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Benznidazole

Class: Antiprotozoals, Miscellaneous
VA Class: AP100
Chemical Name: N-Benzyl-2-nitroimidazole-1-acetamide
Molecular Formula: C12H12N4O3
CAS Number: 22994-85-0

Medically reviewed by Drugs.com. Last updated on April 22, 2019.

Introduction

Antiprotozoal agent; nitroimidazole derivative with antitrypanosomal activity.1 2 9 14

Uses for Benznidazole

Chagas Disease

Treatment of Chagas disease (American trypanosomiasis) caused by Trypanosoma cruzi.1 2 3 4 6 7 8 9 20

Became commercially available in US for treatment of Chagas disease in pediatric patients 2–12 years of age under FDA’s accelerated review process based on results of 2 clinical trials that used a surrogate end point to evaluate efficacy (i.e., number of treated patients who became IgG antibody negative against recombinant antigens derived from T. cruzi);1 23 continued approval for this indication in US may be contingent on verification and description of clinical benefits in confirmatory studies.1 Designated an orphan drug by FDA for treatment of Chagas disease.5

Chagas disease is caused by T. cruzi, a protozoan parasite usually transmitted to humans by the bite of infected triatomine insects (reduviid bugs, “kissing” bugs, cone-nosed bugs, blood suckers);2 6 7 8 9 20 also can be transmitted via blood (e.g., blood transfusions), via organ transplants, perinatally from mother to infant, by ingestion of contaminated drink or food, and via accidental laboratory exposure.2 6 7 8 13 20 Vector-borne transmission of T. cruzi via triatomine bugs primarily occurs in rural areas of Mexico, Central America, and South America where the disease is endemic.2 7 8 In US, Chagas disease reported with increasing frequency in immigrants from endemic areas;2 8 20 22 however, triatomine vectors that can transmit T. cruzi and mammalian reservoir hosts of the organism (e.g., raccoons, opossums, domestic dogs) are found in the US and autochthonous transmission has been documented in US, especially in southern states.2 8 20 22 Chagas disease is not transmitted person-to-person.8

Following infection with T. cruzi, Chagas disease includes an acute and chronic phase.2 6 7 8 20 The acute phase occurs within weeks of infection and usually lasts for up to 1–3 months; although parasitemia is present and trypomastigotes usually detectable in blood by microscopy, patients typically are asymptomatic or have mild, nonspecific symptoms.2 6 7 8 20 If untreated, acute phase is followed by a prolonged asymptomatic chronic phase (“chronic indeterminate”) that may last for decades or for life.2 6 7 8 20 Up to 20–30% of chronically infected patients develop clinically evident advanced disease with potential life-threatening cardiovascular disorders (e.g., cardiomyopathy, heart failure, arrhythmias, cardiac arrest) and/or GI disorders (e.g., megaesophagus, megacolon).2 6 7 8 20 In addition, reactivation of chronic T. cruzi infection can occur in those who become immunocompromised because of other disease or drug therapy;2 reactivated infections may have features that differ from those of acute infection and can involve severe disease.2 8

Recommendations for use of antitrypanosomal agents for treatment of Chagas disease vary depending on patient age and phase and form of the disease.2 6 8 9 14 20 Treatment with an antitrypanosomal agent generally recommended in all pediatric patients with acute T. cruzi infection (including congenital infections) and in those <18 years of age with chronic T. cruzi infection.2 6 8 9 20 Use of antitrypanosomal agents in adults with chronic infections, including those with chronic indeterminate Chagas disease, is more controversial.2 8 9 11 14 21

