DOSAGE FORMS & STRENGTHS SECTION.


3 DOSAGE FORMS AND STRENGTHS Azithromycin Tablets, USP 250 mg are supplied as white, oval, biconvex film coated tablets engraved APO on one side and AZ250 on the other side. Azithromycin Tablets, USP 500 mg are supplied as white, oval, biconvex film coated tablets engraved APO on one side and AZ500 on the other side. Azithromycin tablets, USP 250mg and 500mg

WARNINGS AND PRECAUTIONS SECTION.


5 WARNINGS AND PRECAUTIONS 4.Serious(includingfatal)allergicandskinreactions:Discontinueazithromycin if reaction occurs.(5.1) 5.Hepatotoxicity:Severe,andsometimesfatal,hepatotoxicityhasbeenreported,Discontinueazithromycin immediatelyifsignsandsymptomsofhepatitisoccur.(5.2) 6.Prolongation of 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 torsades de pointes, those with proarrhythmic conditions, and with other drugs that prolong the QT interval. (5.3) Clostridiumdifficile-associateddiarrhea:Evaluatepatientsifdiarrheaoccurs. (5.4) Azithromycin mayexacerbatemuscleweaknessinpersonswithmyasthenia gravis.(5.5) 5.1 Hypersensitivity Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported in patients on azithromycin therapy [see Contraindications (4.1)]. 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 prolonged exposure to antigen is presently unknown. If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that allergic symptoms may reappear when symptomatic therapy has been 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 QT Prolongation Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen with 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. 5.4 Clostridium difficile-Associated Diarrhea (CDAD) Clostridium difficile-associated diarrhea has been reported with use of nearly all antibacterial agents, including azithromycin, 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 antibacterial 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. 5.5 ExacerbationofMyastheniaGravis Exacerbationofsymptomsofmyastheniagravisandnewonsetofmyasthenicsyndromehavebeenreportedinpatientsreceivingazithromycintherapy. 5.6 UseinSexuallyTransmittedInfections Azithromycin tablets, at the recommended dose, should not be relied upon to treat syphilis. Antibacterial agents used 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 testing for gonorrhea performed at the time of diagnosis. Appropriate antibacterial therapy and follow-up tests for these diseases should be initiated if infection is confirmed. 5.7 DevelopmentofDrug-ResistantBacteria Prescribing azithromycin tablets 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.

DRUG INTERACTIONS SECTION.


7 DRUG INTERACTIONS Nelfinavir:Closemonitoringforknownadversereactionsofazithromycin,suchasliverenzymeabnormalitiesandhearingimpairment, is warranted.(7.1) Warfarin:Usewithazithromycinmayincreasecoagulationtimes;monitorprothrombintime. (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 Interactions with Macrolides Interactions with digoxin or phenytoin have not been reported in clinical trials with azithromycin; however, no specific drug interaction studies have been performed to evaluate potential drug-drug interactions. However, drug interactions have been observed with other macrolide products. Until further data are developed regarding drug interactions when digoxin or phenytoin are used concomitantly with azithromycin careful monitoring of patients is advised.

NONCLINICAL TOXICOLOGY SECTION.


13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis,Mutagenesis,ImpairmentofFertility Long-term studies in animals have not been performed to evaluate carcinogenic potential. Azithromycin has shown no mutagenic potential in standard laboratory tests: mouse lymphoma assay, human lymphocyte clastogenic assay, and mouse bone marrow clastogenic assay. No evidence of impaired fertility due to azithromycin was found in rats given daily doses up to 10 mg/kg (approximately 0.2 times an adult daily dose of 500 mg based on body surface area). 13.2 Animal Toxicology and/or Pharmacology Phospholipidosis (intracellular phospholipid accumulation) has been observed in some tissues of mice, rats, and dogs given multiple doses of azithromycin. It has been demonstrated in numerous organ systems (e.g., eye, dorsal root ganglia, liver, gallbladder, kidney, spleen, and/or pancreas) in dogs and rats treated with azithromycin at doses which, expressed on the basis of body surface area, are similar to or less than the highest recommended adult human dose. This effect has been shown to be reversible after cessation of azithromycin treatment. Based on the pharmacokinetic data, phospholipidosis has been seen in the rat (50 mg/kg/day dose) at the observed maximal plasma concentration of 1.3 mcg/mL (1.6 times the observed Cmax of 0.821 mcg/mL at the adult dose of 2 g). Similarly, it has been shown in the dog (10 mg/kg/day dose) at the observed maximal serum concentration of 1 mcg/mL (1.2 times the observed Cmax of 0.821 mcg/mL at the adult dose of 2 g). Phospholipidosis was also observed in neonatal rats dosed for 18 days at 30 mg/kg/day, which is less than the pediatric dose of 60 mg/kg based on the surface area. It was not observed in neonatal rats treated for 10 days at 40 mg/kg/day with mean maximal serum concentrations of 1.86 mcg/mL, approximately 1.5 times the Cmax of 1.27 mcg/mL at the pediatric dose. Phospholipidosis has been observed in neonatal dogs (10 mg/kg/day) at maximum mean whole blood concentrations of 3.54 mcg/mL, approximately 3 times the pediatric dose Cmax. The significance of these findings for animals and for humans is unknown.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.


Package/Label Display Panel Azithromycin Tablets, USP 250 mg 50 Tablets

USE IN SPECIFIC POPULATIONS SECTION.


8 USE IN SPECIFIC POPULATIONS Pediatricuse:Safety andeffectivenessinthetreatmentofpatients under6monthsofage have not beenestablished.(8.4) Geriatricuse: Elderly patientsmaybe moresusceptible to developmentoftorsadesde pointesarrhythmias.(8.5) 8.1 Pregnancy Teratogenic Effects PregnancyCategoryB Reproduction studies have been performed in rats and mice at doses up to moderately maternally toxic dose concentrations (i.e., 200 mg/kg/day). These daily doses in rats and mice, based on body surface area, are estimated to be 4 and 2 times, respectively, an adult daily dose of 500 mg. In the animal studies, no evidence of harm to the fetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed. 8.3 Nursing Mothers Azithromycinhasbeenreportedtobeexcretedinhumanbreastmilkinsmallamounts.Cautionshouldbeexercised whenazithromycinisadministeredtoanursingwoman. 8.4 Pediatric Use [see Clinical Pharmacology (12.3), Indications and Usage (1.2), and Dosage and Administration (2.2)] Safety and effectiveness in the treatment of pediatric patients with acute otitis media, acute bacterial sinusitis and community-acquired pneumonia under 6 months of age have not been established. Use of azithromycin for the treatment of acute bacterial sinusitis and community-acquired pneumonia in pediatric patients (6 months of age or greater) is supported by adequate and well-controlled trials in adults Pharyngitis/Tonsillitis Safety and effectiveness in the treatment of pediatric patients with pharyngitis/tonsillitis under 2 years of age have not been established. 8.5 Geriatric Use In multiple-dose clinical trials of oral azithromycin, 9% of patients were at least 65 years of age (458/4949) and 3% of patients (144/4949) were at least 75 years of age. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than younger patients [see Warnings and Precautions (5.3)].

