PEDIATRIC USE SECTION.

8.4 Pediatric Use. [see Clinical Pharmacology (12.3), Indications and Usage (1.2), and Dosage and Administration (2.2)] Safety and effectiveness in the treatment of pediatric patients with acute otitis media, acute bacterial sinusitis and community-acquired pneumonia under months of age have not been established. Use of ZITHROMAX for the treatment of acute bacterial sinusitis and community-acquired pneumonia in pediatric patients (6 months of age or greater) is supported by adequate and well-controlled trials in adults.. Pharyngitis/Tonsillitis: Safety and effectiveness in the treatment of pediatric patients with pharyngitis/tonsillitis under years of age have not been established.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. 6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 side effects were mild to moderate in severity and were reversible upon discontinuation of the drug. Potentially serious adverse reactions of angioedema and cholestatic jaundice were reported. Approximately 0.7% of the patients (adults and pediatric patients) from the 5-day multiple-dose clinical trials discontinued ZITHROMAX (azithromycin) therapy because of treatment-related adverse reactions. In adults given 500 mg/day for days, the discontinuation rate due to treatment-related adverse reactions was 0.6%. In clinical trials in pediatric patients given 30 mg/kg, either as single dose or over days, discontinuation from the trials due to treatment-related adverse reactions was approximately 1%. 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 (14.2)] Adults. Multiple-dose regimens: Overall, the most common treatment-related adverse reactions in adult patients receiving multiple-dose regimens of ZITHROMAX were related to the gastrointestinal system with diarrhea/loose stools (4 to 5%), nausea (3%), and abdominal pain (2 to 3%) being the most frequently reported.No other adverse reactions occurred in patients on the multiple-dose regimens of ZITHROMAX with frequency greater than 1%. Adverse reactions that occurred with frequency of 1% or less included the following:Cardiovascular: Palpitations, 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, pruritus, photosensitivity, and angioedema.. Single 1-gram dose regimen:Overall, the most common adverse reactions in patients receiving single-dose regimen of 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 frequency of 1% or greater included diarrhea/loose stools (7%), nausea (5%), abdominal pain (5%), vomiting (2%), dyspepsia (1%), and vaginitis (1%).. Single 2-gram dose regimen:Overall, the most common adverse reactions in patients receiving single 2-gram dose of ZITHROMAX were related to the gastrointestinal system. Adverse reactions that occurred in patients in this study with frequency of 1% or greater included nausea (18%), diarrhea/loose stools (14%), vomiting (7%), abdominal pain (7%), vaginitis (2%), dyspepsia (1%), and dizziness (1%). The majority of these complaints were mild in nature.. Pediatric Patients. Single and Multiple-dose regimens: The types of adverse reactions in pediatric patients were comparable to those seen in adults, with different incidence rates for the dosage regimens recommended in pediatric patients.. Acute Otitis Media: For the recommended total dosage regimen of 30 mg/kg, the most frequent adverse reactions (>=1%) attributed to treatment were diarrhea, abdominal pain, vomiting, nausea, and rash. [see Dosage and Administration (2) and Clinical Studies (14.2)] The incidence, based on dosing regimen, is described in the table below:Dosage RegimenDiarrhea %Abdominal Pain %Vomiting %Nausea %Rash %1-day4.3%1.4%4.9%1.0%1.0%3-day2.6%1.7%2.3%0.4%0.6%5-day1.8%1.2%1.1%0.5%0.4%. Community-Acquired Pneumonia: For the recommended dosage regimen of 10 mg/kg on Day followed by mg/kg on Days 2-5, the most frequent adverse reactions attributed to treatment were diarrhea/loose stools, abdominal pain, vomiting, nausea, and rash.The incidence is described in the table below:Dosage RegimenDiarrhea/Loose stools %Abdominal Pain %Vomiting %Nausea %Rash %5-day5.8%1.9%1.9%1.9%1.6%. Pharyngitis/Tonsillitis: For the recommended dosage regimen of 12 mg/kg on Days 1-5, the most frequent adverse reactions attributed to treatment were diarrhea, vomiting, abdominal pain, nausea, and headache.The incidence is described in the table below:Dosage RegimenDiarrhea %Abdominal Pain %Vomiting %Nausea %Rash %Headache %5-day5.4%3.4%5.6%1.8%0.7%1.1%With any of the treatment regimens, no other adverse reactions occurred in pediatric patients treated with ZITHROMAX with frequency greater than 1%. Adverse reactions that occurred with frequency of 1% or less included the following:Cardiovascular: Chest pain.Gastrointestinal: Dyspepsia, constipation, anorexia, enteritis, flatulence, gastritis, jaundice, loose stools, and oral moniliasis.Hematologic and Lymphatic: Anemia and leukopenia.Nervous System: Headache (otitis media dosage), hyperkinesia, dizziness, agitation, nervousness, and insomnia.General: Fever, face edema, fatigue, fungal infection, malaise, and pain.Allergic: Rash and allergic reaction.Respiratory: Cough, pharyngitis, pleural effusion, and rhinitis.Skin and Appendages: Eczema, fungal dermatitis, pruritus, sweating, urticaria, and vesiculobullous rash.Special Senses: Conjunctivitis.. 6.2Postmarketing Experience. The following adverse reactions have been identified during post-approval use of azithromycin. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Adverse reactions reported with azithromycin during the postmarketing period in adult and/or pediatric patients for which 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.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 (5.2)]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, AGEP, 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.. 6.3Laboratory Abnormalities. Adults:Clinically significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows: with an incidence of greater than 1%: decreased hemoglobin, hematocrit, lymphocytes, neutrophils, and blood glucose; elevated serum creatine phosphokinase, potassium, ALT, GGT, AST, BUN, creatinine, blood glucose, platelet count, lymphocytes, neutrophils, and eosinophils; with an incidence of less than 1%: leukopenia, neutropenia, decreased sodium, potassium, platelet count, elevated monocytes, basophils, bicarbonate, serum alkaline phosphatase, bilirubin, LDH, and phosphate. The majority of subjects with elevated serum creatinine also had abnormal values at baseline. When follow-up was provided, changes in laboratory tests appeared to be reversible.In multiple-dose clinical trials involving more than 5000 patients, four patients discontinued therapy because of treatment-related liver enzyme abnormalities and one because of renal function abnormality.. Pediatric Patients:. One, Three, and Five-Day RegimensLaboratory data collected from comparative clinical trials employing two 3-day regimens (30 mg/kg or 60 mg/kg in divided doses over days), or two 5-day regimens (30 mg/kg or 60 mg/kg in divided doses over days) were similar for regimens of azithromycin and all comparators combined, with most clinically significant laboratory abnormalities occurring at incidences of 1-5%. Laboratory data for patients receiving 30 mg/kg as single dose were collected in one single center trial. In that trial, an absolute neutrophil count between 500-1500 cells/mm3 was observed in 10/64 patients receiving 30 mg/kg as single dose, 9/62 patients receiving 30 mg/kg given over days, and 8/63 comparator patients. No patient had an absolute neutrophil count <500 cells/mm3.In multiple-dose clinical trials involving approximately 4700 pediatric patients, no patients discontinued therapy because of treatment-related laboratory abnormalities.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 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 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 g). Similarly, it has been shown in the dog (10 mg/kg/day dose) at the observed maximal serum concentration of mcg/mL (1.2 times the observed Cmax of 0.821 mcg/mL at the adult dose of 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 times the pediatric dose Cmax. The significance of these findings for animals and for humans is unknown.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 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. In fertility studies conducted in male and female rats, oral administration of azithromycin for 64 to 66 days (males) or 15 days (females) prior to and during cohabitation resulted in decreased pregnancy rate at 20 and 30 mg/kg/day when both males and females were treated with azithromycin. This minimal effect on pregnancy rate (approximately 12% reduction compared to concurrent controls) did not become more pronounced when the dose was increased from 20 to 30 mg/kg/day (approximately 0.4 to 0.6 times the adult daily dose of 500 mg based on body surface area) and it was not observed when only one animal in the mated pair was treated. There were no effects on any other reproductive parameters, and there were no effects on fertility at 10 mg/kg/day. The relevance of these findings to patients being treated with azithromycin at the doses and durations recommended in the prescribing information is uncertain.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Azithromycin is macrolide antibacterial drug. [see Microbiology (12.4)] 12.2 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 ElectrophysiologyQTc interval prolongation was studied in 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 dose- and concentration- dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were (10) ms, (12) ms and (14) ms with the co-administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.. 12.3 Pharmacokinetics. Following oral administration of single 500 mg dose (two 250 mg tablets) to 36 fasted healthy male volunteers, the mean (SD) pharmacokinetic parameters were AUC0-72=4.3 (1.2) mcghr/mL; Cmax=0.5 (0.2) mcg/mL; Tmax=2.2 (0.9) hours. Two azithromycin 250 mg tablets are bioequivalent to single 500 mg tablet.In two-way crossover study, 12 adult healthy volunteers (6 males, females) received 1500 mg of azithromycin administered in single daily doses over either days (two 250 mg tablets on day 1, followed by one 250 mg tablet on days 2-5) or days (500 mg per day for days 1-3). Due to limited serum samples on day (3-day regimen) and days 2-4 (5-day regimen), the serum concentration-time profile of each subject was fit to 3-compartment model and the AUC0- for the fitted concentration profile was comparable between the 5-day and 3-day regimens.3-Day Regimen5-Day RegimenPharmacokinetic Parameter [mean (SD)]Day 1Day 3Day 1Day 5Cmax (serum, mcg/mL)0.44 (0.22)0.54 (0.25)0.43 (0.20)0.24 (0.06)Serum AUC0- (mcghr/mL)17.4 (6.2)Total AUC for the entire 3-day and 5-day regimens. 