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AZITHROMYCIN TABLETS
250 mg and 500 mg
Rx only
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 bacteria.
DESCRIPTION
Azithromycin tablets 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-α-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-1-oxa-6-azacyclopentadecan-15-one. Azithromycin is derived from erythromycin; however, it differs chemically from erythromycin in that amethyl-substituted nitrogen atom is incorporated into the lactone ring. Its molecular formula is C38H72N2O12, and its molecular weight is 749.0. Azithromycin has the following structural formula:
Azithromycin, as the monohydrate, is a white to off-white crystalline powder with a molecular formula of C38H72N2O12•H2O and a molecular weight of 767.0.
Azithromycin tablets are supplied for oral administration as blue, film-coated tablets containing azithromycin (monohydrate) equivalent to 250 mg or 500 mg azithromycin, USP and the following inactive ingredients: cetyl alcohol, colloidal silicon dioxide, croscarmellose sodium, dibasic calcium phosphate, FD&C Blue No. 2 aluminum lake, hypromellose, magnesium stearate, polydextrose, polyethylene glycol, sodium lauryl sulfate, titanium dioxide and triacetin.
CLINICAL PHARMACOLOGY
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∙h/mL; Cmax = 0.5(0.2) mcg/mL; Tmax = 2.2 (0.9) hours.
With a regimen of 500 mg (two 250 mg capsules
| Pharmacokinetic Parameters (Mean) | Total n = 12 | |
|---|---|---|
| Day 1 | Day 5 | |
| Cmax (mcg/mL) | 0.41 | 0.24 |
| Tmax (h) | 2.5 | 3.2 |
| AUC0–24 (mcg∙h/mL) | 2.6 | 2.1 |
| Cmin (mcg/mL) | 0.05 | 0.05 |
| Urinary Excret. (% dose) | 4.5 | 6.5 |
In a two-way crossover study, 12 adult healthy volunteers (6 males, 6 females) received 1,500 mg of azithromycin administered in single daily doses over either 5 days (two 250 mg tablets on day 1, followed by one 250 mg tablet on days 2 to 5) or 3 days (500 mg per day for days 1 to 3). Due to limited serum samples on day 2 (3-day regimen) and days 2 to 4 (5-day regimen), the serum concentration-time profile of each subject was fit to a 3-compartment model and the AUC0–∞ for the fitted concentration profile was comparable between the 5-day and 3-day regimens.
| 3-Day Regimen | 5-Day Regimen | |||
|---|---|---|---|---|
| Pharmacokinetic Parameter [mean (SD)] | Day 1 | Day 3 | Day 1 | Day 5 |
| Cmax (serum, mcg/mL) | 0.44 (0.22) | 0.54 (0.25) | 0.43 (0.20) | 0.24 (0.06) |
| Serum AUC0–∞(mcg∙hr/mL) | 17.4 (6.2) | 14.9 (3.1) | ||
| Serum T1/2 | 71.8 hr | 68.9 hr | ||
Median azithromycin exposure (AUC0–288) in mononuclear (MN) and polymorphonuclear (PMN) leukocytes following either the 5-day or 3-day regimen was more than a 1,000-fold and 800-fold greater than in serum, respectively. Administration of the same total dose with either the 5-day or 3-day regimen may be expected to provide comparable concentrations of azithromycin within MN and PMN leukocytes.
Two azithromycin 250 mg tablets are bioequivalent to a single 500 mg tablet.
Absorption
The absolute bioavailability of azithromycin 250 mg capsules is 38%.
In a two-way crossover study in which 12 healthy subjects received a single 500 mg dose of azithromycin (two 250 mg tablets) with or without a high fat meal, food was shown to increase Cmax by 23% but had no effect on AUC.
When azithromycin suspension was administered with food to 28 adult healthy male subjects, Cmax increased by 56% and AUC was unchanged.
