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MEBENDAZOLE AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) The compounds in this class are antinematodes and anthelmintic agents used in both human and veterinary practice.

Specific Substances

    A) CAMBENDAZOLE
    1) MK-905
    2) CAS 26097-80-3
    MEBENDAZOLE
    1) Methyl 5-benzoyl-benzimidazole-2-carbamate
    2) CAS 31431-39-7
    THIABENDAZOLE
    1) 2-(4-thiazolyl)benimidazole
    2) MK-360
    3) CAS 148-79-8

    1.2.1) MOLECULAR FORMULA
    1) MEBENDAZOLE: C16H13N3O3

Available Forms Sources

    A) FORMS
    1) Mebendazole is available as 100 mg chewable tablets (Prod Info mebendazole oral tablets, chewable tablets, 2004).
    2) Thiabendazole is no longer available in the US.
    B) USES
    1) MEBENDAZOLE
    a) Mebendazole is an antihelmintic indicated in the treatment of singular or mixed infections involving Enterobius vermicularis (pinworm), Trichuris trichiura (whipworm), Ascaris lumbricoides (common roundworm), Ancylostoma duodenale (common hookworm), or Necator americanus (American hookworm) (Prod Info mebendazole oral tablets, chewable tablets, 2004).
    2) THIABENDAZOLE
    a) Thiabendazole, an antihelmintic, is indicated in the treatment of strongyloidiasis (threadworm), cutaneous larva migrans (creeping eruption), or visceral larva migrans (Prod Info Mintezol(R), thiabendazole, 1998).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: The compounds in this class are used as anthelmintic agents used in both human and veterinary practice.
    B) PHARMACOLOGY: Broad spectrum antihelmintic agents that can inhibit the formation of worm microtubules and cause worm glucose depletion.
    C) EPIDEMIOLOGY: Overdose is rare; severe toxicity is not anticipated.
    D) WITH THERAPEUTIC USE
    1) Mild gastrointestinal events may occur. Hematuria has been occasionally reported during therapy with these agents. Elevated liver enzymes, hepatitis, neutropenia and agranulocytosis are rare events associated with prolonged, high-dose therapy. Seizures have been reported very rarely. Mental status changes (drowsiness, dizziness, irritability) and headaches have been reported during therapeutic use; one case of seizures and one case of Guillain-Barre syndrome have been reported.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. There have been few reported cases of overdose with these agents, and the events were similar to adverse reactions seen with therapeutic administration at high doses.
    2) MILD TO MODERATE TOXICITY: Gastrointestinal events (eg, abdominal pain, nausea, diarrhea and vomiting) are likely to occur.
    3) SEVERE TOXICITY: Severe toxicity is not anticipated. Hepatic injury (elevated liver enzymes, hepatitis) or alterations in hematopoietic function (eg, neutropenia, agranulocytosis) may develop following a significant exposure.
    0.2.3) VITAL SIGNS
    A) Fever is an idiosyncratic reaction with mebendazole.
    0.2.20) REPRODUCTIVE
    A) The manufacturer has classified mebendazole as FDA pregnancy category C. Administration of mebendazole at single oral doses (equivalent to a human dose) in rats has been embryotoxic and teratogenic. Advise pregnant women of the potential for fetal harm if mebendazole is used during pregnancy, especially during the first trimester. It is not known if mebendazole is distributed into human breast milk. Exercise caution when administering to a lactating woman.

