METROGEL Gel Ref.[10873] Active ingredients: Methronidazole

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

Cardiac Electrophysiology

The effect of METROGEL on the QTc interval has not been adequately characterized.

Topical administration of a one-gram dose of METROGEL to the face of 13 subjects with moderate to severe rosacea once daily for 7 days resulted in a mean + SD C_max of metronidazole of 32 + 9 ng/mL. The mean + SD AUC_(0-24) was 595 + 154 ng*hr/mL. The mean C_max 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 (T_max) was 6-10 hours after topical application.

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.

In a randomized, vehicle-controlled trial, 746 subjects with rosacea were treated with METROGEL or vehicle once daily for 10 weeks. Most subjects had a disease severity score of 3 (“moderate”) on the 5-point Investigator Global Assessment (IGA) scale, with 8 to 50 inflammatory lesions and no more than two nodules at baseline. The co-primary efficacy endpoints were the percent reduction in inflammatory lesion counts and percentage of subjects with success on IGA, defined as an IGA score of 0 (“clear”) or 1 (“almost clear”) at Week 10.

The efficacy results are shown in the following table:

Table 3. Inflammatory Lesion Counts and Global Scores in Subjects with Rosacea at Week 10 in a Clinical Trial:

Subjects treated with METROGEL experienced a mean reduction of 9.4 inflammatory lesions in the Week-10 LOCF group, compared to a reduction of 5.6 for those treated with vehicle, or a difference in means of 3.8 lesions.