There is no human experience with overdosage of metronidazole vaginal gel. Vaginally applied metronidazole gel, 0.75% could be absorbed in sufficient amounts to produce systemic effects.
The use of VANDAZOLE (metronidazole vaginal gel) 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.
Psychotic Reaction with DisulfiramUse of oral metronidazole is associated with psychotic reactions in alcoholic patients who were using disulfiram concurrently. Do not administer VANDAZOLE (metronidazole vaginal gel) to patients who have taken disulfiram within the last two weeks.
Interaction with AlcoholUse of oral metronidazole is associated with a disulfiram-like reaction to alcohol, including abdominal cramps, nausea, vomiting, headaches, and flushing . Discontinue alcohol consumption during and for at least three days after therapy with VANDAZOLE (metronidazole vaginal gel).
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 (metronidazole vaginal gel) 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 (metronidazole vaginal gel) was discontinued in 5 patients (2.3%) due to adverse reactions.
The incidence of all adverse reactions in VANDAZOLE (metronidazole vaginal gel) -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 (metronidazole vaginal gel). Approximately 10% of patients treated with VANDAZOLE (metronidazole vaginal gel) developed Candida vaginitis during or immediately after therapy.
Additional uncommon events, reported by < 1% of those women treated with VANDAZOLE (metronidazole vaginal gel) included:
General: allergic reaction, back pain, flu syndrome, mucous membrane disorder, pain
Gastrointestinal: anorexia, constipation, dyspepsia, flatulence, gingivitis, vomiting
Nervous System: depression, dizziness, insomnia
Respiratory System: asthma, rhinitis
Skin and Appendages: acne, sweating, urticaria
Urogenital System: breast enlargement, dysuria, female lactation, labial edema, leucorrhea, menorrhagia, pyleonephritis, salpingitis, urinary frequency, urinary tract infection, vaginitis, vulvovaginal disorder
Other Metronidazole Formulations Other Vaginal FormulationsOther 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) FormulationsOther 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 FormulationsThe 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.
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.
Renal: Dysuria, cystitis, polyuria, incontinence, a sense of pelvic pressure, darkened urine.
VANDAZOLE (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) in non-pregnant women.
VANDAZOLE (metronidazole vaginal gel) should be used during pregnancy only if clearly needed. There are no adequate and well-controlled studies in pregnant women.
There are published data from case-control studies, cohort studies, and two meta-analyses that include more than 5000 pregnant women who used metronidazole systemically during pregnancy. 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. In addition, more than ten randomized, placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use of systemic antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three 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.
Oral 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 impaired fertility or harm to the fetus. However, in a single small study where the drug was administered intraperitoneally, some intrauterine deaths were observed.
Animal studies have shown that metronidazole crosses the placental barrier and enters the fetal circulation rapidly. Because animal reproduction studies are not always predictive of human response, and because metronidazole crosses the placental barrier and is a carcinogen in rodents, this drug should be used during pregnancy only if clearly needed.
VANDAZOLE (metronidazole vaginal gel) is a vaginal gel 0.75% in a 70 g tube with 5 vaginal applicators (each applicator delivers approximately 5 g of gel containing 37.5 mg of metronidazole).
Storage And HandlingVANDAZOL E (metronidazo le vaginal gel, 0.75%) is supplied in a 70 gram tube and packaged with 5 vaginal applicators.
Store at 20° to 25°C (68° to 77°F). Avoid exposure to extreme heat or cold. Protect from freezing.
Manufactured For: UPSHER-SMITH LABORATORIES, INC. Minneapolis, MN 55447. Rev. 1/2011
Included as part of the PRECAUTIONS section.
PRECAUTIONS Central and Peripheral Nervous System EffectsUse of oral or intravenous metronidazole is associated with convulsive seizures, encephalopathy, aseptic meningitis, optic and peripheral neuropathy, the latter characterized mainly by numbness or parethesia of an extremity. VANDAZOLE (metronidazole vaginal gel) should be administered with caution to patients with central nervous system diseases. Discontinue VANDAZOLE (metronidazole vaginal gel) promptly if a patient develops abnormal neurologic signs.
Carcinogenicity in AnimalsMetronidazole has been shown to be carcinogenic in mice and rats. Unnecessary use of metronidazole should be avoided. Use of VANDAZOLE (metronidazole vaginal gel) should be reserved for the treatment of bacterial vaginosis
Interference with Laboratory TestsMetronidazole may interfere with certain types of determinations of serum chemistry values, such as aspartate aminotransferase (AST, SGOT), alanine aminostransferase (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 to after treatment with VANDAZOLE (metronidazole vaginal gel).
