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1 INDICATIONS AND USAGE Azithromycin for oral suspension USP is a macrolide antibacterial drug indicated for the treatment of patients with mild to moderate infections caused by susceptible strains of the designated microorganisms in the specific conditions listed below. Recommended dosages and durations of therapy in adult and pediatric patient populations vary in these indications. [see Dosage and Administration (2) ] Azithromycin for oral suspension USP is a macrolide antibacterial drug indicated for mild to moderate infections caused by designated, susceptible bacteria: • Acute bacterial exacerbations of chronic bronchitis in adults () • Acute bacterial sinusitis in adults () • Uncomplicated skin and skin structure infections in adults () • Urethritis and cervicitis in adults () • Genital ulcer disease in men () • Acute otitis media in pediatric patients (6 months of age and older) ( 1.2 ) • Community-acquired pneumonia in adults and pediatric patients (6 months of age and older) (, 1.2 ) • Pharyngitis/tonsillitis in adults and pediatric patients (2 years of age and older) (, 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 • Acute bacterial exacerbations of chronic bronchitis due to Hae mophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae . • Acute bacterial sinusitis due to Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae . • Community-acquired pneumonia due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, or Streptococcus pneumoniae in patients appropriate for oral therapy. • Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy. • Uncomplicated skin and skin structure infections due to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae . • Urethritis and cervicitis due to Chlamydia trachomatis or Neisseria gonorrhoeae . • Genital ulcer disease in men due to Haemophilus ducreyi (chancroid). Due to the small number of women included in clinical trials, the efficacy of azithromycin in the treatment of chancroid in women has not been established. 1.2 Pediatric Patients [see and ] • Acute otitis media (> 6 months of age ) caused by Haemophilus influenzae, Moraxella catarrhalis, or Streptococcus pneumoniae . • Community-acquired pneumonia ( >6 months of age ) due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, or Streptococcus pneumoniae in patients appropriate for oral therapy. • Pharyngitis/tonsillitis ( >2 years of age ) caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy.

) due to Chlamydophila pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae, or Streptococcus pneumoniae in patients appropriate for oral therapy. • Pharyngitis/tonsillitis ( >2 years of age ) caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy. 1.3 Limitations of Use Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors such as any of the following: • patients with cystic fibrosis, • patients with nosocomial infections, • patients with known or suspected bacteremia, • patients requiring hospitalization, • elderly or debilitated patients, or • patients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia). 1.4 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin 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.

2 DOSAGE AND ADMINISTRATION • Adult Patients ( ) 2. Infection 3. Recommended Dose/Duration 4. of Therapy 4. Community-acquired pneumonia (mild severity) 5. Pharyngitis/tonsillitis (second-line therapy) 6. Skin/skin structure (uncomplicated) 2. 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5. 2. Acute bacterial exacerbations of chronic bronchitis (mild to moderate) 2. 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. 2. Acute bacterial sinusitis 2. 500 mg once daily for 3 days. 2. Genital ulcer disease (chancroid) Non-gonococcal urethritis and cervicitis 2. One single 1 gram dose. 2. Gonococcal urethritis and cervicitis 2. One single 2 gram dose. • Pediatric Patients ( ) Infection Recommended Dose/Duration of Therapy Acute otitis media (6 months of age and older) 30 mg/kg as a single dose or 10 mg/kg once daily for 3 days or 10 mg/kg as a single dose on Day 1 followed by 5 mg/kg/day on Days 2 through 5. Acute bacterial sinusitis (6 months of age and older) 10 mg/kg once daily for 3 days. Community-acquired pneumonia (6 months of age and older) 10 mg/kg as a single dose on Day 1 followed by 5 mg/kg once daily on Days 2 through 5. Pharyngitis/tonsillitis (2 years of age and older) 12 mg/kg once daily for 5 days. 2.1 Adult Patients [see and ] Infection * Recommended Dose/Duration of Therapy Community-acquired pneumonia Pharyngitis/tonsillitis (second-line therapy) Skin/skin structure (uncomplicated) 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5 Acute bacterial exacerbations of chronic obstructive pulmonary disease 500 mg once daily for 3 days OR 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5 Acute bacterial sinusitis 500 mg-once daily for 3 days Genital ulcer disease (chancroid) One single 1 gram dose Non-gonococcal urethritis and cervicitis One single 1 gram dose Gonococcal urethritis and cervicitis One single 2 gram dose * DUE TO THE INDICATED ORGANISMS [see ] Azithromycin tablets can be taken with or without food. 2.2 Pediatric Patients 1 Infection * Recommended Dose/Duration of Therapy Acute otitis media 30 mg/kg as a single dose or 10 mg/kg once daily for 3 days or 10 mg/kg as a single dose on Day 1 followed by 5 mg/kg/day on Days 2 through 5. Acute bacterial sinusitis 10 mg/kg once daily for 3 days. Community-acquired pneumonia 10 mg/kg as a single dose on Day 1 followed by 5 mg/kg once daily on Days 2 through 5. Pharyngitis/tonsillitis 12 mg/kg once daily for 5 days. *DUE TO THE INDICATED ORGANISMS [see Indications and Usage (1.2) ] 1 see dosing tables below for maximum doses evaluated by indication Azithromycin for oral suspension can be taken with or without food. PEDIATRIC DOSAGE GUIDELINES FOR OTITIS MEDIA, ACUTE BACTERIAL SINUSITIS, AND COMMUNITY-ACQUIRED PNEUMONIA (Age 6 months and above, [see ]) Based on Body Weight OTITIS MEDIA AND COMMUNITY-ACQUIRED PNEUMONIA: (5-Day Regimen) * Dosing Calculated on 10 mg/kg/day Day 1 and 5 mg/kg/day Days 2 to 5.

aken with or without food. PEDIATRIC DOSAGE GUIDELINES FOR OTITIS MEDIA, ACUTE BACTERIAL SINUSITIS, AND COMMUNITY-ACQUIRED PNEUMONIA (Age 6 months and above, [see ]) Based on Body Weight OTITIS MEDIA AND COMMUNITY-ACQUIRED PNEUMONIA: (5-Day Regimen) * Dosing Calculated on 10 mg/kg/day Day 1 and 5 mg/kg/day Days 2 to 5. Weight 100mg/5mL 100mg/5mL 200 mg/5 mL 200 mg/5 mL Total Total Kg Day 1 Days 2-5 Day 1 Days 2-5 5 2.5 mL; (½ tsp) 1.25 mL; (¼ tsp) 7.5 mL 150 mg 10 5 mL; (1 tsp) 2.5 mL; (½ tsp) 15 mL 300 mg 20 5 mL; (1 tsp) 2.5 mL; (½ tsp) 15 mL 600 mg 30 7.5 mL; (1½ tsp) 3.75 mL; (¾ tsp) 22.5 mL 900 mg 40 10 mL; (2 tsp) 5 mL; (1 tsp) 30 mL 1200 mg 50 and above 12.5 mL; (2½ tsp) 6.25 mL; (1¼ tsp) 37.5 mL 1500 mg * Effectiveness of the 3-day or 1-day regimen in pediatric patients with community-acquired pneumonia has not been established. OTITIS MEDIA AND ACUTE BACTERIAL SINUSITIS: (3-Day Regimen) * Dosing Calculated on 10 mg/kg/day. Weight 100 mg/5 mL 200 mg/5 mL Total mL per Treatment Course Total mg per Treatment Course Kg Days 1-3 Days 1-3 5 2.5 mL; (½ tsp) 7.5 mL 150 mg 10 5 mL; (1 tsp) 15 mL 300 mg 20 5 mL (1 tsp) 15 mL 600 mg 30 7.5 mL (1½ tsp) 22.5 mL 900 mg 40 10 mL (2 tsp) 30 mL 1200 mg 50 and above 12.5 mL (2½ tsp) 37.5 mL 1500 mg * Effectiveness of the 5-day or 1-day regimen in pediatric patients with acute bacterial sinusitis has not been established. OTITIS MEDIA: (1-Day Regimen) Dosing Calculated on 30 mg/kg as a single dose. Weight 200 mg/5 mL Total mL per Treatment Course Total mg per Treatment Course Kg 1-Day Regimen 5 3.75 mL; (¾ tsp) 3.75 mL 150 mg 10 7.5 mL; (1½ tsp) 7.5 mL 300 mg 20 15 mL; (3 tsp) 15 mL 600 mg 30 22.5 mL; (4½ tsp) 22.5 mL 900 mg 40 30 mL; (6 tsp) 30 mL 1200 mg 50 and above 37.5 mL; (7½ tsp) 37.5 mL 1500 mg The safety of re-dosing azithromycin in pediatric patients who vomit after receiving 30 mg/kg as a single dose has not been established. In clinical studies involving 487 patients with acute otitis media given a single 30 mg/kg dose of azithromycin, 8 patients who vomited within 30 minutes of dosing were re-dosed at the same total dose. Pharyngitis/Tonsillitis : The recommended dose of azithromycin for children with pharyngitis/tonsillitis is 12 mg/kg once daily for 5 days. (See chart below.) PEDIATRIC DOSAGE GUIDELINES FOR PHARYNGITIS/TONSILLITIS (Age 2 years and above, [see ]) Based on Body Weight PHARYNGITIS/TONSILLITIS: (5-Day Regimen) Dosing Calculated on 12 mg/kg/day for 5 days. Weight 200 mg/5 mL Total mL per Treatment Course Total mg per Treatment Course Kg Day 1-5 8 2.5 mL; (½ tsp) 12.5 mL 500 mg 17 5 mL; (1 tsp) 25 mL 1000 mg 25 7.5 mL; (1½ tsp) 37.5 mL 1500 mg 33 10 mL; (2 tsp) 50 mL 2000 mg 40 12.5 mL; (2½ tsp) 62.5 mL 2500 mg Constituting instructions for azithromycin Oral Suspension 300, 600, 900, 1200 mg bottles. The table below indicates the volume of water to be used for constitution: Amount of water to be added Total volume after constitution (azithromycin content) Azithromycin concentration after constitution 9 mL (300 mg) 15 mL (300 mg) 100 mg/5 mL 9 mL (600 mg) 15 mL (600 mg) 200 mg/5 mL 12 mL (900 mg) 22.5 mL (900 mg) 200 mg/5 mL 15 mL (1200 mg) 30 mL (1200 mg) 200 mg/5 mL Shake well before each use. Oversized bottle provides shake space. Keep tightly closed. After mixing, store suspension at 5° to 30°C (41° to 86°F) and use within 10 days. Discard after full dosing is completed.

3 DOSAGE FORMS AND STRENGTHS Azithromycin for oral suspension USP after constitution contains a banana-cherry flavored suspension. Azithromycin for oral suspension USP is supplied to provide 100 mg/5 mL or 200 mg/5 mL suspension in bottles. • Azithromycin for oral suspension 100 mg/5 mL and 200 mg/5 mL ()

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

5 WARNINGS AND PRECAUTIONS • Serious (including fatal) allergic and skin reactions: Discontinue azithromycin if reaction occurs. () • Hepatotoxicity: Severe, and sometimes fatal, hepatotoxicity has been reported. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur. () • Infantile Hypertrophic Pyloric Stenosis (IHPS): Following the use of azithromycin in neonates (treatment up to 42 days of life), IHPS has been reported. Direct parents and caregivers to contact their physician if vomiting or irritability with feeding occurs. () • 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. ( 5.4 ) • Cardiovascular Death: Some observational studies have shown an approximately two-fold increased short-term potential risk of acute cardiovascular death in adults exposed to azithromycin relative to other antibacterial drugs, including amoxicillin. Consider balancing this potential risk with treatment benefits when prescribing azithromycin. () • Clostridioides difficile -associated diarrhea: Evaluate patients if diarrhea occurs. () • Azithromycin may exacerbate muscle weakness in persons with myasthenia gravis. () 5.1 Hypersensitivity Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported in patients on azithromycin therapy. [see ] 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 Infantile Hypertrophic Pyloric Stenosis (IHPS) Following the use of azithromycin in neonates (treatment up to 42 days of life), IHPS has been reported. Direct parents and caregivers to contact their physician if vomiting or irritability with feeding occurs. 5.4 QT Prolongation Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen with treatment with macrolides, including azithromycin. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving azithromycin.

ed 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. 5.5 Cardiovascular Death Some observational studies have shown an approximately two-fold increased short-term potential risk of acute cardiovascular death in adults exposed to azithromycin relative to other antibacterial drugs, including amoxicillin. The five-day cardiovascular mortality observed in these studies ranged from 20 to 400 per million azithromycin treatment courses. This potential risk was noted to be greater during the first five days of azithromycin use and does not appear to be limited to those patients with preexisting cardiovascular diseases. The data in these observational studies are insufficient to establish or exclude a causal relationship between acute cardiovascular death and azithromycin use. Consider balancing this potential risk with treatment benefits when prescribing azithromycin. 5.6 Clostridioides difficile -Associated Diarrhea (CDAD) Clostridioides 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. difficil e. 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. 5.7 Exacerbation of Myasthenia Gravis Exacerbation of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy. 5.8 Use in Sexually Transmitted Infections Azithromycin, 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.

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. 5.9 Development of Drug-Resistant Bacteria Prescribing azithromycin in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6 ADVERSE REACTIONS 1. The following clinically significant adverse reactions are described elsewhere in labeling: 2. Hypersensitivity [see ] 3. Hepatotoxicity [see ] 4. Infantile Hypertrophic Pyloric Stenosis (IHPS) [see ] 5. QT Prolongation [see Warnings and Precautions (5.4) ] 6. Cardiovascular Death [see ] 7. Clostridioides difficile-Associated Diarrhea (CDAD) [see ] 8. Exacerbation of Myasthenia Gravis [see ] Most common adverse reactions are diarrhea (5 to 14%), nausea (3 to 18%), abdominal pain (3 to 7 %), or vomiting (2 to 7 %). () To report SUSPECTED ADVERSE REACTIONS, contact Epic Pharma, LLC at 1-888-374-2791 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 ] 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. Allergi c: 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.

quency 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 ] The incidence, based on dosing regimen, is described in the table below: Dosage Regimen Diarrhea % Abdominal Pain % Vomiting % Nausea % Rash % 1-day 4.3% 1.4% 4.9% 1.0% 1.0% 3-day 2.6% 1.7% 2.3% 0.4% 0.6% 5-day 1.8% 1.2% 1.1% 0.5% 0.4% Community-Acquired Pneumonia: For the recommended dosage regimen of 10 mg/kg on Day 1 followed by 5 mg/kg on Days 2-5, the most frequent adverse reactions attributed to treatment were diarrhea/loose stools, abdominal pain, vomiting, nausea, and rash. The incidence is described in the table below: Dosage Regimen Diarrhea % Abdominal Pain % Vomiting % Nausea % Rash % Headache % 5-day 5.4% 3.4% 5.6% 1.8% 0.7% 1.1% With any of the treatment regimens, no other adverse reactions occurred in pediatric patients treated with azithromycin with a frequency greater than 1%. Adverse reactions that occurred with a frequency of 1% or less included the following: Cardiovascula r: Chest pain. Gastrointestinal : Dyspepsia, constipation, anorexia, enteritis, flatulence, gastritis, jaundice, loose stools, and oral moniliasis. Hematologic and Lymphatic : Anemia and leukopenia. Nervous System : Headache (otitis media dosage), hyperkinesia, dizziness, agitation, nervousness, and insomnia. General : Fever, face edema, fatigue, fungal infection, malaise, and pain. Allergic : Rash and allergic reaction. Respiratory : Cough, pharyngitis, pleural effusion, and rhinitis. Skin and Appendages : Eczema, fungal dermatitis, pruritus, sweating, urticaria, and vesiculobullous rash. Special Senses : Conjunctivitis. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of azithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported with azithromycin during the postmarketing period in adult and/or pediatric patients for which a causal relationship may not be established include: Allergic : Arthralgia, edema, urticaria, and angioedema. Cardiovascular : Arrhythmias including ventricular tachycardia and hypotension. There have been reports of QT prolongation, torsades de pointes, and cardiovascular death. Gastrointestinal : Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea, pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and reports of tongue discoloration. General : Asthenia, paresthesia, fatigue, malaise, and anaphylaxis. Genitourinary : Interstitial nephritis and acute renal failure and vaginitis. Hematopoietic : Thrombocytopenia.

tulence, vomiting/diarrhea, pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and reports of tongue discoloration. General : Asthenia, paresthesia, fatigue, malaise, and anaphylaxis. Genitourinary : Interstitial nephritis and acute renal failure and vaginitis. Hematopoietic : Thrombocytopenia. Liver/Biliary : Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure. [see Warnings and Precautions (5.2)] Nervous System : Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation, and syncope. Psychiatric : Aggressive reaction and anxiety. Skin/Appendages : Pruritus serious skin reactions including erythema multiforme, AGEP, Stevens-Johnson Syndrome, toxic epidermal necrolysis, and DRESS. Special Senses : Hearing disturbances including hearing loss, deafness and/or tinnitus, and reports of taste/smell perversion and/or loss. 6.3 Laboratory Abnormalities Adults : Clinically significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows: with an incidence of greater than 1%: decreased hemoglobin, hematocrit, lymphocytes, neutrophils, and blood glucose; elevated serum creatine phosphokinase, potassium, ALT, GGT, AST, BUN, creatinine, blood glucose, platelet count, lymphocytes, neutrophils, and eosinophils; with an incidence of less than 1%: leukopenia, neutropenia, decreased sodium, potassium, platelet count, elevated monocytes, basophils, bicarbonate, serum alkaline phosphatase, bilirubin, LDH, and phosphate. The majority of subjects with elevated serum creatinine also had abnormal values at baseline. When follow-up was provided, changes in laboratory tests appeared to be reversible. In multiple-dose clinical trials involving more than 5000 patients, four patients discontinued therapy because of treatment-related liver enzyme abnormalities and one because of a renal function abnormality. Pediatric Patients : One, Three, and Five-Day Regimens Laboratory data collected from comparative clinical trials employing two 3-day regimens (30 mg/kg or 60 mg/kg in divided doses over 3 days), or two 5-day regimens (30 mg/kg or 60 mg/kg in divided doses over 5 days) were similar for regimens of azithromycin and all comparators combined, with most clinically significant laboratory abnormalities occurring at incidences of 1-5%. 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 500-1500 cells/mm 3 was observed in 10/64 patients receiving 30 mg/kg as a single dose, 9/62 patients receiving 30 mg/kg given over 3 days, and 8/63 comparator patients. No patient had an absolute neutrophil count <500 cells/mm 3 . In multiple-dose clinical trials involving approximately 4700 pediatric patients, no patients discontinued therapy because of treatment-related laboratory abnormalities.

