These Highlights Do Not Include All The Information Needed To Use Metronidazole Gel Safely And Effectively. See Full Prescribing Information For Metronidazole Gel.

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.

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.

5201281-1222-01

782

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:

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 is a colorless to slightly yellow gel; each gram contains 10 mg of metronidazole in a base of alcohol (9.3% w/w), edetate disodium, hydroxyethylcellulose, polyethylene glycol 400, propylene glycol, sorbic acid, and purified water.

Metronidazole Gel USP, 1% is colorless to slightly yellow in color, and supplied as follows:

45 gram tube - (NDC 51672-4215-6)

60 gram tube - (NDC 51672-4215-3)

55 gram pump - (NDC 51672-4215-9)

Safety and effectiveness in pediatric patients have not been established.

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

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

In a randomized, vehicle-controlled trial, 746 subjects with rosacea were treated with metronidazole gel 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:

Subjects treated with metronidazole gel 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.

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

Most common adverse reactions (incidence > 2%) are nasopharyngitis, upper respiratory tract infection, and headache. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Taro Pharmaceuticals U.S.A., Inc. at 1-866-923-4914 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

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

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

Topical administration of a one-gram dose of metronidazole gel 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.

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 therapy. Metronidazole should be administered with caution to patients with central nervous system diseases.

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

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

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

• •
  Neurologic Disease: 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 therapy. (5.1)
• •
  Blood Dyscrasias: Metronidazole is a nitroimidazole and should be used with care in patients with evidence of, or history of, blood dyscrasia. (5.2)
• •
  Contact Dermatitis: If dermatitis occurs, patients may need to discontinue use. (5.3)
• •
  Eye Irritation: Topical metronidazole has been reported to cause tearing of the eyes. Therefore, avoid contact with the eyes. (5.4)

For topical use only, not for oral, ophthalmic, or intravaginal use.

Cleanse treated areas before the application of metronidazole gel.

Apply and rub in a thin film of metronidazole gel once daily to affected area(s).

Cosmetics may be applied after the application of metronidazole gel.

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

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)]

• •
  Lactation: Breastfeeding not recommended. (8.2)

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 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%:

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.

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

NDC 51672-4215-3

Metronidazole

Gel USP, 1%

60 g

FOR TOPICAL USE ONLY. NOT FOR ORAL, OPHTHALMIC OR INTRAVAGINAL USE.

Rx only

Keep this and all medications out of the reach of children.

TARO

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.

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.

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.

5201281-1222-01

782

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:

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 is a colorless to slightly yellow gel; each gram contains 10 mg of metronidazole in a base of alcohol (9.3% w/w), edetate disodium, hydroxyethylcellulose, polyethylene glycol 400, propylene glycol, sorbic acid, and purified water.

Metronidazole Gel USP, 1% is colorless to slightly yellow in color, and supplied as follows:

45 gram tube - (NDC 51672-4215-6)

60 gram tube - (NDC 51672-4215-3)

55 gram pump - (NDC 51672-4215-9)

Safety and effectiveness in pediatric patients have not been established.

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

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

In a randomized, vehicle-controlled trial, 746 subjects with rosacea were treated with metronidazole gel 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:

Subjects treated with metronidazole gel 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.

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

Most common adverse reactions (incidence > 2%) are nasopharyngitis, upper respiratory tract infection, and headache. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Taro Pharmaceuticals U.S.A., Inc. at 1-866-923-4914 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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

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

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

Topical administration of a one-gram dose of metronidazole gel 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.

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 therapy. Metronidazole should be administered with caution to patients with central nervous system diseases.

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

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

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

• •
  Neurologic Disease: 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 therapy. (5.1)
• •
  Blood Dyscrasias: Metronidazole is a nitroimidazole and should be used with care in patients with evidence of, or history of, blood dyscrasia. (5.2)
• •
  Contact Dermatitis: If dermatitis occurs, patients may need to discontinue use. (5.3)
• •
  Eye Irritation: Topical metronidazole has been reported to cause tearing of the eyes. Therefore, avoid contact with the eyes. (5.4)

For topical use only, not for oral, ophthalmic, or intravaginal use.

Cleanse treated areas before the application of metronidazole gel.

Apply and rub in a thin film of metronidazole gel once daily to affected area(s).

Cosmetics may be applied after the application of metronidazole gel.

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

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)]

• •
  Lactation: Breastfeeding not recommended. (8.2)

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 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%:

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.

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

NDC 51672-4215-3

Metronidazole

Gel USP, 1%

60 g

FOR TOPICAL USE ONLY. NOT FOR ORAL, OPHTHALMIC OR INTRAVAGINAL USE.

Rx only

Keep this and all medications out of the reach of children.

TARO

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.