ewable is used at higher doses or for prolonged duration. 5.3 metronidazole drug interaction and serious skin reactions stevens-johnson syndrome/toxic epidermal necrolysis (sjs/ten) have been reported with the concomitant use of mebendazole and metronidazole. avoid concomitant use of mebendazole and metronidazole.

he tablets ( 2 )

als are shown in table 1 below. table 1: adverse reactions reported in mebendazole-treated subjects from 39 clinical trials includes mebendazole formulations, dosages and treatment duration other than vermox™ chewable 500 mg tablet adverse reaction(s) gastrointestinal disorders anorexia abdominal pain diarrhea flatulence nausea vomiting skin and subcutaneous tissue disorders rash clinical studies with mebendazole chewable 500 mg tablet the safety profile of mebendazole chewable 500 mg tablets administered as a single dose was evaluated in 677 pediatric subjects aged 1 to 16 years and in 34 adults. the safety profile was consistent with the known safety profile of mebendazole. 6.2 postmarketing experience the following adverse reactions have been identified in adult and pediatric patients postmarketing with mebendazole formulations and dosages other than the vermox™ chewable 500 mg tablet. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. table 2: adverse reactions identified during postmarketing experience with mebendazole includes mebendazole formulations, dosages and treatment durations other than vermox™ chewable 500 mg tablet adverse reaction(s) blood and lymphatic system disorders agranulocytosis, neutropenia immune system disorders hypersensitivity including anaphylactic reactions nervous system disorders convulsions, dizziness hepatobiliary disorders hepatitis, abnormal liver tests renal and urinary disorders glomerulonephritis skin and subcutaneous tissue disorders toxic epidermal necrolysis, stevens-johnson syndrome, exanthema, angioedema, urticaria, alopecia

t, 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 2–4% and 15–20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risks untreated soil-transmitted helminth infections in pregnancy are associated with adverse outcomes including maternal iron deficiency anemia, low birth weight, neonatal and maternal death. data human data several published studies, including prospective pregnancy registries, case-control, retrospective cohort, and randomized controlled studies, have reported no association between mebendazole use and a potential risk of major birth defects or miscarriage. overall, these studies did not identify a specific pattern or frequency of major birth defects with mebendazole use. however, these studies cannot definitely establish the absence of any mebendazole-associated risk because of methodological limitations, including recall bias, confounding factors and, in some cases, small sample size or exclusion of first trimester mebendazole exposures. animal data embryo-fetal developmental toxicity studies in rats revealed no adverse effects on dams or their progeny at doses up to 2.5 mg/kg/day on gestation days 6–15 (the period of organogenesis). dosing at ≥10 mg/kg/day resulted in a lowered body weight gain and a decreased pregnancy rate. maternal toxicity, including body weight loss in one animal and maternal death in 11 of 20 animals, was seen at 40 mg/kg/day. at 10 mg/kg/day, increased embryo-fetal resorption (100% were resorbed at 40 mg/kg/day), decreased pup weight and increased incidence of malformations (primarily skeletal) were observed. mebendazole was also embryotoxic and teratogenic in pregnant rats at single oral doses during organogenesis as low as 10 mg/kg (approximately 0.2-fold the mrhd, based on mg/m 2 ). in embryo-fetal developmental toxicity studies in mice dosed on gestation days 6–15, doses of 10 mg/kg/day and higher resulted in decreased body weight gain at 10 and 40 mg/kg/day and a higher mortality rate at 40 mg/kg/day. at doses of 10 mg/kg/day (approximately 0.1-fold the mrhd, based on mg/m 2 ) and higher, embryo-fetal resorption increased (100% at 40 mg/kg) and fetal malformations, including skeletal, cranial, and soft tissue anomalies, were present. dosing of hamsters and rabbits did not result in embryotoxicity or teratogenicity at doses up to 40 mg/kg/day (0.6 to 1.6-fold the mrhd, based on mg/m 2 ). in a peri- and post-natal toxicity study in rats, mebendazole did not adversely affect dams or their progeny at 20 mg/kg/day. at 40 mg/kg (0.8-fold the mrhd, based on mg/m 2 ), a reduction of the number of live pups was observed and there was no survival at weaning. no abnormalities were found on gross and radiographic examination of pups at birth. 8.2 lactation risk summary limited data from case reports demonstrate that a small amount of mebendazole is present in human milk following oral administration. there are no reports of effects on the breastfed infant, and the limited reports on the effects on milk production are inconsistent. the limited clinical data during lactation precludes a clear determination of the risk of vermox™ chewable to a breastfed infant; therefore, developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for vermox™ chewable and any potential adverse effects on the breastfed infant from vermox™ chewable or from the underlying maternal condition. 8.4 pediatric use the safety and effectiveness of vermox™ chewable 500 mg tablets have been established in pediatric patients 1 to 16 years of age. use of vermox™ chewable 500 mg tablets in children is supported by evidence from adequate and well-controlled studies of vermox™ chewable 500 mg tablets [see clinical studies (14) ] . the safety and effectiveness of mebendazole, including vermox™ chewable have not been established in pediatric patients less than one year of age. convulsions have been reported with mebendazole use in this age group [see warnings and precautions (5.1) and adverse reactions (6.2) ]. 8.5 geriatric use clinical studies of mebendazole did not include sufficient numbers of subjects aged 65 and older to determine whether they respond differently from younger subjects. 8.6 adult use the safety and effectiveness of vermox™ chewable 500 mg tablets have been established in adults for the treatment of gastrointestinal infections by t. trichiura and a. lumbricoides . use of vermox™ chewable 500 mg tablets in adults for these indications is supported by evidence from an adequate and well-controlled trial in pediatric patients ages 1 to 16 years [see clinical studies (14.1)] , safety data in adults [see adverse reactions (6.1) ] , pharmacokinetic data in adults [see clinical pharmacology (12.3) ] , and the evidence from published literature.

