Source: FDA, National Drug Code (US) Revision Year: 2020
When a one gram dose of Noritate Cream, 1%, was applied in a single application to the face of 16 healthy volunteers, low concentrations of metronidazole were detected in the plasma of 7 of the volunteers. The mean±SD Cmax of metronidazole was 27.6±7.3 ng/mL, which is about 1% of the value reported for a single 250 mg oral dose of metronidazole. The time to maximum plasma concentration (Tmax) in the volunteers with detectable metronidazole was 8-12 hours after topical application.
The mechanisms by which metronidazole acts in reducing inflammatory lesions of rosacea are unknown.
Safety and efficacy of Noritate were evaluated in two randomized vehicle-controlled clinical studies for the treatment of rosacea, which excluded patients who had nodules, moderate or severe rhinophyma, dense telangiectases, plaque-like facial edema or ocular involvement and those who had a history of not responding to metronidazole therapy for rosacea. Of the patients included in the efficacy database (n=416), there were 142 men and 274 women. Endpoint efficacy data comparisons for patients treated with daily Noritate or vehicle applications are listed below.
Inflammatory Lesion Counts and Erythema Severity Scores in Two Clinical Trials for Rosacea:
| Noritate | Vehicle | |||||||
|---|---|---|---|---|---|---|---|---|
| Study 1 | Study 2 | Study 1 | Study 2 | |||||
| N | Result | N | Result | N | Result | N | Result | |
| Papules + Pustules Count | ||||||||
| Baseline | 89 | 15 | 92 | 19 | 50 | 18 | 49 | 17 |
| Week 10 | 80 | 7* | 82 | 8 | 45 | 15 | 41 | 12 |
| Reduction | 49%* | 58%* | 17% | 30% | ||||
| Papules Count | ||||||||
| Baseline | 89 | 13 | 92 | 17 | 50 | 15 | 49 | 15 |
| Week 10 | 80 | 7* | 82 | 7 | 45 | 12 | 41 | 11 |
| Reduction | 41%* | 55%* | 14% | 28% | ||||
| Erythema Score | ||||||||
| Baseline | 89 | 2.2 | 92 | 2.3 | 50 | 2.2 | 49 | 2.2 |
| Week 10 | 80 | 1.3* | 82 | 1.4* | 45 | 1.7 | 40 | 1.8 |
| Reduction | 42%* | 40%* | 25% | 19% | ||||
* Statistically significant differences between Noritate and vehicle groups with p ≤0.05. Erythema scores: 0=none, 1=mild, 2=moderate and 3=severe.
Studies of contact sensitization (n=258), phototoxicity (n=21), and photocontact sensitization (n=29) of Noritate were conducted. No evidence of sensitization or phototoxicity was seen in these studies.
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 topical 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 Noritate or any marketed metronidazole formulations.
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