PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Agents for Leishmaniasis and Trypanosomiasis

    DEA CLASS

    Rx

    DESCRIPTION

    Antiprotozoal
    Used for the treatment of Chagas disease or American trypanosomiasis, a parasitic infection caused by Trypanosoma cruzi
    Only approved for pediatric patients 2 to 12 years, although used off-label in patients of all ages

    COMMON BRAND NAMES

    Benznidazole

    HOW SUPPLIED

    Benznidazole Oral Tab: 12.5mg, 100mg

    DOSAGE & INDICATIONS

    For the treatment of American trypanosomiasis (Chagas disease).
    Oral dosage
    Adults†

    Safety and efficacy have not been established; however, 5 to 7 mg/kg/day PO divided twice daily for 60 days is recommended by the CDC.

    Adolescents†

    Safety and efficacy have not been established; however, 5 to 7 mg/kg/day PO divided twice daily for 60 days is recommended by the CDC.

    Children 2 to 12 years weighing 60 kg or more

    5 to 8 mg/kg/day PO divided twice daily for 60 days; for ease of administration, a dose of 200 mg PO twice daily is recommended.

    Children 2 to 12 years weighing 40 to 59 kg

    5 to 8 mg/kg/day PO divided twice daily for 60 days; for ease of administration, a dose of 150 mg PO twice daily is recommended.

    Children 2 to 12 years weighing 30 to 39 kg

    5 to 8 mg/kg/day PO divided twice daily for 60 days; for ease of administration, a dose of 100 mg PO twice daily is recommended.

    Children 2 to 12 years weighing 20 to 29 kg

    5 to 8 mg/kg/day PO divided twice daily for 60 days; for ease of administration, a dose of 75 mg PO twice daily is recommended.

    Children 2 to 12 years weighing 15 to 19 kg

    5 to 8 mg/kg/day PO divided twice daily for 60 days; for ease of administration, a dose of 62.5 mg PO twice daily is recommended.

    Children 2 to 12 years weighing less than 15 kg

    5 to 8 mg/kg/day PO divided twice daily for 60 days; for ease of administration, a dose of 50 mg PO twice daily is recommended.

    Infants and Children younger than 2 years†

    Safety and efficacy have not been established; however, 5 to 7.5 mg/kg/day PO divided twice daily for 60 days is recommended by the CDC.

    MAXIMUM DOSAGE

    Adults

    Safety and efficacy have not been established; however, doses up to 7 mg/kg/day PO have been used off-label.

    Geriatric

    Safety and efficacy have not been established; however, doses up to 7 mg/kg/day PO have been used off-label.

    Adolescents

    Safety and efficacy have not been established; however, doses up to 7 mg/kg/day PO have been used off-label.

    Children

    2 to 12 years: 8 mg/kg/day PO (Usual Max: 400 mg/day).
    younger than 2 years: Safety and efficacy have not been established; however, doses up to 7.5 mg/kg/day PO have been used off-label.

    Infants

    Safety and efficacy have not been established; however, doses up to 7.5 mg/kg/day PO have been used off-label.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Benznidazole has not been evaluated in patients with hepatic impairment.

    Renal Impairment

    Benznidazole has not been evaluated in patients with renal impairment.

    ADMINISTRATION

    Oral Administration
    Oral Solid Formulations

    May be taken with or without food.
    Benznidazole 100 mg tablets are scored and may be split into one-half (50 mg) or one-quarter (25 mg) tablets to provide doses less than 100 mg.
    Tablets can also be made into a slurry as an alternative method of administration.

    Extemporaneous Compounding-Oral

    Preparation and Administration of slurry using 12.5 mg or 100 mg tablets
    Place the required amount of tablets in a cup with water:
    Less than 15 kg: 4 x 12.5 mg tablets (50 mg) in 40 mL of water
    15 to 19 kg: 5 x 12.5 mg tablets (62.5 mg) in 50 mL of water
    20 to 29 kg: 6 x 12.5 mg tablets (75 mg) in 60 mL of water
    30 to 39 kg: 1 x 100 mg tablet (100 mg) in 80 mL of water
    40 to 59 kg: 1.5 x 100 mg tablets (150 mg) in 120 mL of water
    60 kg or more: 2 x 100 mg tablets (200 mg) in 160 mL of water
    Allow the tablets to disintegrate in the cup over a period of approximately 1 to 2 minutes.
    Shake the contents of the cup gently to mix.
    Administer the contents of the cup (slurry of tablets and water) immediately.
    Less than 30 kg: Rinse the cup with an additional 10 mL of water and administer the whole amount to patient.
    30 kg or more: Rinse the cup with an additional 80 mL of water and administer the whole amount to patient. Repeat this rinse with another 80 mL of water and administer the whole amount to patient.

    STORAGE

    Generic:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Benznidazole:
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    Benznidazole is contraindicated in patients with a prior history of hypersensitivity to benznidazole or other nitroimidazole derivatives. Reactions have included severe skin and soft tissue reactions.