Laboratory Monitoring

    A) Monitor fluid and electrolyte balance in patients that develop significant diarrhea and/or vomiting.
    B) Monitor renal function and liver enzymes after significant overdose. Liver enzymes and renal function tests may be elevated while on these agents.
    C) Monitor CBC with differential following a significant exposure; neutropenia and agranulocytosis have been rarely observed following chronic therapy.
    D) Although levels can be obtained for these agents, they are not readily available or useful for guiding management.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Replace fluids and electrolytes in patients that develop significant diarrhea and/or vomiting. Monitor liver enzymes in patients with a significant exposure.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive; severe toxicity is not anticipated. Monitor liver enzymes and hematopoietic function in patients at risk. Hepatitis has been rarely reported with therapy. Monitor for alterations in CNS function.
    C) DECONTAMINATION
    1) PREHOSPITAL: Decontamination is unlikely to be necessary; vomiting may occur following an acute exposure.
    2) HOSPITAL: Decontamination is unlikely to be necessary. Activated charcoal may be considered if a significant, recent ingestion has occurred and the patient is able to protect their airway.
    D) AIRWAY MANAGEMENT
    1) Airway management is unlikely to be necessary. In rare cases, airway protection and support may be necessary in patients that develop significant CNS depression or seizures.
    E) ANTIDOTE
    1) None.
    F) ENHANCED ELIMINATION
    1) Limited data. Hemodialysis was not found to be effective in altering mebendazole kinetics.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: An asymptomatic adult or child with an inadvertent minor exposure (eg, a single dose) may be monitored at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve. Patients with gastrointestinal or CNS effects should be treated and monitored until symptoms resolve. Patients may be discharged to home once symptoms have resolved and laboratory studies (ie, hematologic, hepatic) are within normal limits.
    3) ADMISSION CRITERIA: Patients with persistent symptoms should be admitted for further treatment.
    4) CONSULT CRITERIA: Contact a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.
    H) PHARMACOKINETICS
    1) Mebendazole is poorly absorbed, bioavailability 5% to 10%. Extensive hepatic metabolism. Volume of distribution 1 to 2 L/kg. Elimination 95% fecal and 5% or less renal. Half-life 2.5 to 5.5 hours.
    I) DIFFERENTIAL DIAGNOSIS
    1) Alterations in fluid balance, electrolytes and gastrointestinal symptoms may be related to the underlying infection caused by an intestinal parasite or bacterial or viral illnesses.

Range Of Toxicity

    A) TOXICITY: A specific toxic dose has not been established for these agents. Mebendazole has been well tolerated and relatively free of side effects even when given at 32 to 62 times the therapeutic dose. Gastrointestinal symptoms may occur following overdose.
    B) THERAPEUTIC DOSE: MEBENDAZOLE: ADULT and CHILDREN: ORAL: Usual dose: 100 mg/dose, twice daily for 3 days. It has not been studied in children less than 2 years of age. THIABENDAZOLE: SUMMARY: No longer available in the US. ADULT: ORAL: Doses range from 0.75 to 1.5 g/dose depending on weight; maximum daily dose: 3 g. CHILDREN: ORAL: Doses range from 0.25 to 1.5 g/dose depending on weight (not indicated in children less than 30 pounds); maximum daily dose: 3 g.

Clinical Effects

Summary Of Exposure

    A) USES: The compounds in this class are used as anthelmintic agents used in both human and veterinary practice.
    B) PHARMACOLOGY: Broad spectrum antihelmintic agents that can inhibit the formation of worm microtubules and cause worm glucose depletion.
    C) EPIDEMIOLOGY: Overdose is rare; severe toxicity is not anticipated.
    D) WITH THERAPEUTIC USE
    1) Mild gastrointestinal events may occur. Hematuria has been occasionally reported during therapy with these agents. Elevated liver enzymes, hepatitis, neutropenia and agranulocytosis are rare events associated with prolonged, high-dose therapy. Seizures have been reported very rarely. Mental status changes (drowsiness, dizziness, irritability) and headaches have been reported during therapeutic use; one case of seizures and one case of Guillain-Barre syndrome have been reported.
    E) WITH POISONING/EXPOSURE
    1) OVERDOSE: Limited data. There have been few reported cases of overdose with these agents, and the events were similar to adverse reactions seen with therapeutic administration at high doses.
    2) MILD TO MODERATE TOXICITY: Gastrointestinal events (eg, abdominal pain, nausea, diarrhea and vomiting) are likely to occur.
    3) SEVERE TOXICITY: Severe toxicity is not anticipated. Hepatic injury (elevated liver enzymes, hepatitis) or alterations in hematopoietic function (eg, neutropenia, agranulocytosis) may develop following a significant exposure.

