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warnings and cautions
5 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.
6 ADVERSE REACTIONS The following serious and otherwise important adverse reactions are discussed in greater detail in other sections of labeling: Potential for Genotoxicity, Carcinogenicity, and Mutagenicity [see Warnings and Precautions ( 5.1 )] Hypersensitivity Skin Reactions [see Warnings and Precautions ( 5.3 )] Central and Peripheral Nervous System Effects [see Warnings and Precautions ( 5.4 )] Hematological Manifestations of Bone Marrow Depression [see Warnings and Precautions ( 5.5 )] Most common adverse reactions observed were abdominal pain, rash, decreased weight, headache, nausea, vomiting, neutropenia, urticaria, pruritus, eosinophilia, decreased appetite ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Exeltis USA, Inc. at 1-877-324-9349 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Table 4: Adverse Reactions Occurring in Pediatric Patients with Chagas Disease aged 6 to 12 Years in Trial 1 Body System Adverse Reaction Benznidazole (N=55) N (%) Placebo (N=51) N (%) Gastrointestinal Abdominal pain 14 (25) 4 (8) Weight decreased 7 (13) 1 (2) Nausea 3 (5) 1 (2) Vomiting 3 (5) 0 Diarrhea 2 (4) 0 Decreased appetite 3 (5) 0 Skin and subcutaneous tissue Rash 9 (16) 0 Metabolism/Laboratory Transaminases increased 3 (5) 0 Nervous system Disorders Dizziness 2 (4) 2 (4) Peripheral neuropathy 1 (2) 0 Tremor 1 (2) 0 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: Table 5: Adverse Reactions Reported in the Published Literature Body System Adverse Reactions Dermatological Maculo-papular cutaneous eruptions Erythematous plaques Rash, generalized Rash, erythematous Pruritic rash Blistering eruptions Peeling skin Exfoliative dermatitis Toxic epidermal necrolysis AGEP Erythema multiforme Drug reaction with eosinophilia and systemic symptoms (DRESS) Neurological (central and peripheral nervous system) Paresthesia Hypoesthesia Headaches Insomnia Convulsions Inability to concentrate Amnesia, temporary Disorientation, temporary Gastrointestinal Epigastric pain Dry mouth Ageusia Hepatobiliary disorders Hepatitis Toxic hepatitis Skeletal Muscle Myalgia Musculoskeletal pain Migratory arthritis General / Constitutional Symptoms Fever Asthenia Fatigue Lymphatic Generalized edema Eyelid edema Edema in the extremities Lymphadenopathy Bone Marrow Thrombocytopenia Granulocytopenia Agranulocytosis Metabolism / Laboratory Elevation of alkaline phosphatase Elevation of bilirubin 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 )] .