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When are Benznidazole Tablets prescribed?
Benznidazole Tablets are an antimicrobial indicated in pediatric patients 2 to 12 years of age for the treatment of Chagas disease caused by Trypanosoma cruzi.1 This indication received accelerated approval based on the number of treated patients who were successfully treated in clinical trials.2
Benznidazole Tablets are contraindicated in patients with a history of hypersensitivity to benznidazole or other nitroimidazole derivatives or if disulfiram has been used within the past 2 weeks.1
How do Benznidazole Tablets work?
Benznidazole exhibits antimicrobial activity against all 3 stages of the T cruzi parasite.1 Resistance to Benznidazole Tablets may develop, but the clinical relevance of the mechanisms by which this may occur is not known.1
What is the clinical efficacy of Benznidazole Tablets?
The efficacy of Benznidazole Tablets for the treatment of Chagas disease in patients 6 to 12 years of age was established in 2 randomized, double-blind, placebo-controlled trials with more than 200 people.1,*,† All patients had chronic indeterminate Chagas disease.1 Results from both trials indicate a significantly higher percentage of seronegative patients by a nonconventional assay following treatment with Benznidazole Tablets vs placebo.1
Nonconventional assay
Serologic status at end of follow-up1
| Status | Trial 1* (Ages 6-12 years, N=77) |
Difference (95% CI) |
Trial 2† (Ages 7-12 years, N=129) |
Difference (95% CI) |
||
|---|---|---|---|---|---|---|
| Benznidazole (n=40) |
Placebo (n=37) |
46.5 (24.5%, 64.4%) |
Benznidazole (n=64) |
Placebo (n=65) |
50.1 (35.8%, 63.4%) |
|
| Seronegative (%) | 24 (60.0) | 5 (13.5) | 35 (54.7) | 3 (4.6) | ||
| Seropositive | 15 | 29 | 23 | 51 | ||
| Missing | 1 | 3 | 6 | 11 | ||
| Benznidazole Tablets resulted in a significantly higher percentage of seronegative patients by a nonconventional assay following treatment.1 | ||||||
Nonconventional assay
Serologic status at end of follow-up1
| Status | Trial 1* (Ages 6-12 years, N=77) |
Difference (95% CI) |
|
|---|---|---|---|
| Benznidazole (n=40) |
Placebo (n=37) |
46.5 (24.5%, 64.4%) |
|
| Seronegative (%) | 24 (60.0) |
5 (13.5) |
|
| Seropositive | 15 | 29 | |
| Missing | 1 | 3 |
| Status | Trial 2† (Ages 7-12 years, N=129) |
Difference (95% CI) |
|
|---|---|---|---|
| Benznidazole (n=64) |
Placebo (n=65) |
50.1 (35.8%, 63.4%) |
|
| Seronegative (%) | 35 (54.7) | 3 (4.6) | |
| Seropositive | 23 | 51 | |
| Missing | 6 | 11 | |
| Benznidazole Tablets resulted in a significantly higher percentage of seronegative patients by a nonconventional assay following treatment.1 | |||
What is the clinical safety of Benznidazole Tablets?