Vital Signs

    3.3.1) SUMMARY
    A) Fever is an idiosyncratic reaction with mebendazole.
    3.3.3) TEMPERATURE
    A) FEVER is an idiosyncratic reaction reported after use of mebendazole (Harris, 1979).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) KERATOCONJUNCTIVITIS SICCA is a rare complication of treatment with thiabendazole (Fink et al, 1978).
    2) COLOR VISION DISTURBANCES have been reported during thiabendazole therapy (Lloyd-Mostyn, 1968).
    3.4.4) EARS
    A) WITH THERAPEUTIC USE
    1) TINNITUS is a reported side effect with thiabendazole (Tchao & Templeton, 1983).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) ALTERED MENTAL STATUS
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Dizziness and headache have been reported after therapeutic use of mebendazole (Beard et al, 1978) and thiabendazole (Tchao & Templeton, 1983). Thiabendazole therapy has been associated with hyperirritability (Tchao & Templeton, 1983; Lloyd-Mostyn, 1968).
    B) SEIZURE
    1) WITH THERAPEUTIC USE
    a) MEBENDAZOLE: There have been very rare reports of seizures with therapy (Prod Info mebendazole oral chewable tablet, 2004).
    b) THIABENDAZOLE: One patient with Down's Syndrome who was taking 1000 mg twice daily for 2 doses experienced a grand mal seizure. This has not been a commonly reported side effect, and the relationship of the thiabendazole to the seizure is unclear with only this single case report (Tchao & Templeton, 1983).
    C) GUILLAIN-BARRé SYNDROME
    1) WITH THERAPEUTIC USE
    a) THIABENDAZOLE: Katznelson & Gross (1978) reported a case of Guillain-Barre syndrome associated with the use of thiabendazole.

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTRITIS
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Nausea, vomiting, diarrhea, and anorexia are common side effects of therapy with these agents (Prod Info mebendazole oral chewable tablet, 2004; Katz, 1982). Persistent nausea and vomiting occurred in a patient receiving 50 mg/kg mebendazole for treatment of intra-abdominal echinococcal cysts (Miskovitz & Javitt, 1980).
    2) WITH POISONING/EXPOSURE
    a) MEBENDAZOLE: Gastrointestinal complaints are likely to occur following overdose, and may last for several hours (Prod Info mebendazole oral chewable tablet, 2004).
    B) HYPERTROPHY OF SALIVARY GLAND
    1) WITH THERAPEUTIC USE
    a) THIABENDAZOLE: Sicca complex was reported in a 55-year-old who was given a 3 day course of 40 mg/kg/day of thiabendazole (Rex et al, 1983), a 43-year-old receiving 15 mg/kg/day for 2 doses (Fink et al, 1978), and a 17-year-old receiving a single dose of 15 mg/kg (Fink et al, 1978).
    1) This sicca, which included dry mouth and reduced tear production, persisted for one year after cessation of treatment. This is a very rare side effect of this agent (Rex et al, 1983).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) CHOLESTATIC HEPATITIS
    1) WITH THERAPEUTIC USE
    a) MEBENDAZOLE: There have been rare reports of hepatitis following prolonged therapy at higher than recommended doses (Prod Info mebendazole oral chewable tablet, 2004).
    b) THIABENDAZOLE: It has rarely caused drug-induced intrahepatic cholestatic reaction during therapeutic use (Rex et al, 1983; Fink et al, 1978). Signs and symptoms included jaundice, anorexia, acholic stools, and severe pruritus.
    B) LIVER ENZYMES ABNORMAL
    1) WITH THERAPEUTIC USE
    a) MEBENDAZOLE: Elevated SGOT, SGPT, alkaline phosphatase, and BUN have been reported during prolonged therapy at higher than recommended doses (Prod Info mebendazole oral chewable tablet, 2004; Beard et al, 1978).

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) BLOOD IN URINE
    1) WITH THERAPEUTIC USE
    a) SUMMARY: Hematuria was reported in a few cases of thiabendazole (London, 1965) and mebendazole therapy (Golden et al, 1984) (Beard et al, 1978).
    3.10.3) ANIMAL EFFECTS
    A) ANIMAL STUDIES
    1) TESTIS DISORDER
    a) MEBENDAZOLE: Testicular atrophy was reported when rats were administered prolonged, high doses of mebendazole (Miskovitz & Javitt, 1980).