RECENT MAJOR CHANGES SECTION.


RECENT MAJOR CHANGES Warnings and Precautions, Hypersensitivity (5.1) 02/2016

REFERENCES SECTION.


15 REFERENCES Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Ninth Edition. CLSI document M07-A9, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-third Informational Supplement, CLSI document M100-S23. CLSI document M100-S23, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2013. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard Eleventh Edition CLSI document M02-A11, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2012.

INFORMATION FOR PATIENTS SECTION.


17 PATIENT COUNSELING INFORMATION General Patient Counseling Azithromycin tablets and oral suspension can be taken with or without food. Patients should also be cautioned not to take aluminum- and magnesium-containing antacids and azithromycin simultaneously. The patient should be directed to discontinue azithromycin immediately and contact a physician if any signs of an allergic reaction occur. Patients should be counseled that antibacterial drugs including azithromycin should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When azithromycin is prescribed to treat a bacterial infection, patients should be told that although it is common to feel better early in the course of the therapy, the medication should be taken exactly as directed. Skipping doses or not completing the full course of therapy may (1) decrease the effectiveness of the immediate treatment and (2) increase the likelihood that bacteria will develop resistance and will not be treatable by azithromycin or other antibacterial drugs in the future. Diarrhea is a common problem caused by antibacterials which usually ends when the antibacterial is discontinued. Sometimes after starting treatment with antibacterials patients can develop watery and bloody stools (with or without stomach cramps and fever) even as late as two or more months after having taken the last dose of the antibacterial drug. If this occurs, patients should contact their physician as soon as possible. See FDA-approved Patient Labeling APOTEX CORP. AZITHROMYCIN TABLETS, USP 250 mg and 500 mg Manufactured by Manufactured for Apotex Inc. Apotex Corp. Toronto, Ontario Weston, Florida Canada M9L 1T9 33326 Distributed By: MAJOR PHARMACEUTICALS 17177 N Laurel Park Dr., Suite 233 Livonia, MI 48152 Revised: July 2016 Rev. 13a

ADVERSE REACTIONS SECTION.


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 ClinicalTrialsExperience 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: DosageRegimen Diarrhea% AbdominalPain% 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-AcquiredPneumonia Fortherecommendeddosageregimenof10mg/kgonDay1followedby5mg/kgonDays2 to 5, the most frequent adverse reactions attributed to treatment were diarrhea/loosestools,abdominalpain,vomiting,nausea,andrash. Theincidenceisdescribedinthetablebelow: Dosage Regimen Diarrhea/Loosestools% AbdominalPain% Vomiting% Nausea% Rash% 5-day 5.8 % 1.9 % 1.9 % 1.9 % 1.6 % Pharyngitis/Tonsillitis Fortherecommendeddosageregimenof12mg/kgonDays1 to 5, the most frequent adverse reactions attributed to treatment were diarrhea, vomiting, abdominal pain, nausea,andheadache. Theincidenceisdescribedinthetablebelow: Dosage Regimen Diarrhea% AbdominalPain% Vomiting% Nausea% Rash% Headache % 5-day 5.4 % 3.4 % 5.6 % 1.8 % 0.7 % 1.1 % Withanyofthetreatmentregimens,nootheradversereactionsoccurredinpediatricpatientstreatedwithazithromycin with a frequency greater than 1%. Adverse reactions thatoccurredwithafrequencyof1%orlessincludedthefollowing: Cardiovascular Chestpain. Gastrointestinal Dyspepsia,constipation,anorexia,enteritis,flatulence,gastritis,jaundice,loosestools,andoralmoniliasis. HematologicandLymphatic Anemiaandleukopenia. NervousSystem Headache(otitismediadosage),hyperkinesia,dizziness, agitation,nervousness,andinsomnia. General Fever,faceedema,fatigue,fungalinfection,malaise,andpain. Allergic Rashandallergicreaction. Respiratory Cough,pharyngitis,pleuraleffusion,andrhinitis. SkinandAppendages Eczema,fungaldermatitis,pruritus,sweating,urticaria,andvesiculobullousrash. SpecialSenses Conjunctivitis. 6.2 PostmarketingExperience 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, 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 LaboratoryAbnormalities 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. PediatricPatients 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.

CLINICAL STUDIES SECTION.


