) and 175 (±60%), respectively, and the AUC ratios were 804 (±31%) and 541 (±28%) respectively. The clinical relevance of these findings is unknown. Following oral administration of multiple daily doses of 600 mg (1 tablet/day) to asymptomatic HIV-positive adults, mean maximum concentration in peripheral leukocytes was 252 μg/mL (±49%). Trough concentrations in peripheral leukocytes at steady-state averaged 146 μg/mL (±33%). The mean leukocyte-to-serum Cmax ratio was 456 (±38%) and the mean leukocyte to serum AUC ratio was 816 (±31%). The clinical relevance of these findings is unknown. Metabolism In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed. Elimination Plasma concentrations of azithromycin following single 500 mg oral and IV doses declined in a polyphasic pattern resulting in an average terminal half-life of 68 hr. 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. Specific Populations Renal Insufficiency Azithromycin pharmacokinetics was investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1.0 g dose of azithromycin (4 x 250 mg capsules), the mean Cmax and AUC0-120 increased by 5.1% and 4.2%, respectively, in subjects with GFR 10 to 80 mL/min compared to subjects with normal renal function (GFR > 80 mL/min). The mean Cmax and AUC0-120 increased 61% and 35%, respectively, in subjects with end-stage renal disease (GFR < 10 mL/min) compared to subjects with normal renal function (GFR > 80 mL/min). Hepatic Insufficiency The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established. Gender There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended on the basis of gender. Geriatric Patients 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 Geriatric Use] Pediatric Patients For information regarding the pharmacokinetics of ZITHROMAX (azithromycin for oral suspension) in pediatric patients, see the prescribing information for ZITHROMAX (azithromycin for oral suspension) 100 mg/5 mL and 200 mg/5 mL bottles. Drug-drug Interactions 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 effects 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 Cmax and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2. [see 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/without azithromycin) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Mean Cmax Mean AUC Atorvastatin 10 mg/day for 8 days 500 mg/day orally on days 6-8 12 0.83 (0.63 to 1.08) 1.01 (0.81 to 1.25) Carbamazepine 200 mg/day for 2 days, then 200 mg twice a day for 18 days 500 mg/day orally for days 16-18 7 0.97 (0.88 to 1.06) 0.96 (0.88 to 1.06) Cetirizine 20 mg/day for 11 days 500 mg orally on day 7, then 250 mg/day on days 8-11 14 1.03 (0.93 to 1.14) 1.02 (0.92 to 1.13) Didanosine 200 mg orally twice a day for 21 days 1,200 mg/day orally on days 8-21 6 1.44 (0.85 to 2.43) 1.14 (0.83 to 1.57) Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.04* 0.95* Fluconazole 200 mg orally single dose 1,200 mg orally single dose 18 1.04 (0.98 to 1.11) 1.01 (0.97 to 1.05) Indinavir 800 mg three times a day for 5 days 1,200 mg orally on day 5 18 0.96 (0.86 to 1.08) 0.90 (0.81 to 1.00) Midazolam 15 mg orally on day 3 500 mg/day orally for 3 days 12 1.27 (0.89 to 1.81) 1.26 (1.01 to 1.56) Nelfinavir 750 mg three times a day for 11 days 1,200 mg orally on day 9 14 0.90 (0.81 to 1.01) 0.85 (0.78 to 0.93) Sildenafil 100 mg on days 1 and 4 500 mg/day orally for 3 days 12 1.16 (0.86 to 1.57) 0.92 (0.75 to 1.12) Theophylline 4 mg/kg IV on days 1, 11, 25 500 mg orally on day 7, 250 mg/day on days 8-11 10 1.19 (1.02 to 1.40) 1.02 (0.86 to 1.22) Theophylline 300 mg orally BID x 15 days 500 mg orally on day 6, then 250 mg/day on days 7-10 8 1.09 (0.92 to 1.29) 1.08 (0.89 to 1.31) Triazolam 0.125 mg on day 2 500 mg orally on day 1, then 250 mg/day on day 2 12 1.06* 1.02* Trimethoprim/ Sulfamethoxazole 160 mg/800 mg/day orally for 7 days 1,200 mg orally on day 7 12 0.85 (0.75 to 0.97)/ 0.90 (0.78 to 1.03) 0.87 (0.80 to 0.95/ 0.96 (0.88 to 1.03) Zidovudine 500 mg/day orally for 21 days 600 mg/day orally for 14 days 5 1.12 (0.42 to 3.02) 0.94 (0.52 to 1.70) Zidovudine 500 mg/day orally for 21 days 1,200 mg/day orally for 14 days 4 1.31 (0.43 to 3.97) 1.30 (0.69 to 2.43) * - 90% Confidence interval not reported Table 2: Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs. [see DRUG INTERACTIONS] Co-administered Drug Dose of Coadministered Drug Dose of Azithromycin n Ratio (with/without co-administered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Mean Cmax Mean AUC Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.22 (1.04 to 1.42) 0.92* Fluconazole 200 mg orally single dose 1,200 mg orally single dose 18 0.82 (0.66 to 1.02) 1.07 (0.94 to 1.22) Nelfinavir 750 mg three times a day for 11 days 1,200 mg orally on day 9 14 2.36 (1.77 to 3.15) 2.12 (1.80 to 2.50) * - 90% Confidence interval not reported Microbiology Azithromycin has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in [see INDICATIONS AND USAGE]. Aerobic Gram-Positive Microorganisms Staphylococcus aureus Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenes NOTE: Azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive strains. Most strains of Enterococcus faecalis and methicillin-resistant staphylococci are resistant to azithromycin. Aerobic Gram-Negative Microorganisms Haemophilus influenzae Moraxella catarrhalis Other Microorganisms Chlamydia trachomatis Beta-lactamase production should have no effect on azithromycin activity. Azithromycin has been shown to be active in vitro and in the prevention and treatment of disease caused by the following microorganisms: Mycobacteria Mycobacterium avium complex (MAC) consisting of: Mycobacterium avium Mycobacterium intracellulare The following in vitro data are available, but their clinical significance is unknown. Azithromycin exhibits in vitro minimal inhibitory concentrations (MICs) of 2.0 μg/mL or less against most ( ≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of azithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials. Aerobic Gram-Positive Microorganisms Streptococci (Groups C, F, G) Viridans group streptococci Aerobic Gram-Negative Microorganisms Bordetella pertussis Campylobacter jejuni Haemophilus ducreyi Legionella pneumophila Anaerobic Microorganisms Bacteroides bivius Clostridium perfringens Peptostreptococcus species Other Microorganisms Borrelia burgdorferi Mycoplasma pneumoniae Treponema pallidum Ureaplasma urealyticum Susceptibility Testing of Bacteria Excluding Mycobacteria The in vitro potency of azithromycin is markedly affected by the pH of the microbiological growth medium during incubation. Incubation in a 10% CO2 atmosphere will result in lowering of media pH (7.2 to 6.6) within 18 hr and in an apparent reduction of the in vitro potency of azithromycin. Thus, the initial pH of the growth medium should be 7.2-7.4, and the CO2 content of the incubation atmosphere should be as low as practical. Azithromycin can be solubilized for in vitro susceptibility testing by dissolving in a minimum amount of 95% ethanol and diluting to working concentration with water. Dilution Techniques Quantitative methods are used to determine minimal inhibitory concentrations that provide reproducible estimates of the susceptibility of bacteria to antibacterial compounds. One such standardized procedure uses a standardized dilution method1 (broth, agar or microdilution) or equivalent with azithromycin powder. The MIC values should be interpreted according to the following criteria: MIC (μg/mL) Interpretation < 2 Susceptible (S) 4 Intermediate (I) > 8 Resistant (R) A report of “Susceptible” indicates that the pathogen is likely to respond to monotherapy with azithromycin. 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 also provides a buffer zone which prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that usually achievable drug concentrations are unlikely to be inhibitory and that other therapy should be selected. Measurement of MIC or minimum bacterial concentration (MBC) and achieved antibacterial compound concentrations may be appropriate to guide therapy in some infections. [see CLINICAL PHARMACOLOGY] section for further information on drug concentrations achieved in infected body sites and other pharmacokinetic properties of this antibacterial drug product.) Standardized susceptibility test procedures require the use of laboratory control microorganisms. Standard azithromycin powder should provide the following MIC values: Microorganism MIC (pg/mL) Escherichia coli ATCC 25922 2.0-8.0 Enterococcus faecalis ATCC 29212 1.0-4.0 Staphylococcus aureus ATCC 29213 0.25-1.0 Diffusion Techniques Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antibacterial compounds. One such standardized procedure2 that has been recommended for use with disks to test the susceptibility of microorganisms to azithromycin uses the 15 μg azithromycin disk. Interpretation involves the correlation of the diameter obtained in the disk test with the MIC for azithromycin. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 15 μg azithromycin disk should be interpreted according to the following criteria: Zone Diameter (mm) Interpretation ≥ 18 Susceptible (S) 14-17 Intermediate (I) ≤ 13 Resistant (R) Interpretation should be as stated above for results using dilution techniques. As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms. The 15 μg azithromycin disk should provide the following zone diameters in these laboratory test quality control strains: Microorganism Zone Diameter (mm) Staphylococcus aureus ATCC 25923 21-26 In Vitro Activity of Azithromycin Against Mycobacteria Azithromycin has demonstrated in vitro activity against MAC organisms. While gene probe techniques may be used to distinguish between M. avium and M. intracellulare, many studies only reported results on MAC isolates. Azithromycin has also been shown to be active against phagocytized MAC organisms in mouse and human macrophage cell cultures as well as in the beige mouse infection model. Various in vitro methodologies employing broth or solid media at different pHs, with and without oleic acid-albumindextrose- catalase (OADC), have been used to determine azithromycin MIC values for MAC strains. In general, azithromycin MIC values decreased 4-8 fold as the pH of Middlebrook 7H11 agar media increased from 6.6 to 7.4. At pH 7.4, azithromycin MIC values determined with Mueller-Hinton agar were 4 fold higher than that observed with Middlebrook 7H12 media at the same pH. Utilization of oleic OADC in these assays has been shown to further alter MIC values. The relationship between azithromycin and clarithromycin MIC values has not been established. In general, azithromycin MIC values were observed to be 2-32 fold higher than clarithromycin independent of the susceptibility method employed. The ability to correlate MIC values and plasma drug levels is difficult as azithromycin concentrates in macrophages and tissues. [see CLINICAL PHARMACOLOGY] Drug Resistance Complete cross-resistance between azithromycin and clarithromycin has been observed with MAC isolates. In most isolates, a singlepoint mutation at a position that is homologous to the Escherichia coli positions 2058 or 2059 on the 23S rRNA gene is the mechanism producing this cross-resistance pattern.3,4 MAC isolates exhibiting cross-resistance show an increase in azithromycin MICs to ≥ 128 μg/mL with clarithromycin MICs increasing to ≥ 32 μg/mL. These MIC values were determined employing the radiometric broth dilution susceptibility testing method with Middlebrook 7H12 medium. The clinical significance of azithromycin and clarithromycin cross-resistance is not fully understood at this time but preclinical data suggest that reduced activity to both agents will occur after MAC strains produce the 23S rRNA mutation. Susceptibility Testing for MAC The disk diffusion techniques and dilution methods for susceptibility testing against gram-positive and gram-negative bacteria should not be used for determining azithromycin MIC values against mycobacteria. In vitro susceptibility testing methods and diagnostic products currently available for determining MIC values against MAC organisms have not been standardized or validated. Azithromycin MIC values will vary depending on the susceptibility testing method employed, composition and pH of media, and the utilization of nutritional supplements. Breakpoints to determine whether clinical isolates of M. avium or M. intracellulare are susceptible or resistant to azithromycin have not been established. The clinical relevance of azithromycin in vitro susceptibility test results for other mycobacterial species, including Mycobacterium tuberculosis, using any susceptibility testing method has not been determined. 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/or pancreas) in dogs and rats treated with azithromycin at doses which, expressed on the basis of body surface area, are similar to or less than the highest recommended adult human dose. This effect has been shown to be reversible after cessation of azithromycin treatment. Based on the pharmacokinetic data, phospholipidosis has been seen in the rat (50 mg/kg/day dose) at the observed maximal plasma concentration of 1.3 mcg/mL (1.6 times the observed Cmax of 0.821 mcg/mL at the adult dose of 2 g.) Similarly, it has been shown in the dog (10 mg/kg/day dose) at the observed maximal serum concentration of 1 mcg/mL (1.2 times the observed Cmax of 0.821 mcg/mL at the adult dose of 2 g). Phospholipidosis was also observed in neonatal rats dosed for 18 days at 30 mg/kg/day, which is less than the pediatric dose of 60 mg/kg based on the surface area. It was not observed in neonatal rats treated for 10 days at 40 mg/kg/day with mean maximal serum concentrations of 1.86 mcg/mL, approximately 1.5 times the Cmax of 1.27 mcg/mL at the pediatric dose. Phospholipidosis has been observed in neonatal dogs (10 mg/kg/day) at maximum mean whole blood concentrations of 3.54 mcg/mL, approximately 3 times the pediatric dose Cmax. The significance of the finding for animals and for humans is unknown. Clinical Studies Clinical Studies In Patients With Advanced HIV Infection For The Prevention And Treatment Of Disease Due To Disseminated Mycobacterium avium Complex (MAC) [see INDICATIONS AND USAGE] Prevention of Disseminated MAC Disease Two randomized, double-blind clinical trials were performed in patients with CD4 counts < 100 cells/μL. The first trial (Study 155) compared azithromycin (1200 mg once weekly) to placebo and enrolled 182 patients with a mean CD4 count of 35 cells/mcgL. The second trial (Study 174) randomized 723 patients to either azithromycin (1200 mg once weekly), rifabutin (300 mg daily), or the combination of both. The mean CD4 count was 51 cells/mcgL. The primary endpoint in these trials was disseminated MAC disease. Other endpoints included the incidence of clinically significant MAC disease and discontinuations from therapy for drug-related side effects. MAC Bacteremia In Study 155, 85 patients randomized to receive azithromycin and 89 patients randomized to receive placebo met the entrance criteria. Cumulative incidences at 6, 12, and 18 months of the possible outcomes are in the following table: Cumulative Incidence Rate, %: Placebo (n=89) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 69.7 13.5 6.7 10.1 12 47.2 19.1 15.7 18.0 18 37.1 22.5 18.0 22.5 Cumulative Incidence Rate, %: Azithromycin (n=85) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 84.7 3.5 9.4 2.4 12 63.5 8.2 16.5 11.8 18 44.7 11.8 25.9 17.6 The difference in the one-year cumulative incidence rates of disseminated MAC disease (placebo – azithromycin) is 10.9%. This difference is statistically significant (p=0.037) with a 95% confidence interval for this difference of 0.8%, 20.9%. The comparable number of patients experiencing adverse events and the fewer number of patients lost to follow-up on azithromycin should be taken into account when interpreting the significance of this difference. In Study 174, 223 patients randomized to receive rifabutin, 223 patients randomized to receive azithromycin, and 218 patients randomized to receive both rifabutin and azithromycin met the entrance criteria. Cumulative incidences at 6, 12, and 18 months of the possible outcomes are recorded in the following table: Cumulative Incidence Rate, %: Rifabutin (n=223) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 83.4 7.2 8.1 1.3 12 60.1 15.2 16.1 8.5 18 40.8 21.5 24.2 13.5 Cumulative Incidence Rate, %: Azithromycin (n=223) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 85.2 3.6 5.8 5.4 12 65.5 7.6 16.1 10.8 18 45.3 12.1 23.8 18.8 Cumulative Incidence Rate, %: Azithromycin/Rifabutin Combination (n=218) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 89.4 1.8 5.5 3.2 12 71.6 2.8 15.1 10.6 18 49.1 6.4 29.4 15.1 Comparing the cumulative one-year incidence rates, azithromycin monotherapy is at least as effective as rifabutin monotherapy. The difference (rifabutin – azithromycin) in the one-year rates (7.6%) is statistically significant (p=0.022) with an adjusted 95% confidence interval (0.9%, 14.3%). Additionally, azithromycin/rifabutin combination therapy is more effective than rifabutin alone. The difference (rifabutin – azithromycin/rifabutin) in the cumulative one-year incidence rates (12.5%) is statistically significant (p < 0.001) with an adjusted 95% confidence interval of 6.6%, 18.4%. The comparable number of patients experiencing adverse events and the fewer number of patients lost to follow-up on rifabutin should be taken into account when interpreting the significance of this difference. In Study 174, sensitivity testing5 was performed on all available MAC isolates from subjects randomized to either azithromycin, rifabutin, or the combination. The distribution of MIC values for azithromycin from susceptibility testing of the breakthrough isolates was similar between trial arms. As the efficacy of azithromycin in the treatment of disseminated MAC has not been established, the clinical relevance of these in vitro MICs as an indicator of susceptibility or resistance is not known. Clinically Significant Disseminated MAC Disease In association with the decreased incidence of bacteremia, patients in the groups randomized to either azithromycin alone or azithromycin in combination with rifabutin showed reductions in the signs and symptoms of disseminated MAC disease, including fever or night sweats, weight loss, and anemia. Discontinuations from Therapy for Drug-Related Side Effects In Study 155, discontinuations for drug-related toxicity occurred in 8.2% of subjects treated with azithromycin and 2.3% of those given placebo (p=0.121). In Study 174, more subjects discontinued from the combination of azithromycin and rifabutin (22.7%) than from azithromycin alone (13.5%; p=0.026) or rifabutin alone (15.9%; p=0.209). Safety As these patients with advanced HIV disease were taking multiple concomitant medications and experienced a variety of intercurrent illnesses, it was often difficult to attribute adverse reactions to study medication. Overall, the nature of adverse reactions seen on the weekly dosage regimen of azithromycin over a period of approximately one year in patients with advanced HIV disease were similar to that previously reported for shorter course therapies. INCIDENCE OF ONE OR MORE TREATMENT-RELATEDa ADVERSE REACTIONSb IN HIV INFECTED PATIENTS RECEIVING PROPHYLAXIS FOR DISSEMINATED MAC OVER APPROXIMATELY 1 YEAR Study 155 Study 174 Placebo (N=91) Azithromycin 1200 mg weekly (N=89) Azithromycin 1200 mg weekly (N=233) Rifabutin 300 mg daily (N=236) Azithromycin + Rifabutin (N=224) Mean Duration of Therapy (days) 303.8 402.9 315 296.1 344.4 Discontinuation of Therapy 2.3 8.2 13.5 15.9 22.7 Autonomic Nervous System Mouth Dry 0 0 0 3.0 2.7 Central Nervous System Dizziness 0 1.1 3.9 1.7 0.4 Headache 0 0 3.0 5.5 4.5 Gastrointestinal Diarrhea 15.4 52.8 50.2 19.1 50.9 Loose Stools 6.6 19.1 12.9 3.0 9.4 Abdominal Pain 6.6 27 32.2 12.3 31.7 Dyspepsia 1.1 9 4.7 1.7 1.8 Flatulence 4.4 9 10.7 5.1 5.8 Nausea 11 32.6 27.0 16.5 28.1 Vomiting 1.1 6.7 9.0 3.8 5.8 General Fever 1.1 0 2.1 4.2 4.9 Fatigue 0 2.2 3.9 2.1 3.1 Malaise 0 1.1 0.4 0 2.2 Musculoskeletal Arthralgia 0 0 3.0 4.2 7.1 Psychiatric Anorexia 1.1 0 2.1 2.1 3.1 Skin & Appendages Pruritus 3.3 0 3.9 3.4 7.6 Rash 3.2 3.4 8.1 9.4 11.1 Skin discoloration 0 0 0 2.1 2.2 Special Senses Tinnitus 4.4 3.4 0.9 1.3 0.9 Hearing Decreased 2.2 1.1 0.9 0.4 0 Uveitis 0 0 0.4 1.3 1.8 Taste Perversion 0 0 1.3 2.5 1.3 a Includes those reactions considered possibly or probably related to study drug b > 2% adverse reaction rates for any group (except uveitis) Adverse reactions related to the gastrointestinal tract were seen more frequently in patients receiving azithromycin than in those receiving placebo or rifabutin. In Study 174, 86% of diarrheal episodes were mild to moderate in nature with discontinuation of therapy for this reason occurring in only 9/233 (3.8%) of patients. Changes in Laboratory Values In these immunocompromised patients with advanced HIV infection, it was necessary to assess laboratory abnormalities developing on trial with additional criteria if baseline values were outside the relevant normal range. PROPHYLAXIS AGAINST DISSEMINATED MAC ABNORMAL LABORATORY VALUESa Placebo Azithromycin 1200 mg weekly Rifabutin 300 mg daily Azithromycin & Rifabutin Hemoglobin < 8 g/dL 1/51 2% 4/170 2% 4/114 4% 8/107 8% Platelet Count < 50 x 103/mm³ 1/71 1% 4/260 2% 2/182 1% 6/181 3% WBC Count < 1 x 103/mm³ 0/8 0% 2/70 3% 2/47 4% 0/43 0% Neutrophils < 500/mm³ 0/26 0% 4/106 4% 3/82 4% 2/78 3% SGOT > 5 x ULNb 1/41 2% 8/158 5% 3/121 3% 6/114 5% SGPT > 5 x ULN 0/49 0% 8/166 5% 3/130 2% 5/117 4% Alk Phos > 5 x ULN 1/80 1% 4/247 2% 2/172 1% 3/164 2% aexcludes subjects outside of the relevant normal range at baseline bUpper Limit of Normal Treatment of Disseminated MAC Disease One randomized, double-blind clinical trial (Study 189) was performed in patients with disseminated MAC. In this trial, 246 HIV infected patients with disseminated MAC received either azithromycin 250 mg daily (N=65), azithromycin 600 mg daily (N=91), or clarithromycin 500 mg twice a day (N=90), each administered with ethambutol 15 mg/kg daily, for 24 weeks. Blood cultures and clinical assessments were performed every 3 weeks through week 12 and monthly thereafter through week 24. After week 24, patients were switched to any open-label therapy at the discretion of the investigator and followed every 3 months through the last follow-up visit of the trial. Patients were followed from the baseline visit for a period of up to 3.7 years (median: 9 months). MAC isolates recovered during treatment or post-treatment were obtained whenever possible. The primary endpoint was sterilization by week 24. Sterilization was based on data from the central laboratory, and was defined as two consecutive observed negative blood cultures for MAC, independent of missing culture data between the two negative observations. Analyses were performed on all randomized patients who had a positive baseline culture for MAC. The azithromycin 250 mg arm was discontinued after an interim analysis at 12 weeks showed a significantly lower clearance of bacteremia compared to clarithromycin 500 mg twice a day . Efficacy results for the azithromycin 600 mg daily and clarithromycin 500 mg twice a day treatment regimens are described in the following table: RESPONSE TO THERAPY OF PATIENTS TAKING ETHAMBUTOL AND EITHER AZITHROMYCIN 600 MG DAILY OR CLARITHROMYCIN 500 MG TWICE A DAY Azithromycin 600 mg daily Clarithromycin 500 mg twice a day a95.1% CI on difference Patients with positive culture at baseline 68 57 Week 24 Two consecutive negative blood culturesb 31/68 (46%) 32/57 (56%) [-28, 7] Mortality 16/68 (24%) 15/57 (26%) [-18, 13] a [95% confidence interval] on difference in rates (azithromycin-clarithromycin) b Primary endpoint The primary endpoint, rate of sterilization of blood cultures (two consecutive negative cultures) at 24 weeks, was lower in the azithromycin 600 mg daily group than in the clarithromycin 500 mg twice a day group. Sterilization by Baseline Colony Count Within both treatment groups, the sterilization rates at week 24 decreased as the range of MAC cfu/mL increased. Azithromycin 600 mg (N=68) Clarithromycin 500 mg twice a day (N=57) groups stratified by MAC colony counts at baseline no. (%) subjects in stratified group sterile at week 24 no. (%) subjects in stratified group sterile at week 24 ≤ 10 cfu/mL 10/15 (66.7%) 12/17 (70.6%) 11-100 cfu/mL 13/28 (46.4%) 13/19 (68.4%) 101-1,000 cfu/mL 7/19 (36.8%) 5/13 (38.5%) 1,001-10,000 cfu/mL 1/5 (20.0%) 1/5 (20%) > 10,000 cfu/mL 0/1 (0.0%) 1/3 (33.3%) Susceptibility Pattern of MAC Isolates Susceptibility testing was performed on MAC isolates recovered at baseline, at the time of breakthrough on therapy or during posttherapy follow-up. The T100 radiometric broth method was employed to determine azithromycin and clarithromycin MIC values. Azithromycin MIC values ranged from < 4 to > 256 μg/mL and clarithromycin MICs ranged from < 1 to > 32 μg/mL. The individual MAC susceptibility results demonstrated that azithromycin MIC values could be 4 to 32-fold higher than clarithromycin MIC values. During treatment and post-treatment follow-up for up to 3.7 years (median: 9 months) in Study 189, a total of 6/68 (9%) and 6/57 (11%) of the patients randomized to azithromycin 600 mg daily and clarithromycin 500 mg twice a day respectively, developed MAC blood culture isolates that had a sharp increase in MIC values. All twelve MAC isolates had azithromycin MICs ≥ 256 μg/mL and clarithromycin MICs > 32 μg/mL. These high MIC values suggest development of drug resistance. However, at this time, specific breakpoints for separating susceptible and resistant MAC isolates have not been established for either macrolide. REFERENCES 1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012. 2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Eleventh Edition CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012. 3. Dunne MW, Foulds G, Retsema JA. Rationale for the use of azithromycin as Mycobacterium avium chemoprophylaxis. Am J Med 1997;102(5C):37-49. 4. Meier A, Kirshner P, Springer B, et al. Identification of mutations in 23S rRNA gene of clarithromycin-resistant Mycobacterium intracellulare. Antimicrob Agents Chemother. 1994;38:381-384. 5. Methodology per Inderlied CB, et al. Determination of In Vitro Susceptibility of Mycobacterium avium Complex Isolates to Antimicrobial Agents by Various Methods. Antimicrob Agents Chemother. 1987;31:1697-1702.

