Benznidazole (Systemic)


VA CLASSIFICATION
Primary: AP109

Commonly used brand name(s): Radanil; Ro7–1051; Rochagan.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

*Not commercially available in the U.S.

Not commercially available in Canada.



Category:


Antiprotozoal (systemic){16}

Indications

Note: Because benznidazole is not commercially available in the U.S. or Canada, the bracketed information and the use of the superscript 1 in this monograph reflect the lack of labeled (approved) indications for this medication in these countries.

Accepted

[Trypanosomiasis, American (treatment)]1—Benznidazole is used as an alternative agent in the treatment of American trypanosomiasis (Chagas' disease) caused by Trypanosoma cruzi . {01} {02} {03} {08} {09} {10} {13} {14} {16} {18} {21} However, nifurtimox is considered the primary agent in the treatment of American trypanosomiasis. {08} {10}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Source—
    Nitroimidazole derivative. {05}
Molecular weight—
    260.25 {07}

Mechanism of action/Effect:

Trypanocidal; {16} although the mode of action has not been studied in detail, benznidazole appears to inhibit protein and ribonucleic acid (RNA) synthesis in the trypanosome parasite. {01} {04} {09}

Absorption:

Rapidly absorbed from the gastrointestinal tract of healthy volunteers following a single oral 100-mg dose. {05} {16} {17} {18}

Distribution:

Rapidly and evenly distributed between the plasma and the red blood cells in humans. {16}

Relative volume of distribution—Average 0.56 L per kg (L/kg). {05}

Protein binding:

About 44%. {05}

Half-life:

Elimination—Approximately 10.5 to 13.6 hours with an average of 12 hours. {05} {06} {16} {17} {18}

Time to peak concentration:

About 3 to 4 hours in healthy volunteers following a single oral 100-mg dose. {05} {16} {17} {18}

Peak plasma concentration

About 2.2 to 2.8 mcg per mL (mcg/mL) with an average of 2.54 mcg/mL in healthy volunteers following a single oral 100-mg dose. {05} {17}

Elimination:
    Renal—60 to 67% of the medication was eliminated in the urine within 4 days in healthy volunteers given a dose of 14 mg per kg of body weight (mg/kg) of 14C-tagged benznidazole. {05} {17}
    Fecal—About 22 to 28%. {17}


Precautions to Consider

Carcinogenicity/Tumorigenicity

Carcinogenicity bioassays of mice given 8 mg per kg of body weight (mg/kg) per day of benznidazole for 60 days have shown an increase in lymphomas. {12}

Mutagenicity

A small study assessing the cytogenetic effect of benznidazole in 14 patients (aged 11 months to 11 years) with Chagas' disease has shown a two-fold increase in chromosomal aberrations (CA). {12}

Benznidazole has been shown to be mutagenic for Klebsiella pneumoniae {07} and Salmonella typhimurium . {09}

Pregnancy/Reproduction

Pregnancy—
Studies have not been done in humans. The World Health Organization (WHO) prescribing information does not recommend the use of benznidazole during the first trimester of pregnancy. {16}

Studies done in female rats given benznidazole in oral doses of 25 to 75 mg/kg a day from the seventh to the sixteenth day of pregnancy and in rabbits given oral doses of 25 mg/kg a day from the seventh to the nineteenth day of pregnancy, have not shown benznidazole to be embryotoxic or teratogenic. {17}

Breast-feeding

It is not known whether benznidazole is distributed into breast milk. However, problems in humans have not been documented.

Pediatrics

Appropriate studies on the relationship of age to the effects of benznidazole have not been performed in the pediatric population. No pediatrics-specific problems have been documented to date.


Geriatrics


Appropriate studies on the relationship of age to the effects of benznidazole have not been performed in the geriatric population. However, no geriatrics-specific problems have been documented to date.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.

» Alcohol{19}    (benznidazole should not be used concurrently with alcohol; accumulation of acetaldehyde may occur due to interference of benznidazole with the oxidation of alcohol, resulting in disulfiram-like effects causing extreme discomfort such as abdominal cramps, nausea, vomiting, headache, or flushing)


» Aspirin{20}    (concurrent use with benznidazole may increase the chance of bleeding)


» Anticoagulants, coumarin-derivative, such as warfarin{19}    (effects may be potentiated when these agents are used concurrently with benznidazole, due to inhibition of enzymatic metabolism of anticoagulants)



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
» Complete blood count (CBC)    (benznidazole may decrease the concentration of leukocytes and platelets on rare occasion {16} {18})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Hematological impairment or
» Hepatic function impairment or
» Renal function impairment{16}    (patients with these conditions may have an increased risk of side effects {16} {18})


Hypersensitivity to benznidazole{16}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

» Complete blood count (CBC)    (should be monitored throughout treatment since benznidazole may cause leukopenia or thrombocytopenia on rare occasion; treatment may have to be interrupted if these blood changes occur {16} {18})




Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Peripheral neuropathy{01}{02}{08}{09}{15}{16}{17} (numbness; tingling pain; weakness in hands or feet)
    
progressive purpuric dermatitis (reddish spots on skin or reddish discoloration of skin{02}{14}{21})
    
seizures{19}

Incidence rare
    
Blood dyscrasias, specifically leukopenia (fever or chills; sore throat), and thrombocytopenia (pinpoint red spots on skin; unusual bleeding or bruising{16}{18})
    
skin rash{08}{09}{15}{16}{17}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Gastrointestinal disturbances {08}{11}{14}{16}{17}(abdominal or stomach pain; diarrhea; nausea; vomiting)

Incidence rare
    
Fatigue (unusual tiredness or weakness)
    
headache
    
psychic disturbances such as:{08}{11} disorientation{02}{17} (confusion), insomnia{02}{17} (trouble in sleeping), inability to concentrate{14}
restlessness{02}
amnesia, transient{14} (temporary loss of memory), vertigo (dizziness{16}{18})





Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Benznidazole (Systemic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to benznidazole



Tumorigenicity—
Mutagenicity—A small study of 14 pediatric patients has shown a two-fold increase in chromosomal aberrations

Pregnancy—WHO does not recommend use during the first trimester of pregnancy
Other medications, especially aspirin, alcohol, and coumarin-derivative anticoagulants
Other medical problems, especially hematological conditions, hepatic function impairment, or renal function impairment

Proper use of this medication
Taking with meals to minimize gastrointestinal irritation

» Compliance with full course of therapy

» Proper dosing
Missed dose

» Proper storage

Precautions while using this medication
Regular visits to physician to check progress

» Checking with physicians if symptoms get worse

Caution if leukopenia or thrombocytopenia occurs:

» Checking with physician immediately if fever or chills occur or if you think you are getting an infection

» Checking with physician immediately if unusual bleeding or bruising; black, tarry stools; blood in urine or stools; or pinpoint red spots on skin occur

» Avoiding use of alcoholic beverages or other alcohol-containing preparations while taking this medication


Side/adverse effects
Signs of potential side effects, especially peripheral neuropathy; seizures; blood dyscrasias; progressive purpuric dermatitis; and skin rash


General Dosing Information
Nausea and mild rashes may occur during the initial phase (generally within the first 2 weeks) of therapy with benznidazole. Reduction of dose may not be necessary since these side/adverse effects may disappear spontaneously with continuous treatment. However, if rashes become severe or are accompanied by fever or purpura, treatment should be discontinued. {16} {17} {18}

Symptoms of peripheral neuropathy are dose-related effects. If these symptoms occur, treatment should be discontinued immediately. {16}

The daily dose of benznidazole should be taken after meals, in 2 divided doses, with a 12-hour interval between doses. {18}


Oral Dosage Forms

Note: Because benznidazole is not commercially available in the U.S. or Canada, the bracketed uses and the use of superscript 1 in the Dosage Forms section reflect the lack of labeled (approved) indications for this product in these countries.

BENZNIDAZOLE TABLETS

Usual adult and adolescent dose
[Trypanosomiasis, American]1
Oral, 5 to 7 mg per kg of body weight per day taken after meals, in two doses with an interval of twelve hours between doses. Therapy should continue for thirty to sixty days. {01} {03} {09} {11} {16} {18}


Note: Some medical authorities recommend treatment for up to one hundred and twenty days. {08} {11}


Usual pediatric dose
[Trypanosomiasis, American]1
Children up to 12 years of age: Oral, 10 mg per kg of body weight per day taken after meals, in two doses with an interval of twelve hours between doses. Therapy should continue for thirty to sixty days. {01} {09} {11} {16} {18}

Children 12 years of age and over: See Usual adult and adolescent dose.


Note: Some medical authorities recommend treatment for up to one hundred and twenty days. {08} {11}


Usual pediatric prescribing limits
Up to a maximum of 10 mg per kg of body weight per day. {18}

Strength(s) usually available
U.S.—
Not commercially available {08}.

Canada—
Not commercially available.

Other (Brazil)—


100 mg (Rx) [Rochagan{16}{18}] [Radanil] [Ro7–1051]

Packaging and storage:
Store in a well-closed container below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Protect from light. {16} {17}

Auxiliary labeling:
   • Avoid alcoholic beverages. {16} {18}
   • Continue medication for the full time of treatment.



Developed: 08/31/1994



References
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  1. Marr JJ, Docampo R. Chemotherapy for Chagas disease: a perspective of current therapy and considerations for future research. Rev Infect Dis 1986; 8(6): 884-903.
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  1. Apt W, Arribada A, Arab F, Ugarte JM, Luksic I, Sole C. Clinical trial of benznidazole and an immunopotentiator against Chagas disease in Chile. Trans R Soc Trop Med Hyg 1986; 80: 1010.
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  1. Dukes MNG, editor. Meyler's side effects of drugs. An encyclopedia of adverse reactions and interactions. 10th ed. Amsterdam: Elsevier, 1994: 706.
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