When treatment of Chagas disease indicated in pediatric or adult patients, drugs of choice are benznidazole and nifurtimox (not commercially available in US but may be available from CDC).2 6 7 Unless contraindicated, benznidazole generally preferred since it may be better tolerated.2 6 Although labeled by FDA for use only in pediatric patients 2–12 years of age,1 CDC recommends treatment of Chagas disease in all pediatric patients <18 years of age, including those with congenital, acute, chronic, or reactivated disease.6 8 CDC also states treatment strongly recommended in adults 18–50 years of age with chronic Chagas disease who do not already have advanced disease (Chagas cardiomyopathy).6 8 When considering antitrypanosomal treatment in adults >50 years of age, CDC and others recommend considering risks versus benefits of such treatment based on patient's age, clinical status, preference, and overall health.2 6 Antitrypanosomal agents not recommended in patients with advanced Chagas disease who have cardiomyopathy or megaesophagus since no evidence that such treatment would reverse the extensive disease pathology at this stage.2 6

Diagnosis and treatment of Chagas disease is complex and consultation with experts recommended.2 For assistance with diagnosis or treatment of Chagas disease in the US, contact CDC at Parasitic Diseases Hotline at 404-718-4745 from 8:00 a.m. to 4:00 p.m. Eastern Standard Time Monday through Friday, Emergency Operations Center at 770-488-7100 after business hours and on weekends and holidays, or by email at chagas@cdc.gov.6 8 Contact CDC Drug Service at 404-639-3670 or by email at drugservice@cdc.gov for information on how to obtain antiparasitic drugs not commercially available in US (e.g., nifurtimox).15

Benznidazole Dosage and Administration

General

  • Prior to initiation of benznidazole in females of reproductive potential, exclude pregnancy using appropriate tests.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

  • Alcohol or preparations containing alcohol or propylene glycol contraindicated during benznidazole treatment and for at least 3 days after last dose of the drug.1 (See Specific Drugs under Interactions.)

Administration

Oral Administration

Administer orally twice daily (approximately every 12 hours) with or without food.1 Administration with or after meals may minimize adverse GI effects.14 134

Commercially available as 12.5-mg tablets (unscored) and 100-mg tablets (scored).1 The 100-mg tablets may be split into halves or quarters to provide 50- or 25-mg doses, respectively.1

For patients unable to swallow tablets, an oral slurry may be prepared extemporaneously using the tablets.1

Extemporaneous Oral Slurry

Dose and number of benznidazole tablets and volume of water used to prepare oral slurry are based on body weight (kg).1 Use 12.5-mg tablets to prepare oral slurry for pediatric patients weighing <30 kg (see Table 1).1 Use 100-mg tablets to prepare oral slurry for pediatric patients weighing ≥30 kg (see Table 2).1

Patients weighing <30 kg: Place appropriate number of 12.5-mg tablets into clean cup and add appropriate volume of water indicated in Table 1.1 Allow tablets to disintegrate slowly over approximately 1–2 minutes.1 Then, gently shake cup to mix and immediately swallow cup contents.1 Add an additional 10 mL of water to cup to resuspend any remaining drug and then swallow entire cup contents.1

Table 1. Preparation of Benznidazole Oral Slurry for Pediatric Patients 2–12 Years of Age Weighing <30 kg Using 12.5-mg Tablets.1

Weight (kg)

Each Dose (mg)

Number of Benznidazole 12.5-mg Tablets For Each Dose of Oral Slurry

Initial Volume of Water to Prepare Each Dose of Oral Slurry (mL)

<15 kg

50 mg

4 tablets

40 mL

15 to <20 kg

62.5 mg

5 tablets

50 mL

20 to <30 kg

75 mg

6 tablets

60 mL

Patients weighing ≥30 kg: Place appropriate number of 100-mg tablets into clean cup and add appropriate volume of water indicated in Table 2.1 Allow tablets to disintegrate slowly over approximately 1–2 minutes.1 Then, gently shake cup to mix and immediately swallow cup contents.1 Add 80 mL of water to cup to resuspend any remaining drug and swallow entire cup contents;1 repeat this step by adding an additional 80 mL of water to cup and swallow entire cup contents.1

Table 2. Preparation of Benznidazole Oral Slurry for Pediatric Patients 2–12 Years of Age Weighing ≥30 kg Using 100-mg Tablets.1

Weight (kg)

Each Dose (mg)

Number of Benznidazole 100-mg Tablets for Each Dose of Oral Slurry

Initial Volume of Water to Prepare Each Dose of Oral Slurry (mL)

30 to <40 kg

100 mg

1 tablet

80 mL

40 to <60 kg

150 mg

1½ tablets

120 mL

≥60 kg

200 mg

2 tablets

160 mL

Dosage

Pediatric Patients

Chagas Disease
Oral

Pediatric patients 2–12 years of age: Manufacturer recommends 5–8 mg/kg daily given in 2 divided doses for 60 days.1 (See Table 3.)

