General
Because azithromycin is principally excreted 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 Zmax 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.
Information for Patients
Patients should be instructed to take Zmax on an empty stomach (at least 1 hour
before or 2 hours following a meal).
Patients should be instructed to immediately contact a physician if any signs of
an allergic reaction occur.
Patients who vomit within the first hour should contact their health care provider
about further treatment.
Keep bottle tightly closed. Store at room temperature. Use within 12 hours of constitution.
Shake bottle well before use. The entire contents of the bottle should be consumed.
Patients should be advised that Zmax may be taken without regard to antacids containing
magnesium hydroxide and/or aluminum hydroxide.
Patients should be counseled that antibacterial drugs including Zmax should only
be used to treat bacterial infections. They do not treat viral infections (e.g.,
the common cold). Not taking the complete prescribed dose 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 Zmax or other antibacterial drugs in the
future.
Drug Interactions
Co-administration of nelfinavir at steady-state with a single dose of azithromycin
(2 × 600 mg tablets) results 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 co-administered 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.
Cyclosporine, hexobarbital and phenytoin concentrations.
Laboratory Test Interactions
There are no reported laboratory test interactions.
Repeat Treatment
Studies evaluating the use of repeated courses of Zmax have not been conducted.
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 in rats given
daily doses up to 10 mg/kg (approximately 0.05 times the single 2.0 g oral adult
human dose on a mg/m2 basis).
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 daily doses in rats and mice, based on mg/m2,
are estimated to be approximately equivalent to one or one-half of, respectively,
the single adult oral dose of 2.0 g. 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.
Geriatric Use
Data collected from the azithromycin capsule and tablet formulations indicate that
a dosage adjustment does not appear to be necessary for older patients with normal
renal function (for their age) and hepatic function receiving treatment with Zmax.
In clinical trials of Zmax, 16.6% of subjects were at least 65 years of age (214/1292)
and 4.6% of subjects (59/1292) were at least 75 years of age. No overall differences
in safety or effectiveness were observed between these subjects and younger subjects.
Zmax 2.0 g oral suspension contains 148 mg of sodium.
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 treated with azithromycin
at doses which, expressed on the basis of mg/m2, are approximately
one-sixth the recommended adult dose, and in rats treated at doses approximately
one-fourth the recommended adult 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 µg/mL (1.6 times the observed Cmax of 0.821 µg/mL
at the adult dose of 2.0 g). Similarly, it has been shown in the dog (10 mg/kg/day
dose) at the observed maximal serum concentration of 1.0 µg/mL (1.2 times the observed
Cmax of 0.821 µg/mL at the adult dose of 2.0 g. The significance
of the finding for animals and for humans is unknown.
