BENZNIDAZOLE SIDE EFFECTS

SIDE EFFECTS

The following serious and otherwise important adverse reactions are discussed in greater detail in other sections of labeling:

• Potential for Genotoxicity, Carcinogenicity, and Mutagenicity
• Hypersensitivity Skin Reactions
• Central and Peripheral Nervous System Effects
• Hematological Manifestations of Bone Marrow Depression

Clinical Trials 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 (Tril 1¹ and Trial 2²) and one uncontrolled trial (Trial 3³).

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 1: Adverse Reactions Occurring in Pediatric Patients with Chagas Disease aged 6 to 12 Years 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.

Postmarketing Experience

The following adverse reactions have been identified during the use of other formulations of benznidazole outside of the United States. 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.

Table 2: Adverse Reactions Reported in the Published Literature