14 CLINICAL STUDIES 14.1 Adult Patients Acute Bacterial Exacerbations of Chronic Bronchitis In a randomized, double-blind controlled clinical trial of acute exacerbation of chronic bronchitis (AECB), azithromycin (500 mg once daily for 3 days) was compared with clarithromycin (500 mg twice daily for 10 days). The primary endpoint of this trial was the clinical cure rate at Days 21 to 24. For the 304 patients analyzed in the modified intent-to-treat analysis at the Days 21 to 24 visit, the clinical cure rate for 3 days of azithromycin was 85% (125/147) compared to 82% (129/157) for 10 days of clarithromycin. The following outcomes were the clinical cure rates at the Days 21 to 24 visit for the bacteriologically evaluable patients by pathogen: Pathogen Azithromycin(3Days) Clarithromycin(10Days) S.pneumoniae 29/32(91%) 21/27(78%) H.influenzae 12/14(86%) 14/16(88%) M.catarrhalis 11/12(92%) 12/15(80%) Acute Bacterial Sinusitis In a randomized, double-blind, double-dummy controlled clinical trial of acute bacterial sinusitis, azithromycin (500 mg once daily for 3 days) was compared with amoxicillin/clavulanate (500/125 mg three times a day for 10 days). Clinical response assessments were made at Day 10 and Day 28. The primary endpoint of this trial was prospectively defined as the clinical cure rate at Day 28. For the 594 patients analyzed in the modified intent to treat analysis at the Day 10 visit, the clinical cure rate for 3 days of azithromycin was 88% (268/303) compared to 85% (248/291) for 10 days of amoxicillin/clavulanate. For the 586 patients analyzed in the modified intent to treat analysis at the Day 28 visit, the clinical cure rate for 3 days of azithromycin was 71.5% (213/298) compared to 71.5% (206/288), with a 97.5% confidence interval of 8.4 to 8.3, for 10 days of amoxicillin/clavulanate. In an open label, non-comparative study requiring baseline transantral sinus punctures, the following outcomes were the clinical success rates at the Day 7 and Day 28 visits for the modified intent to treat patients administered 500 mg of azithromycin once daily for 3 days with the following pathogens: ClinicalSuccessRatesofAzithromycin(500mgperdayfor3Days) Pathogen Day7 Day28 S.pneumoniae 23/26(88%) 21/25(84%) H.influenzae 28/32(87%) 24/32(75%) M.catarrhalis 14/15(93%) 13/15(87%) 14.2 Pediatric Patients From the perspective of evaluating pediatric clinical trials, Days 11 to 14 were considered on-therapy evaluations because of the extended half-life of azithromycin. Days 11 to 14 data are provided for clinical guidance. Days 24 to 32 evaluations were considered the primary test of cure endpoint. Pharyngitis/Tonsillitis In three double-blind controlled studies, conducted in the United States, azithromycin (12 mg/kg once a day for 5 days) was compared to penicillin V (250 mg three times a day for 10 days) in the treatment of pharyngitis due to documented Group A -hemolytic streptococci (GABHS or S. pyogenes). Azithromycin was clinically and microbiologically statistically superior to penicillin at Day 14 and Day 30 with the following clinical success (i.e., cure and improvement) and bacteriologic efficacy rates (for the combined evaluable patient with documented GABHS): ThreeU.S.StreptococcalPharyngitisStudies Azithromycinvs.PenicillinV EFFICACYRESULTS Day14 Day30 BacteriologicEradication: Azithromycin 323/340(95%) 255/330(77%) PenicillinV 242/332(73%) 206/325(63%) ClinicalSuccess(cureplusimprovement): Azithromycin 336/343(98%) 310/330(94%) PenicillinV 284/338(84%) 241/325(74%) Approximately 1% of azithromycin-susceptible S. pyogenes isolates were resistant to azithromycin following therapy. Acute Otitis Media Efficacyusingazithromycingiven over 5 days(10 mg/kg on Day 1 followed by 5 mg/kg on Days 2 to 5). Trial 1 In a double-blind, controlled clinical study of acute otitis media performed in the United States, azithromycin (10 mg/kg on Day 1 followed by 5 mg/kg on Days 2 to 5) was compared to amoxicillin/clavulanate potassium (4:1). For the 553 patients who were evaluated for clinical efficacy, the clinical success rate (i.e., cure plus improvement) at the Day 11 visit was 88% for azithromycin and 88% for the control agent. For the 521 patients who were evaluated at the Day 30 visit, the clinical success rate was 73% for azithromycin and 71% for the control agent. Trial 2 In a non-comparative clinical and microbiologic trial performed in the United States, where significant rates of beta-lactamase producing organisms (35%) were found, 131 patients were evaluable for clinical efficacy. The combined clinical success rate (i.e., cure and improvement) at the Day 11 visit was 84% for azithromycin. For the 122 patients who were evaluated at the Day 30 visit, the clinical success rate was 70% for azithromycin. Microbiologic determinations were made at the pre-treatment visit. Microbiology was not reassessed at later visits. The following clinical success rates were obtained from the evaluable group: Pathogen Day11 Day30 Azithromycin Azithromycin S.pneumoniae 61/74(82%) 40/56(71%) H.influenzae 43/54(80%) 30/47(64%) M.catarrhalis 28/35(80%) 19/26(73%) S.pyogenes 11/11(100%) 7/7(100%) Overall 177/217(82%) 97/137(73%) Trial 3 In another controlled comparative clinical and microbiologic study of otitis media performed in the United States, azithromycin (10 mg/kg on Day 1 followed by 5 mg/kg on Days 2 to 5) was compared to amoxicillin/clavulanate potassium (4:1). This study utilized two of the same investigators as Protocol 2 (above), and these two investigators enrolled 90% of the patients in Protocol 3. For this reason, Protocol 3 was not considered to be an independent study. Significant rates of beta-lactamase producing organisms (20%) were found. Ninety-two (92) patients were evaluable for clinical and microbiologic efficacy. The combined clinical success rate (i.e., cure and improvement) of those patients with a baseline pathogen at the Day 11 visit was 88% for azithromycin vs. 100% for control; at the Day 30 visit, the clinical success rate was 82% for azithromycin vs. 80% for control. Microbiologic determinations were made at the pre-treatment visit. Microbiology was not reassessed at later visits. At the Day 11 and Day 30 visits, the following clinical success rates were obtained from the evaluable group: Pathogen Day11 Day30 Azithromycin Control Azithromycin Control S.pneumoniae 25/29(86%) 26/26(100%) 22/28(79%) 18/22(82%) H.influenzae 9/11(82%) 9/9(100%) 8/10(80%) 6/8(75%) M.catarrhalis 7/7(100%) 5/5(100%) 5/5(100%) 2/3(66%) S.pyogenes 2/2(100%) 5/5(100%) 2/2(100%) 4/4(100%) Overall 43/49(88%) 45/45(100%) 37/45(82%) 30/37(81%) Efficacy using azithromycin given over 3 days (10 mg/kg/day). Trial 4 In a double-blind, controlled, randomized clinical study of acute otitis media in pediatric patients from 6 months to 12 years of age, azithromycin (10 mg/kg per day for 3 days) was compared to amoxicillin/clavulanate potassium (7:1) in divided doses q12h for 10 days. Each patient received active drug and placebo matched for the comparator. For the 366 patients who were evaluated for clinical efficacy at the Day 12 visit, the clinical success rate (i.e., cure plus improvement) was 83% for azithromycin and 88% for the control agent. For the 362 patients who were evaluated at the Days 24 to 28 visit, the clinical success rate was 74% for azithromycin and 69% for the control agent. Efficacy using azithromycin 30 mg/kg given as a single dose Trial 5 A double-blind, controlled, randomized trial was performed at nine clinical centers. Pediatric patients from 6 months to 12 years of age were randomized 1:1 to treatment with either azithromycin (given at 30 mg/kg as a single dose on Day 1) or amoxicillin/clavulanate potassium (7:1), divided q12h for 10 days. Each child received active drug, and placebo matched for the comparator. Clinical response (Cure, Improvement, Failure) was evaluated at End of Therapy (Days 12 to 16) and Test of Cure (Days 28 to 32). Safety was evaluated throughout the trial for all treated subjects. For the 321 subjects who were evaluated at End of Treatment, the clinical success rate (cure plus improvement) was 87% for azithromycin, and 88% for the comparator. For the 305 subjects who were evaluated at Test of Cure, the clinical success rate was 75% for both azithromycin and the comparator. Trial 6 In a non-comparative clinical and microbiological trial, 248 patients from 6 months to 12 years of age with documented acute otitis media were dosed with a single oral dose of azithromycin (30 mg/kg on Day 1). For the 240 patients who were evaluable for clinical modified Intent-to-Treat (MITT) analysis, the clinical success rate (i.e., cure plus improvement) at Day 10 was 89% and for the 242 patients evaluable at Days 24 to 28, the clinical success rate (cure) was 85%. PresumedBacteriologicEradication Day10 Days24 to 28 S.pneumoniae 70/76(92%) 67/76(88%) H.influenzae 30/42(71%) 28/44(64%) M.catarrhalis 10/10(100%) 10/10(100%) Overall 110/128(86%) 105/130(81%)

INDICATIONS & USAGE SECTION.


