PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Topical administration of one-gram dose of metronidazole gel to the face of 13 subjects with moderate to severe rosacea once daily for days resulted in mean +- SD max of metronidazole of 32 +- ng/mL. The mean +- SD AUC (0-24) was 595 +- 154 nghr/mL. The mean max and AUC (0-24) are less than 1% of the value reported for single 250 mg oral dose of metronidazole. The time to maximum plasma concentration (T max) was 6-10 hours after topical application.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAvailable 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. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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.

SPL UNCLASSIFIED SECTION.

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

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 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/m 2/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/m 2/day. Metronidazole has shown evidence of mutagenic activity in several in vitro bacterial assay systems. In addition, 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 Crohns disease who were treated with 200 to 1200 mg/day of metronidazole for to 24 months. However, in another study, no increase in chromosomal aberrations in circulating lymphocytes was observed in patients with Crohns disease treated with the drug for months.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL. NDC 0713- 0574-60 Rx onlyMetronidazole Gel, USP 1%For Topical Use Only.Net Wt. 60 gCosette Pharmaceuticals, Inc.NDC 0713- 0574-60 Rx onlyMetronidazole Gel, USP 1%For Topical Use Only.Net Wt. 60 gCosette Pharmaceuticals, Inc.. carton-60gm. tube-60gm.

PATIENT MEDICATION INFORMATION SECTION.

PATIENT INFORMATION. Metronidazole (met roe nid zole)GelImportant: Metronidazole gel is for use on the skin only (topical use). Do not use metronidazole gel in your mouth, eyes, or vagina. What is metronidazole gelMetronidazole gel is prescription medicine used on the skin (topical) to treat pimples and bumps (inflammatory lesions) caused by condition called rosacea. It is not known if metronidazole gel is safe and effective in children. Do not use metronidazole gel if you are allergic to metronidazole or any of the ingredients in metronidazole gel. See the end of this leaflet for complete list of ingredients in metronidazole gel. Before using metronidazole gel, tell your healthcare provider about all your medical conditions, including if you:have tingling or numbness in your hands or feethave or have had blood disorder or diseaseare pregnant or plan to become pregnant. It is not known if metronidazole gel will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if metronidazole passes into your breast milk. Do not breastfeed during treatment with metronidazole gel. Talk to your healthcare provider about the best way to feed your baby during treatment with metronidazole gel.Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Know the medicines you take. Keep list of them to show your healthcare provider and pharmacist when you get new medicineHow should use metronidazole gelUse metronidazole gel exactly as your healthcare provider tells you to.Cleanse the treated area before applying metronidazole gel.Apply and rub in thin film of metronidazole gel time day to the affected area(s).You can apply cosmetics after applying metronidazole gel.Avoid contact of metronidazole gel with your eyes.What are the possible side effects of metronidazole gelMetronidazole gel may cause serious side effects, including:Peripheral neuropathy. Tingling, burning, pain or numbness in the hands or feet (peripheral neuropathy) have happened in people treated with metronidazole used on the skin. Tell your healthcare provider if you experience tingling, burning, pain or numbness in your hands or feet during treatment with metronidazole gel. Skin reactions, including allergic reactions. Tell your healthcare provider if you develop any skin reactions, including rash, itching, redness, swelling, or blisters during treatment with metronidazole gel. Eye irritation. Tearing from eye irritation has happened in people treated with metronidazole used on the skin. Tell your healthcare provider if you experience tearing, redness or discomfort of the eyes during treatment with metronidazole gel. The most common side effects of metronidazole gel include:sore throat and nasal congestionupper respiratory tract infectionsheadacheTell your healthcare provider if you get any side effects during treatment with metronidazole gel.These are not all of the possible side effects of metronidazole gel. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects to Cosette Pharmaceuticals, Inc. at 1-800-922-1038. How should store metronidazole gelStore metronidazole gel at room temperature between 68F to 77F (20C to 25C).Keep metronidazole gel and all medicines out of the reach of children.General information about the safe and effective use of metronidazole gel.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use metronidazole gel for condition for which it was not prescribed. Do not give metronidazole gel to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about metronidazole gel that is written for health professionals.What are the ingredients in metronidazole gelActive ingredient: metronidazole Inactive ingredients: betadex, edetate disodium, hydroxyethyl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparaben and purified water Distributed by:Cosette Pharmaceuticals, Inc. South Plainfield, NJ 07080 8-0574CPLNC2 VC7695This Patient Information has been approved by the U.S. Food and Drug AdministrationRevised: 10/2022. have tingling or numbness in your hands or feet. have or have had blood disorder or disease. are pregnant or plan to become pregnant. It is not known if metronidazole gel will harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if metronidazole passes into your breast milk. Do not breastfeed during treatment with metronidazole gel. Talk to your healthcare provider about the best way to feed your baby during treatment with metronidazole gel.. Use metronidazole gel exactly as your healthcare provider tells you to.. Cleanse the treated area before applying metronidazole gel.. Apply and rub in thin film of metronidazole gel time day to the affected area(s).. You can apply cosmetics after applying metronidazole gel.. Avoid contact of metronidazole gel with your eyes.. Peripheral neuropathy. Tingling, burning, pain or numbness in the hands or feet (peripheral neuropathy) have happened in people treated with metronidazole used on the skin. Tell your healthcare provider if you experience tingling, burning, pain or numbness in your hands or feet during treatment with metronidazole gel. Skin reactions, including allergic reactions. Tell your healthcare provider if you develop any skin reactions, including rash, itching, redness, swelling, or blisters during treatment with metronidazole gel. Eye irritation. Tearing from eye irritation has happened in people treated with metronidazole used on the skin. Tell your healthcare provider if you experience tearing, redness or discomfort of the eyes during treatment with metronidazole gel. sore throat and nasal congestion. upper respiratory tract infections. headache. Store metronidazole gel at room temperature between 68F to 77F (20C to 25C).

