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  • CLASSES

    Antinematodal Agents

    DEA CLASS

    Rx

    DESCRIPTION

    Oral, broad-spectrum, synthetic anthelmintic agent
    Used for infections caused by GI nematodes, such as roundworms, whipworms, pinworms, and hookworms
    Along with pyrantel pamoate, drug of choice for these infections

    COMMON BRAND NAMES

    Emverm

    HOW SUPPLIED

    Emverm Oral Tab Chew: 100mg

    DOSAGE & INDICATIONS

    For the treatment of trichuriasis (whipworm infection) or ascariasis (roundworm infection) or mixed infections with these parasites.
    Oral dosage (single-dose regimen)
    Adults

    500 mg PO as a single dose.

    Children and Adolescents

    500 mg PO as a single dose.

    Oral dosage (3-day regimen)
    Adults

    100 mg PO twice daily for 3 days. If not cured 3 weeks after treatment, a second course of therapy is recommended.

    Children and Adolescents 2 to 17 years

    100 mg PO twice daily for 3 days. If not cured 3 weeks after treatment, a second course of therapy is recommended.

    Children 1 year†

    100 mg PO twice daily for 3 days.

    For the treatment of enterobiasis (pinworm infection).
    Oral dosage
    Adults

    100 mg PO as a single dose; repeat dose in 2 weeks.

    Children and Adolescents 2 to 17 years

    100 mg PO as a single dose; repeat dose in 2 weeks.

    Children 1 year†

    100 mg PO as a single dose; repeat dose in 2 weeks.

    For the treatment of hookworm infection.
    Oral dosage (single-dose regimen)†
    Adults

    500 mg PO as a single dose.

    Children and Adolescents

    500 mg PO as a single dose.

    Oral dosage (3-day regimen)
    Adults

    100 mg PO twice daily for 3 days. If not cured 3 weeks after treatment, a second course of therapy is recommended.

    Children and Adolescents 2 to 17 years

    100 mg PO twice daily for 3 days. If not cured 3 weeks after treatment, a second course of therapy is recommended.

    Children 1 year†

    100 mg PO twice daily for 3 days. If not cured 3 weeks after treatment, a second course of therapy is recommended.

    For the treatment of cystic echinococcosis† (hydatid cyst disease†) and alveolar echinococcosis†.
    Oral dosage
    Adults

    40 to 50 mg/kg PO once daily as an alternative. Treat for 1 to 6 months for cystic disease and for at least 2 years with patient monitoring for at least 10 years for alveolar disease. Surgery may be used in conjunction to drug therapy.

    Children and Adolescents 2 to 17 years

    40 to 50 mg/kg PO once daily as an alternative. Treat for 1 to 6 months for cystic disease and for at least 2 years with patient monitoring for at least 10 years for alveolar disease. Surgery may be used in conjunction to drug therapy.

    For the treatment of capillariasis†.
    Oral dosage
    Adults

    200 mg PO twice daily for 20 days as first line therapy.

    Children and Adolescents 2 to 17 years

    200 mg PO twice daily for 20 days as first line therapy.

    For the treatment of toxocariasis† (visceral larva migrans).
    Oral dosage
    Adults

    100 to 200 mg PO twice daily for 5 days.

    Children and Adolescents 2 to 17 years

    100 to 200 mg PO twice daily for 5 days.

    For the treatment of trichinosis†.
    Oral dosage
    Adults

    200 to 400 mg PO 3 times daily for 3 days, then 400 to 500 mg PO 3 times daily for 10 days.

    Children and Adolescents 2 to 17 years

    200 to 400 mg PO 3 times daily for 3 days, then 400 to 500 mg PO 3 times daily for 10 days.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    500 mg/day PO for single dose regimen; 200 mg/day PO is FDA-approved maximum for 3-day regimen; a dose of 40 mg/kg PO has been used off-label for hydatid cyst disease.

    Geriatric

    500 mg/day PO for single dose regimen; 200 mg/day PO is FDA-approved maximum for 3-day regimen; a dose of 40 mg/kg PO has been used off-label for hydatid cyst disease.

    Adolescents

    500 mg/day PO for single dose regimen; 200 mg/day PO is FDA-approved maximum for 3-day regimen; a dose of 40 mg/kg PO has been used off-label for hydatid cyst disease.

    Children

    2 to 12 years: 500 mg/day PO for single dose regimen; 200 mg/day PO is FDA-approved maximum for 3-day regimen; a dose of 40 mg/kg PO has been used off-label for hydatid cyst disease.
    1 to 2 years: 500 mg/day PO for single dose regimen; safety and efficacy have not been established for 3-day regimen.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    No dosage adjustment needed.

    ADMINISTRATION

    For storage information, see specific product information within the How Supplied section.

