Azithromycin

Warnings and Precautions, Hypersensitivity ( 5.1 ) 3/2017 Warnings and Precautions, Infantile Hypertrophic Pyloric Stenosis ( 5.3 ) 2/2017

INDICATIONS AND USAGE Azithromycin tablets USP are indicated for the treatment of patients with mild to moderate infections (pneumonia: see WARNINGS) caused by susceptible strains of the designated microorganisms in the specific conditions listed below. As recommended dosages, durations of therapy and applicable patient populations vary among these infections, please see DOSAGE AND ADMINISTRATION for specific dosing recommendations. Adults Acute bacterial exacerbations of chronic obstructive pulmonary disease 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. NOTE: 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 nosocomially acquired 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). Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy. NOTE: Penicillin by the intramuscular route is the usual drug of choice in the treatment of Streptococcus pyogenes infection and the prophylaxis of rheumatic fever. Azithromycin tablets USP are often effective in the eradication of susceptible strains of Streptococcus pyogenes from the nasopharynx. Because some strains are resistant to azithromycin tablets USP, susceptibility tests should be performed when patients are treated with azithromycin tablets USP. Data establishing efficacy of azithromycin in subsequent prevention of rheumatic fever are not available. Uncomplicated skin and skin structure infections due to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae. Abscesses usually require surgical drainage. 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. Azithromycin tablets USP, at the recommended dose, should not be relied upon to treat syphilis. Antimicrobial agents used in high doses for short periods of time to treat non-gonococcal urethritis may mask or delay the symptoms of incubating syphilis. All patients with sexually-transmitted urethritis or cervicitis should have a serologic test for syphilis and appropriate cultures for gonorrhea performed at the time of diagnosis. Appropriate antimicrobial therapy and follow-up tests for these diseases should be initiated if infection is confirmed. Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to azithromycin, USP. Therapy with azithromycin tablets USP may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly. To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin tablets USP and other antibacterial drugs, azithromycin tablets USP should be used only to treat or prevent 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 …

2 DOSAGE AND ADMINISTRATION Recommended Dosage for 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. Recommended Dosage for 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 Recommended Dosage for Adult Patients Recommended dosages and durations of therapy in adult patient populations vary by indications [see Indications and Usage ( 1.1 ) and Clinical Pharmacology ( 12.3 )]. Azithromycin tablets can be taken with or without food. Table 1. Recommended dosage for Adult Patients by Indication 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 microorganisms [see INDICATIONS AND USAGE ( 1.1 )] 2.2 Recommended Dosage for Pediatric Patients Recommended dosages and durations of therapy in pediatric patient populations vary by indications [see Indications and Usage ( 1.2 ) and Clinical Pharmacology ( 12.3 )] . Azithromycin suspension can be taken with or without food. Table 2. Recommended dose for Pediatric Patients by Indication Infection* Recommended Dose/Duration of Therapy 1 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 microorganisms [see INDICATIONS AND USAGE ( 1.2 ) and USE IN SPECIFIC POPULATIONS ( 8.4 )]. 1 see dosing tables below for maximum doses evaluated by indication. 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 * Effectiveness of the 3-day or 1-day regimen in pediatric patients with community-acquired pneumonia has not been established [ see USE IN SPECIFIC POPULATIONS ( 8.4 ) ]. Table 3. 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 100 mg/5 mL 200 mg/5 mL Total mL per Treatment Course Total mg per Treatment Course Kg Day 1 Days 2 to 5 Day 1 Days 2 …

3 DOSAGE FORMS AND STRENGTHS Azithromycin Tablets USP, 250 mg are supplied as white, oval, biconvex, unscored, film-coated tablets, debossed with “787” on one side and “PLIVA” on the other, containing azithromycin monohydrate equivalent to 250 mg of azithromycin, USP, available in boxes of 1 card x 6 tablets, in a bundle of 3 boxes x 6 tablets (18), and in bottles of 30 tablets. Azithromycin Tablets USP, 500 mg are supplied as blue, capsule shaped, biconvex, unscored, film-coated tablets, debossed with “788” on one side and “PLIVA” on the other, containing azithromycin monohydrate equivalent to 500 mg of azithromycin, USP, available in boxes of 1 card x 3 tablets, in a bundle of 3 boxes x 3 tablets (9), and in bottles of 30 tablets. Azithromycin tablets 250 mg and 500 mg ( 3 )

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

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 Bionpharma Inc. at 1-888-235-BION or 1-888-235-2466 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 % …

