INDICATIONS & USAGE SECTION

INDICATIONS AND USAGE

Azithromycin tablets are indicated for the treatment of patients with mild to moderate infections (pneumonia: seeWARNINGS) caused by susceptible strains of the designated microorganisms in the specific conditions listed below. As recommended dosages, durations of therapy and applicable patient populations vary among these infections, please seeDOSAGE AND ADMINISTRATION for specific dosing recommendations.

Adults:

Acute bacterial exacerbations of chronic obstructive pulmonary disease due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.

Acute bacterial sinusitis due to Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.

Community-acquired pneumoniadue to Chlamydia pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients appropriate for oral therapy.

NOTE: Azithromycin should not be used in patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors such as any of the following:
** patients with cystic fibrosis,**
** patients with nosocomially acquired infections,**
** patients with known or suspected bacteremia,**
** patients requiring hospitalization,**
** elderly or debilitated patients, or**
** patients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia).**

Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy.

NOTE: Penicillin by the intramuscular route is the usual drug of choice in the treatment of Streptococcus pyogenes infection and the prophylaxis of rheumatic fever. Azithromycin tablet is often effective in the eradication of susceptible strains of Streptococcus pyogenes from the nasopharynx. Because some strains are resistant to azithromycin tablet, susceptibility tests should be performed when patients are treated with azithromycin tablet. Data establishing efficacy of azithromycin in subsequent prevention of rheumatic fever are not available.

Uncomplicated skin and skin structure infections due to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae. Abscesses usually require surgical drainage.

Urethritis and cervicitis due to Chlamydia trachomatis or Neisseria gonorrhoeae.

Genital ulcer disease in men due to Haemophilus ducreyi (chancroid). Due to the small number of women included in clinical trials, the efficacy of azithromycin in the treatment of chancroid in women has not been established.

Azithromycin tablet, at the recommended dose, should not be relied upon to treat syphilis. Antimicrobial agents used in high doses for short periods of time to treat non-gonococcal urethritis may mask or delay the symptoms of incubating syphilis. All patients with sexually-transmitted urethritis or cervicitis should have a serologic test for syphilis and appropriate cultures for gonorrhea performed at the time of diagnosis. Appropriate antimicrobial therapy and follow-up tests for these diseases should be initiated if infection is confirmed.

Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to azithromycin. Therapy with azithromycin tablet may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly.

To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin tablet 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. 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.

Pediatric Patients:

(SeePRECAUTIONS—Pediatric UseandCLINICAL STUDIES IN PEDIATRIC PATIENTS).

Acute otitis mediacaused by Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae.(For specific dosage recommendation, seeDOSAGE AND ADMINISTRATION).

Community-acquired pneumonia due to Chlamydia pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients appropriate for oral therapy. (For specific dosage recommendation, see DOSAGE AND ADMINISTRATION).

NOTE: Azithromycin should not be used in pediatric patients with pneumonia who are judged to be inappropriate for oral therapy because of moderate to severe illness or risk factors such as any of the following:
** patients with cystic fibrosis,**
** patients with nosocomially acquired infections,**
** patients with known or suspected bacteremia,**
** patients requiring hospitalization, or**
** patients with significant underlying health problems that may compromise their ability to respond to their illness (including immunodeficiency or functional asplenia).**

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Pharyngitis/tonsillitiscaused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy.(For specific dosage recommendation, seeDOSAGE AND ADMINISTRATION).

NOTE: Penicillin by the intramuscular route is the usual drug of choice in the treatment of Streptococcus pyogenes infection and the prophylaxis of rheumatic fever. Azithromycin tablet is often effective in the eradication of susceptible strains of Streptococcus pyogenes from the nasopharynx. Because some strains are resistant to azithromycin tablet, susceptibility tests should be performed when patients are treated with azithromycin tablet. Data establishing efficacy of azithromycin in subsequent prevention of rheumatic fever are not available.

Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to azithromycin. Therapy with azithromycin tablet may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly.

DOSAGE & ADMINISTRATION SECTION

DOSAGE AND ADMINISTRATION

(SeeINDICATIONS AND USAGEandCLINICAL PHARMACOLOGY.)

