Vandazole

1 INDICATIONS AND USAGE VANDAZOLE ® is indicated in the treatment of bacterial vaginosis (formerly referred to as Haemophilus vaginitis, Gardnerella vaginitis, nonspecific vaginitis, Corynebacterium vaginitis, or anaerobic vaginosis) in post-menarchal females. VANDAZOLE is a nitroimidazole antimicrobial indicated for the treatment of bacterial vaginosis in post-menarchal females. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dose is one applicator full of VANDAZOLE, (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 [see Patient Counseling Information ( 17.4 )] . Not for ophthalmic, dermal, or oral use. One applicator full of VANDAZOLE administered intravaginally once a day for 5 days. ( 2 ) Not for ophthalmic, dermal, or oral use. ( 2 )

4 CONTRAINDICATIONS History of hypersensitivity to metronidazole, other nitroimidazole derivatives or parabens ( 4 ) Disulfiram: Psychotic reactions have been reported with disulfiram and oral metronidazole; do not administer concurrently with or within the last 2 weeks of disulfiram ( 4.2 , 7.1 ). Alcohol: Disulfiram-like reactions to alcohol have been reported with oral metronidazole; do not consume alcohol during and for at least three days following treatment ( 4.3 , 7.2 ) 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 WARNINGS AND PRECAUTIONS Central and Peripheral Nervous System Effects: Convulsive seizures and peripheral neuropathy have been reported in patients treated with oral or intravenous metronidazole; discontinue if abnormal neurologic signs develop. ( 5.1 ) Carcinogenicity in Animals: Metronidazole has been shown to be carcinogenic in mice and rats. ( 5.2 , 13.1 ) Interference with laboratory tests: Metronidazole may interfere with certain serum chemistry laboratory values ( 5.3 ) 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.

7 DRUG INTERACTIONS The intravaginal administration of a single 5 gram dose of VANDAZOLE results in relatively lower mean systemic exposure to metronidazole that is approximately 2% to 5% of that achieved following a 500 mg oral dose of metronidazole [see Clinical Pharmacology ( 12.3 )] . The following drug interactions were reported for oral metronidazole. Warfarin and other coumarin anticoagulants: Prolonged anticoagulant effects reported with oral metronidazole; monitor INR and prothrombin time. ( 7.3 ) Lithium: Elevated lithium concentrations reported with oral metronidazole; monitor serum concentrations of lithium. ( 7.4 ) 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.

6 ADVERSE REACTIONS Adverse reactions occurring in ≥ 1% of patients are: fungal infection, headache, pruritus, abdominal pain, nausea, dysmenorrhea, pharyngitis, rash, infection, diarrhea, breast pain, and metrorrhagia. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals USA, Inc. at 1-888-838-2872 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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: 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, pyelonephritis, salpingitis, urinary frequency, urinary tract infection, vaginitis, vulvovaginal disorder 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.

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.