Table 3. Recommended Benznidazole Dosage in Pediatric Patients 2–12 Years of Age.1

Weight (Kg)

Dosage (mg)

Number of Tablets for Each Dose

<15 kg

50 mg twice daily

Four 12.5-mg tablets OR ½ of one 100-mg tablet

15 to <20 kg

62.5 mg twice daily

Five 12.5-mg tablets

20 to <30 kg

75 mg twice daily

Six 12.5-mg tablets OR ¾ of one 100-mg tablet

30 to <40 kg

100 mg twice daily

One 100-mg tablet

40 to <60 kg

150 mg twice daily

One 100-mg tablet AND ½ of one 100-mg tablet

≥60 kg

200 mg twice daily

Two 100-mg tablets

Pediatric patients >12 years of age: 5–7 mg/kg daily given in 2 divided doses for 60 days recommended by CDC and some clinicians.6 134

Adults

Chagas Disease
Oral

If used in adults (see Chagas Disease under Uses), 5–7 mg/kg daily given in 2 divided doses for 60 days recommended by CDC and some clinicians.2 6 14 134

Prescribing Limits

Pediatric Patients

Chagas Disease
Oral

Children 2–12 years of age: Maximum 8 mg/kg daily in 2 divided doses.1

Special Populations

Hepatic Impairment

Manufacturer makes no specific dosage recommendations.1 CDC and some clinicians state benznidazole contraindicated in patients with severe hepatic impairment.2 6

Renal Impairment

Manufacturer makes no specific dosage recommendations.1 CDC and some clinicians state benznidazole contraindicated in patients with severe renal impairment.2 6

Cautions for Benznidazole

Contraindications

  • Hypersensitivity to benznidazole or other nitroimidazole derivatives.1 (See Dermatologic and Sensitivity Reactions under Cautions.)

  • Patients who have taken disulfiram within preceding 2 weeks.1 (See Specific Drugs under Interactions.)

  • Consumption of alcohol or preparations containing alcohol or propylene glycol contraindicated during benznidazole treatment and for at least 3 days after last dose.1 (See Specific Drugs under Interactions.)

Warnings/Precautions

Sensitivity Reactions

Dermatologic and Sensitivity Reactions

Serious dermatologic reactions (e.g., acute generalized exanthematous pustulosis [AGEP],1 toxic epidermal necrolysis,1 erythema multiforme,1 drug reaction with eosinophilia and systemic symptoms [DRESS])1 16 18 reported.

Potentially extensive rash (e.g., maculopapular, pruritic, erythematous),1 16 18 eczema,1 pustules,1 urticaria,16 bullous eruptions,16 angioedema,16 18 skin peeling,16 allergic dermatitis,1 2 and exfoliative dermatitis1 2 reported. Photosensitivity rash also reported.2 14 16

Dermatologic reactions generally occur approximately 10 days after initiation of benznidazole and usually resolves after drug discontinuance.1 Some clinicians recommend monitoring for adverse dermatologic effects (e.g., dermatitis) beginning 9–10 days after benznidazole initiated.2 20

Immediately discontinue benznidazole if signs or symptoms of serious dermatologic reaction occur.1 2 Also discontinue benznidazole if dermatologic reaction occurs with additional signs or symptoms of systemic involvement (e.g., lymphadenopathy, fever, purpura).1 2

Genotoxicity and Carcinogenicity.