Patient Counseling Information Interaction with AlcoholInstruct the patient not to consume alcoholic beverages and preparations containing ethanol or propylene glycol during and for at least 3 days after treatment with VANDAZOLE.
Drug InteractionsInstruct the patient not to use VANDAZOLE (metronidazole vaginal gel) if disulfiram had been used within the last two weeks , and to inform their healthcare provider if they are taking oral anticoagulants, or lithium.
Vaginal Intercourse and Use with Vaginal ProductsInstruct the patient not to engage in vaginal intercourse, or use other vaginal products (such as tampons or douches) during treatment with VANDAZOLE (metronidazole vaginal gel).
Fungal Vaginal InfectionsInform the patient that vaginal fungal infections can occur following use of VANDAZOLE (metronidazole vaginal gel) and may require treatment with an antifungal drug.
Human Milk FeedingAdvise women that they may consider discontinuing milk feeding or pump and discard their milk during treatment and for 24 hours after the last dose of VANDAZOLE (metronidazole vaginal gel).
Accidental Exposure to the EyeInform the patient that VANDAZOLE (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 and consult a healthcare provider.
Vaginal IrritationInform the patient to discontinue use and consult a healthcare provider if vaginal irritation occurs with use of VANDAZOLE (metronidazole vaginal gel).
Administration of DrugInstruct the patient that VANDAZOLE (metronidazole vaginal gel, 0.75%) is supplied with 5 vaginal applicators. For once daily dosing, one applicator should be used per dose. See DIRECTIONS FOR USE for complete instructions on how to use the product and the vaginal applicator.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment of FertilityMetronidazole 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 vaginal gel, 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.
Use In Specific Populations Pregnancy Pregnancy Category BVANDAZOLE (metronidazole vaginal gel) should be used during pregnancy only if clearly needed. There are no adequate and well-controlled studies in pregnant women.
There are published data from case-control studies, cohort studies, and two meta-analyses that include more than 5000 pregnant women who used metronidazole systemically during pregnancy. 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. In addition, more than ten randomized, placebo-controlled clinical trials enrolled more than 5000 pregnant women to assess the use of systemic antibiotic treatment (including metronidazole) for bacterial vaginosis on the incidence of preterm delivery. Most studies did not show an increased risk for congenital anomalies or other adverse fetal outcomes following metronidazole exposure during pregnancy. Three 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.
Oral 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 impaired fertility or harm to the fetus. However, in a single small study where the drug was administered intraperitoneally, some intrauterine deaths were observed.
Animal studies have shown that metronidazole crosses the placental barrier and enters the fetal circulation rapidly. Because animal reproduction studies are not always predictive of human response, and because metronidazole crosses the placental barrier and is a carcinogen in rodents, this drug should be used during pregnancy only if clearly needed.
Nursing MothersCaution should be exercised when VANDAZOLE is administered to a nursing woman. Following oral metronidazole administration, concentrations of metronidazole in human milk are similar to concentrations in plasma. Since some metronidazole is systemically absorbed following vaginal administration of metronidazole, excretion in human milk is possible.
Because of the potential for tumorigenicity shown for metronidazole in animal studies, a decision should be made whether to discontinue nursing or to discontinue VANDAZOLE (metronidazole vaginal gel) , taking into account the importance of the therapy to the mother. A nursing mother may choose to pump and discard her milk for the duration of VANDAZOLE (metronidazole vaginal gel) therapy, and for 24 hours after therapy ends and feed her infant stored human milk or formula.
Pediatric UseThe safety and efficacy of VANDAZOLE (metronidazole vaginal gel) in the treatment of bacterial vaginosis in post-menarchal females have been established on the extrapolation of clinical trial data from adult women. The safety and efficacy of VANDAZOLE (metronidazole vaginal gel) in premenarchal females have not been established.
Geriatric UseClinical studies with VANDAZOLE (metronidazole vaginal gel) 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.
The recommended dose is one applicator full of VANDAZOLE (metronidazole vaginal gel) , (approximately 5 grams of gel containing approximately 37.5 mg of metronidazole) administered intravaginally once a day for 5 days. For once a day dosing, VANDAZOLE should be administered at bedtime.
Not for ophthalmic, dermal, or oral use.
Instruct the patient not to use VANDAZOLE (metronidazole vaginal gel) if disulfiram had been used within the last two weeks , and to inform their healthcare provider if they are taking oral anticoagulants, or lithium.
