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 Apotex Corp. at 1-800-706-5575 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. 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 azithromycin therapy because of treatment-related adverse reactions. In adults given 500 mg/day for 3 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 a single dose or over 3 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 azithromycin were related to the gastrointestinal system with diarrhea/loose stools (4 to 5%), nausea (3%), and abdominal pain (2 to 3%) being the most frequently reported. No other adverse reactions occurred in patients on the multiple-dose regimens of azithromycin with a frequency greater than 1%. Adverse reactions that occurred with a 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 a single-dose regimen of 1 gram of azithromycin were related to the gastrointestinal system and were more frequently reported than in patients receiving the multiple-dose regimen. Adverse reactions that occurred in patients on the single 1-gram dosing regimen of azithromycin with a frequency of 1% or greater included diarrhea/loose stools (7%), nausea (5%), abdominal pain (5%), vomiting (2%), dyspepsia (1%), and vaginitis (1%). Single 2-gram dose regimen Overall, the most common adverse reactions in patients receiving a single 2-gram dose of azithromycin were related to the gastrointestinal system. Adverse reactions that occurred in patients in this study with a frequency of 1% or greater included nausea (18%), diarrhea/loose stools (14%), vomiting (7%), abdominal pain (7%), vaginitis (2%), dyspepsia (1%), and dizziness (1%). The majority of these complaints were mild in nature. 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 Regimen Diarrhea % Abdominal Pain % Vomiting % Nausea % Rash % 1-day 4.3 % 1.4 % 4.9 % 1.0 % 1.0 % 3-day 2.6 % 1.7 % 2.3 % 0.4 % 0.6 % 5-day 1.8 % 1.2 % 1.1 % 0.5 % 0.4 % Community-Acquired Pneumonia For the recommended dosage regimen of 10 mg/kg on Day 1 followed by 5 mg/kg on Days 2 to 5, the most frequent adverse reactions attributed to treatment were diarrhea/loose stools, abdominal pain, vomiting, nausea, and rash. The incidence is described in the table below: Dosage Regimen Diarrhea/ Loose stools % Abdominal Pain % Vomiting % Nausea % Rash % 5-day 5.8 % 1.9 % 1.9 % 1.9 % 1.6 % Pharyngitis/Tonsillitis For the recommended dosage regimen of 12 mg/kg on Days 1 to 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 Regimen Diarrhea % Abdominal Pain % Vomiting % Nausea % Rash % Headache % 5-day 5.4 % 3.4 % 5.6 % 1.8 % 0.7 % 1.1 % With any of the treatment regimens, no other adverse reactions occurred in pediatric patients treated with azithromycin with a frequency greater than 1%. Adverse reactions that occurred with a frequency of 1% or less included the following: Cardiovascular Chest pain. Gastrointestinal Dyspepsia, constipation, anorexia, enteritis, flatulence, gastritis, jaundice, loose stools, and oral moniliasis. 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. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of azithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported with azithromycin during the postmarketing period in adult and/or pediatric patients for which a causal relationship may not be established include: Allergic Arthralgia, edema, urticaria, and angioedema. Cardiovascular Arrhythmias including ventricular tachycardia and hypotension. There have been reports of QT prolongation and torsades de pointes. Gastrointestinal Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea, pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and 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. 6.3 Laboratory 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 5,000 patients, four patients discontinued therapy because of treatment-related liver enzyme abnormalities and one because of a renal function abnormality. Pediatric Patients One, Three, and Five Day Regimens Laboratory data collected from comparative clinical trials employing two 3-day regimens (30 mg/kg or 60 mg/kg in divided doses over 3 days), or two 5-day regimens (30 mg/kg or 60 mg/kg in divided doses over 5 days) were similar for regimens of azithromycin and all comparators combined, with most clinically significant laboratory abnormalities occurring at incidences of 1 to 5%. Laboratory data for patients receiving 30 mg/kg as a single dose were collected in one single center trial. In that trial, an absolute neutrophil count between 500 to 1,500 cells/mm3 was observed in 10/64 patients receiving 30 mg/kg as a single dose, 9/62 patients receiving 30 mg/kg given over 3 days, and 8/63 comparator patients. No patient had an absolute neutrophil count <500 cells/mm3. In multiple-dose clinical trials involving approximately 4,700 pediatric patients, no patients discontinued therapy because of treatment-related laboratory abnormalities.