1 INDICATIONS AND USAGE To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin and other antibacterial drugs, azithromycin 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. Azithromycin tablets, are 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 exacerbationsofchronic bronchitisinadults(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 (1.2) Community-acquired pneumonia in adults and pediatric patients (1.1, 1.2) Pharyngitis/tonsillitisin adultsand pediatric patients(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 and other antibacterial drugs, azithromycin should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. 1.1 Adult Patients 1.AcutebacterialexacerbationsofchronicbronchitisduetoHaemophilusinfluenzae,Moraxellacatarrhalis,or Streptococcuspneumoniae. 2.AcutebacterialsinusitisduetoHaemophilusinfluenzae,MoraxellacatarrhalisorStreptococcuspneumoniae. 3.Community-acquiredpneumoniaduetoChlamydophilapneumoniae,Haemophilusinfluenzae,Mycoplasmapneumoniae,or Streptococcus pneumoniae in patients appropriatefororaltherapy. 4.Pharyngitis/tonsillitiscausedbyStreptococcuspyogenesasanalternativetofirst-linetherapyinindividualswhocannotusefirst-linetherapy. 5.UncomplicatedskinandskinstructureinfectionsduetoStaphylococcusaureus,Streptococcuspyogenes,orStreptococcusagalactiae. 6.Urethritis and cervicitis due to Chlamydia trachomatis orNeisseriagonorrhoeae. 7.GenitalulcerdiseaseinmenduetoHaemophilusducreyi(chancroid).Duetothesmallnumberofwomenincludedinclinicaltrials,the efficacy of azithromycin in the treatmentofchancroidinwomenhasnotbeenestablished. 1.2 Pediatric Patients [seeUseinSpecificPopulations(8.4)and Clinical Studies (14.2)] Acuteotitismedia (>6monthsofage) causedbyHaemophilusinfluenzae,Moraxellacatarrhalis,orStreptococcuspneumoniae Community-acquired pneumonia (>6 months of age) due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumonia, 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).

DOSAGE & ADMINISTRATION SECTION.


2 DOSAGE AND ADMINISTRATION 2. Adult Patients (2.1) Infection RecommendedDose/Durationof Therapy Community-acquired pneumonia (mild severity) Pharyngitis/tonsillitis(second-linetherapy) Skin/skinstructure (uncomplicated) 500mgasasingle dose onDay1,followedby250 mg once dailyonDays 2through 5. Acute bacterial exacerbationsofchronic bronchitis(mildtomoderate) 500mgasasingle dose onDay1,followedby250 mg once dailyonDays 2through 5or500mgonce dailyfor 3 days. Acute bacterial sinusitis 500mg oncedailyfor 3days. Genitalulcerdisease (chancroid)Non-gonococcal urethritisandcervicitis One single 1gramdose. Gonococcal urethritisand cervicitis One single 2gramdose. 2. Pediatric Patients (2.2) Infection RecommendedDose/Durationof Therapy Acute otitismedia 30 mg/kg asasingle dose or 10mg/kg once dailyfor 3daysor 10 mg/kg asa single dose onDay1 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. 2.1 AdultPatients [seeIndicationsandUsage(1.1)andClinicalPharmacology(12.3)] Infection* Recommended Dose/Duration of Therapy Community-acquiredpneumonia Pharyngitis/tonsillitis(second-line therapy) Skin/skinstructure (uncomplicated) 500mg as a single-dose on Day 1, followed by 250 mgoncedailyonDays 2through 5 Acute bacterialexacerbations ofchronicobstructive pulmonarydisease 500mgoncedaily for 3days OR 500mg as a single dose on Day 1, followed by 250 mg oncedailyonDays 2through 5 Acute bacterial sinusitis 500mgoncedaily for 3days Genitalulcerdisease (chancroid) One single 1gramdose Non-gonococcalurethritisandcervicitis One single 1gramdose Gonococcal urethritisandcervicitis One single 2gramdose *DUETOTHEINDICATEDORGANISMS[seeIndications and Usage(1.1)] Azithromycin tabletscanbetakenwithorwithoutfood. 2.2 Pediatric Patients1 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. PEDIATRICDOSAGEGUIDELINESFOROTITISMEDIA,ACUTEBACTERIALSINUSITIS,ANDCOMMUNITY-ACQUIREDPNEUMONIA (Age6monthsandabove, [seeUseinSpecificPopulations(8.4)]) BasedonBodyWeight OTITISMEDIA ANDCOMMUNITY-ACQUIREDPNEUMONIA:(5-DayRegimen)* DosingCalculatedon10mg/kg/dayDay1and5mg/kg/dayDays 2to5. Weight 100mg/5mL 200mg/5mL TotalmLperTreatmentCourse TotalmgperTreatmentCourse Kg Lbs. Day 1 Days 2 to 5 Day 1 Days 2 to 5 5 11 2.5 mL; ( tsp) 1.25mL;(tsp) 7.5 mL 150 mg 10 22 5mL; (1 tsp) 2.5 mL; ( tsp) 15 mL 300 mg 20 44 5mL; (1tsp) 2.5 mL; ( tsp) 15 mL 600 mg 30 66 7.5 mL; (1 tsp) 3.75mL; ( tsp) 22.5 mL 900 mg 40 88 10mL; (2tsp) 5mL; (1tsp) 30 mL 1200 mg 50 and above 110 and above 12.5 mL; (2 tsp) 6.25mL; (1tsp) 37.5 mL 1500 mg *Effectivenessofthe3-dayor1-dayregimeninpediatricpatientswithcommunity-acquired pneumoniahasnotbeenestablished. OTITISMEDIA ANDACUTEBACTERIALSINUSITIS:(3-DayRegimen)* DosingCalculatedon10mg/kg/day. Weight 100mg/5mL 200mg/5mL TotalmLperTreatmentCourse TotalmgperTreatmentCourse Kg Lbs. Days 1 to 3 Days 1 to 3 5 11 2.5 mL; ( tsp) 7.5 mL 150 mg 10 22 5mL; (1 tsp) 15 mL 300 mg 20 44 5mL; (1tsp) 15 mL 600 mg 30 66 7.5 mL; (1 tsp) 22.5 mL 900 mg 40 88 10mL; (2tsp) 30 mL 1200 mg 50 and above 110 and above 12.5 mL; (2 tsp) 37.5 mL 1500 mg *Effectivenessofthe5-dayor1-dayregimeninpediatricpatientswithacute bacterial sinusitishasnotbeenestablished. OTITISMEDIA:(1-DayRegimen) DosingCalculatedon30mg/kg as a single dose. Weight 200mg/5mL TotalmLperTreatmentCourse TotalmgperTreatmentCourse Kg Lbs. 1-Day Regimen 5 11 3.75mL; (3/4tsp) 3.75 mL 150 mg 10 22 7.5 mL; (1 tsp) 7.5 mL 300 mg 20 44 15mL; (3tsp) 15 mL 600 mg 30 66 22.5 mL; (4 tsp) 22.5 mL 900 mg 40 88 30mL; (6tsp) 30 mL 1200 mg 50 and above 110 and above 37.5 mL; (7 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, eight 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). PEDIATRICDOSAGEGUIDELINESFORPHARYNGITIS/TONSILLITIS (Age2yearsandabove, [seeUseinSpecificPopulations(8.4)]) BasedonBodyWeight PHARYNGITIS/TONSILLITIS: (5-Day Regimen) Dosing Calculated on 12 mg/kg/day for 5 days. Weight 200mg/5mL TotalmLperTreatmentCourse TotalmgperTreatmentCourse Kg Lbs. Day 1 to 5 8 18 2.5 mL; (tsp) 12.5 mL 500 mg 17 37 5mL; (1 tsp) 25 mL 1000 mg 25 55 7.5 mL; (1tsp) 37.5 mL 1500 mg 33 73 10mL; (2 tsp) 50 mL 2000 mg 40 88 12.5 mL; (2tsp) 62.5 mL 2500 mg