omes. in the u.s. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively. clinical considerations disease-associated maternal and/or embryo/fetal risks untreated soil-transmitted helminth infections in pregnancy are associated with adverse outcomes including maternal iron deficiency anemia, low birth weight, neonatal and maternal death. data human data several published studies, including prospective pregnancy registries, case-control, retrospective cohort, and randomized controlled studies, have reported no association between mebendazole use and a potential risk of major birth defects or miscarriage. overall, these studies did not identify a specific pattern or frequency of major birth defects with mebendazole use. however, these studies cannot definitely establish the absence of any mebendazole-associated risk because of methodological limitations, including recall bias, confounding factors and, in some cases, small sample size or exclusion of first trimester mebendazole exposures. animal data embryo-fetal developmental toxicity studies in rats revealed no adverse effects on dams or their progeny at doses up to 2.5 mg/kg/day on gestation days 6–15 (the period of organogenesis). dosing at ≥10 mg/kg/day resulted in a lowered body weight gain and a decreased pregnancy rate. maternal toxicity, including body weight loss in one animal and maternal death in 11 of 20 animals, was seen at 40 mg/kg/day. at 10 mg/kg/day, increased embryo-fetal resorption (100% were resorbed at 40 mg/kg/day), decreased pup weight and increased incidence of malformations (primarily skeletal) were observed. mebendazole was also embryotoxic and teratogenic in pregnant rats at single oral doses during organogenesis as low as 10 mg/kg (approximately 0.2-fold the mrhd, based on mg/m 2 ). in embryo-fetal developmental toxicity studies in mice dosed on gestation days 6–15, doses of 10 mg/kg/day and higher resulted in decreased body weight gain at 10 and 40 mg/kg/day and a higher mortality rate at 40 mg/kg/day. at doses of 10 mg/kg/day (approximately 0.1-fold the mrhd, based on mg/m 2 ) and higher, embryo-fetal resorption increased (100% at 40 mg/kg) and fetal malformations, including skeletal, cranial, and soft tissue anomalies, were present. dosing of hamsters and rabbits did not result in embryotoxicity or teratogenicity at doses up to 40 mg/kg/day (0.6 to 1.6-fold the mrhd, based on mg/m 2 ). in a peri- and post-natal toxicity study in rats, mebendazole did not adversely affect dams or their progeny at 20 mg/kg/day. at 40 mg/kg (0.8-fold the mrhd, based on mg/m 2 ), a reduction of the number of live pups was observed and there was no survival at weaning. no abnormalities were found on gross and radiographic examination of pups at birth.

