Metronidazole

6 ADVERSE REACTIONS Most common adverse reactions (incidence > 2%) are nasopharyngitis, upper respiratory tract infection, and headache. To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747, 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 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 % System Organ Class/Preferred Term Metronidazole Gel USP, 1% Vehicle N= 557 N= 189 Patients with at least one AE Number (%) of Patients 186 (33.4) 51 (27.0) Infections and infestations 76 (13.6) 28 (14.8) Bronchitis 6 (1.1) 3 (1.6) Influenza 8 (1.4) 1 (0.5) Nasopharyngitis 17 (3.1) 8 (4.2) Sinusitis 8 (1.4) 3 (1.6) Upper respiratory tract infection 14 (2.5) 4 (2.1) Urinary tract infection 6 (1.1) 1 (0.5) Vaginal mycosis 1 (0.2) 2 (1.1) Musculoskeletal and connective tissue disorders 19 (3.4) 5 (2.6) Back pain 3 (0.5) 2 (1.1) Neoplasms 4 (0.7) 2 (1.1) Basal cell carcinoma 1 (0.2) 2 (1.1) Nervous system disorders 18 (3.2) 3 (1.6) Headache 12 (2.2) 1 (0.5) Respiratory, thoracic and mediastinal disorders 22 (3.9) 5 (2.6) Nasal congestion 6 (1.1) 3 (1.6) Skin and subcutaneous tissue disorders 36 (6.5) 12 (6.3) Contact dermatitis 7 (1.3) 1 (0.5) Dry skin 6 (1.1) 3 (1.6) Vascular disorders 8 (1.4) 1 (0.5) Hypertension 6 (1.1) 1 (0.5) Table 2: Local Cutaneous Signs and Symptoms of Irritation That Were Worse Than Baseline Metronidazole Gel USP, 1% Vehicle Sign/Symptom N= 544 N= 184 Dryness 138 (25.4) 63 (34.2) Mild 93 (17.1) 41 (22.3) Moderate 42 (7.7) 20 (10.9) Severe 3 (0.6) 2 (1.1) Scaling 134 (24.6) 60 (32.6) Mild 88 (16.2) 32 (17.4) Moderate 43 (7.9) 27 (14.7) Severe 3 (0.6) 1 (0.5) Pruritus 86 (15.8) 35 (19.0) Mild 53 (9.7) 21 (11.4) Moderate 27 (5.0) 13 (7.1) Severe 6 (1.1) 1 (0.5) Stinging/burning 56 (10.3) 28 (15.2) Mild 39 (7.2) 18 (9.8) Moderate 7 (1.3) 9 (4.9) Severe 10 (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 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 )]

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

11 DESCRIPTION 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 C 6 H 9 N 3 O 3 . 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 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. efb30dd0-figure-01

2 DOSAGE & ADMINISTRATION 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%. ● Not for oral, ophthalmic, or intravaginal use. ( 2 ) ● Cleanse treated areas before the application of metronidazole gel USP, 1%. ( 2 ) ● Apply and rub in a thin film of metronidazole gel USP, 1% once daily to affected area(s). ( 2 ) ● Cosmetics may be applied after the application of metronidazole gel USP, 1%. ( 2 )

1 INDICATIONS & USAGE Metronidazole gel USP, 1% is indicated for the topical treatment of inflammatory lesions of rosacea. Metronidazole gel USP, 1% is a nitroimidazole indicated for the topical treatment of inflammatory lesions of rosacea. ( 1 )

7 DRUG INTERACTIONS 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. Oral metronidazole has been reported to potentiate the anticoagulant effect of coumarin and warfarin, resulting in a prolongation of prothrombin time. Use caution when administering metronidazole gel USP, 1% concomitantly to patients who are receiving anticoagulant treatment.

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 USP, 1% on the QTc interval has not been adequately characterized. 12.3 Pharmacokinetics 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.

20220401

8

3 DOSAGE FORMS & STRENGTHS 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. Gel, 1%.

Metronidazole Metronidazole METRONIDAZOLE METRONIDAZOLE CETETH-20 EDETATE DISODIUM HYDROXYETHYL CELLULOSE (4000 MPA.S AT 1%) METHYLPARABEN NIACINAMIDE PHENOXYETHANOL PROPYLENE GLYCOL PROPYLPARABEN WATER

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, 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.