Has been genotoxic in humans, in vitro in bacteria and in mammalian cell systems, and in vivo in rodents.1 Twofold increase in chromosomal aberrations reported in pediatric patients receiving benznidazole.1

Carcinogenic potential of benznidazole in humans not known.1 Carcinogenic effects reported in mice and rats following long-term oral administration of metronidazole (a chemically related nitroimidazole anti-infective).1 10

Fetal/Neonatal Morbidity and Mortality.

Based on results of animal studies, benznidazole may cause fetal harm if used in pregnant women.1 Embryofetal toxicity (fetal death, teratogenicity) reported in rats and rabbits.1 (See Pregnancy under Cautions.)

Exclude pregnancy before initiating benznidazole in women of reproductive potential.1 Avoid pregnancy during benznidazole treatment and for 5 days after last dose.1

Nervous System Effects

Paresthesia,1 2 14 16 peripheral neuropathy,1 2 14 18 polyneuropathy,2 and hypoesthesia1 reported. May be dose dependent.2 14 20

Headache,1 dizziness,1 2 vertigo,2 16 tremor,1 2 convulsions,1 insomnia or sleep disturbances,1 2 16 irritability,2 anxiety,18 depression,16 mood changes,2 inability to concentrate,1 general malaise,18 adynamia,16 temporary amnesia,1 and temporary disorientation1 2 reported.

Some clinicians recommend monitoring for signs and symptoms of peripheral neuropathy every 2 weeks, especially after first month of treatment.2

Immediately discontinue benznidazole if abnormal neurologic symptoms develop.1 In most reported cases, nervous system effects generally occurred late in the course of treatment and such effects may take several months to resolve after drug discontinuance.1 2 20

Hematologic Effects

Bone marrow depression (neutropenia, thrombocytopenia, anemia, leukopenia) reported rarely;1 2 14 17 generally reversible following discontinuance of the drug.1

Perform CBC (including total and differential leukocyte counts) prior to initiation of benznidazole and monitor during therapy (e.g., every 2–3 weeks) and after treatment completed.1 2

If hematologic manifestations of bone marrow depression occur, manufacturer states continue benznidazole only under strict medical supervision.1 Some clinicians state immediately interrupt benznidazole treatment if bone marrow suppression develops.2 14

Impairment of Male Fertility

Based on results of animal studies, benznidazole may impair fertility in males of reproductive potential.1

In male rats, dose-dependent testicular atrophy and epididymal atrophy reported;1 testicular atrophy and inhibition of spermatogenesis reported in pubertal and adult rats and mice.1 Not known whether effects on male fertility are reversible.1

Specific Populations

Pregnancy

May cause fetal harm if used in pregnant women.1

In animal reproduction studies, fetal malformations reported in rats (anasarca, anophthalmia, and/or microphthalmia)1 and in rabbits (ventricular septal defect).1

Insufficient data from published postmarketing reports to inform a drug-associated risk of adverse pregnancy-related outcomes.1

Prior to initiation of benznidazole in females of reproductive potential, perform appropriate pregnancy tests.1 Advise females of reproductive potential about potential risk to a fetus and caution them to use effective contraception to prevent pregnancy during benznidazole treatment and for 5 days after last dose.1

CDC states benznidazole treatment is typically delayed until after pregnancy.6

Manufacturer states benznidazole not recommended for treatment of chronic Chagas disease in pregnant women.1 If a pregnant woman presents with acute symptomatic Chagas disease, manufacturer states evaluate risks and benefits of benznidazole treatment for the mother and fetus on a case-by-case basis.1

Lactation

Distributed into human milk.1 Not known whether benznidazole affects milk production.1

Because of potential for serious adverse reactions to benznidazole in nursing infants and possibility of transmission of Chagas disease from mother to nursing infant, advise women not to breast-feed during benznidazole treatment.1 6

Pediatric Use

Safety and efficacy not established in pediatric patients <2 years of age or in pediatric patients >12 years of age.1

Safety and efficacy for treatment of Chagas disease in pediatric patients 2–12 years of age established based on results of controlled trials in pediatric patients 6–12 years of age and additional safety and pharmacokinetic data from pediatric patients 2–6 years of age.1

Hepatic Impairment

CDC and some clinicians state benznidazole contraindicated in patients with severe hepatic impairment.2 6