The AUC of azithromycin was unaffected by coadministration of an antacid containing aluminum and magnesium hydroxide with azithromycin capsules; however, the Cmax was reduced by 24%. Administration of cimetidine (800 mg) two hours prior to azithromycin had no effect on azithromycin absorption.
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.
Following oral administration, azithromycin is widely distributed throughout the body with an apparent steady-state volume of distribution of 31.1 L/kg. Greater azithromycin concentrations in tissues than in plasma or serum were observed. High tissue concentrations should not be interpreted to be quantitatively related to clinical efficacy. The antimicrobial 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.
Selected tissue (or fluid) concentration and tissue (or fluid) to plasma/serum concentration ratios are shown in the following table:
| TISSUE OR FLUID | TIME AFTER DOSE (h) | TISSUE OR FLUID CONCENTRATION (mcg/g or mcg/mL) | CORRESPONDING PLASMA OR SERUM LEVEL (mcg/mL) | TISSUE (FLUID) PLASMA (SERUM) RATIO |
|---|---|---|---|---|
| SKIN | 72 to 96 | 0.4 | 0.012 | 35 |
| LUNG | 72 to 96 | 4 | 0.012 | > 100 |
| SPUTUM | 2 to 4 | 1 | 0.64 | 2 |
| SPUTUM | 10 to 12 | 2.9 | 0.1 | 30 |
| TONSIL | 9 to 18 | 4.5 | 0.03 | > 100 |
| TONSIL | 180 | 0.9 | 0.006 | > 100 |
| CERVIX | 19 | 2.8 | 0.04 | 70 |
The 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.
Following a regimen of 500 mg on the first day and 250 mg daily for 4 days, only very low concentrations were noted in cerebrospinal fluid (less than 0.01 mcg/mL) in the presence of non-inflamed 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 i.v. doses declined in a polyphasic pattern with 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.
Special Populations
Drug-Drug Interactions
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 effect 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 uled in Table 1. No dosage adjustment of drugs uled 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 Cmax and AUC of azithromycin. No dosage adjustment of azithromycin is recommended when administered with drugs uled in Table 2. (See PRECAUTIONS: Drug Interactions.)
| Coadministered Drug | Dose of Co-Administered Drug | Dose of Azithromycin | n | Ratio (with/without azithromycin) of Coadministered Drug Pharmacokinetic Parameters (90% CI); No Effect = 1.00 | |
|---|---|---|---|---|---|
| Mean Cmax | Mean AUC | ||||
| NA - Not Available | |||||
| Mean rifabutin concentrations one-half day after the last dose of rifabutin were 60 ng/mL when coadministered with azithromycin and 71 ng/mL when coadministered with placebo. | |||||
| Atrovastatin | 10 mg/day × 8 days | 500 mg/day PO on days 6 to 8 | 12 | 0.83 (0.63 to 1.08) | 1.01 (0.81 to 1.25) |
| Carbamazepine | 200 mg/day × 2 days, then 200 mg BID × 18 days | 500 mg/day PO for days 16 to 18 | 7 | .97 (0.88 to 1.06) | 0.96 (0.88 to 1.06) |
| Certirizine | 20 mg/day × 11 days | 500 mg PO 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 PO BID × 21 days | 1200 mg/day PO on days 8 to 21 | 6 | 1.44 (0.85 to 2.43) | 1.14 (0.83 to 1.57) |
| Efavirenz | 400 mg/day × 7 days | 600 mg PO on day 7 | 14 | 1.04 | 0.95 |
| Fluconazole | 200 mg PO single dose | 1200 mg PO on single dose | 18 | 1.04 (0.98 to 1.11) | 1.01 (0.97 to 1.05) |
| Indinavir | 800 mg TID × 5 days | 1200 mg PO day 5 | 18 | 0.96 (0.86 to 1.08) | 0.90 (0.81 to 1.00) |
| Midazolam | 15 mg PO on day 3 | 500 mg/day PO × 3 days | 12 | 1.27 (0.89 to 1.81) | 1.26 (1.01 to 1.56) |
| Nelfinavir | 750 mg TID × 11 days | 1200 mg PO on day 9 | 14 | 0.90 (0.81 to 1.01) | 0.85 (0.78 to 0.93) |