14.9 (3.1) Serum T1/2 71.8 hr68.9 hr. AbsorptionThe absolute bioavailability of azithromycin 250 mg capsules is 38%.In two-way crossover study in which 12 healthy subjects received single 500 mg dose of azithromycin (two 250 mg tablets) with or without high fat meal, food was shown to increase Cmax by 23% but had no effect on AUC.When azithromycin oral suspension was administered with food to 28 adult healthy male subjects, Cmax increased by 56% and AUC was unchanged.. DistributionThe 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 mcg/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 human tissues, 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 significance of these tissue concentration data is unknown.Following regimen of 500 mg on the first day and 250 mg daily for days, very low concentrations were noted in cerebrospinal fluid (less than 0.01 mcg/mL) in the presence of noninflamed meninges.. MetabolismIn vitro and in vivo studies to assess the metabolism of azithromycin have not been performed.. EliminationPlasma concentrations of azithromycin following single 500 mg oral and IV doses declined in polyphasic pattern resulting in mean apparent plasma clearance of 630 mL/min and terminal elimination half-life of 68 hr. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues. Biliary excretion of azithromycin, predominantly as unchanged drug, is major route of elimination. Over the course of week, approximately 6% of the administered dose appears as unchanged drug in urine.. Specific Populations. Patients with Renal ImpairmentAzithromycin pharmacokinetics was investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of single 1.0 dose of azithromycin (4 250 mg capsules), 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 Cmax and AUC0-120 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).. Patients with Hepatic ImpairmentThe pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established.. Male and Female PatientsThere are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended based on gender.. Geriatric PatientsPharmacokinetic parameters in older volunteers (65 to 85 years old) were similar to those in young adults (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 (8.5)] Pediatric PatientsIn two clinical studies, azithromycin for oral suspension was dosed at 10 mg/kg on day 1, followed by mg/kg on days through in two groups of pediatric patients (aged 1-5 years and 5-15 years, respectively). The mean pharmacokinetic parameters on day were Cmax=0.216 mcg/mL, Tmax=1.9 hr, and AUC0-24=1.822 mcghr/mL for the to 5-year-old group and were Cmax=0.383 mcg/mL, Tmax=2.4 hr, and AUC0-24=3.109 mcghr/mL for the to 15-year-old group.In another study, 33 pediatric patients received doses of 12 mg/kg/day (maximum daily dose 500 mg) for days, of whom 31 patients were evaluated for azithromycin pharmacokinetics following low fat breakfast. In this study, azithromycin concentrations were determined over 24 hr period following the last daily dose. Patients weighing above 41.7 kg received the maximum adult daily dose of 500 mg. Seventeen patients (weighing 41.7 kg or less) received total dose of 60 mg/kg. The following table shows pharmacokinetic data in the subset of pediatric patients who received total dose of 60 mg/kg.Pharmacokinetic Parameter[mean (SD)]5-Day Regimen(12 mg/kg for days)N17Cmax (mcg/mL)0.5 (0.4)Tmax (hr)2.2 (0.8)AUC0-24(mcghr/mL)3.9 (1.9)Single dose pharmacokinetics of azithromycin in pediatric patients given doses of 30 mg/kg have not been studied. [see Dosage and Administration (2)] Drug Interaction StudiesDrug interaction studies were performed with azithromycin and other drugs likely to be co-administered. The effects of co-administration of azithromycin on the pharmacokinetics of other drugs are shown in Table and the effects of other drugs on the pharmacokinetics of azithromycin are shown in Table 2.Co-administration of azithromycin at therapeutic doses had modest effect on the pharmacokinetics of the drugs listed in Table 1. No dosage adjustment of drugs listed in Table is recommended when co-administered with azithromycin.Co-administration of azithromycin with efavirenz or fluconazole had 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 (7.3)] Table 1. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of AzithromycinCo-administered DrugDose of Co-administered DrugDose of AzithromycinnRatio (with/without azithromycin) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect 1.00Mean Cmax Mean AUCAtorvastatin10 mg/day for days500 mg/day orally on days 6-8120.83(0.63 to 1.08)1.01(0.81 to 1.25)Carbamazepine200 mg/day for days, then 200 mg twice day for 18 days500 mg/day orally for days 16-1870.97(0.88 to 1.06)0.96(0.88 to 1.06)Cetirizine20 mg/day for 11 days500 mg orally on day 7, then 250 mg/day on days 8-11141.03(0.93 to 1.14)1.02(0.92 to 1.13)Didanosine200 mg orally twice day for 21 days1200 mg/day orally on days 8-2161.44(0.85 to 2.43)1.14(0.83 to 1.57)Efavirenz400 mg/day for days600 mg orally on day 7141.04 90% Confidence interval not reported 0.95 Fluconazole200 mg orally single dose1200 mg orally single dose181.04(0.98 to 1.11)1.01(0.97 to 1.05)Indinavir800 mg three times day for days1200 mg orally on day 5180.96(0.86 to 1.08)0.90(0.81 to 1.00)Midazolam15 mg orally on day 3500 mg/day orally for days121.27(0.89 to 1.81)1.26(1.01 to 1.56)Nelfinavir750 mg three times day for 11 days1,200 mg orally on day 9140.90(0.81 to 1.01)0.85(0.78 to 0.93)Sildenafil100 mg on days and 4500 mg/day orally for days121.16(0.86 to 1.57)0.92(0.75 to 1.12)Theophylline4 mg/kg IV on days 1, 11, 25500 mg orally on day 7, 250 mg/day on days 8-11101.19(1.02 to 1.40)1.02(0.86 to 1.22)Theophylline300 mg orally twice day for 15 days500 mg orally on day 6, then 250 mg/day on days 7-1081.09(0.92 to 1.29)1.08(0.89 to 1.31)Triazolam0.125 mg on day 2500 mg orally on day 1, then 250 mg/day on day 2121.06 1.02 Trimethoprim/Sulfamethoxazole160 mg/800 mg/day orally for days1200 mg orally on day 7120.85(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)Zidovudine500 mg/day orally for 21 days600 mg/day orally for 14 days51.12(0.42 to 3.02)0.94(0.52 to 1.70)Zidovudine500 mg/day orally for 21 days1200 mg/day orally for 14 days41.31(0.43 to 3.97)1.30(0.69 to 2.43)Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs. [see Drug Interactions (7)]Co-administered DrugDose of Co-administered DrugDose of AzithromycinnRatio (with/without co-administered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect 1.00Mean Cmax Mean AUCEfavirenz400 mg/day for days600 mg orally on day 7141.22(1.04 to 1.42)0.92 90% Confidence interval not reported Fluconazole200 mg orally single dose1,200 mg orally single dose180.82(0.66 to 1.02)1.07(0.94 to 1.22)Nelfinavir750 mg three times day for 11 days1,200 mg orally on day 9142.36(1.77 to 3.15)2.12(1.80 to 2.50). 12.4 Microbiology. Mechanism of ActionAzithromycin acts by binding to the 23S rRNA of the 50S ribosomal subunit of susceptible microorganisms inhibiting bacterial protein synthesis and impeding the assembly of the 50S ribosomal subunit.. ResistanceAzithromycin 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 (MLSB phenotype).. Antimicrobial ActivityAzithromycin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections. [see Indications and Usage (1)] Gram-Positive Bacteria Staphylococcus aureus Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenesGram-Negative Bacteria Haemophilus ducreyi Haemophilus influenzae Moraxella catarrhalis Neisseria gonorrhoeaeOther Bacteria Chlamydophila pneumoniae Chlamydia trachomatis Mycoplasma pneumoniaeThe following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for azithromycin against isolates of similar genus or organism group. However, the efficacy of azithromycin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.Gram-Positive Bacteria Beta-hemolytic streptococci (Groups C, F, G) Viridans group streptococciGram-Negative Bacteria Bordetella pertussis Legionella pneumophilaAnaerobic Bacteria Prevotella bivia Peptostreptococcus speciesOther Bacteria Ureaplasma urealyticum. Staphylococcus aureus. Streptococcus agalactiae. Streptococcus pneumoniae. Streptococcus pyogenes. Haemophilus ducreyi. Haemophilus influenzae. Moraxella catarrhalis. Neisseria gonorrhoeae. Chlamydophila pneumoniae. Chlamydia trachomatis. Mycoplasma pneumoniae. Beta-hemolytic streptococci (Groups C, F, G). Viridans group streptococci. Bordetella pertussis. Legionella pneumophila. Prevotella bivia. Peptostreptococcus species. Ureaplasma urealyticum. Susceptibility TestingFor specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Adult Patients. Acute Bacterial Exacerbations of Chronic BronchitisIn randomized, double-blind controlled clinical trial of acute exacerbation of chronic bronchitis (AECB), azithromycin (500 mg once daily for days) was compared with clarithromycin (500 mg twice daily for 10 days). The primary endpoint of this trial was the clinical cure rate at Days 21- 24. For the 304 patients analyzed in the modified intent-to-treat analysis at the Days 21-24 visit, the clinical cure rate for days of azithromycin was 85% (125/147) compared to 82% (129/157) for 10 days of clarithromycin.The following outcomes were the clinical cure rates at the Days 21-24 visit for the bacteriologically evaluable patients by pathogen:PathogenAzithromycin (3 Days)Clarithromycin (10 Days)S. pneumoniae29/32 (91%)21/27 (78%)H. influenzae12/14 (86%)14/16 (88%)M. catarrhalis11/12 (92%)12/15 (80%). Acute Bacterial SinusitisIn randomized, double-blind, double-dummy controlled clinical trial of acute bacterial sinusitis, azithromycin (500 mg once daily for days) was compared with amoxicillin/clavulanate (500/125 mg three times day for 10 days). Clinical response assessments were made at Day 10 and Day 28. The primary endpoint of this trial was prospectively defined as the clinical cure rate at Day 28. For the 594 patients analyzed in the modified intent to treat analysis at the Day 10 visit, the clinical cure rate for days of azithromycin was 88% (268/303) compared to 85% (248/291) for 10 days of amoxicillin/clavulanate. For the 586 patients analyzed in the modified intent to treat analysis at the Day 28 visit, the clinical cure rate for days of azithromycin was 71.5% (213/298) compared to 71.5% (206/288), with 97.5% confidence interval of -8.4 to 8.3, for 10 days of amoxicillin/clavulanate.In an open label, non-comparative study requiring baseline transantral sinus punctures, the following outcomes were the clinical success rates at the Day and Day 28 visits for the modified intent to treat patients administered 500 mg of azithromycin once daily for days with the following pathogens:Clinical Success Rates of Azithromycin (500 mg per day for Days)PathogenDay 7Day28S. pneumoniae23/26 (88%)21/25 (84%)H. influenzae28/32 (87%)24/32 (75%)M. catarrhalis14/15 (93%)13/15 (87%). 