HOW SUPPLIED SECTION.


16 HOW SUPPLIED/STORAGE AND HANDLING Azithromycin Tablets, USP 250 mg are supplied as white, oval, biconvex film coated tablets containing azithromycin dihydrate equivalent to 250 mg of azithromycin. Azithromycin Tablets, USP 250 mg are engraved APO on one side and AZ250 on the other side. These are packaged in bottles and blister cards of 6 tablets as follows: Carton of 50 tablets (10 tablets each blister pack x 5) , NDC 0904-6405-06 Carton of 100 tablets (10 tablets each blister pack x 10), NDC 0904-6405-61 Storage: Store at 20 to 25C (68 to 77F); excursions permitted from 15 to 30C (59 to 86F) [See USP Controlled Room Temperature].

DESCRIPTION SECTION.


11 DESCRIPTION Azithromycin tablets, USP contain the active ingredient azithromycin, 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--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)--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 C38H72N2O12, and its molecular weight is 749. Azithromycin has the following structural formula: Azithromycin, as the dihydrate, is a white to almost white crystalline powder, with a molecular formula of C38H72N2O122H2O and a molecular weight of 785.02. Azithromycin tablets, USP are supplied for oral administration as film-coated, white, oval, biconvex tablets containing azithromycin dihydrate equivalent to either 250 mg or 500 mg azithromycin and the following inactive ingredients: dibasic calcium phosphate dihydrate, hydroxypropyl cellulose, croscarmellose sodium, magnesium stearate and Opadry II white (Opadry II white contains the following components: hypromellose, lactose monohydrate, titanium dioxide and triacetin).

OVERDOSAGE SECTION.


10 OVERDOSAGE Adversereactionsexperiencedathigherthanrecommendeddosesweresimilartothoseseenatnormaldosesparticularlynausea,diarrhea, and vomiting. In the event of overdosage, general symptomatic and supportive measures are indicated as required.

CLINICAL PHARMACOLOGY SECTION.