| Rifabutin | 300 mg/day × 10 days | 500 mg PO on day 1, then 250 mg/day on days 2 to 10 | 6 | See footnote below | NA |
| Sildenafil | 100 mg on day 1 and 4 | 500 mg/day PO × 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 PO 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 PO BID × 15 days | 500 mg PO 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 PO on day 1, then 250 mg/day on day 2 | 12 | 1.06 | 1.02 |
| Trimethoprim/ Sulfamethoxazole | 160 mg/800 mg/day PO × 7 days | 1200 mg PO 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 PO × 21 days | 600 mg/day PO × 14 days | 5 | 1.12 (0.42 to 3.02) | 0.94 (0.52 to 1.70) |
| Zidovudine | 500 mg/day PO × 21 day | 1200 mg/day PO × 14 days | 4 | 1.31 (0.43 to 3.97) | 1.30 (0.69 to 2.43) |
| 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 Cmax | Mean AUC | ||||
| NA – Not Available | |||||
| Mean azithromycin concentrations one day after the last dose were 53 ng/mL when coadministered with 300 mg daily rifabutin and 49 ng/mL when coadministered with placebo. | |||||
| Efavirenz | 400 mg/day × 7 days | 600 mg PO on day 7 | 14 | 1.22 (1.04 to 1.42) | 0.92 |
| Fluconazole | 200 mg PO single dose | 1200 mg PO single dose | 18 | 0.82 (0.66 to 1.02) | 1.07 (0.94 to 1.22) |
| Nelfinavir | 750 mg TID × 11 days | 1200 mg PO on day 9 | 14 | 2.36 (1.77 to 3.15) | 2.12 (1.80 to 2.50) |
| Rifabutin | 300 mg/day × 10 days | 500 mg PO on day 1, then 250 mg/day on days 2 to 10 | 6 | See footnote below | NA |
Microbiology
Azithromycin acts by binding to the 50S ribosomal subunit of susceptible microorganisms and, thus, interfering with microbial protein synthesis. Nucleic acid synthesis is not affected.
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 hour incubation. In vivo studies suggest that concentration in phagocytes may contribute to drug distribution to inflamed tissues.
Azithromycin has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the INDICATIONS AND USAGE section.
Aerobic and facultative gram-positive microorganisms:
Staphylococcus aureus
Streptococcus agalactiae
Streptococcus pneumoniae
Streptococcus pyogenes
NOTE: Azithromycin demonstrates cross-resistance with erythromycin-resistant gram-positive strains. Most strains of Enterococcus faecalis and methicillin-resistant staphylococci are resistant to azithromycin.
Aerobic and facultative gram-negative microorganisms:
Haemophilus ducreyi
Haemophilus influenzae
Moraxella catarrhalis
Neisseria gonorrhoeae
"Other" microorganisms:
Chlamydia pneumoniae
Chlamydia trachomatis
Mycoplasma pneumoniae
Beta-lactamase production should have no effect on azithromycin activity.
The following in vitro data are available, but their clinical significance is unknown.
At least 90% of the following microorganisms exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoints for azithromycin. However, the safety and effectiveness of azithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well controlled trials.
Aerobic and facultative gram-positive microorganisms:
Streptococci (Groups C, F, G)
Viridans group streptococci
Aerobic and facultative gram-negative microorganisms:
Bordetella pertussis
Legionella pneumophila
Anaerobic microorganisms:
Peptostreptococcus species
Prevotella bivia
"Other" microorganisms:
Ureaplasma urealyticum
Susceptibility Testing Methods
When available, the results of in vitro susceptibility test results for antimicrobial drugs used in resident hospitals should be provided to the physician as periodic reports which describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports may differ from susceptibility data obtained from outpatient use, but could aid the physician in selecting the most effective antimicrobial.