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOPENIA
    1) WITH THERAPEUTIC USE
    a) MEBENDAZOLE: Reversible neutropenia may occur in up to 5% of patients on high-dose mebendazole therapy. In one reported case, reversible platelet and RBC suppression was also seen (Levin et al, 1983). There have also been rare reports of neutropenia following chronic mebendazole therapy (Prod Info mebendazole oral chewable tablet, 2004).
    b) MEBENDAZOLE: Leukopenia has rarely been associated with high-dose mebendazole therapy and may represent an idiosyncratic reaction (Miskovitz & Javitt, 1980).
    B) AGRANULOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) MEBENDAZOLE: There have been rare reports of agranulocytosis following chronic mebendazole therapy (Prod Info mebendazole oral chewable tablet, 2004).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) ALOPECIA
    1) WITH THERAPEUTIC USE
    a) MEBENDAZOLE: Patchy alopecia occurred in a patient receiving 50 mg/kg mebendazole for treatment of intra-abdominal echinococcal cysts (Miskovitz & Javitt, 1980).
    B) ERUPTION
    1) WITH THERAPEUTIC USE
    a) MEBENDAZOLE: Rash, urticaria and angioedema have been rarely reported with mebendazole therapy (Prod Info mebendazole oral chewable tablet, 2004).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) WITH THERAPEUTIC USE
    a) THIABENDAZOLE: Cunliffe & Shuster (1967) reported 2 patients that developed muscle aches on exercise 3 weeks after starting thiabendazole 3 g for strongyloides stercoralis infection. A cause and effect relationship could not be established.