<table width="100%"><col width="17%"/><col width="17%"/><col width="19%"/><col width="18%"/><col width="16%"/><col width="14%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Dosage Regimen</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Diarrhea %</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Abdominal Pain %</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Vomiting %</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Nausea %</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Rash %</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>1-day</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.3%</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.4%</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4.9%</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.0%</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.0%</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>3-day</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.6%</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.7%</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.3%</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.4%</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.6%</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>5-day</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1.8%</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1.2%</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1.1%</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.5%</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.4%</paragraph></td></tr></tbody></table>

ragraph>1.2%</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1.1%</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.5%</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.4%</paragraph></td></tr></tbody></table> <table width="100%"><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><col width="14%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Dosage Regimen</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Diarrhea %</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Abdominal Pain %</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Vomiting %</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Nausea %</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Rash %</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Headache %</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>5-day</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>5.4%</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>3.4%</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>5.6%</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1.8%</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>0.7%</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1.1%</paragraph></td></tr></tbody></table>

7 DRUG INTERACTIONS • Nelfinavir: Close monitoring for known adverse reactions of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. () • Warfarin: Use with azithromycin may increase coagulation times; monitor prothrombin time. () 7.1 Nelfinavir Co-administration of nelfinavir at steady-state with a single oral dose of azithromycin resulted in increased azithromycin serum concentrations. Although a dose adjustment of azithromycin is not recommended when administered in combination with nelfinavir, close monitoring for known adverse reactions of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. [see Adverse Reactions (6) ] 7.2 Warfarin Spontaneous postmarketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants such as warfarin, although the prothrombin time was not affected in the dedicated drug interaction study with azithromycin and warfarin. Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly. 7.3 Potential Drug-Drug Interaction with Macrolides Interactions with digoxin, colchicine or phenytoin have not been reported in clinical trials with azithromycin. No specific drug interaction studies have been performed to evaluate potential drug-drug interaction. However, drug interactions have been observed with other macrolide products. Until further data are developed regarding drug interactions when digoxin, colchicine or phenytoin are used with azithromycin careful monitoring of patients is advised.

8 USE IN SPECIFIC POPULATIONS • Pediatric use: Safety and effectiveness in the treatment of patients under 6 months of age have not been established. () • Geriatric use: Elderly patients may be more susceptible to development of torsades de pointes arrhythmias. () 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 Clinical Considerations). There are no available data on the effects of azithromycin on milk production.

cy 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 Clinical Considerations). 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. Breastmilk samples collected on days 3 and 6 postpartum as well as 2 and 4 weeks postpartum revealed the presence of azithromycin in breastmilk up to 4 weeks after dosing. In another study, a single dose of azithromycin 500 mg was administered intravenously to 8 women prior to incision for cesarean section. Breastmilk (colostrum) samples obtained between 12 and 48 hours after dosing revealed that azithromycin persisted in breastmilk up to 48 hours. 8.4 Pediatric Use [see , Indications and Usage (1.2) , and ] 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 (5.4) ]

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.

8.4 Pediatric Use [see , Indications and Usage (1.2) , and ] 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 (5.4) ]

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.

11 DESCRIPTION Azithromycin for oral suspension USP contains the active ingredient azithromycin monohydrate, 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 monohydrate. 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 ∙H2O, and its molecular weight is 767.00. Azithromycin has the following structural formula: Azithromycin, USP, as the monohydrate, is a white to off-white crystalline powder with a molecular formula of C 38 H 72 N 2 O 12 •H2O and a molecular weight of 767.00. Azithromycin for Oral Suspension USP is supplied in bottles containing azithromycin monohydrate powder equivalent to 300 mg, 600 mg, 900 mg, or 1200 mg azithromycin, USP per bottle and the following inactive ingredients: colloidal silicon dioxide, FD & C Red No. 40 Aluminum Lake, hydroxypropyl cellulose, sodium phosphate tribasic anhydrous, sucrose, natural and artificial banana flavor, natural and artificial cherry flavor and xanthan gum. After constitution, each 5 mL of suspension contains 100 mg or 200 mg of azithromycin, USP. The dry powder before constitution is off-white to pinkish in color. The suspension after constitution is pink to red in color. structure-formula.jpg

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Azithromycin is a macrolide antibacterial drug. [see Microbiology (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 (1000 mg) alone or in combination with oral azithromycin (500 mg, 1000 mg, and 1500 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, 1000 mg and 1500 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) mcg∙hr/mL; C max =0.5 (0.2) mcg/mL; T max =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 1500 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-Day Regimen 5-Day Regimen Pharmacokinetic Parameter [mean (SD)] Day 1 Day 3 Day 1 Day 5 C max (serum, mcg/mL) 0.44 (0.22) 0.54 (0.25) 0.43 (0.20) 0.24 (0.06) Serum AUC 0-∞ mcg∙hr/mL) 17.4 (6.2) * 14.9 (3.1) * Serum T ½ 71.8 hr 68.9 hr 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 C max by 23% but had no effect on AUC. When azithromycin oral suspension was administered with food to 28 adult healthy male subjects, C max 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).

es 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. Specific Populations Patients with Renal Impairment 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 C max 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 C max and AUC0-120 increased 61% and 35%, respectively, in subjects with severe renal impairment (GFR < 10 mL/min) compared to subjects with normal renal function (GFR > 80 mL/min). Patients with Hepatic Impairment The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established. Male and Female Patients 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 ] 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 C max = 0.216 mcg/mL, T max = 1.9 hr, and AUC0-24 = 1.822 mcg·hr/mL for the 1 to 5-year-old group and were C max = 0.383 mcg/mL, T max = 2.4 hr, and AUC0-24 = 3.109 mcg·hr/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.

harmacokinetics 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-Day Regimen (12 mg/kg for 5 days) N 17 C max (mcg/mL) 0.5 (0.4) T max (hr) 2.2 (0.8) AUC 0-24 (mcg∙hr/mL) 3.9 (1.9) Single dose pharmacokinetics of azithromycin in pediatric patients given doses of 30 mg/kg have not been studied. [see Dosage and Administration (2) ] Drug interaction studies 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 C max and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2. [see ] Table 1.

hromycin. Co-administration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the C max and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2. [see ] Table 1. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin Co-administered Drug Dose of Co-administered Drug Dose of Azithromycin n Ratio (with/without azithromycin) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Mean C max Mean AUC Atorvastatin 10 mg/day for 8 days 500 mg/day orally on days 6-8 12 0.83 (0.63 to 1.08) 1.01 (0.81 to 1.25) Carbamazepine 200 mg/day for 2 days, then 200 mg twice a day for 18 days 500 mg/day orally for days 16-18 7 0.97 (0.88 to 1.06) 0.96 (0.88 to 1.06) Cetirizine 20 mg/day for 11 days 500 mg orally on day 7, then 250 mg/day on days 8-11 14 1.03 (0.93 to 1.14) 1.02 (0.92 to 1.13) Didanosine 200 mg orally twice a day for 21 days 1200 mg/day orally on days 8-21 6 1.44 (0.85 to 2.43) 1.14 (0.83 to 1.57) Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.04* 0.95* Fluconazole 200 mg orally single dose 1200 mg orally single dose 18 1.04 (0.98 to 1.11) 1.01 (0.97 to 1.05) Indinavir 800 mg three times a day for 5 days 1200 mg orally on day 5 18 0.96 (0.86 to 1.08) 0.90 (0.81 to 1.00) Midazolam 15 mg orally on day 3 500 mg/day orally for 3 days 12 1.27 (0.89 to 1.81) 1.26 (1.01 to 1.56) Nelfinavir 750 mg three times a day for 11 days 1,200 mg orally on day 9 14 0.90 (0.81 to 1.01) 0.85 (0.78 to 0.93) Sildenafil 100 mg on days 1 and 4 500 mg/day orally for 3 days 12 1.16 (0.86 to 1.57) 0.92 (0.75 to 1.12) Theophylline 4 mg/kg IV on days 1, 11, 25 500 mg orally on day 7, 250 mg/day on days 8-11 10 1.19 (1.02 to 1.40) 1.02 (0.86 to 1.22) Theophylline 300 mg orally twice a day for 15 days 500 mg orally on day 6, then 250 mg/day on days 7-10 8 1.09 (0.92 to 1.29) 1.08 (0.89 to 1.31) Triazolam 0.125 mg on day 2 500 mg orally on day 1, then 250 mg/day on day 2 12 1.06* 1.02* Trimethoprim/ Sulfamethoxazole 160 mg/800 mg/day orally for 7 days 1200 mg orally on day 7 12 0.85 (0.75 to 0.97) / 0.90 (0.78 to 1.03) 0.87 (0.80 to 0.95) / 0.96 (0.88 to 1.03) Zidovudine 500 mg/day orally for 21 days 600 mg/day orally for 14 days 5 1.12 (0.42 to 3.02) 0.94 (0.52 to 1.70) Zidovudine 500 mg/day orally for 21 days 1200 mg/day orally for 14 days 4 1.31 (0.43 to 3.97) 1.30 (0.69 to 2.43) 1. * - 90% Confidence interval not reported Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs. [see Drug Interactions (7)] Co-administered Drug Dose of Co-administered Drug Dose of Azithromycin n Ratio (with/without co-administered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Mean C max Mean AUC Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.22 (1.04 to 1.42) 0.92* Fluconazole 200 mg orally single dose 1,200 mg orally single dose 18 0.82 (0.66 to 1.02) 1.07 (0.94 to 1.22) Nelfinavir 750 mg three times a day for 11 days 1,200 mg orally on day 9 14 2.36 (1.77 to 3.15) 2.12 (1.80 to 2.50) * - 90% Confidence interval not reported 12.4 Microbiology 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.

icroorganisms 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 (MLSB 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 1. Staphylococcus aureus 2. Streptococcus agalactiae 3. Streptococcus pneumoniae 4. Streptococcus pyogenes Gram-Negative Bacteria 1. Haemophilus ducreyi 2. Haemophilus influenzae 3. Moraxella catarrhalis 4. Neisseria gonorrhoeae Other Bacteria 1. Chlamydophila pneumoniae 2. Chlamydia trachomatis 3. 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 1. Beta-hemolytic streptococci (Groups C, F, G) 2. Viridans group streptococci Gram-Negative Bacteria 1. Bordetella pertussis 2. Legionella pneumophila Anaerobic Bacteria 1. Prevotella bivia 2. Peptostreptococcus species Other Bacteria 1. Ureaplasma urealyticum Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

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 (1000 mg) alone or in combination with oral azithromycin (500 mg, 1000 mg, and 1500 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, 1000 mg and 1500 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) mcg∙hr/mL; C max =0.5 (0.2) mcg/mL; T max =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 1500 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-Day Regimen 5-Day Regimen Pharmacokinetic Parameter [mean (SD)] Day 1 Day 3 Day 1 Day 5 C max (serum, mcg/mL) 0.44 (0.22) 0.54 (0.25) 0.43 (0.20) 0.24 (0.06) Serum AUC 0-∞ mcg∙hr/mL) 17.4 (6.2) * 14.9 (3.1) * Serum T ½ 71.8 hr 68.9 hr 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 C max by 23% but had no effect on AUC. When azithromycin oral suspension was administered with food to 28 adult healthy male subjects, C max 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. Specific Populations Patients with Renal Impairment Azithromycin pharmacokinetics was investigated in 42 adults (21 to 85 years of age) with varying degrees of renal impairment.

rug, is a major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine. Specific Populations Patients with Renal Impairment 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 C max 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 C max and AUC0-120 increased 61% and 35%, respectively, in subjects with severe renal impairment (GFR < 10 mL/min) compared to subjects with normal renal function (GFR > 80 mL/min). Patients with Hepatic Impairment The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established. Male and Female Patients 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 ] 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 C max = 0.216 mcg/mL, T max = 1.9 hr, and AUC0-24 = 1.822 mcg·hr/mL for the 1 to 5-year-old group and were C max = 0.383 mcg/mL, T max = 2.4 hr, and AUC0-24 = 3.109 mcg·hr/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-Day Regimen (12 mg/kg for 5 days) N 17 C max (mcg/mL) 0.5 (0.4) T max (hr) 2.2 (0.8) AUC 0-24 (mcg∙hr/mL) 3.9 (1.9) Single dose pharmacokinetics of azithromycin in pediatric patients given doses of 30 mg/kg have not been studied. [see Dosage and Administration (2) ] Drug interaction studies 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 C max and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2. [see ] Table 1.

hromycin. Co-administration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the C max and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs listed in Table 2. [see ] Table 1. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin Co-administered Drug Dose of Co-administered Drug Dose of Azithromycin n Ratio (with/without azithromycin) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Mean C max Mean AUC Atorvastatin 10 mg/day for 8 days 500 mg/day orally on days 6-8 12 0.83 (0.63 to 1.08) 1.01 (0.81 to 1.25) Carbamazepine 200 mg/day for 2 days, then 200 mg twice a day for 18 days 500 mg/day orally for days 16-18 7 0.97 (0.88 to 1.06) 0.96 (0.88 to 1.06) Cetirizine 20 mg/day for 11 days 500 mg orally on day 7, then 250 mg/day on days 8-11 14 1.03 (0.93 to 1.14) 1.02 (0.92 to 1.13) Didanosine 200 mg orally twice a day for 21 days 1200 mg/day orally on days 8-21 6 1.44 (0.85 to 2.43) 1.14 (0.83 to 1.57) Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.04* 0.95* Fluconazole 200 mg orally single dose 1200 mg orally single dose 18 1.04 (0.98 to 1.11) 1.01 (0.97 to 1.05) Indinavir 800 mg three times a day for 5 days 1200 mg orally on day 5 18 0.96 (0.86 to 1.08) 0.90 (0.81 to 1.00) Midazolam 15 mg orally on day 3 500 mg/day orally for 3 days 12 1.27 (0.89 to 1.81) 1.26 (1.01 to 1.56) Nelfinavir 750 mg three times a day for 11 days 1,200 mg orally on day 9 14 0.90 (0.81 to 1.01) 0.85 (0.78 to 0.93) Sildenafil 100 mg on days 1 and 4 500 mg/day orally for 3 days 12 1.16 (0.86 to 1.57) 0.92 (0.75 to 1.12) Theophylline 4 mg/kg IV on days 1, 11, 25 500 mg orally on day 7, 250 mg/day on days 8-11 10 1.19 (1.02 to 1.40) 1.02 (0.86 to 1.22) Theophylline 300 mg orally twice a day for 15 days 500 mg orally on day 6, then 250 mg/day on days 7-10 8 1.09 (0.92 to 1.29) 1.08 (0.89 to 1.31) Triazolam 0.125 mg on day 2 500 mg orally on day 1, then 250 mg/day on day 2 12 1.06* 1.02* Trimethoprim/ Sulfamethoxazole 160 mg/800 mg/day orally for 7 days 1200 mg orally on day 7 12 0.85 (0.75 to 0.97) / 0.90 (0.78 to 1.03) 0.87 (0.80 to 0.95) / 0.96 (0.88 to 1.03) Zidovudine 500 mg/day orally for 21 days 600 mg/day orally for 14 days 5 1.12 (0.42 to 3.02) 0.94 (0.52 to 1.70) Zidovudine 500 mg/day orally for 21 days 1200 mg/day orally for 14 days 4 1.31 (0.43 to 3.97) 1.30 (0.69 to 2.43) 1. * - 90% Confidence interval not reported Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs. [see Drug Interactions (7)] Co-administered Drug Dose of Co-administered Drug Dose of Azithromycin n Ratio (with/without co-administered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Mean C max Mean AUC Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.22 (1.04 to 1.42) 0.92* Fluconazole 200 mg orally single dose 1,200 mg orally single dose 18 0.82 (0.66 to 1.02) 1.07 (0.94 to 1.22) Nelfinavir 750 mg three times a day for 11 days 1,200 mg orally on day 9 14 2.36 (1.77 to 3.15) 2.12 (1.80 to 2.50) * - 90% Confidence interval not reported

<table width="100%"><col width="25%"/><col width="15%"/><col width="20%"/><col width="20%"/><col width="20%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">3-Day Regimen</content></paragraph></td><td colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">5-Day Regimen</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Pharmacokinetic Parameter [mean (SD)]</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Day 1</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Day 3</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Day 1</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Day 5</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>C_max (serum, mcg/mL)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.44 (0.22)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.54 (0.25)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.43 (0.20)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.24 (0.06)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Serum AUC_0-&#x221E; mcg&#x2219;hr/mL)</paragraph></td><td colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>17.4 (6.2)^*</paragraph></td><td colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14.9 (3.1)^*</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Serum T_&#xBD;</paragraph></td><td colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>71.8 hr</paragraph></td><td colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>68.9 hr</paragraph></td></tr></tbody></table>

="Rrule Botrule Lrule " valign="top"><paragraph>Serum T_&#xBD;</paragraph></td><td colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>71.8 hr</paragraph></td><td colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>68.9 hr</paragraph></td></tr></tbody></table> <table width="100%"><col width="50%"/><col width="50%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Pharmacokinetic Parameter</content></paragraph><paragraph><content styleCode="bold">[mean (SD)]</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">5-Day Regimen</content></paragraph><paragraph><content styleCode="bold">(12 mg/kg for 5 days)</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">N</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">17</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>C_max (mcg/mL)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.5 (0.4)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>T_max (hr)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.2 (0.8)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>AUC_0-24 (mcg&#x2219;hr/mL)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>3.9 (1.9)</paragraph></td></tr></tbody></table> <table width="100%"><col width="19%"/><col width="17%"/><col width="18%"/><col width="8%"/><col width="21%"/><col width="17%"/><tbody><tr><td colspan="6" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Table 1.