    Serious rash

    Serious rash events, including acute generalized exanthematous pustulosis (AGEP), toxic epidermal necrolysis (TEN), erythema multiforme, and drug reaction with eosinophilia and systemic symptoms (DRESS), have been reported with benznidazole therapy. Discontinue benznidazole treatment at the first sign of serious skin reactions. Other extensive skin reactions, such as maculopapular rash, pruritic macules, eczema, pustules, erythematous, generalized, and allergic dermatitis, and exfoliative dermatitis, have also been reported. Most cases occurred after approximately 10 days of treatment with benznidazole and resolved with treatment discontinuation. In cases of skin reactions presenting with systemic symptoms (i.e., lymphadenopathy, fever and/or purpura), discontinuation of treatment is recommended.

    Cockayne syndrome

    Benznidazole is contraindicated in patients with Cockayne syndrome. Cases of severe irreversible hepatotoxicity and acute hepatic failure, including fatal outcomes with very rapid onset, have been reported in these patients after treatment initiation with systemic metronidazole, another nitroimidazole agent, structurally related to benznidazole. The latency period from starting metronidazole to signs of liver failure was as short as 2 days.

    Bone marrow suppression, hematological disease

    Use benznidazole with caution in patients with a history of hematological disease or bone marrow suppression. Hematological abnormalities, such as neutropenia, thrombocytopenia, anemia, and leukopenia, which resolved after treatment discontinuation, have been reported. Monitor CBC with differential before, during, and after benznidazole therapy.

    Pregnancy

    Benznidazole is not approved for use in adolescent or adult females and there are no adequate and well-controlled studies regarding use of benznidazole in pregnant women to inform a drug-associated risk of adverse pregnancy outcomes. However, based on animal findings, benznidazole may cause fetal harm when administered during pregnancy. In animal reproduction studies, benznidazole administered orally during organogenesis was associated with fetal malformations at doses approximately 1 to 3 times the maximum recommended human dose (MRHD) in rats (anasarca, anophthalmia, and/or microphthalmia) and approximately 0.3 to 1 time the MRHD in rabbits (ventricular septal defect). There are risks to the fetus associated with Chagas disease; however, pregnancy findings are inconsistent. Treatment of chronic Chagas disease during pregnancy is not recommended due to the risk of fetal toxicity associated with benznidazole. Consider the risks versus benefits to the mother and fetus of treatment of acute, symptomatic Chagas disease during pregnancy.

    Contraception requirements, infertility, pregnancy testing, reproductive risk

    Counsel patients of appropriate age about the reproductive risk associated with benznidazole and contraception requirements. Females of reproductive age are advised to use effective contraception during treatment and for at least 5 days after the last dose. Pregnancy testing is recommended for females of reproductive age. In addition, based on animal data, benznidazole may cause infertility in males of reproductive age; it is unknown if effects on fertility are reversible.

    Breast-feeding

    Benznidazole is not approved for use in adolescent or adult females. Breast-feeding is not recommended during treatment with benznidazole due to the potential for serious adverse reactions and transmission of Chagas disease. Limited data show that benznidazole is present in human milk at infant doses of 5.5% to 17% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging from 0.3 to 2.79. There are no reports of adverse effects on the breast-fed infant or information on the effects of benznidazole on milk production.

    Neoplastic disease

    Although not reported with benznidazole, nitroimidazole agents, which are structurally similar to benznidazole, have been reported to be carcinogenic in mice and rats. It is not known whether benznidazole is associated with carcinogenicity in humans. Also, benznidazole has shown mutagenic activity in humans, animal studies, and a number of in vitro assay systems. In a study evaluating the cytogenetic effect of benznidazole in pediatric patients ranging in age from 11 months to 11 years of age with Chagas disease, a 2-fold increase in chromosomal aberrations was noted. The median incidence of micronucleated interphase lymphocytes in 20 patients increased 2-fold compared to pre-dose values. In the same study, the mean incidence of chromosomal aberrations in 10 patients also increased 2-fold compared with pre-dose values. Human data are not available to describe the potential for neoplastic disease secondary to benznidazole use.

