FDA label ae1ea915-cad8-410f-acfe-ad56c711a4a9

5 WARNINGS AND PRECAUTIONS • Serious (including fatal) allergic and skin reactions: Discontinue Zmax if reaction occurs. ( 5.1 ) • Hepatotoxicity: severe, and sometimes fatal, hepatotoxicity has been reported. Discontinue 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 the 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 of torsades de pointes, those with proarrhythmic conditions, and with other drugs that prolong the QT interval. ( 5.4 ) • Cardiovascular Death: Some observational studies have shown an approximately two-fold increased short-term potential risk of acute cardiovascular death in adults exposed to azithromycin relative to other antibacterial drugs, including amoxicillin. Consider balancing this potential risk with treatment benefits when prescribing Zmax. ( 5.5 ) • Clostridioides difficile -Associated Diarrhea: Evaluate patients if diarrhea occurs. ( 5.6 ) • Zmax may exacerbate muscle weakness in persons with myasthenia gravis. ( 5.7 ) • Gastrointestinal Disturbances: higher incidence in patients with GFR<10 mL/min. ( 5.8 ) 5.1 Hypersensitivity Serious allergic reactions, including angioedema, anaphylaxis, Acute Generalized Exanthematous Pustulosis (AGEP), Stevens Johnson syndrome, and toxic epidermal necrolysis have been reported in patients on azithromycin therapy using other formulations. Fatalities have been reported. Cases of Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) have also been reported. Despite initially successful symptomatic treatment of the allergic symptoms, when symptomatic therapy was discontinued, the allergic symptoms recurred soon thereafter in some patients without further azithromycin exposure. These patients required prolonged periods of observation and symptomatic treatment. The relationship of these episodes to the long tissue half-life of azithromycin and subsequent exposure to antigen has not been determined. If an allergic reaction occurs, appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued. 5.2 Hepatotoxicity Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur. 5.3 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. 5.4 QT Prolongation Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen in treatment with macrolides, including azithromycin. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving azithromycin. Providers should consider the risk of QT prolongation which can be fatal when weighing the risks and benefits of azithromycin for at-risk groups including: • patients with known prolongation of the QT interval, a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure • patients on drugs known to prolong the QT interval • patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and in patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, amiodarone, sotalol) antiarrhythmic agents Elderly patients may be more susceptible to drug-associated effects on the QT interval. 5.5 Cardiovascular Death Some observational studies have shown an approximately two-fold increased short-term potential risk of acute cardiovascular death in adults exposed to azithromycin relative to other antibacterial drugs, including amoxicillin. The five-day cardiovascular mortality observed in these studies ranged from 20 to 400 per million azithromycin treatment courses. This potential risk was noted to be greater during the first five days of azithromycin use and does not appear to be limited to those patients with preexisting cardiovascular diseases. The data in these observational studies are insufficient to establish or exclude a causal relationship between acute cardiovascular death and azithromycin use. Consider balancing this potential risk with treatment benefits when prescribing Zmax. 5.6 Clostridioides difficile -Associated Diarrhea (CDAD) Clostridioides 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. 5.7 Exacerbation of Myasthenia Gravis Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy. 5.8 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) ] 5.9 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 The following clinically significant adverse reactions are described elsewhere in labeling: • Hypersensitivity [see Warnings and Precautions (5.1) ] • Hepatotoxicity [see Warnings and Precautions (5.2) ] • Infantile Hypertrophic Pyloric Stenosis (IHPS) [see Warnings and Precautions (5.3) ] • QT Prolongation [see Warnings and Precautions (5.4) ] • Cardiovascular Death [see Warnings and Precautions (5.5) ] • Clostridioides difficile- Associated Diarrhea (CDAD) [see Warnings and Precautions (5.6) ] • Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.7) ] 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 Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adults : The data described below reflect exposure to Zmax in 728 adult patients. All patients received a single 2 g oral dose of Zmax. The population studied had community-acquired pneumonia and acute bacterial sinusitis. In controlled clinical trials with Zmax, the majority of the reported treatment-related adverse reactions were gastrointestinal in nature and mild to moderate in severity. Overall, the most common treatment-related adverse reactions in adult patients receiving a single 2 g dose of Zmax were diarrhea/loose stools (12%), nausea (4%), abdominal pain (3%), headache (1%), and vomiting (1%). The incidence of treatment-related gastrointestinal adverse reactions was 17% for Zmax and 10% for pooled comparators. Treatment-related