Metronidazole

INDICATIONS AND USAGE Metronidazole vaginal gel is indicated in the treatment of bacterial vaginosis (formerly referred to as Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, or anaerobic vaginosis). NOTE: For purposes of this indication, a clinical diagnosis of bacterial vaginosis is usually defined by the presence of a homogeneous vaginal discharge that (a) has a pH of greater than 4.5, (b) emits a “fishy” amine odor when mixed with a 10% KOH solution, and (c) contains clue cells on microscopic examination. Gram’s stain results consistent with a diagnosis of bacterial vaginosis include (a) markedly reduced or absent Lactobacillus morphology, (b) predominance of Gardnerella morphotype, and (c) absent or few white blood cells. Other pathogens commonly associated with vulvovaginitis, e.g., Trichomonas vaginalis , Chlamydia trachomatis , N. gonorrhoeae , Candida albicans , and Herpes simplex virus should be ruled out.

2 DOSAGE AND ADMINISTRATION 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. Cleanse treated areas before the application of Metronidazole Gel. ( 2 ) Apply and rub in a 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 )

3 DOSAGE FORMS AND STRENGTHS Gel, 1%. Metronidazole gel USP is a clear, colorless to pale yellow aqueous gel. Each gram of metronidazole gel USP contains 10 mg (1%) of metronidazole. Gel, 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. ( 4 )

ADVERSE EVENTS Clinical Trials There were no deaths or serious adverse events related to drug therapy in clinical trials involving 800 non-pregnant women who received metronidazole vaginal gel. In a randomized, single-blind clinical trial of 505 non-pregnant women who received metronidazole vaginal gel once or twice a day, 2 patients (one from each regimen) discontinued therapy early due to drug-related adverse events. One patient discontinued drug because of moderate abdominal cramping and loose stools, while the other patient discontinued drug because of mild vaginal burning. These symptoms resolved after discontinuation of drug. Medical events judged to be related, probably related, or possibly related to administration of metronidazole vaginal gel once or twice a day were reported for 195/505 (39%) patients. The incidence of individual adverse reactions were not significantly different between the two regimens. Unless percentages are otherwise stipulated, the incidence of individual adverse reactions listed below was less than 1%: Reproductive: Vaginal discharge (12%), Symptomatic Candida cervicitis/vaginitis (10%), Vulva/vaginal irritative symptoms (9%), Pelvic discomfort (3%). Gastrointestinal: Gastrointestinal discomfort (7%), Nausea and/or vomiting (4%), Unusual taste (2%), Diarrhea/loose stools (1%), Decreased appetite (1%), Abdominal bloating/gas; thirsty, dry mouth. Neurologic: Headache (5%), Dizziness (2%), Depression. Dermatologic: Generalized itching or rash. Other: Unspecified cramping (1%), Fatigue, Darkened urine. In previous clinical trials submitted for approved labeling of metronidazole vaginal gel the following was also reported: Laboratory: Increased/decreased white blood cell counts (1.7%). Other Metronidazole Formulations Other effects that have been reported in association with the use of topical (dermal) formulations of metronidazole include skin irritation, transient skin erythema, and mild skin dryness and burning. None of these adverse events exceeded an incidence of 2% of patients. Metronidazole vaginal gel affords minimal peak serum levels and systemic exposure (AUC) of metronidazole compared to 500 mg oral metronidazole dosing. Although these lower levels of exposure are less likely to produce the common reactions seen with oral metronidazole, the possibility of these and other reactions cannot be excluded presently. The following adverse reactions and altered laboratory tests have been reported with the oral or parenteral use of metronidazole: Cardiovascular: Flattening of the T-wave may be seen in electrocardiographic tracings. Central Nervous System: (See WARNINGS ) Headache, dizziness, syncope, ataxia, confusion, convulsive seizures, peripheral neuropathy, vertigo, incoordination, irritability, depression, weakness, insomnia. Gastrointestinal: Abdominal discomfort, nausea, vomiting, diarrhea, an unpleasant metallic taste, anorexia, epigastric distress, abdominal cramping, constipation, “furry” tongue, glossitis, stomatitis, pancreatitis, and modification of taste of alcoholic beverages. Genitourinary: Overgrowth of Candida in the vagina, dyspareunia, decreased libido, proctitis. Hematopoietic: Reversible neutropenia, reversible thrombocytopenia. Hypersensitivity Reactions: Urticaria; erythematous rash; flushing; nasal congestion; dryness of the mouth, vagina, or vulva; fever; pruritus; fleeting joint pains. Renal: Dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure, darkened urine. To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Drug Interactions Oral metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other coumarin anticoagulants, resulting in a prolongation of prothrombin time. This possible drug interaction should be considered when metronidazole vaginal gel is prescribed for patients on this type of anticoagulant therapy. In patients stabilized on relatively high doses of lithium, short-term oral metronidazole therapy has been associated with elevation of serum lithium levels and, in a few cases, signs of lithium toxicity. Use of cimetidine with oral metronidazole may prolong the half-life and decrease plasma clearance of metronidazole. Drug/Laboratory Test Interactions Metronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminotransferase (ALT, SGPT), lactate dehydrogenase (LDH), triglycerides, and glucose hexokinase. Values of zero may be observed. All of the assays in which interference has been reported involve enzymatic coupling of the assay to oxidation-reduction of nicotinamide-adenine dinucleotides (NAD + NADH). Interference is due to the similarity in absorbance peaks of NADH (340 nm) and metronidazole (322 nm) at pH 7.