Find Lowest Prices on ZMAX® (azithromycin) Extended-release Microspheres for Oral Suspension DESCRIPTION Zmax (azithromycin extended-release) for oral suspension contains the active ingredient azithromycin (as azithromycin dihydrate), an azalide, a subclass of macrolide antibacterial drug. Azithromycin has the chemical name (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)13-[(2,6-Dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyra nosyl) oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)β-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one. Azithromycin is derived from erythromycin; however, it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring. Its molecular formula is C38H72N2O12, and its molecular weight is 749.0. Azithromycin has the following structural formula: Azithromycin, as the dihydrate, is a white crystalline powder with a molecular formula of C38H72N2O12•2H2O and a molecular weight of 785.0. Zmax is a single-dose, extended-release formulation of microspheres for oral suspension containing azithromycin (as azithromycin dihydrate) and the following excipients: glyceryl behenate, poloxamer 407, sucrose, sodium phosphate tribasic anhydrous, magnesium hydroxide, hydroxypropyl cellulose, xanthan gum, colloidal silicon dioxide, titanium dioxide, artificial cherry flavor, and artificial banana flavor. Note: Each bottle of Zmax 2 g for oral suspension contains approximately 148 mg of sodium and 19 g of sucrose. Constituted Zmax oral suspension contains approximately 2 mg/mL of sodium and 0.26 g/mL of sucrose.