12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Azithromycinisamacrolideantibacterialdrug[seeMicrobiology(12.4)]. 12.2 Pharmacodynamics Based on animal models of infection, the antibacterial activity of azithromycin appears to correlate with the ratio of area under the concentration-time curve to minimum inhibitory concentration (AUC/MIC) for certain pathogens (S. pneumoniae and S. aureus). The principal pharmacokinetic/pharmacodynamic parameter best associated with clinical and microbiological cure has not been elucidated in clinical trials with azithromycin. Cardiac Electrophysiology QTc interval prolongation was studied in a randomized, placebo-controlled parallel trial in 116 healthy subjects who received either chloroquine (1,000 mg) alone or in combination with oral azithromycin (500 mg, 1,000 mg, and 1,500 mg once daily). Co-administration of azithromycin increased the QTc interval in a dose- and concentration-dependent manner. In comparison to chloroquine alone, the maximum mean (95% upper confidence bound) increases in QTcF were 5 (10) ms, 7 (12) ms and 9 (14) ms with the co-administration of 500 mg, 1,000 mg and 1,500 mg azithromycin, respectively. 12.3 Pharmacokinetics Following oral administration of a single 500 mg dose (two 250 mg tablets) to 36 fasted healthy male volunteers, the mean (SD) pharmacokinetic parameters were AUC0-72= 4.3 (1.2) mcghr/mL; Cmax=0.5 (0.2) mcg/mL; Tmax= 2.2 (0.9) hours. Two azithromycin 250 mg tablets are bioequivalent to a single 500 mg tablet. In a two-way crossover study, 12 adult healthy volunteers (6 males, 6 females) received 1,500 mg of azithromycin administered in single daily doses over either 5 days (two 250 mg tablets on day 1, followed by one 250 mg tablet on days 2 to 5) or 3 days (500 mg per day for days 1 to 3). Due to limited serum samples on day 2 (3-day regimen) and days 2 to 4 (5-day regimen), the serum concentration-time profile of each subject was fit to a 3-compartment model and the AUC0- for the fitted concentration profile was comparable between the 5-day and 3-day regimens. 3-DayRegimen 5-DayRegimen Pharmacokinetic Parameter [mean(SD)] Day1 Day3 Day1 Day5 Cmax(serum, mcg/mL) 0.44(0.22) 0.54(0.25) 0.43(0.20) 0.24(0.06) SerumAUC0- (mcghr/mL) 17.4(6.2)* 14.9(3.1)* SerumT1/2 71.8 hr 68.9 hr *TotalAUCfortheentire3-dayand5-dayregimens. Absorption The absolute bioavailability of azithromycin 250 mg capsules is 38%. In a two-way crossover study in which 12 healthy subjects received a single 500 mg dose of azithromycin (two 250 mg tablets) with or without a high fat meal, food was shown to increase Cmax by 23% but had no effect on AUC. When azithromycin oral suspension was administered with food to 28 adult healthy male subjects, Cmax increased by 56% and AUC was unchanged. Distribution The serum protein binding of azithromycin is variable in the concentration range approximating human exposure, decreasing from 51% at 0.02 mcg/mL to 7% at 2 mcg/mL. The antibacterial activity of azithromycin is pH related and appears to be reduced with decreasing pH, However, the extensive distribution of drug to tissues may be relevant to clinical activity. Azithromycin has been shown to penetrate into human tissues, including skin, lung, tonsil, and cervix. Extensive tissue distribution was confirmed by examination of additional tissues and fluids (bone, ejaculum, prostate, ovary, uterus, salpinx, stomach, liver, and gallbladder). As there are no data from adequate and well-controlled studies of azithromycin treatment of infections in these additional body sites, the clinical significance of these tissue concentration data is unknown. Following a regimen of 500 mg on the first day and 250 mg daily for 4 days, very low concentrations were noted in cerebrospinal fluid (less than 0.01 mcg/mL) in the presence of noninflamed meninges. Metabolism In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed. Elimination Plasma concentrations of azithromycin following single 500 mg oral and IV doses declined in a polyphasic pattern resulting in a mean apparent plasma clearance of 630 mL/min and terminal elimination half-life of 68 hours. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues. Biliary excretion of azithromycin, predominantly as unchanged drug, is a major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine. SpecificPopulations Renal Insufficiency Azithromycin pharmacokinetics was investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment. Following the oral administration of a single 1.0 g dose of azithromycin (4 x 250 mg capsules), mean Cmax and AUC0-120 increased by 5.1% and 4.2%, respectively, in subjects with mild to moderate renal impairment (GFR 10 to 80 mL/min) compared to subjects with normal renal function (GFR >80 mL/min). The mean Cmax and AUC0-120increased 61% and 35%, respectively, in subjects with severe renal impairment (GFR 80 mL/min). Hepatic Insufficiency The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established. Gender There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended based on gender. Geriatric Patients Pharmacokinetic parameters in older volunteers (65 to 85 years old) were similar to those in young adults (18 to 40 years old) for the 5-day therapeutic regimen. Dosage adjustment does not appear to be necessary for older patients with normal renal and hepatic function receiving treatment with this dosage regimen [see Geriatric Use (8.5)]. Pediatric Patients In two clinical studies, azithromycin for oral suspension was dosed at 10 mg/kg on day 1, followed by 5 mg/kg on days 2 through 5 in two groups of pediatric patients (aged 1 to 5 years and 5 to 15 years, respectively). The mean pharmacokinetic parameters on day 5 were Cmax =0.216 mcg/mL, Tmax =1.9 hours, and AUC0-24 =1.822 mcghr/mL for the 1- to 5-year-old group and were Cmax =0.383 mcg/mL, Tmax =2.4 hours, and AUC0-24 =3.109 mcghr/mL for the 5- to 15-year-old group. In another study, 33 pediatric patients received doses of 12 mg/kg/day (maximum daily dose 500 mg) for 5 days, of whom 31 patients were evaluated for azithromycin pharmacokinetics following a low fat breakfast. In this study, azithromycin concentrations were determined over a 24 hour period following the last daily dose. Patients weighing above 41.7 kg received the maximum adult daily dose of 500 mg. Seventeen patients (weighing 41.7 kg or less) received a total dose of 60 mg/kg. The following table shows pharmacokinetic data in the subset of pediatric patients who received a total dose of 60 mg/kg. Pharmacokinetic Parameter [mean(SD)] 5-DayRegimen (12mg/kgfor 5days) N 17 Cmax(mcg/mL) 0.5(0.4) Tmax(hr) 2.2(0.8) AUC0-24(mcg hr/mL) 3.9(1.9) Singledosepharmacokineticsofazithromycininpediatricpatientsgivendosesof30mg/kghavenotbeenstudied[seeDosageand Administration(2)]. Drug interaction studies were performed with azithromycin and other drugs likely to be co-administered. The effects of co-administration of azithromycin on the pharmacokinetics of other drugs are shown in Table 