2.1 Important Administration Instructions

• Benznidazole Tablets (12.5 mg and 100 mg) are for oral use and may be taken with or without food [see Clinical Pharmacology ( 12.3)] .
• Benznidazole Tablets are dosed by body weight (kg) [see Dosage and Administration ( 2.2)] .
• 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 [see Instructions for Use] .
• Benznidazole Tablets 12.5 mg and 100 mg can be made into slurry as an alternative method of administration [see Dosage and Administration ( 2.4)] .

2.2 Recommended Dosage in Pediatric Patients (2 to 12 Years of Age)

The total daily dose for pediatric patients 2 to 12 years of age 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 (see Table 1).

2.3 Assessment Prior to Initiating Benznidazole Tablets

Obtain a pregnancy test in females of reproductive potential prior to therapy with Benznidazole Tablets [see Use is Specific Populations ( 8.3)] .

2.4 Preparation of Slurry as an Alternative Method of Administration

A. Preparation of Slurry Using Benznidazole Tablets 12.5 mg for the Pediatric Population with Body Weight Less Than 30 kg

Benznidazole Tablets 12.5 mg may be made into slurry in a specified volume of water for the pediatric population with body weight less than 30 kg (see Table 2). The 12.5 mg tablet slurry is prepared by the following method:

B. Preparation of Slurry Using Benznidazole Tablets 100 mg for the Pediatric Population with Body Weight (30 kg or greater)

Benznidazole Tablets 100 mg may be made into a slurry in a specified volume of water for the pediatric population with body weight of 30 kg or greater (see Table 3). The 100 mg tablet slurry is prepared as follows:

4.1 Hypersensitivity

Benznidazole Tablets are contraindicated in patients with a history of hypersensitivity reaction to benznidazole or other nitroimidazole derivatives. Reactions have included severe skin and soft tissue reactions [see Adverse Reactions ( 6.1)] .

4.2 Disulfiram

Benznidazole Tablets are contraindicated in patients who have taken disulfiram within the last two weeks. Psychotic reactions may occur in patients who are using benznidazole and disulfiram concurrently [see Drug Interactions ( 7.1)] .

4.3 Patients with Cockayne Syndrome

Benznidazole Tablets are contraindicated in patients with Cockayne syndrome. Severe irreversible hepatotoxicity/acute liver failure with fatal outcomes have been reported after initiation of metronidazole, another nitroimidazole drug, structurally related to benznidazole in patients with Cockayne syndrome [see Adverse Reactions ( 6.2)] .

5.1 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 ( 13.1)] .

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 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 ( 13.1)] . It is not known whether benznidazole is associated with carcinogenicity in humans.

5.2 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 ( 8.1)] . Advise pregnant women of the potential risk to a fetus. Pregnancy testing is recommended for females of reproductive potential [see Dosage and Administration ( 2.3)] . 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 ( 8.1, 8.3) and Clinical Pharmacology ( 12.3)] .

5.3 Hypersensitivity Skin Reactions

Serious skin and subcutaneous disorders 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. Discontinue treatment at the first evidence of these serious cutaneous reactions [see Adverse Reactions ( 6.2)] .

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.

5.4 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.

5.5 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 ( 6.1)] . 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.

6.1 Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Benznidazole was evaluated in two randomized, double-blind, placebo-controlled trials (Trial 1 1 and Trial 2 2) and one uncontrolled trial (Trial 3 3).

Trial 1 was conducted in pediatric patients 6 to 12 years of age with chronic indeterminate Chagas disease in Argentina. The chronic indeterminate form includes patients with serologic evidence of T. cruzi infection without symptoms of cardiac or gastrointestinal disease. A total of 106 patients were randomized to receive either benznidazole (5 mg/kg/day twice daily for 60 days; N= 55) or placebo (N=51) and followed for 4 years.

Trial 2 was conducted in pediatric patients 7 to 12 years of age with chronic indeterminate Chagas disease in Brazil. A total of 129 patients were randomized to receive either benznidazole (7.5 mg/kg/day twice daily for 60 days; N = 64) or placebo (N = 65) and followed for 3 years.

Trial 3 was an uncontrolled study in pediatric patients 2 to 12 years of age with chronic indeterminate Chagas disease. A total of 37 pediatric patients with Chagas disease were enrolled in this safety and pharmacokinetics study. Patients were treated with benznidazole 5 to 8 mg/kg/day twice daily for 60 days.