Pharmacokinetics not studied.1

Renal Impairment

CDC and some clinicians state benznidazole contraindicated in patients with severe renal impairment.2 6

Pharmacokinetics not studied.1

Common Adverse Effects

GI effects (abdominal pain, abdominal bloating, decreased appetite, decreased weight, nausea, vomiting, diarrhea, constipation),1 2 3 4 9 16 headache,1 3 16 rash,3 9 16 urticaria,1 16 pruritus,1 3 16 dizziness,1 tremor,1 eosinophilia,1 16 neutropenia,1 myalgia,16 arthralgia or arthritis,1 3 14 16 18 elevated aminotransferase (transaminase) concentrations.1 16

Interactions for Benznidazole

Does not induce CYP1A2, 2B6, or 3A4 in vitro.1 24

P-glycoprotein (P-gp) substrate.1

Specific Drugs

Drug

Interaction

Comments

Alcohol and propylene glycol

Alcoholic beverages and preparations containing alcohol or propylene glycol: Disulfiram-like reactions (abdominal cramps, nausea, vomiting, headaches, flushing) reported when alcoholic beverages consumed during or following treatment with metronidazole (a chemically related nitroimidazole);1 10 not reported to date with benznidazole1

Alcoholic beverages and preparations containing alcohol or propylene glycol: Do not use during benznidazole treatment or for 3 days following last dose1

Disulfiram

Psychotic reactions reported when disulfiram used concomitantly with metronidazole (a chemically related nitroimidazole);1 10 not reported to date with benznidazole1

Do not use benznidazole in patients who have taken disulfiram within the preceding 2 weeks1

Benznidazole Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed following oral administration;2 9 peak plasma concentrations usually attained within 2–3 hours.1

Average relative oral bioavailability is 91.7%.9

Plasma Concentrations

In healthy fasting adults, peak plasma concentrations and median time to peak plasma concentrations are similar following single 100-mg oral dose given as a whole tablet, as an extemporaneous oral slurry prepared using a 100-mg tablet, or an extemporaneous oral slurry prepared using eight 12.5-mg tablets.1

In a limited study in healthy adults 19–32 years of age, peak plasma concentrations were lower and volume of distribution higher in men than in women.19

Food

Administration with food does not affect peak plasma concentrations or AUC.1

Distribution

Extent

Widely distributed following oral administration.14

Distribution into CSF reported.12

Distributed into human milk.1 Infant dose available from human milk may be 5.5–17% of maternal weight-adjusted dosage;1 milk-to-plasma ratio ranges from 0.3–2.79.1

Plasma Protein Binding

Approximately 44–60%.1

Elimination

Metabolism

Metabolic pathway not fully characterized.1 Preclinical studies indicated the drug is primarily metabolized in the liver.14

Elimination Route

Benznidazole and unknown metabolites eliminated in urine and feces.1 2 9

Half-life

Approximately 12–13 hours.1 2 9 14 19

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C);1 protect from moisture.1

Actions and Spectrum

  • A nitroimidazole antiprotozoal agent with trypanocidal activity.1 2 9 14 Active against T. cruzi, causative agent of Chagas disease (American trypanosomiasis).1 2 Active against all 3 life cycle stages of the organism (trypomastigotes, amastigotes, epimastigotes).1 2

  • Exact mechanism of action not known.1 9 14 Benznidazole is a prodrug that requires nitroreductase-catalyzed activation within T. cruzi to exert its trypanocidal activity.14 Appears to be reduced by a type I nitroreductase produced by T. cruzi and converted to a series of intermediates that may promote damage to several macromolecules (e.g., DNA) and inhibit DNA, RNA, and protein synthesis in the parasite.1 9 14 Some evidence that proinflammatory cytokines (e.g., interferon-γ) may be involved and result in enhanced trypanocidal activity, including improved phagocytosis.9 14

  • Susceptibility of T. cruzi to benznidazole varies depending on geographic area of origin.1 14 Naturally-occurring T. cruzi strains resistant to benznidazole reported.9 14 In addition, in vitro studies and studies in mice indicate T. cruzi can develop benznidazole resistance.1 14