    Oral Administration

    Tablets can be taken without regards to food intake.
    500 mg chewable tablets: Chew completely before swallowing; do not swallow whole. For patients with difficulty swallowing, add approximately 2 to 3 mL of drinking water to a suitably sized spoon and place the tablet into the water. Within 2 minutes the tablet absorbs the water and turns into a small mass with semi-solid consistency which can then be swallowed.
    100 mg chewable tablets: The tablets may be chewed, swallowed, or crushed and mixed with food.

    STORAGE

    Emverm:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Vermox:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Mebendazole is contraindicated in patients with known hypersensitivity to the drug or any component of the drug.

    Pregnancy

    The available data on mebendazole use during pregnancy have not reported a clear association between mebendazole and a potential risk of major birth defects or miscarriage. Animal studies have revealed embryotoxic and teratogenic effects in pregnant rats at single oral doses as low as 10 mg/kg (approximately 0.2-fold the maximum recommended human dose). The World Health Organization (WHO) supports use of mebendazole after the first trimester. Untreated soil-transmitted helminth infections in pregnancy are associated with adverse outcomes, including maternal iron deficiency anemia, low birth weight, and neonatal and maternal death.

    Breast-feeding

    Limited data of mebendazole use during breast-feeding reveal that a small amount of mebendazole is present in human milk after oral administration. There are no data on the breast-fed infant, and the limited reports on the effect on milk production are inconsistent. The World Health Organization (WHO) supports single-dose oral antihelmintic treatment in breast-feeding women. In a case series of 45 breast-feeding women treated with mebendazole with both single- and multiple-dose regimens, mebendazole was well tolerated and was not associated with any adverse effects in the babies. Consider the benefits of breast-feeding along with the mother's clinical need for mebendazole and any potential adverse effects on the infant from mebendazole or the underlying maternal condition.

    Hepatic disease

    Mebendazole should be used with caution in patients with hepatic disease. Mebendazole is primarily eliminated by the liver and can accumulate in patients with hepatic impairment, increasing the risk of adverse reactions. Periodic assessment of organ system functions, including hematopoietic and hepatic, is advisable during prolonged therapy.

    Infants, neonates

    Safety and efficacy of mebendazole have not been established in neonates and infants. Convulsions or seizures have been reported in infants less than 1 year of age receiving mebendazole during postmarketing surveillance.

    Agranulocytosis, neutropenia

    Agranulocytosis and neutropenia have been reported with mebendazole use at higher doses and for prolonged durations than what is recommended for the treatment of soil-transmitted helminth infections. Monitor blood counts if mebendazole is used at higher doses or for prolonged duration.

    ADVERSE REACTIONS

    Severe

    agranulocytosis / Delayed / Incidence not known
    seizures / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    angioedema / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    glomerulonephritis / Delayed / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known

    Mild

    vomiting / Early / Incidence not known
    diarrhea / Early / Incidence not known
    nausea / Early / Incidence not known
    anorexia / Delayed / Incidence not known
    flatulence / Early / Incidence not known
    abdominal pain / Early / Incidence not known
    dizziness / Early / Incidence not known
    rash / Early / Incidence not known
    alopecia / Delayed / Incidence not known
    urticaria / Rapid / Incidence not known

    DRUG INTERACTIONS

    Barbiturates: (Moderate) Barbiturates induce hepatic microsomal enzymes and may increase the metabolism of mebendazole if given concomitantly. This effect can cause decreased levels of plasma mebendazole but is probably important only in the treatment of extraintestinal infections, such as hydatid cyst disease, and not in the treatment of intestinal helminths.
    Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Major) Avoid the concomitant use of mebendazole and metronidazole. Serious skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with coadministration.
    Bismuth Subsalicylate; Metronidazole; Tetracycline: (Major) Avoid the concomitant use of mebendazole and metronidazole. Serious skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with coadministration.
    Carbamazepine: (Moderate) Carbamazepine may potentially accelerate the hepatic metabolism of mebendazole. Dosage adjustments may be necessary, and closer monitoring of clinical and/or adverse effects is warranted when carbamazepine is used with mebendazole.
    Cimetidine: (Minor) Cimetidine may reduce the metabolism of mebendazole and increase mebendazole serum concentrations. Adverse hematological effects have been observed during concurrent use of cimetidine with high doses or prolonged mebendazole therapy. In a study of 7 patients, cimetidine significantly increased mebendazole concentrations; however, it was not considered to be of therapeutic relevance. In another study of 8 patients, concomitant use of cimetidine and a 30-day mebendazole treatment regimen resulted in a significant increase in mebendazole serum concentrations.
    Fosphenytoin: (Moderate) Mebendazole is metabolized by hepatic cytochrome P450 enzymes and other enzymes. Fosphenytoin induces hepatic microsomal enzymes and may increase the metabolism of mebendazole if given concomitantly.
    Metronidazole: (Major) Avoid the concomitant use of mebendazole and metronidazole. Serious skin reactions, such as Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with coadministration.
    Phenytoin: (Moderate) Hydantoin anticonvulsants induce hepatic microsomal enzymes and may increase the metabolism of other drugs, including mebendazole, leading to reduced efficacy of the concomitant medication.
    Rifamycins: (Moderate) Mebendazole is metabolized by hepatic cytochrome P450 enzymes and other enzymes. Rifamycins induce hepatic microsomal enzymes and may increase the metabolism of mebendazole if given concomitantly.