<table width="100%"><col width="50%"/><col width="50%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Pharmacokinetic Parameter</content></paragraph><paragraph><content styleCode="bold">[mean (SD)]</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">5-Day Regimen</content></paragraph><paragraph><content styleCode="bold">(12 mg/kg for 5 days)</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">N</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">17</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>C_max (mcg/mL)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.5 (0.4)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="top"><paragraph>T_max (hr)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2.2 (0.8)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>AUC_0-24 (mcg&#x2219;hr/mL)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>3.9 (1.9)</paragraph></td></tr></tbody></table> <table width="100%"><col width="19%"/><col width="17%"/><col width="18%"/><col width="8%"/><col width="21%"/><col width="17%"/><tbody><tr><td colspan="6" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Table 1. Drug Interactions: Pharmacokinetic Parameters for Co-administered Drugs in the Presence of Azithromycin</content></paragraph></td></tr><tr><td rowspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Co-administered Drug</content></paragraph></td><td rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Dose of </content></paragraph><paragraph><content styleCode="bold">Co-administered Drug</content></paragraph></td><td rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Dose of Azithromycin</content></paragraph></td><td rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">n</content></paragraph></td><td colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Ratio (with/without azithromycin) of Co-administered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Mean C_max</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Mean AUC</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Atorvastatin</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10 mg/day for 8 days</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>500 mg/day orally on days 6-8</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.83</paragraph><paragraph>(0.63 to 1.08)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.01</paragraph><paragraph>(0.81 to 1.25)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Carbamazepine</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>200 mg/day for 2 days, then 200 mg twice a day for 18 days</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>500 mg/day orally for days 16-18</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.97</paragraph><paragraph>(0.88 to 1.06)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.96</paragraph><paragraph>(0.88 to 1.06)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Cetirizine</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>20 mg/day for 11 days</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>500 mg orally on day 7, then 250 mg/day on days 8-11</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.03</paragraph><paragraph>(0.93 to 1.14)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.02</paragraph><paragraph>(0.92 to 1.13)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Didanosine</paragraph></td><td styleCode="Rrule Lrule Toprul

raph>1.03</paragraph><paragraph>(0.93 to 1.14)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.02</paragraph><paragraph>(0.92 to 1.13)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Didanosine</paragraph></td><td styleCode="Rrule Lrule Toprul e Botrule " valign="top"><paragraph>200 mg orally twice a day for 21 days</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1200 mg/day orally on days 8-21</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.44</paragraph><paragraph>(0.85 to 2.43)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.14</paragraph><paragraph>(0.83 to 1.57)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Efavirenz</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>400 mg/day for 7 days</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>600 mg orally on day 7</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.04*</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.95*</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Fluconazole</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>200 mg orally single dose</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1200 mg orally single dose</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>18</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.04</paragraph><paragraph>(0.98 to 1.11)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.01</paragraph><paragraph>(0.97 to 1.05)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Indinavir</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>800 mg three times a day for 5 days</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1200 mg orally on day 5</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>18</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.96</paragraph><paragraph>(0.86 to 1.08)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.90</paragraph><paragraph>(0.81 to 1.00)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Midazolam</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>15 mg orally on day 3</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>500 mg/day orally for 3 days</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.27</paragraph><paragraph>(0.89 to 1.81)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.26</paragraph><paragraph>(1.01 to 1.56)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nelfinavir</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>750 mg three times a day for 11 days</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1,200 mg orally on day 9</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign=

aragraph>Nelfinavir</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>750 mg three times a day for 11 days</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1,200 mg orally on day 9</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign= "top"><paragraph>14</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.90</paragraph><paragraph>(0.81 to 1.01)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.85</paragraph><paragraph>(0.78 to 0.93)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Sildenafil</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>100 mg on days 1 and 4</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>500 mg/day orally for 3 days</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.16</paragraph><paragraph>(0.86 to 1.57)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.92</paragraph><paragraph>(0.75 to 1.12)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Theophylline</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4 mg/kg IV on days 1, 11, 25</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>500 mg orally on day 7, 250 mg/day on days 8-11</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.19</paragraph><paragraph>(1.02 to 1.40)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.02</paragraph><paragraph>(0.86 to 1.22)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Theophylline</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>300 mg orally twice a day for 15 days</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>500 mg orally on day 6, then 250 mg/day on days 7-10</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.09</paragraph><paragraph>(0.92 to 1.29)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.08</paragraph><paragraph>(0.89 to 1.31)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Triazolam</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.125 mg on day 2</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>500 mg orally on day 1, then 250 mg/day on day 2</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.06*</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.02*</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Trimethoprim/</paragraph><paragraph>Sulfamethoxazole</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>160 mg/800 mg/day orally for 7 days</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1200 mg orally on day 7</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.85</paragraph><paragraph>(0.7

7 days</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1200 mg orally on day 7</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.85</paragraph><paragraph>(0.7 5 to 0.97) / </paragraph><paragraph>0.90 </paragraph><paragraph>(0.78 to 1.03)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.87</paragraph><paragraph>(0.80 to 0.95) /</paragraph><paragraph>0.96 </paragraph><paragraph>(0.88 to 1.03)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Zidovudine</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>500 mg/day orally for 21 days</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>600 mg/day orally for 14 days</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.12</paragraph><paragraph>(0.42 to 3.02)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.94</paragraph><paragraph>(0.52 to 1.70)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Zidovudine</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>500 mg/day orally for 21 days</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1200 mg/day orally for 14 days</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.31</paragraph><paragraph>(0.43 to 3.97)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.30</paragraph><paragraph>(0.69 to 2.43)</paragraph></td></tr><tr><td colspan="6" valign="top"><list listType="ordered"><item><caption>1.</caption>^* - 90% Confidence interval not reported</item></list></td></tr><tr><td colspan="6" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> <content styleCode="bold">Table 2.

><paragraph>(0.69 to 2.43)</paragraph></td></tr><tr><td colspan="6" valign="top"><list listType="ordered"><item><caption>1.</caption>^* - 90% Confidence interval not reported</item></list></td></tr><tr><td colspan="6" styleCode="Rrule Lrule Botrule " valign="top"><paragraph> <content styleCode="bold">Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Co-administered Drugs.</content><content styleCode="italics">[see Drug Interactions (7)]</content></paragraph></td></tr><tr><td rowspan="2" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Co-administered Drug</content></paragraph></td><td rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Dose of </content></paragraph><paragraph><content styleCode="bold">Co-administered Drug</content></paragraph></td><td rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Dose of Azithromycin</content></paragraph></td><td rowspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">n</content></paragraph></td><td colspan="2" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Ratio (with/without co-administered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Mean C_max</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Mean AUC</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Efavirenz</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>400 mg/day for 7 days</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>600 mg orally on day 7</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.22</paragraph><paragraph>(1.04 to 1.42)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.92*</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Fluconazole</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>200 mg orally single dose</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1,200 mg orally single dose</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>18</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0.82</paragraph><paragraph>(0.66 to 1.02)</paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1.07</paragraph><paragraph>(0.94 to 1.22)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Nelfinavir</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>750 mg three times a day for 11 days</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1,200 mg orally on day 9</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>14</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2.36</paragraph><paragraph>(1.77 to 3.15)</paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2.12</paragraph><paragraph>(1.80 to 2.50)</paragraph></td></tr></tbody></table>

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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. In fertility studies conducted in male and female rats, oral administration of azithromycin for 64 to 66 days (males) or 15 days (females) prior to and during cohabitation resulted in decreased pregnancy rate at 20 and 30 mg/kg/day when both males and females were treated with azithromycin. This minimal effect on pregnancy rate (approximately 12% reduction compared to concurrent controls) did not become more pronounced when the dose was increased from 20 to 30 mg/kg/day (approximately 0.4 to 0.6 times the adult daily dose of 500 mg based on body surface area) and it was not observed when only one animal in the mated pair was treated. There were no effects on any other reproductive parameters, and there were no effects on fertility at 10 mg/kg/day. The relevance of these findings to patients being treated with azithromycin at the doses and durations recommended in the prescribing information is uncertain. 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 C max 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 C max 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 C max 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 C max . The significance of these findings for animals and for humans is unknown.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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. In fertility studies conducted in male and female rats, oral administration of azithromycin for 64 to 66 days (males) or 15 days (females) prior to and during cohabitation resulted in decreased pregnancy rate at 20 and 30 mg/kg/day when both males and females were treated with azithromycin. This minimal effect on pregnancy rate (approximately 12% reduction compared to concurrent controls) did not become more pronounced when the dose was increased from 20 to 30 mg/kg/day (approximately 0.4 to 0.6 times the adult daily dose of 500 mg based on body surface area) and it was not observed when only one animal in the mated pair was treated. There were no effects on any other reproductive parameters, and there were no effects on fertility at 10 mg/kg/day. The relevance of these findings to patients being treated with azithromycin at the doses and durations recommended in the prescribing information is uncertain.

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 C max 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 C max 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 C max 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 C max . The significance of these findings for animals and for humans is unknown.

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 (3 Days) Clarithromycin (10 Days) 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: Clinical Success Rates of Azithromycin (500 mg per day for 3 Days) Pathogen Day 7 Day 28 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 β-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): Three U.S. Streptococcal Pharyngitis Studies Azithromycin vs.

mycin 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): Three U.S. Streptococcal Pharyngitis Studies Azithromycin vs. Penicillin V EFFICACY RESULTS Day 14 Day 30 Bacteriologic Eradication: Azithromycin 323/340 (95%) 255/330 (77%) Penicillin V 242/332 (73%) 206/325 (63%) Clinical Success (cure plus improvement): Azithromycin 336/343 (98%) 310/330 (94%) Penicillin V 284/338 (84%) 241/325 (74%) Approximately 1% of azithromycin-susceptible S. pyogenes isolates were resistant to azithromycin following therapy. Acute Otitis Media Efficacy using azithromycin given 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 Day 11 Day 30 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: Day 11 Day 30 Pathogen 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).

(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%. Presumed Bacteriologic Eradication Day 10 Days 24-28 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%)

<table width="100%"><col width="32%"/><col width="30%"/><col width="37%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Pathogen</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Azithromycin (3 Days)</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Clarithromycin (10 Days)</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">S. pneumoniae</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>29/32 (91%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>21/27 (78%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">H. influenzae</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12/14 (86%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14/16 (88%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="italics">M. catarrhalis</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>11/12 (92%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>12/15 (80%)</paragraph></td></tr></tbody></table>

raph><content styleCode="italics">M. catarrhalis</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>11/12 (92%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>12/15 (80%)</paragraph></td></tr></tbody></table> <table width="100%"><col width="34%"/><col width="34%"/><col width="32%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Pathogen</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Day 7</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Day 28</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">S. pneumoniae</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>23/26 (88%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>21/25 (84%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">H. influenzae</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>28/32 (87%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>24/32 (75%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="italics">M. catarrhalis</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>14/15 (93%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>13/15 (87%)</paragraph></td></tr></tbody></table>

raph><content styleCode="italics">M. catarrhalis</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>14/15 (93%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>13/15 (87%)</paragraph></td></tr></tbody></table> <table width="100%"><col width="42%"/><col width="29%"/><col width="29%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Day 14</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Day 30</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Bacteriologic Eradication:</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Azithromycin</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>323/340 (95%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>255/330 (77%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Penicillin V</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>242/332 (73%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>206/325 (63%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Clinical Success (cure plus improvement):</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>Azithromycin</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>336/343 (98%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>310/330 (94%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Penicillin V</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>284/338 (84%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>241/325 (74%)</paragraph></td></tr></tbody></table>

e Lrule Toprule " valign="top"><paragraph>Penicillin V</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>284/338 (84%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>241/325 (74%)</paragraph></td></tr></tbody></table> <table width="100%"><col width="33%"/><col width="33%"/><col width="33%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Pathogen</content></paragraph></td><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Day 11</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Day 30</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Azithromycin</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Azithromycin</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">S. pneumoniae</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>61/74 (82%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>40/56 (71%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">H. influenzae</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>43/54 (80%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>30/47 (64%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">M. catarrhalis</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>28/35 (80%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>19/26 (73%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">S. pyogenes</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>11/11 (100%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7/7 (100%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Overall</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>177/217 (82%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>97/137 (73%)</paragraph></td></tr></tbody></table>

Botrule Lrule Toprule " valign="top"><paragraph>Overall</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>177/217 (82%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>97/137 (73%)</paragraph></td></tr></tbody></table> <table width="100%"><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><col width="20%"/><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"/><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Day 11</content></paragraph></td><td align="center" colspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Day 30</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Pathogen</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Azithromycin</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Control</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Azithromycin</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Control</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">S. pneumoniae</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>25/29 (86%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>26/26 (100%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>22/28 (79%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>18/22 (82%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">H. influenzae</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9/11 (82%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9/9 (100%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>8/10 (80%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6/8 (75%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">M. catarrhalis</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7/7 (100%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5/5 (100%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5/5 (100%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2/3 (66%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">S.

d align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5/5 (100%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2/3 (66%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">S. pyogenes</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2/2 (100%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5/5 (100%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2/2 (100%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4/4 (100%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Overall</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>43/49 (88%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>45/45 (100%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>37/45 (82%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>30/37 (81%)</paragraph></td></tr></tbody></table>

trule Lrule Toprule " valign="top"><paragraph>45/45 (100%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>37/45 (82%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>30/37 (81%)</paragraph></td></tr></tbody></table> <table width="100%"><col width="33%"/><col width="32%"/><col width="35%"/><tbody><tr><td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Presumed Bacteriologic Eradication</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"/><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Day 10</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph><content styleCode="bold">Days 24-28</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">S. pneumoniae</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>70/76 (92%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>67/76 (88%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">H. influenzae</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>30/42 (71%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>28/44 (64%)</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="italics">M. catarrhalis</content></paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10/10 (100%)</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>10/10 (100%)</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Overall</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>110/128 (86%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>105/130 (81%)</paragraph></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING Azithromycin for oral suspension USP after constitution contains a banana-cherry flavored suspension. Azithromycin for oral suspension USP is supplied to provide 100 mg/5 mL or 200 mg/5 mL suspension in bottles as follows: Azithromycin contents per bottle NDC 1200 mg (30 mL bottle) 68788-7549-3 [see Dosage and Administration (2) ] for constitution instructions with each bottle type. Storage: Store dry powder below 30°C (86°F). Store constituted suspension between 5° to 30°C (41° to 86°F) and discard when full dosing is completed.