Adverse Reactions Leading to Discontinuation

In Trial 1, benznidazole was discontinued due to an adverse reaction in 5/55 (9%) patients. Some patients had more than one adverse reaction resulting in treatment discontinuation. The adverse reactions included abdominal pain, nausea, vomiting, rash, decreased appetite, headache, and transaminases increased.

Common Adverse Reactions in Pediatric Patients

The most frequently reported adverse reactions in pediatric patients treated with benznidazole in Trial 1 were abdominal pain (25%), rash (16%), decreased weight (13%), and headache (7%). Table 4 lists adverse reactions occurring at a rate of 1% or greater in pediatric patients with Chagas disease aged 6 to 12 years of age in Trial 1.

In Trial 2, skin lesions were reported in 7 of 64 (11%) pediatric patients treated with benznidazole and in 2 of 65 patients receiving placebo. Adverse reactions reported in fewer than 5% of benznidazole-treated patients included nausea, anorexia, headache, abdominal pain and arthralgia.

In a subset of 19 pediatric patients 2 to 6 years of age treated with benznidazole in Trial 3, 6 patients (32%) had the following adverse reactions: rash, leukopenia, urticaria, eosinophilia, decreased appetite, and neutropenia. These adverse reactions were similar to those observed in the overall population of 37 patients.

6.2 Postmarketing Experience

The following adverse reactions have been identified during the use of other formulations of benznidazole outside of the United States, or other nitroimidazole agents . Because these reactions are reported from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Other Formulations of Benznidazole:

Metronidazole, Another Nitroimidazole Agent, Structurally Related to Benznidazole

Cases of severe irreversible hepatotoxicity/acute liver failure, including cases with fatal outcomes with very rapid onset after initiation of systemic use of metronidazole, another nitroimidazole agent structurally related to benznidazole, have been reported in patients with Cockayne syndrome (latency from drug start to signs of liver failure as short as 2 days) [see Contraindications ( 4.3)] .

7.1 Disulfiram

Psychotic reactions have been reported in patients who are concurrently taking disulfiram and nitroimidazole agents (structurally related to benznidazole, but not with benznidazole). Benznidazole Tablets should not be given to patients who have taken disulfiram within the last two weeks [see Contraindications ( 4.2)] .

7.2 Alcohol and Products Containing Propylene Glycol

In vitro studies showed that benznidazole, at concentrations from 0.03 μM to 100 μM, does not inhibit the enzymatic activity of human alcohol dehydrogenase (ALDH). Benznidazole Tablets are not expected to cause alcohol aversion or a disulfiram-like reaction as a result of ethanol ingestion.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 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 ( 2.2), Adverse Reactions ( 6.1), Clinical Studies ( 14)] .

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

8.6 Hepatic Impairment

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

8.7 Renal Impairment

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

12.1 Mechanism of Action

Benznidazole is a nitroimidazole antimicrobial drug [see Microbiology ( 12.4)] .

12.2 Pharmacodynamics

The pharmacodynamics of benznidazole is unknown.

12.3 Pharmacokinetics

Absorption

The absorption of benznidazole from three different 100 mg benznidazole preparations was comparable when administered as a single dose under fasting conditions in adult healthy volunteers ( Table 6).

a Tmax is presented as median (range)

Effect of Food

Benznidazole Cmax and AUC were not affected by the administration of Benznidazole 100 mg tablet with a high-fat, high-caloric meal (approximately 1034 total kcal, 67 kcal from fat, 42 kcal from carbohydrates, 59 kcal from protein) compared with fasted conditions in adult healthy volunteers. Serum concentrations of benznidazole reached peak levels at 3.2 hours (1-10 hours) after administration of Benznidazole Tablets 100 mg tablet after a high-fat, high-caloric meal, and at 2.0 hours (0.5-4 hours) in fasted conditions [see Dosage and Administration ( 2.1)] .

Distribution

Protein binding is reported to be approximately 44 to 60 %. The mean blood:plasma radioactivity ratios, ranging from 0.63 to 1.10, suggest that there is no preferential distribution of benznidazole into the red blood cells. The apparent volume of distribution of benznidazole is approximately 45 L.

Elimination

The elimination half-life of benznidazole is approximately 13 hours in healthy volunteers following single dose. The apparent total clearance of benznidazole is about 2.3 L/h.

