Nuvessa

NUVESSA- metronidazole gel
Exeltis USA, Inc.

1 INDICATIONS AND USAGE

NUVESSA is indicated in the treatment of bacterial vaginosis in non-pregnant women.

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. NUVESSA should be administered at bedtime.

NUVESSA is not for ophthalmic, dermal or oral use.

3 DOSAGE FORMS AND STRENGTHS

Vaginal gel (1.3%) containing 65 mg of metronidazole in 5 grams of gel in a pre-filled applicator.

4 CONTRAINDICATIONS

4.1 Hypersensitivity

NUVESSA 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 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.

5 WARNINGS AND PRECAUTIONS

5.1 Central and Peripheral Nervous System Effects

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. NUVESSA should be administered with caution to patients with central nervous system diseases.

5.2 Carcinogenicity in Animals

Metronidazole has been shown to be carcinogenic at high doses administered orally in mice and rats [see Nonclinical Toxicology (13.1) ]. Unnecessary use of metronidazole should be avoided. Use of NUVESSA should be reserved for the treatment of bacterial vaginosis [see Indications and Usage (1) ].

5.3 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.

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.

6.1 Clinical Trials Experience

The safety of NUVESSA 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 NUVESSA. Subjects were primarily Black/African American (58.3%) or White (39.3%). Subjects administered a single dose of NUVESSA at bedtime on the first day of the study.

There were no deaths or serious adverse events in this trial. Adverse events were reported by 19.0% of subjects treated with NUVESSA versus 16.1% of subjects treated with Vehicle Gel.

Adverse events occurring in ≥1% of subjects receiving NUVESSA 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 events.

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.

7 DRUG INTERACTIONS

The intravaginal administration of a single dose ofNUVESSAresults 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.

7.1 Disulfiram

Use of oral metronidazole has been associated with psychotic reactions in alcoholic patients who are using disulfiram concurrently. NUVESSA 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 NUVESSA 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 NUVESSA 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 NUVESSA is necessary.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category B. NUVESSA should be used during pregnancy only if clearly needed. There are no adequate and well-controlled studies in pregnant women. Metronidazole crosses the placental barrier and enters the fetal circulation rapidly.

No fetotoxicity or teratogenicity was observed when metronidazole was administered orally to pregnant rabbits at up to 200 mg/kg (about 60 times the maximum human dose based on mg/m2). Similarly no fetotoxic or teratogenic effects were observed in five studies in rats where dosing was administered orally in the diet or by gastric intubation at doses up to 200 mg/kg (about 30 times the maximum human dose based on mg/m2).

As well, no fetotoxicity or teratogenicity was observed when metronidazole was administered orally to pregnant mice at doses up to 100 mg/kg (about 7 times the maximum human dose based on mg/m2). However, some intrauterine deaths were observed in Swiss Webster mice administered metronidazole intraperitoneally at doses up to 15 mg/kg (about 1 times the maximum human dose based on mg/m2). The relationship of these intraperitoneal findings in mice to the topical use of NUVESSA is unknown.

Because animal reproduction and development studies are not always predictive of human response, and because metronidazole is a carcinogen in rodents, this drug should be used during pregnancy only if clearly needed.

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