benznidazole (Rx)

>10%

Abdominal pain (25%)

Rash or skin lesions (11-16%)

Weight decreased (13%)

1-10%

Nausea (5%)

Vomiting (5%)

Increased AST/ALT (5%)

Diarrhea (4%)

Dizziness (4%)

Peripheral neuropathy (2%)

Tremor (2%)

Postmarketing Reports

severe irreversible hepatotoxicity/acute liver failure (patients with Cockayne syndrome)

Contraindications

Patients who have taken disulfiram within the last 2 weeks; psychotic reactions may occur

Patients with Cockayne syndrome

History of hypersensitivity reaction to benznidazole or other nitroimidazole derivatives; severe skin and soft tissue reactions reported

Cautions

Genotoxicity of benznidazole has been demonstrated in humans, in vitro in several bacterial species and mammalian cell systems, and in vivo in rodent

Carcinogenicity observed in mice and rats treated chronically with nitroimidazole agents which are structurally similar to benznidazole

Severe irreversible hepatotoxicity/acute liver failure with fatal outcomes reported after initiation of metronidazole, another nitroimidazole drug, structurally related to benznidazole in patients with Cockayne syndrome

Embryofetal toxicity may occur (see Pregnancy)

Skin disorders

• Serious skin and subcutaneous disorders reported, including acute generalized exanthematous pustulosis (AGEP), toxic epidermal necrolysis (TEN), erythema multiforme, and eosinophilic drug reaction
• Extensive skin reactions reported, such as rash (maculopapular, pruritic macules, eczema, pustules, erythematous, generalized, and allergic dermatitis, exfoliative dermatitis); most occurred after ~10 days of treatment; most rashes resolved with treatment discontinuation
• Discontinue drug for skin reactions presenting with additional symptoms or signs of systemic involvement (eg, lymphadenopathy, fever and/or purpura)
• Also see Contraindications

Central and peripheral nervous system effects

• Can cause paresthesia or symptoms of peripheral neuropathy that may take several months to resolve
• Headache and dizziness have been reported
• Immediately discontinue drug in cases where neurological symptoms occur; symptoms mostly occur late in the course of treatment

Hematological manifestations of bone marrow depression

• Hematological manifestations of bone marrow depression reported (eg, neutropenia, thrombocytopenia, anemia, leukopenia); typically resolves after discontinuing drug
• Patients with hematological manifestations of bone marrow depression must take benznidazole only under strict medical supervision
• Monitor complete blood count; total and differential leukocyte counts recommended before, during, and after therapy

Drug interaction overview

• Psychotic reactions reported with coadministration of disulfiram and nitroimidazole agents (structurally related to benznidazole); do not coadminister or use in patients who have taken disulfiram within the last 2 weeks (see Contraindications)
• Disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, flushing) may occur if alcoholic beverages or products containing propylene glycol are consumed during or following therapy with nitroimidazole agents (structurally related to benznidazole); discontinue alcohol/propylene glycol use during and for at least 3 days following benznidazole therapy completion (see Contraindications)

Pregnancy

Based on findings from animal studies, can cause fetal harm when administered to pregnant women

Obtain pregnancy test in females of reproductive potential before initiating treatment

Animal studies

• Benznidazole administered PO to pregnant rats and rabbits during organogenesis was associated with fetal malformations at doses ~1-3 times the maximum recommended human dose (MRHD) in rats (anasarca, anophthalmia, and/or microphthalmia) and doses ~0.3-1 times the MRHD in rabbits (ventricular septal defect)

Contraception

• Advise females of reproductive potential to use effective contraception during treatment and for 5 days after the final dose

Fertility

• Based on findings in rodents, may impair fertility in males of reproductive potential
• Unknown whether effects on fertility are reversible

Lactation

Present in human milk at infant doses of 5.5-17% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.3­2.79

Because of the potential for serious adverse reactions and transmission of Chagas disease, advise patients that breastfeeding is not recommended during treatment

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Nitroimidazole antimicrobial; generates radical species in both aerobic and anaerobic conditions that are capable of damaging parasitic DNA

Inhibits DNA, RNA, and protein synthesis within the T cruzi parasite

Studies suggest 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

Absorption

Peak plasma concentration: 2.4 mg/L

Peak plasma time: 2 hr (fasting); 3.2 hr (high-fat, high-caloric meal)

AUC: 41.8-44.1 mg·h/L

Distribution

Protein bound: 44-60%

Metabolism

Unknown pathway

Elimination

Half-life: 13 hr (single-dose in healthy volunteers)

Excretion: Urine and feces

Oral Preparation

Dosage based on body weight; 100-mg tablets are scored and can be split in half (50 mg) or quarters (25 mg) to enable precise dosing

Slurry preparation

• 12.5-mg and 100-mg tablets can be made into slurry as an alternative method of administration
• Place prescribed dose of 12.5-mg or 100-mg tablets into a cup and add specific volume of water per number of tablets
• Allow tablets to disintegrate in cup over ~1-2 minutes
• Shake contents of cup gently to mix
• Drink the contents of the cup (slurry of tablets with water) immediately
• Rinse the cup with an additional water, 10 mL (weight <30 kg) or 80 mL (weight ≥30 kg), and drink the whole amount; repeat rinse with 80 mL (weight ≥30 kg) and drink again

• Weight <30 kg (prepare slurry with 12.5-mg tab)

  • <15 kg: 50 mg (4 tab)/dose in 40 mL water
  • 15 to <20 kg: 62.5 mg (5 tab)/dose in 50 mL water
  • 20 kg to <30 kg: 75 mg (6 tab)/dose in 60 mL water

• Weight ≥30 kg (prepare slurry with 100-mg tab)

  • 30 to <40 kg: 100 mg (1 tab)/dose in 80 mL water
  • 40 to <60 kg: 150 mg (1.5 tab)/dose in 120 mL water
  • ≥60 kg: 200 mg (2 tab)/dose in 160 mL water

Oral Administration

May take with or without food

Storage

Store at controlled room temperature 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)

Keep bottle tightly closed and protect from moisture