Zithromax tablets, 250 mg, 500 mg

ZITHROMAX (azithromycin tablets and azithromycin for oral suspension) contain the active ingredient azithromycin, an azalide, a subclass of macrolide antibiotics, 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-(alpha)- 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)-(beta)- D-xylo -hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one. Azithromycin is derived from erythromycin; however, it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring. Its molecular formula is C 38 H 72 N 2 O 12 , and its molecular weight is 749.00. Azithromycin has the following structural formula:

Azithromycin, as the dihydrate, is a white crystalline powder with a molecular formula of C 38 H 72 N 2 O 12 ·2H 2 O and a molecular weight of 785.0.

ZITHROMAX is supplied for oral administration as film-coated, modified capsular shaped tablets containing azithromycin dihydrate equivalent to either 250 mg or 500 mg azithromycin and the following inactive ingredients: dibasic calcium phosphate anhydrous, pregelatinized starch, sodium croscarmellose, magnesium stearate, sodium lauryl sulfate, hypromellose, lactose, titanium dioxide, triacetin and D&C Red #30 aluminum lake.

ZITHROMAX for oral suspension is supplied in bottles containing azithromycin dihydrate powder equivalent to 300 mg, 600 mg, 900 mg, or 1200 mg azithromycin per bottle and the following inactive ingredients: sucrose; sodium phosphate, tribasic, anhydrous; hydroxypropyl cellulose; xanthan gum; FD&C Red #40; and spray dried artificial cherry, creme de vanilla and banana flavors. After constitution, each 5 mL of suspension contains 100 mg or 200 mg of azithromycin.

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

Adults:

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

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

Community -acquired pneumonia due to 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 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. ZITHROMAX is often effective in the eradication of susceptible strains of Streptococcus pyogenes from the nasopharynx. Because some strains are resistant to ZITHROMAX, susceptibility tests should be performed when patients are treated with ZITHROMAX. 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.

ZITHROMAX, 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 ZITHROMAX 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 ZITHROMAX (azithromycin) and other antibacterial drugs, ZITHROMAX (azithromycin) 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:   (See PRECAUTIONS -- Pediatric Use and CLINICAL STUDIES IN PEDIATRIC PATIENTS .)

Acute otitis media caused by Haemophilus influenzae, Moraxella catarrhalis or Streptococcus pneumoniae . (For specific dosage recommendation, see DOSAGE 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).

Pharyngitis/tonsillitis caused by Streptococcus pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy. (For specific dosage recommendation, see DOSAGE 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. ZITHROMAX is often effective in the eradication of susceptible strains of Streptococcus pyogenes from the nasopharynx. Because some strains are resistant to ZITHROMAX, susceptibility tests should be performed when patients are treated with ZITHROMAX. 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 ZITHROMAX may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly.

Serious allergic reactions, including angioedema, anaphylaxis, and dermatologic reactions including Stevens Johnson Syndrome and toxic epidermal necrolysis have been reported rarely in patients on azithromycin therapy. Although rare, fatalities have been reported. (See CONTRAINDICATIONS .) 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 unknown at present.

If an allergic reaction occurs, the drug should be discontinued and appropriate therapy should be instituted. Physicians should be aware that reappearance of the allergic symptoms may occur when symptomatic therapy is discontinued.

In the treatment of pneumonia, azithromycin has only been shown to be safe and effective in the treatment of community-acquired pneumonia due to Chlamydia pneumoniae, Haemophilus influenzae, Mycoplasma pneumoniae or Streptococcus pneumoniae in patients appropriate for oral therapy. 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).

Pseudomembranous colitis has been reported with nearly all antibacterial agents and may range in severity from mild to life-threatening. Therefore, it is important to consider this diagnosis in patients who present with diarrhea subsequent to the administration of antibacterial agents.

Treatment with antibacterial agents alters the normal flora of the colon and may permit overgrowth of clostridia. Studies indicate that a toxin produced by Clostridium difficile is a primary cause of "antibiotic-associated colitis."

After the diagnosis of pseudomembranous colitis has been established, therapeutic measures should be initiated. Mild cases of pseudomembranous colitis usually respond to discontinuation of the drug alone. In moderate to severe cases, consideration should be given to management with fluids and electrolytes, protein supplementation, and treatment with an antibacterial drug clinically effective against Clostridium difficile colitis.

General:    Because azithromycin is principally eliminated via the liver, caution should be exercised when azithromycin is administered to patients with impaired hepatic function. Due to the limited data in subjects with GFR <10 mL/min, caution should be exercised when prescribing azithromycin in these patients. (See CLINICAL PHARMACOLOGY - Special Populations - Renal Insufficiency .)

Prolonged cardiac repolarization and QT interval, imparting a risk of developing cardiac arrhythmia and torsades de pointes , have been seen in treatment with other macrolides. A similar effect with azithromycin cannot be completely ruled out in patients at increased risk for prolonged cardiac repolarization.

Prescribing ZITHROMAX (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.

Information for Patients:

ZITHROMAX tablets and oral suspension can be taken with or without food.

Patients should also be cautioned not to take aluminum- and magnesium-containing antacids and azithromycin simultaneously.