    PREGNANCY AND LACTATION

    Pregnancy

    The available data on mebendazole use during pregnancy have not reported a clear association between mebendazole and a potential risk of major birth defects or miscarriage. Animal studies have revealed embryotoxic and teratogenic effects in pregnant rats at single oral doses as low as 10 mg/kg (approximately 0.2-fold the maximum recommended human dose). The World Health Organization (WHO) supports use of mebendazole after the first trimester. Untreated soil-transmitted helminth infections in pregnancy are associated with adverse outcomes, including maternal iron deficiency anemia, low birth weight, and neonatal and maternal death.

    Limited data of mebendazole use during breast-feeding reveal that a small amount of mebendazole is present in human milk after oral administration. There are no data on the breast-fed infant, and the limited reports on the effect on milk production are inconsistent. The World Health Organization (WHO) supports single-dose oral antihelmintic treatment in breast-feeding women. In a case series of 45 breast-feeding women treated with mebendazole with both single- and multiple-dose regimens, mebendazole was well tolerated and was not associated with any adverse effects in the babies. Consider the benefits of breast-feeding along with the mother's clinical need for mebendazole and any potential adverse effects on the infant from mebendazole or the underlying maternal condition.

    MECHANISM OF ACTION

    Mebendazole selectively damages cytoplasmic microtubules in the absorptive and intestinal cells of nematodes but not of the host. This microtubular deterioration is irreversible and leads to disruption of absorptive and secretory functions of the cells, which are essential to the worm's survival. This disruption results in accumulation of secretory substances in Golgi apparatus, decreased glucose uptake, and depleted endogenous glycogen stores. The excess secretory substances present in the Golgi apparatus are hydrolytic and proteolytic enzymes, which are released intracellularly, produce autolysis of the cell, and subsequently, cause the death of the worm. These effects do not occur in the host cells.
     
    Mebendazole is effective in eradicating infections caused by the following human pathogenic intestinal parasites: Trichinella spiralis (pork worm), Trichuris trichiura (whipworm), Enterobius vermicularis (pinworm), Strongyloides stercoralis (threadworm), Ascaris lumbricoides (roundworm), Ancylostoma duodenale (hookworm), and Necator americanus (hookworm). The drug also has some activity against certain cestodes (tapeworms) including Hymenolepis nana (dwarf tapeworm), Taenia saginata (beef tapeworm), T. solium (pork tapeworm), and Echinococcus granulosus (hydatid cyst). Clinicians should be aware that efficacy can be affected by such factors as preexisting diarrhea and gastrointestinal transit time, the degree of infection, and the strain of the particular helminth.
     
    Resistance of mebendazole can occur, likely due to changes of beta-tubulin protein, which reduces the binding of mebendazole to beta-tubulin. However, the clinical significance of this is unknown.

    PHARMACOKINETICS

    Mebendazole is administered orally. The plasma protein binding of mebendazole is 90% to 95%. The volume of distribution is 1 to 2 L/kg, indicating penetration outside vascular areas. Mebendazole is extensively metabolized, primarily in the liver. Plasma concentrations of its major metabolites (hydrolyzed and reduced forms of mebendazole) are higher than those of mebendazole. Mebendazole, the conjugated forms of mebendazole, and its metabolites likely undergo some degree of enterohepatic recirculation. All metabolites are devoid of anthelmintic activity. Less than 2% of an oral dose is excreted in the urine and the remainder is eliminated in the feces as unchanged drug or metabolites. The elimination half-life of mebendazole ranges from 3 to 6 hours in most patients.
     
    Affected cytochrome P450 isoenzymes and drug transporters: none
    While mebendazole is extensively metabolized, specific cytochrome P450 enzyme involvement has not been described. However, reports of a drug interaction with cimetidine suggest cytochrome P450 involvement.

    Oral Route

    After oral administration, the majority of the mebendazole dose remains in the gastrointestinal tract where it exerts an anthelmintic effect locally. Administration of the 500 mg chewable tablets with a high fat meal increases the bioavailability. In a clinical study with adult subjects (n = 16), the mean Cmax, median Tmax, and mean AUC were 14 ng/mL, 1.5 hours (range: 0.5 to 3 hours), and 175 ng x hour/mL when given in the fasted state compared with 56.2 ng/mL, 4 hours (range: 2 to 6 hours), and 456 ng x hour/mL when given with a high fat meal. After administration of the 100 mg tablets twice daily for 3 consecutive days, plasma concentrations did not exceed 0.03 mcg/mL. Dosing with a high fat meal increased the bioavailability of mebendazole; however, the overall effect of food on the amount of drug remaining in the gastrointestinal tract is not expected to be substantial.