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Metrogel (Metronidazole Topical Gel) - Description and Clinical Pharmacology

 
 



DESCRIPTION

METROGEL (metronidazole) Gel, 1% contains metronidazole, USP. Chemically, metronidazole is 2-methyl-5-nitro-1 H-imidazole-1-ethanol. The molecular formula for metronidazole is C6H9N3O3. It has the following structural formula:

Metronidazole has a molecular weight of 171.16. It is a white to pale yellow crystalline powder. It is slightly soluble in alcohol and has solubility in water of 10 mg/mL at 20˚C. Metronidazole belongs to the nitroimidazole class of compounds.

METROGEL is a clear, colorless to pale yellow, aqueous gel; each gram contains 10 mg of metronidazole in a base of betadex, edetate disodium, hydroxyethyl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparaben and purified water.

CLINICAL PHARMACOLOGY


Mechanism of Action

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

Pharmacodynamics

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

Pharmacokinetics

Topical administration of a one gram dose of METROGEL 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.

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/day 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.

CLINICAL STUDIES

In a randomized, vehicle-controlled trial, 746 subjects with rosacea were treated with metronidazole gel, 1% or gel vehicle once daily for 10 weeks.  Most subjects had “moderate” rosacea at baseline. Efficacy was determined by recording reduction in inflammatory lesion counts and success rate in the Investigator Global Assessment (percentage of subjects “clear” and “almost clear” of rosacea at the end of the study). The scale is based on the following definitions:

Table 3: Investigator Global Assessment Scale
Score Grade Definition
0 Clear No signs or symptoms present; at most, mild erythema
1 Almost Clear Very mild erythema present. Very few small papules/pustules
2 Mild Mild erythema.  Several small papules/pustules
3 Moderate Moderate erythema.  Several small or large papules/pustules, and up to 2 nodules
4 Severe Severe erythema.  Numerous small and/or large papules/pustules, up to several nodules

The results are shown in the following table:

Table 4: Inflammatory Lesion Counts and Global Scores in a Clinical Trial of Rosacea
  Metronidazole Gel, 1% Vehicle
N Results N (%) N Results N (%)
Inflammatory lesions 557   189  
Baseline, mean count   18.3   18.4
Week-10, mean count   8.9   12.8
Reduction   9.4 (50.7)   5.6 (32.6)
Investigator Global Assessment 557   189  
Subject clear or almost clear   214 (38.42)   52 (27.51)
Subject with no change   159 (28.5)   77 (40.7)

Subjects treated with metronidazole gel, 1% 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.

The contribution to efficacy of individual components of the vehicle has not been established.

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