Metabolism

In plasma, benznidazole parent drug is the most abundant component, accounting for approximately 80% of the total drug related exposure and no major circulating metabolites were identified. The primary benznidazole metabolism pathway is indicated to be nitro reduction followed by glucuronidation.

Excretion

Following oral administration of 100 mg radiolabeled benznidazole, about 68% and 21% of the radioactivity is recovered in urine (6% of total dose as unchanged parent drug) and feces (unchanged parent drug not detected), respectively.

Specific Populations

The effect of sex, race, renal impairment, or hepatic impairment on the pharmacokinetics of benznidazole is unknown.

Drug Interaction Studies

In vitro studies showed that benznidazole is a P-gp substrate and does not notably induce Cytochrome P450 enzymes 1A2, 2B6, and 3A4 at concentrations up to 100 mcM.

12.4 Microbiology

Mechanism of Action

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.

Antimicrobial Activity

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.

Resistance

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

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 TcPGP 1 and TcPGP 2 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.

13.1 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 benznidazole dose that was not associated with adverse effects 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 whole 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 mice 5-7.

In a male fertility study, benznidazole was administered by oral (gavage) administration in daily doses of 10, 30, and 100 mg/kg/day to male Wistar rats beginning 10 weeks before mating, through mating, and for two weeks after mating for a total of 14-weeks. At the end of the dosing period, testicular and epididymal weights and the percent of normal sperm were decreased in mid- and high-dose males compared to control values. Also altered gonadal function, mating behavior and reduced fertility associated with morphologically and functionally altered sperm and histological changes in the testes and epididymides was observed in high-dose males. However, after a 22-week treatment-free period, almost complete recovery was observed with fully restored fertility compared to control values. After the 22-week treatment-free period the remaining benznidazole-related effects included reduced testicular and epididymal weights (10-22% reduction in absolute weight) compared to control values at the high benznidazole dose of 100 mg/kg/day (equivalent to approximately 2 times the MRHD based on whole body surface area comparison). The benznidazole dose at which no adverse effect was observed was 10 mg/kg/day which is equivalent to approximately 0.2 times the MRHD based on whole body surface area comparison.

In a female fertility study, benznidazole was administered by oral gavage to female Wistar rats in doses of 15, 50, and 150 mg/kg/day for a 2-week pre-mating period, during mating, and through day 7 of gestation. The high dose was associated with transient lower body weight gain and food consumption. There were no benznidazole-related effects on mating performance or fertility and no adverse macroscopic or reproductive organ weight changes. However, higher post-implantation loss with lower live litter size was observed at the high dose of 150 mg/kg/day (equivalent to approximately 3 times the MRHD based on whole body surface area comparison). The benznidazole dose that was not associated with adverse effects 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.

13.2 Animal Toxicology and/or Pharmacology

Single oral dose toxicity studies in rats have established that benznidazole causes ultrastructural changes in the adrenal cortex, colon, esophagus, ovaries, and testis 5, 8-11. In these tissues, these changes were associated with the presences of nitro reductase activity, the production of reactive metabolites, and/or covalent binding of metabolites.

Neurotoxicity including brain axonal degeneration and Purkinje cell degeneration was observed with repeated-oral dosing in dogs without adverse changes in peripheral nerves 12-14. Neurological signs included: apathy, hypertonia, hyperreflexia, ataxia, loss of balance, oscillatory movements of the trunk and head, strong contractions of the back and leg muscles, opisthotonos and nystagmus. Neurotoxicity was not observed in other test species, including mouse, rat, guinea pig, and rabbit.

16.1 How Supplied

Benznidazole Tablets (12.5 mg or 100 mg) are supplied as follows:

• 100 mg white tablets, round and functionally scored twice as a cross on both sides. Each tablet is about 10 mm in diameter debossed with “E” on one side of each quarter portion.
• 12.5 mg white tablets, round and unscored. Each tablet is about 5 mm in diameter debossed with “E” on one side.

Benznidazole Tablets 100 mg are available in bottles of 100 tablets (NDC 0642-7464-10).

Benznidazole Tablets 12.5 mg are available in bottles of 100 tablets (NDC 0642-7463-12).

16.2 Storage and Handling

Store at controlled room temperature 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [See USP Controlled Room Temperature]. Keep bottle tightly closed and protect from moisture.