FDA label c61229e8-75cb-4776-9883-c5630bc38a32

5 WARNINGS AND PRECAUTIONS Severe (including fatal) allergic and skin reactions: Discontinue Zmax if reaction occurs. ( 5.1 ) Clostridium difficile -associated diarrhea: Evaluate patients if diarrhea occurs. ( 5.2 ) Exacerbation of myasthenia gravis ( 5.3 ) Gastrointestinal Disturbances: higher incidence in patients with GFR<10 mL/min. ( 5.4 ) 5.1 Allergic and skin reactions Serious allergic reactions, including angioedema, anaphylaxis, Stevens Johnson syndrome and toxic epidermal necrolysis have been reported rarely in patients on azithromycin therapy using other formulations. Although rare, fatalities have been reported. Despite initially successful symptomatic treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms recurred soon thereafter in some patients without further azithromycin exposure . These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin and subsequent exposure to antigen has not been determined. If an allergic reaction occurs, appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued. 5.2 Clostridium difficile-associated diarrhea Clostridium difficile -associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including Zmax, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile . C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. 5.3 Exacerbation of myasthenia gravis Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy. 5.4 Gastrointestinal Disturbances A higher incidence of gastrointestinal adverse events (8 of 19 subjects) was observed when Zmax was administered to a limited number of subjects with GFR< 10 mL/min [See USE IN SPECIFIC POPULATIONS (8.6) ] 5.5 Prolongation of the QT interval Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes , have been seen in treatment with other macrolides. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarization. 5.6 Development of drug resistant bacteria Prescribing Zmax in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥1%) are diarrhea/loose stools, nausea, abdominal pain, headache, and vomiting ( 6.1 , 6.2 ) 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 6.1 Clinical studies experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults : The data described below reflect exposure to Zmax in 728 adult patients. All patients received a single 2 g oral dose of Zmax. The population studied had community-acquired pneumonia and acute bacterial sinusitis. In controlled clinical trials with Zmax, the majority of the reported treatment-related adverse reactions were gastrointestinal in nature and mild to moderate in severity. Overall, the most common treatment-related adverse reactions in adult patients receiving a single 2 g dose of Zmax were diarrhea/loose stools (12%), nausea (4%), abdominal pain (3%), headache (1%), and vomiting (1%). The incidence of treatment-related gastrointestinal adverse reactions was 17% for Zmax and 10% for pooled comparators. Treatment-related adverse reactions following Zmax treatment that occurred with a frequency of <1% included the following: Cardiovascular: palpitations, chest pain Gastrointestinal : constipation, dyspepsia, flatulence, gastritis, oral moniliasis Genitourinary : vaginitis Nervous System: dizziness, vertigo General: asthenia Allergic: rash, pruritus, urticaria Special Senses : taste perversion Laboratory Abnormalities In subjects with normal baseline values, the following clinically significant laboratory abnormalities (irrespective of drug relationship) were reported in Zmax clinical trials: -with an incidence of greater than or equal to 1%: reduced lymphocytes and increased eosinophils; reduced bicarbonate; -with an incidence of less than 1%: leukopenia, neutropenia, elevated bilirubin, AST, ALT, BUN, creatinine, alterations in potassium. Where follow-up was provided, changes in laboratory tests appeared to be reversible. Pediatric Patients: The data described below reflect exposure to Zmax in 907 pediatric patients. The population was 3 months to 12 years of age. All patients received a single 60 mg/kg oral dose of Zmax. As in adults, the most common treatment-related adverse reactions in pediatric subjects were gastrointestinal in nature. The pediatric subjects all received a single 60 mg/kg dose (equivalent to 27 mg/lb) of Zmax. In a study with 450 pediatric subjects (ages 3 months to 48 months), vomiting (11%), diarrhea (10%) loose stools (9%), and abdominal