Azithromycin Dihydrate (Page 3 of 6)

7.3 Potential Drug-Drug Interaction with Macrolides

Interactions with digoxin, colchicine or phenytoin have not been reported in clinical trials with azithromycin. No specific drug interaction studies have been performed to evaluate potential drug-drug interaction. However, drug interactions have been observed with other macrolide products. Until further data are developed regarding drug interactions when digoxin, colchicine or phenytoin are used with azithromycin careful monitoring of patients is advised.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Available data from published literature and postmarketing experience over several decades with azithromycin use in pregnant women have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data).

Developmental toxicity studies with azithromycin in rats, mice, and rabbits showed no drug-induced fetal malformations at doses up to 3, 2, and 1 times, respectively, an adult human daily dose of 600 mg based on body surface area. Decreased viability and delayed development were observed in the offspring of pregnant rats administered azithromycin from day 6 of pregnancy through weaning at a dose equivalent to 3 times an adult human daily dose of 600 mg based on body surface area (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Data

Human Data

Available data from published observational studies, case series, and case reports over several decades do not suggest an increased risk for major birth defects, miscarriage, or adverse maternal or fetal outcomes with azithromycin use in pregnant women. Limitations of these data include the lack of randomization and inability to control for confounders such as underlying maternal disease and maternal use of concomitant medications.

Animal Data

Azithromycin administered during the period of organogenesis did not cause fetal malformations in rats and mice at oral doses up to 200 mg/kg/day (moderately maternally toxic). Based on body surface area, this dose is approximately 3 (rats) and 2 (mice) times an adult human daily dose of 600 mg. In rabbits administered azithromycin at oral doses of 10 mg/kg/day, 20 mg/kg/day, and 40 mg/kg/day during organogenesis, reduced maternal body weight and food consumption were observed in all groups; no evidence of fetotoxicity or teratogenicity was observed at these doses, the highest of which is approximately equal to an adult human daily dose of 600 mg based on body surface area.

In a pre- and postnatal development study, azithromycin was administered orally to pregnant rats from day 6 of pregnancy until weaning at doses of 50 mg/kg/day or 200 mg/kg/day. Maternal toxicity (reduced food consumption and body weight gain; increased stress at parturition) was observed at the higher dose. Effects in the offspring were noted at 200 mg/kg/day during the postnatal development period (decreased viability, delayed developmental landmarks). These effects were not observed in a pre- and postnatal rat study when up to 200 mg/kg/day of azithromycin was given orally beginning on day 15 of pregnancy until weaning.

8.2 Lactation

Risk Summary

Azithromycin is present in human milk (see Data). Non-serious adverse reactions have been reported in breastfed infants after maternal administration of azithromycin (see Clinical Considerations). There are no available data on the effects of azithromycin on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for azithromycin and any potential adverse effects on the breastfed infant from azithromycin or from the underlying maternal condition.

Clinical Considerations

Advise women to monitor the breastfed infant for diarrhea, vomiting, or rash.

Data

Azithromycin breastmilk concentrations were measured in 20 women after receiving a single 2 g oral dose of azithromycin during labor. Breastmilk samples collected on days 3 and 6 postpartum as well as 2 and 4 weeks postpartum revealed the presence of azithromycin in breastmilk up to 4 weeks after dosing. In another study, a single dose of azithromycin 500 mg was administered intravenously to 8 women prior to incision for cesarean section. Breastmilk (colostrum) samples obtained between 12 and 48 hours after dosing revealed that azithromycin persisted in breastmilk up to 48 hours.

8.4 Pediatric Use

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, [see Indications and Usage (1) and Dosage and Administration (2)] of the prescribing information for azithromycin for oral suspension 100 mg/ 5 mL and 200 mg/5 mL bottles.

HIV-Infected Pediatric Patients: The 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 to 2,004 days) at doses of < 1 mg/kg/day to 52 mg/kg/day (mean 12 mg/kg/day). Adverse reactions 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 adverse reactions: 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 mg/kg/day to 20 mg/kg/day (oral and/or IV) of azithromycin.

8.5 Geriatric Use

In multiple-dose clinical trials of oral azithromycin, 9% of patients were at least 65 years of age (458/4,949) and 3% of patients (144/4,949) 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.

Elderly patients may be more susceptible to development of torsades de pointes arrhythmias than younger patients. [see Warnings and Precautions (5.4)]

Azithromycin 600 mg tablets contain 2.1 mg of sodium per tablet.

Geriatric Patients with Opportunistic Infections, Including (MAC) Disease: Safety data are available for 30 patients (65 to 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 adverse reaction was generally similar to that seen in younger patients, except for a higher incidence of adverse reactions relating to the gastrointestinal system and to reversible impairment of hearing. [see Dosage and Administration (2)]

10 OVERDOSAGE

Adverse reactions experienced in higher than recommended doses were similar to those seen at normal doses. In the event of overdosage, general symptomatic and supportive measures are indicated as required.

11 DESCRIPTION

Azithromycin tablets, USP contain the active ingredient azithromycin, a macrolide antibacterial drug, 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 a methyl-substituted nitrogen atom is incorporated into the lactone ring. Its molecular formula is C₃₈ H₇₂ N₂ O₁₂ , and its molecular weight is 749.0. Azithromycin has the following structural formula:

Azithromycin, as the dihydrate, is a white crystalline powder with a molecular formula of C₃₈ H₇₂ N₂ O₁₂ ∙2H₂ O and a molecular weight of 785.0.

Azithromycin tablets, USP contain azithromycin dihydrate equivalent to 600 mg azithromycin. They also contain the following inactive ingredients: croscarmellose sodium, dibasic calcium phosphate anhydrous, magnesium stearate, pregelatinized starch, and an aqueous film coat of macrogol/PEG, polyvinyl alcohol, talc, and titanium dioxide.