(ng/ml) 14.0 (9.17) 56.2 (35.8) t max (h) median (range) 1.5 (0.5–3.0) 4.0 (2.0–6.0) auc last (ng.h/ml) 175 (129) 456 (249) distribution the plasma protein binding of mebendazole is 90 to 95%. the volume of distribution is 1 to 2 l/kg, indicating that absorbed mebendazole penetrates areas outside the vascular space. metabolism orally administered mebendazole is extensively metabolized primarily by the liver. plasma concentrations of its major metabolites (hydrolyzed and reduced forms of mebendazole) are higher than those of mebendazole. impaired hepatic function, impaired metabolism, or impaired biliary elimination may lead to higher plasma levels of mebendazole. elimination mebendazole, the conjugated forms of mebendazole, and its metabolites likely undergo some degree of enterohepatic recirculation. the apparent elimination half-life after an oral dose ranges from 3 to 6 hours in most patients. less than 2% of orally administered mebendazole is excreted in urine and the remainder in the feces as unchanged drug or its metabolites. specific populations pediatric based on a limited number of blood samples, the pharmacokinetic results following single-dose administration of a 500 mg mebendazole chewable tablet to pediatric patients (age 1 to 16 years) with single or mixed infections of t. trichiura and/or a. lumbricoides indicated that children aged 1 to 3 years have higher systemic exposure than adults. 12.4 microbiology mechanism of action mebendazole interferes with cellular tubulin formation in the helminth and causes ultrastructural degenerative changes in its intestine. as a result, its glucose uptake and the digestive and reproductive functions are disrupted, leading to immobilization, inhibition of egg production and death of the helminth. antimicrobial activity mebendazole is active against: ascaris lumbricoides trichuris trichiura resistance there is a potential for development of resistance to mebendazole. the mechanism of resistance to mebendazole is likely due to changes of beta-tubulin protein, which reduces binding of mebendazole to beta-tubulin; however, the clinical significance of this is not known.

(249) distribution the plasma protein binding of mebendazole is 90 to 95%. the volume of distribution is 1 to 2 l/kg, indicating that absorbed mebendazole penetrates areas outside the vascular space. metabolism orally administered mebendazole is extensively metabolized primarily by the liver. plasma concentrations of its major metabolites (hydrolyzed and reduced forms of mebendazole) are higher than those of mebendazole. impaired hepatic function, impaired metabolism, or impaired biliary elimination may lead to higher plasma levels of mebendazole. elimination mebendazole, the conjugated forms of mebendazole, and its metabolites likely undergo some degree of enterohepatic recirculation. the apparent elimination half-life after an oral dose ranges from 3 to 6 hours in most patients. less than 2% of orally administered mebendazole is excreted in urine and the remainder in the feces as unchanged drug or its metabolites. specific populations pediatric based on a limited number of blood samples, the pharmacokinetic results following single-dose administration of a 500 mg mebendazole chewable tablet to pediatric patients (age 1 to 16 years) with single or mixed infections of t. trichiura and/or a. lumbricoides indicated that children aged 1 to 3 years have higher systemic exposure than adults.

on type vermox™ chewable 500 mg all patients=149 some patients had mixed infection. placebo all patients=146 difference difference in cure rates, expressed in percentages, and based on mantel haenszel methods to account for stratification by site. (95% ci) a. lumbricoides n=86 n (%) n=81 n (%) cure 72 (83.7) 9 (11.1) 72.6 (62.3, 82.7) p-value <0.001 based on the cochran-mantel-haenszel test, controlling for the effect of site. failure failures include patients who tested positive for the worm at visit 3 (day 19, i.e. test-of-cure). 9 (10.5) 67 (82.7) missing patients with missing stool sample at day 19. 5 (5.8) 5 (6.2) t. trichiura n=124 n (%) n=119 n (%) cure 42 (33.9) 9 (7.6) 26.2 (16.7, 35.6) failure 76 (61.3) 103 (86.6) missing 6 (4.8) 7 (5.8) in patients treated with vermox™ chewable 500 mg, egg count reduction rate at the end of the double-blind period (day 19) in patients with a. lumbricoides and/or t. trichiura was statistically significant (p<0.001) compared to placebo, 100% compared to 30.0% for a. lumbricoides , respectively, and 81.2% compared to 27.4% for t. trichiura , respectively.