Aluminum- and magnesium-containing antacids reduce the peak serum levels (rate) but not the AUC (extent) of azithromycin (500 mg) absorption.
Administration of cimetidine (800 mg) two hours prior to azithromycin had no effect on azithromycin (500 mg) absorption.
A single oral dose of 1200 mg azithromycin (2 x 600 mg azithromycin tablets) did not alter the pharmacokinetics of a single 800 mg oral dose of fluconazole in healthy adult subjects.
Total exposure (AUC) and half-life of azithromycin following the single oral tablet dose of 1200 mg were unchanged and the reduction in C
was not significant (mean decrease of 18%) by coadministration with 800 mg fluconazole.
A single oral dose of 1200 mg azithromycin (2 x 600 mg azithromycin tablets) had no significant effect on the pharmacokinetics of indinavir (800 mg indinavir tid for 5 days) in healthy adult subjects.
Coadministration of a single oral dose of 1200 mg azithromycin (2 x 600 mg azithromycin tablets) with steady-state nelfinavir (750 mg tid) to healthy adult subjects produced a decrease of approximately 15% in mean AUC
of nelfinavir and its M8 metabolite. Mean C
of nelfinavir and its M8 metabolite were not significantly affected. No dosage adjustment of nelfinavir is required when nelfinavir is coadministered with azithromycin.
Coadministration of nelfinavir (750 mg tid) at steady state with a single oral dose of 1200 mg azithromycin increased the mean AUC
of azithromycin by approximately a factor of 2-times (range of up to 4 times) of that when azithromycin was given alone. The mean C
of azithromycin was also increased by approximately a factor of 2-times (range of up to 5 times) of that when azithromycin was given alone. Dose adjustment of azithromycin is not recommended. However, when administered in conjunction with nelfinavir, close monitoring for known side effects of azithromycin, such as liver enzyme abnormalities and hearing impairment, is warranted. (See ADVERSE REACTIONS.)
Following administration of trimethoprim/sulfamethoxazole DS (160 mg/800 mg) for 7 days to healthy adult subjects, coadministration of 1200 mg azithromycin (2 x 600 mg azithromycin tablets) on the 7
day had no significant effects on peak concentrations (C
), total exposure (AUC), and the urinary excretion of either trimethoprim or sulfamethoxazole.
Coadministration of trimethoprim/sulfamethoxazole DS for 7 days had no significant effect on the peak concentration (C
) and total exposure (AUC) of azithromycin following administration of the single 1200 mg tablet dose to healthy adult subjects.
Administration of a 600 mg single oral dose of azithromycin had no effect on the pharmacokinetics of efavirenz given at 400 mg doses for 7 days to healthy adult subjects.
Efavirenz, when administered at a dose of 400 mg for seven days produced a 22% increase in the C
of azithromycin administered as a 600 mg single oral dose, while the AUC of azithromycin was not affected.
Azithromycin (500 mg Day 1, 250 mg Days 2-5) did not affect the plasma levels or pharmacokinetics of theophylline administered as a single intravenous dose. The effect of azithromycin on the plasma levels or pharmacokinetics of theophylline administered in multiple doses resulting in therapeutic steady-state levels of theophylline is not known. However, concurrent use of macrolides and theophylline has been associated with increases in the serum concentrations of theophylline. Therefore, until further data are available, prudent medical practice dictates careful monitoring of plasma theophylline levels in patients receiving azithromycin and theophylline concomitantly.
Although, in a study of 22 healthy men, a 5-day course of azithromycin did not affect the prothrombin time from a subsequently administered dose of warfarin, spontaneous post-marketing reports suggest that concomitant administration of azithromycin may potentiate the effects of oral anticoagulants. Prothrombin times should be carefully monitored while patients are receiving azithromycin and oral anticoagulants concomitantly.
Dose adjustments are not indicated when azithromycin and zidovudine are coadministered. When zidovudine (100 mg q3h x 5) was coadministered with daily azithromycin (600 mg, n=5 or 1200 mg, n=7), mean C
, AUC and Clr increased by 26% (CV 54%), 10% (CV 26%) and 38% (CV 114%), respectively. The mean AUC of phosphorylated zidovudine increased by 75% (CV 95%), while zidovudine glucuronide C
and AUC increased by less than 10%. In another study, addition of 1 gram azithromycin per week to a regimen of 10 mg/kg daily zidovudine resulted in 25% (CV 70%) and 13% (CV 37%) increases in zidovudine C
and AUC, respectively. Zidovudine glucuronide mean C
and AUC increased by 16% (CV 61%) and 8% (CV 32%), respectively.
Doses of 1200 mg/day azithromycin for 14 days in 6 subjects increased C
of concurrently administered didanosine (200 mg q.12h) by 44% (54% CV) and AUC by 14% (23% CV). However, none of these changes were significantly different from those produced in a parallel placebo control group of subjects.
Preliminary data suggest that coadministration of azithromycin and rifabutin did not markedly affect the mean serum concentrations of either drug. Administration of 250 mg azithromycin daily for 10 days (500 mg on the first day) produced mean concentrations of azithromycin 1 day after the last dose of 53 ng/mL when coadministered with 300 mg daily rifabutin and 49 mg/mL when coadministered with placebo. Mean concentrations 5 days after the last dose were 23 ng/mL and 21 ng/mL in the two groups of subjects. Administration of 300 mg rifabutin for 10 days produced mean concentrations of rifabutin one half day after the last dose of 60 mg/ml when coadministered with daily 250 mg azithromycin and 71 ng/mL when coadministered with placebo. Mean concentrations 5 days after the last dose were 8.1 ng/mL and 9.2 ng/mL in the two groups of subjects.
The following drug interactions 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 levels.
Ergotamine or dihydroergotamine-acute ergot toxicity characterized by severe peripheral vasospasm and dysesthesia.
Triazolam-decrease the clearance of triazolam and thus may increase the pharmacologic effect of triazolam.
Drugs metabolized by the cytochrome P
system-elevations of serum carbamazepine, cyclosporine, hexobarbital, and phenytoin
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.
Teratogenic Effects. Pregnancy Category B: Reproduction studies have been performed in rats and mice at doses up to moderately maternally toxic dose levels (i.e., 200 mg/kg/day). These doses, based on a mg/m
basis, are estimated to be 4 and 2 times, respectively, the human daily dose of 500 mg.
With regard to the MAC treatment dose of 600 mg daily, on a mg/m
/day basis, the doses in rats and mice are approximately 3.3 and
1.7 times the human dose, respectively.
With regard to the MAC prophylaxis dose of 1200 mg weekly, on a mg/m
/day basis, the doses in rats and mice are approximately 2 and 1 times the human dose, respectively.
No evidence of impaired fertility or 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.
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.
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, 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.
Safety in HIV-Infected Pediatric Patients:
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 3-2004 days) at doses of <1 to
52 mg/kg/day (mean 12 mg/kg/day). Adverse events 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 side effects: 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 10-20 mg/kg/day (oral and/or i.v.) of azithromycin.
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 responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Azithromycin 600 mg tablets contain 2.9 mg of sodium per tablet.
Geriatric Patients with Opportunistic Infections, Including Mycobacterium avium complex (MAC) Disease:
Safety data are available for 30 patients (65-94 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 side effect profile was generally similar to that seen in younger patients, except for a higher incidence of side effects relating to the gastrointestinal system and to reversible impairment of hearing. (See DOSAGE AND ADMINISTRATION.)