Reproductive

    3.20.1) SUMMARY
    A) The manufacturer has classified mebendazole as FDA pregnancy category C. Administration of mebendazole at single oral doses (equivalent to a human dose) in rats has been embryotoxic and teratogenic. Advise pregnant women of the potential for fetal harm if mebendazole is used during pregnancy, especially during the first trimester. It is not known if mebendazole is distributed into human breast milk. Exercise caution when administering to a lactating woman.
    3.20.2) TERATOGENICITY
    A) LACK OF EFFECT
    1) MEBENDAZOLE
    a) The use of mebendazole during pregnancy was not associated with a significant risk of fetal congenital defects in a cross-sectional study in Sri Lanka; however, mebendazole should be avoided during the first trimester. Women who gave birth in 2 state hospitals were administered a questionnaire that included questions about their use of mebendazole. Overall, 5275 of 7087 women used mebendazole at least once during their pregnancy, and 1737 did not use any anthelmintic (control group). The rate of major congenital birth defects was 1.8% and 1.5% for the mebendazole and control groups, respectively (NS). Use of mebendazole in the first trimester (contrary to medical advice) was associated with a higher (but not significantly so) rate of birth defects (2.5%). The incidence of stillbirths and perinatal deaths was lower in the mebendazole group (1.9% vs 3.3%), as was the rate of low birthweight babies (1.1% vs 2.3%). The dosing of mebendazole was 100 mg twice daily for 3 days (de Silva et al, 1999).
    B) ANIMAL STUDIES
    1) MEBENDAZOLE: It has been shown to produce teratogenic activity in pregnant rats at single oral doses as low as 10 mg/kg (approximately equal to a human dose based on mg/m(2)). Based on these findings, mebendazole use is not recommended in pregnant women (Prod Info mebendazole oral tablets, chewable tablets, 2004).
    2) SKELETAL MALFORMATION
    a) THIABENDAZOLE: A 10 times human dose given in an oily suspension to mice produced cleft palate and axial skeletal defects (Prod Info Mintezol(R), thiabendazole, 1998).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) MEBENDAZOLE
    a) The manufacturer has classified mebendazole as FDA pregnancy category C (Prod Info Emverm(TM) oral chewable tablets, 2015)
    b) Advise pregnant women of the potential for fetal harm if mebendazole is used during pregnancy, especially during the first trimester (Prod Info Emverm(TM) oral chewable tablets, 2015).
    2) THIABENDAZOLE: Pregnancy Category C
    B) SPONTANEOUS ABORTION
    1) Based on data from women that inadvertently consumed mebendazole during the first trimester of pregnancy, the incidence of spontaneous abortion and malformations did not exceed the number found in pregnant women in the general population (Prod Info Emverm(TM) oral chewable tablets, 2015)
    C) LACK OF EFFECT
    1) MEBENDAZOLE
    a) The use of mebendazole during pregnancy was not associated with a significant risk of fetal congenital defects in a cross-sectional study in Sri Lanka; however, mebendazole should be avoided during the first trimester. Women who gave birth in 2 state hospitals were administered a questionnaire that included questions about their use of mebendazole. Overall, 5275 of 7087 women used mebendazole at least once during their pregnancy, and 1737 did not use any anthelmintic (control group). The rate of major congenital birth defects was 1.8% and 1.5% for the mebendazole and control groups, respectively (NS). Use of mebendazole in the first trimester (contrary to medical advice) was associated with a higher (but not significantly so) rate of birth defects (2.5%). The incidence of stillbirths and perinatal deaths was lower in the mebendazole group (1.9% vs 3.3%), as was the rate of low birthweight babies (1.1% vs 2.3%). The dosing of mebendazole was 100 mg twice daily for 3 days (de Silva et al, 1999).
    b) Based on data from women that inadvertently consumed mebendazole during the first trimester of pregnancy, the incidence of spontaneous abortion and malformations did not exceed the number found in pregnant women in the general population. No teratogenic activity was observed in 170 infants exposed to mebendazole in utero (Prod Info Emverm(TM) oral chewable tablets, 2015)
    D) ANIMAL STUDIES
    1) MEBENDAZOLE
    a) Embryotoxic and teratogenic effects were reported in pregnant animals administered single oral doses of mebendazole approximately equal to the human dose based on mg/m(2) (Prod Info Emverm(TM) oral chewable tablets, 2015).
    2) THIABENDAZOLE
    a) LACK OF EFFECT: No effect was seen when rats (human dose equivalent), rabbits (15 times human dose), and mice (2.5 times human dose) were given thiabendazole (Prod Info Mintezol(R), thiabendazole, 1998).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) MEBENDAZOLE
    a) Exercise caution when administering to a lactating woman (Prod Info Emverm(TM) oral chewable tablets, 2015).
    b) It is not known if mebendazole is distributed into human breast milk (Prod Info Emverm(TM) oral chewable tablets, 2015); however, the drug is minimally absorbed from the gastrointestinal tract and is highly protein bound suggesting transfer is limited. The World Health Organization (WHO) considers all pregnant and lactating women with helmintic infections to be a high-risk group and recommends that they be individually offered treatment in order to avoid schistosomiasis-induced organ damage and anemia. Where otherwise appropriate, single-dose oral anthelmintic treatment may also be used in lactating women (Allen et al, 2002).
    2) THIABENDAZOLE: It is unknown if thiabendazole is excreted in human milk (Prod Info Mintezol(R), thiabendazole, 1998).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor fluid and electrolyte balance in patients that develop significant diarrhea and/or vomiting.
    B) Monitor renal function and liver enzymes after significant overdose. Liver enzymes and renal function tests may be elevated while on these agents.
    C) Monitor CBC with differential following a significant exposure; neutropenia and agranulocytosis have been rarely observed following chronic therapy.
    D) Although levels can be obtained for these agents, they are not readily available or useful for guiding management.