14.2Pediatric Patients. From the perspective of evaluating pediatric clinical trials, Days 11-14 were considered on-therapy evaluations because of the extended half-life of azithromycin. Days 11-14 data are provided for clinical guidance. Days 24-32 evaluations were considered the primary test of cure endpoint.. Pharyngitis/TonsillitisIn three double-blind controlled studies, conducted in the United States, azithromycin (12 mg/kg once day for days) was compared to penicillin (250 mg three times day for 10 days) in the treatment of pharyngitis due to documented Group -hemolytic streptococci (GABHS or S. pyogenes). Azithromycin was clinically and microbiologically statistically superior to penicillin at Day 14 and Day 30 with the following clinical success (i.e., cure and improvement) and bacteriologic efficacy rates (for the combined evaluable patient with documented GABHS):Three U.S. Streptococcal Pharyngitis Studies Azithromycin vs. Penicillin EFFICACY RESULTSDay 14Day 30Bacteriologic Eradication: Azithromycin323/340 (95%)255/330 (77%) Penicillin V242/332 (73%)206/325 (63%)Clinical Success (cure plus improvement): Azithromycin336/343 (98%)310/330 (94%) Penicillin V284/338 (84%)241/325 (74%)Approximately 1% of azithromycin-susceptible S. pyogenes isolates were resistant to azithromycin following therapy.. Acute Otitis MediaEfficacy using azithromycin given over days (10 mg/kg on Day followed by mg/kg on Days 2-5).. Trial 1In double-blind, controlled clinical study of acute otitis media performed in the United States, azithromycin (10 mg/kg on Day followed by mg/kg on Days 2-5) was compared to amoxicillin/clavulanate potassium (4:1). For the 553 patients who were evaluated for clinical efficacy, the clinical success rate (i.e., cure plus improvement) at the Day 11 visit was 88% for azithromycin and 88% for the control agent. For the 521 patients who were evaluated at the Day 30 visit, the clinical success rate was 73% for azithromycin and 71% for the control agent.. Trial 2In non-comparative clinical and microbiologic trial performed in the United States, where significant rates of beta-lactamase producing organisms (35%) were found, 131 patients were evaluable for clinical efficacy. The combined clinical success rate (i.e., cure and improvement) at the Day 11 visit was 84% for azithromycin. For the 122 patients who were evaluated at the Day 30 visit, the clinical success rate was 70% for azithromycin.Microbiologic determinations were made at the pre-treatment visit. Microbiology was not reassessed at later visits. The following clinical success rates were obtained from the evaluable group:PathogenDay 11Day 30AzithromycinAzithromycinS. pneumoniae61/74 (82%)40/56 (71%)H. influenzae43/54 (80%)30/47 (64%)M. catarrhalis28/35 (80%)19/26 (73%)S. pyogenes11/11 (100%)7/7 (100%)Overall177/217 (82%)97/137 (73%). Trial 3In another controlled comparative clinical and microbiologic study of otitis media performed in the United States, azithromycin (10 mg/kg on Day followed by mg/kg on Days 2-5) was compared to amoxicillin/clavulanate potassium (4:1). This study utilized two of the same investigators as Protocol (above), and these two investigators enrolled 90% of the patients in Protocol 3. For this reason, Protocol was not considered to be an independent study. Significant rates of beta-lactamase producing organisms (20%) were found. Ninety-two (92) patients were evaluable for clinical and microbiologic efficacy. The combined clinical success rate (i.e., cure and improvement) of those patients with baseline pathogen at the Day 11 visit was 88% for azithromycin vs. 100% for control; at the Day 30 visit, the clinical success rate was 82% for azithromycin vs. 80% for control.Microbiologic determinations were made at the pre-treatment visit. Microbiology was not reassessed at later visits. At the Day 11 and Day 30 visits, the following clinical success rates were obtained from the evaluable group:Day 11Day 30PathogenAzithromycinControlAzithromycinControlS. pneumoniae25/29 (86%)26/26 (100%)22/28 (79%)18/22 (82%)H. influenzae9/11 (82%)9/9 (100%)8/10 (80%)6/8 (75%)M. catarrhalis7/7 (100%)5/5 (100%)5/5 (100%)2/3 (66%)S. pyogenes2/2 (100%)5/5 (100%)2/2 (100%)4/4 (100%)Overall43/49 (88%)45/45 (100%)37/45 (82%)30/37 (81%)Efficacy using azithromycin given over days (10 mg/kg/day).. Trial 4In double-blind, controlled, randomized clinical study of acute otitis media in pediatric patients from months to 12 years of age, azithromycin (10 mg/kg per day for days) was compared to amoxicillin/clavulanate potassium (7:1) in divided doses q12h for 10 days. Each patient received active drug and placebo matched for the comparator.For the 366 patients who were evaluated for clinical efficacy at the Day 12 visit, the clinical success rate (i.e., cure plus improvement) was 83% for azithromycin and 88% for the control agent. For the 362 patients who were evaluated at the Days 24-28 visit, the clinical success rate was 74% for azithromycin and 69% for the control agent.Efficacy using azithromycin 30 mg/kg given as single dose. Trial 5A double-blind, controlled, randomized trial was performed at nine clinical centers. Pediatric patients from months to 12 years of age were randomized 1:1 to treatment with either azithromycin (given at 30 mg/kg as single dose on Day 1) or amoxicillin/clavulanate potassium (7:1), divided q12h for 10 days. Each child received active drug, and placebo matched for the comparator.Clinical response (Cure, Improvement, Failure) was evaluated at End of Therapy (Days 12-16) and Test of Cure (Days 28-32). Safety was evaluated throughout the trial for all treated subjects. For the 321 subjects who were evaluated at End of Treatment, the clinical success rate (cure plus improvement) was 87% for azithromycin, and 88% for the comparator. For the 305 subjects who were evaluated at Test of Cure, the clinical success rate was 75% for both azithromycin and the comparator.. Trial 6In non-comparative clinical and microbiological trial, 248 patients from months to 12 years of age with documented acute otitis media were dosed with single oral dose of azithromycin (30 mg/kg on Day 1).For the 240 patients who were evaluable for clinical modified Intent-to-Treat (MITT) analysis, the clinical success rate (i.e., cure plus improvement) at Day 10 was 89% and for the 242 patients evaluable at Days 24-28, the clinical success rate (cure) was 85%.Presumed Bacteriologic EradicationDay 10Days 24-28S. pneumoniae70/76 (92%)67/76 (88%)H. influenzae30/42 (71%)28/44 (64%)M. catarrhalis10/10 (100%)10/10 (100%)Overall110/128 (86%)105/130 (81%).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 side effects were mild to moderate in severity and were reversible upon discontinuation of the drug. Potentially serious adverse reactions of angioedema and cholestatic jaundice were reported. Approximately 0.7% of the patients (adults and pediatric patients) from the 5-day multiple-dose clinical trials discontinued ZITHROMAX (azithromycin) therapy because of treatment-related adverse reactions. In adults given 500 mg/day for days, the discontinuation rate due to treatment-related adverse reactions was 0.6%. In clinical trials in pediatric patients given 30 mg/kg, either as single dose or over days, discontinuation from the trials due to treatment-related adverse reactions was approximately 1%. 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 (14.2)] Adults. Multiple-dose regimens: Overall, the most common treatment-related adverse reactions in adult patients receiving multiple-dose regimens of ZITHROMAX were related to the gastrointestinal system with diarrhea/loose stools (4 to 5%), nausea (3%), and abdominal pain (2 to 3%) being the most frequently reported.No other adverse reactions occurred in patients on the multiple-dose regimens of ZITHROMAX with frequency greater than 1%. Adverse reactions that occurred with frequency of 1% or less included the following:Cardiovascular: Palpitations, 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, pruritus, photosensitivity, and angioedema.. Single 1-gram dose regimen:Overall, the most common adverse reactions in patients receiving single-dose regimen of 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 frequency of 1% or greater included diarrhea/loose stools (7%), nausea (5%), abdominal pain (5%), vomiting (2%), dyspepsia (1%), and vaginitis (1%).. Single 2-gram dose regimen:Overall, the most common adverse reactions in patients receiving single 2-gram dose of ZITHROMAX were related to the gastrointestinal system. Adverse reactions that occurred in patients in this study with frequency of 1% or greater included nausea (18%), diarrhea/loose stools (14%), vomiting (7%), abdominal pain (7%), vaginitis (2%), dyspepsia (1%), and dizziness (1%). The majority of these complaints were mild in nature.. Pediatric Patients. Single and Multiple-dose regimens: The types of adverse reactions in pediatric patients were comparable to those seen in adults, with different incidence rates for the dosage regimens recommended in pediatric patients.. Acute Otitis Media: For the recommended total dosage regimen of 30 mg/kg, the most frequent adverse reactions (>=1%) attributed to treatment were diarrhea, abdominal pain, vomiting, nausea, and rash. [see Dosage and Administration (2) and Clinical Studies (14.2)] The incidence, based on dosing regimen, is described in the table below:Dosage RegimenDiarrhea %Abdominal Pain %Vomiting %Nausea %Rash %1-day4.3%1.4%4.9%1.0%1.0%3-day2.6%1.7%2.3%0.4%0.6%5-day1.8%1.2%1.1%0.5%0.4%. Community-Acquired Pneumonia: For the recommended dosage regimen of 10 mg/kg on Day followed by mg/kg on Days 2-5, the most frequent adverse reactions attributed to treatment were diarrhea/loose stools, abdominal pain, vomiting, nausea, and rash.The incidence is described in the table below:Dosage RegimenDiarrhea/Loose stools %Abdominal Pain %Vomiting %Nausea %Rash %5-day5.8%1.9%1.9%1.9%1.6%. Pharyngitis/Tonsillitis: For the recommended dosage regimen of 12 mg/kg on Days 1-5, the most frequent adverse reactions attributed to treatment were diarrhea, vomiting, abdominal pain, nausea, and headache.The incidence is described in the table below:Dosage RegimenDiarrhea %Abdominal Pain %Vomiting %Nausea %Rash %Headache %5-day5.4%3.4%5.6%1.8%0.7%1.1%With any of the treatment regimens, no other adverse reactions occurred in pediatric patients treated with ZITHROMAX with frequency greater than 1%. Adverse reactions that occurred with frequency of 1% or less included the following:Cardiovascular: Chest pain.Gastrointestinal: Dyspepsia, constipation, anorexia, enteritis, flatulence, gastritis, jaundice, loose stools, and oral moniliasis.Hematologic and Lymphatic: Anemia and leukopenia.Nervous System: Headache (otitis media dosage), hyperkinesia, dizziness, agitation, nervousness, and insomnia.General: Fever, face edema, fatigue, fungal infection, malaise, and pain.Allergic: Rash and allergic reaction.Respiratory: Cough, pharyngitis, pleural effusion, and rhinitis.Skin and Appendages: Eczema, fungal dermatitis, pruritus, sweating, urticaria, and vesiculobullous rash.Special Senses: Conjunctivitis.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. 4.1Hypersensitivity. ZITHROMAX is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide drug.. 4.2Hepatic Dysfunction. ZITHROMAX is contraindicated in patients with history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.