  • Resistance to benznidazole in T. cruzi appears to be multifactorial and may include mutations in the nitroreductase (TcNTR) gene and increased efflux activity due to overexpression of TcPGP1 and TcPGP2 genes that encode P-gp as well as TcABCG1 genes that encode ATP-binding cassette transporters.1 14

Advice to Patients

  • Advise patients to read the manufacturer's patient information.1

  • Depending on indicated dosage, instruct patient and/or parent or caregiver that 100-mg benznidazole tablets can be taken whole or may be broken at scored lines.1 If necessary for patients unable to swallow tablets, instruct patient and/or parent or caregiver how to prepare the appropriate dose of oral slurry using 12.5- or 100-mg benznidazole tablets.1 (See Administration under Dosage and Administration.)

  • Advise patients to avoid alcoholic beverages and preparations containing alcohol or propylene glycol during benznidazole treatment and for at least 3 days after last dose of the drug.1

  • Inform patients that serious skin reactions can occur with benznidazole.1 Importance of discontinuing the drug and contacting clinician if skin reactions with additional symptoms of systemic involvement (e.g., lymphadenopathy, fever, and/or purpura) occur.1

  • Inform patients that paresthesia or symptoms of peripheral neuropathy can occur with benznidazole.1 Importance of immediately discontinuing benznidazole and contacting clinician if abnormal neurologic symptoms occur.1

  • Inform patients that hematologic manifestations of bone marrow depression (e.g., anemia, leukopenia) have been reported with benznidazole and are reversible after the drug is discontinued.1 Importance of routine hematologic monitoring before, during, and after benznidazole treatment.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, and any concomitant illnesses.1

  • Advise male patients of reproductive potential that benznidazole may impair fertility.1 (See Impairment of Male Fertility under Cautions.)

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

  • Inform pregnant women and females of reproductive potential that benznidazole may cause fetal harm.1 Importance of being tested for pregnancy prior to initiation of benznidazole and importance of using effective contraception to prevent pregnancy during benznidazole treatment and for 5 days after last dose of the drug.1 Advise women not to breast-feed during benznidazole treatment.1

  • Importance of advising patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Benznidazole

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

12.5 mg

Benznidazole Tablets

Exeltis

100 mg

Benznidazole Tablets (scored)

Exeltis

AHFS DI Essentials™. © Copyright 2021, Selected Revisions April 22, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Exeltis USA. Benznidazole tablets prescribing information. Florham Park, NJ; 2017 Aug.

2. Bern, C, Montgomery SP, Herwaldt BL et al. Evaluation and treatment of Chagas disease: a systematic review. JAMA. 2007; 298:2171-81.

3. de Andrade AL, Zicker F, de Oliveira FM et al. Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Lancet. 1996; 348:1407-13.

4. Sosa Estani S, Segura EL, Ruiz AM et al. Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas' disease. Am J Trop Med Hyg. 1998; 59:526-9.

5. Food and Drug Administration. Search orphan drug designations and approvals. From FDA website. Accessed 2018 Dec 13. https://www.accessdata.fda.gov/scripts/opdlisting/oopd/

6. Centers for Disease Control and Prevention. Parasites - American Trypanosomiasis (also known as Chagas disease). Resources for health professionals. From CDC website. Accessed 2018 Dec 10. https://www.cdc.gov/parasites/chagas/health_professionals/index.html

7. World Health Organization. Chagas disease (American trypanosomiasis). From WHO website. Accessed 2018 Dec 10. https://www.who.int/chagas/en/

8. Centers for Disease Control and Prevention. Parasites - American Trypanosomiasis (also known as Chagas disease). General information. From CDC website. Accessed 2018 Dec 10. https://www.cdc.gov/parasites/chagas/

9. Sales Junior PA, Molina I, Fonseca Murta SM et al. Experimental and clinical treatment of Chagas disease: A review. Am J Trop Med Hyg. 2017; :1-33.