Methods

    A) CHROMATOGRAPHY
    1) MEBENDAZOLE may be measured by a high performance liquid chromatographic assay (Alton et al, 1979).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients with persistent symptoms should be admitted for further treatment.
    6.3.1.2) HOME CRITERIA/ORAL
    A) An asymptomatic adult or child with an inadvertent minor exposure (eg, a single dose) may be monitored at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Contact a medical toxicologist or Poison Center for assistance in managing patients with severe toxicity or in whom the diagnosis is unclear. Patients with a deliberate self-harm ingestion should be evaluated by a mental health specialist.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate self-harm ingestion should be evaluated in a healthcare facility and monitored until symptoms resolve. Patients with gastrointestinal or CNS effects should be treated and monitored until symptoms resolve. Patients may be discharged to home once symptoms have resolved and laboratory studies (ie, hematologic, hepatic) are within normal limits.

Monitoring

    A) Monitor fluid and electrolyte balance in patients that develop significant diarrhea and/or vomiting.
    B) Monitor renal function and liver enzymes after significant overdose. Liver enzymes and renal function tests may be elevated while on these agents.
    C) Monitor CBC with differential following a significant exposure; neutropenia and agranulocytosis have been rarely observed following chronic therapy.
    D) Although levels can be obtained for these agents, they are not readily available or useful for guiding management.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Decontamination is unlikely to be necessary, vomiting may occur following an acute exposure.
    6.5.2) PREVENTION OF ABSORPTION
    A) Decontamination is unlikely to be necessary. Activated charcoal may be considered if a significant, recent ingestion has occurred and the patient is able to protect their airway.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment is symptomatic and supportive. Alterations in fluid balance and electrolytes may develop after exposure. Significant toxicity is not anticipated.
    B) MONITORING OF PATIENT
    1) Monitor fluid and electrolyte balance. Liver enzymes may be elevated while on these agents, and might be evaluated following an overdose. Monitor CBC with differential following a significant exposure; neutropenia and agranulocytosis have been rarely observed following chronic therapy.
    2) Even high doses of these agents cause only mild CNS depression, or dizziness. Coma is not expected.
    3) Large amounts given therapeutically have caused hematuria and decreased renal function. Patients who overdose on these medications should be monitored for normal renal function. Kidney damage has NOT been reported in overdose with these agents.
    C) FLUID/ELECTROLYTE BALANCE REGULATION
    1) An overdose with these agents may cause considerable nausea, vomiting, and diarrhea. Patients experiencing these symptoms should be monitored for fluid and electrolyte replacement.
    D) INJURY OF LIVER
    1) Hepatic injury has generally responded to supportive care (Rex et al, 1983).
    E) SEIZURE
    1) There have been very rare reports of seizure with mebendazole or thiabendazole therapy. Seizure has not been reported following overdose.
    2) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    3) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    4) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    5) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    6) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    7) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

Enhanced Elimination

    A) HEMODIALYSIS
    1) MEBENDAZOLE: Hemodialysis was not effective in altering mebendazole kinetics (Allgayer et al, 1984).

Range Of Toxicity

Summary

    A) TOXICITY: A specific toxic dose has not been established for these agents. Mebendazole has been well tolerated and relatively free of side effects even when given at 32 to 62 times the therapeutic dose. Gastrointestinal symptoms may occur following overdose.
    B) THERAPEUTIC DOSE: MEBENDAZOLE: ADULT and CHILDREN: ORAL: Usual dose: 100 mg/dose, twice daily for 3 days. It has not been studied in children less than 2 years of age. THIABENDAZOLE: SUMMARY: No longer available in the US. ADULT: ORAL: Doses range from 0.75 to 1.5 g/dose depending on weight; maximum daily dose: 3 g. CHILDREN: ORAL: Doses range from 0.25 to 1.5 g/dose depending on weight (not indicated in children less than 30 pounds); maximum daily dose: 3 g.