Find Lowest Prices on ZITHROMAX (azithromycin) For Injection DESCRIPTION ZITHROMAX for injection contains the active ingredient azithromycin, an azalide, a subclass of macrolide antibacterial drug, for intravenous injection. Azithromycin has the chemical name (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13- [(2,6-dideoxy-3-C-methyl-3-O -methyl-α-L-ribohexopyranosyl) oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-hepta-methyl- 11- [[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-1-oxa- 6-azacyclopentadecan-15-one. Azithromycin is derived from erythromycin; however, it differs chemically from erythromycin in that a methylsubstituted nitrogen atom is incorporated into the lactone ring. Its molecular formula is C38H72N2O12, and its molecular weight is 749.00. Azithromycin has the following structural formula: Azithromycin, as the dihydrate, is a white crystalline powder with a molecular formula of C38H72N2O12•2H2O and a molecular weight of 785.0. ZITHROMAX for injection consists of azithromycin dihydrate and the following inactive ingredients: citric acid and sodium hydroxide. ZITHROMAX for injection is supplied in lyophilized form in a 10 mL vial equivalent to 500 mg of azithromycin for intravenous administration. Reconstitution, according to label directions, results in approximately 5 mL of ZITHROMAX for intravenous injection with each mL containing azithromycin dihydrate equivalent to 100 mg of azithromycin.

Find Lowest Prices on ZITHROMAX® (azithromycin) Tablets and Oral Suspension DESCRIPTION ZITHROMAX (azithromycin tablets and oral suspension) contains the active ingredient azithromycin, a macrolide antibacterial drug , for oral administration. Azithromycin has the chemical name (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-2-ethyl- 3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6- trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one. Azithromycin is derived from erythromycin; however, it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring. Its molecular formula is C38H72N2O12, and its molecular weight is 749.0. Azithromycin has the following structural formula: Azithromycin, as the dihydrate, is a white crystalline powder with a molecular formula of C38H72N2O12•2H2O and a molecular weight of 785.0. ZITHROMAX tablets contain azithromycin dihydrate equivalent to 600 mg azithromycin. They also contain the following inactive ingredients: dibasic calcium phosphate anhydrous, pregelatinized starch, sodium croscarmellose, magnesium stearate, sodium lauryl sulfate, and an aqueous film coat consisting of hypromellose, titanium dioxide, lactose, and triacetin. ZITHROMAX for oral suspension is supplied in a single-dose packet containing azithromycin dihydrate equivalent to 1 g azithromycin. It also contains the following inactive ingredients: colloidal silicon dioxide, sodium phosphate tribasic, anhydrous; spray dried artificial banana flavor, spray dried artificial cherry flavor, and sucrose.

