Mebendazole

6 ADVERSE REACTIONS Adverse reactions reported in clinical trials were anorexia, abdominal pain, diarrhea, flatulence, nausea, vomiting and rash. ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Janssen Pharmaceuticals, Inc. at 1-800-JANSSEN (1-800-526-7736) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Studies 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 safety of mebendazole was evaluated in 6276 adult and pediatric subjects one year of age and older who participated in 39 clinical trials for treatment of single or mixed parasitic infections of the gastrointestinal tract. In these trials, the formulations, dosages and duration of mebendazole treatment varied. Adverse reactions reported in mebendazole-treated subjects from the 39 clinical trials 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

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary The available published literature on mebendazole use in pregnant women has not reported a clear association between mebendazole and a potential risk of major birth defects or miscarriages [see Data ]. There are risks to the mother and fetus associated with untreated helminthic infection during pregnancy [see Clinical Considerations ] . In animal reproduction studies, adverse developmental effects (i.e., skeletal malformations, soft tissue malformations, decreased pup weight, embryolethality) were observed when mebendazole was administered to pregnant rats during the period of organogenesis at single oral doses as low as 10 mg/kg (approximately 0.2-fold the maximum recommended human dose (MRHD)). Maternal toxicity was present at the highest of these doses [see Data ]. The estimated background risk of major birth defects and miscarriage for the indicated populations 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 2–4% 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.

8.1 Pregnancy Risk Summary The available published literature on mebendazole use in pregnant women has not reported a clear association between mebendazole and a potential risk of major birth defects or miscarriages [see Data ]. There are risks to the mother and fetus associated with untreated helminthic infection during pregnancy [see Clinical Considerations ] . In animal reproduction studies, adverse developmental effects (i.e., skeletal malformations, soft tissue malformations, decreased pup weight, embryolethality) were observed when mebendazole was administered to pregnant rats during the period of organogenesis at single oral doses as low as 10 mg/kg (approximately 0.2-fold the maximum recommended human dose (MRHD)). Maternal toxicity was present at the highest of these doses [see Data ]. The estimated background risk of major birth defects and miscarriage for the indicated populations 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 2–4% 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.