Therapeutic Dose

    7.2.1) ADULT
    A) SPECIFIC SUBSTANCE
    1) MEBENDAZOLE
    a) COMMON ROUNDWORM (ASCARIASIS): 100 mg/dose, twice daily for 3 days; repeat after 3 weeks, if needed (Prod Info Emverm(TM) oral chewable tablets, 2015).
    b) ENTEROBIUS VERMICULARIS (PINWORM): A single dose of 100 mg; repeat after 3 weeks, if needed (Prod Info Emverm(TM) oral chewable tablets, 2015).
    c) TRICHURIASIS (WHIPWORM): 100 mg/dose, twice daily for 3 days; repeat after 3 weeks, if needed (Prod Info Emverm(TM) oral chewable tablets, 2015).
    d) HOOKWORM: 100 mg/dose, twice daily for 3 days; repeat after 3 weeks, if needed (Prod Info Emverm(TM) oral chewable tablets, 2015).
    2) THIABENDAZOLE
    a) 75 POUNDS: 0.75 g/dose orally twice daily after meals (Prod Info MINTEZOL(R) chewable tablets, oral suspension, 2003)
    b) 100 POUNDS: 1 g/dose orally twice daily after meals (Prod Info MINTEZOL(R) chewable tablets, oral suspension, 2003)
    c) 125 POUNDS: 1.25 g/dose orally twice daily after meals (Prod Info MINTEZOL(R) chewable tablets, oral suspension, 2003)
    d) GREATER THAN OR EQUAL TO 150 POUNDS: 1.5 g/dose given twice daily after meals (Prod Info MINTEZOL(R) chewable tablets, oral suspension, 2003)
    e) The maximum recommended daily dose is 3 g (Prod Info MINTEZOL(R) chewable tablets, oral suspension, 2003)
    7.2.2) PEDIATRIC
    A) SPECIFIC SUBSTANCE
    1) MEBENDAZOLE
    a) SUMMARY: Mebendazole has not been extensively studied in children under 2 years of age (Prod Info Emverm(TM) oral chewable tablets, 2015).
    b) The same dose schedule applies to adults and children:
    1) COMMON ROUNDWORM (ASCARIASIS): 100 mg/dose, twice daily for 3 days; repeat after 3 weeks, if needed (Prod Info Emverm(TM) oral chewable tablets, 2015).
    2) ENTEROBIUS VERMICULARIS (PINWORM): A single dose of 100 mg; repeat after 3 weeks, if needed (Prod Info Emverm(TM) oral chewable tablets, 2015).
    3) TRICHURIASIS (WHIPWORM): 100 mg/dose, twice daily for 3 days; repeat after 3 weeks, if needed (Prod Info Emverm(TM) oral chewable tablets, 2015).
    4) HOOKWORM: 100 mg/dose, twice daily for 3 days; repeat after 3 weeks, if needed (Prod Info Emverm(TM) oral chewable tablets, 2015).
    2) THIABENDAZOLE
    a) There is limited clinical experience with thiabendazole in pediatric patients weighing less than 30 pounds(Prod Info MINTEZOL(R) chewable tablets, oral suspension, 2003).
    b) 30 POUNDS: 0.25 g/dose orally twice daily after meals (Prod Info MINTEZOL(R) chewable tablets, oral suspension, 2003).
    c) 50 POUNDS: 0.5 g/dose orally twice daily after meals (Prod Info MINTEZOL(R) chewable tablets, oral suspension, 2003).
    d) 75 POUNDS: 0.75 g/dose orally twice daily after meals (Prod Info MINTEZOL(R) chewable tablets, oral suspension, 2003).
    e) 100 POUNDS: 1 g/dose orally twice daily after meals (Prod Info MINTEZOL(R) chewable tablets, oral suspension, 2003).
    f) 125 POUNDS: 1.25 g/dose orally twice daily after meals (Prod Info MINTEZOL(R) chewable tablets, oral suspension, 2003).
    g) GREATER THAN OR EQUAL TO 150 POUNDS: 1.5 g/dose given twice daily after meals (Prod Info MINTEZOL(R) chewable tablets, oral suspension, 2003).
    h) The maximum recommended daily dose is 3 g (Prod Info MINTEZOL(R) chewable tablets, oral suspension, 2003)

