These Highlights Do Not Include All The Information Needed To Use Metronidazole Gel, 1% Safely And Effectively. See Full Prescribing Information For Metronidazole Gel, 1%.

This Patient Information has been approved by the U.S. Food and Drug Administration. 

 Issued: March 2024

Risk Summary



Available data have not established an association between 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.

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 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.

Metronidazole gel USP 1% is a nitroimidazole for topical use. Metronidazole gel, USP is a clear colorless to pale yellow gel. Each gram contains 10 mg of 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, odourless crystals or crystalline powder. It is sparingly soluble in water and alcohol, slightly soluble in ether and chloroform. Soluble in dilute hydrochloric acid. 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.

Safety and effectiveness of metronidazole have not been established in pediatric patients.

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.

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

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Neurologic Disease [see Warnings and Precautions (5.1)]
• Contact Dermatitis [see Warnings and Precautions (5.3)]
• Eye Irritation [see Warnings and Precautions (5.4)]

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.

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.

Cardiac Electrophysiology: The effect of metronidazole gel on the QTc interval has not been adequately characterized.

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. Immediately reevaluate metronidazole therapy if abnormal neurologic signs appear. Administer metronidazole 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, 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. Immediate reevaluate metronidazole therapy if abnormal neurologic signs appear. (5.1)
• Blood Dyscrasias: Metronidazole is a nitroimidazole; use 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. Avoid contact with the eyes. (5.4)

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

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

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

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% and at a higher rate than vehicle:

The following additional adverse reactions 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).



Administration Instructions



Use as directed. Avoid contact with the eyes [see Warnings and Precautions (5.4)]

Cleanse treated areas before the application of metronidazole gel [see Dosage and Administration (2)]

Advise patients to report any adverse reaction to their healthcare providers.

Neurologic Disease



Advise patients to immediately report any abnormal neurologic signs to their healthcare provider [see Warnings and Precautions (5.1)].

Lactation



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

Rx only

Distributed by:

Aurobindo Pharma USA, Inc.

279 Princeton-Hightstown Road

East Windsor, NJ 08520



Manufactured by:

Aurobindo Pharma Limited

Hyderabad-500 032, India



Issued: March 2024

How Supplied

Metronidazole gel USP, 1% is clear colorless to pale yellow in color, and supplied as follows:

60 gram tube                               NDC 59651-813-60

Storage and Handling



Storage Conditions: Store at 20º to 25ºC (68º to 77ºF); excursions permitted between to 15º to 30ºC (59º and 86ºF) [See USP Controlled Room Temperature].

NDC  59651-813-60

Metronidazole Gel, USP

1%

For topical use only

AUROBINDO                        Rx only                                NET WT. 60 g

NDC  59651-813-60

Metronidazole Gel, USP

1%

For topical use only

AUROBINDO             Rx only                       NET WT. 60 g

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.

This Patient Information has been approved by the U.S. Food and Drug Administration. 

 Issued: March 2024

Risk Summary



Available data have not established an association between 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.

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 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.

Metronidazole gel USP 1% is a nitroimidazole for topical use. Metronidazole gel, USP is a clear colorless to pale yellow gel. Each gram contains 10 mg of 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, odourless crystals or crystalline powder. It is sparingly soluble in water and alcohol, slightly soluble in ether and chloroform. Soluble in dilute hydrochloric acid. 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.

Safety and effectiveness of metronidazole have not been established in pediatric patients.

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.

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

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Neurologic Disease [see Warnings and Precautions (5.1)]
• Contact Dermatitis [see Warnings and Precautions (5.3)]
• Eye Irritation [see Warnings and Precautions (5.4)]

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.

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.

Cardiac Electrophysiology: The effect of metronidazole gel on the QTc interval has not been adequately characterized.

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. Immediately reevaluate metronidazole therapy if abnormal neurologic signs appear. Administer metronidazole 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, 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. Immediate reevaluate metronidazole therapy if abnormal neurologic signs appear. (5.1)
• Blood Dyscrasias: Metronidazole is a nitroimidazole; use 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. Avoid contact with the eyes. (5.4)

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

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

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

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% and at a higher rate than vehicle:

The following additional adverse reactions 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).



Administration Instructions



Use as directed. Avoid contact with the eyes [see Warnings and Precautions (5.4)]

Cleanse treated areas before the application of metronidazole gel [see Dosage and Administration (2)]

Advise patients to report any adverse reaction to their healthcare providers.

Neurologic Disease



Advise patients to immediately report any abnormal neurologic signs to their healthcare provider [see Warnings and Precautions (5.1)].

Lactation



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

Rx only

Distributed by:

Aurobindo Pharma USA, Inc.

279 Princeton-Hightstown Road

East Windsor, NJ 08520



Manufactured by:

Aurobindo Pharma Limited

Hyderabad-500 032, India



Issued: March 2024

How Supplied

Metronidazole gel USP, 1% is clear colorless to pale yellow in color, and supplied as follows:

60 gram tube                               NDC 59651-813-60

Storage and Handling



Storage Conditions: Store at 20º to 25ºC (68º to 77ºF); excursions permitted between to 15º to 30ºC (59º and 86ºF) [See USP Controlled Room Temperature].

NDC  59651-813-60

Metronidazole Gel, USP

1%

For topical use only

AUROBINDO                        Rx only                                NET WT. 60 g

NDC  59651-813-60

Metronidazole Gel, USP

1%

For topical use only

AUROBINDO             Rx only                       NET WT. 60 g

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.