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 0.5-fold the total daily 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 0.5-fold the total daily MRHD, based on mg/m2).

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 0.2-fold the total daily MRHD, based on mg/m2) 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 (1.6 to 3.9-fold the total daily MRHD, based on mg/m2).

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 (1.9-fold the total daily MRHD, based on mg/m2), 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.

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 EMVERM® to a breastfed infant; therefore, developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for EMVERM® and any potential adverse effects on the breastfed infant from EMVERM® or from the underlying maternal condition.

Absorption

Following oral administration of mebendazole, the majority of the dose remains in the gastrointestinal tract where it exerts an anthelmintic effect locally. Following administration of 100 mg twice daily for three consecutive days, plasma concentrations of EMVERM® (mebendazole) and its primary metabolite, the 2-amine hydrolyzed metabolite, do not exceed 0.03 mcg/mL and 0.09 mcg/mL, respectively. Dosing with a high fat meal increases the bioavailability of mebendazole, although the overall effect of food on the amount of drug remaining in the gastrointestinal tract is not expected to be substantial.

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. All metabolites are devoid of anthelmintic activity. Impaired hepatic function, impaired metabolism, or impaired biliary elimination may lead to higher plasma concentrations of mebendazole.

Excretion

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.

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:

Ancylostoma duodenale

Ascaris lumbricoides

Enterobius vermicularis

Necator americanus

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.