adverse reactions following Zmax treatment that occurred with a frequency of <1% included the following: Cardiovascular: Palpitations, chest pain Gastrointestinal : Constipation, dyspepsia, flatulence, gastritis, oral moniliasis Genitourinary : Vaginitis Nervous system: Dizziness, vertigo General: Asthenia Allergic: Rash, pruritus, urticaria Special senses : Taste perversion Pediatric Patients: The data described below reflect exposure to Zmax in 907 pediatric patients. The population was 3 months to 12 years of age. All patients received a single 60 mg/kg oral dose of Zmax. As in adults, the most common treatment-related adverse reactions in pediatric subjects were gastrointestinal in nature. The pediatric subjects all received a single 60 mg/kg dose of Zmax. In a trial with 450 pediatric subjects (ages 3 months to 48 months), vomiting (11%), diarrhea (10%) loose stools (9%), and abdominal pain (2%) were the most frequently reported treatment-related gastrointestinal adverse reactions. Many treatment related gastrointestinal adverse reactions with an incidence greater than 1% began on the day of dosing in these subjects [43% (68/160)] and most [53% (84/160)] resolved within 48 hr of onset. Treatment-related adverse events that were not gastrointestinal, occurring with a frequency ≥1% were: rash (5%), anorexia (2%), fever (2%), and dermatitis (2%). In a second trial of 337 pediatric subjects, ages 2 years to 12 years, the most frequently reported treatment-related adverse reactions also included vomiting (14%), diarrhea (7%), loose stools (2%), nausea (4%) and abdominal pain (4%). A third trial investigated the tolerability of two different concentrations of azithromycin oral suspension in 120 pediatric subjects (ages 3 months to 48 months), all of whom were treated with azithromycin. The study evaluated the hypothesis that a more dilute, less viscous formulation (the recommended 27 mg/mL concentration of Zmax) is less likely to induce vomiting in young children than a more concentrated suspension used in other pediatric studies. The vomiting rate for subjects taking the dilute concentration azithromycin was 3% (2/61). The rate was numerically lower but not statistically different from the vomiting for the more concentrated suspension. Across both treatment arms, the only treatment-related adverse events with a frequency of ≥1% were vomiting (6%, 7/120) and diarrhea (2%, 2/120). Treatment-related adverse reactions with a frequency of <1% following Zmax treatment in all 907 pediatric subjects in the Phase 3 studies were: Body as a whole: Chills, fever, flu syndrome, headache; Digestive: Abnormal stools, constipation, dyspepsia, flatulence, gastritis, gastrointestinal disorder, hepatitis; Hematologic and lymphatic : Leukopenia; Nervous system : Agitation, emotional liability, hostility, hyperkinesia, insomnia, irritability, paresthesia, Somnolence; Respiratory: Asthma, bronchitis, cough, dyspnea, pharyngitis, rhinitis; Skin and appendages: Dermatitis, fungal dermatitis, maculopapular rash, pruritus, urticaria; Special senses: Otitis media, taste perversion; Urogenital: Dysuria. 6.2 Postmarketing Experience with Other Azithromycin Products The following adverse reactions have been identified during post-approval use of azithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported with azithromycin during the postmarketing period in adult and/or pediatric patients for which a causal relationship may not be established include: Allergic : Arthralgia, edema, urticaria and angioedema. Cardiovascular: Palpitations and arrhythmias including ventricular tachycardia and hypotension. There have been reports of QT prolongation, torsades de pointes, and cardiovascular death. Gastrointestinal: Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea, pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and rare reports of tongue discoloration. General: Asthenia, paresthesia, fatigue, malaise and anaphylaxis. Genitourinary: Interstitial nephritis, acute renal failure and vaginitis. Hematopoietic: Thrombocytopenia, mild neutropenia. Liver/biliary: Adverse reactions related to hepatic dysfunction have been reported in postmarketing experience with azithromycin. [See Warnings and Precautions (5.2) ]. Nervous system: Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation and syncope. Psychiatric: Aggressive reaction and anxiety. Skin/appendages: Pruritus, rash, photosensitivity, serious skin reactions including erythema multiforme, 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. 6.3 Laboratory Abnormalities In subjects with normal baseline values, the following clinically significant laboratory abnormalities (irrespective of drug relationship) were reported in Zmax clinical trials in adults and pediatric patients: Adults: Laboratory abnormalities with an incidence of greater than or equal to 1%: reduced lymphocytes and increased eosinophils; reduced bicarbonate. Laboratory abnormalities with an incidence of less than 1%: leukopenia, neutropenia, elevated bilirubin, AST, ALT, BUN, creatinine, alterations in potassium. Where follow-up was provided, changes in laboratory tests appeared to be reversible. Pediatric Patients: Laboratory abnormalities with an incidence of greater than or equal to 1%: elevated eosinophils, BUN, and potassium; decreased lymphocytes; and alterations in neutrophils; with an incidence of less than 1%: elevated SGOT, SGPT and creatinine; decreased potassium; and alterations in sodium and glucose.