    ADVERSE REACTIONS

    Severe

    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known
    acute generalized exanthematous pustulosis (AGEP) / Delayed / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    agranulocytosis / Delayed / Incidence not known
    hepatic failure / Delayed / Incidence not known
    hepatotoxicity / Delayed / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 5.0-5.0
    peripheral neuropathy / Delayed / Incidence not known
    amnesia / Delayed / Incidence not known
    confusion / Early / Incidence not known
    anemia / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    eosinophilia / Delayed / Incidence not known
    neutropenia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known
    edema / Delayed / Incidence not known
    peripheral edema / Delayed / Incidence not known

    Mild

    abdominal pain / Early / 0-25.0
    rash / Early / 11.0-16.0
    weight loss / Delayed / 13.0-13.0
    headache / Early / 0-7.0
    vomiting / Early / 5.0-5.0
    anorexia / Delayed / 0-5.0
    nausea / Early / 0-5.0
    arthralgia / Delayed / 0-5.0
    diarrhea / Early / 4.0-4.0
    dizziness / Early / 4.0-4.0
    tremor / Early / 2.0-2.0
    xerostomia / Early / Incidence not known
    pruritus / Rapid / Incidence not known
    maculopapular rash / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    paresthesias / Delayed / Incidence not known
    insomnia / Early / Incidence not known
    hypoesthesia / Delayed / Incidence not known
    myalgia / Early / Incidence not known
    musculoskeletal pain / Early / Incidence not known
    asthenia / Delayed / Incidence not known
    blepharedema / Early / Incidence not known
    fatigue / Early / Incidence not known
    fever / Early / Incidence not known

    DRUG INTERACTIONS

    Disulfiram: (Contraindicated) Coadministration of benznidazole with disulfiram or in patients who have taken disulfiram within the last 2 weeks is contraindicated. Although not reported with benznidazole, psychotic reactions have been reported in patients concurrently taking disulfiram and other nitroimidazole agents, of which benznidazole is structurally similar to.

    PREGNANCY AND LACTATION

    Pregnancy

    Benznidazole is not approved for use in adolescent or adult females and there are no adequate and well-controlled studies regarding use of benznidazole in pregnant women to inform a drug-associated risk of adverse pregnancy outcomes. However, based on animal findings, benznidazole may cause fetal harm when administered during pregnancy. In animal reproduction studies, benznidazole administered orally during organogenesis was associated with fetal malformations at doses approximately 1 to 3 times the maximum recommended human dose (MRHD) in rats (anasarca, anophthalmia, and/or microphthalmia) and approximately 0.3 to 1 time the MRHD in rabbits (ventricular septal defect). There are risks to the fetus associated with Chagas disease; however, pregnancy findings are inconsistent. Treatment of chronic Chagas disease during pregnancy is not recommended due to the risk of fetal toxicity associated with benznidazole. Consider the risks versus benefits to the mother and fetus of treatment of acute, symptomatic Chagas disease during pregnancy.

    Benznidazole is not approved for use in adolescent or adult females. Breast-feeding is not recommended during treatment with benznidazole due to the potential for serious adverse reactions and transmission of Chagas disease. Limited data show that benznidazole is present in human milk at infant doses of 5.5% to 17% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging from 0.3 to 2.79. There are no reports of adverse effects on the breast-fed infant or information on the effects of benznidazole on milk production.

    MECHANISM OF ACTION

    Benznidazole is an nitroimidazole antiprotozoal agent. It inhibits the synthesis of DNA, RNA, and proteins within the Trypanosoma cruzi parasite. Studies suggest that benznidazole is reduced by a Type I nitroreductase (NTR) enzyme of T. cruzi producing a series of short-lived intermediates that may promote damage to several macromolecules including DNA. In mammalian cells, however, benznidazole is metabolized by reduction of the nitro group to an amino group by a Type II NTR enzyme. The precise mechanism of action is unknown.
     
    Benznidazole is active against all three stages, trypomastigotes, amastigotes, and epimastigotes, of T. cruzi. However, the sensitivity of T. cruzi strains to benznidazole from different geographic regions may vary. Animal studies suggest a potential for development of resistance to benznidazole. The mechanisms of drug resistance appear to be multifactorial and include decreased activity due to a mutation in the NTR (TcNTR) gene, higher efflux activity due to overexpression of TcPGP1 and TcPGP2 genes that encode P-glycoprotein as well as TcABCG1 genes that encode ATP-binding cassette transporters, and overexpression of other genes TcFeSOD-A and TcCyP19 that encode superoxide dismutase and cyclophilin, respectively, which have diverse biological function and may help parasite survival.

    PHARMACOKINETICS

    Benznidazole is given orally. Protein binding is reported to be approximately 44% to 60%. The pathway of benznidazole metabolism is unknown. Benznidazole and unknown metabolites are reported to be excreted in the urine and feces. The elimination half-life of benznidazole is approximately 13 hours in healthy volunteers after a single dose.
     
    Affected cytochrome P450 isoenzymes: none
    In vitro studies show that benznidazole is a P-glycoprotein (P-gp) substrate and does not notably induce CYP1A2, CYP2B6, and CYP3A4 at concentrations up to 100 micromolar.

    Oral Route

    The absorption of benznidazole from 3 different preparations (tablet, slurry with 100 mg tablets, slurry with 25 mg tablets) was comparable when given as a single dose under fasting conditions in healthy adult volunteers. Mean peak concentrations of 2.4 mg/L were achieved at a median of 2 hours for all 3 preparations. The absorption of benznidazole was not significantly affected when administered with food.