Benznidazole (benznidazole)

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Benznidazole is administered orally twice daily (approximately every 12 hours) and may be administered without regard to meals. Administration with or after meals may minimize adverse GI effects.

Benznidazole is commercially available as 12.5-mg tablets (unscored) and 100-mg tablets (scored). The 100-mg tablets are functionally scored so that they can be split into halves or quarters to provide 50- or 25-mg doses, respectively.

For patients unable to swallow tablets, an oral slurry of benznidazole may be prepared extemporaneously using the commercially available tablets of the drug. The dose and number of benznidazole tablets and the volume of water used to prepare the oral slurry are based on body weight (kg).

Store benznidazole tablets at controlled room temperature (20-25degreesC; excursions permitted to 15-30degreesC); protect from moisture.

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Benznidazole does not induce cytochrome P-450 (CYP) isoenzymes 1A2, 2B6, or 3A4 in vitro.

In vitro studies indicate that benznidazole is a substrate of P-glycoprotein (P-gp).

Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

Selected Nitroimidazole Antimicrobials/Disulfiram

SEVERITY LEVEL: 1-Contraindicated Drug Combination: This drug combination is contraindicated and generally should not be dispensed or administered to the same patient.

MECHANISM OF ACTION: Since disulfiram has been associated with psychotic behavior in some patients, this interaction has been attributed to a combined toxicity with metronidazole or benznidazole.(1)

CLINICAL EFFECTS: May observe psychotic reactions of confusional states.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The manufacturers of benznidazole,(2) fexinidazole,(3) metronidazole,(4) and tinidazole(5) state that these agents should not be administered to patients who have received disulfiram in the previous two weeks.

DISCUSSION: In a study in hospitalized alcoholics, six of 29 patients receiving concurrent disulfiram and metronidazole developed acute psychosis or confusion. Of these six, five had paranoid delusions and three experienced visual and auditory hallucinations. These reactions were not reported in any of the 29 patients who received placebo with disulfiram.(6,7) An increased central effect of ethyl alcohol was observed in a single patient during concurrent disulfiram and metronidazole.(8) Psychotic symptoms were reported during concurrent use in another case report.(9)

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Myelosuppressives; Immunomodulators/Sodium Iodide I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Sodium iodide I 131 can cause depression of the hematopoetic system. Myelosuppressives and immunomodulators also suppress the immune system.(1)

CLINICAL EFFECTS: Concurrent use of sodium iodide I 131 with agents that cause bone marrow depression, including myelosuppressives or immunomodulators, may result in an enhanced risk of hematologic disorders, including anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia. Bone marrow depression may increase the risk of serious infections and bleeding.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: The US manufacturer of sodium iodide I 131 states that concurrent use with bone marrow depressants may enhance the depression of the hematopoetic system caused by large doses of sodium iodide I 131.(1) Sodium iodide I 131 causes a dose-dependent bone marrow suppression, including neutropenia or thrombocytopenia, in the 3 to 5 weeks following administration. Patients may be at increased risk of infections or bleeding during this time. Monitor complete blood counts within one month of therapy. If results indicate leukopenia or thrombocytopenia, dosimetry should be used to determine a safe sodium iodide I 131 activity.(1)

DISCUSSION: Hematologic disorders including death have been reported with sodium iodide I 131. The most common hematologic disorders reported include anemia, blood dyscrasias, bone marrow depression, leukopenia, and thrombocytopenia.(1)

There are no moderate interactions for this drug.

*Hypersensitivity to benznidazole or other nitroimidazole derivatives.

*Patients who have taken disulfiram within preceding 2 weeks.

*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.

• Cockayne syndrome
• Lactation

• Peripheral neuropathy
• Pregnancy

• Bone marrow depression

The most common adverse effects reported in patients receiving benznidazole include abdominal pain, rash, decreased weight, headache, nausea, vomiting, neutropenia, urticaria, pruritus, eosinophilia, and decreased appetite.

Less Frequent

• Abnormal hepatic function tests
• Eosinophilia
• Leukopenia
• Neutropenic disorder

Rare or Very Rare

• Acute generalized exanthematous pustulosis
• Agranulocytosis
• Anemia
• DRESS syndrome
• Erythema multiforme
• Exfoliative dermatitis
• Hepatitis
• Hyperbilirubinemia
• Maculopapular rash
• Seizure disorder
• Thrombocytopenic disorder
• Toxic epidermal necrolysis

More Frequent

• Acute abdominal pain
• Anorexia
• Headache disorder
• Skin rash
• Vomiting
• Weight loss

Less Frequent

• Arthralgia
• Dizziness
• Nausea
• Peripheral neuropathy
• Urticaria

Rare or Very Rare

• Concentration difficulty
• Diarrhea
• Eczema
• Edema
• Eyelid edema
• Fatigue
• General weakness
• Loss of taste
• Memory impairment
• Musculoskeletal pain
• Myalgia
• Paresthesia
• Pruritus of skin
• Tremor
• Xerostomia

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Safety and efficacy of benznidazole have not been established in pediatric patients younger than 2 years of age or in pediatric patients older than 12 years of age.

Safety and efficacy of benznidazole for the treatment of Chagas disease in pediatric patients 2-12 years of age have been established based on results of 2 adequate and well-controlled trials in pediatric patients 6-12 years of age and additional safety and pharmacokinetic data from pediatric patients 2-6 years of age.

Based on animal studies, benznidazole may cause harm to the fetus if used in pregnant women. Data from published postmarketing reports on benznidazole use during pregnancy are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes.

In animal reproduction studies in rats and rabbits, oral benznidazole administered during organogenesis was associated with fetal malformations. In rats, anasarca, anophthalmia, and/or microphthalmia occurred at benznidazole dosages approximately 1-3 times the MRHD; reduced maternal weights and smaller litter sizes occurred at a dosage approximately 3 times the MRHD. In rabbits, ventricular septal defect occurred at dosages approximately 0.3-1 times the MRHD; reduced maternal weight gain and abortions (2/20 females) occurred at a dosage approximately equal to the MRHD.

Prior to initiation of benznidazole, females of reproductive potential should receive appropriate pregnancy tests. Females of reproductive potential should be advised of the potential risk to a fetus and to use effective contraception during benznidazole treatment and for 5 days after the last dose of the drug.

Data based on case-control and observational studies are conflicting regarding the risk of chronic Chagas disease during pregnancy with some but not all, showing an increased risk of pregnancy loss, prematurity, and neonatal mortality. While acute symptomatic Chagas disease is uncommon in pregnant women, a risk versus benefit assessment for both mother and fetus prior to administering benznidazole should be conducted on a case-by-case basis.

Benznidazole is distributed into human milk. Data indicate that the infant dose of benznidazole available from human milk may be 5.5-17% of the maternal weight-adjusted dosage and that the milk-to-plasma ratio of the drug ranges from 0.3-2.79. It is not known whether benznidazole affects milk production.

Because of the potential for serious adverse reactions to benznidazole in nursing infants and the possibility of transmission of Chagas disease from mother to nursing infant, patients should be advised not to breast-feed during benznidazole treatment.

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