INDICATIONS Acute Bacterial Sinusitis In Adults And Community-Acquired Pneumonia Zmax (azithromycin) is a macrolide antibacterial drug indicated for the treatment with mild to moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below. [See Clinical Studies] Acute bacterial sinusitis in adults due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae. Community-acquired pneumonia in adults and pediatric patients six months of age or older due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae, in patients appropriate for oral therapy. Pediatric use in this indication is based on extrapolation of adult efficacy. [See Use in Specific Populations] Limitations Of Use Zmax is not recommended for use 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 nosocomial 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). Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of Zmax (azithromycin) and other antibacterial drugs, Zmax (azithromycin) should be used only to treat 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 Adults Zmax should be taken as a single 2 g dose. Zmax provides a full course of antibacterial therapy in a single oral dose. It is recommended that Zmax be taken on an empty stomach (at least 1 hr before or 2 hr following a meal). Pediatric Patients For pediatric patients 6 months and older, Zmax should be taken as a single dose of 60 mg/kg (equivalent to 27 mg/lb) body weight. The Zmax dose in mL is equivalent to the child's weight in lb (1 mL/lb dose, see Table 1 below), for a body weight of less than 75 lb (34 kg). It is recommended that Zmax be taken on an empty stomach (at least 1 hr before or 2 hrs following a meal). Pediatric patients weighing 75 lb (34 kg) or more should receive the adult dose (2 g). Table 1: Zmax Pediatric Dosage Guidelines: 1-dose regimen Dosing Calculated on 1 mL/lb, Dose 1 mL of Suspension for every 1 lb of Body Weight for Children < 75 lb (34 kg)a Weight 1 mL/lb Dose Lb Kg Dose (mg) Volume (mL) 10 5 270 10 15 7 405 15 20 9 540 20 25 11 675 25 30 14 810 30 35 16 945 35 40 18 1080 40 45 20 1215 45 50 23 1350 50 55 25 1485 55 60 27 1620 60 65 30 1755 65 70 32 1890 70 > 75 34 2000 Consume entire contents of bottle a To ensure accurate dosing, a dosing spoon, medicine syringe, or cup is recommended. Additional Treatment After Vomiting With Zmax In the event that a patient vomits within 5 minutes of administration, the health care provider should consider additional antibiotic treatment since there would be minimal absorption of azithromycin. Since insufficient data exist on absorption of azithromycin if a patient vomits between 5 and 60 minutes following administration, alternative therapy should be considered. Neither a second dose of Zmax nor alternative treatment is warranted if vomiting occurs ≥ 60 minutes following administration, in patients with normal gastric emptying. In patients with delayed gastric emptying, alternative therapy should be considered. Instructions For The Pharmacist Constitute with 60 mL of water and replace cap. Shake bottle well before dispensing. Do not refrigerate. Constituted suspension should be consumed within 12 hr. For pediatric dosing in patients weighing less than 75 lb (34 kg), use of a dosing device is recommended. The pharmacist should inform the patient's caregiver that any suspension remaining after dosing MUST be discarded. HOW SUPPLIED Dosage Forms And Strengths Each bottle of Zmax contains azithromycin dihydrate equivalent to 2 g of azithromycin. After constitution with 60 mL of water, each mL of suspension contains 27 mg of azithromycin. The suspension is a white or off-white color and has a cherry/banana flavor. Storage And Handling NDC 0069-4170-34 for combined adult and pediatric use is supplied in bottles containing 2 g of azithromycin and should be constituted with 60 mL of water. Storage Before constitution, store dry powder at or below 30°C (86°F). After constitution, store suspension at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature]. Do not refrigerate or freeze. Constituted suspension should be consumed within 12 hr. For adult patients, the entire bottle should be consumed. For pediatric patients, any suspension remaining after dosing MUST be discarded. Distributed by: Pfizer Labs, Division of Pfizer Inc., NY, NY 10017. Revised: Feb 2016

INDICATIONS To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZITHROMAX (azithromycin) and other antibacterial drugs, ZITHROMAX (azithromycin) should be used only to treat 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. ZITHROMAX (azithromycin) for injection is a macrolide antibacterial drug indicated for the treatment of patients with infections caused by susceptible strains of the designated microorganisms in the conditions listed below. Community-Acquired Pneumonia due to Chlamydophila pneumoniae, Haemophilus influenzae, Legionella pneumophila, Moraxella catarrhalis, Mycoplasma pneumoniae, Staphylococcus aureus, or Streptococcus pneumoniae in patients who require initial intravenous therapy. Pelvic Inflammatory Disease due to Chlamydia trachomatis, Neisseria gonorrhoeae, or Mycoplasma hominis in patients who require initial intravenous therapy. If anaerobic microorganisms are suspected of contributing to the infection, an antimicrobial agent with anaerobic activity should be administered in combination with ZITHROMAX. ZITHROMAX for injection should be followed by ZITHROMAX by the oral route as required. [see DOSAGE AND ADMINISTRATION] DOSAGE AND ADMINISTRATION [see INDICATIONS AND USAGE and CLINICAL PHARMACOLOGY] Community-Acquired Pneumonia The recommended dose of ZITHROMAX for injection for the treatment of adult patients with community-acquired pneumonia due to the indicated organisms is 500 mg as a single daily dose by the intravenous route for at least two days. Intravenous therapy should be followed by azithromycin by the oral route at a single, daily dose of 500 mg, administered as two 250 mg tablets to complete a 7- to 10- day course of therapy. The timing of the switch to oral therapy should be done at the discretion of the physician and in accordance with clinical response. Pelvic Inflammatory Disease The recommended dose of ZITHROMAX for injection for the treatment of adult patients with pelvic inflammatory disease due to the indicated organisms is 500 mg as a single daily dose by the intravenous route for one or two days. Intravenous therapy should be followed by azithromycin by the oral route at a Sections or subsections omitted from the full prescribing information are not listed. single, daily dose of 250 mg to complete a 7-day course of therapy. The timing of the switch to oral therapy should be done at the discretion of the physician and in accordance with clinical response. Preparation Of The Solution For Intravenous Administration The infusate concentration and rate of infusion for ZITHROMAX for injection should be either 1 mg/mL over 3 hr or 2 mg/mL over 1 hr. ZITHROMAX for injection should not be given as a bolus or as an intramuscular injection. Reconstitution Prepare the initial solution of ZITHROMAX for injection by adding 4.8 mL of Sterile Water for Injection to the 500 mg vial, and shaking the vial until all of the drug is dissolved. Since ZITHROMAX for injection is supplied under vacuum, it is recommended that a standard 5 mL (non-automated) syringe be used to ensure that the exact amount of 4.8 mL of Sterile Water is dispensed. Each mL of reconstituted solution contains 100 mg azithromycin. Reconstituted solution is stable for 24 hr when stored below 30°C (86°F). Parenteral drug products should be inspected visually for particulate matter prior to administration. If particulate matter is evident in reconstituted fluids, the drug solution should be discarded. Dilute this solution further prior to administration as instructed below. Dilution To provide azithromycin over a concentration range of 1.0-2.0 mg/mL, transfer 5 mL of the 100 mg/mL azithromycin solution into the appropriate amount of any of the diluents listed below: Normal Saline (0.9% sodium chloride) ½ Normal Saline (0.45% sodium chloride) 5% Dextrose in Water Lactated Ringer's Solution 5% Dextrose in ½ Normal Saline (0.45% sodium chloride) with 20 mEq KCl 5% Dextrose in Lactated Ringer's Solution 5% Dextrose in 1/3 Normal Saline (0.3% sodium chloride) 5% Dextrose in ½ Normal Saline (0.45% sodium chloride) Normosol® -M in 5% Dextrose Normosol®-R in 5% Dextrose When used with the Vial-Mate® drug reconstitution device, please reference the Vial-Mate instructions for assembly and reconstitution. Final Infusion Solution Concentration (mg/mL) Amount of Diluent (mL) 1.0 mg/mL 500 mL 2.0 mg/mL 250 mL Other intravenous substances, additives, or medications should not be added to ZITHROMAX for injection, or infused simultaneously through the same intravenous line. Storage When diluted according to the instructions (1.0 mg/mL to 2.0 mg/mL), ZITHROMAX for injection is stable for 24 hr at or below room temperature 30°C (86°F), or for 7 days if stored under refrigeration 5°C (41°F). HOW SUPPLIED Dosage Forms And Strengths ZITHROMAX for injection is supplied in lyophilized form in a 10 mL vial equivalent to 500 mg of azithromycin for intravenous administration. Storage And Handling ZITHROMAX (azithromycin for injection) is supplied in lyophilized form under a vacuum in a 10 mL vial equivalent to 500 mg of azithromycin for intravenous administration. Each vial also contains sodium hydroxide and 413.6 mg citric acid. These are packaged as follows: 10 vials of 500 mg NDC 0069-0400-10 Distributed by: Pfizer Labs, Division of Pfizer Inc, New York, NY 10017. Revised: Jun 2016

