benznidazole

Agents for Leishmaniasis and/or Trypanosomiasis

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.

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.

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

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

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

Benznidazole

Rx

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

5 to 8 mg/kg/day (Max: 400 mg/day) PO divided twice daily for 60 days.

5 to 8 mg/kg/day (Max: 400 mg/day) PO divided twice daily for 60 days.

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.

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.

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.

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.

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.

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.

5 to 8 mg/kg/day PO divided twice daily for 60 days.

Benznidazole has not been evaluated in patients with hepatic impairment.

Benznidazole has not been evaluated in patients with renal impairment.

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.

Benznidazole Oral Tab: 12.5mg, 100mg

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

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

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

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

Safety and efficacy have not been established; however, doses up to 8 mg/kg/day PO have been used off-label.

Safety and efficacy have not been established.

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.

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.

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.

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.