1 and the effects of other drugs on the pharmacokinetics of azithromycin are shown in Table 2. Co-administration of azithromycin at therapeutic doses had a modest effect on the pharmacokinetics of the drugs listed in Table 1. No dosage adjustment of drugs listed in Table 1 is recommended when co-administered with azithromycin. Co-administration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the Cmax and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2 [see Drug Interactions (7.3)]. Table 1.DrugInteractions:Pharmacokinetic Parameters for Co-administeredDrugs inthe Presence ofAzithromycin Co-administeredDrug Dose of Co-administeredDrug Dose ofAzithromycin n Ratio (with/withoutazithromycin)of Co-administeredDrug PharmacokineticParameters (90%CI); NoEffect =1.00 MeanCmax MeanAUC Atorvastatin 10mg/dayfor 8days 500 mg/dayorallyondays6 to 8 12 0.83 (0.63to1.08) 1.01 (0.81to1.25) Carbamazepine 200 mg/day for 2days,then 200mg twice aday for18 days 500 mg/dayorally fordays 16 to 18 7 0.97 (0.88to1.06) 0.96 (0.88to1.06) Cetirizine 20mg/dayfor 11days 500mgorallyonday7,then250mg/dayondays 8 to 11 14 1.03 (0.93to1.14) 1.02 (0.92to1.13) Didanosine 200mgorallytwice adayfor 21 days 1200mg/dayorallyondays8 to 21 6 1.44 (0.85to2.43) 1.14 (0.83to1.57) Efavirenz 400 mg/day for 7days 600mgorallyonday7 14 1.04* 0.95* Fluconazole 200mgorallysingle dose 1200mgorallysingle dose 18 1.04 (0.98to1.11) 1.01 (0.97to1.05) Indinavir 800mgthree times adayfor 5days 1200mgorallyonday5 18 0.96 (0.86to1.08) 0.90 (0.81to1.00) Midazolam 15mgorallyonday3 500 mg/dayorally for 3days 12 1.27 (0.89to1.81) 1.26 (1.01to1.56) Nelfinavir 750mgthree times adayfor11 days 1,200mgorallyonday9 14 0.90 (0.81to1.01) 0.85 (0.78to0.93) Sildenafil 100mgondays 1and4 500 mg/dayorally for 3days 12 1.16 (0.86to1.57) 0.92 (0.75to1.12) Theophylline 4mg/kg IVon days 1,11, 25 500mgorallyonday7,250mg/dayondays 8 to 11 10 1.19 (1.02to1.40) 1.02 (0.86to1.22) Theophylline 300mgorallytwice adayfor 15 days 500mgorallyonday6,then250mg/dayondays 7 to 10 8 1.09 (0.92to1.29) 1.08 (0.89to1.31) Triazolam 0.125mgonday2 500mgorallyonday1,then250mg/dayonday2 12 1.06* 1.02* Trimethoprim/Sulfamethoxazole 160 mg/800mg/dayorallyfor 7days 1200mgorallyonday7 12 0.85 (0.75to0.97)/ 0.90 (0.78to1.03) 0.87 (0.80to0.95/0.96(0.88to1.03) Zidovudine 500 mg/dayorally for21days 600 mg/dayorally for 14 days 5 1.12 (0.42to3.02) 0.94 (0.52to1.70) Zidovudine 500 mg/dayorally for21days 1200mg/dayorally for 14days 4 1.31 (0.43to3.97) 1.30 (0.69to2.43) *-90%Confidenceintervalnotreported Table 2.DrugInteractions:Pharmacokinetic Parameters for Azithromycininthe PresenceofCo-administeredDrugs [see DrugInteractions(7)]. Co-administeredDrug Dose of Co-administeredDrug Dose ofAzithromycin n Ratio (with/without co-administereddrug) ofAzithromycin PharmacokineticParameters(90%CI); NoEffect =1.00 MeanCmax MeanAUC Efavirenz 400 mg/day for 7days 600mgorallyonday7 14 1.22 (1.04to1.42) 0.92* Fluconazole 200mgorallysingle dose 1,200mgorallysingle dose 18 0.82 (0.66to1.02) 1.07 (0.94to1.22) Nelfinavir 750mgthree times adayfor 11days 1,200mgorallyonday9 14 2.36 (1.77to3.15) 2.12 (1.80to2.50) *-90%Confidenceintervalnotreported 12.4 Microbiology Mechanism of Action Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms and interferes with bacterial protein synthesis. Nucleic acid synthesis is not affected. Cross Resistance Azithromycin demonstrates cross resistance with erythromycin resistant Gram positive isolates. Azithromycin has been shown to be active against most isolates of the following bacteria, both in vitro and in clinical [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. Azithromycin exhibits in vitro minimal inhibitory concentrations (MICs) of 4.0 mcg/ml or less against most (90%) isolates of the following bacteria; however, the safety and effectiveness of azithromycin in treating clinical infections due to these bacteria have not been established in adequate and well-controlled 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 Susceptibility Testing Methods When available, the clinical microbiology laboratory should provide the results of in vitro susceptibility test results for antibacterial drugs used in resident hospitals to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug product for treatment. Dilution Techniques Quantitative methods are used to determine minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antibacterial compounds. The MICs should be determined using a standardized test method1,2,3 (broth or agar). The MIC values should be interpreted according to criteria provided in Table 3. Diffusion Techniques Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antibacterial compounds. The zone size provides an estimate of the susceptibility of bacteria to antibacterial compounds. The zone size should be determined using a standardized method2,3. This procedure uses paper disk impregnated with 15 mcg azithromycin to test the susceptibility of bacteria to azithromycin. The disk diffusion interpretive criteria are provided in Table 3. Table 3: Susceptibility Test Interpretive Criteria for Azithromycina Pathogen Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameter in mm) S I R S I R Haemophilus influenzae b 4 - - 12 Staphylococcus aureus 2 4 8 18 14 to 17 13 Streptococci including S. pneumoniae 0.5 1 2 18 14 to 17 13 aClarithromycinisusedforsusceptibilitytestingduetoitsbettersolubility bInsufficientinformationisavailabletodetermineIntermediateorResistantinterpretivecriteria The ability to correlate MIC values and plasma drug levels is difficult as azithromycin concentrates in macrophages and tissues [see Clinical Pharmacology (12)]. A report of Susceptible indicates that the pathogen is likely to inhibit growth of the pathogen if the antibacterial compound reaches the concentration at the infection site necessary to inhibit growth of the pathogen. A report of Intermediate indicates that the result should be considered equivocal, and if the microorganism is not fully susceptible to alternative clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant indicates that the antibacterial is not likely to inhibit growth of the pathogen if the antibacterial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected. Quality Control Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individuals performing the test1,2,3. Standard azithromycin powder should provide the following range of MIC values provided in Table 4. For the diffusion technique using the 15 mcg azithromycin disk the criteria provided in Table 4 should be achieved. Table 4: Acceptable Quality Control Ranges for Susceptibility Testing Quality Control Organism Minimum Inhibitory Concentrations (mcg/mL) Disk Diffusion (zone diameters in mm) Staphylococcus aureus ATCC* 25923 Not Applicable 21 to 26 Staphylococcus aureus ATCC 29213 0.5 to 2 Not Applicable Haemophilus Influenzae ATCC 49247 1.0 to 4.0 13 to 21 Streptococcus pneumoniae ATCC 49619 0.06 to 0.25 19 to 25 *ATCC = American Type Culture Collection