<table width="100%"><col width="50%"/><col width="50%"/><tbody><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Azithromycin contents per bottle</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">NDC</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1200 mg (30 mL bottle)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>68788-7549-3</paragraph></td></tr></tbody></table>

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). General Patient Counseling Azithromycin for 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. Direct parents or caregivers to contact their physician if vomiting and irritability with feeding occurs in the infant. 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 Manufactured by: Epic Pharma, LLC Laurelton, NY 11413 Rev.01-2022-00 MF0147REV01/22 OE1490

Patient Information Azithromycin (a-ZITH-roe-MYE-sin) for Oral Suspension USP Read this Patient Information leaflet before you start taking azithromycin for oral suspension and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. What is azithromycin for oral suspension? Azithromycin for oral suspension is a macrolide antibiotic prescription medicine used in adults 18 years or older to treat certain infections caused by certain germs called bacteria. These bacterial infections include: • acute worsening of chronic bronchitis • acute sinus infection • community-acquired pneumonia • infected throat or tonsils • skin infections • infections of the urethra or cervix • genital ulcers in men Azithromycin for oral suspension is also used in children to treat: • ear infections • community-acquired pneumonia • infected throat or tonsils Azithromycin should not be taken by people who cannot tolerate oral medications because they are very ill or have certain other risk factors including: • have cystic fibrosis • have hospital acquired infections • have known or suspected bacteria in the blood • need to be in the hospital • are elderly • have any medical problems that can lower the ability of the immune system to fight infections Azithromycin for oral suspension is not for viral infections such as the common cold. It is not known if azithromycin for oral suspension is safe and effective for genital ulcers in women. It is not known if azithromycin for oral suspension is safe and effective for children with ear infections, sinus infections, and community-acquired pneumonia under 6 months of age. It is not known if azithromycin for oral suspension is safe and effective for infected throat or tonsils in children under 2 years of age. Who should not take azithromycin for oral suspension? Do not take azithromycin for oral suspension if you: • have had a severe allergic reaction to certain antibiotics known as macrolides or ketolides including azithromycin and erythromycin. • have a history of cholestatic jaundice or hepatic dysfunction that happened with the use of azithromycin. What should I tell my healthcare provider before taking azithromycin for oral suspension? Before you take azithromycin for oral suspension, tell your healthcare provider if you: • have pneumonia • have cystic fibrosis • have known or suspected bacteremia (bacterial infection in the blood) • have liver or kidney problems • have an irregular heartbeat, especially a problem called “QT prolongation” • have a problem that causes muscle weakness (myasthenia gravis) • have any other medical problems • are pregnant or plan to become pregnant. It is not known if azithromycin for oral suspension will harm your unborn baby. • are breastfeeding or plan to breastfeed. Azithromycin has been reported to pass into breast milk. Talk to your healthcare provider about the best way to feed your baby while you take azithromycin for oral suspension. Contact your healthcare provider immediately if you are giving azithromycin for oral suspension to a young child (less than 6 weeks of age) and he or she vomits or becomes irritable when fed. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements.

provider immediately if you are giving azithromycin for oral suspension to a young child (less than 6 weeks of age) and he or she vomits or becomes irritable when fed. Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, and herbal supplements. Azithromycin for oral suspension and other medicines may affect each other causing side effects. Azithromycin for oral suspension may affect the way other medicines work, and other medicines may affect how azithromycin for oral suspension works. Especially tell your healthcare provider if you take: • nelfinavir • a blood thinner (warfarin) • digoxin • colchicine • phenytoin • an antacid that contains aluminum or magnesium Know the medicines you take. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. How should I take azithromycin for oral suspension? • Take azithromycin for oral suspension exactly as your healthcare provider tells you to take it. • Azithromycin for oral suspension can be taken with or without food. • If you take azithromycin for oral suspension, shake the bottle well just before you take it. • Do not skip any doses of azithromycin for oral suspension 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 for oral suspension. See “What are the possible side effects of azithromycin for oral suspension?” If you skip doses, or do not complete the total course of azithromycin for oral suspension your treatment may not work as well and your infection may be harder to treat. Taking all of your azithromycin for oral suspension doses will help lower the chance that the bacteria will become resistant to azithromycin for oral suspension. • If the bacteria becomes resistant to azithromycin for oral suspension, azithromycin for oral suspension and other antibiotic medicines may not work for you in the future. • If you take too much azithromycin for oral suspension, call your healthcare provider or get medical help right away. What are the possible side effects of azithromycin for oral suspension? Azithromycin for oral suspension can cause serious side effects, including: • Serious allergic reactions. Allergic reactions can happen in people taking azithromycin the active ingredient in azithromycin for oral suspension, even after only 1 dose. Stop taking azithromycin for oral suspension and get emergency medical help right away if you have any of the following symptoms of a severe allergic reaction: • trouble breathing or swallowing • swelling of the lips, tongue, face • throat tightness, hoarseness • rapid heartbeat • faintness • skin rash (hives) • new onset of fever and swollen lymph nodes • Stop taking azithromycin for oral suspension at the first sign of a skin rash and call your healthcare provider. Skin rash may be a sign of a more serious reaction to azithromycin for oral suspension. • Liver damage (hepatotoxicity). Hepatotoxicity can happen in people who take azithromycin for oral suspension. Call your healthcare provider right away if you have unexplained symptoms such as: • nausea or vomiting • unusual tiredness • stomach pain • loss of appetite • fever • change in the color of your bowel movements • weakness • dark colored urine • abdominal pain or tenderness • yellowing of your skin or of the whites of your eyes • itching • Serious heart rhythm changes that can be life-threatening, including heart stopping (cardiac arrest), QT prolongation, torsades de pointes, feeling that your heart is pounding or racing (palpitations), chest discomfort, or irregular heartbeat.

enderness • yellowing of your skin or of the whites of your eyes • itching • Serious heart rhythm changes that can be life-threatening, including heart stopping (cardiac arrest), QT prolongation, torsades de pointes, feeling that your heart is pounding or racing (palpitations), chest discomfort, or irregular heartbeat. o Tell your healthcare provider right away if you or your child feel a fast or irregular heartbeat, get dizzy or faint. Azithromycin for oral suspension may cause a rare heart problem known as prolongation of the QT interval. This condition can cause an abnormal heartbeat and can be very dangerous. The chances of this happening are higher in people: • who are elderly • with a family history of prolonged QT interval • with low blood potassium • who take certain medicines to control heart rhythm (antiarrhythmics) • Worsening of myasthenia gravis (a problem that causes muscle weakness). Certain antibiotics like azithromycin for oral suspension may cause worsening of myasthenia gravis symptoms, including muscle weakness and breathing problems. Call your healthcare provider right away if you have any worsening muscle weakness or breathing problems. • Diarrhea. Tell your healthcare provider right away if you have watery diarrhea, diarrhea that does not go away, or bloody stools. You may experience cramping and a fever. This could happen after you have finished your azithromycin for oral suspension. o The most common side effects of azithromycin for oral suspension include: • nausea • stomach pain • vomiting These are not all the possible side effects of azithromycin for oral suspension. Tell your healthcare provider about any side effect that bothers you or that does not go away. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store azithromycin for oral suspension? • Store azithromycin for oral suspension at 41°F to 86°F (5°C to 30°C). • Keep azithromycin for oral suspension in a tightly closed container. • Safely throw away any medicine that is out of date or no longer needed. Keep azithromycin for oral suspension and all medicines out of the reach of children. General information about the safe and effective use of azithromycin for oral suspension. Medicines are sometimes prescribed for purposes other than those listed in the Patient Information leaflet. Do not use azithromycin for oral suspension for a condition for which it was not prescribed. Do not give azithromycin for oral suspension to other people, even if they have the same symptoms you have. It may harm them. This Patient Information leaflet summarizes the most important information about azithromycin for oral suspension. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about azithromycin for oral suspension that is written for health professionals. For more information, call Epic Pharma, LLC at 1-888-374-2791. What are the ingredients in azithromycin for oral suspension USP? Active ingredient: azithromycin monohydrate, USP Inactive ingredients: colloidal silicon dioxide, FD & C Red No. 40 Aluminum Lake, hydroxypropyl cellulose, sodium phosphate tribasic anhydrous, sucrose, natural and artificial banana flavor, natural and artificial cherry flavor and xanthan gum. This Patient Information has been approved by the U.S. Food and Drug Administration. Manufactured by: Epic Pharma, LLC Laurelton, NY 11413 Rev. 01-2023-00 OE1490 Relabeled By: Preferred Pharmaceuticals Inc.

<table width="100%"><col width="42%"/><col width="58%"/><tbody><tr><td styleCode="Toprule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>nausea or vomiting</item></list></td><td styleCode="Toprule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>unusual tiredness</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>stomach pain</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>loss of appetite</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>fever</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>change in the color of your bowel movements</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>weakness</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>dark colored urine</item></list></td></tr><tr><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>abdominal pain or tenderness</item></list></td><td valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>yellowing of your skin or of the whites of your eyes</item></list></td></tr><tr><td styleCode="Botrule " valign="top"><list listType="unordered"><item><caption>&#x2022;</caption>itching</item></list></td><td styleCode="Botrule " valign="top"/></tr></tbody></table>

<table border="0" cellspacing="0" cellpadding="0"><col width="210.95pt"/><col width="51.85pt"/><tbody><tr><td>Warnings and Precautions, Cardiovascular Death (5.5)</td><td> 11/2021</td></tr></tbody></table>

1 INDICATIONS AND USAGE 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. Azithromycin tablets are a macrolide antibacterial indicated for mild to moderate infections caused by designated, susceptible bacteria: Mycobacterial Infections ( 1.2 ) To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin tablets and other antibacterial drugs, azithromycin tablets should be used only to treat or prevent infections that are proven or strongly suspected to be caused by susceptible bacteria. ( 1.3 ) 1.2 Mycobacterial Infections Prophylaxis of Disseminated Mycobacterium avium complex (MAC) Disease Azithromycin tablets, taken alone or in combination with rifabutin at its approved dose, are indicated for the prevention of disseminated MAC disease in persons with advanced HIV infection [see Dosage and Administration (2) ] . Treatment of Disseminated MAC Disease Azithromycin tablets, taken in combination with ethambutol, are indicated for the treatment of disseminated MAC infections in persons with advanced HIV infection [see Use in Specific Populations (8.4) and Clinical Studies (14.1) ] . 1.3 Usage To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin tablets and other antibacterial drugs, azithromycin tablets should be used only to treat infections that are proven or strongly suspected to be caused by susceptible bacteria. When culture and susceptibility information are available, they should be considered in selecting or modifying antibacterial therapy. In the absence of such data, local epidemiology and susceptibility patterns may contribute to the empiric selection of therapy.

2 DOSAGE AND ADMINISTRATION [see Indications and Usage (1) ] Not for pediatric use. For pediatric patients, please refer to the INDICATIONS AND USAGE and DOSAGE AND ADMINISTRATION sections of the prescribing information for azithromycin for oral suspension 100 mg/5 mL and 200 mg/5 mL bottles. Azithromycin tablets may be taken without regard to food. However, increased tolerability has been observed when tablets are taken with food. Mycobacterial Infections ( 2.2 ) 2.2 Mycobacterial Infections Prevention of Disseminated MAC Infections The recommended dose of azithromycin tablets for the prevention of disseminated Mycobacterium avium complex (MAC) disease is: 1200 mg taken once weekly. This dose of azithromycin tablets may be combined with the approved dosage regimen of rifabutin. Treatment of Disseminated MAC Infections Azithromycin tablets should be taken at a daily dose of 600 mg, in combination with ethambutol at the recommended daily dose of 15 mg/kg. Other antimycobacterial drugs that have shown in vitro activity against MAC may be added to the regimen of azithromycin plus ethambutol at the discretion of the physician or health care provider.

3 DOSAGE FORMS AND STRENGTHS Azithromycin tablets USP, 600 mg are supplied as white, capsule shaped, unscored, biconvex film-coated tablets, debossed with “789” on one side and “PLIVA” on the other, containing azithromycin monohydrate equivalent to 600 mg of azithromycin, USP. Tablets: 600 mg ( 3 )

4 CONTRAINDICATIONS Patients with known hypersensitivity to azithromycin, erythromycin, any macrolide, or ketolide antibiotic. ( 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 Hepatic Dysfunction Azithromycin tablets are contraindicated in patients with a history of cholestatic jaundice/hepatic dysfunction associated with prior use of azithromycin.

5 WARNINGS AND PRECAUTIONS Serious (including fatal) allergic and skin reactions. Discontinue azithromycin and initiate appropriate therapy if reaction occurs. ( 5.1 ) Hepatotoxicity: Discontinue azithromycin immediately if signs and symptoms of hepatitis occur. ( 5.2 ) Infantile Hypertrophic Pyloric Stenosis (IHPS): Following the use of azithromycin in neonates (treatment up to 42 days of life), IHPS has been reported. Direct parents and caregivers to contact their physician if vomiting or irritability with feeding occurs. ( 5.3 ) Prolongation of 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. ( 5.4 ) Cardiovascular Death: Some observational studies have shown an approximately two-fold increased short-term potential risk of acute cardiovascular death in adults exposed to azithromycin relative to other antibacterial drugs, including amoxicillin. Consider balancing this potential risk with treatment benefits when prescribing azithromycin tablets. (5.5) Clostridioides difficile -Associated Diarrhea: Evaluate patients if diarrhea occurs. ( 5.6 ) Azithromycin may exacerbate muscle weakness in persons with myasthenia gravis. ( 5.7 ) 5.1 Hypersensitivity Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Acute Generalized Exanthematous Pustulosis (AGEP), Stevens-Johnson Syndrome, and toxic epidermal necrolysis, have been reported rarely 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 is discontinued. 5.2 Hepatotoxicity Abnormal liver function, hepatitis, cholestatic jaundice, hepatic necrosis, and hepatic failure have been reported, some of which have resulted in death. Discontinue azithromycin immediately if signs and symptoms of hepatitis occur. 5.3 Infantile Hypertrophic Pyloric Stenosis (IHPS) Following the use of azithromycin in neonates (treatment up to 42 days of life), IHPS has been reported. Direct parents and caregivers to contact their physician if vomiting or irritability with feeding occurs. 5.4 QT Prolongation Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes, have been seen with treatment with macrolides, including azithromycin. Cases of torsades de pointes have been spontaneously reported during postmarketing surveillance in patients receiving azithromycin.

ed 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. 5.5 Cardiovascular Death Some observational studies have shown an approximately two-fold increased short-term potential risk of acute cardiovascular death in adults exposed to azithromycin relative to other antibacterial drugs, including amoxicillin. The five-day cardiovascular mortality observed in these studies ranged from 20 to 400 per million azithromycin treatment courses. This potential risk was noted to be greater during the first five days of azithromycin use and does not appear to be limited to those patients with preexisting cardiovascular diseases. The data in these observational studies are insufficient to establish or exclude a causal relationship between acute cardiovascular death and azithromycin use. Consider balancing this potential risk with treatment benefits when prescribing azithromycin tablets. 5.6 Clostridioides difficile -Associated Diarrhea (CDAD) CDAD 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. 5.7 Exacerbation of Myasthenia Gravis Exacerbations of symptoms of myasthenia gravis and new onset of myasthenic syndrome have been reported in patients receiving azithromycin therapy. 5.9 Development of Drug-Resistant Bacteria Prescribing azithromycin in the absence of a proven or strongly suspected bacterial infection or a prophylactic indication is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: Hypersensitivity [see Warnings and Precautions (5.1) ] Hepatotoxicity [see Warnings and Precautions (5.2) ] Infantile Hypertrophic Pyloric Stenosis (IHPS) [see Warnings and Precautions (5.3) ] QT Prolongation [see Warnings and Precautions (5.4) ] Cardiovascular Death [see Warnings and Precautions (5.5) ] Clostridioides difficile -Associated Diarrhea (CDAD) [see Warnings and Precautions (5.6) ] Exacerbation of Myasthenia Gravis [see Warnings and Precautions (5.7) ] The most common adverse reactions are diarrhea (5%), nausea (3%), abdominal pain (3%), or vomiting, (no percent given). ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE at 1-855-361-3993 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 adverse reactions were mild to moderate in severity and were reversible upon discontinuation of the drug. Approximately 0.7% of the patients from the multiple-dose clinical trials discontinued azithromycin therapy because of treatment-related adverse reactions. Serious adverse reactions included angioedema and cholestatic jaundice. 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)]. Multiple-dose regimen Overall, the most common adverse reactions in adult patients receiving a multiple-dose regimen of azithromycin were related to the gastrointestinal system with diarrhea/loose stools (5%), nausea (3%), and abdominal pain (3%) being the most frequently reported. No other adverse reactions occurred in patients on the multiple-dose regimen of azithromycin with a frequency greater than 1%. Adverse reactions that occurred with a frequency of 1% or less included the following: Cardiovascular: Palpitations and 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, photosensitivity, and angioedema. Chronic therapy with 1200 mg weekly regimen The nature of adverse reactions seen with the 1200 mg weekly dosing regimen for the prevention of Mycobacterium avium infection in severely immunocompromised HIV-infected patients were similar to those seen with short-term dosing regimens [see Clinical Studies (14) ] . Chronic therapy with 600 mg daily regimen combined with ethambutol The nature of adverse reactions seen with the 600 mg daily dosing regimen for the treatment of Mycobacterium avium complex infection in severely immunocompromised HIV-infected patients were similar to those seen with short term dosing regimens. Five percent of patients experienced reversible hearing impairment in the pivotal clinical trial for the treatment of disseminated MAC in patients with AIDS. Hearing impairment has been reported with macrolide antibiotics, especially at higher doses.

