benznidazole 100 MG Oral Tablet

INDICATIONS AND USAGE Benznidazole Tablets are indicated in pediatric patients 2 to 12 years of age for the treatment of Chagas disease (American trypanosomiasis) caused by Trypanosoma cruzi . 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 [see Clinical Studies ( 14 )] . Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Benznidazole Tablets, a nitroimidazole antimicrobial, 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 , 14 ).

DOSAGE AND ADMINISTRATION 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 ( 2.2 ). See Full Prescribing Information for important administration instructions ( 2.1 , 2.3 , 2.4 ). 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 ). Table 1: Recommended Dosage of Benznidazole Tablets in Pediatric Patients (2 to 12 Years of Age) Body Weight Range (kg) Dose (mg) Number of Benznidazole Tablets 12.5 mg Number of Benznidazole Tablets 100mg Duration and Frequency of Therapy Less than 15 kg 50 mg 4 tablets ½ tablet Administered twice daily approximately 12 hours apart for 60 days. 15 kg to less than 20 kg 62.5 mg 5 tablets 20 kg to less than 30 kg 75 mg 6 tablets ¾ tablet 30 kg to less than 40 kg 100 mg 1 tablet 40 kg to less than 60 kg 150 mg 1 ½ tablets Greater than or equal to 60 kg 200 mg 2 tablets 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: Table 2: Preparation and Administration of Slurry Using Benznidazole Tablets 12.5 mg for the Pediatric Population with Body Weight of Less than 30 kg Place the prescribed dose of Benznidazole Tablets 12.5 mg into a cup. Add the specified volume of water per number of 12.5 mg tablets as shown below. Body Weight Range (kg) Dose (mg) Number of Benznidazole Tablets 12.5 mg Quantity of Water for Preparing the Slurry Less than 15 kg 50 mg 4 tablets 40 mL 15 kg to less than 20 kg 62.5 mg 5 tablets 50 mL 20 kg to less than 30 kg 75 mg 6 tablets 60 mL Allow the tablets to disintegrate in the cup over a period of approximately 1-2 minutes. Shake the contents of the cup gently to mix. Drink the contents of the cup (slurry of tablets with water) immediately. Rinse the cup with an additional 10 mL of water and drink the whole amount. 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: Table 3: Preparation and Administration of Slurry Using Benznidazole Tablets 100 mg for the Pediatric Population with Body Weight 30 kg or greater Place the prescribed dose of Benznidazole Tablets 100 mg tablets into a cup. Add the specified volume of water per number of 100 mg tablets as shown below. Body Weight Range (kg) Dose (mg) Number of Benznidazole Tablets 100 mg Quantity of Water for Preparing the Slurry 30 kg to less than 40 kg 100 mg 1 tablet 80 mL 40 kg to less than 60 kg 150 mg 1 ½ tablets 120 mL Greater than or equal to 60 kg 200 mg 2 tablets 160 mL Allow the tablet(s) to disintegrate in the cup over a period of approximately 1- 2 minutes. Shake the contents of the cup gently to mix. Drink the contents of the cup (slurry of tablet(s) with water) immediately. Rinse the cup by adding 80 mL of water and drink the whole amount. Repeat this rinse with 80 mL of water and drink again.

WARNINGS AND PRECAUTIONS Potential Risk for Genotoxicity and Carcinogenicity ( 5.1 ). Embryo-Fetal Toxicity: Can cause fetal harm. Pregnancy testing is recommended for females of reproductive potential. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception ( 2.3 , 5.2 , 8.1 , 8.3 ). Hypersensitivity skin reactions have been reported 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 recommended ( 5.3 ). Treatment with Benznidazole Tablets can potentially cause paresthesia or symptoms of peripheral neuropathy. In cases where neurological symptoms occur, immediate discontinuation of treatment is recommended ( 5.4 ). There have been hematological manifestations of bone marrow depression, such as neutropenia, thrombocytopenia, anemia, and leukopenia ( 5.5 ). 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.

CONTRAINDICATIONS • History of hypersensitivity reaction to benznidazole or other nitroimidazole derivatives ( 4.1 ). • Disulfiram usage within the last two weeks ( 4.2 ). • Patients with Cockayne Syndrome ( 4.3 , 6.2 ). 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 )] .

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