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Benznidazole

Class: Antiprotozoals, Miscellaneous
Chemical Name: N-benzyl-2-(2-nitroimidazol-1-yl)acetamide
Molecular Formula: C12H12N4O3
CAS Number: 22994-85-0
Brands: Benznidazole

Medically reviewed on Jan 8, 2018

Introduction

Benznidazole is a nitroimidazole antimicrobial drug.

Uses for Benznidazole

Benznidazole has the following uses:

Benznidazole is indicated in pediatric patients 2 to 12 years of age for the treatment of Chagas disease (American trypanosomiasis), caused by Trypanosoma cruzi.1

This indication is approved under accelerated approval based on the number of treated patients who became Immunoglobulin G (IgG) antibody negative against the recombinant antigens of T. cruzi. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.1

Benznidazole Dosage and Administration

General

Benznidazole is available in the following dosage form(s) and strength(s):

  • Tablets: 100 mg (functionally scored).1

  • Tablets: 12.5 mg.1

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Pediatric Patients

  • Pediatric patients 2 to 12 years of age: The total daily dose is 5 mg/kg to 8 mg/kg orally administered in two divided doses separated by approximately 12 hours for a duration of 60 days.1

  • See Full Prescribing Information for important administration instructions.1

Cautions for Benznidazole

Contraindications

  • History of hypersensitivity reaction to benznidazole or other nitroimidazole derivatives.1

  • Disulfiram usage within the last two weeks.1

  • Alcoholic beverage consumption during and for at least three days after therapy.1

Warnings/Precautions

Potential for Genotoxicity And Carcinogenicity

Genotoxicity: Genotoxicity of benznidazole has been demonstrated in humans, in vitro in several bacterial species and mammalian cell systems, and in vivo in rodents. 1

A study evaluating the cytogenetic effect of benznidazole in pediatric patients ranging from 11 months to 11 years of age (the safety and effectiveness of benznidazole in patients less than 2 years old has not been established) with Chagas disease demonstrated a twofold increase in chromosomal aberrations. In pediatric patients with Chagas disease who were treated with benznidazole, the median incidence of micronucleated interphase lymphocytes in 20 patients increased twofold compared to pre-dose values. In the same study, the mean incidence of chromosomal aberrations in 10 patients also increased twofold compared to pre-dose values.1

Carcinogenicity: Carcinogenicity has been observed in mice and rats treated chronically with nitroimidazole agents that are structurally similar to benznidazole. Similar data have not been reported for benznidazole. It is not known whether benznidazole is associated with carcinogenicity in humans.1

Embryo-fetal Toxicity

Based on findings from animal studies, benznidazole can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, benznidazole administered orally to pregnant rats and rabbits during organogenesis was associated with fetal malformations at doses approximately 1-3 times the maximum recommended human dose (MRHD) in rats (anasarca, anophthalmia, and/or microphthalmia) and doses approximately 0.3-1 times the MRHD in rabbits (ventricular septal defect). In rats, reduced maternal weights and smaller litter sizes occurred at a dose approximately 3 times the MRHD. In rabbits, reduced maternal weight gain and abortions in 2/20 females occurred at a dose approximately equal to the MHRD. Advise pregnant women of the potential risk to a fetus. Pregnancy testing is recommended for females of reproductive potential. Advise females of reproductive potential to use effective contraception during treatment with benznidazole and for 5 days after the last dose.1

Hypersensitivity Skin Reactions

Serious skin and subcutaneous disorders including acute generalized exanthematous pustulosis (AGEP), toxic epidermal necrolysis (TEN), erythema multiforme, and eosinophilic drug reaction have been reported with benznidazole. Discontinue treatment at the first evidence of these serious cutaneous reactions.1

Extensive skin reactions, such as rash (maculopapular, pruritic macules, eczema, pustules, erythematous, generalized, and allergic dermatitis, exfoliative dermatitis) have also been reported. Most cases occurred after approximately 10 days of treatment with benznidazole. Most rashes resolved with treatment discontinuation.1

In case of skin reactions presenting with additional symptoms or signs of systemic involvement such as lymphadenopathy, fever and/or purpura, discontinuation of treatment is recommended.1

Central and Peripheral Nervous System Effects

Treatment with benznidazole can cause paresthesia or symptoms of peripheral neuropathy that may take several months to resolve. Headache and dizziness have been reported. In cases where neurological symptoms occur, immediate discontinuation of treatment is recommended. In most cases, symptoms occur late in the course of treatment.1