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, 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.

ANDA090903

Metronidazole

Metronidazole

0781-7080

HUMAN PRESCRIPTION DRUG

TOPICAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL efb30dd0-figure-02 efb30dd0-figure-03 efb30dd0-figure-04 efb30dd0-figure-05 efb30dd0-figure-06

17 PATIENT COUNSELING INFORMATION 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

PATIENT INFORMATION PATIENT INFORMATION Metronidazole Gel USP, 1% (me troe ni ’ da zole) Important: Metronidazole gel USP, 1% is for use on the skin only (topical use). Do not use metronidazole gel USP, 1% in your mouth, eyes, or vagina. What is metronidazole gel USP, 1%? Metronidazole gel USP, 1% is a prescription medicine used on the skin (topical) to treat pimples and bumps (inflammatory lesions) caused by a condition called rosacea. It is not known if metronidazole gel USP, 1% is safe and effective in children. Do not use metronidazole gel USP, 1% if you are allergic to metronidazole or any of the ingredients in metronidazole gel USP, 1%. See the end of this leaflet for a complete list of ingredients in metronidazole gel USP, 1%. Before using metronidazole gel USP, 1%, tell your healthcare provider about all your medical conditions, including if you: have tingling or numbness in your hands or feet have or have had a blood disorder or disease are pregnant or plan to become pregnant. It is not known if metronidazole gel USP, 1% will harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if metronidazole gel USP, 1% passes into your breast milk. Do not breastfeed during treatment with metronidazole gel USP, 1%. Talk to your healthcare provider about the best way to feed your baby during treatment with metronidazole gel USP, 1%. 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 a list of them to show your healthcare provider and pharmacist when you get a new medicine. How should I use metronidazole gel USP, 1%? Use metronidazole gel USP, 1% exactly as your healthcare provider tells you to. Cleanse the treated area before applying metronidazole gel USP, 1%. Apply and rub in a thin film of metronidazole gel USP, 1% 1 time a day to the affected area(s). You can apply cosmetics after applying metronidazole gel USP, 1%. Avoid contact of metronidazole gel USP, 1%with your eyes. What are the possible side effects of metronidazole gel USP, 1%? Metronidazole gel USP, 1% 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 USP, 1%. 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 USP, 1%. 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 USP, 1%. The most common side effects of metronidazole gel USP, 1% include: sore throat and nasal congestion upper respiratory tract infections headache Tell your healthcare provider if you get any side effects during treatment with metronidazole gel USP, 1%. These are not all of the possible side effects of metronidazole gel USP, 1%. 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 Sandoz Inc. at 1-800-525-8747. How should I store metronidazole gel USP, 1%? Store metronidazole gel USP, 1% at room temperature between 68°F to 77°F (20°C to 25°C). Keep metronidazole gel USP, 1% and all medicines out of the reach of children. General information about the safe and effective use of metronidazole gel USP, 1%. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use metronidazole gel USP, 1% for a condition for which it was not prescribed. Do not give metronidazole gel USP, 1% 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 USP, 1% that is written for health professionals. What are the ingredients in metronidazole gel USP, 1%? Active ingredient: metronidazole Inactive ingredients: betadex, edetate disodium, hydroxyethyl cellulose, methylparaben, niacinamide, phenoxyethanol, propylene glycol, propylparaben and purified water Manufactured by Tolmar, Inc. Fort Collins, CO 80526 for Sandoz Inc. Princeton, NJ 08540 For more information, call 1-866-735-4137. This Patient Information has been approved by the U.S. Food and Drug Administration. Issued: 04/2022 44445 Rev. 2 04/22

14 CLINICAL STUDIES 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 Metronidazole Gel USP, 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 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.

8.5 Geriatric Use 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.

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 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%.

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

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 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.

8 USE IN SPECIFIC POPULATIONS Lactation: Breastfeeding not recommended. ( 8.2 ) 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 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. 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 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%. 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 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.

16 HOW SUPPLIED 16.1 How Supplied Metronidazole Gel USP, 1% is clear, colorless to pale yellow in color, and supplied as follows: 60 gram tube – NDC 0781-7080-35 55 gram pump – NDC 0781-7080-55 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].