4.1 Hypersensitivity

The use of VANDAZOLE is contraindicated in patients with a history of hypersensitivity to metronidazole, other nitroimidazole derivatives, or parabens. Reported reactions include 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 Adverse Reactions (6.2)].

4.2 Psychotic Reaction with Disulfiram

Use of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently. Do not administer VANDAZOLE to patients who have taken disulfiram within the last two weeks [see Adverse Reactions (6.2)].

4.3 Interaction with Alcohol

Use of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing [see Adverse Reactions (6.2)]. Discontinue alcohol consumption during and for at least three days after therapy with VANDAZOLE.

5.1 Central and Peripheral Nervous System Effects

Use of oral or intravenous metronidazole is associated with convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or paresthesia of an extremity [see Adverse Reactions (6.2)]. VANDAZOLE should be administered with caution to patients with central nervous system diseases. Discontinue VANDAZOLE promptly if a patient develops abnormal neurologic signs.

5.2 Carcinogenicity in Animals

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

5.3 Interference with Laboratory Tests

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. Consider postponing chemistry laboratory tests until treatment with VANDAZOLE is completed.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the 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 data described below reflect exposure to VANDAZOLE compared to another formulation of vaginal metronidazole in 220 women in a single trial. The population was non-pregnant females (age range 18 to 72 years, the mean was 33 years +/- 11 years) with bacterial vaginosis. The racial demographic of those enrolled was 71 (32%) of White, 143 (65%) of Black, 3 (1%) of Hispanic, 2 (1%) of Asian, and 1 (0%) of other. Patients administered an applicator full of VANDAZOLE intravaginally once daily at bedtime for 5 days.

There were no deaths or serious adverse reactions related to drug therapy in the clinical trial. VANDAZOLE was discontinued in 5 patients (2.3%) due to adverse reactions.

The incidence of all adverse reactions in VANDAZOLE-treated patients was 42% (92/220). Adverse reactions occurring in ≥ 1% of patients were: fungal infection* (12%), headache (7%), pruritus (6%), abdominal pain (5%), nausea (3%), dysmenorrhea (3%), pharyngitis (2%), rash (1%), infection (1%), diarrhea (1%), breast pain (1%), and metrorrhagia (1%).

* Known or previously unrecognized vaginal candidiasis may present more prominent symptoms during therapy with VANDAZOLE. Approximately 10% of patients treated with VANDAZOLE developed Candida vaginitis during or immediately after therapy.

Additional uncommon events, reported by < 1% of those women treated with VANDAZOLE included:

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 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 (4.1)].

Renal: Dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure, darkened urine.

7.1 Disulfiram

Use of oral metronidazole has been associated with psychotic reactions in alcoholic patients who are using disulfiram concurrently. VANDAZOLE 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 three days after VANDAZOLE 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 VANDAZOLE is prescribed for patients on this type of anticoagulant therapy. In patients on oral anticoagulants, consider monitoring prothrombin time, international normalized ratio (INR), and other coagulation parameters while on VANDAZOLE.

7.4 Lithium

Short-term use of oral metronidazole has been associated with elevation of serum lithium concentrations and, in a few cases signs of lithium toxicity, in patients stabilized on relatively high doses of lithium. Use VANDAZOLE with caution in patients treated with lithium and consider monitoring lithium serum concentrations while on VANDAZOLE.

7.5 Cimetidine

Use of oral metronidazole with cimetidine may prolong the half-life and decrease plasma clearance of metronidazole. No dose adjustment of VANDAZOLE is necessary.

8.1 Pregnancy

Risk Summary

Available data on metronidazole use in pregnant women from published cohort studies, case-control studies, case series, meta analyses, and case reports over several decades have not established a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, no adverse developmental effects were demonstrated when oral metronidazole was administered to mice at doses up to six times the recommended human dose (see Data).

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Human Data

Published case-control studies, cohort studies, meta analyses, case series, and case reports over several decades have not established a risk with metronidazole use in pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. Many studies included first trimester exposures. One study showed an increased risk of cleft lip, with or without cleft palate, in infants exposed to metronidazole in-utero; however, these findings were not confirmed. Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Studies conducted to assess the risk of infant cancer following systemic metronidazole exposure during pregnancy did not show an increased risk; however, the ability of these studies to detect such a signal was limited.

Animal Data

Animal studies have shown that metronidazole crosses the placental barrier and enters the fetal circulation rapidly. Oral metronidazole reproductive toxicity studies have been performed in mice at doses up to six times the recommended human dose based on body surface area comparisons and have revealed no evidence of harm to the fetus. However, in a single small study where the drug was administered intraperitoneally, some intrauterine deaths were observed.

8.2 Lactation

Risk Summary

There are no data on the presence of metronidazole in human milk following intravaginal administration. Metronidazole is present in human milk following oral metronidazole administration at concentrations similar to those found in plasma (see Data). The metronidazole vaginal gel achieves 2% of the mean maximum serum concentration of a 500 mg oral metronidazole dose [see Clinical Pharmacology (12.3)]. The published literature reports no adverse effects in infants exposed through breastmilk to maternal orally administered metronidazole. There are no data on the effects on milk production.

