MetroGel

Dosage Forms And Strengths

Gel, 1%. Clear, colorless to pale yellow gel.

Storage And Handling

METROGEL® (metronidazole) is supplied as follows:

60 gram tube – NDC 0299-3820-60

Storage Conditions: Store at controlled room temperature: 20° to 25°C (68° to 77°F), excursions permitted between 15° and 30°C (59° and 86°F).

Manufactured by: Galderma Production Canada Inc. Baie d'Urfé, QC, H9X 3S4 Canada. Made in Canada. Marketed by: Galderma Laboratories, L.P. Fort Worth, Texas 76177 USA

METROGEL® (metronidazole) is indicated for the topical treatment of inflammatory lesions of rosacea.

Apply and rub in a thin film of METROGEL (metronidazole) once daily to affected area(s).

A gentle cleanser may be used before the application of METROGEL (metronidazole).

Cosmetics may be applied after the application of METROGEL (metronidazole).

Not for oral, ophthalmic or intravaginal use.

METROGEL (metronidazole) is contraindicated in patients with a history of hypersensitivity to metronidazole or to any other ingredient in the formulation.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Neurologic Disease

Peripheral neuropathy, characterized by numbness or paresthesia of an extremity has been reported in patients treated with systemic metronidazole. Although not evident in clinical trials for topical metronidazole, peripheral neuropathy has been reported with the post approval use. The appearance of abnormal neurologic signs should prompt immediate reevaluation of METROGEL therapy. Metronidazole should be administered with caution to patients with central nervous system diseases.

Blood Dyscrasias

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

Contact Dermatitis

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

Eye Irritation

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

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Metronidazole has shown evidence of carcinogenic activity in a number of 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 (approximately 37 times the human topical dose on a mg/m² basis) 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 (144 times the human dose).

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.

In one published study, using albino hairless mice, intraperitoneal administration of metronidazole at a dose of 45 mg/m²/day (approximately 7 times the human topical dose on a mg/m² basis) was associated with an increase in ultraviolet radiation-induced skin carcinogenesis. Neither dermal carcinogenicity nor photocarcinogenicity studies have been performed with METROGEL or any marketed metronidazole formulations.

Use In Specific Populations

Pregnancy

Teratogenic Effects - Pregnancy Category B

There are no adequate and well-controlled studies with the use of METROGEL in pregnant women. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. No fetotoxicity was observed after oral administration of metronidazole in rats or mice at 200 and 20 times, respectively, the expected clinical dose. However, oral metronidazole has shown carcinogenic activity in rodents. Because animal reproduction studies are not always predictive of human response, METROGEL (metronidazole) should be used during pregnancy only if clearly needed.

Nursing Mothers

After oral administration, metronidazole is secreted in breast milk in concentrations similar to those found in the plasma. Even though blood levels taken after topical metronidazole application are significantly lower than those achieved after oral metronidazole a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother and the risk to the infant.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Sixty-six subjects aged 65 years and older were treated with metronidazole gel, 1% 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.

SIDE EFFECTS

Clinical Studies 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 patients used metronidazole gel, 1% and 189 patients 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%:

Table 1: Adverse Reactions That Occurred at a Rate of ≥ 1%

Table 2: Local Cutaneous Signs and Symptoms of Irritation That Were Worse Than Baseline

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

Post Marketing Experience

The following adverse reaction has been identified during post approval use of topical metronidazole: peripheral neuropathy. 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.

DRUG INTERACTIONS

Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and warfarin, resulting in a prolongation of prothrombin time. Drug interactions should be kept in mind when METROGEL (metronidazole) is prescribed for patients who are receiving anticoagulant treatment, although they are less likely to occur with topical metronidazole administration because of low absorption.

Teratogenic Effects - Pregnancy Category B

There are no adequate and well-controlled studies with the use of METROGEL in pregnant women. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly. No fetotoxicity was observed after oral administration of metronidazole in rats or mice at 200 and 20 times, respectively, the expected clinical dose. However, oral metronidazole has shown carcinogenic activity in rodents. Because animal reproduction studies are not always predictive of human response, METROGEL (metronidazole) should be used during pregnancy only if clearly needed.

Clinical Studies 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 patients used metronidazole gel, 1% and 189 patients 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%:

Table 1: Adverse Reactions That Occurred at a Rate of ≥ 1%

Table 2: Local Cutaneous Signs and Symptoms of Irritation That Were Worse Than Baseline

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

Post Marketing Experience

The following adverse reaction has been identified during post approval use of topical metronidazole: peripheral neuropathy. 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.

There are no reported human experiences with overdosage of METROGEL. Topically applied metronidazole can be absorbed in sufficient amount to produce systemic effects.

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

Topical administration of a one gram dose of METROGEL (metronidazole) to the face of 13 patients 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 6-10 hours after topical application.