BENZNIDAZOLE Drug Interactions: What You Need to Know

INTERACTIONS

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.

4 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> .

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 <span class="opacity-50 text-xs">[see Drug Interactions ( 7.1 )]</span> .

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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> .

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 <span class="opacity-50 text-xs">[see Nonclinical Toxicology ( 13.1 )]</span> . 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span> . Advise pregnant women of the potential risk to a fetus. Pregnancy testing is recommended for females of reproductive potential <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.3 )]</span> . Advise females of reproductive potential to use effective contraception during treatment with Benznidazole Tablets and for 5 days after the last dose <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 , 8.3 ) and Clinical Pharmacology ( 12.3 )]</span> .

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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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.