Maximum Tolerated Exposure

    A) SUMMARY
    1) MEBENDAZOLE: Patients have tolerated total daily doses of 1200 to 1800 mg for 21 to 30 days (Bekhti et al, 1977).
    B) SPECIFIC SUBSTANCE
    1) MEBENDAZOLE
    a) Mebendazole has been well tolerated and relatively free of side effects even when given 32 to 62 times therapeutic dose. In one study where 37 patients took 1200 to 1800 mg daily for 21 to 30 days, no hematologic abnormalities were noted (Miskovitz & Javitt, 1980). Gastrointestinal events, lasting up to a few hours, may develop following overdose (Prod Info mebendazole oral tablets, chewable tablets, 2004).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) MEBENDAZOLE: A serum level of 239 ng/mL has been associated with neutropenia, but serum levels have yet to be correlated with toxic effects (Levin et al, 1983).
    2) CONCENTRATION LEVEL
    a) A single dose of 1.5 g of mebendazole produced plasma concentrations of 17 to 134 nanomoles/liter in 3 volunteers only if mebendazole was given with a fatty meal (Munst et al, 1980).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) MEBENDAZOLE
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 712 mg/kg (RTECS, 2002)
    2) LD50- (ORAL)MOUSE:
    a) 620 mg/kg (RTECS, 2002)
    3) LD50- (INTRAMUSCULAR)RAT:
    a) 350 mg/kg (RTECS, 2002)
    4) LD50- (ORAL)RAT:
    a) 714 mg/kg (RTECS, 2002)
    B) THIABENDAZOLE
    1) LD50- (ORAL)MOUSE:
    a) 1300 mg/kg (RTECS, 2002)
    2) LD50- (ORAL)RAT:
    a) 2080 mg/kg (RTECS, 2002)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) MEBENDAZOLE: It is a benzimidazole compound. It irreversibly inhibits glucose uptake by the helminth without doing the same to the host, even in large doses (Katz, 1982).
    B) THIABENDAZOLE: The mode of action of this agent is unknown, but it may inhibit the helminth-specific enzyme fumarate reductase (Prod Info Mintezol(R), thiabendazole, 1998).

Toxicologic Mechanism

    A) HEPATIC INJURY: Thiabendazole's hepatic injury is most likely due to host idiosyncrasy and drug hypersensitivity (Rex et al, 1983).
    B) NEUTROPENIA: Bone marrow examinations showed a mild to severe hypocellularity consistent with marrow suppression following mebendazole therapy (Levin et al, 1983).

Physicochemical

Physical Characteristics

    A) CAMBENDAZOLE is an odorless white crystalline solid that is soluble in alcohol, sparingly soluble in acetone, and very slightly soluble in 0.1 M hydrochloric acid (0.02 mg/mL), and practically insoluble in water (0.02 mg/mL). .
    B) MEBENDAZOLE is a white to slightly yellow powder that is less than 0.05% soluble in alcohol, chloroform, dilute mineral acid solutions, ether, and water; soluble in formic acid (Prod Info Emverm(TM) oral chewable tablets, 2015).
    C) THIABENDAZOLE consists of white to off-white crystals that are insoluble in water. The maximum solubility of thiabendazole at pH 2.2 is 3.84%.

Molecular Weight

    A) CAMBENDAZOLE: 302.35
    B) MEBENDAZOLE: 295.29 (Prod Info Emverm(TM) oral chewable tablets, 2015)
    C) THIABENDAZOLE: 201.26

Animal Toxicology

Clinical Effects

    11.1.3) CANINE/DOG
    A) HEPATIC INJURY has been reported in dogs treated with the combination product diethylcarbamazine and oxibendazole. The reaction is thought to be idiosyncratic (Vaden et al, 1988).

References

General Bibliography

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    4) Alton KB, Patrick JE, & McGuire JL: High-performance liquid chromatographic assay for the anthelmintic agent mebendazole in human plasma. J Pharm Sci 1979; 68:880-882.
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    36) Product Information: lorazepam IM, IV injection, lorazepam IM, IV injection. Akorn, Inc, Lake Forest, IL, 2008.
    37) Product Information: mebendazole oral chewable tablet, mebendazole oral chewable tablet. Teva Pharmaceuticals, Sellersville, PA, 2004.
    38) Product Information: mebendazole oral tablets, chewable tablets, mebendazole oral tablets, chewable tablets. Teva Pharmaceuticals USA, Sellersville, PA, 2004.
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