CONTRAINDICATIONS SECTION.


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 tablets are contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, any macrolide or ketolide drug. 4.2 HepaticDysfunction Azithromycin tablets are contraindicatedinpatientswithahistoryofcholestaticjaundice/hepaticdysfunctionassociatedwithprioruseof azithromycin.

SPL PATIENT PACKAGE INSERT SECTION.


Patient Information Azithromycin Tablets (ay zith" roe mye' sin) Read this PatientInformationleafletbefore youstarttakingazithromycin tablets andeach time yougetarefill.There maybe newinformation.This informationdoes nottake the place oftalkingtoyourhealthcare provideraboutyourmedicalconditionoryourtreatment. What areazithromycin tablets? Azithromycin tabletsareamacrolide antibioticprescriptionmedicine usedinadults 18years oroldertotreatcertaininfections causedbycertaingerms calledbacteria.These bacterialinfectionsinclude: acute worseningofchronic bronchitis acute sinusinfection community-acquiredpneumonia infectedthroatortonsils skininfections infections ofthe urethraorcervix genitalulcersinmen Azithromycintablets are also used in childrento treat: earinfections community-acquiredpneumonia infectedthroatortonsils Azithromycinshouldnotbe takenbypeoplewho cannottolerateoralmedications because theyare veryillorhave certainotherriskfactors including: 1.have cystic fibrosis 2.have hospitalacquiredinfections 3.have knownorsuspectedbacteriainthe blood 4.needto be in the hospital 5.are elderly 6.have anymedicalproblems thatcanlowerthe abilityoftheimmune systemto fightinfections Azithromycintablets are notforviralinfections suchas the commoncold. It is notknownifazithromycintablets are safe andeffective forgenitalulcers in women. It is notknownif azithromycintablets are safe andeffective forchildrenwithearinfections,sinusinfections,andcommunity-acquiredpneumoniaunder6 monthsofage. It is notknownifazithromycintablets are safe andeffective forinfectedthroatortonsilsin childrenunder2years ofage. Whoshouldnot takeazithromycin tablets? Donot takeazithromycin tablets if you: 1.have hadasevere allergic reactionto certainantibiotics knownasmacrolidesorketolidesincludingazithromycinanderythromycin. 2.have ahistoryofcholestatic jaundice orhepaticdysfunctionthathappened withthe useofazithromycin. WhatshouldItellmy healthcareprovider beforetakingazithromycin tablets? Beforeyoutakeazithromycin tablets,tellyourhealthcareproviderif you: have pneumonia have cysticfibrosis have knownorsuspectedbacteremia(bacterialinfectioninthe blood) haveliver orkidneyproblems have anirregularheartbeat,especially aproblemcalledQTprolongation have aproblemthatcauses muscle weakness (myastheniagravis) have anyothermedicalproblems are pregnantorplanto become pregnant.It is notknownifazithromycin willharmyourunbornbaby. are breastfeedingorplanto breastfeed.Azithromycin has beenreportedto pass intobreast milk. Talkto yourhealthcare provideraboutthe bestwayto feed your baby while youtake azithromycin tablets. Tellyourhealthcareprovider about all themedicinesyoutake,includingprescriptionandnon-prescriptionmedicines,vitamins,andherbalsupplements. Azithromycin tablets andothermedicines mayaffecteachothercausingside effects. Azithromycin tablets mayaffectthe wayothermedicines work,andothermedicines mayaffecthowazithromycin tablets work. Especiallytellyourhealthcare providerif youtake: nelfinavir a bloodthinner(warfarin) digoxin phenytoin anantacidthatcontains aluminumormagnesium Knowthe medicinesyoutake.Keepalistofyourmedicines andshow it to yourhealthcareproviderandpharmacistwhenyougetanewmedicine. HowshouldItakeazithromycin tablets? Take azithromycin tabletsexactlyas yourhealthcare providertells youto takeit. Azithromycin tablets canbe taken withorwithoutfood. 1. Do not skip any doses of azithromycin tablets or stop taking it, even if you begin to feel better, until you finish your prescribed treatment unless you have a serious allergic reaction or your healthcare provider tells you to stop taking azithromycin tablets. See What are the possible side effects of azithromycin tablets? If you skip doses, or do not complete the total course of azithromycin tablets your treatment may not work as well and your infection may be harder to treat. Taking all of your azithromycin tablet doses will help lower the chance that the bacteria will become resistant to azithromycin tablets. Ifthe bacteriabecomes resistantto azithromycin,azithromycin tabletsand otherantibioticmedicines maynotworkforyouin the future. Ifyoutake too manyazithromycin tablets,callyourhealthcare providerorgetmedicalhelprightaway. What arethepossiblesideeffectsof azithromycin tablets? Azithromycin tablets cancauseserioussideeffects, including: Seriousallergic reactions.Allergicreactions canhappeninpeople takingazithromycinthe activeingredient inazithromycin tablets,evenafteronly 1 dose. Stop taking azithromycin tablets andgetemergencymedicalhelprightawayif youhave anyofthe followingsymptoms ofasevere allergic reaction: trouble breathing orswallowing swellingofthelips,tongue,face throattightness,hoarseness rapidheartbeat faintness skinrash (hives) new onset of fever and swollen lymph nodes Stoptakingazithromycin tablets atthe firstsignofaskinrashandcallyourhealthcare provider.Skinrashmaybe asignofamore serious reactionto azithromycin tablets. Liver damage (hepatotoxicity).Hepatotoxicitycanhappeninpeople who takeazithromycin tablets.Callyourhealthcare providerrightawayifyouhave unexplainedsymptomssuchas: 1.nausea or vomiting 2.stomach pain 3.fever 4.weakness 5.abdominal pain or tenderness 6.itching 7.unusual tiredness 8.loss of appetite 9.change in the color of your bowel movements 10.dark colored urine 11.yellowing of your skin or of the whites of your eyes Stop taking azithromycin tablets and tell your healthcare provider right away if you have yellowing of your skin or white part of your eyes, or if you have dark urine. These can be signs of a serious reaction to azithromycin tablets (a liver problem). Seriousheart rhythmchanges(QT prolongationandtorsadesdepointes). Tellyourhealthcare providerrightawayif youhave achange inyourheartbeat(afastorirregularheartbeat), or ifyoufeelfaintanddizzy.Azithromycin tablets may cause arare heartproblemknownas prolongationofthe QTinterval.This conditioncancause anabnormalheartbeatandcanbe verydangerous.The chances of this happeningare higherinpeople: 1.who are elderly 2.withafamilyhistory ofprolongedQTinterval 3.withlowbloodpotassium 4.who take certainmedicines to controlheartrhythm(antiarrhythmics) Worseningof myastheniagravis (aproblemthat causesmuscleweakness).Certainantibioticslike azithromycin tablets maycause worsening of myasthenia gravis symptoms,includingmuscle weakness andbreathingproblems.Callyourhealthcare providerrightawayif youhave anyworseningmuscle weakness or breathing problems. Diarrhea.Tellyourhealthcare providerrightawayifyouhavewaterydiarrhea,diarrheathatdoes notgo away,orbloodystools.Youmayexperience cramping and a fever.Thiscouldhappenafteryouhave finishedyourazithromycin tablets. The mostcommonside effects ofazithromycin tablets include: 1.nausea 2.stomach pain 3.vomiting These are notallthepossible side effects ofazithromycin tablets. Tellyour healthcare provideraboutanyside effectthatbothers youorthatdoes notgo away. Callyourdoctorformedicaladvice aboutside effects. Youmayreportside effects to FDA at 1-800-FDA-1088. HowshouldIstoreazithromycin tablets? Store azithromycin tablets at20 to 25C (68 to 77F), excursions permitted to 15to 30 C (59to 86 F) [see Controlled Room Temperature]. Safelythrowawayanymedicine thatis outofdate orno longerneeded. Keepazithromycin tablets and all medicinesout of the reachof children. Generalinformationabout thesafe and effectiveuseof azithromycin tablets. Medicines are sometimes prescribedforpurposes otherthanthose listedin the PatientInformationleaflet. Do notuse azithromycin tablets foraconditionforwhichitwas notprescribed.Do not giveazithromycin tablets to otherpeople,even iftheyhave the same symptoms youhave.Itmayharmthem. This PatientInformationleafletsummarizes the mostimportantinformationaboutazithromycin tablets.Ifyouwouldlike more information,talkwithyourhealthcare provider. You canaskyourpharmacistorhealthcare providerforinformationaboutazithromycin tablets that is writtenfor healthprofessionals. For more information, go to www.apotex.com or call 1-800-706-5575. What aretheingredientsinazithromycin tablets? Activeingredient: azithromycindihydrate Inactive ingredients: dibasic calcium phosphate dihydrate, hydroxypropyl cellulose, croscarmellose sodium, magnesium stearate and Opadry II white (Opadry II white contains the following components: hypromellose, lactose monohydrate, titanium dioxide and triacetin). ThisPatientInformationhasbeenapprovedby theU.S.FoodandDrugAdministration. APOTEX CORP. AZITHROMYCIN TABLETS, USP 250 mg and 500 mg Manufactured by Manufactured for Apotex Inc. Toronto, Ontario Apotex Corp. Weston, Florida Canada M9L 1T9 33326 Distributed By: MAJOR PHARMACEUTICALS 17177 N Laurel Park Dr., Suite 233 Livonia, MI 48152 Revised: July 2016 Rev. 13a