patients were similar to those seen with short term dosing regimens. Five percent of patients experienced reversible hearing impairment in the pivotal clinical trial for the treatment of disseminated MAC in patients with AIDS. Hearing impairment has been reported with macrolide antibiotics, especially at higher doses. Other treatment-related adverse reactions occurring in >5% of subjects and seen at any time during a median of 87.5 days of therapy include: abdominal pain (14%), nausea (14%), vomiting (13%), diarrhea (12%), flatulence (5%), headache (5%), and abnormal vision (5%). Discontinuations from treatment due to laboratory abnormalities or adverse reactions considered related to study drug occurred in 8 of 88 (9.1%) of subjects. 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of azithromycin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported with azithromycin during the postmarketing period in adult and/or pediatric patients for which a causal relationship may not be established include: Allergic: Arthralgia, edema, urticaria, and angioedema. Cardiovascular: Arrhythmias, including ventricular tachycardia, and hypotension. There have been reports of QT prolongation, torsades de pointes, and cardiovascular death. Gastrointestinal: Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and tongue discoloration. General: Asthenia, paresthesia, fatigue, malaise, and anaphylaxis. Genitourinary: Interstitial nephritis, 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, and serious skin reactions including erythema multiforme, AGEP, Stevens-Johnson Syndrome, toxic epidermal necrolysis, and DRESS. Special Senses: Hearing disturbances including hearing loss, deafness, and/or tinnitus, and reports of taste/smell perversion and/or loss. 6.3 Laboratory Abnormalities Significant abnormalities (irrespective of drug relationship) occurring during the clinical trials were reported as follows: With an incidence of 1 to 2%, elevated serum creatine phosphokinase, potassium, ALT (SGPT), GGT, and AST (SGOT). With an incidence of less than 1%, leukopenia, neutropenia, decreased platelet count, elevated serum alkaline phosphatase, bilirubin, BUN, creatinine, blood glucose, LDH, and phosphate. When follow-up was provided, changes in laboratory tests appeared to be reversible. In multiple-dose clinical trials involving more than 3000 patients, 3 patients discontinued therapy because of treatment-related liver enzyme abnormalities and 1 because of a renal function abnormality. In a phase 1 drug interaction study performed in normal volunteers, 1 of 6 subjects given the combination of azithromycin and rifabutin, 1 of 7 given rifabutin alone, and 0 of 6 given azithromycin alone developed a clinically significant neutropenia (<500 cells/mm 3 ). Laboratory abnormalities seen in clinical trials for the prevention of disseminated Mycobacterium avium disease in severely immunocompromised HIV-infected patients [see Clinical Studies (14) ] .

given rifabutin alone, and 0 of 6 given azithromycin alone developed a clinically significant neutropenia (<500 cells/mm 3 ). Laboratory abnormalities seen in clinical trials for the prevention of disseminated Mycobacterium avium disease in severely immunocompromised HIV-infected patients [see Clinical Studies (14) ] . Chronic therapy (median duration: 87.5 days, range: 1 to 229 days) that resulted in laboratory abnormalities in >5% of subjects with normal baseline values in the pivotal trial for treatment of disseminated MAC in severely immunocompromised HIV - infected patients treated with azithromycin 600 mg daily in combination with ethambutol include: a reduction in absolute neutrophils to <50% of the lower limit of normal (10/52, 19%) and an increase to five times the upper limit of normal in alkaline phosphatase (3/35, 9%). These findings in subjects with normal baseline values are similar when compared to all subjects for analyses of neutrophil reductions (22/75, 29%) and elevated alkaline phosphatase (16/80, 20%). Causality of these laboratory abnormalities due to the use of study drug has not been established.

7 DRUG INTERACTIONS Nelfinavir: Close monitoring for known side effects of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. ( 7.1 ) Warfarin: Use with azithromycin may increase coagulation times; monitor prothrombin time. ( 7.2 ) 7.1 Nelfinavir 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 adverse reactions of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted [see Adverse Reactions (6) ] . 7.2 Warfarin Spontaneous postmarketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants such as warfarin, although the prothrombin time was not affected in the dedicated drug interaction study with azithromycin and warfarin. Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly. 7.3 Potential Drug-Drug Interaction with Macrolides Interactions with digoxin, colchicine or phenytoin have not been reported in clinical trials with azithromycin. No specific drug interaction studies have been performed to evaluate potential drug-drug interaction. However, drug interactions have been observed with other macrolide products. Until further data are developed regarding drug interactions when digoxin, colchicine or phenytoin are used with azithromycin careful monitoring of patients is advised.

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 3, 2, and 1 times, respectively, an adult human daily dose of 600 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 3 times an adult human daily dose of 600 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 3 (rats) and 2 (mice) times an adult human daily dose of 600 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 approximately equal to an adult human daily dose of 600 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 Clinical Considerations) . There are no available data on the effects of azithromycin on milk production.

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 Clinical Considerations) . 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. Breastmilk samples collected on days 3 and 6 postpartum as well as 2 and 4 weeks postpartum revealed the presence of azithromycin in breastmilk up to 4 weeks after dosing. In another study, a single dose of azithromycin 500 mg was administered intravenously to 8 women prior to incision for cesarean section. Breastmilk (colostrum) samples obtained between 12 and 48 hours after dosing revealed that azithromycin persisted in breastmilk up to 48 hours. 8.4 Pediatric Use In controlled clinical studies, azithromycin has been administered to pediatric patients ranging in age from 6 months to 12 years. For information regarding the use of azithromycin for oral suspension in the treatment of pediatric patients, [see Indications and Usage (1) and Dosage and Administration (2) ] of the prescribing information for azithromycin for oral suspension, 100 mg/5 mL and 200 mg/5 mL bottles. HIV-Infected Pediatric Patients: The safety and efficacy of azithromycin for the prevention or treatment of MAC in HIV-infected children have not been established. Safety data are available for 72 children 5 months to 18 years of age (mean 7 years) who received azithromycin for treatment of opportunistic infections. The mean duration of therapy was 242 days (range 3 to 2004 days) at doses of <1 to 52 mg/kg/day (mean 12 mg/kg/day). Adverse reactions were similar to those observed in the adult population, most of which involved the gastrointestinal tract. Treatment - related reversible hearing impairment in children was observed in 4 subjects (5.6%). Two (2.8%) children prematurely discontinued treatment due to adverse reactions: one due to back pain and one due to abdominal pain, hot and cold flushes, dizziness, headache, and numbness. A third child discontinued due to a laboratory abnormality (eosinophilia). The protocols upon which these data are based specified a daily dose of 10 to 20 mg/kg/day (oral and/or IV) of azithromycin. 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 responses 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 (5.4) ] . Azithromycin 600 mg tablets contain 1.08 mg of sodium per tablet. Geriatric Patients with Opportunistic Infections, Including (MAC) Disease : Safety data are available for 30 patients (65 to 94 years old) treated with azithromycin at doses >300 mg/day for a mean of 207 days. These patients were treated for a variety of opportunistic infections, including MAC.

mg of sodium per tablet. Geriatric Patients with Opportunistic Infections, Including (MAC) Disease : Safety data are available for 30 patients (65 to 94 years old) treated with azithromycin at doses >300 mg/day for a mean of 207 days. These patients were treated for a variety of opportunistic infections, including MAC. The adverse reaction were generally similar to that seen in younger patients, except for a higher incidence of adverse reactions relating to the gastrointestinal system and to reversible impairment of hearing [see Dosage and Administration (2) ] .

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 3, 2, and 1 times, respectively, an adult human daily dose of 600 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 3 times an adult human daily dose of 600 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 3 (rats) and 2 (mice) times an adult human daily dose of 600 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 approximately equal to an adult human daily dose of 600 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.

8.4 Pediatric Use In controlled clinical studies, azithromycin has been administered to pediatric patients ranging in age from 6 months to 12 years. For information regarding the use of azithromycin for oral suspension in the treatment of pediatric patients, [see Indications and Usage (1) and Dosage and Administration (2) ] of the prescribing information for azithromycin for oral suspension, 100 mg/5 mL and 200 mg/5 mL bottles. HIV-Infected Pediatric Patients: The safety and efficacy of azithromycin for the prevention or treatment of MAC in HIV-infected children have not been established. Safety data are available for 72 children 5 months to 18 years of age (mean 7 years) who received azithromycin for treatment of opportunistic infections. The mean duration of therapy was 242 days (range 3 to 2004 days) at doses of <1 to 52 mg/kg/day (mean 12 mg/kg/day). Adverse reactions were similar to those observed in the adult population, most of which involved the gastrointestinal tract. Treatment - related reversible hearing impairment in children was observed in 4 subjects (5.6%). Two (2.8%) children prematurely discontinued treatment due to adverse reactions: one due to back pain and one due to abdominal pain, hot and cold flushes, dizziness, headache, and numbness. A third child discontinued due to a laboratory abnormality (eosinophilia). The protocols upon which these data are based specified a daily dose of 10 to 20 mg/kg/day (oral and/or IV) of azithromycin.

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 responses 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 (5.4) ] . Azithromycin 600 mg tablets contain 1.08 mg of sodium per tablet. Geriatric Patients with Opportunistic Infections, Including (MAC) Disease : Safety data are available for 30 patients (65 to 94 years old) treated with azithromycin at doses >300 mg/day for a mean of 207 days. These patients were treated for a variety of opportunistic infections, including MAC. The adverse reaction were generally similar to that seen in younger patients, except for a higher incidence of adverse reactions relating to the gastrointestinal system and to reversible impairment of hearing [see Dosage and Administration (2) ] .

10 OVERDOSAGE Adverse reactions experienced in higher than recommended doses were similar to those seen at normal doses. In the event of overdosage, general symptomatic and supportive measures are indicated as required.

11 DESCRIPTION Azithromycin tablets USP, contain the active ingredient azithromycin, USP, a macrolide antibacterial drug, for oral administration. Azithromycin, USP has the chemical name (2 R ,3 S ,4 R ,5 R ,8 R ,10 R ,11 R ,12 S ,13 S ,14 R )-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, USP 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 749.0. Azithromycin, USP has the following structural formula: C 38 H 72 N 2 O 12 •H 2 O M.W. 767.0 Azithromycin USP, as the monohydrate, is a white crystalline powder. Each tablet for oral administration contains azithromycin monohydrate equivalent to 600 mg azithromycin, USP. In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, dibasic calcium phosphate anhydrous, hypromellose, lactose monohydrate, polyethylene glycol, magnesium stearate, microcrystalline cellulose, partially pregelantinized corn starch, sodium citrate, sodium lauryl sulfate and titanium dioxide. structural formula

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Azithromycin is a macrolide antibacterial drug [see Microbiology (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 (1000 mg) alone or in combination with oral azithromycin (500 mg, 1000 mg, and 1500 mg once daily). Coadministration 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 coadministration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively. 12.3 Pharmacokinetics The pharmacokinetic parameters of azithromycin in plasma after dosing as per labeled recommendations in healthy young adults and asymptomatic HIV-positive adults (age 18 to 40 years old) are portrayed in the following chart: MEAN (CV%) PK PARAMETER DOSE/DOSAGE FORM (serum, except as indicated) Subjects Day No. C max (mcg/mL) T max (hr) C 24 (mcg/mL) AUC (mcg●hr/mL) T ½ (hr) Urinary Excretion (% of dose) 500 mg/250 mg capsule 12 1 0.41 2.5 0.05 2.6 a – 4.5 and 250 mg on Days 2 to 5 12 5 0.24 3.2 0.05 2.1 a – 6.5 1200 mg/600 mg tablets 12 1 0.66 2.5 0.074 6.8 b 40 – %CV (62%) (79%) (49%) (64%) (33%) 600 mg tablet/day 7 1 0.33 2.0 0.039 2.4 a %CV 25% (50%) (36%) (19%) 7 22 0.55 2.1 0.14 5.8 a 84.5 - %CV (18%) (52%) (26%) (25%) - 600 mg tablet/day (leukocytes) 7 22 252 10.9 146 4763 a 82.8 - %CV (49%) (28%) (33%) (42%) - - a AUC 0–24 ; b 0 to last. With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2 to 5, C min and C max remained essentially unchanged from Day 2 through Day 5 of therapy. However, without a loading dose, azithromycin C min levels required 5 to 7 days to reach steady state. In asymptomatic HIV-positive adult subjects receiving 600 mg azithromycin tablets once daily for 22 days, steady state azithromycin serum levels were achieved by Day 15 of dosing. The high values in adults for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 mL/min) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues. Absorption The 1 gram single - dose packet is bioequivalent to four 250 mg azithromycin capsule. When the oral suspension of azithromycin was administered with food, the C max increased by 46% and the AUC by 14%. The absolute bioavailability of two 600 mg tablets was 34% (CV=56%). Administration of two 600 mg tablets with food increased C max by 31% (CV=43%) while the extent of absorption (AUC) was unchanged (mean ratio of AUCs=1.00; CV=55%). 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.

nged (mean ratio of AUCs=1.00; CV=55%). 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 tissues in humans, 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 importance of these tissue concentration data is unknown. Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. Using such methodology, the ratio of intracellular to extracellular concentration was >30 after one hr of incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. Following oral administration of a single 1200 mg dose (two 600 mg tablets), the mean maximum concentration in peripheral leukocytes was 140 mcg/mL. Concentration remained above 32 mcg/mL, for approximately 60 hr. The mean half-lives for 6 males and 6 females were 34 hr and 57 hr, respectively. Leukocyte-to-plasma C max ratios for males and females were 258 (±77%) and 175 (±60%), respectively, and the AUC ratios were 804 (±31%) and 541 (±28%) respectively. The clinical relevance of these findings is unknown. Following oral administration of multiple daily doses of 600 mg (1 tablet/day) to asymptomatic HIV-positive adults, mean maximum concentration in peripheral leukocytes was 252 mcg/mL (±49%). Trough concentrations in peripheral leukocytes at steady-state averaged 146 mcg/mL (±33%). The mean leukocyte-to-serum C max ratio was 456 (±38%) and the mean leukocyte to serum AUC ratio was 816 (±31%). The clinical relevance of these findings is unknown. 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 an average terminal half-life of 68 hr. 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. Specific Populations Patients with Renal Impairment 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 × 250 mg capsules), the mean C max and AUC 0–120 increased by 5.1% and 4.2%, respectively, in subjects with GFR 10 to 80 mL/min compared to subjects with normal renal function (GFR >80 mL/min). The mean C max and AUC 0–120 increased 61% and 35%, respectively, in subjects with end-stage renal disease (GFR <10 mL/min) compared to subjects with normal renal function (GFR >80 mL/min) . Patients with Hepatic Impairment The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established. Male and Female Patients There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended on the basis of gender.

tients with Hepatic Impairment The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established. Male and Female Patients There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended on the basis of gender. Geriatric Patients Pharmacokinetic parameters in older volunteers (65 to 85 years old) were similar to those in younger volunteers (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 For information regarding the pharmacokinetics of azithromycin for oral suspension in pediatric patients, see the prescribing information for azithromycin for oral suspension 100 mg/5 mL and 200 mg/5 mL bottles. Drug Interaction Studies Drug interaction studies were performed with azithromycin and other drugs likely to be coadministered. The effects of coadministration 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. Coadministration 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 coadministered with azithromycin. Coadministration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the C max 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.

on of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the C max 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. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Azithromycin Coadministered Drug Dose of Coadministered Drug Dose of Azithromycin n Ratio (with/without azithromycin) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Mean C max Mean AUC Atorvastatin 10 mg/day for 8 days 500 mg/day orally on days 6 to 8 12 0.83 (0.63 to 1.08) 1.01 (0.81 to 1.25) Carbamazepine 200 mg/day for 2 days, then 200 mg twice a day for 18 days 500 mg/day orally for days 16 to 18 7 0.97 (0.88 to 1.06) 0.96 (0.88 to 1.06) Cetirizine 20 mg/day for 11 days 500 mg orally on day 7, then 250 mg/day on days 8 to 11 14 1.03 (0.93 to 1.14) 1.02 (0.92 to 1.13) Didanosine 200 mg orally twice a day for 21 days 1,200 mg/day orally on days 8 to 21 6 1.44 (0.85 to 2.43) 1.14 (0.83 to 1.57) Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.04 * 0.95 * Fluconazole 200 mg orally single dose 1,200 mg orally single dose 18 1.04 (0.98 to 1.11) 1.01 (0.97 to 1.05) Indinavir 800 mg three times a day for 5 days 1,200 mg orally on day 5 18 0.96 (0.86 to 1.08) 0.90 (0.81 to 1.00) Midazolam 15 mg orally on day 3 500 mg/day orally for 3 days 12 1.27 (0.89 to 1.81) 1.26 (1.01 to 1.56) Nelfinavir 750 mg three times a day for 11 days 1,200 mg orally on day 9 14 0.90 (0.81 to 1.01) 0.85 (0.78 to 0.93) Sildenafil 100 mg on days 1 and 4 500 mg/day orally for 3 days 12 1.16 (0.86 to 1.57) 0.92 (0.75 to 1.12) Theophylline 4 mg/kg IV on days 1, 11, 25 500 mg orally on day 7, 250 mg/day on days 8 to 11 10 1.19 (1.02 to 1.40) 1.02 (0.86 to 1.22) Theophylline 300 mg orally BID ×15 days 500 mg orally on day 6, then 250 mg/day on days 7 to 10 8 1.09 (0.92 to 1.29) 1.08 (0.89 to 1.31) Triazolam 0.125 mg on day 2 500 mg orally on day 1, then 250 mg/day on day 2 12 1.06 * 1.02 * Trimethoprim/ Sulfamethoxazole 160 mg/800 mg/day orally for 7 days 1,200 mg orally on day 7 12 0.85 (0.75 to 0.97)/ 0.90 (0.78 to 1.03) 0.87 (0.80 to 0.95/ 0.96 (0.88 to 1.03) Zidovudine 500 mg/day orally for 21 days 600 mg/day orally for 14 days 5 1.12 (0.42 to 3.02) 0.94 (0.52 to 1.70) Zidovudine 500 mg/day orally for 21 days 1,200 mg/day orally for 14 days 4 1.31 (0.43 to 3.97) 1.30 (0.69 to 2.43) * - 90% Confidence interval not reported Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Coadministered Drugs[see Drug Interactions (7.3) ] Coadministered Drug Dose of Coadministered Drug Dose of Azithromycin n Ratio (with/without coadministered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Mean C max Mean AUC Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.22 (1.04 to 1.42) 0.92 * Fluconazole 200 mg orally single dose 1,200 mg orally single dose 18 0.82 (0.66 to 1.02) 1.07 (0.94 to 1.22) Nelfinavir 750 mg three times a day for 11 days 1,200 mg orally on day 9 14 2.36 (1.77 to 3.15) 2.12 (1.80 to 2.50) * - 90% Confidence interval not reported 12.4 Microbiology 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 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).

he assembly of the 50S ribosomal subunit. Resistance 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). The mechanism of acquired mutational resistance in isolates of Mycobacterium avium complex (i.e., 23S rRNA genemutation) is the same for both clarithromycin and azithromycin. Antimicrobial Activity Azithromycin has been shown to be active against the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1) ]. Mycobacteria Mycobacterium avium complex (MAC) consisting of: Mycobacterium avium Mycobacterium intracellulare Other Microorganisms Chlamydia trachomatis Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

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 (1000 mg) alone or in combination with oral azithromycin (500 mg, 1000 mg, and 1500 mg once daily). Coadministration 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 coadministration of 500 mg, 1000 mg and 1500 mg azithromycin, respectively.