Drug Interactions Coadministration 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 side effects of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted (see ADVERSE REACTIONS ). Although, in a study of 22 healthy men, a 5 day course of azithromycin did not affect the prothrombin time from a subsequently administered dose of warfarin, spontaneous postmarketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly. Drug interaction studies were performed with azithromycin and other drugs likely to be coadministered (see CLINICAL PHARMACOLOGY, Drug-Drug Interactions ). When used in therapeutic doses, azithromycin had a modest effect on the pharmacokinetics of atorvastatin, carbamazepine, cetirizine, didanosine, efavirenz, fluconazole, indinavir, midazolam, rifabutin, sildenafil, theophylline (intravenous and oral), triazolam, trimethoprim/sulfamethoxazole or zidovudine. Coadministration with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. No dosage adjustment of either drug is recommended when azithromycin is coadministered with any of the above agents. Interactions with the drugs listed below have not been reported in clinical trials with azithromycin; however, no specific drug interaction studies have been performed to evaluate potential drug-drug interaction. Nonetheless, they have been observed with macrolide products. Until further data are developed regarding drug interactions when azithromycin and these drugs are used concomitantly, careful monitoring of patients is advised: Digoxin–elevated digoxin concentrations. Ergotamine or dihydroergotamine–acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia. Terfenadine, cyclosporine, hexobarbital and phenytoin concentrations.

8 USE IN SPECIFIC POPULATIONS • Pediatric Use: Safety and effectiveness in the treatment of patients under 6 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 ) 8.1 Pregnancy Risk Summary Available 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 2 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 6 of pregnancy through weaning at a dose equivalent to 4 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 a 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 2 to 4% and 15 to 20%, respectively. Data Human Data Available 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 Data Azithromycin 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 4 (rats) and 2 (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 2 times an adult human daily dose of 500 mg based on body surface area. In a pre-and postnatal development study, azithromycin was administered orally to pregnant rats from day 6 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 a 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 Error! Hyperlink reference not valid. ) . 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 mother’s clinical need for azithromycin and any potential adverse effects on the breastfed infant from azithromycin or from the underlying maternal condition. Clinical Considerations Advise women to monitor the breastfed infant for diarrhea, vomiting, or rash. Data Azithromycin breastmilk concentrations were measured in 20 women after receiving a single 2 g oral dose of azithromycin during labor. …

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

Mechanism of Action Azithromycin 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. Resistance Azithromycin 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 B (MLS B phenotype). Antimicrobial Activity Azithromycin 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 pyogenes Gram-Negative Bacteria Haemophilus ducreyi Haemophilus influenzae Moraxella catarrhalis Neisseria gonorrhoeae Other Bacteria Chlamydophila pneumoniae Chlamydia trachomatis Mycoplasma pneumoniae The 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 streptococci Gram-Negative Bacteria Bordetella pertussis Legionella pneumophila Anaerobic Bacteria Prevotella bivia Peptostreptococcus species Other Bacteria Ureaplasma urealyticum

11 DESCRIPTION Azithromycin tablets, USP contain the active ingredient azithromycin, USP a 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-α-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)-β-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one. Azithromycin is derived from erythromycin; however, it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring. Its molecular formula is C 38 H 72 N 2 O 12 , and its molecular weight is 749. Azithromycin has the following structural formula: Azithromycin as the dihydrate, is a white or almost white powder with a molecular formula of C 38 H 72 N 2 O 12 •2H 2 O and a molecular weight of 785.02. Azithromycin tablets, USP are supplied for oral administration as pink modified capsule shaped, film-coated tablets containing azithromycin dihydrate equivalent to 500 mg azithromycin, USP and the following inactive ingredients: anhydrous dibasic calcium phosphate, croscarmellose sodium, hydroxypropyl cellulose, magnesium stearate, sodium lauryl sulfate, lactose monohydrate, hypromellose, titanium dioxide, triacetin and D&C Red #30 Aluminum Lake. FDA approved dissolution specification differs from the USP dissolution specification. Structure

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Azithromycin tablets USP are supplied in the following strengths and package configurations: Azithromycin tablets USP, 250 mg are supplied as pink, modified capsule shaped, film-coated tablets, engraved with 'LU' on one side and 'L04' on the other side containing azithromycin dihydrate equivalent to 250 mg of azithromycin USP. These are packaged in: Cartons of 50 film-coated tablets (10 film-coated tablets each blister pack x 5), NDC 0904-7350-06 Cartons of 100 film-coated tablets (10 film-coated tablets each blister pack x 10), NDC 0904-7350-61 Azithromycin tablets USP, 500 mg are supplied as pink, modified capsule shaped, film-coated tablets, engraved with 'LU' on one side and 'L05' on the other side containing azithromycin dihydrate equivalent to 500 mg of azithromycin USP. These are packaged in: Cartons of 30 film-coated tablets (10 film-coated tablets each blister pack x 3), NDC 0904-7351-04 WARNING: These Unit Dose packages are not child resistant and are Intended for Institutional Use Only. Keep this and all drugs out of the reach of children. Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].