Metronidazole (Page 2 of 3)
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
7 DRUG INTERACTIONS
Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and warfarin, resulting in a prolongation of prothrombin time. Use caution when prescribing for patients who are receiving anticoagulant treatment.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Risk Summary
Available data have not established an association with 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, 1%.
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 2-4% and 15-20%, 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, 1%.
8.4 Pediatric Use
Safety and effectiveness of Metronidazole Gel, 1% have not been established in pediatric patients.
8.5 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.
11 DESCRIPTION
Metronidazole Gel, 1% is a nitromidazole for topical use. Metronidazole Gel, 1% is a clear, colorless to pale yellow, aqueous gel. Each gram contains 10 mg of metronidazole. Chemically, metronidazole is 2-methyl-5-nitro-1 H- imidazole-1-ethanol. The molecular formula for metronidazole is C6 H9 N3 O3 . 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.The inactive ingredients are betadex, edetate disodium, hydroxyethyl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparaben and purified water.
12 CLINICAL PHARMACOLOGY
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, 1% on the QTc interval has not been adequately characterized.
12.3 Pharmacokinetics
Topical administration of a one gram dose of Metronidazole Gel, 1% 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 6-10 hours after topical application.
13 NONCLINICAL TOXICOLOGY
13.1 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 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.
14 CLINICAL STUDIES
In a randomized, vehicle-controlled trial, 746 subjects with rosacea were treated with Metronidazole Gel, 1% 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:
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.
All MedLibrary.org resources are included in as near-original form as possible, meaning that the information from the original provider has been rendered here with only typographical or stylistic modifications and not with any substantive alterations of content, meaning or intent.