METRONIDAZOLE

Metronidazole vaginal gel, 0.75% 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, 0.75% 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 974P , edetate disodium, methyl paraben, propyl paraben, propylene glycol, and sodium hydroxide. Each applicator full of 5 grams of vaginal gel contains approximately 37.5 mg of metronidazole. structure

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.

The recommended dose is one applicator full of metronidazole vaginal gel, 0.75% (approximately 5 grams containing approximately 37.5 mg of metronidazole) intravaginally once or twice a day for 5 days. For once a day dosing, metronidazole vaginal gel, 0.75% should be administered at bedtime.

Metronidazole vaginal gel is contraindicated in patients with a prior history of hypersensitivity to metronidazole, parabens, other ingredients of the formulation, or other nitroimidazole derivatives.

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 Solaris Pharma Corporation at 1-833-919-0527 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.