Azithromycin

1 INDICATIONS AND USAGE Azithromycin is a macrolide antibacterial drug indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below. Recommended dosages and durations of therapy in adult and pediatric patient populations vary in these indications. [see Dosage and Administration (2) ] Azithromycin is a 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 azithromycin tablets and other antibacterial drugs, azithromycin tablets should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. ( 1.4 ) 1.1 Adult 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. 1.2 Pediatric 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. 1.3 Limitations 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, 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 azithromycin tablets and other antibacterial drugs, azithromycin tablets 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.

2 DOSAGE AND ADMINISTRATION • Adult Patients ( 2.1 ) Infection Recommended Dose/Duration of Therapy Community-acquired pneumonia (mild severity) Pharyngitis/tonsillitis (second-line therapy) Skin/skin structure (uncomplicated) 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5. Acute bacterial exacerbations of chronic bronchitis (mild to moderate) 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5 or 500 mg once daily for 3 days. Acute bacterial sinusitis 500 mg once daily for 3 days. Genital ulcer disease (chancroid) Non-gonococcal urethritis and cervicitis One single 1 gram dose. Gonococcal urethritis and cervicitis One single 2 gram dose. • Pediatric Patients ( 2.2 ) Infection Recommended Dose/Duration of Therapy Acute otitis media (6 months of age and older) 30 mg/kg as a single dose or 10 mg/kg once daily for 3 days or 10 mg/kg as a single dose on Day 1 followed by 5 mg/kg/day on Days 2 through 5. Acute bacterial sinusitis (6 months of age and older) 10 mg/kg once daily for 3 days. Community-acquired pneumonia (6 months of age and older) 10 mg/kg as a single dose on Day 1 followed by 5 mg/kg once daily on Days 2 through 5. Pharyngitis/tonsillitis (2 years of age and older) 12 mg/kg once daily for 5 days. 2.1 Adult Patients [see Indications and Usage (1.1) and Clinical Pharmacology (12.3) ] Infection* Recommended Dose/Duration of Therapy Community-acquired pneumonia Pharyngitis/tonsillitis (second-line therapy) Skin/skin structure (uncomplicated) 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5 Acute bacterial exacerbations of chronic obstructive pulmonary disease 500 mg once daily for 3 days OR 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5 Acute bacterial sinusitis 500 mg once daily for 3 days Genital ulcer disease (chancroid) One single 1 gram dose Non-gonococcal urethritis and cervicitis One single 1 gram dose Gonococcal urethritis and cervicitis One single 2 gram dose * DUE TO THE INDICATED ORGANISMS [see Indications and Usage (1.1) ] Azithromycin tablets can be taken with or without food. 2.2 Pediatric Patients 1 Infection* Recommended Dose/Duration of Therapy Acute otitis media 30 mg/kg as a single dose or 10 mg/kg once daily for 3 days or 10 mg/kg as a single dose on Day 1 followed by 5 mg/kg/day on Days 2 through 5. Acute bacterial sinusitis 10 mg/kg once daily for 3 days. Community-acquired pneumonia 10 mg/kg as a single dose on Day 1 followed by 5 mg/kg once daily on Days 2 through 5. Pharyngitis/tonsillitis 12 mg/kg once daily for 5 days. * DUE TO THE INDICATED ORGANISMS [see Indications and Usage (1.2) ] 1 see dosing tables below for maximum doses evaluated by indication Azithromycin for oral suspension can be taken with or without food. PEDIATRIC DOSAGE GUIDELINES FOR OTITIS MEDIA, ACUTE BACTERIAL SINUSITIS, AND COMMUNITY-ACQUIRED PNEUMONIA (Age 6 months and above, [see Use in Specific Populations (8.4) ] ) Based on Body Weight OTITIS MEDIA AND COMMUNITY-ACQUIRED PNEUMONIA: (5-Day Regimen)* Dosing Calculated on 10 mg/kg/day Day 1 and 5 