INDICATIONS AND USAGE
Azithromycin tablets are indicated for the treatment of patients with mild to moderate infections (pneumonia: see WARNINGS) caused by susceptible strains of the designated microorganisms in the specific conditions uled 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 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.
Uncomplicated Skin and Skin Structure Infections due to Staphylococcus aureus, Streptococcus pyogenes, or Streptococcus agalactiae. Abscesses usually require surgical drainage.
Urethritis and Cervicitis due to Chlamydia trachomatis or Neisseria gonorrhoeae.
Genital Ulcer Disease in men due to Haemophilus ducreyi (chancroid). Due to the small number of women included in clinical trials, the efficacy of azithromycin in the treatment of chancroid in women has not been established.
Azithromycin tablets, 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 tablets may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly.
To reduce the development of drug-resistant bacteria and maintain the effectiveness of azithromycin tablets 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
(See PRECAUTIONS: Pediatric Use and CLINICAL STUDIES IN PEDIATRIC PATIENTS.)
Acute Otitis Media caused by 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 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.
Appropriate culture and susceptibility tests should be performed before treatment to determine the causative organism and its susceptibility to azithromycin. Therapy with azithromycin tablets may be initiated before results of these tests are known; once the results become available, antimicrobial therapy should be adjusted accordingly.
CONTRAINDICATIONS
Azithromycin tablets are contraindicated in patients with known hypersensitivity to azithromycin, erythromycin or any macrolide antibiotic.
WARNINGS
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.
PRECAUTIONS
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.
Information for Patients
Azithromycin tablets can be taken with or without food.
Patients should also be cautioned not to take aluminum- and magnesium-containing antacids and azithromycin simultaneously.
The patient should be directed to discontinue azithromycin immediately and contact a physician if any signs of an allergic reaction occur.
Patients should be counseled that antibacterial drugs, including azithromycin tablets should only be used to treat bacterial infections. They do not treat viral infections (e.g., the common cold). When azithromycin tablets are prescribed to treat a 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 tablets or other antibacterial drugs in the future.
Drug Interactions
Coadministration of nelfinavir at steady-state with a single oral dose of azithromycin resulted in increased azithromycin serum concentrations. Although a dose adjustment of azithromycin is not recommended when administered in combination with nelfinavir, close monitoring for known side effects of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. (See ADVERSE REACTIONS.)
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 coadministered. (See CLINICAL PHARMACOLOGY-Drug-Drug Interactions.) When used in therapeutic doses, azithromycin had a modest effect on the pharmacokinetics of atorvastatin, carbamazepine, cetirizine, didanosine, efavirenz, fluconazole, indinavir, midazolam, rifabutin, sildenafil, theophylline (intravenous and oral), triazolam, trimethoprim/sulfamethoxazole or zidovudine. Coadministration with efavirenz, or fluconazole had a modest effect on the pharmacokinetics of azithromycin. No dosage adjustment of either drug is recommended when azithromycin is coadministered with any of the above agents.
Interactions with the drugs uled 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:
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
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
Geriatric Use
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 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.
Azithromycin 250 mg tablets contain 5.2 mg of sodium per tablet.
Azithromycin 500 mg tablets contain 10.4 mg of sodium per tablet.
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 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%. Most of the side effects leading to discontinuation were related to the gastrointestinal tract, e.g., nausea, vomiting, diarrhea, or abdominal pain. (See CLINICAL STUDIES IN PEDIATRIC PATIENTS.)
Clinical
Adults
Pediatric Patients
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 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 rare reports of taste perversion.
Laboratory Abnormalities
Pediatric Patients
DOSAGE AND ADMINISTRATION
(See INDICATIONS AND USAGE and CLINICAL PHARMACOLOGY.)
