ke 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.

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.

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.

ke 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.

gnancies 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.

s 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.

uc 0-∞ 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 )] .

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.

%, 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/m 2 ) 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.

wn 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/m 2 ) 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.

vandazole patients and 243 patients treated with another vaginal formulation of metronidazole. therapeutic cure defined as a clinical cure and nugent score < 4 was assessed day 22-31. table 1 shows the therapeutic, clinical and nugent score cure rates in this trial. the therapeutic cure rate was 42.8% for the vandazole group and 30.9% for the comparator group (95% confidence interval about the 11.9% difference in therapeutic cure rate: 2.8% to 21.0%). table 1 efficacy of vandazole for the treatment of bacterial vaginosis in a randomized, double-blind active controlled study 1 outcome vandazole n = 229 active control n = 243 treatment difference (%) [95% confidence interval] % cure % cure therapeutic cure 42.8 30.9 11.9 [2.8, 21.0] clinical cure 52.4 45.3 7.1 [-2.3, 16.5] nugent score cure 52.0 41.1 10.9 [1.5, 20.3] 1 modified intent-to-treat population

th an antifungal drug [see adverse reactions ( 6.1 )] . lactation a patient may choose to pump and discard breastmilk during treatment with vandazole and for 48 hours after last dose, and feed her infant previously stored human milk or formula [see use in specific populations ( 8.2 )] . accidental exposure to the eye inform the patient that vandazole 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 irritation inform the patient to discontinue use and consult a healthcare provider if vaginal irritation occurs with use of vandazole. administration of drug instruct the patient that vandazole (metronidazole gel, usp), 0.75% is supplied with 5 vaginal applicators. for once daily dosing, one applicator full should be used per dose. us patent no. 7,456,207 manufactured in croatia by: pliva hrvatska d.o.o. zagreb, croatia manufactured for: upsher-smith laboratories, llc maple grove, mn 55369 rev. h 2/2021