INDICATIONS To reduce the development of drug-resistant bacteria and maintain the effectiveness of ZITHROMAX and other antibacterial drugs, ZITHROMAX should be used only to treat 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. ZITHROMAX is a macrolide antibacterial drug indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below. Sexually Transmitted Diseases Non-gonococcal urethritis and cervicitis due to Chlamydia trachomatis Mycobacterial Infections Prophylaxis of Disseminated Mycobacterium Avium Complex (MAC) Disease ZITHROMAX, taken alone or in combination with rifabutin at its approved dose, is indicated for the prevention of disseminated MAC disease in persons with advanced HIV infection. [see DOSAGE AND ADMINISTRATION] Treatment of Disseminated MAC Disease ZITHROMAX, taken in combination with ethambutol, is indicated for the treatment of disseminated MAC infections in persons with advanced HIV infection [see Use in Specific Populations and Clinical Studies]. DOSAGE AND ADMINISTRATION [see INDICATIONS AND USAGE] ZITHROMAX for oral suspension (single dose 1 g packet) can be taken with or without food after constitution. However, increased tolerability has been observed when tablets are taken with food. Zithromax for oral suspension (single dose 1 g packet) is not for pediatric use. For pediatric suspension see the prescribing information for ZITHROMAX (azithromycin for oral suspension) 100 mg/5 mL and 200 mg/5 mL bottles. Directions for administration of ZITHROMAX for oral suspension in the single dose packet (1 g): The entire contents of the packet should be mixed thoroughly with two ounces (approximately 60 mL) of water. Drink the entire contents immediately; add an additional two ounces of water, mix, and drink to ensure complete consumption of dosage. The single dose packet should not be used to administer doses other than 1000 mg of azithromycin. Sexually Transmitted Diseases The recommended dose of ZITHROMAX for the treatment of non-gonococcal urethritis and cervicitis due to C. trachomatis is a single 1 gram (1000 mg) dose of ZITHROMAX. This dose can be administered as one single dose packet (1 g). Mycobacterial Infections Prevention of Disseminated MAC Infections The recommended dose of ZITHROMAX for the prevention of disseminated Mycobacterium avium complex (MAC) disease is: 1200 mg taken once weekly. This dose of ZITHROMAX may be combined with the approved dosage regimen of rifabutin. Treatment of Disseminated MAC Infections ZITHROMAX should be taken at a daily dose of 600 mg, in combination with ethambutol at the recommended daily dose of 15 mg/kg. Other antimycobacterial drugs that have shown in vitro activity against MAC may be added to the regimen of azithromycin plus ethambutol at the discretion of the physician or health care provider. HOW SUPPLIED Dosage Forms And Strengths ZITHROMAX 600 mg tablets (engraved on front with “PFIZER” and on back with “308”) are supplied as white, modified oval-shaped, film-coated tablets containing azithromycin dihydrate equivalent to 600 mg azithromycin. These are packaged in bottles of 30 tablets. ZITHROMAX for oral suspension 1000 mg/5 mL is supplied in single-dose packets containing azithromycin dihydrate equivalent to 1 gram of azithromycin. Storage And Handling ZITHROMAX 600 mg tablets (engraved on front with “PFIZER” and on back with “308”) are supplied as white, modified oval-shaped, film-coated tablets containing azithromycin dihydrate equivalent to 600 mg azithromycin. These are packaged in bottles of 30 tablets. ZITHROMAX tablets are supplied as follows: Bottles of 30 NDC 0069-3080-30 Tablets should be stored at or below 30°C (86°F). ZITHROMAX for oral suspension is supplied in single-dose packets containing azithromycin dihydrate equivalent to 1 gram of azithromycin as follows: Boxes of 10 single-dose packets (1 g) NDC 0069-3051-07 Boxes of 3 single-dose packets (1 g) NDC 0069-3051-75 Store single-dose packets between 5° and 30°C (41° and 86°F). Distributed by: Pfizer Labs Division of Pfizer Inc., NY, NY 10017. Revised: Dec 2015

PATIENT INFORMATION Zmax® (azithromycin extended release) Oral suspension Read the Patient Information that comes with Zmax® carefully before you or your child take it. This leaflet does not take the place of talking with your doctor about you or your child's medical condition or treatment. Only your doctor can decide if Zmax is right for you or your child. What is Zmax? Zmax is an antibiotic that kills certain bacteria. Zmax is dosed differently from other antibiotics. You take just one dose, one time. Day 1: Take Zmax in one dose. Zmax starts working. Days 2 – 3: As with most antibiotics, you may not feel better right away. After Day 3: Zmax continues to work over time. If your symptoms are not better, call your doctor. Zmax is used in adults and in children over the age of 6 months against bacteria to treat certain kinds of pneumonia (lung infections) Zmax is used in adults against bacteria to treat sinus infections. Zmax only works against bacteria. It does not work against viruses, like the common cold or flu. Zmax has not been studied in children under 6 months of age. Who should not take Zmax? You or your child should not take Zmax if allergic to: anything in Zmax. See the end of this leaflet for a complete list of ingredients in Zmax. antibiotics like erythromycin or telithromycin (Ketek®). Talk with your doctor or pharmacist if you have questions about your medicine allergies. Before you start Zmax Tell your doctor about all your or your child's medical problems including if you or your child: have liver problems. have kidney problems. have myasthenia gravis. are pregnant, or might be pregnant. It is not known if Zmax could harm your baby. are breast-feeding. Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins and herbal supplements. Especially tell your doctor if you or your child are taking warfarin (Coumadin®, Jantoven) Know the medicines you take. Keep a list of your medicines and show it to your doctor or pharmacist when you get a new prescription. Do I need to prepare Zmax? If you get Zmax in liquid form, it is ready to take. If you get Zmax as dry powder, you must add water to the bottle before you take it. To prepare Zmax: Open the bottle: To open the bottle, press down on the cap and twist. Use a measuring cup to add 60 mL (1/4 cup) water to the Zmax bottle. Tightly close the bottle and shake to mix it. How do I take Zmax? Keep Zmax at room temperature between 59°F to 86°F (15° to 30°C). Shake the bottle well before using. Take Zmax or give it to your child within 12 hr after it has been prepared by the pharmacy or you add water to the powder. Take Zmax or give it to your child exactly how your doctor prescribes it. This will help to treat you or your child's infection and decrease the chance that Zmax or other antibiotics will not work to treat infections in the future. Adults: take all the medicine in the bottle. Children: give your child the amount of Zmax prescribed by your doctor and throw away the rest of the medicine. To be sure that you give your child the right dose of Zmax, use a dosing spoon, medicine syringe, or cup. Take Zmax on an empty stomach (at least 1 hr before eating or 2 hr after eating). You can take antacids with Zmax. If you or your child throws up (vomits) within one hr of taking Zmax, call your doctor right away to see if more medicine is needed. Do not give your child more Zmax unless your doctor tells you to. If your child takes too much Zmax, call your doctor right away or go to the nearest hospital emergency room. How will I know Zmax is working? Zmax needs time to work, so you or your child may not feel better right away. If you or your child's symptoms do not get better in a few days, call your doctor. What are the possible side effects of Zmax? Zmax may cause serious side effects. These happened in a small number of patients. Call your doctor right away or get emergency treatment if you or your child have any of the following: Serious allergic reaction or serious skin reaction: Get emergency help right away if you or your child has: Skin rash (hives), sores in your mouth, or your skin blisters and peels Trouble swallowing, Swelling of your face, eyes, lips, tongue or throat Wheezing or trouble breathing New onset of fever and swollen lymph nodes These symptoms could go away and then come back. Diarrhea: Call your doctor right away if you have diarrhea that does not go away, is severe, watery, or has blood in it. Diarrhea can occur as late as two or more months after you take an antibiotic such as Zmax. Abnormal heart rhythm. Tell your doctor right away if you or your child feel your heart beating in your chest or an abnormal heart beat, get dizzy or faint. This has been seen with other antibiotics like Zmax. The most common side effects in adults are: Diarrhea/loose stools Nausea Stomach pain Headache Vomiting The most common side effects in children are: Vomiting Diarrhea/loose stools Nausea Stomach pain Tell your doctor if you have any side effects that bother your or your child, or that does not go away. These are not all of the possible side effects with Zmax. For a list of all reported side effects, ask your doctor or pharmacist. General information about Zmax Doctors sometimes prescribe medicines for conditions that are not in the patient leaflets. Do not use Zmax for anything other than what your doctor prescribed. Do not give it to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet is a summary of the most important information about Zmax. For more information, talk with your doctor. You can ask your doctor or pharmacist for information about Zmax that is written for healthcare professionals. For more information, go to our website at www.zmaxinfo.com or call 1-800-438-1985. What is in Zmax? Active ingredient: azithromycin dihydrate Inactive ingredients: glyceryl behenate, poloxamer 407, sucrose, sodium phosphate tribasic anhydrous, magnesium hydroxide, hydroxypropyl cellulose, xanthan gum, colloidal silicon dioxide, titanium dioxide, artificial cherry flavor, and artificial banana flavor Brand names are registered trademarks of their respective owners. Coumadin® is a registered trademark of Bristol-Myers Squibb, Inc. Ketek® is a registered trademark of Aventis Pharmaceuticals Inc. This product's label may have been updated. For current full prescribing information, please visit www.pfizer.com. This Patient Information has been approved by the U.S. Food and Drug Administration.

PATIENT INFORMATION Patients should be informed of the following serious and potentially serious adverse reactions that have been associated with ZITHROMAX (azithromycin for injection). Diarrhea Inform patients that diarrhea is a common problem caused by antibacterial drugs which usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial. If this occurs, patients should notify their physician as soon as possible. This product's label may have been updated. For current full prescribing information, please visit www.intalere.com.

PATIENT INFORMATION ZITHROMAX tablets may be taken with or without food. However, increased tolerability has been observed when tablets are taken with food. ZITHROMAX for oral suspension in single 1 g packets can be taken with or without food after constitution. Patients should also be cautioned not to take aluminum- and magnesium-containing antacids and azithromycin simultaneously. The patient should be directed to discontinue azithromycin immediately and contact a physician if any signs of an allergic reaction occur. Patients should be counseled that antibacterial drugs, including ZITHROMAX, should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ZITHROMAX is prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by ZITHROMAX or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibacterial which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibacterials, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial. If this occurs, patients should contact their physician as soon as possible.

OVERDOSE Adverse reactions experienced at higher than recommended doses were similar to those seen at normal doses. In the event of overdosage, general symptomatic and supportive measures are indicated as required. CONTRAINDICATIONS Hypersensitivity Reactions Zmax is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin or any macrolide or ketolide drug. Cholestatic Jaundice/Hepatic Dysfunction Zmax is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.

OVERDOSE Adverse reactions experienced in higher than recommended doses were similar to those seen at normal doses particularly nausea, diarrhea, and vomiting. In the event of overdosage, general symptomatic and supportive measures are indicated as required. CONTRAINDICATIONS Hypersensitivity ZITHROMAX is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide drugs. Hepatic Dysfunction ZITHROMAX is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.

OVERDOSE Adverse reactions experienced in higher than recommended doses were similar to those seen at normal doses. In the event of overdosage, general symptomatic and supportive measures are indicated as required. CONTRAINDICATIONS Hypersensitivity ZITHROMAX is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, any macrolide, or ketolide drug. Hepatic Dysfunction ZITHROMAX is contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.