Hematological Manifestations of Bone Marrow Depression

There have been reports of hematological manifestations of bone marrow depression, such as neutropenia, thrombocytopenia, anemia and leukopenia, which resolved after treatment discontinuation. 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 are recommended before, during and after therapy.1

Specific Populations

Pregnancy

Risk Summary: Based on findings from animal studies, benznidazole may cause fetal harm when administered to a pregnant woman. Published postmarketing reports on benznidazole use during pregnancy are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes. There are risks to the fetus associated with Chagas disease. In animal reproduction studies, benznidazole administered orally to pregnant rats and rabbits during organogenesis was associated with fetal malformations at doses approximately 1-3 times the MRHD in rats (anasarca, anophthalmia, and/or microphthalmia) and doses approximately 0.3-1.0 times the MRHD in rabbits (ventricular septal defect). Advise pregnant women of the potential risk to a fetus.1

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.1

Disease-associated Maternal and/or Embryo/Fetal Risk: Published data from case-control and observational studies on chronic Chagas disease during pregnancy are inconsistent in their findings. Some studies showed an increased risk of pregnancy loss, prematurity and neonatal mortality in pregnant women who have chronic Chagas disease while other studies did not demonstrate these findings. Chronic Chagas disease is usually not life-threatening. Since pregnancy findings are inconsistent, treatment of chronic Chagas disease during pregnancy is not recommended due to risk of embryo-fetal toxicity from benznidazole.1

Acute symptomatic Chagas disease is rare in pregnant women; however, symptoms may be serious or life-threatening. There have been reports of pregnant women with life-threatening symptoms associated with acute Chagas disease who were treated with benznidazole. If a pregnant woman presents with acute symptomatic Chagas disease, the risks versus benefits of treatment with benznidazole to the mother and the fetus should be evaluated on a case-by-case basis.1

Animal Data: In an embryo-fetal toxicity study in pregnant rats, an oral dose of benznidazole of 150 mg/kg/day during organogenesis (days 6-17 of gestation) was associated with maternal weight loss, reduced fetal weights, and smaller litter sizes. Benznidazole was also associated with a low incidence of fetal malformations including anasarca in one fetus at a dose of 50 mg/kg/day and anasarca and eye abnormalities (anophthalmia and microphthalmia) in 5 fetuses in 5 litters at a high dose of 150 mg/kg/day (approximately equivalent to 1 and 3 times, respectively, the MRHD based on whole body surface area comparisons). The No Observed Adverse Effect Level (NOAEL) dose for maternal toxicity in this study, 50 mg/kg/day, is approximately equal to the MRHD based on body surface area comparisons. The NOAEL dose for fetal toxicity was 15 mg/kg/day which is approximately equivalent to 0.3 times the MRHD based on whole body surface area comparisons.1

In an embryo-fetal study in pregnant rabbits, oral (gavage) administration of benznidazole during organogenesis (days 6 to 19 of gestation) at a high dose of 25 mg/kg/day was associated with maternal toxicity including reduced weight gain and food consumption and abortions in 2/20 females. Benznidazole was also associated with a low incidence of fetal abnormalities including ventricular septal defect in 2 fetuses in 2 litters at a dose of 7.5 mg/kg/day and in 1 fetus at a dose of 25 mg/kg/day (approximately equivalent to 0.3 and 1 times respectively the MRHD based on whole body surface area comparisons). The NOAEL values for maternal and fetal toxicity in this study were 7.5 and 2.5 mg/kg/day respectively, which are respectively equivalent to approximately 0.3 and 0.1 times the MRHD based on body surface area comparisons.1

In a pre- postnatal study in rats, first generation (F1 pups born to dams administered 15, 50, and 75 mg/kg/day benznidazole demonstrated normal pre-weaning behavior, physical and functional development, neurological findings, and reproductive parameters. However, cesarean section data for the pregnant first generation (F1) females in the high-dose group included significantly higher pre-implantation loss and significantly lower mean values for corpora lutea counts, number of implantations, and number of live embryos. Also small testes and/or epididymides were observed in 1/20 and 2/20 first generation males in the mid- and high-dose groups respectively, and two of the affected animals failed to mate or induce pregnancy. However, the mean values for mating performance, fertility index, testes weight, testes and epididymides sperm counts, and epididymal sperm motility and progression were not altered in any of the F1males in benznidazole treatment groups. The number of live second generation (F2) fetuses born to F1 dams was reduced in the high-dose group. The NOAEL value was considered to be 50 mg/kg/day which is approximately equal to the MRHD based on body surface area comparisons.1

