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Benznidazole

WARNINGS

Included as part of the “PRECAUTIONS” Section

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 [see Nonclinical Toxicology].

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 Tablets in patients less than 2 years old has not been
established) with Chagas disease demonstrated a two-fold 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 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 to pre-dose values.

Carcinogenicity

Carcinogenicity has been observed in mice and rats treated chronically with nitroimidazole agents which are structurally similar to benznidazole. Similar data have not been reported for benznidazole [see Nonclinical Toxicology]. It is not known whether benznidazole is associated with carcinogenicity in humans.

Embryo-Fetal Toxicity

Based on findings from animal studies, Benznidazole Tablets 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 [see Use In Specific Populations]. Advise pregnant women of the potential risk to a fetus. Pregnancy testing is recommended for females of reproductive potential [see DOSAGE AND ADMINISTRATION]. Advise females of reproductive potential to use effective contraception during treatment with Benznidazole Tablets and for 5 days after the last dose [see Use In Specific Populations and CLINICAL PHARMACOLOGY].

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 [see ADVERSE REACTIONS].

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.

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.

Central And Peripheral Nervous System Effects

Treatment with Benznidazole Tablets 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.

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 [see ADVERSE REACTIONS]. Patients with hematological manifestations of bone marrow depression must take Benznidazole Tablets only under strict medical supervision. Monitor complete blood count. Total and differential leukocyte counts are recommended before, during and after therapy.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenicity

Long-term carcinogenicity studies for benznidazole have not been performed.

Nitroimidazoles, which have similar chemical structures to benznidazole have been reported to be carcinogenic
in mice and rats.

Genetic Toxicity

Genotoxicity of benznidazole has been demonstrated in vitro in several bacterial species and mammalian cell systems and in vivo in mammals.

Benznidazole was mutagenic in several strains of S. typhimurium (TA 100, 102 1535, 1537, 1538, 97, 98 99 53 and UTH8414), E.coli, and K. pneumoniae.

Benznidazole was genotoxic in several in vitro mammalian cell assays including a chromosome aberration assay in human lymphocytes and in sister chromatid exchange assays in human lymphocytes and in Human Hep G2 cells

In vivo, benznidazole was shown to be positive for genotoxicity in a mouse bone marrow micronucleus assay, in mouse and human red blood cell micronucleus assays, in a mouse abnormal sperm head assay and in a human peripheral blood lymphocyte assay. However in other micronucleus studies in mice and rats, oral doses of benznidazole did not cause a significant increase in the frequency of chromosomal aberrations in bone marrow cells or micronuclei in peripheral blood cells.

Impairment Of Fertility

In a 6-month, chronic repeated-dosing study with Wistar rats, benznidazole was shown to produce dose-dependent testicular and epididymal atrophy at a dose of 30 mg/kg/day (approximately equivalent to 0.6 times the MRHD based on whole body surface area comparisons). Aspermia was also evident in affected rats, but fertility was not assessed in this study. The NOAEL value in this study was considered to be 10 mg/kg/day (5 mg/kg twice daily) in males which is approximately 0.2-times the MRHD based on body surface area comparison. In other literature reports, benznidazole has been shown to cause testicular atrophy and inhibit spermatogenesis in pubertal and adult rats and mice5-7 .

In a female fertility study, oral (gavage) administration of benznidazole to female Wistar rats twice daily for a 2-week pre-mating period, during mating, and through day 7 of gestation was associated with transient lower body weight gain and food consumption. There was no benznidazole-related effect on mating performance or fertility and no adverse macroscopic or reproductive organ weight changes. However, benznidazole reproductive performance was associated with a higher post-implantation loss with lower live litter size at a dose of 150 mg/kg/day (equivalent to approximately 3 times the MRHD based on whole body surface area comparisons). The NOAEL value for this study was considered to be 50 mg/kg/day which is approximately equivalent to the MRHD based on whole body surface area comparison.

Use In Specific Populations

Pregnancy

Risk Summary

Based on findings from animal studies, Benznidazole Tablets 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 (see Clinical Considerations). 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) (see Data). Advise pregnant women of the potential risk to a fetus.

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.

Clinical Considerations

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 Tablets.

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 women presents with acute symptomatic Chagas disease, the risks versus benefits of treatment with Benznidazole Tablets to the mother and the fetus should be evaluated on a case-by-case basis.

Data

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.

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.

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 F1 males 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.

Lactation

Risk Summary

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 0.32.79.
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 Tablets.

Females And Males Of Reproductive Potential

Pregnancy Testing

Pregnancy testing is recommended for females of reproductive potential.

Contraception

Females

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

Infertility

Males

Based on findings in rodents, Benznidazole Tablets may impair fertility in males of reproductive potential. It is not known whether effects on fertility are reversible [see Nonclinical Toxicology].

Pediatric Use

The safety and effectiveness of Benznidazole Tablets 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. [see DOSAGE AND ADMINISTRATION , ADVERSE REACTIONS , Clinical Studies].

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

Hepatic Impairment

Use of Benznidazole Tablets has not been evaluated in patients with hepatic impairment.

Renal Impairment

Use of Benznidazole Tablets has not been evaluated in patients with renal impairment.

REFERENCES

5. Bernacchi, AS, CR de Castro, EG de Toranzo, and JA Castro, 1986, Effects of Nifurtimox or Benznidazole Administration on Rat Testes: Ultrastructural Observations and Biochemical Studies, Exp Mol Pathol 45: 245-256.

6. Vieira, CL, TL Lamano-Carvalho, AL Favaretto, MM Valenca, J Antunes-Rodridgues, and AA Barreira, 1989, Testes Alterations in Pubertal Benznidazole-treated Rats, Braz J Med Biol Res, 22: 695-698.

7. Navarro, ML and R Nagel, 1990, Abnormal Sperm Induced in Mice by Oral Administration of Antichagasic Drugs, Comunicaciones Biologicas, 8: 251-258.

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