DESCRIPTION SECTION.

11 DESCRIPTION. ZITHROMAX (azithromycin tablets and azithromycin for oral suspension) contain the active ingredient azithromycin, 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--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)--D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one. Azithromycin is derived from erythromycin; however, it differs chemically from erythromycin in that methyl-substituted 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 white crystalline powder with molecular formula of C38H72N2O122H2O and molecular weight of 785.0.ZITHROMAX is supplied as tablets containing azithromycin dihydrate equivalent to either 250 mg or 500 mg azithromycin and the following inactive ingredients: dibasic calcium phosphate anhydrous, pregelatinized starch, sodium croscarmellose, magnesium stearate, sodium lauryl sulfate, hypromellose, lactose, titanium dioxide, triacetin, and D&C Red 30 aluminum lake.ZITHROMAX for oral suspension is supplied in bottles containing azithromycin dihydrate powder equivalent to 300 mg, 600 mg, 900 mg, or 1200 mg azithromycin per bottle and the following inactive ingredients: sucrose; sodium phosphate, tribasic, anhydrous; hydroxypropyl cellulose; xanthan gum; FD&C Red 40; and spray dried artificial cherry, creme de vanilla, and banana flavors. After constitution, each mL of suspension contains 100 mg or 200 mg of azithromycin.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. 2.1Adult Patients. [see Indications and Usage (1.1) and Clinical Pharmacology (12.3)]InfectionDUE TO THE INDICATED ORGANISMS [see Indications and Usage (1.1)] Recommended Dose/Duration of TherapyCommunity-acquired pneumonia Pharyngitis/tonsillitis (second-line therapy)Skin/skin structure (uncomplicated)500 mg as single dose on Day 1, followed by 250 mg once daily on Days through 5Acute bacterial exacerbations of chronic obstructive pulmonary disease500 mg once daily for daysOR500 mg as single dose on Day 1, followed by 250 mg once daily on Days through 5Acute bacterial sinusitis500 mg once daily for daysGenital ulcer disease (chancroid)One single gram doseNon-gonococcal urethritis and cervicitisOne single gram doseGonococcal urethritis and cervicitisOne single gram doseZITHROMAX tablets can be taken with or without food.. 2.2Pediatric Patients1 InfectionDUE TO THE INDICATED ORGANISMS [see Indications and Usage (1.2)] Recommended Dose/Duration of Therapy1 see dosing tables below for maximum doses evaluated by indicationAcute otitis media30 mg/kg as single dose or 10 mg/kg once daily for days or 10 mg/kg as single dose on Day followed by mg/kg/day on Days through 5.Acute bacterial sinusitis10 mg/kg once daily for days.Community-acquired pneumonia10 mg/kg as single dose on Day followed by mg/kg once daily on Days through 5.Pharyngitis/tonsillitis12 mg/kg once daily for days.ZITHROMAX for oral suspension can be taken with or without food.PEDIATRIC DOSAGE GUIDELINES FOR OTITIS MEDIA, ACUTE BACTERIAL SINUSITIS, AND COMMUNITY-ACQUIRED PNEUMONIA(Age months and above, [see Use in Specific Populations (8.4)])Based on Body WeightOTITIS MEDIA AND COMMUNITY-ACQUIRED PNEUMONIA: (5-Day Regimen)Effectiveness of the 3-day or 1-day regimen in pediatric patients with community-acquired pneumonia has not been established. Dosing Calculated on 10 mg/kg/day Day and mg/kg/day Days to 5.Weight100 mg/5 mL200 mg/5 mLTotal mL per Treatment CourseTotal mg per Treatment CourseKgDay 1Days 2-5Day 1Days 2-552.5 mL; 1/2 tsp)1.25 mL;( 1/4 tsp)7.5 mL150 mg105 mL; (1tsp)2.5 mL; 1/2 tsp)15 mL300 mg205 mL; (1 tsp)2.5 mL; 1/2 tsp)15 mL600 mg307.5 mL; (1 1/2 tsp)3.75 mL; 3/4 tsp)22.5 mL900 mg4010 mL; (2 tsp)5 mL; (1 tsp)30 mL1200 mg50 and above12.5 mL; (2 1/2 tsp)6.25 mL; (1 1/4 tsp)37.5 mL1500 mgOTITIS MEDIA AND ACUTE BACTERIAL SINUSITIS: (3-Day Regimen)Effectiveness of the 5-day or 1-day regimen in pediatric patients with acute bacterial sinusitis has not been established. Dosing Calculated on 10 mg/kg/day.Weight100 mg/5 mL200 mg/5 mLTotal mL per Treatment CourseTotal mg per Treatment CourseKgDays 1-3Days 1-352.5 mL; (1/2 tsp)7.5 mL150 mg105 mL; (1 tsp)15 mL300 mg205 mL (1 tsp)15 mL600 mg307.5 mL (1 1/2 tsp)22.5 mL900 mg4010 mL (2 tsp)30 mL1200 mg50 and above12.5 mL (2 1/2 tsp)37.5 mL1500 mgOTITIS MEDIA: (1-Day Regimen)Dosing Calculated on 30 mg/kg as single dose.Weight200 mg/5 mLTotal mL per Treatment CourseTotal mg per Treatment CourseKg1-Day Regimen53.75 mL;(3/4 tsp)3.75 mL150 mg107.5 mL;(1 1/2 tsp)7.5 mL300 mg2015 mL;(3 tsp)15 mL600 mg3022.5 mL;(4 1/2 tsp)22.5 mL900 mg4030 mL;(6 tsp)30 mL1200 mg50 and above37.5 mL;(7 1/2 tsp)37.5 mL1500 mgThe safety of re-dosing azithromycin in pediatric patients who vomit after receiving 30 mg/kg as single dose has not been established. In clinical studies involving 487 patients with acute otitis media given single 30 mg/kg dose of azithromycin, patients who vomited within 30 minutes of dosing were re-dosed at the same total dose.. Pharyngitis/Tonsillitis: The recommended dose of ZITHROMAX for children with pharyngitis/tonsillitis is 12 mg/kg once daily for days. (See chart below.)PEDIATRIC DOSAGE GUIDELINES FOR PHARYNGITIS/TONSILLITIS (Age years and above, [see Use in Specific Populations (8.4)])Based on Body WeightPHARYNGITIS/TONSILLITIS: (5-Day Regimen)Dosing Calculated on 12 mg/kg/day for days.Weight200 mg/5 mLTotal mL per Treatment CourseTotal mg per Treatment CourseKgDay 1-582.5 mL; 1/2 tsp)12.5 mL500 mg175 mL; (1 tsp)25 mL1000 mg257.5 mL; (1 1/2 tsp)37.5 mL1500 mg3310 mL; (2 tsp)50 mL2000 mg4012.5 mL; (2 1/2 tsp)62.5 mL2500 mgConstituting instructions for ZITHROMAX Oral Suspension 300, 600, 900, 1200 mg bottles. The table below indicates the volume of water to be used for constitution:Amount of water to be addedTotal volume after constitution (azithromycin content)Azithromycin concentration after constitution9 mL (300 mg)15 mL (300 mg)100 mg/5 mL9 mL (600 mg)15 mL (600 mg)200 mg/5 mL12 mL (900 mg)22.5 mL (900 mg)200 mg/5 mL15 mL (1200 mg)30 mL (1200 mg)200 mg/5 mLShake well before each use. Oversized bottle provides shake space. Keep tightly closed.After mixing, store suspension at to 30C (41 to 86F) and use within 10 days. Discard after full dosing is completed.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. ZITHROMAX 250 mg tablets are supplied as pink modified capsular shaped, engraved, film-coated tablets containing azithromycin dihydrate equivalent to 250 mg of azithromycin. ZITHROMAX 250 mg tablets are engraved with PFIZER on one side and 306 on the other, or Pfizer on one side and ZTM 250 on the other. These are packaged in bottles and blister cards of tablets (Z-PAKS(R)).ZITHROMAX 500 mg tablets are supplied as pink modified capsular shaped, engraved, film-coated tablets containing azithromycin dihydrate equivalent to 500 mg of azithromycin. ZITHROMAX 500 mg tablets are engraved with Pfizer on one side and ZTM500 on the other. These are packaged in bottles and blister cards of tablets (TRI-PAKS(TM)).ZITHROMAX for oral suspension after constitution contains flavored suspension. ZITHROMAX for oral suspension is supplied to provide 100 mg/5 mL or 200 mg/5 mL suspension in bottles.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. 7.1Nelfinavir. Co-administration of nelfinavir at steady-state with single oral dose of azithromycin resulted in increased azithromycin serum concentrations. Although 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 (6)] 7.2Warfarin. Spontaneous postmarketing 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.. 7.3 Potential Drug-Drug Interaction with Macrolides. Interactions with digoxin, colchicine or phenytoin have not been reported in clinical trials with azithromycin. 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, colchicine or phenytoin are used with azithromycin careful monitoring of patients is advised.

GERIATRIC USE SECTION.

8.5 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 response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than younger patients. [see Warnings and Precautions (5.4)].

HEALTH CARE PROVIDER LETTER SECTION.

URGENT: Important Drug InformationSubject:Zithromax(R) (azithromycin) 250 mg Tablets to Assist with U.S. Drug Shortage; Product Package and Label Contain Differences from the U.S. Approved Package and LabelApril 2020Dear Health Care Provider,Due to the current critical shortage of Azithromycin tablets in the United States (U.S.) market, Pfizer Inc. (Pfizer) is coordinating with the U.S. Food and Drug Administration (FDA) to increase the availability of the drug.In support of the public health and medical response to the COVID-19 pandemic, Pfizer initiated one-time distribution of Zithromax(R) (azithromycin) 250 mg Tablets to the U.S. market. This product was originally intended for use outside of the United States, so its packaging states, DONATION FOR TREATMENT OF TRACHOMA ONLY and its labeling does not comply with the U.S. approved labeling for azithromycin.At this time, no other entity except Pfizer and Direct Relief are authorized by the FDA to distribute this Zithromax(R) (azithromycin) 250 mg tablets labeled or Trachoma donation in the United States.This product is manufactured in Pfizers Puerto Rico facility, an FDA-registered facility, and is the same manufacturing site that manufactures Zithromax(R) (azithromycin) 250 mg tablets for the U.S market.Effective immediately, and during this temporary period as part of this distribution, Pfizer is mak in the following presentation of Zithromax(R) (azithromycin) 250 mg tablets available:ProductStrengthPackagingNDC NumberMarketing Authorization Zithromax(R) (azithromycin)250 mg500 count bottle0069-9500-01N/AAzithromycin is an antibiotic indicated to treat patients with certain bacterial infections caused by susceptible organisms.T e Zithromax(R) (azithromycin) 250 mg tablets labeled DONATION FOR TREATMENT OF TRACHOMA ONLY are manufactured using the same process and specifications as the U.S. approved 250 mg tablets. The key substantive differences are in the format and content of the labeling between U.S approved Zithromax(R) (azithromycin) 250 mg tablets and the donated Trachoma labeled product.The U.S. prescribing information for azithromycin, including the FDA approved indications for azithromycin, is contained in the U.S. approved package insert at the end of this letter and is also available on line at https://www.pfizer.com/products/product-detail/zithromax.The health care provider should refer to the U.S. prescribing information when prescribing the Zithromax(R) (azithromycin) 250 mg tablets.Azithromycin is not approved for the treatment of COVID--19 or other viral infections. The safety of azithromycin treatment, either alone or in combination with other therapies, has not been evaluated in patients with COVID-19.The barcode may not register accurately on the U.S. scanning systems. Institutions should manually input the product into their systems and confirm that barcode systems do not provide incorrect information when the product is scanned. Alternative procedures should be followed to assure that the correct drug product is being used and administered to individual patients.Zithromax(R) (azithromycin) 250 mg tablets are available only by prescription in the U.S.This letter and the attachments are not intended as complete description of the benefits and risks related to the use of Zithromax(R) (azithromycin) 250 mg tablets.Contact InformationPlease Pfizer customer Service at 1-844-646-4398 (Mon.-Fri. 8am-7pm ET) for any questions you may have regarding this notification.Adverse Events, Medical Information and Product Quality ComplaintsTo report adverse reactions or quality issues, contact Pfizer at 1-800-438-1985.Adverse reactions or quality problems experienced with the use of this product may be reported to the FDAs MedWatch Adverse Event Reporting Program either online, by regular mail, or by fax:Complete and submit the report Online: www.fda.gov/medwatch/report.htm Regular mail or Fax: download form www.fda.gov/MedWatch/getforms.htm or call 1- 800-332-1088 to request reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178 (1-800-332-0178)Sincerely,Eddie M Power PhD MBAVice President, US Medical Affairs, Chief Medical OfficePfizer Hospital Business Unit. The barcode may not register accurately on the U.S. scanning systems. Institutions should manually input the product into their systems and confirm that barcode systems do not provide incorrect information when the product is scanned. Alternative procedures should be followed to assure that the correct drug product is being used and administered to individual patients.. Complete and submit the report Online: www.fda.gov/medwatch/report.htm Regular mail or Fax: download form www.fda.gov/MedWatch/getforms.htm or call 1- 800-332-1088 to request reporting form, then complete and return to the address on the pre-addressed form, or submit by fax to 1-800-FDA-0178 (1-800-332-0178). Logo. Signature.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. ZITHROMAX is supplied in the following strengths and package configurations:Tablet strengthTablet Color/ShapeTablet MarkingsPackage SizeNDC Code250 mg(containing azithromycin dihydrate equivalent to 250 mg of azithromycin)Pink modified capsular shaped, engraved, film-coatedEngraved with PFIZER on one side and 306 on the otherBottles of 30NDC 0069-3060-30Boxes of (Z-PAKS(R) of 6)NDC 0069-3060-75Unit Dose package of 50NDC 0069-3060-86Engraved with Pfizer on one side and ZTM 250 on the otherBottles of 30NDC 0069-4061-01Boxes of (Z-PAKS(R) of 6)NDC 0069-4061-75Unit Dose package of 50NDC 0069-4061-89500 mg (containing azithromycin dihydrate equivalent to 500 mg of azithromycin)Pink modified capsular shaped, engraved, film coatedEngraved with Pfizer on one side and ZTM500 on the otherBottles of 30NDC 0069-3070-30Boxes of (TRI-PAKS(TM) of tablets)NDC 0069-3070-75Unit Dose package of 50NDC 0069-3070-86ZITHROMAX tablets should be stored between 15 to 30C (59 to 86F).ZITHROMAX for oral suspension after constitution contains flavored suspension. ZITHROMAX for oral suspension is supplied to provide 100 mg/5 mL or 200 mg/5 mL suspension in bottles as follows:Azithromycin contents per bottleNDC300 mg0069-3110-19600 mg0069-3120-19900 mg0069-3130-191200 mg0069-3140-19[see Dosage and Administration (2)] for constitution instructions with each bottle type.. Storage: Store dry powder below 30C (86F). Store constituted suspension between to 30C (41 to 86F) and discard when full dosing is completed.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. ZITHROMAX (azithromycin) is 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. Recommended dosages and durations of therapy in adult and pediatric patient populations vary in these indications. [see Dosage and Administration (2)] 1.1Adult Patients. Acute bacterial exacerbations of chronic bronchitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.Acute bacterial sinusitis due to Haemophilus influenzae, Moraxella catarrhalis. or Streptococcus pneumoniae.Community-acquired pneumonia due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, or Streptococcus pneumoniae in patients appropriate for oral therapy.Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy.Uncomplicated skin and skin structure infections due to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae.Urethritis and cervicitis due to Chlamydia trachomatis or Neisseria gonorrhoeae.Genital ulcer disease in men due to Haemophilus ducreyi (chancroid). Due to the small number of women included in clinical trials, the efficacy of azithromycin in the treatment of chancroid in women has not been established.. Acute bacterial exacerbations of chronic bronchitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae.. Acute bacterial sinusitis due to Haemophilus influenzae, Moraxella catarrhalis. or Streptococcus pneumoniae.. Community-acquired pneumonia due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, or Streptococcus pneumoniae in patients appropriate for oral therapy.. Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy.. Uncomplicated skin and skin structure infections due to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae.. Urethritis and cervicitis due to Chlamydia trachomatis or Neisseria gonorrhoeae.. Genital ulcer disease in men due to Haemophilus ducreyi (chancroid). Due to the small number of women included in clinical trials, the efficacy of azithromycin in the treatment of chancroid in women has not been established.. 1.2Pediatric Patients. [see Use in Specific Populations (8.4) and Clinical Studies (14.2)]Acute otitis media (>6 months of age) caused by Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae. Community-acquired pneumonia (>6 months of age) due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, or Streptococcus pneumoniae in patients appropriate for oral therapy.Pharyngitis/tonsillitis (>2 years of age) caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy.. Acute otitis media (>6 months of age) caused by Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae. Community-acquired pneumonia (>6 months of age) due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, or Streptococcus pneumoniae in patients appropriate for oral therapy.. Pharyngitis/tonsillitis (>2 years of age) caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy.. 1.3Limitations of Use. Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors such as any of the following:patients with cystic fibrosis,patients with nosocomial infections,patients with known or suspected bacteremia,patients requiring hospitalization,elderly or debilitated patients, orpatients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia).. 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).. 1.4 Usage. 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).. General Patient CounselingZITHROMAX tablets and oral suspension can be taken with or without food.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 physician if any signs of an allergic reaction occur.Direct parents or caregivers to contact their physician if vomiting and irritability with feeding occurs in the infant.Patients should be counseled that antibacterial drugs including ZITHROMAX (azithromycin) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ZITHROMAX (azithromycin) is prescribed to treat bacterial infection, patients should be told that although it is common to feel better early in the course of the 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 (azithromycin) or other antibacterial drugs in the future.Diarrhea is common problem caused by antibacterials 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 drug. If this occurs, patients should contact their physician as soon as possible.. Licensed from PlivaThis products label may have been updated. For current full prescribing information, please visit www.pfizer.com. LAB-0023-21.0. Logo.

