benznidazole (Rx)

Brand and Other Names:
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 12.5mg
  • 100mg (functionally scored)

Chagas Disease (Off-label)

CDC guidelines

  • Treatment is strongly recommended for adults up to 50 years old with chronic infection who do not already have advanced Chagas cardiomyopathy
  • For adults older than 50 years with chronic T cruzi infection, the decision to treat with antiparasitic drugs should be individualized, weighing the potential benefits and risks for the patient
  • 5-7 mg/kg/day PO divided in 2 doses separated by ~12 hr x 60 days
  • https://www.cdc.gov/parasites/chagas/health_professionals/tx.html

Dosage Forms & Strengths

tablet

  • 12.5mg
  • 100mg (functionally scored)

Chagas Disease

Indicated in children aged 2-12 years for treatment of Chagas disease (American trypanosomiasis) caused by Trypanosoma cruzi

<2 years: Safety and efficacy not established

2-12 years: 5-8 mg/kg/day PO divided in 2 doses separated by ~12 hr x 60 days

Also see Administration

Recommended weight-based doses

  • <15 kg: 50 mg PO q12hr
  • 15 kg to <20 kg: 62.5 mg PO q12hr
  • 20 kg to <30 kg: 75 mg PO q12hr
  • 30 kg to <40 kg: 100 mg PO q12hr
  • 40 kg to <60 kg: 150 mg PO q12hr
  • ≥60 kg: 100 mg PO q12hr

CDC guidelines

  • Antiparasitic treatment is indicated for all cases of acute or reactivated Chagas disease and for chronic T cruzi infection in children up to age 18 years; congenital infections are considered acute disease
  • <12 years: 5-7.5 mg/kg/day PO divided in 2 doses separated by ~12 hr x 60 days
  • ≥12 years: 5-7 mg/kg/day PO divided in 2 doses separated by ~12 hr x 60 days
  • https://www.cdc.gov/parasites/chagas/health_professionals/tx.html

Dosage Modifications

Not evaluated in patients with renal or hepatic impairment

Dosing Considerations

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 may be contingent upon verification and description of clinical benefit in confirmatory trials

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Interactions

Interaction Checker

and benznidazole

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    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Abdominal pain (25%)

            Rash or skin lesions (11-16%)

            Weight decreased (13%)

            1-10%

            Nausea (5%)

            Vomiting (5%)

            Increased AST/ALT (5%)

            Diarrhea (4%)

            Dizziness (4%)

            Peripheral neuropathy (2%)

            Tremor (2%)

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            Warnings

            Contraindications

            Patients who have taken disulfiram within the last 2 weeks; psychotic reactions may occur

            Consumption of alcoholic beverages or products containing propylene glycol during and for at least 3 days after the last dose; disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) may occur owing to the interaction between alcohol or propylene glycol and benznidazole

            History of hypersensitivity reaction to benznidazole or other nitroimidazole derivatives; severe skin and soft tissue reactions reported

            Cautions

            Genotoxicity of benznidazole has been demonstrated in humans, in vitro in several bacterial species and mammalian cell systems, and in vivo in rodent

            Carcinogenicity observed in mice and rats treated chronically with nitroimidazole agents which are structurally similar to benznidazole

            Embryofetal toxicity may occur (see Pregnancy)

            Skin disorders

            • Serious skin and subcutaneous disorders reported, including acute generalized exanthematous pustulosis (AGEP), toxic epidermal necrolysis (TEN), erythema multiforme, and eosinophilic drug reaction
            • Extensive skin reactions reported, such as rash (maculopapular, pruritic macules, eczema, pustules, erythematous, generalized, and allergic dermatitis, exfoliative dermatitis); most occurred after ~10 days of treatment; most rashes resolved with treatment discontinuation
            • Discontinue drug for skin reactions presenting with additional symptoms or signs of systemic involvement (eg, lymphadenopathy, fever and/or purpura)
            • Also see Contraindications

            Central and peripheral nervous system effects

            • Can cause paresthesia or symptoms of peripheral neuropathy that may take several months to resolve
            • Headache and dizziness have been reported
            • Immediately discontinue drug in cases where neurological symptoms occur; symptoms mostly occur late in the course of treatment

            Hematological manifestations of bone marrow depression

            • Hematological manifestations of bone marrow depression reported (eg, neutropenia, thrombocytopenia, anemia, leukopenia); typically resolves after discontinuing drug
            • Patients with hematological manifestations of bone marrow depression must take benznidazole only under strict medical supervision
            • Monitor complete blood count; total and differential leukocyte counts recommended before, during, and after therapy