Adults
| Infection | Recommended Dose/Duration of Therapy |
|---|---|
| Community-acquired pneumonia (mild severity) | 500 mg as a single dose on Day 1, followed by 250 mg once daily on Days 2 through 5. |
| Pharyngitis/tonsillitis (second line therapy) | |
| Skin/skin structure (uncomplicated) | |
| Acute bacterial exacerbations of chronic obstructive pulmonary disease (mild to moderate) | 500 mg QD × 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 QD × 3 days |
| Genital ulcer disease (chancroid) | One single 1 gram dose |
| Non-gonoccocal urethritis or cervicitis | One single 1 gram dose |
| Gonococcal urethritis and cervicitis | One single 2 gram dose |
Azithromycin tablets can be taken with or without food.
Pediatric Patients
Azithromycin for oral suspension can be taken with or without food.
HOW SUPPLIED
Azithromycin tablets are available containing 250 mg or 500 mg azithromycin, USP (monohydrate).
The 250 mg tablets are blue, film-coated, round, unscored tablets debossed with M over 533 on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-1533-83
Carton of 3 buler cards × 6 tablets
NDC 0378-1533-93
bottles of 30 tablets
NDC 0378-1533-05
bottles of 500 tablets
The 500 mg tablets are blue, film-coated, modified capsule-shaped, unscored tablets debossed with M 534 on one side of the tablet and blank on the other side. They are available as follows:
NDC 0378-1534-59
Carton of 3 buler cards × 3 tablets
NDC 0378-1534-93
bottles of 30 tablets
NDC 0378-1534-05
bottles of 500 tablets
Store at 20° to 25°C (68° to 77°F). [See USP for Controlled Room Temperature.]
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
CLINICAL STUDIES
(See INDICATIONS AND USAGE and Pediatric Use.)
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. Day 11 to 14 data are provided for clinical guidance. Day 24 to 32 evaluations were considered the primary test of cure endpoint.
Acute Otitis Media
Adult Patients
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 pancreas) in dogs treated with azithromycin at doses which, expressed on the basis of mg/m2, are approximately equal to the recommended adult human dose, and in rats treated at doses approximately one-sixth of the recommended adult human dose. This effect has been shown to be reversible after cessation of azithromycin treatment. Phospholipidosis has been observed to a similar extent in the tissues of neonatal rats and dogs given daily doses of azithromycin ranging from 10 days to 30 days. Based on the pharmacokinetic data, phospholipidosis has been seen in the rat (30 mg/kg dose) at observed Cmax value of 1.3 mcg/mL (six times greater than the observed Cmax of 0.216 mcg/mL at the pediatric dose of 10 mg/kg). Similarly, it has been shown in the dog (10 mg/kg dose) at observed Cmax value of 1.5 mcg/mL (seven times greater than the observed same Cmax and drug dose in the studied pediatric population). On a mg/m2 basis, 30 mg/kg dose in the neonatal rat (135 mg/m2) and 10 mg/kg dose in the neonatal dog (79 mg/m2) are approximately 0.5 and 0.3 times, respectively, the recommended dose in the pediatric patients with an average body weight of 25 kg. Phospholipidosis, similar to that seen in the adult animals, is reversible after cessation of azithromycin treatment. The significance of these findings for animals and for humans is unknown.
REFERENCES
- National Committee for Clinical Laboratory Standards, Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically – Fifth Edition. Approved Standard NCCLS Document M7-A5, Vol. 20, No. 2 (ISBN 1-56238-394-9). NCCLS, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898, January 2000.
- National Committee for Clinical Laboratory Standards, Performance Standards for Antimicrobial Disk Susceptibility Tests - Seventh Edition. Approved Standard NCCLS Document M2-A7, Vol. 20, No. 1 (ISBN 1-56238-393-0). NCCLS, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898, January 2000.
- National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Susceptibility Testing – Eleventh Informational Supplement. NCCLS Document M100-S11, Vol. 21, No. 1 (ISBN 1-56238-426-0). NCCLS, 940 West Valley Road, Suite 1400, Wayne, PA 19087-1898, January 2001.
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505
REVISED APRIL 2007
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