Lactation

Limited published literature based on breast milk sampling reports 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 between 0.3-2.79. There are no reports of adverse effects on the breastfed infant and no information on the effects of benznidazole on milk production. Because of the potential for serious adverse reactions, and transmission of Chagas disease, advise patients that breastfeeding is not recommended during treatment with benznidazole.1

Females And Males Of Reproductive Potential

Pregnancy testing is recommended for females of reproductive potential.1

Benznidazole can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with benznidazole and for 5 days after the final dose.1

Based on findings in rodents, benznidazole may impair fertility in males of reproductive potential. It is not known whether effects on fertility are reversible.1

Pediatric Use

The safety and effectiveness of benznidazole have been established in pediatric patients 2 to 12 years of age for the treatment of Chagas disease. Use in pediatric patients 2 to 12 years of age was established in two adequate and well-controlled trials in pediatric patients 6 to 12 years old with additional safety and pharmacokinetic data from pediatric patients 2 to 6 years of age.1

Safety and effectiveness in pediatric patients below the age of 2 years and above the age of 12 years have not been established.1

Hepatic Impairment

Use of benznidazole has not been evaluated in patients with hepatic impairment.1

Renal Impairment

Use of benznidazole has not been evaluated in patients with renal impairment.1

Common Adverse Effects

Most common adverse reactions observed were abdominal pain, rash, decreased weight, headache, nausea, vomiting, neutropenia, urticaria, pruritus, eosinophilia, decreased appetite.1

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

Please see product labeling for drug interaction information.

Actions and Spectrum

Mechanism Of Action

Benznidazole is a nitroimidazole antimicrobial drug.1

Benznidazole inhibits the synthesis of DNA, RNA, and proteins within the T. 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 not known.1

Spectrum

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.1

Resistance

Studies in vitro and in mice infected with T. cruzi suggest a potential for development of resistance to benznidazole.1

The mechanisms of drug resistance appear to be multifactorial. These mechanisms include decreased activity due to a mutation in the nitroreductase (TcNTR) gene. Other mechanisms include higher efflux activity due to over expression of TcPGP1 and TcPGP2 genes that encode p-glycoprotein as well as TcABCG1 genes that encode ATP-binding cassette transporters. Also, some studies reported 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. However, the clinical relevance of these findings is not known.1

Advice to Patients

Advise the patient to read the FDA-approved patient labeling. 1

Embryo-Fetal Toxicity

Advise pregnant women and females of reproductive potential that exposure to benznidazole during pregnancy can result in fetal harm.1

Advise females to inform their healthcare provider of a known or suspected pregnancy.1

Advise females of reproductive potential to use effective contraception while taking benznidazole and for 5 days after the last dose.1

Lactation

Advise women not to breastfeed during treatment with benznidazole.1

Infertility

Advise males of reproductive potential that benznidazole may impair fertility.1

Important Administration Instructions

Advise patients and parents/caregivers of pediatric patients taking benznidazole that: 1

Benznidazole tablets 100 mg are functionally scored tablets which can be split into one-half (50 mg) or one-quarter (25 mg) at the scored lines to provide doses less than 100 mg.1

Benznidazole tablets 12.5 mg and 100 mg (whole or split) can be made into a slurry in a specified volume of water for the pediatric population.1

Hypersensitivity Skin Reactions

Advise patients that serious skin reactions can occur with benznidazole. In case of skin reactions, presenting with additional symptoms of systemic involvement such as lymphadenopathy, fever and/or purpura, discontinuation of treatment is necessary.1

Central and Peripheral Nervous System Effects

Advise patients that treatment can potentially cause paresthesia or symptoms of peripheral neuropathy. In cases where neurological symptoms occur, immediate discontinuation of treatment is recommended.1

Hematological Manifestations of Bone Marrow Depression

Advise patients that there have been hematological manifestations of bone marrow depression, such as anemia and leukopenia, which are reversible, and normalized after treatment discontinuation.1

Interaction with Alcohol

Advise patients to discontinue consumption of alcoholic beverages or products containing propylene glycol while taking benznidazole and for at least three days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Benznidazole

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablet

12.5 mg

Benznidazole

Exeltis USA Inc.

100 mg

Benznidazole (scored)

Exeltis USA Inc.

AHFS Drug Information. © Copyright 2018, Selected Revisions January 8, 2018. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Exeltis USA, Inc.. Benznidazole (benznidazole) ORAL prescribing information. 2017 Aug. http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8983d6a0-f63f-4f8e-bba4-38223f39e29b

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