5.1 Neurologic Disease

Peripheral neuropathy, characterized by numbness or paresthesia of an extremity, has been reported in patients treated with systemic metronidazole. Peripheral neuropathy has been reported with the post approval use of topical metronidazole. Immediately reevaluate metronidazole therapy if abnormal neurologic signs appear. Administer metronidazole with caution to patients with central nervous system diseases.

5.2 Blood Dyscrasias

Metronidazole is a nitroimidazole; use with care in patients with evidence of, or history of, blood dyscrasia.

5.3 Contact Dermatitis

Irritant and allergic contact dermatitis have been reported with metronidazole gel. If dermatitis occurs, patients may need to discontinue use.

5.4 Eye Irritation

Topical metronidazole has been reported to cause tearing of the eyes. Avoid contact with the eyes.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In a controlled clinical trial, 557 subjects used metronidazole gel and 189 subjects used the gel vehicle once daily for up to 10 weeks. The following table summarizes selected adverse reactions that occurred at a rate of ≥1% and at a higher rate than vehicle:

The following additional adverse reactions have been reported with the topical use of metronidazole: transient redness, metallic taste, tingling or numbness of extremities, and nausea.

6.2 Post Marketing Experience

The following adverse reaction has been identified during post-approval use of topical metronidazole. Because this reaction is reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate the frequency or establish a causal relationship to drug exposure.

Nervous System Disorders: Peripheral neuropathy

Ophthalmic Adverse Reactions: Tearing of the eyes

8.1 Pregnancy

Risk Summary

Available data have not established an association between metronidazole use during pregnancy and major birth defects, miscarriage or other adverse maternal or fetal outcomes. No fetotoxicity was observed after oral administration of metronidazole in pregnant rats or mice. The available data do not allow the calculation of relevant comparisons between the systemic exposures of metronidazole observed in animal studies to the systemic exposures that would be expected in humans after topical use of metronidazole gel.

The background risk of major birth defects and miscarriage for the indicated population 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.

8.2 Lactation

Risk Summary

It is not known whether metronidazole is present in human milk after topical administration. Published literature reports the presence of metronidazole in human milk after oral administration. There are no data on the effects of metronidazole on milk production. Because of the potential for serious adverse reactions, advise patients that breastfeeding is not recommended during treatment with metronidazole gel.

8.4 Pediatric Use

Safety and effectiveness of metronidazole have not been established in pediatric patients.

8.5 Geriatric Use

Sixty-six subjects aged 65 years and older were treated with metronidazole gel in the clinical study. 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.

12.1 Mechanism of Action

The mechanism of action of metronidazole in the treatment of rosacea is unknown.

12.2 Pharmacodynamics

The pharmacodynamics of metronidazole in association with the treatment of rosacea are unknown.

Cardiac Electrophysiology: The effect of metronidazole gel on the QTc interval has not been adequately characterized.

12.3 Pharmacokinetics

Topical administration of a one-gram dose of metronidazole gel to the face of 13 subjects with moderate to severe rosacea once daily for 7 days resulted in a mean ± SD Cmax of metronidazole of 32 ± 9 ng/mL. The mean ± SD AUC(0-24) was 595 ± 154 ng*hr/mL. The mean Cmax and AUC(0-24) are less than 1% of the value reported for a single 250 mg oral dose of metronidazole. The time to maximum plasma concentration (Tmax) was 6 to 10 hours after topical application.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Metronidazole has shown evidence of carcinogenic activity in studies involving chronic oral administration in mice and rats, but not in studies involving hamsters.

In several long-term studies in mice, oral doses of approximately 225 mg/m2/day or greater were associated with an increase in pulmonary tumors and lymphomas. Several long-term oral studies in the rat have shown statistically significant increases in mammary and hepatic tumors at doses >885 mg/m2/day.

Metronidazole has shown evidence of mutagenic activity in several in vitro bacterial assay systems. In addition, a dose-related increase in the frequency of micronuclei was observed in mice after intraperitoneal injections. An increase in chromosomal aberrations in peripheral blood lymphocytes was reported in patients with Crohn’s disease who were treated with 200 to 1200 mg/day of metronidazole for 1 to 24 months. However, in another study, no increase in chromosomal aberrations in circulating lymphocytes was observed in patients with Crohn’s disease treated with the drug for 8 months.