Adults:

*** DUE TO THE INDICATED ORGANISMS (See INDICATIONS AND USAGE.)**Azithromycin tablets can be taken with or without food.

Renal Insufficiency:
No dosage adjustment is recommended for subjects with renal impairment (GFR ≤80 mL/min). The mean AUC0-120 was similar in subjects with GFR 10-80 mL/min compared to subjects with normal renal function, whereas it increased 35% in subjects with GFR <10 mL/min compared to subjects with normal renal function. Caution should be exercised when azithromycin is administered to subjects with severe renal impairment. (SeeCLINICAL PHARMACOLOGY, Special Populations, Renal Insufficiency.)

Hepatic Insufficiency:
The pharmacokinetics of azithromycin in subjects with hepatic impairment have not been established. No dose adjustment recommendations can be made in patients with impaired hepatic function (SeeCLINICAL PHARMACOLOGY, Special Populations, Hepatic Insufficiency.)

No dosage adjustment is recommended based on age or gender. (SeeCLINICAL PHARMACOLOGY, Special Populations.)

Pediatric Patients:
Azithromycin for oral suspension can be taken with or without food.

Acute Otitis Media: The recommended dose of azithromycin for oral suspension for the treatment of pediatric patients with acute otitis media is 30 mg/kg given as a single dose or 10 mg/kg once daily for 3 days or 10 mg/kg as a single dose on the first day followed by 5 mg/kg/day on Days 2 through 5. (See chart below.)

**Acute bacterial Sinusitis:**The recommended dose of azithromycin for oral suspension for the treatment of pediatric patients with acute bacterial sinusitis is 10 mg/kg once daily for 3 days.(See chart below.)

Community-Acquired Pneumonia: The recommended dose of azithromycin for oral suspension for the treatment of pediatric patients with community- acquired pneumonia is 10 mg/kg as a single dose on the first day followed by 5 mg/kg on Days 2 through 5. (See chart below.)

PEDIATRIC DOSAGE GUIDELINES FOR OTITIS MEDIA,ACUTE BACTERIAL SINUSITIS AND COMMUNITY-ACQUIRED PNEUMONIA (Age 6 months and above, see PRECAUTIONS- Pediatric Use.) Based on Body Weight *Effectiveness of the 3-day or 1-day regimen in pediatric patients with community-acquired pneumonia has not been established. *Effectiveness of the 5-day or 1-day regimen in pediatric patients with acute bacterial sinusitis has not been established. The safety of re-dosing azithromycin in pediatric patients who vomit after receiving 30 mg/kg as a single dose has not been established. In clinical studies involving 487 patients with acute otitis media given a single 30 mg/kg dose of azithromycin, eight patients who vomited within 30 minutes of dosing were re-dosed at the same total dose.

**Pharyngitis/Tonsillitis:**The recommended dose of azithromycin for children with pharyngitis/tonsillitis is 12 mg/kg once daily for 5 days. (See chart below.)

PEDIATRIC DOSAGE GUIDELINES FOR PHARYNGITIS /TONSILLITIS
(Age 2 years and above, see PRECAUTIONS-Pediatric Use.)
Based on Body weight

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ADVERSE REACTIONS SECTION

ADVERSE REACTIONS

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 side effects of angioedema and cholestatic jaundice were reported rarely. Approximately 0.7% of the patients (adults and pediatric patients) from the 5-day multiple-dose clinical trials discontinued azithromycin tablet therapy because of treatment-related side effects. In adults given 500 mg/day for 3 days, the discontinuation rate due to treatment-related side effects 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 side effects was approximately 1%. (SeeDOSAGE AND ADMINISTRATION.) Most of the side effects leading to discontinuation were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, or abdominal pain. (SeeCLINICAL STUDIES IN PEDIATRIC PATIENTS.)

Clinical:

Adults:
Multiple-dose regimens: Overall, the most common treatment-related side effects in adult patients receiving multiple-dose regimens of azithromycin tablet were related to the gastrointestinal system with diarrhea/loose stools (4-5%), nausea (3%) and abdominal pain (2-3%) being the most frequently reported.

