METRONIDAZOLE VAGINAL GEL

Metronidazole vaginal gel contains 1.3% metronidazole, USP in a single-dose prefilled disposable applicator. It is intended for intravaginal use. Metronidazole is a nitroimidazole antimicrobial. Chemically, metronidazole is a 2-methyl-5-nitroimidazole-1-ethanol. Its structural formula is: The molecular formula is C 6 H 9 N 3 O 3 with a molecular weight of 171.16. Metronidazole vaginal gel is an aqueous gel containing metronidazole at a concentration of 13 mg/g (1.3%). The gel is formulated at pH 4.0. The gel also contains benzyl alcohol, methyl paraben, polycarbophil, polyethylene glycol 400, propylene glycol, propyl paraben, and purified water. Each applicator contains approximately 65 mg of metronidazole in 5 g of vaginal gel. str

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 )

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)

• History of hypersensitivity to metronidazole, parabens, other ingredients of the formulation, or other nitroimidazole derivatives (4.1) • Concomitant use of disulfiram or within 2 weeks of disulfiram ( 4.2 , 7.1 ) • Concomitant use of alcohol ( 4.3 , 7.2 ) 4.1 Hypersensitivity Metronidazole vaginal gel is contraindicated in persons who have shown hypersensitivity to metronidazole, parabens, other ingredients of the formulation, or other nitroimidazole derivatives. 4.2 Use of Disulfiram Psychotic reactions have been reported with co-administration of disulfiram and oral metronidazole. Do not administer concurrently with or within 2 weeks of disulfiram. 4.3 Concomitant Alcohol Disulfiram-like reactions to alcohol have been reported with co-administration of oral metronidazole; do not consume ethanol or propylene glycol, during and for at least 24 hours following treatment.

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.

The intravaginal administration of a single dose of metronidazole vaginal gel results in lower systemic exposure to metronidazole that is approximately 2% to 4% of that achieved following oral administration of 500 mg metronidazole tablets [see Clinical Pharmacology ( 12.3 )]. The following drug interactions were reported for oral metronidazole. • Warfarin and other coumarin anticoagulants: Prolonged anticoagulant effects of warfarin and other coumarin anticoagulants have been reported with co-administration of oral metronidazole. ( 7.3 ) • Lithium: Elevated plasma lithium concentrations have been reported with oral metronidazole. ( 7.4 ) 7.1 Disulfiram Use of oral metronidazole has been associated with psychotic reactions in alcoholic patients who are using disulfiram concurrently. Metronidazole vaginal gel should not be used by patients who have taken disulfiram within the last two weeks [see Contraindications ( 4.2 )]. 7.2 Alcoholic Beverages Use of oral metronidazole has been associated with a disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) to alcohol. Alcoholic beverages and preparations containing ethanol or propylene glycol should not be consumed during and for at least 24 hours after metronidazole vaginal gel therapy [see Contraindications ( 4.3 )] . 7.3 Coumarin and Other Oral Anticoagulants Use of 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. 7.4 Lithium Short-term use of oral metronidazole has been associated with elevation of plasma lithium concentrations and, in a few cases, signs of lithium toxicity in patients stabilized on relatively high doses of lithium. 7.5 Cimetidine Use of oral metronidazole with cimetidine may prolong the half-life and decrease plasma clearance of metronidazole. No dose adjustment of metronidazole vaginal gel is necessary.