Metronidazole Vaginal Gel, 1.3 %

1 INDICATIONS AND USAGE Metronidazole vaginal gel is indicated for the treatment of bacterial vaginosis in females 12 years of age and older. Metronidazole vaginal gel is a nitroimidazole antimicrobial indicated for the treatment of bacterial vaginosis in females 12 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION A single-dose, pre-filled disposable applicator (which delivers approximately 5 g of gel containing 65 mg of metronidazole) administered once intravaginally. Metronidazole vaginal gel should be administered at bedtime. Metronidazole vaginal gel, 1.3% is not for ophthalmic, dermal or oral use. • A single-dose, pre-filled disposable applicator administered once intravaginally at bedtime. (2) • Metronidazole vaginal gel is not for ophthalmic, dermal, or oral use. (2)

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 The most common adverse reactions observed in adult clinical studies (incidence ≥1%) were vulvovaginal candidiasis, headache, vulvovaginal pruritus, nausea, diarrhea, and dysmenorrhea. The most common adverse reactions observed in pediatric clinical studies (incidence ≥1%) was vulvovaginal discomfort. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact. Encube Ethicals Private Limited, at 1-833-285-4151 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Clinical Trial Experience in Adult Patients The safety of metronidazole vaginal gel was evaluated in a randomized, double-blind, vehicle-controlled study in subjects with bacterial vaginosis. A total of 321 non-pregnant females with a mean age of 33.4 years (range 18 to 67 years) received metronidazole vaginal gel. Subjects were primarily Black/African American (58.3%) or White (39.3%).Subjects administered a single dose of metronidazole vaginal gel at bedtime on the first day of the study. There were no deaths or serious adverse reactions in this trial. Adverse reactions were reported by 19.0% of subjects treated with metronidazole vaginal gel versus 16.1% of subjects treated with Vehicle Gel. Adverse reactions occurring in ≥1% of subjects receiving metronidazole vaginal gel were: vulvovaginal candidiasis (5.6%), headache (2.2%), vulvovaginal pruritus (1.6%), nausea (1.6%), diarrhea (1.2%), and dysmenorrhea (1.2%). No subjects discontinued treatment due to adverse reactions. Clinical Trial Experience in Pediatric Patients The safety of metronidazole vaginal gel was evaluated in a multicenter, open-label study evaluating the safety and tolerability of metronidazole vaginal gel in 60 pediatric subjects between the ages of 12 and less than 18 years old all of whom were treated with a single dose of metronidazole vaginal gel administered once at bedtime intravaginally. Most subjects in this study were either Black/African-American, non-Hispanic (47%) or Hispanic (35 %) Safety in pediatric female patients aged 12 to less than 18 years old was comparable to adult women. No deaths occurred and no subjects discontinued due to adverse reactions. Adverse reactions occurring in ≥ 1% of pediatric subjects included: vulvovaginal discomfort (2%). 6.2 Other Metronidazole Formulations Other Vaginal Formulations Other reactions that have been reported in association with the use of other formulations of metronidazole vaginal gel include: unusual taste and decreased appetite. Topical (Dermal) Formulations Other reactions 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 reactions exceeded an incidence of 2% of patients. Oral and Parenteral Formulations 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. Nervous System: The most serious adverse reactions reported in patients treated with oral metronidazole have been convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity. In addition, patients have reported syncope, vertigo, incoordination, ataxia, confusion, dysarthria, irritability, depression, weakness, and insomnia [see Warnings and Precautions ( 5.1 )]. 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; Stevens-Johnson Syndrome, toxic epidermal necrolysis, flushing; nasal congestion; dryness of the mouth, vagina, or vulva; fever; pruritus; fleeting joint pains [see Contraindications ( 4 )]. Renal: Dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure, darkened urine.

12.3 Pharmacokinetics Following a single, intravaginal 5 g dose of metronidazole vaginal gel (equivalent to 65 mg of metronidazole) to 20 healthy female subjects, a mean maximum serum metronidazole concentration (Cmax) of 239 ng/mL was observed (range: 114 to 428 ng/mL). The average time to achieve this Cmax was 7.3 hours (range: 4 to 18 hours). This Cmax is approximately 2% of the mean maximum serum concentration reported in healthy subjects administered a single, oral 500 mg dose of metronidazole tablets (mean Cmax = 12,785 ng/mL). The extent of exposure [area under the curve (AUC)] of metronidazole, when administered as a single intravaginal 5 g dose of metronidazole vaginal gel (equivalent to 65 mg of metronidazole), was 5,434 ng•hr/mL (range: 1382 to 12744 ng•hr/mL). This AUC 0-∞ is approximately 4% of the reported AUC of metronidazole following a single oral 500 mg dose of metronidazole (approximately 125,000 ng•hr/mL).