Animal studies have shown the potential for tumorigenicity after oral metronidazole was administered chronically to rats and mice [see Nonclinical Toxicology (13.1)]. The clinical relevance of these findings is unclear. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for VANDAZOLE, and any potential adverse effects on the breastfed child from VANDAZOLE or from the underlying maternal condition. Alternatively, a lactating patient may interrupt breastfeeding and choose to pump and discard breastmilk during treatment with VANDAZOLE and for 48 hours after the last dose and feed her infant previously stored human milk or formula.

Data

In a study of lactating women receiving oral metronidazole 600 mg (n=11) or 1200 mg (n=4) daily, mean maternal plasma concentrations were 5.0 and 12.5 mcg/mL, respectively, within 2 hours following administration; the milk: maternal plasma ratio was approximately 1.

8.4 Pediatric Use

The safety and efficacy of VANDAZOLE in the treatment of bacterial vaginosis in post-menarchal females have been established on the extrapolation of clinical trial data from adult females.

The safety and efficacy of VANDAZOLE in pre-menarchal females have not been established.

8.5 Geriatric Use

Clinical studies with VANDAZOLE did not include sufficient numbers of subjects 65 years of age or older to determine whether they respond differently than younger subjects. Other reported clinical experience in using metronidazole gel, 1% has not identified differences in responses between elderly and younger patients.

12.1 Mechanism of Action

Metronidazole is an antibacterial drug [see Clinical Pharmacology, Microbiology (12.4)]

12.3 Pharmacokinetics

Healthy Subjects

Following a single, intravaginal 5 gram dose of metronidazole vaginal gel (equivalent to 37.5 mg of metronidazole) to 38 healthy female subjects, a mean maximum serum metronidazole concentration of 281 ng/mL was reported (range: 134 to 464 ng/mL). The average time to achieve this Cmax was 9.5 hours (range: 4 to 17 hours) after dosing with metronidazole vaginal gel. This Cmax is approximately 2% of the mean maximum serum concentration reported in healthy subjects administered a single, oral 500 mg dose of metronidazole (mean Cmax = 12,785 ng/mL).

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 5,989 ng•hr/mL (range: 2,797 to 10,515 ng•hr/mL). This AUC0-∞ is approximately 5% of the reported AUC of metronidazole following a single oral 500 mg dose of metronidazole approximately 125,000 ng•hr/mL.

Patients with Bacterial Vaginosis

Following single and multiple 5 gram doses of a similar metronidazole vaginal gel product 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 5 were reported. Steady state metronidazole serum concentrations following oral dosages of 400 to 500 mg twice a day have been reported to range from 6,000 to 20,000 ng/mL.

12.4 Microbiology

Mechanism of Action

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.

Activity In Vitro

Metronidazole is an antibacterial agent active in vitro against most strains of the following organisms that have been reported to be associated with bacterial vaginosis:

Bacteroides spp.

Gardnerella vaginalis

Mobiluncus spp.

Peptostreptococcus spp.

Standard methodology for the susceptibility testing of the potential bacterial vaginosis pathogens, Gardnerella vaginalis and Mobiluncus spp., has not been defined. Culture and sensitivity testing of bacteria are not routinely performed to establish the diagnosis of bacterial vaginosis [see Clinical Studies (14)].

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Metronidazole has shown evidence of carcinogenic activity after chronic oral administration in mice and rats. Pulmonary tumors and lymphomas were reported in several oral mouse studies in which mice were dosed at 75 mg/kg and above (about 5 times the clinical human dose based on body surface area comparison). Malignant liver tumors were reported in male mice dosed at doses equivalent to a human dose of 41 mg/kg/day (33 times the recommended clinical dose based on body surface area comparisons). Chronic oral dosing of metronidazole in rats at doses above 150 mg/kg (about 20 times the clinical human dose based on body surface area comparison) has resulted in mammary and hepatic tumors. Two lifetime tumorigenicity studies in hamsters have been performed and reported to be negative. Although no life-time studies were performed to evaluate the carcinogenic potential of VANDAZOLE (metronidazole gel, USP) 0.75%, published data have shown that intravaginal administration of metronidazole to Wistar rats for 5 days, at doses 26 times the recommended human dose based on body surface area comparisons, has resulted in an increased frequency of micronuclei in rat vaginal mucosal cells.

Metronidazole has shown mutagenic activity in a number of in vitro assay systems. In addition, a dose dependent increase in the frequency of micronuclei was observed in mice after intraperitoneal injections. An increase in chromosome aberrations has been reported in one study of patients with Crohn’s disease who were treated with 200 to 1200 mg/day of metronidazole for 1 to 24 months. However, in a second study, no increase in chromosome aberrations was reported in patients with Crohn’s disease who were treated with metronidazole for 8 months.

Fertility studies have been performed in mice up to six times the recommended human oral dose (based on mg/m2) and have revealed no evidence of impaired fertility. Metronidazole failed to produce any adverse effects on fertility or testicular function in male rats at doses up to 400 mg/kg/day (about 50 times the maximum recommended clinical dose based on body surface area comparisons) for 28 days. However, male rats treated at the same dose for 6 weeks or longer were infertile and showed severe degeneration of the seminiferous epithelium in the testes as well as marked decreases in testicular spermatid counts and epididymal sperm counts. Fertility was restored in most rats after an eight-week, drug-free recovery period.