12.3 Pharmacokinetics The pharmacokinetic parameters of azithromycin in plasma after dosing as per labeled recommendations in healthy young adults and asymptomatic HIV-positive adults (age 18 to 40 years old) are portrayed in the following chart: MEAN (CV%) PK PARAMETER DOSE/DOSAGE FORM (serum, except as indicated) Subjects Day No. C max (mcg/mL) T max (hr) C 24 (mcg/mL) AUC (mcg●hr/mL) T ½ (hr) Urinary Excretion (% of dose) 500 mg/250 mg capsule 12 1 0.41 2.5 0.05 2.6 a – 4.5 and 250 mg on Days 2 to 5 12 5 0.24 3.2 0.05 2.1 a – 6.5 1200 mg/600 mg tablets 12 1 0.66 2.5 0.074 6.8 b 40 – %CV (62%) (79%) (49%) (64%) (33%) 600 mg tablet/day 7 1 0.33 2.0 0.039 2.4 a %CV 25% (50%) (36%) (19%) 7 22 0.55 2.1 0.14 5.8 a 84.5 - %CV (18%) (52%) (26%) (25%) - 600 mg tablet/day (leukocytes) 7 22 252 10.9 146 4763 a 82.8 - %CV (49%) (28%) (33%) (42%) - - a AUC 0–24 ; b 0 to last. With a regimen of 500 mg on Day 1 and 250 mg/day on Days 2 to 5, C min and C max remained essentially unchanged from Day 2 through Day 5 of therapy. However, without a loading dose, azithromycin C min levels required 5 to 7 days to reach steady state. In asymptomatic HIV-positive adult subjects receiving 600 mg azithromycin tablets once daily for 22 days, steady state azithromycin serum levels were achieved by Day 15 of dosing. The high values in adults for apparent steady-state volume of distribution (31.1 L/kg) and plasma clearance (630 mL/min) suggest that the prolonged half-life is due to extensive uptake and subsequent release of drug from tissues. Absorption The 1 gram single - dose packet is bioequivalent to four 250 mg azithromycin capsule. When the oral suspension of azithromycin was administered with food, the C max increased by 46% and the AUC by 14%. The absolute bioavailability of two 600 mg tablets was 34% (CV=56%). Administration of two 600 mg tablets with food increased C max by 31% (CV=43%) while the extent of absorption (AUC) was unchanged (mean ratio of AUCs=1.00; CV=55%). 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 tissues in humans, 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 importance of these tissue concentration data is unknown. Azithromycin concentrates in phagocytes and fibroblasts as demonstrated by in vitro incubation techniques. Using such methodology, the ratio of intracellular to extracellular concentration was >30 after one hr of incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues. Following oral administration of a single 1200 mg dose (two 600 mg tablets), the mean maximum concentration in peripheral leukocytes was 140 mcg/mL. Concentration remained above 32 mcg/mL, for approximately 60 hr. The mean half-lives for 6 males and 6 females were 34 hr and 57 hr, respectively.

ion to inflamed tissues. Following oral administration of a single 1200 mg dose (two 600 mg tablets), the mean maximum concentration in peripheral leukocytes was 140 mcg/mL. Concentration remained above 32 mcg/mL, for approximately 60 hr. The mean half-lives for 6 males and 6 females were 34 hr and 57 hr, respectively. Leukocyte-to-plasma C max ratios for males and females were 258 (±77%) and 175 (±60%), respectively, and the AUC ratios were 804 (±31%) and 541 (±28%) respectively. The clinical relevance of these findings is unknown. Following oral administration of multiple daily doses of 600 mg (1 tablet/day) to asymptomatic HIV-positive adults, mean maximum concentration in peripheral leukocytes was 252 mcg/mL (±49%). Trough concentrations in peripheral leukocytes at steady-state averaged 146 mcg/mL (±33%). The mean leukocyte-to-serum C max ratio was 456 (±38%) and the mean leukocyte to serum AUC ratio was 816 (±31%). The clinical relevance of these findings is unknown. 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 an average terminal half-life of 68 hr. 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. Specific Populations Patients with Renal Impairment 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 × 250 mg capsules), the mean C max and AUC 0–120 increased by 5.1% and 4.2%, respectively, in subjects with GFR 10 to 80 mL/min compared to subjects with normal renal function (GFR >80 mL/min). The mean C max and AUC 0–120 increased 61% and 35%, respectively, in subjects with end-stage renal disease (GFR <10 mL/min) compared to subjects with normal renal function (GFR >80 mL/min) . Patients with Hepatic Impairment The pharmacokinetics of azithromycin in subjects with hepatic impairment has not been established. Male and Female Patients There are no significant differences in the disposition of azithromycin between male and female subjects. No dosage adjustment is recommended on the basis of gender. Geriatric Patients Pharmacokinetic parameters in older volunteers (65 to 85 years old) were similar to those in younger volunteers (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 For information regarding the pharmacokinetics of azithromycin for oral suspension in pediatric patients, see the prescribing information for azithromycin for oral suspension 100 mg/5 mL and 200 mg/5 mL bottles. Drug Interaction Studies Drug interaction studies were performed with azithromycin and other drugs likely to be coadministered. The effects of coadministration 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. Coadministration 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 coadministered with azithromycin. Coadministration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the C max and AUC of azithromycin.

drugs listed in Table 1. No dosage adjustment of drugs listed in Table 1 is recommended when coadministered with azithromycin. Coadministration of azithromycin with efavirenz or fluconazole had a modest effect on the pharmacokinetics of azithromycin. Nelfinavir significantly increased the C max 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. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Azithromycin Coadministered Drug Dose of Coadministered Drug Dose of Azithromycin n Ratio (with/without azithromycin) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Mean C max Mean AUC Atorvastatin 10 mg/day for 8 days 500 mg/day orally on days 6 to 8 12 0.83 (0.63 to 1.08) 1.01 (0.81 to 1.25) Carbamazepine 200 mg/day for 2 days, then 200 mg twice a day for 18 days 500 mg/day orally for days 16 to 18 7 0.97 (0.88 to 1.06) 0.96 (0.88 to 1.06) Cetirizine 20 mg/day for 11 days 500 mg orally on day 7, then 250 mg/day on days 8 to 11 14 1.03 (0.93 to 1.14) 1.02 (0.92 to 1.13) Didanosine 200 mg orally twice a day for 21 days 1,200 mg/day orally on days 8 to 21 6 1.44 (0.85 to 2.43) 1.14 (0.83 to 1.57) Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.04 * 0.95 * Fluconazole 200 mg orally single dose 1,200 mg orally single dose 18 1.04 (0.98 to 1.11) 1.01 (0.97 to 1.05) Indinavir 800 mg three times a day for 5 days 1,200 mg orally on day 5 18 0.96 (0.86 to 1.08) 0.90 (0.81 to 1.00) Midazolam 15 mg orally on day 3 500 mg/day orally for 3 days 12 1.27 (0.89 to 1.81) 1.26 (1.01 to 1.56) Nelfinavir 750 mg three times a day for 11 days 1,200 mg orally on day 9 14 0.90 (0.81 to 1.01) 0.85 (0.78 to 0.93) Sildenafil 100 mg on days 1 and 4 500 mg/day orally for 3 days 12 1.16 (0.86 to 1.57) 0.92 (0.75 to 1.12) Theophylline 4 mg/kg IV on days 1, 11, 25 500 mg orally on day 7, 250 mg/day on days 8 to 11 10 1.19 (1.02 to 1.40) 1.02 (0.86 to 1.22) Theophylline 300 mg orally BID ×15 days 500 mg orally on day 6, then 250 mg/day on days 7 to 10 8 1.09 (0.92 to 1.29) 1.08 (0.89 to 1.31) Triazolam 0.125 mg on day 2 500 mg orally on day 1, then 250 mg/day on day 2 12 1.06 * 1.02 * Trimethoprim/ Sulfamethoxazole 160 mg/800 mg/day orally for 7 days 1,200 mg orally on day 7 12 0.85 (0.75 to 0.97)/ 0.90 (0.78 to 1.03) 0.87 (0.80 to 0.95/ 0.96 (0.88 to 1.03) Zidovudine 500 mg/day orally for 21 days 600 mg/day orally for 14 days 5 1.12 (0.42 to 3.02) 0.94 (0.52 to 1.70) Zidovudine 500 mg/day orally for 21 days 1,200 mg/day orally for 14 days 4 1.31 (0.43 to 3.97) 1.30 (0.69 to 2.43) * - 90% Confidence interval not reported Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Coadministered Drugs[see Drug Interactions (7.3) ] Coadministered Drug Dose of Coadministered Drug Dose of Azithromycin n Ratio (with/without coadministered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00 Mean C max Mean AUC Efavirenz 400 mg/day for 7 days 600 mg orally on day 7 14 1.22 (1.04 to 1.42) 0.92 * Fluconazole 200 mg orally single dose 1,200 mg orally single dose 18 0.82 (0.66 to 1.02) 1.07 (0.94 to 1.22) Nelfinavir 750 mg three times a day for 11 days 1,200 mg orally on day 9 14 2.36 (1.77 to 3.15) 2.12 (1.80 to 2.50) * - 90% Confidence interval not reported

<table><caption>MEAN (CV%) PK PARAMETER</caption><col/><col/><col/><col/><col/><col/><col/><col/><col/><thead><tr><th styleCode=" Botrule Toprule Lrule Rrule" valign="top"><content styleCode="bold">DOSE/DOSAGE FORM</content> <content styleCode="bold">(serum, except as indicated)</content></th><th align="center" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Subjects</content></th><th align="center" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Day No.</content></th><th align="center" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">C _max</content> <content styleCode="bold">(mcg/mL)</content></th><th align="center" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">T _max</content> <content styleCode="bold">(hr)</content></th><th align="center" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">C ₂₄</content> <content styleCode="bold">(mcg/mL)</content></th><th align="center" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">AUC</content> <content styleCode="bold">(mcg&#x25CF;hr/mL)</content></th><th align="center" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">T _&#xBD;</content> <content styleCode="bold">(hr)</content></th><th align="center" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Urinary Excretion</content> <content styleCode="bold">(% of dose)</content></th></tr></thead><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top"><paragraph>500 mg/250 mg capsule</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>12</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>1</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>0.41</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>2.5</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>0.05</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>2.6 ^a</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>&#x2013;</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>4.5</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>and 250 mg on Days 2 to 5</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>12</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>5</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.24</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.05</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.1 ^a</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>&#x2013;</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>6.5</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>1200 mg/600 mg tablets</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>12</pa

gn="top"><paragraph>&#x2013;</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>6.5</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>1200 mg/600 mg tablets</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>12</pa ragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.66</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.5</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.074</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>6.8 ^b</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>40</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>&#x2013;</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>%CV</paragraph></td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>(62%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>(79%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>(49%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>(64%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>(33%)</paragraph></td><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>600 mg tablet/day</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>7</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.33</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.039</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.4 ^a</paragraph></td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>%CV</paragraph></td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>25%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>(50%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>(36%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>(19%)</paragraph></td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"/><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>7</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>22</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.55</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.14</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>5.8 ^a</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>84.5</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph

rule Rrule" valign="top"><paragraph>0.14</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>5.8 ^a</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>84.5</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph >-</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>%CV</paragraph></td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>(18%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>(52%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>(26%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>(25%)</paragraph></td><td styleCode=" Botrule Rrule" valign="top"/><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>-</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>600 mg tablet/day (leukocytes)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>7</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>22</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>252</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>10.9</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>146</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>4763 ^a</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>82.8</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>-</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>%CV</paragraph></td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>(49%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>(28%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>(33%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>(42%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>-</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>-</paragraph></td></tr><tr><td colspan="9" valign="top"> ^aAUC _0&#x2013;24; ^b0 to last.

ign="top"><paragraph>(42%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>-</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>-</paragraph></td></tr><tr><td colspan="9" valign="top"> ^aAUC _0&#x2013;24; ^b0 to last. </td></tr></tbody></table> <table width="759px"><caption>Table 1.

ign="top"><paragraph>(42%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>-</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>-</paragraph></td></tr><tr><td colspan="9" valign="top"> ^aAUC _0&#x2013;24; ^b0 to last. </td></tr></tbody></table> <table width="759px"><caption>Table 1. Drug Interactions: Pharmacokinetic Parameters for Coadministered Drugs in the Presence of Azithromycin</caption><col/><col/><col/><col/><col/><col/><thead><tr><th align="center" rowspan="2" styleCode=" Botrule Toprule Lrule Rrule" valign="top"><content styleCode="bold">Coadministered Drug</content></th><th align="center" rowspan="2" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Dose of Coadministered Drug</content></th><th align="center" rowspan="2" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Dose of Azithromycin</content></th><th align="center" rowspan="2" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">n</content></th><th align="center" colspan="2" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Ratio (with/without azithromycin) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00</content></th></tr><tr><th align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">Mean C _max</content></th><th align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">Mean AUC</content></th></tr></thead><tbody><tr><td align="center" styleCode=" Botrule Toprule Lrule Rrule" valign="top"><paragraph>Atorvastatin</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>10 mg/day for 8 days</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>500 mg/day orally on days 6 to 8</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>12</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>0.83 (0.63 to 1.08) </paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>1.01 (0.81 to 1.25) </paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Carbamazepine</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>200 mg/day for 2 days, then 200 mg twice a day for 18 days</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>500 mg/day orally for days 16 to 18</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>7</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.97 (0.88 to 1.06) </paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.96 (0.88 to 1.06) </paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Cetirizine</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>20 mg/day for 11 days</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>500 mg orally on day 7, then 250 mg/day on days 8 to 11</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>14</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.03 (0.93 to 1.14) </paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.02 (0.92 to 1.13) </paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Didanosine</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>200 mg orally twice a day for 21 days</paragraph></td><td align="center" styleCode=

="top"><paragraph>1.02 (0.92 to 1.13) </paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Didanosine</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>200 mg orally twice a day for 21 days</paragraph></td><td align="center" styleCode= " Botrule Rrule" valign="top"><paragraph>1,200 mg/day orally on days 8 to 21</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>6</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.44 (0.85 to 2.43) </paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.14 (0.83 to 1.57) </paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Efavirenz</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>400 mg/day for 7 days</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>600 mg orally on day 7</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>14</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.04 ^*</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.95 ^*</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Fluconazole</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>200 mg orally single dose</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1,200 mg orally single dose</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>18</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.04 (0.98 to 1.11) </paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.01 (0.97 to 1.05) </paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Indinavir</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>800 mg three times a day for 5 days</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1,200 mg orally on day 5</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>18</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.96 (0.86 to 1.08) </paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.90 (0.81 to 1.00) </paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Midazolam</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>15 mg orally on day 3</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>500 mg/day orally for 3 days</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>12</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.27 (0.89 to 1.81) </paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.26 (1.01 to 1.56) </paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Nelfinavir</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>750 mg three times a day for 11 days</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1,200 mg orally on day 9</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>14</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.90 (0.81 to 1.01) </paragraph></td><td align="c