No other treatment-related side effects occurred in patients on the multiple- dose regimens of azithromycin tablet with a frequency greater than 1%. Side effects that occurred with a frequency of 1% or less included the following:

**Cardiovascular:**Palpitations, chest pain.
**Gastrointestinal:**Dyspepsia, flatulence, vomiting, melena and cholestatic jaundice.
**Genitourinary:**Monilia, vaginitis and nephritis.
**Nervous System:**Dizziness, headache, vertigo and somnolence.
**General:**Fatigue.
Allergic: Rash, pruritus, photosensitivity and angioedema.

Single 1-gramdose regimen: Overall, the most common side effects in patients receiving a single-dose regimen of 1 gram of azithromycin tablet were related to the gastrointestinal system and were more frequently reported than in patients receiving the multiple-dose regimen.

Side effects that occurred in patients on the single one-gram dosing regimen of azithromycin tablet 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 side effects in patients receiving a single 2-gram dose of azithromycin tablet were related to the gastrointestinal system. Side effects 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 side effects 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 side effects (≥1%) attributed to treatment were diarrhea, abdominal pain, vomiting, nausea and rash. (SeeDOSAGE AND ADMINISTRATION andCLINICAL STUDIES IN PEDIATRIC PATIENTS.)

The incidence, based on dosing regimen, is described in the table below:

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 side effects attributed to treatment were diarrhea/loose stools, abdominal pain, vomiting, nausea and rash. The incidence is described in the table below:

Pharyngitis/tonsillitis: For the recommended dosage regimen of 12 mg/kg on Days 1-5, the most frequent side effects attributed to treatment were diarrhea, vomiting, abdominal pain, nausea and headache.

The incidence is described in the table below:

With any of the treatment regimens, no other treatment-related side effects occurred in pediatric patients treated with azithromycin tablet with a frequency greater than 1%. Side effects that occurred with a frequency of 1% or less included the following:

**Cardiovascular:**Chest pain.
**Gastrointestinal:**Dyspepsia, constipation, anorexia, enteritis, flatulence, gastritis, jaundice, loose stools and oral moniliasis.
**Hematologic and Lymphatic:**Anemia and leukopenia.
Nervous System: Headache (otitis media dosage), hyperkinesia, dizziness, agitation, nervousness and insomnia.
**General:**Fever, face edema, fatigue, fungal infection, malaise and pain.
**Allergic:**Rash and allergic reaction.
**Respiratory:**Cough increased, pharyngitis, pleural effusion and rhinitis.
**Skin and Appendages:**Eczema, fungal dermatitis, pruritus, sweating, urticaria and vesiculobullous rash.
**Special Senses:**Conjunctivitis.

Post-Marketing Experience:

Adverse events reported with azithromycin during the post-marketing 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 rare reports of QT prolongation and torsades de pointes.
Gastrointestinal: Anorexia, constipation, dyspepsia, flatulence, vomiting/diarrhea rarely resulting in dehydration, pseudomembranous colitis, pancreatitis, oral candidiasis, pyloric stenosis, and rare reports of tongue discoloration.
General: Asthenia, paresthesia, fatigue, malaise and anaphylaxis (rarely fatal).
Genitourinary: Interstitial nephritis and acute renal failure and vaginitis.
**Hematopoietic:**Thrombocytopenia.
Liver/Biliary: Abnormal liver function including hepatitis and cholestatic jaundice, as well as rare cases of hepatic necrosis and hepatic failure, some of which have resulted in death.
**Nervous System:**Convulsions, dizziness/vertigo, headache, somnolence, hyperactivity, nervousness, agitation and syncope.
**Psychiatric:**Aggressive reaction and anxiety.
**Skin/Appendages:**Pruritus, rarely serious skin reactions including erythema multiforme, Stevens Johnson Syndrome and toxic epidermal necrolysis.
**Special Senses:**Hearing disturbances including hearing loss, deafness and/or tinnitus and reports of taste/smell perversion and/or loss.

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/mm3 was observed in 10/64 patients receiving 30 mg/kg as a single dose, 9/62 patients receiving 30 mg/kg given over 3 days, and 8/63 comparator patients. No patient had an absolute neutrophil count <500 cells/mm3. (SeeDOSAGE AND ADMINISTRATION.)

In multiple-dose clinical trials involving approximately 4700 pediatric patients, no patients discontinued therapy because of treatment-related laboratory abnormalities.

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