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. 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. 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.

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

DESCRIPTION Metronidazole vaginal gel is the intravaginal dosage form of the synthetic antibacterial agent, metronidazole, USP at a concentration of 0.75%. Metronidazole is a member of the imidazole class of antibacterial agents and is classified therapeutically as an antiprotozoal and antibacterial agent. Chemically, metronidazole is a 2-methyl-5-nitroimidazole-1-ethanol. It has a chemical formula of C 6 H 9 N 3 O 3 , a molecular weight of 171.16, and has the following structure: Metronidazole vaginal gel is a gelled, purified water solution, containing metronidazole at a concentration of 7.5 mg/g (0.75%). The gel is formulated at pH 4.0. The gel also contains carbomer homopolymer type B, edetate disodium, methylparaben, propylparaben, propylene glycol, and sodium hydroxide. Each applicator full of 5 grams of vaginal gel contains approximately 37.5 mg of metronidazole. Chemical Structure

OVERDOSAGE There is no human experience with overdosage of metronidazole vaginal gel. Vaginally applied metronidazole gel, 0.75% could be absorbed in sufficient amounts to produce systemic effects. (See WARNINGS .)

HOW SUPPLIED Metronidazole vaginal gel, 0.75% is supplied in a 70 gram tube and packaged with 5 vaginal applicators. The NDC number for the 70 gram tube is 0713-0575-71. Storage: Store at 20°C to 25°C (68°F to 77°F). Excursions permitted from 15°C to 30°C (59°F to 86°F). Protect from freezing. Clinical Studies In a randomized, single-blind clinical trial of non-pregnant women with bacterial vaginosis who received metronidazole vaginal gel daily for 5 days, the clinical cure rates for evaluable patients determined at 4 weeks after completion of therapy for the QD and BID regimens were 98/185 (53%) and 109/190 (57%), respectively. Distributed by: Cosette Pharmaceuticals, Inc. South Plainfield, NJ 07080 Rev. 03/2022 8-0575CPLNC1 VC7601 Metronidazole Vaginal Gel, 0.75% DIRECTIONS FOR USE 1. Filling the applicator Remove cap and puncture metal seal on tube with the pointed tip of cap. (See Figure 1) Screw end of applicator onto tube. (See Figure 2) Gently squeeze the tube from the bottom to fill applicator. Plunger will stop when the applicator is full. (See Figure 3) Unscrew applicator and replace cap on tube. 2. Inserting the applicator The applicator may be inserted while lying on your back with your knees bent or in any comfortable position. Hold filled applicator by barrel, and gently insert into vagina as far as it will comfortably go. (See Figure 4) Slowly press the plunger until it stops to deposit gel into vagina and then withdraw the applicator. 3. Care of the applicator If physician prescribes twice-a-day dosing: After use, pull the plunger out of the barrel. (See Figure 5) Wash both plunger and barrel in warm soapy water and rinse thoroughly. To reassemble applicator, gently push plunger back into barrel. IMPORTANT For once-a-day dosing, apply one applicator full at bedtime. For twice-a-day dosing, apply one applicator full each morning and evening for 5 days, or as directed by physician. WARNINGS If significant irritation develops from the use of this medication, discontinue use and consult your physician. Do not use during pregnancy except under the supervision of a physician. Keep this and all medications out of reach of children. For vaginal use only. Not for use in the eyes, on the skin or in the mouth. Store at room temperature. Avoid exposure to extreme heat or cold. See end of carton and bottom of tube for lot number and expiration date. Distributed by: Cosette Pharmaceuticals, Inc. South Plainfield, NJ 07080 Rev. 03/2022 8-0575CPLNC1 VC7601 Figure 1 Figure 2 Figure 3 Figure 4 Figure 5