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. 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.

CLINICAL PHARMACOLOGY SECTION.

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 on the QTc interval has not been adequately characterized. 12.3 Pharmacokinetics. Topical administration of one-gram dose of metronidazole gel to the face of 13 subjects with moderate to severe rosacea once daily for days resulted in mean +- SD max of metronidazole of 32 +- ng/mL. The mean +- SD AUC (0-24) was 595 +- 154 nghr/mL. The mean max and AUC (0-24) are less than 1% of the value reported for single 250 mg oral dose of metronidazole. The time to maximum plasma concentration (T max) was 6-10 hours after topical application.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions (incidence 2%) are nasopharyngitis, upper respiratory tract infection, and headache.To report SUSPECTED ADVERSE REACTIONS, contact Cosette Pharmaceuticals, Inc. at 1-800-922-1038 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In 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 rate of >=1%: Table 1: Adverse Reactions That Occurred at Rate of >=1%System Organ Class/Preferred TermMetronidazole GelVehicleN= 557N= 189Patients with at least one AE Number (%) of Patients 186 (33.4)51 (27.0)Infections and infestations76 (13.6)28 (14.8) Bronchitis6 (1.1)3 (1.6) Influenza8 (1.4)1 (0.5) Nasopharyngitis17 (3.1)8 (4.2) Sinusitis8 (1.4)3 (1.6) Upper respiratory tract infection14 (2.5)4 (2.1) Urinary tract infection6 (1.1)1 (0.5) Vaginal mycosis1 (0.2)2 (1.1)Musculoskeletal and connective tissue disorders19 (3.4)5 (2.6) Back pain3 (0.5)2 (1.1)Neoplasms4 (0.7)2 (1.1) Basal cell carcinoma1 (0.2)2 (1.1)Nervous system disorders18 (3.2)3 (1.6) Headache12 (2.2)1 (0.5)Respiratory, thoracic and mediastinal disorders22 (3.9)5 (2.6) Nasal congestion6 (1.1)3 (1.6)Skin and subcutaneous tissue disorders36 (6.5)12 (6.3) Contact dermatitis7 (1.3)1 (0.5) Dry skin6 (1.1)3 (1.6)Vascular disorders8 (1.4)1 (0.5) Hypertension6 (1.1)1 (0.5)Table 2: Local Cutaneous Signs and Symptoms of Irritation That Were Worse Than BaselineMetronidazole GelVehicleSign/SymptomN= 544N= 184Dryness138 (25.4)63 (34.2) Mild93 (17.1)41 (22.3) Moderate42 (7.7)20 (10.9) Severe3 (0.6)2 (1.1)Scaling134 (24.6)60 (32.6) Mild88 (16.2)32 (17.4) Moderate43 (7.9)27 (14.7) Severe3 (0.6)1 (0.5)Pruritus86 (15.8)35 (19.0) Mild53 (9.7)21 (11.4) Moderate27 (5.0)13 (7.1) Severe6 (1.1)1 (0.5)Stinging/burning56 (10.3)28 (15.2) Mild39 (7.2)18 (9.8) Moderate7 (1.3)9 (4.9) Severe10 (1.8)1 (0.5)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.. 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 population of uncertain size, it is not always possible to reliably estimate the frequency or establish causal relationship to drug exposure.Nervous System Disorders: Peripheral neuropathy [see Warnings and Precautions 5.1)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. 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/m 2/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/m 2/day. Metronidazole has shown evidence of mutagenic activity in several in vitro bacterial assay systems. In addition, 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 Crohns disease who were treated with 200 to 1200 mg/day of metronidazole for to 24 months. However, in another study, no increase in chromosomal aberrations in circulating lymphocytes was observed in patients with Crohns disease treated with the drug for months.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. In randomized, vehicle-controlled trial, 746 subjects with rosacea were treated with metronidazole gel or vehicle once daily for 10 weeks. Most subjects had disease severity score of (moderate) on the 5-point Investigator Global Assessment (IGA) scale, with 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 (clear) or (almost clear) at Week 10.The efficacy results are shown in the following table:Table 3: Inflammatory Lesion Counts and Global Scores in Clinical Trial of Rosacea Metronidazole GelVehicleNResults (%)NResults (%)Inflammatory lesions557189Baseline, mean count18.318.4Week-10, mean count8.912.8Reduction9.4 (50.7)5.6 (32.6)Investigator Global Assessment557189Subject clear or almost clear214 (38.42)52 (27.51)Subject with no change159 (28.5)77 (40.7)Subjects treated with metronidazole gel experienced mean reduction of 9.4 inflammatory lesions in the Week-10 LOCF group, compared to reduction of 5.6 for those treated with vehicle, or difference in means of 3.8 lesions. The contribution to efficacy of individual components of the vehicle has not been established.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Metronidazole gel is contraindicated in patients with history of hypersensitivity to metronidazole or to any other ingredient in the formulation.. Metronidazole gel is contraindicated in those patients with history of hypersensitivity to metronidazole or to any other ingredient in this formulation. 4).