            Drug interaction overview

            • Psychotic reactions reported with coadministration of disulfiram and nitroimidazole agents (structurally related to benznidazole); do not coadminister or use in patients who have taken disulfiram within the last 2 weeks (see Contraindications)
            • Disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, flushing) may occur if alcoholic beverages or products containing propylene glycol are consumed during or following therapy with nitroimidazole agents (structurally related to benznidazole); discontinue alcohol/propylene glycol use during and for at least 3 days following benznidazole therapy completion (see Contraindications)
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            Pregnancy

            Pregnancy

            Based on findings from animal studies, can cause fetal harm when administered to pregnant women

            Obtain pregnancy test in females of reproductive potential before initiating treatment

            Animal studies

            • Benznidazole administered PO to pregnant rats and rabbits during organogenesis was associated with fetal malformations at doses ~1-3 times the maximum recommended human dose (MRHD) in rats (anasarca, anophthalmia, and/or microphthalmia) and doses ~0.3-1 times the MRHD in rabbits (ventricular septal defect)

            Contraception

            • Advise females of reproductive potential to use effective contraception during treatment and for 5 days after the final dose

            Fertility

            • Based on findings in rodents, may impair fertility in males of reproductive potential
            • Unknown whether effects on fertility are reversible

            Lactation

            Present in human milk at infant doses of 5.5-17% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.3­2.79

            Because of the potential for serious adverse reactions and transmission of Chagas disease, advise patients that breastfeeding is not recommended during treatment

            Pregnancy Categories

            A:Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B:May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C:Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D:Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X:Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA:Information not available.

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            Pharmacology

            Mechanism of Action

            Nitroimidazole antimicrobial; generates radical species in both aerobic and anaerobic conditions that are capable of damaging parasitic DNA

            Inhibits DNA, RNA, and protein synthesis within the T cruzi parasite

            Studies suggest benznidazole is reduced by a Type I nitroreductase (NTR) enzyme of T cruzi producing a series of short-lived intermediates that may promote damage to several macromolecules including DNA

            Absorption

            Peak plasma concentration: 2.4 mg/L

            Peak plasma time: 2 hr (fasting); 3.2 hr (high-fat, high-caloric meal)

            AUC: 41.8-44.1 mg·h/L

            Distribution

            Protein bound: 44-60%

            Metabolism

            Unknown pathway

            Elimination

            Half-life: 13 hr (single-dose in healthy volunteers)

            Excretion: Urine and feces

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            Administration

            Oral Preparation

            Dosage based on body weight; 100-mg tablets are scored and can be split in half (50 mg) or quarters (25 mg) to enable precise dosing

            Slurry preparation

            • 12.5-mg and 100-mg tablets can be made into slurry as an alternative method of administration
            • Place prescribed dose of 12.5-mg or 100-mg tablets into a cup and add specific volume of water per number of tablets
            • Allow tablets to disintegrate in cup over ~1-2 minutes
            • Shake contents of cup gently to mix
            • Drink the contents of the cup (slurry of tablets with water) immediately
            • Rinse the cup with an additional water, 10 mL (weight <30 kg) or 80 mL (weight ≥30 kg), and drink the whole amount; repeat rinse with 80 mL (weight ≥30 kg) and drink again
            • Weight <30 kg (prepare slurry with 12.5-mg tab)
              • <15 kg: 50 mg (4 tab)/dose in 40 mL water
              • 15 to <20 kg: 62.5 mg (5 tab)/dose in 50 mL water
              • 20 kg to <30 kg: 75 mg (6 tab)/dose in 60 mL water
            • Weight ≥30 kg (prepare slurry with 100-mg tab)
              • 30 to <40 kg: 100 mg (1 tab)/dose in 80 mL water
              • 40 to <60 kg: 150 mg (1.5 tab)/dose in 120 mL water
              • ≥60 kg: 200 mg (2 tab)/dose in 160 mL water

            Oral Administration

            May take with or without food

            Storage

            Store at controlled room temperature 20-25°C (68-77°F); excursions permitted to 15-30°C (59-86°F)

            Keep bottle tightly closed and protect from moisture

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
            PA Prior Authorization
            Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription.
            QL Quantity Limits
            Drugs that have quantity limits associated with each prescription. This restriction typically limits the quantity of the drug that will be covered.
            ST Step Therapy
            Drugs that have step therapy associated with each prescription. This restriction typically requires that certain criteria be met prior to approval for the prescription.
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