LACTATION SECTION.

8.2 Lactation. Risk Summary Azithromycin is present in human milk (see Data). Non-serious adverse reactions have been reported in breastfed infants after maternal administration of azithromycin (see Clinical Considerations). There are no available data on the effects of azithromycin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ZITHROMAX and any potential adverse effects on the breastfed infant from ZITHROMAX or from the underlying maternal condition.. Clinical ConsiderationsAdvise women to monitor the breastfed infant for diarrhea, vomiting, or rash.. DataAzithromycin breastmilk concentrations were measured in 20 women after receiving single g oral dose of azithromycin during labor. Breastmilk samples collected on days and postpartum as well as and weeks postpartum revealed the presence of azithromycin in breastmilk up to weeks after dosing. In another study, single dose of azithromycin 500 mg was administered intravenously to women prior to incision for cesarean section. Breastmilk (colostrum) samples obtained between 12 and 48 hours after dosing revealed that azithromycin persisted in breastmilk up to 48 hours.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Azithromycin is macrolide antibacterial drug. [see Microbiology (12.4)].

MICROBIOLOGY SECTION.

12.4 Microbiology. Mechanism of ActionAzithromycin acts by binding to the 23S rRNA of the 50S ribosomal subunit of susceptible microorganisms inhibiting bacterial protein synthesis and impeding the assembly of the 50S ribosomal subunit.. ResistanceAzithromycin 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 (MLSB phenotype).. Antimicrobial ActivityAzithromycin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections. [see Indications and Usage (1)] Gram-Positive Bacteria Staphylococcus aureus Streptococcus agalactiae Streptococcus pneumoniae Streptococcus pyogenesGram-Negative Bacteria Haemophilus ducreyi Haemophilus influenzae Moraxella catarrhalis Neisseria gonorrhoeaeOther Bacteria Chlamydophila pneumoniae Chlamydia trachomatis Mycoplasma pneumoniaeThe following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for azithromycin against isolates of similar genus or organism group. However, the efficacy of azithromycin in treating clinical infections caused by these bacteria has not been established in adequate and well-controlled clinical trials.Gram-Positive Bacteria Beta-hemolytic streptococci (Groups C, F, G) Viridans group streptococciGram-Negative Bacteria Bordetella pertussis Legionella pneumophilaAnaerobic Bacteria Prevotella bivia Peptostreptococcus speciesOther Bacteria Ureaplasma urealyticum. Staphylococcus aureus. Streptococcus agalactiae. Streptococcus pneumoniae. Streptococcus pyogenes. Haemophilus ducreyi. Haemophilus influenzae. Moraxella catarrhalis. Neisseria gonorrhoeae. Chlamydophila pneumoniae. Chlamydia trachomatis. Mycoplasma pneumoniae. Beta-hemolytic streptococci (Groups C, F, G). Viridans group streptococci. Bordetella pertussis. Legionella pneumophila. Prevotella bivia. Peptostreptococcus species. Ureaplasma urealyticum. Susceptibility TestingFor specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 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. In fertility studies conducted in male and female rats, oral administration of azithromycin for 64 to 66 days (males) or 15 days (females) prior to and during cohabitation resulted in decreased pregnancy rate at 20 and 30 mg/kg/day when both males and females were treated with azithromycin. This minimal effect on pregnancy rate (approximately 12% reduction compared to concurrent controls) did not become more pronounced when the dose was increased from 20 to 30 mg/kg/day (approximately 0.4 to 0.6 times the adult daily dose of 500 mg based on body surface area) and it was not observed when only one animal in the mated pair was treated. There were no effects on any other reproductive parameters, and there were no effects on fertility at 10 mg/kg/day. The relevance of these findings to patients being treated with azithromycin at the doses and durations recommended in the prescribing information is uncertain.. 13.2 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 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 g). Similarly, it has been shown in the dog (10 mg/kg/day dose) at the observed maximal serum concentration of mcg/mL (1.2 times the observed Cmax of 0.821 mcg/mL at the adult dose of 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 times the pediatric dose Cmax. The significance of these findings for animals and for humans is unknown.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Adverse reactions experienced at 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 250 mg Tablet Bottle Label. DONATION FOR TREATMENT OF TRACHOMA ONLYZithromax(R) 250 mg tabletsAzithromycin 250 mg(as dihydrate)500 Tablets. PRINCIPAL DISPLAY PANEL 250 mg Tablet Bottle Label.

PHARMACODYNAMICS SECTION.

