Metronidazole
FDA Label NDC 72162-2159

Metronidazole gel USP, 1% is indicated for the topical treatment of inflammatory lesions of rosacea.

For topical use only, not for oral, ophthalmic, or intravaginal use.
Cleanse treated areas before the application of metronidazole gel USP, 1%.
Apply and rub in a thin film of metronidazole gel USP, 1% once daily to affected area(s).
Cosmetics may be applied after the application of metronidazole gel USP, 1%.

Gel, 1%. Metronidazole gel USP, 1% is a clear, colorless to pale yellow gel.  Each gram of metronidazole gel USP, 1% contains 10 mg (1%) of metronidazole.

Metronidazole gel USP, 1% is contraindicated in patients with a history of  hypersensitivity to metronidazole or to any other ingredient in the formulation.

Peripheral neuropathy, characterized by numbness or paresthesia of an extremity, has been reported in patients treated with systemic metronidazole. Peripheral neuropathy has been reported with the post approval use of topical metronidazole. The appearance of abnormal neurologic signs should prompt immediate reevaluation of  metronidazole gel USP, 1% therapy. Metronidazole should be administered with caution to patients with central nervous system diseases.

Metronidazole gel USP, 1% is a nitroimidazole; use with care in patients with evidence of, or history of, blood dyscrasia.

Irritant and allergic contact dermatitis have been reported with metronidazole gel USP, 1%. If dermatitis occurs, patients may need to discontinue use.

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

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 subjects used metronidazole gel USP, 1% and 189 subjects 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: transient redness, metallic taste, tingling or numbness of extremities, and nausea.

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 [see Warnings and Precautions (5.1)]

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 metronidazole gel USP, 1% is prescribed for patients who are receiving anticoagulant treatment, although they are less likely to occur with topical metronidazole administration because of low absorption.

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 USP, 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 to 4% and 15 to 20%, respectively.

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 reports of diarrhea and candida infection in breastfed infants of mothers receiving oral treatment with metronidazole. 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 USP, 1%.

Safety and effectiveness in pediatric patients have not been established.

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

Metronidazole gel USP, 1% contains metronidazole, USP.  It is intended for topical use. 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:

Efb30dd0-figure-01 (Metronidazole Gel Usp 1)

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.

Metronidazole gel USP, 1% is a clear, colorless to pale yellow,  aqueous gel; each gram contains 10 mg of metronidazole in a base of ceteth-20, edetate disodium, hydroxyethyl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparaben and purified water.

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

The pharmacodynamics of metronidazole in association with the treatment of rosacea are unknown.
Cardiac Electrophysiology: The effect of metronidazole gel USP, 1% on the QTc interval has not been adequately characterized.

Topical administration of a one-gram dose of metronidazole gel USP, 1% 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 to 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 metronidazole gel USP, 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:

Table 3: Inflammatory Lesion Counts and Global Scores in a Clinical Trial of Rosacea

Subjects treated with metronidazole gel USP, 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.

16.1 How Supplied
Metronidazole Gel USP, 1% is clear, colorless to pale yellow in color, and supplied as follows:

NDC: 72162-2159-6: 60 grams in a TUBE

16.2 Storage and Handling
Storage Conditions: Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Repackaged/Relabeled by:
Bryant Ranch Prepack, Inc.
Burbank, CA 91504

Advise the patient to read the FDA-approved patient labeling (Patient Information).

Administration Instructions
Use as directed. Avoid contact with the eyes.
Cleanse treated areas before the application of metronidazole gel USP, 1%
Advise patients to report any adverse reaction to their healthcare providers.

Lactation
Advise women not to breastfeed during treatment with metronidazole gel USP, 1% [see Use in Specific Populations (8.2)].

Rx Only

Manufactured by
Tolmar, Inc.
Fort Collins, CO 80526 for
Sandoz Inc.
Princeton, NJ 08540
44445 Rev. 2 04/22

 This Patient Information has been approved by the U.S. Food and Drug Administration.                                 Issued: 04/2022
 44445 Rev. 2 04/22

Metronidazole 1% Gel #60

Label (Lbl721622159)