mg/kg/day Days 2 to 5. Weight in kG 100 mg/5 mL 100 mg/5 mL 200 mg/5 mL 200 mg/5 mL Total mg per Treatment Course Total mg per Treatment Course Day 1 Days 2 to 5 Day 1 Days 2 to 5 5 2.5 mL; (½ tsp) 1.25 mL; (¼ tsp) 7.5 mL 150 mg 10 5 mL; (1tsp) 2.5 mL; (½ tsp) 15 mL 300 mg 20 5 mL; (1 tsp) 2.5 mL; (½ tsp) 15mL 600mg 30 7.5 mL; (1½ tsp) 5 mL; (1 tsp) 22.5 mL 900mg 40 10 mL; (2 tsp) 5 mL; (1 tsp) 30 mL 1200mg 50 + 12.5 mL; (2½ tsp) 6.25 mL; (1¼ tsp) 37.5 mL 1500mg * Effectiveness of the 3-day or 1-day regimen in pediatric patients with community-acquired pneumonia has not been established. OTITIS MEDIA AND ACUTE BACTERIAL SINUSITIS: (3-Day Regimen)* Dosing Calculated on 10 mg/kg/day. Weight 100 mg/5 mL 200 mg/5 mL Total mL per Treatment Course Total mg per Treatment Course Kg Days 1 to 3 Days 1 to 3 5 2.5 mL; (1/2 tsp) 7.5 mL 150 mg 10 5 mL; (1 tsp) 15 mL 300 mg 20 5 mL (1 tsp) 15 mL 600 mg 30 7.5 mL (1½ tsp) 22.5 mL 900 mg 40 10 mL (2 tsp) 30 mL 1200 mg 50 and above 12.5 mL (2 ½ tsp) 37.5 mL 1500 mg *Effectiveness of the 5-day or 1-day regimen in pediatric patients with acute bacterial sinusitis has not been established. OTITIS MEDIA: (1-Day Regimen) Dosing Calculated on 30 mg/kg as a single dose. Weight 200 mg/5 mL Total mL per Treatment Course Total mg per Treatment Course Kg 1-Day Regimen 5 3.75 mL;(3/4 tsp) 3.75 mL 150 mg 10 7.5 mL;(1½ tsp) 7.5 mL 300 mg 20 15 mL;(3 tsp) 15 mL 600 mg 30 22.5 mL;(4½ tsp) 22.5 mL 900 mg 40 30 mL;(6 tsp) 30 mL 1200 mg 50 and above 37.5 mL;(7½ tsp) 37.5 mL 1500 mg The safety of re-dosing azithromycin in pediatric patients who vomit after receiving 30 mg/kg as a single dose has not been established. In clinical studies involving 487 patients with acute otitis media given a single 30 mg/kg dose of azithromycin, 8 patients who vomited within 30 minutes of dosing were re-dosed at the same total dose. Pharyngitis/Tonsillitis: The recommended dose of azithromycin for children with pharyngitis/tonsillitis is 12 mg/kg once daily for 5 days. (See chart below.) PEDIATRIC DOSAGE GUIDELINES FOR PHARYNGITIS/TONSILLITIS (Age 2 years and above, [see Use in Specific Populations (8.4)] ) Based on Body Weight PHARYNGITIS/TONSILLITIS: (5-Day Regimen) Dosing Calculated on 12 mg/kg/day for 5 days. Weight Day 1 to 5 Total mL Total mG 8 2.5 mL; (½ tsp) 12.5 mL 500 mg 17 5 mL; (1 tsp) 25 mL 1000 mg 25 7.5 mL; (1½ tsp) 37.5 mL 1500 mg 33 10 mL; (2 tsp) 50 mL 2000 mg 40 12.5 mL; (2½ tsp) 62.5 mL 2500 mg

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 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 Aurobindo Pharma USA, Inc. at 1-866-850-2876 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, torsades de pointes, and cardiovascular death. 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 5000 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 1500 cells/mm 3 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/mm 3 . In multiple-dose clinical trials involving approximately 4700 pediatric patients, no patients discontinued therapy because of treatment-related laboratory abnormalities.

7 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 ) 7.1 Nelfinavir Co-administration of nelfinavir at steady-state with a single oral dose of azithromycin resulted in increased azithromycin serum concentrations. Although a dose adjustment of azithromycin is not recommended when administered in combination with nelfinavir, close monitoring for known adverse reactions of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. [see Adverse Reactions (6) ] 7.2 Warfarin 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.

16 HOW SUPPLIED/STORAGE AND HANDLING Azithromycin Tablets USP, 500 mg are white to off-white, oval shaped, film-coated biconvex tablets, debossed with “67” on one side and “D” on other side. Carton of 3 (1 X 3) Unit-dose Tablets NDC 68788-7598-3 Azithromycin tablets should be stored at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].