10. Pfizer. Flagyl (metronidazole) tablets prescribing information. New York, NY; 2017 Jul.

11. Cardoso CS, Ribeiro ALP, Oliveira CDL et al. Beneficial effects of benznidazole in Chagas disease: NIH SaMi-Trop cohort study. PLoS Negl Trop Dis. 2018; 12:e0006814. http://www.ncbi.nlm.nih.gov/pubmed/30383777?dopt=AbstractPlus

12. Montero M, Mir M, Sulleiro E et al. High-dose benznidazole in a 62-year-old Bolivian kidney transplant recipient with Chagas central nervous system involvement. Int J Infect Dis. 2019; 78:103-106. http://www.ncbi.nlm.nih.gov/pubmed/30391324?dopt=AbstractPlus

13. Chin-Hong PV, Schwartz BS, Bern C et al. Screening and treatment of chagas disease in organ transplant recipients in the United States: recommendations from the chagas in transplant working group. Am J Transplant. 2011; 11:672-80. http://www.ncbi.nlm.nih.gov/pubmed/21401868?dopt=AbstractPlus

14. Junckerstorff RK, Murray RJ. Benznidazole, In: Grayson ML, ed. Kucers' the use of antibiotics: a clinical review of antibacterial, antifungal, antiparasitic, and antiviral drugs. 7th ed. Boca Raton, FL: CRC Press; 2018:3205-10.

15. Centers for Disease Control and Prevention. CDC drug service. From CDC website. Accessed 2018 Dec16. https://www.cdc.gov/laboratory/drugservice/index.html

16. Olivera MJ, Cucunubá ZM, Valencia-Hernández CA et al. Risk factors for treatment interruption and severe adverse effects to benznidazole in adult patients with Chagas disease. PLoS One. 2017; 12:e0185033. http://www.ncbi.nlm.nih.gov/pubmed/28949997?dopt=AbstractPlus

17. Crespillo-Andújar C, Calbacho Robles M, Norman FF et al. Severe immune thrombocytopaenia in a patient taking benznidazole for chronic Chagas disease. BMJ Case Rep. 2018; 2018 http://www.ncbi.nlm.nih.gov/pubmed/29588298?dopt=AbstractPlus

18. Aldasoro E, Posada E, Requena-Méndez A et al. What to expect and when: benznidazole toxicity in chronic Chagas' disease treatment. J Antimicrob Chemother. 2018; 73:1060-1067. http://www.ncbi.nlm.nih.gov/pubmed/29351667?dopt=AbstractPlus

19. Molina I, Salvador F, Sánchez-Montalvá A et al. Pharmacokinetics of Benznidazole in Healthy Volunteers and Implications in Future Clinical Trials. Antimicrob Agents Chemother. 2017; 61 http://www.ncbi.nlm.nih.gov/pubmed/28167552?dopt=AbstractPlus

20. Bern C, Kjos S, Yabsley MJ et al. Trypanosoma cruzi and Chagas' Disease in the United States. Clin Microbiol Rev. 2011; 24:655-81. http://www.ncbi.nlm.nih.gov/pubmed/21976603?dopt=AbstractPlus

21. Morillo CA, Marin-Neto JA, Avezum A et al. Randomized Trial of Benznidazole for Chronic Chagas' Cardiomyopathy. N Engl J Med. 2015; 373:1295-306. http://www.ncbi.nlm.nih.gov/pubmed/26323937?dopt=AbstractPlus

22. Manne-Goehler J, Umeh CA, Montgomery SP et al. Estimating the Burden of Chagas Disease in the United States. PLoS Negl Trop Dis. 2016; 10:e0005033. http://www.ncbi.nlm.nih.gov/pubmed/27820837?dopt=AbstractPlus

23. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 209570Orig1s000: Summary review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209570Orig1s000SumR.pdf

24. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 209570Orig1s000: Non-clinical review(s). From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2017/209570Orig1s000PharmR.pdf

134. . Drugs for parasitic infections. Treat Guidel Med Lett. 2013; 11:e1-31.

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