SIDE EFFECTS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults The data described below reflect exposure to Zmax in 728 adult patients. All patients received a single 2 g oral dose of Zmax. The population studied had community-acquired pneumonia and acute bacterial sinusitis. In controlled clinical trials with Zmax, the majority of the reported treatment-related adverse reactions were gastrointestinal in nature and mild to moderate in severity. Overall, the most common treatment-related adverse reactions in adult patients receiving a single 2 g dose of Zmax were diarrhea/loose stools (12%), nausea (4%), abdominal pain (3%), headache (1%), and vomiting (1%). The incidence of treatment-related gastrointestinal adverse reactions was 17% for Zmax and 10% for pooled comparators. Treatment-related adverse reactions following Zmax treatment that occurred with a frequency of < 1% included the following: Cardiovascular: Palpitations, chest pain Gastrointestinal: Constipation, dyspepsia, flatulence, gastritis, oral moniliasis Genitourinary: Vaginitis Nervous system: Dizziness, vertigo General: Asthenia Allergic: Rash, pruritus, urticaria Special senses: Taste perversion Pediatric Patients The data described below reflect exposure to Zmax in 907 pediatric patients. The population was 3 months to 12 years of age. All patients received a single 60 mg/kg oral dose of Zmax. As in adults, the most common treatment-related adverse reactions in pediatric subjects were gastrointestinal in nature. The pediatric subjects all received a single 60 mg/kg dose (equivalent to 27 mg/lb) of Zmax. In a trial with 450 pediatric subjects (ages 3 months to 48 months), vomiting (11%), diarrhea (10%) loose stools (9%), and abdominal pain (2%) were the most frequently reported treatment-related gastrointestinal adverse reactions. Many treatment related gastrointestinal adverse reactions with an incidence greater than 1% began on the day of dosing in these subjects [43% (68/160)] and most [53% (84/160)] resolved within 48 hr of onset. Treatment-related adverse events that were not gastrointestinal, occurring with a frequency > 1% were: rash (5%), anorexia (2%), fever (2%), and dermatitis (2%). In a second trial of 337 pediatric subjects, ages 2 years to 12 years, the most frequently reported treatment-related adverse reactions also included vomiting (14%), diarrhea (7%), loose stools (2%), nausea (4%) and abdominal pain (4%). A third trial investigated the tolerability of two different concentrations of azithromycin oral suspension in 120 pediatric subjects (ages 3 months to 48 months), all of whom were treated with azithromycin. The study evaluated the hypothesis that a more dilute, less viscous formulation (the recommended 27 mg/mL concentration of Zmax) is less likely to induce vomiting in young children than a more concentrated suspension used in other pediatric studies. The vomiting rate for subjects taking the dilute concentration azithromycin was 3% (2/61). The rate was numerically lower but not statistically different from the vomiting for the more concentrated suspension Across both treatment arms, the only treatment-related adverse events with a frequency of > 1% were vomiting (6%, 7/120) and diarrhea (2%, 2/120). Treatment-related adverse reactions with a frequency of < 1% following Zmax treatment in all 907 pediatric subjects in the Phase 3 studies were: Body as a whole: Chills, fever, flu syndrome, headache; Digestive: Abnormal stools, constipation, dyspepsia, flatulence, gastritis, gastrointestinal disorder, hepatitis; Hematologic and lymphatic: Leukopenia; Nervous system: Agitation, emotional liability, hostility, hyperkinesia, insomnia, irritability, paresthesia, Somnolence; Respiratory: Asthma, bronchitis, cough, dyspnea, pharyngitis, rhinitis; Skin and appendages: Dermatitis, fungal dermatitis, maculopapular rash, pruritus, urticaria; Special senses: Otitis media, taste perversion; Urogenital: Dysuria. Postmarketing Experience With Other Azithromycin Products Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible. Adverse events reported with azithromycin immediate release formulations during the postmarketing period for which a causal relationship may not be established include: Allergic: Arthralgia, edema, urticaria and angioedema Cardiovascular: Palpitations and arrhythmias including ventricular tachycardia and hypotension There have been reports of QT prolongation and torsades de pointes. Gastrointestinal: Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea, pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and rare reports of tongue discoloration General: Asthenia, paresthesia, fatigue, malaise and anaphylaxis Genitourinary: Interstitial nephritis, acute renal failure and vaginitis Hematopoietic: Thrombocytopenia, mild neutropenia Liver/biliary: Adverse reactions related to hepatic dysfunction have been reported in postmarketing experience with azithromycin. [See WARNINGS AND PRECAUTIONS] Nervous system: Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation and syncope Psychiatric: Aggressive reaction and anxiety Skin/appendages: Pruritus, rash, photosensitivity, serious skin reactions including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS. Special senses: Hearing disturbances including hearing loss, deafness and/or tinnitus and reports of taste/smell perversion and/or loss Laboratory Abnormalities In subjects with normal baseline values, the following clinically significant laboratory abnormalities (irrespective of drug relationship) were reported in Zmax clinical trials in adults and pediatric patients: Adults Laboratory abnormalities with an incidence of greater than or equal to 1%: reduced lymphocytes and increased eosinophils; reduced bicarbonate. Laboratory abnormalities with an incidence of less than 1%: leukopenia, neutropenia, elevated bilirubin, AST, ALT, BUN, creatinine, alterations in potassium. Where follow-up was provided, changes in laboratory tests appeared to be reversible. Pediatric Patients Laboratory abnormalities with an incidence of greater than or equal to 1%: elevated eosinophils, BUN, and potassium; decreased lymphocytes; and alterations in neutrophils; with an incidence of less than 1%: elevated SGOT, SGPT and creatinine; decreased potassium; and alterations in sodium and glucose. DRUG INTERACTIONS Nelfinavir 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 adverse reactions of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. [see ADVERSE REACTIONS] Warfarin Spontaneous post-marketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants such as warfarin, although the prothrombin time was not affected in the dedicated drug interaction study with azithromycin and warfarin. Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly. Potential Drug-Drug Interactions With Macrolides Interactions with digoxin or phenytoin have not been reported in clinical trials with azithromycin; however, no specific drug interaction studies have been performed to evaluate potential drug-drug interactions. However, drug interactions have been observed with other macrolide products. Until further data are developed regarding drug interactions when digoxin or phenytoin are used concomitantly with azithromycin careful monitoring of patients is advised.

SIDE EFFECTS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials of intravenous azithromycin for community-acquired pneumonia, in which 2 to 5 IV doses were given, the reported adverse reactions were mild to moderate in severity and were reversible upon discontinuation of the drug. The majority of patients in these trials had one or more comorbid diseases and were receiving concomitant medications. Approximately 1.2% of the patients discontinued intravenous ZITHROMAX therapy, and a total of 2.4% discontinued azithromycin therapy by either the intravenous or oral route because of clinical or laboratory side effects. In clinical trials conducted in patients with pelvic inflammatory disease, in which 1 to 2 IV doses were given, 2% of women who received monotherapy with azithromycin and 4% who received azithromycin plus metronidazole discontinued therapy due to clinical side effects. Clinical adverse reactions leading to discontinuations from these studies were gastrointestinal (abdominal pain, nausea, vomiting, diarrhea), and rashes; laboratory side effects leading to discontinuation were increases in transaminase levels and/or alkaline phosphatase levels. Overall, the most common adverse reactions associated with treatment in adult patients who received IV/Oral ZITHROMAX in studies of community-acquired pneumonia were related to the gastrointestinal system with diarrhea/loose stools (4.3%), nausea (3.9%), abdominal pain (2.7%), and vomiting (1.4%) being the most frequently reported. Approximately 12% of patients experienced a side effect related to the intravenous infusion; most common were pain at the injection site (6.5%) and local inflammation (3.1%). The most common adverse reactions associated with treatment in adult women who received IV/Oral ZITHROMAX in trials of pelvic inflammatory disease were related to the gastrointestinal system. Diarrhea (8.5%) and nausea (6.6%) were most commonly reported, followed by vaginitis (2.8%), abdominal pain (1.9%), anorexia (1.9%), rash and pruritus (1.9%). When azithromycin was coadministered with metronidazole in these trials, a higher proportion of women experienced adverse reactions of nausea (10.3%), abdominal pain (3.7%), vomiting (2.8%), infusion site reaction, stomatitis, dizziness, or dyspnea (all at 1.9%). Adverse reactions that occurred with a frequency of 1% or less included the following: Gastrointestinal: Dyspepsia, flatulence, mucositis, oral moniliasis, and gastritis. Nervous system: Headache, somnolence. Allergic: Bronchospasm. Special senses: Taste perversion. Postmarketing Experience The following adverse reactions have been identified during post-approval use of azithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported with azithromycin during the post-marketing period in adult and/or pediatric patients for which a causal relationship may not be established include: Allergic: Arthralgia, edema, urticaria and angioedema. Cardiovascular: Arrhythmias including ventricular tachycardia and hypotension. There have been reports of QT prolongation and torsades de pointes. Gastrointestinal: Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea, pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and reports of tongue discoloration. General: Asthenia, paresthesia, fatigue, malaise and anaphylaxis (including fatalities). Genitourinary: Interstitial nephritis and acute renal failure and vaginitis. Hematopoietic: Thrombocytopenia. Liver/biliary: Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure. [see WARNINGS AND PRECAUTIONS] Nervous system: Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation and syncope. Psychiatric: Aggressive reaction and anxiety. Skin/appendages: Pruritus, serious skin reactions including, erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis, and DRESS. Special senses: Hearing disturbances including hearing loss, deafness and/or tinnitus and reports of taste/smell perversion and/or loss. Laboratory Abnormalities Significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows: elevated ALT (SGPT), AST (SGOT), creatinine (4 to 6%) elevated LDH, bilirubin (1 to 3%) leukopenia, neutropenia, decreased platelet count, and elevated serum alkaline phosphatase (less than 1%) When follow-up was provided, changes in laboratory tests appeared to be reversible. In multiple-dose clinical trials involving more than 750 patients treated with ZITHROMAX (IV/Oral), less than 2% of patients discontinued azithromycin therapy because of treatment-related liver enzyme abnormalities. DRUG INTERACTIONS Nelfinavir 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 adverse reactions of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. [see ADVERSE REACTIONS] Warfarin Spontaneous post-marketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants such as warfarin, although the prothrombin time was not affected in the dedicated drug interaction study with azithromycin and warfarin. Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly. Potential Drug-Drug Interaction With Macrolides Interactions with the following 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. However, drug interactions have been observed with other macrolide products. Until further data are developed regarding drug interactions when digoxin or phenytoin are used with azithromycin careful monitoring of patients is advised.