><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1,200 mg orally on day 9</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>14</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.90 (0.81 to 1.01) </paragraph></td><td align="c enter" styleCode=" Botrule Rrule" valign="top"><paragraph>0.85 (0.78 to 0.93) </paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Sildenafil</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>100 mg on days 1 and 4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>500 mg/day orally for 3 days</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>12</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.16 (0.86 to 1.57) </paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.92 (0.75 to 1.12) </paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Theophylline</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>4 mg/kg IV on days 1, 11, 25</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>500 mg orally on day 7, 250 mg/day on days 8 to 11</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>10</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.19 (1.02 to 1.40) </paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.02 (0.86 to 1.22) </paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Theophylline</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>300 mg orally BID &#xD7;15 days</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>500 mg orally on day 6, then 250 mg/day on days 7 to 10</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>8</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.09 (0.92 to 1.29) </paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.08 (0.89 to 1.31) </paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Triazolam</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.125 mg on day 2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>500 mg orally on day 1, then 250 mg/day on day 2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>12</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.06 ^*</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.02 ^*</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Trimethoprim/ Sulfamethoxazole </paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>160 mg/800 mg/day orally for 7 days</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1,200 mg orally on day 7</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>12</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.85 (0.75 to 0.97)/ 0.90 (0.78 to 1.03) </paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.87 (0.80 to 0.95/ 0.96 (0.88 to 1.03) </paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" val

><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.85 (0.75 to 0.97)/ 0.90 (0.78 to 1.03) </paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.87 (0.80 to 0.95/ 0.96 (0.88 to 1.03) </paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" val ign="top"><paragraph>Zidovudine</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>500 mg/day orally for 21 days</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>600 mg/day orally for 14 days</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>5</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.12 (0.42 to 3.02) </paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.94 (0.52 to 1.70) </paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Zidovudine</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>500 mg/day orally for 21 days</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1,200 mg/day orally for 14 days</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.31 (0.43 to 3.97) </paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.30 (0.69 to 2.43) </paragraph></td></tr><tr><td colspan="6" valign="top"> ^* - 90% Confidence interval not reported </td></tr></tbody></table>

center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.31 (0.43 to 3.97) </paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.30 (0.69 to 2.43) </paragraph></td></tr><tr><td colspan="6" valign="top"> ^* - 90% Confidence interval not reported </td></tr></tbody></table> <table><caption>Table 2. Drug Interactions: Pharmacokinetic Parameters for Azithromycin in the Presence of Coadministered Drugs[see <linkHtml href="#LINK_03dfa34d-0b08-4f11-ac4d-56c26b064b93">Drug Interactions (7.3)</linkHtml>] </caption><col/><col/><col/><col/><col/><col/><thead><tr><th align="center" rowspan="2" styleCode=" Botrule Toprule Lrule Rrule" valign="top"><content styleCode="bold">Coadministered Drug</content></th><th align="center" rowspan="2" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Dose of Coadministered Drug</content></th><th align="center" rowspan="2" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Dose of Azithromycin</content></th><th align="center" rowspan="2" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">n</content></th><th colspan="2" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Ratio (with/without coadministered drug) of Azithromycin Pharmacokinetic Parameters (90% CI); No Effect = 1.00</content></th></tr><tr><th align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">Mean C _max</content></th><th align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">Mean AUC</content></th></tr></thead><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top"><paragraph>Efavirenz</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>400 mg/day for 7 days</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>600 mg orally on day 7</paragraph></td><td styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>14</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>1.22 (1.04 to 1.42) </paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>0.92 ^*</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Fluconazole</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>200 mg orally single dose</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1,200 mg orally single dose</paragraph></td><td styleCode=" Botrule Rrule" valign="top"><paragraph>18</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.82 (0.66 to 1.02) </paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.07 (0.94 to 1.22) </paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Nelfinavir</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>750 mg three times a day for 11 days</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1,200 mg orally on day 9</paragraph></td><td styleCode=" Botrule Rrule" valign="top"><paragraph>14</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.36 (1.77 to 3.15) </paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.12 (1.80 to 2.50) </paragraph></td></tr><tr><td colspan="6" valign="top"> ^*- 90% Confidence interval not reported </td></tr></tbody></table>

12.4 Microbiology 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 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). The mechanism of acquired mutational resistance in isolates of Mycobacterium avium complex (i.e., 23S rRNA genemutation) is the same for both clarithromycin and azithromycin. Antimicrobial Activity Azithromycin has been shown to be active against the following microorganisms, both in vitro and in clinical infections [see Indications and Usage (1) ]. Mycobacteria Mycobacterium avium complex (MAC) consisting of: Mycobacterium avium Mycobacterium intracellulare Other Microorganisms Chlamydia trachomatis Susceptibility Testing For specific information regarding susceptibility test interpretive criteria and associated test methods and quality control standards recognized by FDA for this drug, please see: https://www.fda.gov/STIC.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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. In fertility studies conducted in male and female rats, oral administration of azithromycin for 64 to 66 days (males) or 15 days (females) prior to and during cohabitation resulted in decreased pregnancy rate at 20 and 30 mg/kg/day when both males and females were treated with azithromycin. This minimal effect on pregnancy rate (approximately 12% reduction compared to concurrent controls) did not become more pronounced when the dose was increased from 20 to 30 mg/kg/day (approximately 0.3 to 0.5 times the adult human daily dose of 600 mg based on body surface area) and it was not observed when only one animal in the mated pair was treated. There were no effects on any other reproductive parameters, and there were no effects on fertility at 10 mg/kg/day. The relevance of these findings to patients being treated with azithromycin at the doses and durations recommended in the prescribing information is uncertain. 13.2 Animal Toxicology 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 C max 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 C max 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 C max 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 C max . The significance of the finding for animals and for humans is unknown.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 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. In fertility studies conducted in male and female rats, oral administration of azithromycin for 64 to 66 days (males) or 15 days (females) prior to and during cohabitation resulted in decreased pregnancy rate at 20 and 30 mg/kg/day when both males and females were treated with azithromycin. This minimal effect on pregnancy rate (approximately 12% reduction compared to concurrent controls) did not become more pronounced when the dose was increased from 20 to 30 mg/kg/day (approximately 0.3 to 0.5 times the adult human daily dose of 600 mg based on body surface area) and it was not observed when only one animal in the mated pair was treated. There were no effects on any other reproductive parameters, and there were no effects on fertility at 10 mg/kg/day. The relevance of these findings to patients being treated with azithromycin at the doses and durations recommended in the prescribing information is uncertain.

13.2 Animal Toxicology 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 C max 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 C max 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 C max 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 C max . The significance of the finding for animals and for humans is unknown.

14 CLINICAL STUDIES 14.1 Clinical Studies in Patients with Advanced HIV Infection for the Prevention and Treatment of Disease Due to Disseminated Mycobacterium avium Complex (MAC) [see Indications and Usage (1) ] Prevention of Disseminated MAC Disease Two randomized, double - blind clinical trials were performed in patients with CD4 counts <100 cells/µL. The first trial (Study 155) compared azithromycin (1200 mg once weekly) to placebo and enrolled 182 patients with a mean CD4 count of 35 cells/mcgL. The second trial (Study 174) randomized 723 patients to either azithromycin (1200 mg once weekly), rifabutin (300 mg daily), or the combination of both. The mean CD4 count was 51 cells/mcgL. The primary endpoint in these trials was disseminated MAC disease. Other endpoints included the incidence of clinically significant MAC disease and discontinuations from therapy for drug-related side effects. MAC bacteremia In Study 155, 85 patients randomized to receive azithromycin and 89 patients randomized to receive placebo met the entrance criteria. Cumulative incidences at 6, 12, and 18 months of the possible outcomes are in the following table: Cumulative Incidence Rate, %: Placebo (n=89) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 69.7 13.5 6.7 10.1 12 47.2 19.1 15.7 18.0 18 37.1 22.5 18.0 22.5 Cumulative Incidence Rate, %: Azithromycin (n=85) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 84.7 3.5 9.4 2.4 12 63.5 8.2 16.5 11.8 18 44.7 11.8 25.9 17.6 The difference in the one - year cumulative incidence rates of disseminated MAC disease (placebo – azithromycin) is 10.9%. This difference is statistically significant (p=0.037) with a 95% confidence interval for this difference of 0.8%, 20.9%. The comparable number of patients experiencing adverse events and the fewer number of patients lost to follow-up on azithromycin should be taken into account when interpreting the significance of this difference. In Study 174, 223 patients randomized to receive rifabutin, 223 patients randomized to receive azithromycin, and 218 patients randomized to receive both rifabutin and azithromycin met the entrance criteria. Cumulative incidences at 6, 12, and 18 months of the possible outcomes are recorded in the following table: Cumulative Incidence Rate, %: Rifabutin (n=223) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 83.4 7.2 8.1 1.3 12 60.1 15.2 16.1 8.5 18 40.8 21.5 24.2 13.5 Cumulative Incidence Rate, %: Azithromycin (n=223) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 85.2 3.6 5.8 5.4 12 65.5 7.6 16.1 10.8 18 45.3 12.1 23.8 18.8 Cumulative Incidence Rate, %: Azithromycin/Rifabutin Combination (n=218) Month MAC Free and Alive MAC Adverse Experience Lost to Follow-up 6 89.4 1.8 5.5 3.2 12 71.6 2.8 15.1 10.6 18 49.1 6.4 29.4 15.1 Comparing the cumulative one - year incidence rates, azithromycin monotherapy is at least as effective as rifabutin monotherapy. The difference (rifabutin – azithromycin) in the one - year rates (7.6%) is statistically significant (p=0.022) with an adjusted 95% confidence interval (0.9%, 14.3%). Additionally, azithromycin/rifabutin combination therapy is more effective than rifabutin alone. The difference (rifabutin – azithromycin/rifabutin) in the cumulative one - year incidence rates (12.5%) is statistically significant (p<0.001) with an adjusted 95% confidence interval of 6.6%, 18.4%.

nterval (0.9%, 14.3%). Additionally, azithromycin/rifabutin combination therapy is more effective than rifabutin alone. The difference (rifabutin – azithromycin/rifabutin) in the cumulative one - year incidence rates (12.5%) is statistically significant (p<0.001) with an adjusted 95% confidence interval of 6.6%, 18.4%. The comparable number of patients experiencing adverse events and the fewer number of patients lost to follow-up on rifabutin should be taken into account when interpreting the significance of this difference. In Study 174, sensitivity testing 1 was performed on all available MAC isolates from subjects randomized to either azithromycin, rifabutin, or the combination. The distribution of MIC values for azithromycin from susceptibility testing of the breakthrough isolates was similar between trial arms. As the efficacy of azithromycin in the treatment of disseminated MAC has not been established, the clinical relevance of these in vitro MICs as an indicator of susceptibility or resistance is not known. Clinically Significant Disseminated MAC Disease In association with the decreased incidence of bacteremia, patients in the groups randomized to either azithromycin alone or azithromycin in combination with rifabutin showed reductions in the signs and symptoms of disseminated MAC disease, including fever or night sweats, weight loss, and anemia. Discontinuations from Therapy for Drug-Related Side Effects In Study 155, discontinuations for drug-related toxicity occurred in 8.2% of subjects treated with azithromycin and 2.3% of those given placebo (p=0.121). In Study 174, more subjects discontinued from the combination of azithromycin and rifabutin (22.7%) than from azithromycin alone (13.5%; p=0.026) or rifabutin alone (15.9%; p=0.209). Safety As these patients with advanced HIV disease were taking multiple concomitant medications and experienced a variety of intercurrent illnesses, it was often difficult to attribute adverse reactions to study medication. Overall, the nature of adverse reactions seen on the weekly dosage regimen of azithromycin over a period of approximately one year in patients with advanced HIV disease were similar to that previously reported for shorter course therapies. INCIDENCE OF ONE OR MORE TREATMENT-RELATED a ADVERSE REACTIONS b IN HIV INFECTED PATIENTS RECEIVING PROPHYLAXIS FOR DISSEMINATED MAC OVER APPROXIMATELY 1 YEAR Study 155 Study 174 Placebo Azithromycin 1200 mg weekly Azithromycin 1200 mg weekly Rifabutin 300 mg daily Azithromycin + Rifabutin (N=91) (N=89) (N=233) (N=236) (N=224) Mean Duration of Therapy (days) 303.8 402.9 315 296.1 344.4 Discontinuation of Therapy 2.3 8.2 13.5 15.9 22.7 Autonomic Nervous System Mouth Dry 0 0 0 3.0 2.7 Central Nervous System Dizziness 0 1.1 3.9 1.7 0.4 Headache 0 0 3.0 5.5 4.5 Gastrointestinal Diarrhea 15.4 52.8 50.2 19.1 50.9 Loose Stools 6.6 19.1 12.9 3.0 9.4 Abdominal Pain 6.6 27 32.2 12.3 31.7 Dyspepsia 1.1 9 4.7 1.7 1.8 Flatulence 4.4 9 10.7 5.1 5.8 Nausea 11 32.6 27.0 16.5 28.1 Vomiting 1.1 6.7 9.0 3.8 5.8 General Fever 1.1 0 2.1 4.2 4.9 Fatigue 0 2.2 3.9 2.1 3.1 Malaise 0 1.1 0.4 0 2.2 Musculoskeletal Arthralgia 0 0 3.0 4.2 7.1 Psychiatric Anorexia 1.1 0 2.1 2.1 3.1 Skin & Appendages Pruritus 3.3 0 3.9 3.4 7.6 Rash 3.2 3.4 8.1 9.4 11.1 Skin discoloration 0 0 0 2.1 2.2 Special Senses Tinnitus 4.4 3.4 0.9 1.3 0.9 Hearing Decreased 2.2 1.1 0.9 0.4 0 Uveitis 0 0 0.4 1.3 1.8 Taste Perversion 0 0 1.3 2.5 1.3 a Includes those reactions considered possibly or probably related to study drug b >2% adverse reaction rates for any group (except uveitis) Adverse reactions related to the gastrointestinal tract were seen more frequently in patients receiving azithromycin than in those receiving placebo or rifabutin.

0 0 1.3 2.5 1.3 a Includes those reactions considered possibly or probably related to study drug b >2% adverse reaction rates for any group (except uveitis) Adverse reactions related to the gastrointestinal tract were seen more frequently in patients receiving azithromycin than in those receiving placebo or rifabutin. In Study 174, 86% of diarrheal episodes were mild to moderate in nature with discontinuation of therapy for this reason occurring in only 9/233 (3.8%) of patients. Changes in Laboratory Values In these immunocompromised patients with advanced HIV infection, it was necessary to assess laboratory abnormalities developing on trial with additional criteria if baseline values were outside the relevant normal range. PROPHYLAXIS AGAINST DISSEMINATED MAC ABNORMAL LABORATORY VALUES a Placebo Azithromycin 1200 mg weekly Rifabutin 300 mg daily Azithromycin & Rifabutin Hemoglobin <8 g/dL 1/51 2% 4/170 2% 4/114 4% 8/107 8% Platelet Count <50 × 10 3 /mm 3 1/71 1% 4/260 2% 2/182 1% 6/181 3% WBC Count <1 × 10 3 /mm 3 0/8 0% 2/70 3% 2/47 4% 0/43 0% Neutrophils <500/mm 3 0/26 0% 4/106 4% 3/82 4% 2/78 3% SGOT >5 × ULN b 1/41 2% 8/158 5% 3/121 3% 6/114 5% SGPT >5 × ULN 0/49 0% 8/166 5% 3/130 2% 5/117 4% Alk Phos >5 × ULN 1/80 1% 4/247 2% 2/172 1% 3/164 2% a excludes subjects outside of the relevant normal range at baseline b Upper Limit of Normal Treatment of Disseminated MAC Disease One randomized, double - blind clinical trial (Study 189) was performed in patients with disseminated MAC. In this trial, 246 HIV - infected patients with disseminated MAC received either azithromycin 250 mg daily (N=65), azithromycin 600 mg daily (N=91), or clarithromycin 500 mg twice a day (N=90), each administered with ethambutol 15 mg/kg daily, for 24 weeks. Blood cultures and clinical assessments were performed every 3 weeks through week 12 and monthly thereafter through week 24. After week 24, patients were switched to any open - label therapy at the discretion of the investigator and followed every 3 months through the last follow - up visit of the trial. Patients were followed from the baseline visit for a period of up to 3.7 years (median: 9 months). MAC isolates recovered during treatment or post-treatment were obtained whenever possible. The primary endpoint was sterilization by week 24. Sterilization was based on data from the central laboratory, and was defined as two consecutive observed negative blood cultures for MAC, independent of missing culture data between the two negative observations. Analyses were performed on all randomized patients who had a positive baseline culture for MAC. The azithromycin 250 mg arm was discontinued after an interim analysis at 12 weeks showed a significantly lower clearance of bacteremia compared to clarithromycin 500 mg twice a day. Efficacy results for the azithromycin 600 mg daily and clarithromycin 500 mg twice a day treatment regimens are described in the following table: RESPONSE TO THERAPY OF PATIENTS TAKING ETHAMBUTOL AND EITHER AZITHROMYCIN 600 MG DAILY OR CLARITHROMYCIN 500 MG TWICE A DAY Azithromycin 600 mg daily Clarithromycin 500 mg twice a day a 95.1% CI on difference Patients with positive culture at baseline 68 57 Week 24 Two consecutive negative blood cultures b 31/68 (46%) 32/57 (56%) [-28, 7] Mortality 16/68 (24%) 15/57 (26%) [-18, 13] a [95% confidence interval] on difference in rates (azithromycin-clarithromycin) b Primary endpoint The primary endpoint, rate of sterilization of blood cultures (two consecutive negative cultures) at 24 weeks, was lower in the azithromycin 600 mg daily group than in the clarithromycin 500 mg twice a day group. Sterilization by Baseline Colony Count Within both treatment groups, the sterilization rates at week 24 decreased as the range of MAC cfu/mL increased.

of blood cultures (two consecutive negative cultures) at 24 weeks, was lower in the azithromycin 600 mg daily group than in the clarithromycin 500 mg twice a day group. Sterilization by Baseline Colony Count Within both treatment groups, the sterilization rates at week 24 decreased as the range of MAC cfu/mL increased. Azithromycin 600 mg (N=68) Clarithromycin 500 mg twice a day (N=57) groups stratified by MAC colony counts at baseline no. (%) subjects in stratified group sterile at week 24 no. (%) subjects in stratified group sterile at week 24 ≤10 cfu/mL 10/15 (66.7%) 12/17 (70.6%) 11 to 100 cfu/mL 13/28 (46.4%) 13/19 (68.4%) 101 to 1,000 cfu/mL 7/19 (36.8%) 5/13 (38.5%) 1,001 to 10,000 cfu/mL 1/5 (20.0%) 1/5 (20%) >10,000 cfu/mL 0/1 (0.0%) 1/3 (33.3%) Susceptibility Pattern of MAC Isolates Susceptibility testing was performed on MAC isolates recovered at baseline, at the time of breakthrough on therapy or during post-therapy follow-up. The T100 radiometric broth method was employed to determine azithromycin and clarithromycin MIC values. Azithromycin MIC values ranged from < 4 to > 256 mcg/mL and clarithromycin MICs ranged from < 1 to > 32 mcg/mL. The individual MAC susceptibility results demonstrated that azithromycin MIC values could be 4 to 32 fold higher than clarithromycin MIC values. During treatment and post-treatment follow - up for up to 3.7 years (median: 9 months) in Study 189, a total of 6/68 (9%) and 6/57 (11%) of the patients randomized to azithromycin 600 mg daily and clarithromycin 500 mg twice a day respectively, developed MAC blood culture isolates that had a sharp increase in MIC values. All twelve MAC isolates had azithromycin MICs ≥ 256 mcg/mL and clarithromycin MICs > 32 mcg/mL. These high MIC values suggest development of drug resistance. However, at this time, specific breakpoints for separating susceptible and resistant MAC isolates have not been established for either macrolide.