12.2 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 ElectrophysiologyQTc interval prolongation was studied in 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 dose- and concentration- dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were (10) ms, (12) ms and (14) ms with the co-administration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Following oral administration of single 500 mg dose (two 250 mg tablets) to 36 fasted healthy male volunteers, the mean (SD) pharmacokinetic parameters were AUC0-72=4.3 (1.2) mcghr/mL; Cmax=0.5 (0.2) mcg/mL; Tmax=2.2 (0.9) hours. Two azithromycin 250 mg tablets are bioequivalent to single 500 mg tablet.In two-way crossover study, 12 adult healthy volunteers (6 males, females) received 1500 mg of azithromycin administered in single daily doses over either days (two 250 mg tablets on day 1, followed by one 250 mg tablet on days 2-5) or days (500 mg per day for days 1-3). Due to limited serum samples on day (3-day regimen) and days 2-4 (5-day regimen), the serum concentration-time profile of each subject was fit to 3-compartment model and the AUC0- for the fitted concentration profile was comparable between the 5-day and 3-day regimens.3-Day Regimen5-Day RegimenPharmacokinetic Parameter [mean (SD)]Day 1Day 3Day 1Day 5Cmax (serum, mcg/mL)0.44 (0.22)0.54 (0.25)0.43 (0.20)0.24 (0.06)Serum AUC0- (mcghr/mL)17.4 (6.2)Total AUC for the entire 3-day and 5-day regimens. 14.9 (3.1) Serum T1/2 71.8 hr68.9 hr. AbsorptionThe absolute bioavailability of azithromycin 250 mg capsules is 38%.In two-way crossover study in which 12 healthy subjects received single 500 mg dose of azithromycin (two 250 mg tablets) with or without high fat meal, food was shown to increase Cmax by 23% but had no effect on AUC.When azithromycin oral suspension was administered with food to 28 adult healthy male subjects, Cmax increased by 56% and AUC was unchanged.. DistributionThe 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 mcg/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 human tissues, 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 significance of these tissue concentration data is unknown.Following regimen of 500 mg on the first day and 250 mg daily for days, very low concentrations were noted in cerebrospinal fluid (less than 0.01 mcg/mL) in the presence of noninflamed meninges.. MetabolismIn vitro and in vivo studies to assess the metabolism of azithromycin have not been performed.. EliminationPlasma concentrations of azithromycin following single 500 mg oral and IV doses declined in polyphasic pattern resulting in mean apparent plasma clearance of 630 mL/min and terminal elimination half-life of 68 hr. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues. Biliary excretion of azithromycin, predominantly as unchanged drug, is major route of elimination. Over the course of week, approximately 6% of the administered dose appears as unchanged drug in urine.. Specific Populations. Patients with Renal ImpairmentAzithromycin pharmacokinetics was investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of single 1.0 dose of azithromycin (4 250 mg capsules), 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 Cmax and AUC0-120 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).. Patients with Hepatic ImpairmentThe pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established.. Male and Female PatientsThere are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended based on gender.. Geriatric PatientsPharmacokinetic parameters in older volunteers (65 to 85 years old) were similar to those in young adults (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 (8.5)] Pediatric PatientsIn two clinical studies, azithromycin for oral suspension was dosed at 10 mg/kg on day 1, followed by mg/kg on days through in two groups of pediatric patients (aged 1-5 years and 5-15 years, respectively). The mean pharmacokinetic parameters on day were Cmax=0.216 mcg/mL, Tmax=1.9 hr, and AUC0-24=1.822 mcghr/mL for the to 5-year-old group and were Cmax=0.383 mcg/mL, Tmax=2.4 hr, and AUC0-24=3.109 mcghr/mL for the to 15-year-old group.In another study, 33 pediatric patients received doses of 12 mg/kg/day (maximum daily dose 500 mg) for days, of whom 31 patients were evaluated for azithromycin pharmacokinetics following low fat breakfast. In this study, azithromycin concentrations were determined over 24 hr period following the last daily dose. Patients weighing above 41.7 kg received the maximum adult daily dose of 500 mg. Seventeen patients (weighing 41.7 kg or less) received total dose of 60 mg/kg. The following table shows pharmacokinetic data in the subset of pediatric patients who received total dose of 60 mg/kg.Pharmacokinetic Parameter[mean (SD)]5-Day Regimen(12 mg/kg for days)N17Cmax (mcg/mL)0.5 (0.4)Tmax (hr)2.2 (0.8)AUC0-24(mcghr/mL)3.9 (1.9)Single dose pharmacokinetics of azithromycin in pediatric patients given doses of 30 mg/kg have not been studied. [see Dosage and Administration (2)] Drug Interaction StudiesDrug interaction studies were performed with azithromycin and other drugs likely to be co-administered. The effects of co-administration of azithromycin on the pharmacokinetics of other drugs are shown in Table and the effects of other drugs on the pharmacokinetics of azithromycin are shown in Table 2.Co-administration of azithromycin at therapeutic doses had modest effect on the pharmacokinetics of the drugs listed in Table 1. No dosage adjustment of drugs listed in Table is recommended when co-administered with azithromycin.Co-administration of azithromycin with efavirenz or fluconazole had 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 (7.3)] Table 1. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of AzithromycinCo-administered DrugDose of Co-administered DrugDose of AzithromycinnRatio (with/without azithromycin) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect 1.00Mean Cmax Mean AUCAtorvastatin10 mg/day for days500 mg/day orally on days 6-8120.83(0.63 to 1.08)1.01(0.81 to 1.25)Carbamazepine200 mg/day for days, then 200 mg twice day for 18 days500 mg/day orally for days 16-1870.97(0.88 to 1.06)0.96(0.88 to 1.06)Cetirizine20 mg/day for 11 days500 mg orally on day 7, then 250 mg/day on days 8-11141.03(0.93 to 1.14)1.02(0.92 to 1.13)Didanosine200 mg orally twice day for 21 days1200 mg/day orally on days 8-2161.44(0.85 to 2.43)1.14(0.83 to 1.57)Efavirenz400 mg/day for days600 mg orally on day 7141.04 90% Confidence interval not reported 0.95 Fluconazole200 mg orally single dose1200 mg orally single dose181.04(0.98 to 1.11)1.01(0.97 to 1.05)Indinavir800 mg three times day for days1200 mg orally on day 5180.96(0.86 to 1.08)0.90(0.81 to 1.00)Midazolam15 mg orally on day 3500 mg/day orally for days121.27(0.89 to 1.81)1.26(1.01 to 1.56)Nelfinavir750 mg three times day for 11 days1,200 mg orally on day 9140.90(0.81 to 1.01)0.85(0.78 to 0.93)Sildenafil100 mg on days and 4500 mg/day orally for days121.16(0.86 to 1.57)0.92(0.75 to 1.12)Theophylline4 mg/kg IV on days 1, 11, 25500 mg orally on day 7, 250 mg/day on days 8-11101.19(1.02 to 1.40)1.02(0.86 to 1.22)Theophylline300 mg orally twice day for 15 days500 mg orally on day 6, then 250 mg/day on days 7-1081.09(0.92 to 1.29)1.08(0.89 to 1.31)Triazolam0.125 mg on day 2500 mg orally on day 1, then 250 mg/day on day 2121.06 1.02 Trimethoprim/Sulfamethoxazole160 mg/800 mg/day orally for days1200 mg orally on day 7120.85(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)Zidovudine500 mg/day orally for 21 days600 mg/day orally for 14 days51.12(0.42 to 3.02)0.94(0.52 to 1.70)Zidovudine500 mg/day orally for 21 days1200 mg/day orally for 14 days41.31(0.43 to 3.97)1.30(0.69 to 2.43)Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs. [see Drug Interactions (7)]Co-administered DrugDose of Co-administered DrugDose of AzithromycinnRatio (with/without co-administered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect 1.00Mean Cmax Mean AUCEfavirenz400 mg/day for days600 mg orally on day 7141.22(1.04 to 1.42)0.92 90% Confidence interval not reported Fluconazole200 mg orally single dose1,200 mg orally single dose180.82(0.66 to 1.02)1.07(0.94 to 1.22)Nelfinavir750 mg three times day for 11 days1,200 mg orally on day 9142.36(1.77 to 3.15)2.12(1.80 to 2.50).

POSTMARKETING EXPERIENCE SECTION.