DESCRIPTION SECTION.

11 DESCRIPTION. Metronidazole gel USP 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 6H 9N 3O 3. It has the following structural formula: Metronidazole has molecular weight of 171.2. It is white to pale yellow crystalline powder. It is slightly soluble in water, acetone, alcohol and methylene chloride. Metronidazole belongs to the nitroimidazole class of compounds.Metronidazole gel USP is clear, colorless to pale yellow, aqueous gel; each gram contains 10 mg of metronidazole in base of betadex, edetate disodium, hydroxyethyl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparaben and purified water.. structural-formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For topical use only, not for oral, ophthalmic, or intravaginal use.Cleanse treated areas before the application of metronidazole gel.Apply and rub in thin film of metronidazole gel once daily to affected area(s).Cosmetics may be applied after the application of metronidazole gel.. Not for oral, ophthalmic, or intravaginal use. 2) Cleanse treated areas before the application of metronidazole gel.Apply and rub in thin film of metronidazole gel once daily to affected area(s). 2) Cosmetics may be applied after the application of metronidazole gel. 2) Not for oral, ophthalmic, or intravaginal use. 2) Cleanse treated areas before the application of metronidazole gel.. Apply and rub in thin film of metronidazole gel once daily to affected area(s). 2) Cosmetics may be applied after the application of metronidazole gel. 2).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Gel, 1%. Metronidazole gel USP is clear, colorless to pale yellow aqueous gel. Each gram of metronidazole gel USP contains 10 mg (1%) of metronidazole.. Gel, 1%.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and warfarin, resulting in prolongation of prothrombin time. Drug interactions should be kept in mind when metronidazole gel is prescribed for patients who are receiving anticoagulant treatment, although they are less likely to occur with topical metronidazole administration because of low absorption.. Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and warfarin, resulting in prolongation of prothrombin time. Use caution when administering metronidazole gel concomitantly to patients who are receiving anticoagulant treatment.

GERIATRIC USE SECTION.

8.5 Geriatric Use. 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. Metronidazole gel USP is clear, colorless to pale yellow in color aqueous gel, and supplied as follows: 60 gram tube NDC 0713-0574-60 16.2 Storage and Handling. Storage Conditions: Store at 20C to 25C (68F to 77F); excursions permitted from 15C to 30C (59F to 86F) [See USP Controlled Room Temperature].

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Metronidazole gel, 1% is indicated for the topical treatment of inflammatory lesions of rosacea.. Metronidazole gel, 1% is nitroimidazole indicated for the topical treatment of inflammatory lesions of rosacea.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Administration InstructionsUse as directed. Avoid contact with the eyes. Cleanse treated areas before the application of metronidazole gel. Advise patients to report any adverse reaction to their healthcare providers. LactationAdvise women not to breastfeed during treatment with metronidazole gel [see Use in Specific Populations 8.2)] Rx OnlyDistributed by:Cosette Pharmaceuticals, Inc. South Plainfield, NJ 07080 8-0574CPLNC2 VC7695.

LABOR & DELIVERY SECTION.

8.2 Lactation. Risk SummaryIt 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.

MECHANISM OF ACTION SECTION.

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

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Breastfeeding not recommended. 8.2) Lactation: Breastfeeding not recommended. 8.2) 8.1 Pregnancy. Risk SummaryAvailable 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. The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have 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 SummaryIt 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. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.. 8.5 Geriatric Use. 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. 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 gel therapy. 5.1) Blood Dyscrasias: Metronidazole is 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) 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 gel therapy. 5.1) Blood Dyscrasias: Metronidazole is 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) 5.1 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 gel therapy. Metronidazole should be administered with caution to patients with central nervous system diseases.. 5.2 Blood Dyscrasias. Metronidazole is nitroimidazole; use with care in patients with evidence of, or history of, blood dyscrasia.. 5.3 Contact Dermatitis. Irritant and allergic contact dermatitis have been reported with metronidazole gel. If dermatitis occurs, patients may need to discontinue use.. 5.4 Eye Irritation. Topical metronidazole has been reported to cause tearing of the eyes. Avoid contact with the eyes.