<table><col/><col/><col/><col/><col/><tbody><tr><td align="center" colspan="5" styleCode=" Botrule Toprule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Cumulative Incidence Rate, %: Placebo (n=89)</content></paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Month</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">MAC Free and Alive</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">MAC</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">Adverse Experience</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">Lost to Follow-up</content></paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>6</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>69.7</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>13.5</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>6.7</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>10.1</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>12</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>47.2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>19.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>15.7</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>18.0</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>18</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>37.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>22.5</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>18.0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>22.5</paragraph></td></tr><tr><td align="center" colspan="5" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Cumulative Incidence Rate, %: Azithromycin (n=85)</content></paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Month</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">MAC Free and Alive</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">MAC</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">Adverse Experience</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">Lost to Follow-up</content></paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>6</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>84.7</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.5</paragra

Lost to Follow-up</content></paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>6</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>84.7</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.5</paragra ph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>9.4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.4</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>12</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>63.5</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>8.2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>16.5</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>11.8</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>18</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>44.7</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>11.8</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>25.9</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>17.6</paragraph></td></tr></tbody></table>

raph>44.7</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>11.8</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>25.9</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>17.6</paragraph></td></tr></tbody></table> <table><col/><col/><col/><col/><col/><tbody><tr><td align="center" colspan="5" styleCode=" Botrule Toprule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Cumulative Incidence Rate, %: Rifabutin (n=223)</content></paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Month</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">MAC Free and Alive</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">MAC</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">Adverse Experience</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">Lost to Follow-up</content></paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>6</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>83.4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>7.2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>8.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.3</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>12</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>60.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>15.2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>16.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>8.5</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>18</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>40.8</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>21.5</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>24.2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>13.5</paragraph></td></tr><tr><td align="center" colspan="5" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Cumulative Incidence Rate, %: Azithromycin (n=223)</content></paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Month</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">MAC Free and Alive</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">MAC</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">Adverse Experience</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">Lost to Follow-up</content></paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>6</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>85.2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.6</paragr

>Lost to Follow-up</content></paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>6</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>85.2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.6</paragr aph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>5.8</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>5.4</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>12</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>65.5</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>7.6</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>16.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>10.8</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>18</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>45.3</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>12.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>23.8</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>18.8</paragraph></td></tr><tr><td align="center" colspan="5" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Cumulative Incidence Rate, %: Azithromycin/Rifabutin Combination (n=218)</content></paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Month</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">MAC Free and Alive</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">MAC</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">Adverse Experience</content></paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph><content styleCode="bold">Lost to Follow-up</content></paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>6</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>89.4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.8</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>5.5</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.2</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>12</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>71.6</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.8</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>15.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>10.6</paragraph></td></tr><tr><td align="center" styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>18</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>49.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>6.4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>29.4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>15.1</paragraph></td></tr></tbody></table>

graph>49.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>6.4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>29.4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>15.1</paragraph></td></tr></tbody></table> <table><caption>INCIDENCE OF ONE OR MORE TREATMENT-RELATED ^a ADVERSE REACTIONS ^b IN HIV INFECTED PATIENTS RECEIVING PROPHYLAXIS FOR DISSEMINATED MAC OVER APPROXIMATELY 1 YEAR </caption><col/><col/><col/><col/><col/><col/><thead><tr><th styleCode=" Botrule Toprule Lrule Rrule" valign="top"/><th align="center" colspan="2" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Study 155</content></th><th align="center" colspan="3" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Study 174</content></th></tr><tr><th styleCode=" Lrule Rrule" valign="top"/><th align="center" styleCode=" Rrule" valign="top"><content styleCode="bold">Placebo</content></th><th align="center" styleCode=" Rrule" valign="top"><content styleCode="bold">Azithromycin 1200 mg weekly</content></th><th align="center" styleCode=" Rrule" valign="top"><content styleCode="bold">Azithromycin 1200 mg weekly</content></th><th align="center" styleCode=" Rrule" valign="top"><content styleCode="bold">Rifabutin 300 mg daily</content></th><th align="center" styleCode=" Rrule" valign="top"><content styleCode="bold">Azithromycin + Rifabutin</content></th></tr><tr><th styleCode=" Botrule Lrule Rrule" valign="top"/><th align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">(N=91)</content></th><th align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">(N=89)</content></th><th align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">(N=233)</content></th><th align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">(N=236)</content></th><th align="center" styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">(N=224)</content></th></tr></thead><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top"><paragraph>Mean Duration of Therapy (days)</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>303.8</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>402.9</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>315</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>296.1</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>344.4</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Discontinuation of Therapy</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.3</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>8.2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>13.5</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>15.9</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>22.7</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Autonomic Nervous System</content></paragraph></td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Mouth Dry</paragraph></td><td align="center" styleCode=" Botrule Rrul

<td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Mouth Dry</paragraph></td><td align="center" styleCode=" Botrule Rrul e" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.7</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Central Nervous System</content></paragraph></td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Dizziness</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.9</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.7</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.4</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Headache</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>5.5</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>4.5</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Gastrointestinal</content></paragraph></td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Diarrhea</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>15.4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>52.8</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>50.2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>19.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>50.9</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Loose Stools</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>6.6</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>19.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>12.9</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>9.4</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Abdominal Pain</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>6.6

ule Rrule" valign="top"><paragraph>3.0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>9.4</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Abdominal Pain</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>6.6 </paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>27</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>32.2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>12.3</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>31.7</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Dyspepsia</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>9</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>4.7</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.7</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.8</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Flatulence</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>4.4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>9</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>10.7</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>5.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>5.8</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Nausea</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>11</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>32.6</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>27.0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>16.5</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>28.1</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Vomiting</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>6.7</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>9.0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.8</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>5.8</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">General</content></paragraph></td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Fever</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>4.2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>4.9</paragraph></td></tr><tr><td styleCode=" Botrule Lrule R

raph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>4.2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>4.9</paragraph></td></tr><tr><td styleCode=" Botrule Lrule R rule" valign="top"><paragraph> Fatigue</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.9</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.1</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Malaise</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.2</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Musculoskeletal</content></paragraph></td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Arthralgia</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>4.2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>7.1</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Psychiatric</content></paragraph></td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Anorexia</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.1</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Skin &amp; Appendages</content></paragraph></td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Pruritus</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.3</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td

d styleCode=" Botrule Rrule" valign="top"/></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Pruritus</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.3</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.9</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>7.6</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Rash</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>8.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>9.4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>11.1</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Skin discoloration</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.2</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph><content styleCode="bold">Special Senses</content></paragraph></td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Tinnitus</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>4.4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3.4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.9</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.3</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.9</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Hearing Decreased</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.2</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.1</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.9</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Uveitis</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0.4</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.3</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.8</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Taste Perversion</paragraph></td><td align="center" styleCode=" Bot

d><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.3</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.8</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Taste Perversion</paragraph></td><td align="center" styleCode=" Bot rule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.3</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2.5</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.3</paragraph></td></tr><tr><td colspan="6" valign="top">^aIncludes those reactions considered possibly or probably related to study drug ^b&gt;2% adverse reaction rates for any group (except uveitis) </td></tr></tbody></table>

d><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1.3</paragraph></td></tr><tr><td colspan="6" valign="top">^aIncludes those reactions considered possibly or probably related to study drug ^b&gt;2% adverse reaction rates for any group (except uveitis) </td></tr></tbody></table> <table><caption>PROPHYLAXIS AGAINST DISSEMINATED MAC ABNORMAL LABORATORY VALUES ^a</caption><col/><col/><col/><col/><col/><col/><thead><tr><th colspan="2" styleCode=" Botrule Toprule Lrule Rrule" valign="top"/><th align="center" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Placebo</content></th><th align="center" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Azithromycin 1200 mg weekly</content></th><th align="center" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Rifabutin 300 mg daily</content></th><th align="center" styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Azithromycin &amp; Rifabutin</content></th></tr></thead><tbody><tr><td styleCode=" Toprule Lrule" valign="top"><paragraph>Hemoglobin</paragraph></td><td styleCode=" Toprule Rrule" valign="top"><paragraph>&lt;8 g/dL</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>1/51 2%</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>4/170 2%</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>4/114 4%</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>8/107 8%</paragraph></td></tr><tr><td styleCode=" Lrule" valign="top"><paragraph>Platelet Count</paragraph></td><td styleCode=" Rrule" valign="top"><paragraph>&lt;50 &#xD7; 10 ³/mm ³</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1/71 1%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>4/260 2%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2/182 1%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>6/181 3%</paragraph></td></tr><tr><td styleCode=" Lrule" valign="top"><paragraph>WBC Count</paragraph></td><td styleCode=" Rrule" valign="top"><paragraph>&lt;1 &#xD7; 10 ³/mm ³</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0/8 0%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2/70 3%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2/47 4%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0/43 0%</paragraph></td></tr><tr><td styleCode=" Lrule" valign="top"><paragraph>Neutrophils</paragraph></td><td styleCode=" Rrule" valign="top"><paragraph>&lt;500/mm ³</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0/26 0%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>4/106 4%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3/82 4%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2/78 3%</paragraph></td></tr><tr><td styleCode=" Lrule" valign="top"><paragraph>SGOT</paragraph></td><td styleCode=" Rrule" valign="top"><paragraph>&gt;5 &#xD7; ULN ^b</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1/41 2%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>8/158 5%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3/121 3%</paragraph></td><td align="center" styl

ragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1/41 2%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>8/158 5%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3/121 3%</paragraph></td><td align="center" styl eCode=" Botrule Rrule" valign="top"><paragraph>6/114 5%</paragraph></td></tr><tr><td styleCode=" Lrule" valign="top"><paragraph>SGPT</paragraph></td><td styleCode=" Rrule" valign="top"><paragraph>&gt;5 &#xD7; ULN</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0/49 0%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>8/166 5%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3/130 2%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>5/117 4%</paragraph></td></tr><tr><td styleCode=" Botrule Lrule" valign="top"><paragraph>Alk Phos</paragraph></td><td styleCode=" Botrule Rrule" valign="top"><paragraph>&gt;5 &#xD7; ULN</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1/80 1%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>4/247 2%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>2/172 1%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3/164 2%</paragraph></td></tr><tr><td colspan="6" valign="top">^aexcludes subjects outside of the relevant normal range at baseline ^bUpper Limit of Normal </td></tr></tbody></table>

align="top"><paragraph>2/172 1%</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>3/164 2%</paragraph></td></tr><tr><td colspan="6" valign="top">^aexcludes subjects outside of the relevant normal range at baseline ^bUpper Limit of Normal </td></tr></tbody></table> <table><col/><col/><col/><col/><thead><tr><th align="center" colspan="4" styleCode=" Botrule Toprule Lrule Rrule" valign="top"><content styleCode="bold">RESPONSE TO THERAPY OF PATIENTS TAKING ETHAMBUTOL AND EITHER AZITHROMYCIN 600 MG DAILY OR CLARITHROMYCIN 500 MG TWICE A DAY</content></th></tr><tr><th styleCode=" Botrule Toprule Lrule Rrule" valign="top"/><th styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Azithromycin 600 mg daily</content></th><th styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Clarithromycin 500 mg twice a day</content></th><th styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">^a95.1% CI on difference </content></th></tr></thead><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top"><paragraph>Patients with positive culture at baseline</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>68</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>57</paragraph></td><td styleCode=" Botrule Toprule Rrule" valign="top"/></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>Week 24</paragraph></td><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/><td styleCode=" Botrule Rrule" valign="top"/></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Two consecutive negative blood cultures ^b</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>31/68 (46%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>32/57 (56%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>[-28, 7]</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph> Mortality</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>16/68 (24%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>15/57 (26%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>[-18, 13]</paragraph></td></tr><tr><td colspan="4" valign="top">^a[95% confidence interval] on difference in rates (azithromycin-clarithromycin) ^bPrimary endpoint </td></tr></tbody></table>

><paragraph>15/57 (26%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>[-18, 13]</paragraph></td></tr><tr><td colspan="4" valign="top">^a[95% confidence interval] on difference in rates (azithromycin-clarithromycin) ^bPrimary endpoint </td></tr></tbody></table> <table><col/><col/><col/><thead><tr><th styleCode=" Botrule Toprule Lrule Rrule" valign="top"/><th styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Azithromycin 600 mg (N=68)</content></th><th styleCode=" Botrule Toprule Rrule" valign="top"><content styleCode="bold">Clarithromycin 500 mg twice a day (N=57)</content></th></tr><tr><th styleCode=" Botrule Lrule Rrule" valign="top"><content styleCode="bold">groups stratified by MAC colony counts at baseline</content></th><th styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">no. (%) subjects in stratified group sterile at week 24</content></th><th styleCode=" Botrule Rrule" valign="top"><content styleCode="bold">no. (%) subjects in stratified group sterile at week 24</content></th></tr></thead><tbody><tr><td styleCode=" Botrule Toprule Lrule Rrule" valign="top"><paragraph>&#x2264;10 cfu/mL</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>10/15 (66.7%)</paragraph></td><td align="center" styleCode=" Botrule Toprule Rrule" valign="top"><paragraph>12/17 (70.6%)</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>11 to 100 cfu/mL</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>13/28 (46.4%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>13/19 (68.4%)</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>101 to 1,000 cfu/mL</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>7/19 (36.8%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>5/13 (38.5%)</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>1,001 to 10,000 cfu/mL</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1/5 (20.0%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1/5 (20%)</paragraph></td></tr><tr><td styleCode=" Botrule Lrule Rrule" valign="top"><paragraph>&gt;10,000 cfu/mL</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>0/1 (0.0%)</paragraph></td><td align="center" styleCode=" Botrule Rrule" valign="top"><paragraph>1/3 (33.3%)</paragraph></td></tr></tbody></table>

15 REFERENCES Griffith DE, Aksamit T, Brown-Elliot BA, et al. An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med. 2007; 175:367-416.

16 HOW SUPPLIED/STORAGE AND HANDLING Azithromycin tablets USP, 600 mg are supplied as white, capsule shaped, unscored, biconvex film-coated tablets, debossed with “789” on one side and “PLIVA” on the other, containing azithromycin monohydrate equivalent to 600 mg of azithromycin, USP. Tablets are available in bottles of 30 tablets (NDC 42291-044-30). Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required). KEEP THIS AND ALL MEDICATIONS OUT OF THE REACH OF CHILDREN.

17 PATIENT COUNSELING INFORMATION Azithromycin tablets may be taken with or without food. However, increased tolerability has been observed when tablets are taken with 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. Direct parents or caregivers to contact their physician if vomiting and irritability with feeding occurs in the infant. 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 bacterial infection, patients should be told that although it is common to feel better early in the course of 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 antibiotic 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. If this occurs, patients should contact their physician as soon as possible. Manufactured for: AvKARE Pulaski, TN 38478 Mfg. Rev. 06/22 AV 04/24 (P)