SIDE EFFECTS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials, most of the reported adverse reactions were mild to moderate in severity and were reversible upon discontinuation of the drug. Approximately 0.7% of the patients from the multiple-dose clinical trials discontinued ZITHROMAX (azithromycin) therapy because of treatment-related adverse reactions. Serious adverse reactions included angioedema and cholestatic jaundice. Most of the adverse reactions leading to discontinuation were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, or abdominal pain. [see Clinical Studies] Multiple-dose Regimen Overall, the most common adverse reactions in adult patients receiving a multiple-dose regimen of ZITHROMAX were related to the gastrointestinal system with diarrhea/loose stools (5%), nausea (3%), and abdominal pain (3%) being the most frequently reported. No other adverse reactions occurred in patients on the multiple-dose regimen of ZITHROMAX with a frequency greater than 1%. Adverse reactions that occurred with a frequency of 1% or less included the following: Cardiovascular: Palpitations and chest pain. Gastrointestinal: Dyspepsia, flatulence, vomiting, melena, and cholestatic jaundice. Genitourinary: Monilia, vaginitis, and nephritis. Nervous System: Dizziness, headache, vertigo, and somnolence. General: Fatigue. Allergic: Rash, photosensitivity, and angioedema. Chronic therapy with 1200 mg weekly regimen The nature of adverse reactions seen with the 1200 mg weekly dosing regimen for the prevention of Mycobacterium avium infection in severely immunocompromised HIV-infected patients were similar to those seen with short-term dosing regimens. [see Clinical Studies] Chronic Therapy With 600 mg Daily Regimen Combined With Ethambutol The nature of adverse reactions seen with the 600 mg daily dosing regimen for the treatment of Mycobacterium avium complex infection in severely immunocompromised HIV-infected patients were similar to those seen with short term dosing regimens. Five percent of patients experienced reversible hearing impairment in the pivotal clinical trial for the treatment of disseminated MAC in patients with AIDS. Hearing impairment has been reported with macrolide antibiotics, especially at higher doses. Other treatment related adverse reactions occurring in > 5% of subjects and seen at any time during a median of 87.5 days of therapy include: abdominal pain (14%), nausea (14%), vomiting (13%), diarrhea (12%), flatulence (5%), headache (5%), and abnormal vision (5%). Discontinuations from treatment due to laboratory abnormalities or adverse reactions considered related to study drug occurred in 8 of 88 (9.1%) of subjects. Single 1 Gram Dose Regimen Overall, the most common adverse reactions in patients receiving a single-dose regimen of 1 gram of ZITHROMAX were related to the gastrointestinal system and were more frequently reported than in patients receiving the multiple-dose regimen. Adverse reactions that occurred in patients on the single 1 gram dosing regimen of ZITHROMAX with a frequency of 1% or greater included diarrhea/loose stools (7%), nausea (5%), abdominal pain (5%), vomiting (2%), dyspepsia (1%), and vaginitis (1%). Post-marketing Experience The following adverse reactions have been identified during post approval use of azithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported with azithromycin during the postmarketing period in adult and/or pediatric patients for which a causal relationship may not be established include: Allergic: Arthralgia, edema, urticaria, and angioedema. Cardiovascular: Arrhythmias, including ventricular tachycardia, and hypotension. There have been reports of QT prolongation and torsades de pointes. Gastrointestinal: Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and tongue discoloration. General: Asthenia, paresthesia, fatigue, malaise, and anaphylaxis Genitourinary: Interstitial nephritis, acute renal failure, and vaginitis. Hematopoietic: Thrombocytopenia. Liver/Biliary: Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure. [see WARNINGS AND PRECAUTIONS] Nervous System: Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation, and syncope. Psychiatric: Aggressive reaction and anxiety. Skin/Appendages: Pruritus, and serious skin reactions including erythema multiforme, Stevens-Johnson Syndrome, toxic epidermal necrolysis, and DRESS. Special Senses: Hearing disturbances including hearing loss, deafness, and/or tinnitus, and reports of taste/smell perversion and/or loss. Laboratory Abnormalities Significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows: With an incidence of 1-2%, elevated serum creatine phosphokinase, potassium, ALT (SGPT), GGT, and AST (SGOT). With an incidence of less than 1%, leukopenia, neutropenia, decreased platelet count, elevated serum alkaline phosphatase, bilirubin, BUN, creatinine, blood glucose, LDH, and phosphate. When follow-up was provided, changes in laboratory tests appeared to be reversible. In multiple-dose clinical trials involving more than 3000 patients, 3 patients discontinued therapy because of treatment-related liver enzyme abnormalities and 1 because of a renal function abnormality. In a phase 1 drug interaction study performed in normal volunteers, 1 of 6 subjects given the combination of azithromycin and rifabutin, 1 of 7 given rifabutin alone, and 0 of 6 given azithromycin alone developed a clinically significant neutropenia ( < 500 cells/mm³). Laboratory abnormalities seen in clinical trials for the prevention of disseminated Mycobacterium avium disease in severely immunocompromised HIV-infected patients. [see Clinical Studies] Chronic therapy (median duration: 87.5 days, range: 1-229 days) that resulted in laboratory abnormalities in > 5% of subjects with normal baseline values in the pivotal trial for treatment of disseminated MAC in severely immunocompromised HIV-infected patients treated with azithromycin 600 mg daily in combination with ethambutol include: a reduction in absolute neutrophils to < 50% of the lower limit of normal (10/52, 19%) and an increase to five times the upper limit of normal in alkaline phosphatase (3/35, 9%). These findings in subjects with normal baseline values are similar when compared to all subjects for analyses of neutrophil reductions (22/75, 29%) and elevated alkaline phosphatase (16/80, 20%). Causality of these laboratory abnormalities due to the use of study drug has not been established. DRUG INTERACTIONS Nelfinavir 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 adverse reactions of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. [see ADVERSE REACTIONS] Warfarin Spontaneous post-marketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants such as warfarin, although the prothrombin time was not affected in the dedicated drug interaction study with azithromycin and warfarin. Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly. Potential Drug-Drug Interaction With Macrolides Interactions with the following 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. However, drug interactions have been observed with other macrolide products. Until further data are developed regarding drug interactions when digoxin or phenytoin are used with azithromycin careful monitoring of patients is advised.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Allergic And Skin Reactions Serious allergic reactions, including angioedema, anaphylaxis, Stevens Johnson syndrome, and toxic epidermal necrolysis have been reported in patients on azithromycin therapy using other formulations. Fatalities have been reported. Cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also been reported. Despite initially successful symptomatic treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms recurred soon thereafter in some patients without further azithromycin exposure. These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin and subsequent exposure to antigen has not been determined. If an allergic reaction occurs, appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued. 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. QT Prolongation Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with macrolides, including azithromycin. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving azithromycin. Providers should consider the risk of QT prolongation which can be fatal when weighing the risks and benefits of azithromycin for at-risk groups including: patients with known prolongation of the QT interval, a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure patients on drugs known to prolong the QT interval patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents Elderly patients may be more susceptible to drug-associated effects on the QT interval. Clostridium difficile-Associated Diarrhea (CDAD) Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Zmax, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Exacerbation Of Myasthenia Gravis Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy. Gastrointestinal Disturbances A higher incidence of gastrointestinal adverse events (8 of 19 subjects) was observed when Zmax was administered to a limited number of subjects with GFR < 10 mL/min. [See Use In Specific Populations] Development Of Drug Resistant Bacteria Prescribing Zmax in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Patient Counseling Information General Patient Counseling Patients should be instructed to take Zmax on an empty stomach (at least 1 hr before or 2 hr following a meal). To ensure accurate dosing for children, use of a dosing spoon, medicine syringe, or cup is recommended. Patients should be told that Zmax needs time to work, so the patient may not feel better right away. If the patient's symptoms do not improve in a few days, the patient or their guardian should call their doctor. Patients should be instructed to immediately contact a physician if any signs of an allergic reaction occur. Diarrhea is a common problem caused by antibiotics which usually ends when the antibiotic is discontinued. Sometimes after starting treatment with antibiotics, patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibiotic. If this occurs, patients should contact their physician as soon as possible. Patients who vomit within the first hr should contact their health care provider about further treatment. Keep bottle tightly closed. Store at room temperature. Use within 12 hr of constitution. Shake bottle well before use. Adult patients should consume the entire contents of the bottle; pediatric patients should take the recommended dose and MUST discard any unused portion. Patients should be advised that Zmax may be taken without regard to antacids containing magnesium hydroxide and/or aluminum hydroxide. Patients should be counseled that antibacterial drugs including Zmax should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). Not taking the complete prescribed dose may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by Zmax or other antibacterial drugs in the future. See FDA-approved Patient Labeling Nonclinical Toxicology 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 in rats given daily doses up to 10 mg/kg (approximately 0.05 times the single 2 g oral adult human dose based on body surface area). Use In Specific Populations Pregnancy Teratogenic Effects Pregnancy Category B: 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 daily doses in rats and mice, based on body surface area, are estimated to be approximately equivalent to one or one-half of, respectively, the single adult oral dose of 2 g. In the animal studies, no evidence of harm to the fetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed. Nursing Mothers Azithromycin has been reported to be excreted in human breast milk in small amounts. Caution should be exercised when azithromycin is administered to a nursing woman. Pediatric Use Safety and effectiveness in the treatment of pediatric patients under 6 months of age have not been established. Community-Acquired Pneumonia: The safety and effectiveness of Zmax have been established in pediatric patients 6 months of age or older with community-acquired pneumonia due to Chlamydophila pneumoniae, Mycoplasma pneumoniae, Haemophilus influenzae or Streptococcus pneumoniae. Use of Zmax for these patients is supported by evidence from adequate and well-controlled studies of Zmax in adults with additional safety and pharmacokinetic data in pediatric patients. [See DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, CLINICAL PHARMACOLOGY] Acute bacterial sinusitis: Safety and effectiveness in the treatment of pediatric patients with acute bacterial sinusitis have not been established. Geriatric Use Data collected from the azithromycin capsule and tablet formulations indicate that a dosage adjustment does not appear to be necessary for older patients with normal renal function (for their age) and hepatic function receiving treatment with Zmax. In clinical trials of Zmax, 17% of subjects were at least 65 years of age (214/1292) and 5% of subjects (59/1292) were at least 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Elderly patients may be more susceptible to development of torsades de pointes arrhythmia than younger patients. [See WARNINGS AND PRECAUTIONS] Renal Impairment No dosage adjustment is recommended for patients GFR > 10 mL/min. Caution should be exercised when Zmax is administered to patients with GFR < 10 mL/min, due to a higher incidence of gastrointestinal adverse events (8 of 19 subjects) observed in a limited number of subjects with GFR < 10 mL/min. [See CLINICAL PHARMACOLOGY] Gender The impact of gender on the pharmacokinetics of azithromycin has not been evaluated for Zmax. However, previous studies have demonstrated no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment of Zmax is recommended based on gender.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Stevens-Johnson Syndrome, and toxic epidermal necrolysis have been reported in patients on azithromycin therapy. [see CONTRAINDICATIONS] Fatalities have been reported. Cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also been reported. Despite initially successful symptomatic treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms recurred soon thereafter in some patients without further azithromycin exposure. These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin and subsequent prolonged exposure to antigen is unknown at present. If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that the allergic symptoms may reappear after symptomatic therapy has been discontinued. 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. QT Prolongation Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen with treatment with macrolides, including azithromycin. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving azithromycin. Providers should consider the risk of QT prolongation, which can be fatal when weighing the risks and benefits of azithromycin for at-risk groups including: patients with known prolongation of the QT interval, a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure. patients on drugs known to prolong the QT interval. patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval. Clostridium Difficile-Associated Diarrhea Clostridium difficile associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including ZITHROMAX (azithromycin for injection), and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibacterial use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibacterial use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Exacerbation Of Myasthenia Gravis Exacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azitrhromycin therapy. Infusion Site Reactions ZITHROMAX for injection should be reconstituted and diluted as directed and administered as an intravenous infusion over not less than 60 minutes. [see DOSAGE AND ADMINISTRATION] Local IV site reactions have been reported with the intravenous administration of azithromycin. The incidence and severity of these reactions were the same when 500 mg azithromycin was given over 1 hour (2 mg/mL as 250 mL infusion) or over 3 hr (1 mg/mL as 500 mL infusion) [see ADVERSE REACTIONS]. All volunteers who received infusate concentrations above 2.0 mg/mL experienced local IV site reactions and, therefore, higher concentrations should be avoided. Development Of Drug-Resistant Bacteria Prescribing ZITHROMAX in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Nonclinical Toxicology 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 in rats given daily doses up to 10 mg/kg (approximately 0.2 times an adult daily dose of 500 mg based on body surface area). Use In Specific Populations Pregnancy Teratogenic Effects Pregnancy Category B: Reproductive and development studies have not been conducted using IV administration of azithromycin to animals. Reproduction studies have been performed in rats and mice using oral administration at doses up to moderately maternally toxic dose concentrations (i.e., 200 mg/kg/day). These daily doses in rats and mice ]based on body surface area, are estimated to be 4 and 2 times, respectively, an adult daily dose of 500 mg. In the animal studies, no evidence of harm to the fetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed. Nursing Mothers Azithromycin has been reported to be excreted in human breast milk in small amounts. Caution should be exercised when azithromycin is administered to a nursing woman. Pediatric Use Safety and effectiveness of azithromycin for injection in children or adolescents under 16 years have not been established. In controlled clinical studies, azithromycin has been administered to pediatric patients (age 6 months to 16 years) by the oral route. For information regarding the use of ZITHROMAX (azithromycin for oral suspension) in the treatment of pediatric patients, [see INDICATIONS AND USAGE, and DOSAGE AND ADMINISTRATION] of the prescribing information for ZITHROMAX (azithromycin for oral suspension) 100 mg/5 mL and 200 mg/5 mL bottles. Geriatric Use Pharmacokinetic studies with intravenous azithromycin have not been performed in older volunteers. Pharmacokinetics of azithromycin following oral administration in older volunteers (65–85 years old) were similar to those in younger volunteers (18–40 years old) for the 5-day therapeutic regimen. In multiple-dose clinical trials of intravenous azithromycin in the treatment of community-acquired pneumonia, 45% of patients (188/414) were at least 65 years of age and 22% of patients (91/414) were at least 75 years of age. No overall differences in safety were observed between these subjects and younger subjects in terms of adverse reactions, laboratory abnormalities, and discontinuations. Similar decreases in clinical response were noted in azithromycin- and comparator-treated patients with increasing age. ZITHROMAX (azithromycin for injection) contains 114 mg (4.96 mEq) of sodium per vial. At the usual recommended doses, patients would receive 114 mg (4.96 mEq) of sodium. The geriatric population may respond with a blunted natriuresis to salt loading. The total sodium content from dietary and nondietary sources may be clinically important with regard to such diseases as congestive heart failure. Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than younger patients. [see WARNINGS AND PRECAUTIONS]