The patient should be directed to discontinue azithromycin immediately and contact a physician if any signs of an allergic reaction occur.

Patients should be counseled that antibacterial drugs including ZITHROMAX (azithromycin) should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When ZITHROMAX (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 ZITHROMAX (azithromycin) or other antibacterial drugs in the future.

Drug Interactions:

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 side effects of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. (See ADVERSE REACTIONS .)

Azithromycin did not affect the prothrombin time response to a single dose of warfarin. However, prudent medical practice dictates careful monitoring of prothrombin time in all patients treated with azithromycin and warfarin concomitantly. Concurrent use of macrolides and warfarin in clinical practice has been associated with increased anticoagulant effects.

Drug interaction studies were performed with azithromycin and other drugs likely to be co-administered. (See CLINICAL PHARMACOLOGY -- Drug-Drug Interactions .) When used in therapeutic doses, azithromycin had a modest effect on the pharmacokinetics of atorvastatin, carbamazepine, cetirizine, didanosine, efavirenz, fluconazole, indinavir, midazolam, rifabutin, sildenafil, theophylline (intravenous and oral), triazolam, trimethoprim/sulfamethoxazole or zidovudine. Co-administration with efavirenz, or fluconazole had a modest effect on the pharmacokinetics of azithromycin. No dosage adjustment of either drug is recommended when azithromycin is coadministered with any of the above agents.

Interactions with the drugs listed below have not been reported in clinical trials with azithromycin; however, no specific drug interaction studies have been performed to evaluate potential drug-drug interaction. Nonetheless, they have been observed with macrolide products. Until further data are developed regarding drug interactions when azithromycin and these drugs are used concomitantly, careful monitoring of patients is advised:

Digoxin-elevated digoxin concentrations.

Ergotamine or dihydroergotamine-acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia.

Terfenadine, cyclosporine, hexobarbital and phenytoin concentrations.

Laboratory Test Interactions:   There are no reported laboratory test interactions.

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. No evidence of impaired fertility due to azithromycin was found.

Pregnancy:   Teratogenic Effects. Pregnancy Category B: Reproduction studies have been performed in rats and mice at doses up to moderately maternally toxic dose concentrations (i.e., 200 mg/kg/day). These doses, based on a mg/m 2 basis, are estimated to be 4 and 2 times, respectively, the human daily dose of 500 mg. In the animal studies, no evidence of harm to the fetus due to azithromycin was found. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, azithromycin should be used during pregnancy only if clearly needed.

Nursing Mothers:   It is not known whether azithromycin is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when azithromycin is administered to a nursing woman.

Pediatric Use:   (See CLINICAL PHARMACOLOGY , INDICATIONS AND USAGE , and DOSAGE AND ADMINISTRATION .)

Acute Otitis Media (total dosage regimen:  30 mg/kg, see DOSAGE AND ADMINISTRATION ): Safety and effectiveness in the treatment of pediatric patients with otitis media under 6 months of age have not been established.

Acute Bacterial Sinusitis (dosage regimen: 10 mg/kg on Days 1-3):  Safety and effectiveness in the treatment of pediatric patients with acute bacterial sinusitis under 6 months of age have not been established. Use of Zithromax for the treatment of acute bacterial sinusitis pediatric patients (6 months of age or greater) is supported by adequate and well-controlled studies in adults, similar pathophysiology of acute sinusitis in adults and pediatric patients, and studies of acute otitis media in pediatric patients.

Community-Acquired Pneumonia (dosage regimen: 10 mg/kg on Day 1 followed by 5 mg/kg on Days 2-5):  Safety and effectiveness in the treatment of pediatric patients with community-acquired pneumonia under 6 months of age have not been established. Safety and effectiveness for pneumonia due to Chlamydia pneumoniae and Mycoplasma pneumoniae were documented in pediatric clinical trials. Safety and effectiveness for pneumonia due to Haemophilus influenzae and Streptococcus pneumoniae were not documented bacteriologically in the pediatric clinical trial due to difficulty in obtaining specimens. Use of azithromycin for these two microorganisms is supported, however, by evidence from adequate and well-controlled studies in adults.

Pharyngitis/Tonsillitis (dosage regimen: 12 mg/kg on Days 1-5):  Safety and effectiveness in the treatment of pediatric patients with pharyngitis/tonsillitis under 2 years of age have not been established.

Studies evaluating the use of repeated courses of therapy have not been conducted. (See CLINICAL PHARMACOLOGY and ANIMAL TOXICOLOGY .)

Geriatric Use:   Pharmacokinetic parameters in older volunteers (65-85 years old) were similar to those in younger volunteers (18-40 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 CLINICAL PHARMACOLOGY .)

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.

ZITHROMAX 250 mg tablets contain 0.9 mg of sodium per tablet.

ZITHROMAX 500 mg tablets contain 1.8 mg of sodium per tablet.

ZITHROMAX for oral suspension 100 mg/5 mL contains 3.7 mg of sodium per 5 mL of constituted solution.

ZITHROMAX for oral suspension 200 mg/5 mL contains 7.4 mg of sodium per 5 mL of constituted solution.