METROGEL-VAGINAL- metronidazole gel
Graceway Pharmaceuticals, LLC
FOR INTRAVAGINAL USE ONLY
NOT FOR OPHTHALMIC, DERMAL, OR ORAL USE
METROGEL-VAGINAL 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 anti‑bacterial agent. Chemically, metronidazole is a 2-methyl-5-nitroimidazole-1-ethanol. It has a chemical formula of C6 H9 N3 O3 , a molecular weight of 171.16, and has the following structure:
METROGEL-VAGINAL 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 934P, 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.
Following a single, intravaginal 5 gram dose of metronidazole vaginal gel (equivalent to 37.5 mg of metronidazole) to 12 normal subjects, a mean maximum serum metronidazole concentration of 237 ng/mL was reported (range: 152 to 368 ng/mL). This is approximately 2% of the mean maximum serum metronidazole concentration reported in the same subjects administered a single, oral 500 mg dose of metronidazole (mean Cmax = 12,785 ng/mL, range: 10,013 to 17,400 ng/mL). These peak concentrations were obtained in 6 to 12 hours after dosing with metronidazole vaginal gel and 1 to 3 hours after dosing with oral metronidazole.
The extent of exposure [area under the curve (AUC)] of metronidazole, when administered as a single intravaginal 5 gram dose of metronidazole vaginal gel (equivalent to 37.5 mg of metronidazole), was approximately 4% of the AUC of a single oral 500 mg dose of metronidazole (4977 ng-hr/mL and approximately 125,000 ng-hr/mL, respectively).
Dose-adjusted comparisons of AUCs demonstrated that, on a mg to mg comparison basis, the absorption of metronidazole, when administered vaginally, was approximately half that of an equivalent oral dosage.
Following single and multiple 5 gram doses of metronidazole vaginal gel to 4 patients with bacterial vaginosis, a mean maximum serum metronidazole concentration of 214 ng/mL on day 1 and 294 ng/mL (range: 228 to 349 ng/mL) on day five were reported. Steady state metro‑nidazole serum concentrations following oral dosages of 400 to 500 mg BID have been reported to range from 6,000 to 20,000 ng/mL.
The intracellular targets of action of metronidazole on anaerobes are largely unknown. The 5-nitro group of metronidazole is reduced by metabolically active anaerobes, and studies have demonstrated that the reduced form of the drug interacts with ‑bacterial DNA. However, it is not clear whether interaction with DNA alone is an important component in the bactericidal action of metronidazole on anaerobic organisms.
Culture and sensitivity testing of bacteria are not routinely performed to establish the diagnosis of bacterial vaginosis. (See INDICATIONS AND USAGE.)
Standard methodology for the susceptibility testing of the potential bacterial vaginosis pathogens, Gardnerella vaginalis , Mobiluncus spp., and Mycoplasma hominis , has not been defined. Nonetheless, metronidazole is an antimicrobial agent active in vitro against most strains of the following organisms that have been reported to be associated with bacterial vaginosis:
METROGEL-VAGINAL 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.
METROGEL-VAGINAL is contraindicated in patients with a prior history of hypersensitivity to metronidazole, parabens, other ‑ingredients of the formulation, or other nitroimidazole derivatives.
Convulsive seizures and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity, have been reported in patients treated with oral or intravenous metronidazole. The appearance of abnormal neurologic signs demands the prompt discontinuation of metronidazole vaginal gel therapy. Metronidazole vaginal gel should be administered with caution to patients with central nervous system diseases.
Psychotic reactions have been reported in alcoholic patients who were using oral metronidazole and disulfiram ‑concurrently. Metronidazole vaginal gel should not be administered to patients who have taken disulfiram within the last two weeks.
METROGEL-VAGINAL affords minimal peak serum levels and systemic exposure (AUCs) of metronidazole compared to 500 mg oral metro‑nidazole 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. Data from well-controlled trials directly comparing metronidazole administered orally to metronidazole administered vaginally are not available.
Patients with severe hepatic disease metabolize metronidazole slowly. This results in the accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such patients, metronidazole vaginal gel should be administered cautiously.
Known or previously unrecognized vaginal candidiasis may present more prominent symptoms during therapy with metronidazole vaginal gel. Approximately 6-10% of patients treated with METROGEL-VAGINAL developed symptomatic Candida vaginitis during or immediately after therapy.
Disulfiram-like reaction to alcohol has been reported with oral metronidazole, thus the possibility of such a reaction occurring while on metronidazole vaginal gel therapy cannot be excluded.
METROGEL-VAGINAL contains ingredients that may cause burning and irritation of the eye. In the event of accidental contact with the eye, rinse the eye with copious amounts of cool tap water.
The patient should be cautioned about drinking alcohol while being treated with metronidazole vaginal gel. While blood levels are signifi‑cantly lower with METROGEL-VAGINAL than with usual doses of oral metronidazole, a possible interaction with alcohol cannot be excluded.
The patient should be instructed not to engage in vaginal intercourse during treatment with this product.
Oral metronidazole has been reported to potentiate the anticoagulant effect of warfarin and other coumarin anti‑coagulants, 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.
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.
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