6.2Postmarketing Experience. The following adverse reactions have been identified during post-approval use of azithromycin. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Adverse reactions reported with azithromycin during the postmarketing period in adult and/or pediatric patients for which 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.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 (5.2)]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, AGEP, 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable data from published literature and postmarketing experience over several decades with azithromycin use in pregnant women have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Developmental toxicity studies with azithromycin in rats, mice, and rabbits showed no drug-induced fetal malformations at doses up to 4, 2, and times, respectively, an adult human daily dose of 500 mg based on body surface area. Decreased viability and delayed development were observed in the offspring of pregnant rats administered azithromycin from day of pregnancy through weaning at dose equivalent to times an adult human daily dose of 500 mg based on body surface area (see Data).The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Human DataAvailable data from published observational studies, case series, and case reports over several decades do not suggest an increased risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes with azithromycin use in pregnant women. Limitations of these data include the lack of randomization and inability to control for confounders such as underlying maternal disease and maternal use of concomitant medications.. Animal DataAzithromycin administered during the period of organogenesis did not cause fetal malformations in rats and mice at oral doses up to 200 mg/kg/day (moderately maternally toxic). Based on body surface area, this dose is approximately (rats) and (mice) times an adult human daily dose of 500 mg. In rabbits administered azithromycin at oral doses of 10, 20, and 40 mg/kg/day during organogenesis, reduced maternal body weight and food consumption were observed in all groups; no evidence of fetotoxicity or teratogenicity was observed at these doses, the highest of which is estimated to be times an adult human daily dose of 500 mg based on body surface area. In pre- and postnatal development study, azithromycin was administered orally to pregnant rats from day of pregnancy until weaning at doses of 50 or 200 mg/kg/day. Maternal toxicity (reduced food consumption and body weight gain; increased stress at parturition) was observed at the higher dose. Effects in the offspring were noted at 200 mg/kg/day during the postnatal development period (decreased viability, delayed developmental landmarks). These effects were not observed in pre- and postnatal rat study when up to 200 mg/kg/day of azithromycin was given orally beginning on day 15 of pregnancy until weaning.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information. ZITHROMAX(R) (Zith-roe-maks)(azithromycin)TabletsZITHROMAX(R) (azithromycin)Oral SuspensionRead this Patient Information leaflet before you start taking ZITHROMAX and each time you get refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.What is ZITHROMAXZITHROMAX is macrolide antibiotic prescription medicine used in adults 18 years or older to treat certain infections caused by certain germs called bacteria. These bacterial infections include:acute worsening of chronic bronchitisacute sinus infectioncommunity-acquired pneumoniainfected throat or tonsilsskin infectionsinfections of the urethra or cervixgenital ulcers in menZITHROMAX is also used in children to treat:ear infectionscommunity-acquired pneumoniainfected throat or tonsilsAzithromycin should not be taken by people who cannot tolerate oral medications because they are very ill or have certain other risk factors including:have cystic fibrosishave hospital acquired infectionshave known or suspected bacteria in the bloodneed to be in the hospitalare elderlyhave any medical problems that can lower the ability of the immune system to fight infectionsZITHROMAX is not for viral infections such as the common cold.It is not known if ZITHROMAX is safe and effective for genital ulcers in women.It is not known if ZITHROMAX is safe and effective for children with ear infections, sinus infections, and community-acquired pneumonia under months of age.It is not known if ZITHROMAX is safe and effective for infected throat or tonsils in children under years of age.Who should not take ZITHROMAXDo not take ZITHROMAX if you:have had severe allergic reaction to certain antibiotics known as macrolides or ketolides including azithromycin and erythromycin.have history of cholestatic jaundice or hepatic dysfunction that happened with the use of azithromycin.What should tell my healthcare provider before taking ZITHROMAXBefore you take ZITHROMAX, tell your healthcare provider if you:have pneumoniahave cystic fibrosishave known or suspected bacteremia (bacterial infection in the blood)have liver or kidney problemshave an irregular heartbeat, especially problem called QT prolongationhave problem that causes muscle weakness (myasthenia gravis)have any other medical problemsare pregnant or plan to become pregnant. It is not known if ZITHROMAX will harm your unborn baby.are breastfeeding or plan to breastfeed. ZITHROMAX has been reported to pass into breast milk. Talk to your healthcare provider about the best way to feed your baby while you take ZITHROMAX.Contact your healthcare provider immediately if you are giving ZITHROMAX to young child (less than weeks of age) and he or she vomits or becomes irritable when fed.Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.ZITHROMAX and other medicines may affect each other causing side effects. ZITHROMAX may affect the way other medicines work, and other medicines may affect how ZITHROMAX works.Especially tell your healthcare provider if you take:nelfinavira blood thinner (warfarin)digoxincolchicinephenytoinan antacid that contains aluminum or magnesiumKnow the medicines you take. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine.How should take ZITHROMAXTake ZITHROMAX exactly as your healthcare provider tells you to take it.ZITHROMAX can be taken with or without food.If you take ZITHROMAX Oral Suspension, shake the bottle well just before you take it.Do not skip any doses of ZITHROMAX or stop taking it, even if you begin to feel better, until you finish your prescribed treatment unless you have serious allergic reaction or your healthcare provider tells you to stop taking ZITHROMAX. See What are the possible side effects of ZITHROMAX If you skip doses, or do not complete the total course of ZITHROMAX your treatment may not work as well and your infection may be harder to treat. Taking all of your ZITHROMAX doses will help lower the chance that the bacteria will become resistant to ZITHROMAX.If the bacteria becomes resistant to ZITHROMAX, ZITHROMAX and other antibiotic medicines may not work for you in the future.If you take too much ZITHROMAX, call your healthcare provider or get medical help right away.What are the possible side effects of ZITHROMAXZITHROMAX can cause serious side effects, including:Serious allergic reactions. Allergic reactions can happen in people taking azithromcyin the active ingredient in ZITHROMAX, even after only dose. Stop taking ZITHROMAX and get emergency medical help right away if you have any of the following symptoms of severe allergic reaction: trouble breathing or swallowingswelling of the lips, tongue, facethroat tightness, hoarsenessrapid heartbeatfaintnessskin rash (hives)new onset of fever and swollen lymph nodesStop taking ZITHROMAX at the first sign of skin rash and call your healthcare provider. Skin rash may be sign of more serious reaction to ZITHROMAX.Liver damage (hepatotoxicity). Hepatotoxicity can happen in people who take ZITHROMAX. Call your healthcare provider right away if you have unexplained symptoms such as: nausea or vomitingstomach painfeverweaknessabdominal pain or tendernessitchingunusual tirednessloss of appetitechange in the color of your bowel movementsdark colored urineyellowing of your skin or of the whites of your eyesStop taking ZITHROMAX and tell your healthcare provider right away if you have yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of serious reaction to ZITHROMAX (a liver problem).Serious heart rhythm changes (QT prolongation and torsades de pointes).Tell your healthcare provider right away if you have change in your heartbeat (a fast or irregular heartbeat), or if you feel faint and dizzy. ZITHROMAX may cause rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this happening are higher in people:who are elderlywith family history of prolonged QT intervalwith low blood potassiumwho take certain medicines to control heart rhythm (antiarrhythmics)Worsening of myasthenia gravis (a problem that causes muscle weakness).Certain antibiotics like ZITHROMAX may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems.Diarrhea. Tell your healthcare provider right away if you have watery diarrhea, diarrhea that does not go away, or bloody stools. You may experience cramping and fever. This could happen after you have finished your ZITHROMAX.The most common side effects of ZITHROMAX include:nauseastomach painvomiting These are not all the possible side effects of ZITHROMAX. Tell your healthcare provider about any side effect that bothers you or that does not go away.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store ZITHROMAXStore ZITHROMAX Tablets at 59F to 86F (15C to 30C).Store ZITHROMAX Oral Suspension at 41F to 86F (5C to 30C).Keep ZITHROMAX Oral Suspension in tightly closed container.Safely throw away any medicine that is out of date or no longer needed.Keep ZITHROMAX and all medicines out of the reach of children.General information about the safe and effective use of ZITHROMAX.Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use ZITHROMAX for condition for which it was not prescribed. Do not give ZITHROMAX to other people, even if they have the same symptoms you have. It may harm them.This Patient Information leaflet summarizes the most important information about ZITHROMAX. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about ZITHROMAX that is written for health professionals.For more information, go to www.zithromax.com or call 1-800-438-1986.What are the ingredients in ZITHROMAX Tablets and Oral SuspensionZITHROMAX Tablets and Oral SuspensionActive ingredient: azithromycin dehydrateZITHROMAX Tablets: Inactive ingredients: dibasic calcium phosphate anhydrous, pregelatinized starch, sodium croscarmellose, magnesium stearate, sodium lauryl sulfate, hypromellose, lactose, titanium dioxide, triacetin, and D&C Red 30 aluminum lake.ZITHROMAX Oral Suspension:Inactive ingredients: sucrose; sodium phosphate, tribasic, anhydrous; hydroxypropyl cellulose; xanthan gum; FD&C Red 40; and spray dried artificial cherry, creme de vanilla, and banana flavors.This Patient Information has been approved by the U.S. Food and Drug Administration.LAB-0372-6.0Revised April 2019. acute worsening of chronic bronchitis. acute sinus infection. community-acquired pneumonia. infected throat or tonsils. skin infections. infections of the urethra or cervix. genital ulcers in men. ear infections. community-acquired pneumonia. infected throat or tonsils. have cystic fibrosis. have hospital acquired infections. have known or suspected bacteria in the blood. need to be in the hospital. are elderly. have any medical problems that can lower the ability of the immune system to fight infections. have had severe allergic reaction to certain antibiotics known as macrolides or ketolides including azithromycin and erythromycin.. have history of cholestatic jaundice or hepatic dysfunction that happened with the use of azithromycin.. have pneumonia. have cystic fibrosis. have known or suspected bacteremia (bacterial infection in the blood). have liver or kidney problems. have an irregular heartbeat, especially problem called QT prolongation. have problem that causes muscle weakness (myasthenia gravis). have any other medical problems. are pregnant or plan to become pregnant. It is not known if ZITHROMAX will harm your unborn baby.. are breastfeeding or plan to breastfeed. ZITHROMAX has been reported to pass into breast milk. Talk to your healthcare provider about the best way to feed your baby while you take ZITHROMAX.. nelfinavir. blood thinner (warfarin). digoxin. colchicine. phenytoin. an antacid that contains aluminum or magnesium. Take ZITHROMAX exactly as your healthcare provider tells you to take it.. ZITHROMAX can be taken with or without food.. If you take ZITHROMAX Oral Suspension, shake the bottle well just before you take it.. Do not skip any doses of ZITHROMAX or stop taking it, even if you begin to feel better, until you finish your prescribed treatment unless you have serious allergic reaction or your healthcare provider tells you to stop taking ZITHROMAX. See What are the possible side effects of ZITHROMAX If you skip doses, or do not complete the total course of ZITHROMAX your treatment may not work as well and your infection may be harder to treat. Taking all of your ZITHROMAX doses will help lower the chance that the bacteria will become resistant to ZITHROMAX.. If the bacteria becomes resistant to ZITHROMAX, ZITHROMAX and other antibiotic medicines may not work for you in the future.. If you take too much ZITHROMAX, call your healthcare provider or get medical help right away.. Serious allergic reactions. Allergic reactions can happen in people taking azithromcyin the active ingredient in ZITHROMAX, even after only dose. Stop taking ZITHROMAX and get emergency medical help right away if you have any of the following symptoms of severe allergic reaction: trouble breathing or swallowingswelling of the lips, tongue, facethroat tightness, hoarsenessrapid heartbeatfaintnessskin rash (hives)new onset of fever and swollen lymph nodesStop taking ZITHROMAX at the first sign of skin rash and call your healthcare provider. Skin rash may be sign of more serious reaction to ZITHROMAX.. trouble breathing or swallowing. swelling of the lips, tongue, face. throat tightness, hoarseness. rapid heartbeat. faintness. skin rash (hives). new onset of fever and swollen lymph nodes. Liver damage (hepatotoxicity). Hepatotoxicity can happen in people who take ZITHROMAX. Call your healthcare provider right away if you have unexplained symptoms such as: nausea or vomitingstomach painfeverweaknessabdominal pain or tendernessitchingunusual tirednessloss of appetitechange in the color of your bowel movementsdark colored urineyellowing of your skin or of the whites of your eyesStop taking ZITHROMAX and tell your healthcare provider right away if you have yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of serious reaction to ZITHROMAX (a liver problem).. nausea or vomiting. stomach pain. fever. weakness. abdominal pain or tenderness. itching. unusual tiredness. loss of appetite. change in the color of your bowel movements. dark colored urine. yellowing of your skin or of the whites of your eyes. Serious heart rhythm changes (QT prolongation and torsades de pointes).Tell your healthcare provider right away if you have change in your heartbeat (a fast or irregular heartbeat), or if you feel faint and dizzy. ZITHROMAX may cause rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this happening are higher in people:who are elderlywith family history of prolonged QT intervalwith low blood potassiumwho take certain medicines to control heart rhythm (antiarrhythmics). who are elderly. with family history of prolonged QT interval. with low blood potassium. who take certain medicines to control heart rhythm (antiarrhythmics). Worsening of myasthenia gravis (a problem that causes muscle weakness).Certain antibiotics like ZITHROMAX may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems.. Diarrhea. Tell your healthcare provider right away if you have watery diarrhea, diarrhea that does not go away, or bloody stools. You may experience cramping and fever. This could happen after you have finished your ZITHROMAX.The most common side effects of ZITHROMAX include:nauseastomach painvomiting nausea. stomach pain. vomiting. Store ZITHROMAX Tablets at 59F to 86F (15C to 30C).. Store ZITHROMAX Oral Suspension at 41F to 86F (5C to 30C).. Keep ZITHROMAX Oral Suspension in tightly closed container.. Safely throw away any medicine that is out of date or no longer needed.. Logo.