pain (2%) were the most frequently reported treatment-related gastrointestinal adverse reactions. Many treatment related gastrointestinal adverse reactions with an incidence greater than 1% began on the day of dosing in these subjects [43% (68/160)] and most [53% (84/160)] resolved within 48 hours of onset. Treatment-related adverse events that were not gastrointestinal, occurring with a frequency ≥ 1% were: rash (5%), anorexia (2%), fever (2%), and dermatitis (2%). In a second study of 337 pediatric subjects, ages 2 years to 12 years, the most frequently reported treatment-related adverse reactions also included vomiting (14%), diarrhea (7%), loose stools (2%), nausea (4%) and abdominal pain (4%). A third study investigated the tolerability of two different concentrations of azithromycin oral suspension in 120 pediatric subjects (ages 3 months to 48 months), all of whom were treated with azithromycin. The study evaluated the hypothesis that a more dilute, less viscous formulation (the recommended 27 mg/mL concentration of Zmax) is less likely to induce vomiting in young children than a more concentrated suspension used in other pediatric studies. The vomiting rate for subjects taking the dilute concentration azithromycin was 3% (2/61). The rate was numerically lower but not statistically different from the vomiting for the more concentrated suspension Across both treatment arms, the only treatment-related adverse events with a frequency of ≥ 1% were vomiting (6%, 7/120) and diarrhea (2%, 2/120). Treatment-related adverse reactions with a frequency of < 1% following Zmax treatment in all 907 pediatric subjects in the Phase 3 studies were: Body as a whole: chills, fever, flu syndrome, headache; Digestive: abnormal stools, constipation, dyspepsia, flatulence, gastritis, gastrointestinal disorder, hepatitis; Hemic and Lymphatic : leukopenia; Nervous System : agitation, emotional liability, hostility, hyperkinesia, insomnia, irritability, parasthesia, somnolence; Respiratory: asthma, bronchitis, cough increased, dyspnea, pharyngitis, rhinitis; Skin and Appendages: dermatitis, fungal dermatitis, maculopapular rash, pruritus, urticaria; Special Senses: otitis media, taste perversion; Urogenital: dysuria. Laboratory Abnormalities In subjects with normal baseline values, the following clinically significant laboratory abnormalities (irrespective of drug relationship) were reported in Zmax pediatric clinical trials: -with an incidence of greater than or equal to 1%: elevated eosinophils, BUN, and potassium; decreased lymphocytes; and alterations in neutrophils; -with an incidence of less than 1%: elevated SGOT, SGPT and creatinine; decreased potassium; and alterations in sodium and glucose. 6.2 Postmarketing experience with other azithromycin products Because these reactions are reported voluntarily from a population of uncertain size, reliably estimating their frequency or establishing a causal relationship to drug exposure is not always possible. Adverse events reported with azithromycin immediate release formulations during the postmarketing period for which a causal relationship may not be established include: Allergic : arthralgia, edema, urticaria and angioedema Cardiovascular: palpitations and arrhythmias including ventricular tachycardia and hypotension There have been rare reports of QT prolongation and torsades de pointes . Gastrointestinal: anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea rarely resulting in dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis and rare reports of tongue discoloration General: asthenia, paresthesia, fatigue, malaise and anaphylaxis (rarely fatal) Genitourinary: interstitial nephritis, acute renal failure, moniliasis and vaginitis Hematopoietic: thrombocytopenia, mild neutropenia Liver/Biliary: abnormal liver function including hepatitis and cholestatic jaundice, as well as rare cases of hepatic necrosis and hepatic failure, some of which have resulted in death Nervous System: convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation and syncope Psychiatric: aggressive reaction and anxiety Skin/Appendages: pruritus, rash, photosensitivity, rarely serious skin reactions including erythema multiforme, Stevens-Johnson syndrome and toxic epidermal necrolysis Special Senses: hearing disturbances including hearing loss, deafness and/or tinnitus and rare reports of taste/smell perversion and/or loss