Metronidazole 7.5 mg/g Gel — NDC 70518-4495-0 (Billing 70518-4495-00)

WARNINGS Convulsive Seizures and Peripheral Neuropathy 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 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.

ADVERSE REACTIONS 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.

PRECAUTIONS Metronidazole vaginal gel affords minimal peak serum levels and systemic exposure (AUCs) 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. Data from well-controlled trials directly comparing metronidazole administered orally to metronidazole administered vaginally are not available.

General 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 metronidazole vaginal gel 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.

Metronidazole vaginal gel 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. Information for the Patient The patient should be cautioned about drinking alcohol while being treated with metronidazole vaginal gel.

While blood levels are significantly lower with metronidazole vaginal gel 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. 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. Carcinogenesis, Mutagenesis, Impairment of Fertility Metronidazole has shown evidence of carcinogenic activity in a number of studies involving chronic oral administration in mice and rats. Prominent among the effects in the mouse was the promotion of pulmonary tumorigenesis.

This has been observed in all six reported studies in that species, including one study in which the animals were dosed on an intermittent schedule (administration during every fourth week only). At very high dose levels (approximately 500 mg/kg/day), there was a statistically significant increase in the incidence of malignant liver tumors in males. Also, the published results of one of the mouse studies indicate an increase in the incidence of malignant lymphomas as well as pulmonary neoplasms associated with lifetime feeding of the drug.

All these effects are statistically significant. Several long-term oral… [Excerpted — this section continues on DailyMed.]