SPL UNCLASSIFIED SECTION.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use ZITHROMAX(R) safely and effectively. See full prescribing information for ZITHROMAX. ZITHROMAX (azithromycin) 250 mg and 500 mg tablets, for oral use ZITHROMAX (azithromycin) for oral suspension Initial U.S. Approval: 1991-------------------------- INDICATIONS AND USAGE ---------------------------ZITHROMAX is macrolide antibacterial drug indicated for mild to moderate infections caused by designated, susceptible bacteria: Acute bacterial exacerbations of chronic bronchitis in adults (1.1)Acute bacterial sinusitis in adults (1.1)Uncomplicated skin and skin structure infections in adults (1.1)Urethritis and cervicitis in adults (1.1)Genital ulcer disease in men (1.1)Acute otitis media in pediatric patients (6 months of age and older) (1.2)Community-acquired pneumonia in adults and pediatric patients (6 months of age and older) (1.1, 1.2)Pharyngitis/tonsillitis in adults and pediatric patients (2 years of age and older) (1.1, 1.2)Limitation of Use:Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors. (1.3)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. (1.4)---------------------- DOSAGE AND ADMINISTRATION ----------------------Adult Patients (2.1)InfectionRecommended Dose/Duration of TherapyCommunity-acquired pneumonia (mild severity)Pharyngitis/tonsillitis (second-line therapy)Skin/skin structure (uncomplicated)500 mg as single dose on Day 1, followed by 250 mg once daily on Days through 5.Acute bacterial exacerbations of chronic bronchitis (mild to moderate)500 mg as single dose on Day 1, followed by 250 mg once daily on Days through or 500 mg once daily for days.Acute bacterial sinusitis500 mg once daily for days.Genital ulcer disease (chancroid)Non-gonococcal urethritis and cervicitisOne single gram dose.Gonococcal urethritis and cervicitisOne single gram dose.Pediatric Patients (2.2)InfectionRecommended Dose/Duration of TherapyAcute otitis media (6 months of age and older)30 mg/kg as single dose or 10 mg/kg once daily for days or 10 mg/kg as single dose on Day followed by mg/kg/day on Days through 5.Acute bacterial sinusitis (6 months of age and older)10 mg/kg once daily for days.Community-acquired pneumonia (6 months of age and older)10 mg/kg as single dose on Day followed by mg/kg once daily on Days through 5.Pharyngitis/tonsillitis (2 years of age and older)12 mg/kg once daily for days.------------------- DOSAGE FORMS AND STRENGTHS -------------------ZITHROMAX tablets 250 mg and 500 mg (3)ZITHROMAX for oral suspension 100 mg/5 mL and 200 mg/5 mL (3)---------------------------- CONTRAINDICATIONS ----------------------------Patients with known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide drug. (4.1)Patients with history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin. (4.2)--------------------- WARNINGS AND PRECAUTIONS ---------------------Serious (including fatal) allergic and skin reactions: Discontinue ZITHROMAX if reaction occurs. (5.1)Hepatotoxicity: Severe, and sometimes fatal, hepatotoxicity has been reported. Discontinue ZITHROMAX immediately if signs and symptoms of hepatitis occur. (5.2)Infantile Hypertrophic Pyloric Stenosis (IHPS): Following the use of azithromycin in neonates (treatment up to 42 days of life), IHPS has been reported. Direct parents and caregivers to contact their physician if vomiting or irritability with feeding occurs. (5.3)Prolongation of QT interval and cases of torsades de pointes have been reported. This risk which can be fatal should be considered in patients with certain cardiovascular disorders including known QT prolongation or history torsades de pointes, those with proarrhythmic conditions, and with other drugs that prolong the QT interval. (5.4)Clostridium difficile-Associated Diarrhea: Evaluate patients if diarrhea occurs. (5.5)ZITHROMAX may exacerbate muscle weakness in persons with myasthenia gravis. (5.6)---------------------------- ADVERSE REACTIONS ----------------------------Most common adverse reactions are diarrhea (5 to 14%), nausea (3 to 18%), abdominal pain (3 to 7%), or vomiting (2 to 7%). (6.1)To report SUSPECTED ADVERSE REACTIONS, contact Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.---------------------------- DRUG INTERACTIONS-----------------------------Nelfinavir: Close monitoring for known adverse reactions of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. (7.1)Warfarin: Use with azithromycin may increase coagulation times; monitor prothrombin time. (7.2)--------------------- USE IN SPECIFIC POPULATIONS ---------------------Pediatric use: Safety and effectiveness in the treatment of patients under months of age have not been established. (8.4)Geriatric use: Elderly patients may be more susceptible to development of torsades de pointes arrhythmias. (8.5)See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.Revised: 4/2019FULL PRESCRIBING INFORMATION: CONTENTS INDICATIONS AND USAGE 1.1 Adult Patients 1.2 Pediatric Patients 1.3 Limitations of Use 1.4 Usage DOSAGE AND ADMINISTRATION 2.1 Adult Patients 2.2 Pediatric Patients DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS 4.1 Hypersensitivity 4.2 Hepatic Dysfunction WARNINGS AND PRECAUTIONS 5.1 Hypersensitivity 5.2 Hepatotoxicity 5.3 Infantile Hypertrophic Pyloric Stenosis 5.4 QT Prolongation 5.5 Clostridium difficile-Associated Diarrhea 5.6 Exacerbation of Myasthenia Gravis 5.7 Use in Sexually Transmitted Disease 5.8 Development of Drug-Resistant Bacteria ADVERSE REACTIONS 6.1 Clinical Trials Experience 6.2 Postmarketing Experience 6.3 Laboratory Abnormalities DRUG INTERACTIONS 7.1 Nelfinavir 7.2 Warfarin 7.3 Potential Drug-Drug Interaction with Macrolides USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Lactation 8.4 Pediatric Use 8.5 Geriatric Use 10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Adult Patients 14.2 Pediatric Patients 16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION Sections or subsections omitted from the full prescribing information are not listed.FULL PRESCRIBING INFORMATION. Acute bacterial exacerbations of chronic bronchitis in adults (1.1). Acute bacterial sinusitis in adults (1.1). Uncomplicated skin and skin structure infections in adults (1.1). Urethritis and cervicitis in adults (1.1). Genital ulcer disease in men (1.1). Acute otitis media in pediatric patients (6 months of age and older) (1.2). Community-acquired pneumonia in adults and pediatric patients (6 months of age and older) (1.1, 1.2). Pharyngitis/tonsillitis in adults and pediatric patients (2 years of age and older) (1.1, 1.2). Adult Patients (2.1)InfectionRecommended Dose/Duration of TherapyCommunity-acquired pneumonia (mild severity)Pharyngitis/tonsillitis (second-line therapy)Skin/skin structure (uncomplicated)500 mg as single dose on Day 1, followed by 250 mg once daily on Days through 5.Acute bacterial exacerbations of chronic bronchitis (mild to moderate)500 mg as single dose on Day 1, followed by 250 mg once daily on Days through or 500 mg once daily for days.Acute bacterial sinusitis500 mg once daily for days.Genital ulcer disease (chancroid)Non-gonococcal urethritis and cervicitisOne single gram dose.Gonococcal urethritis and cervicitisOne single gram dose.. Pediatric Patients (2.2)InfectionRecommended Dose/Duration of TherapyAcute otitis media (6 months of age and older)30 mg/kg as single dose or 10 mg/kg once daily for days or 10 mg/kg as single dose on Day followed by mg/kg/day on Days through 5.Acute bacterial sinusitis (6 months of age and older)10 mg/kg once daily for days.Community-acquired pneumonia (6 months of age and older)10 mg/kg as single dose on Day followed by mg/kg once daily on Days through 5.Pharyngitis/tonsillitis (2 years of age and older)12 mg/kg once daily for days.. ZITHROMAX tablets 250 mg and 500 mg (3). ZITHROMAX for oral suspension 100 mg/5 mL and 200 mg/5 mL (3). Patients with known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide drug. (4.1). Patients with history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin. (4.2). Serious (including fatal) allergic and skin reactions: Discontinue ZITHROMAX if reaction occurs. (5.1). Hepatotoxicity: Severe, and sometimes fatal, hepatotoxicity has been reported. Discontinue ZITHROMAX immediately if signs and symptoms of hepatitis occur. (5.2). Infantile Hypertrophic Pyloric Stenosis (IHPS): Following the use of azithromycin in neonates (treatment up to 42 days of life), IHPS has been reported. Direct parents and caregivers to contact their physician if vomiting or irritability with feeding occurs. (5.3). Prolongation of QT interval and cases of torsades de pointes have been reported. This risk which can be fatal should be considered in patients with certain cardiovascular disorders including known QT prolongation or history torsades de pointes, those with proarrhythmic conditions, and with other drugs that prolong the QT interval. (5.4). Clostridium difficile-Associated Diarrhea: Evaluate patients if diarrhea occurs. (5.5). ZITHROMAX may exacerbate muscle weakness in persons with myasthenia gravis. (5.6). Nelfinavir: Close monitoring for known adverse reactions of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. (7.1). Warfarin: Use with azithromycin may increase coagulation times; monitor prothrombin time. (7.2). Pediatric use: Safety and effectiveness in the treatment of patients under months of age have not been established. (8.4). Geriatric use: Elderly patients may be more susceptible to development of torsades de pointes arrhythmias. (8.5).

STORAGE AND HANDLING SECTION.

Storage: Store dry powder below 30C (86F). Store constituted suspension between to 30C (41 to 86F) and discard when full dosing is completed.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAvailable data from published literature and postmarketing experience over several decades with azithromycin use in pregnant women have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). Developmental toxicity studies with azithromycin in rats, mice, and rabbits showed no drug-induced fetal malformations at doses up to 4, 2, and times, respectively, an adult human daily dose of 500 mg based on body surface area. Decreased viability and delayed development were observed in the offspring of pregnant rats administered azithromycin from day of pregnancy through weaning at dose equivalent to times an adult human daily dose of 500 mg based on body surface area (see Data).The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Human DataAvailable data from published observational studies, case series, and case reports over several decades do not suggest an increased risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes with azithromycin use in pregnant women. Limitations of these data include the lack of randomization and inability to control for confounders such as underlying maternal disease and maternal use of concomitant medications.. Animal DataAzithromycin administered during the period of organogenesis did not cause fetal malformations in rats and mice at oral doses up to 200 mg/kg/day (moderately maternally toxic). Based on body surface area, this dose is approximately (rats) and (mice) times an adult human daily dose of 500 mg. In rabbits administered azithromycin at oral doses of 10, 20, and 40 mg/kg/day during organogenesis, reduced maternal body weight and food consumption were observed in all groups; no evidence of fetotoxicity or teratogenicity was observed at these doses, the highest of which is estimated to be times an adult human daily dose of 500 mg based on body surface area. In pre- and postnatal development study, azithromycin was administered orally to pregnant rats from day of pregnancy until weaning at doses of 50 or 200 mg/kg/day. Maternal toxicity (reduced food consumption and body weight gain; increased stress at parturition) was observed at the higher dose. Effects in the offspring were noted at 200 mg/kg/day during the postnatal development period (decreased viability, delayed developmental landmarks). These effects were not observed in pre- and postnatal rat study when up to 200 mg/kg/day of azithromycin was given orally beginning on day 15 of pregnancy until weaning.. 8.2 Lactation. Risk Summary Azithromycin is present in human milk (see Data). Non-serious adverse reactions have been reported in breastfed infants after maternal administration of azithromycin (see Clinical Considerations). There are no available data on the effects of azithromycin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ZITHROMAX and any potential adverse effects on the breastfed infant from ZITHROMAX or from the underlying maternal condition.. Clinical ConsiderationsAdvise women to monitor the breastfed infant for diarrhea, vomiting, or rash.. DataAzithromycin breastmilk concentrations were measured in 20 women after receiving single g oral dose of azithromycin during labor. Breastmilk samples collected on days and postpartum as well as and weeks postpartum revealed the presence of azithromycin in breastmilk up to weeks after dosing. In another study, single dose of azithromycin 500 mg was administered intravenously to women prior to incision for cesarean section. Breastmilk (colostrum) samples obtained between 12 and 48 hours after dosing revealed that azithromycin persisted in breastmilk up to 48 hours.. 8.4 Pediatric Use. [see Clinical Pharmacology (12.3), Indications and Usage (1.2), and Dosage and Administration (2.2)] Safety and effectiveness in the treatment of pediatric patients with acute otitis media, acute bacterial sinusitis and community-acquired pneumonia under months of age have not been established. Use of ZITHROMAX for the treatment of acute bacterial sinusitis and community-acquired pneumonia in pediatric patients (6 months of age or greater) is supported by adequate and well-controlled trials in adults.. Pharyngitis/Tonsillitis: Safety and effectiveness in the treatment of pediatric patients with pharyngitis/tonsillitis under years of age have not been established.. 8.5 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 response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than younger patients. [see Warnings and Precautions (5.4)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 5.1Hypersensitivity. Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported in patients on azithromycin therapy. [see Contraindications (4.1)] 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 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 has been discontinued.. 5.2Hepatotoxicity. 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.. 5.3Infantile Hypertrophic Pyloric Stenosis (IHPS). Following the use of azithromycin in neonates (treatment up to 42 days of life), IHPS has been reported. Direct parents and caregivers to contact their physician if vomiting or irritability with feeding occurs. 5.4QT Prolongation. Prolonged cardiac repolarization and QT interval, imparting 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, 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.. patients with known prolongation of the QT interval, 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.. 5.5 Clostridium difficile-Associated Diarrhea (CDAD). Clostridium difficile-associated diarrhea 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 and 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.. 5.6 Exacerbation of Myasthenia Gravis. Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy.. 5.7 Use in Sexually Transmitted Infections. ZITHROMAX, at the recommended dose, should not be relied upon to treat syphilis. Antibacterial agents used to treat non-gonococcal urethritis may mask or delay the symptoms of incubating syphilis. All patients with sexually transmitted urethritis or cervicitis should have serologic test for syphilis and appropriate testing 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.. 5.8Development of Drug-Resistant Bacteria. Prescribing ZITHROMAX in the absence of 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.