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Hypersensitivity Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Stevens-Johnson Syndrome, toxic epidermal necrolysis, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have been reported rarely in patients on azithromycin therapy. [see CONTRAINDICATIONS] Fatalities have been reported. Despite initially successful symptomatic treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms recurred soon thereafter in some patients without further azithromycin exposure. These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin and subsequent prolonged exposure to antigen is presently unknown. If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that allergic symptoms may reappear when symptomatic therapy is discontinued. 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. Infantile Hypertrophic Pyloric Stenosis (IHPS) Following the use of azithromycin in neonates (treatment up to 42 days of life), infantile hypertrophic pyloric stenosis (IHPS) has been reported. Parents and caregivers should be informed to contact their physician if vomiting or irritability with feeding occurs. QT Prolongation Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen with treatment with macrolides, including azithromycin. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving azithromycin. Providers should consider the risk of QT prolongation which can be fatal when weighing the risks and benefits of azithromycin for at-risk groups including: patients with known prolongation of the QT interval, a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure patients on drugs known to prolong the QT interval patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents. Elderly patients may be more susceptible to drug-associated effects on the QT interval. Clostridium Difficile-Associated Diarrhea (CDAD) CDAD has been reported with use of nearly all antibacterial agents, including ZITHROMAX, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon, leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin-producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antibacterial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Exacerbation Of Myasthenia Gravis Exacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azitrhromycin therapy. Use In Sexually Transmitted Infections ZITHROMAX, (single dose 1 g packet) at the recommended dose, should not be relied upon to treat gonorrhea or syphilis. Antibacterial agents used in high doses for short periods of time to treat non-gonococcal urethritis may mask or delay the symptoms of incubating gonorrhea or 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 antibacterial therapy and follow-up tests for these diseases should be initiated if infection is confirmed. Development Of Drug-Resistant Bacteria Prescribing ZITHROMAX in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria. Nonclinical Toxicology 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 in rats given daily doses up to 10 mg/kg (approximately 0.2 times an adult daily dose of 600 mg based on body surface area). Use In Specific Populations Pregnancy Teratogenic Effects Pregnancy Category B: Reproduction studies have been performed in rats and mice at doses up to moderately maternally toxic dose levels (i.e., 200 mg/kg/day). These daily doses in rats and mice, based on body surface area, are estimated to be 3.2 and 1.6 times, respectively, an adult daily dose of 600 mg. In the animal studies, no evidence of harm to the fetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed. Nursing Mothers Azithromycin has been reported to be excreted in breast milk in small amounts. Caution should be exercised when azithromycin is administered to a nursing woman. Pediatric Use In controlled clinical studies, azithromycin has been administered to pediatric patients ranging in age from 6 months to 12 years. For information regarding the use of ZITHROMAX (azithromycin for oral suspension) in the treatment of pediatric patients, [see INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION] of the prescribing information for ZITHROMAX (azithromycin for oral suspension) 100 mg/5 mL and 200 mg/5 mL bottles. HIV-Infected Pediatric Patients: The safety and efficacy of azithromycin for the prevention or treatment of MAC in HIV-infected children have not been established. Safety data are available for 72 children 5 months to 18 years of age (mean 7 years) who received azithromycin for treatment of opportunistic infections. The mean duration of therapy was 242 days (range 3-2004 days) at doses of < 1 to 52 mg/kg/day (mean 12 mg/kg/day). Adverse reactions were similar to those observed in the adult population, most of which involved the gastrointestinal tract. Treatment-related reversible hearing impairment in children was observed in 4 subjects (5.6%). Two (2.8%) children prematurely discontinued treatment due to adverse reactions: one due to back pain and one due to abdominal pain, hot and cold flushes, dizziness, headache, and numbness. A third child discontinued due to a laboratory abnormality (eosinophilia). The protocols upon which these data are based specified a daily dose of 10-20 mg/kg/day (oral and/or IV) of azithromycin. Geriatric Use 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 responses 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 arrhythmias than younger patients. [see WARNINGS AND PRECAUTIONS] ZITHROMAX 600 mg tablets contain 2.1 mg of sodium per tablet. ZITHROMAX for oral suspension 1 gram single-dose packets contain 37.0 mg of sodium per packet. Geriatric Patients with Opportunistic Infections, Including (MAC) Disease Safety data are available for 30 patients (65-94 years old) treated with azithromycin at doses > 300 mg/day for a mean of 207 days. These patients were treated for a variety of opportunistic infections, including MAC. The adverse reaction were generally similar to that seen in younger patients, except for a higher incidence of adverse reactions relating to the gastrointestinal system and to reversible impairment of hearing. [see DOSAGE AND ADMINISTRATION]