The most frequently reported adverse reactions in pediatric patients treated with benznidazole in Trial 1 were abdominal pain (25%), rash (16%), decreased weight (13%), and headache (7%).1,*
In Trial 2, skin lesions were reported in 7 of 64 (11%) pediatric patients treated with benznidazole and in 2 of 65 patients receiving placebo. Adverse reactions reported in fewer than 5% of benznidazole-treated patients included nausea, anorexia, headache, abdominal pain, and arthralgia.1,†
In Trial 3, a subset of 19 pediatric patients 2 to 6 years of age treated with benznidazole, 6 patients (32%) had the following adverse reactions: rash, leukopenia, urticaria, eosinophilia, decreased appetite, and neutropenia. These adverse reactions were similar to those observed in the overall population of 37 patients.1,‡
How are Benznidazole Tablets dosed?1
- Benznidazole Tablets (12.5 mg and 100 mg) are for oral use and may be taken with or without food
- Benznidazole Tablets 100 mg can be taken whole or broken at score lines
- Benznidazole is dosed by body weight
- The total daily dose for pediatric patients 2 to 12 years of age is 5 mg/kg to 8 mg/kg orally, administered in 2 divided doses every 12 hours for 60 days
- Alternatively, benznidazole may be dosed as a slurry
- Please see full Prescribing Information for further directions on dosing and administration
* Study design: Randomized, double-blind, placebo-controlled trial in children 6 to 12 years of age with chronic indeterminate Chagas disease. A total of 106 patients were randomized to receive either Benznidazole Tablets (5 mg/kg/d for 60 days) or placebo and were followed for 4 years. Patients with at least 2 positive conventional serologic tests (indirect hemagglutination assay [IHA], immunofluorescence antibody assay [IFA], and/or enzyme-linked immunosorbent assay [ELISA]) for antibodies against T cruzi were included.1
† Study design: Randomized, double-blind, placebo-controlled trial in pediatric patients 7 to 12 years of age with chronic indeterminate Chagas disease. A total of 129 patients were randomized to receive either Benznidazole Tablets (7.5 mg/kg/d for 60 days) or placebo and were followed for 3 years. Patients with 3 positive conventional serologic tests (IHA, IFA, and/or ELISA) for antibodies against T cruzi were included.1
‡ Study design: Uncontrolled study of the safety and pharmacokinetics of Benznidazole Tablets in 37 pediatric patients 2 to 12 years of age with chronic indeterminate Chagas disease. Patients received Benznidazole Tablets 5 to 8 mg/kg/d twice daily for 60 days or placebo.1
INDICATIONS AND USAGE
Benznidazole Tablets, a nitroimidazole antimicrobial, is indicated in pediatric patients 2 to 12 years of age for the treatment of Chagas disease (American trypanosomiasis) caused by Trypanosoma cruzi.
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 for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
IMPORTANT SAFETY INFORMATION
Contraindications
Benznidazole Tablets are contraindicated in patients with a history of hypersensitivity reactions to benznidazole or other nitroimidazole derivatives. Reactions have included severe skin and soft tissue reactions. Benznidazole Tablets is also 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. Consumption of alcoholic beverages or products containing propylene glycol is contraindicated in patients during and for at least 3 days after therapy with Benznidazole Tablets. A disulfiram-like reaction (abdominal cramps, nausea, vomiting, headaches, and flushing) may occur due to the interaction between alcohol or propylene glycol and benznidazole. 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.
Warnings and Precautions
Potential for Genotoxicity and Carcinogenicity: Genotoxicity has been demonstrated in humans, in vitro in several bacterial species and mammalian cell systems, and in vivo in rodents. 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 two-fold compared to pre-dose values. In the same study, the mean incidence of chromosomal aberrations in 10 patients also increased two-fold compared to pre-dose values.
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. It is not known whether benznidazole is associated with carcinogenicity in humans.
Embryo-Fetal Toxicity: Based on animal studies, Benznidazole Tablets can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Pregnancy testing is recommended for women of reproductive potential prior to Benznidazole Tablets therapy. Advise women of reproductive potential to use effective contraception during treatment with Benznidazole Tablets and for 5 days after the last dose.
Hypersensitivity Skin Reactions: Serious skin and subcutaneous disorders, including acute generalized exanthematous pustulosis (AGEP), toxic epidermal necrolysis (TEN), erythema multiforme, and eosinophilic drug reactions, have been reported with benznidazole. Discontinue treatment at first evidence of these serious cutaneous reactions. Extensive skin reactions, such as rashes, 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.
Central and Peripheral Nervous System Effects: 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.
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. 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.
Adverse Reactions
The most common adverse reactions observed were abdominal pain (25%), rash (16%), decreased weight (13%), and headache (7%).
Use in Specific Populations
Lactation Risk: Limited published literature based on breast milk sampling reports that benznidazole is present in human milk. There are no reports of adverse effects on the breastfed infant and no information on the effects of benznidazole on milk production. Because of the potential for serious adverse reactions, and transmission of Chagas disease, advise patients that breastfeeding is not recommended during treatment with Benznidazole Tablets.
Male Infertility: Based on findings in rodents, Benznidazole Tablets may impair fertility in males of reproductive potential. It is not known whether effects on fertility are reversible.
Before prescribing Benznidazole Tablets and for further safety information, please read the full Prescribing Information here.
References: 1. Benznidazole Tablets [package insert]. Florham Park, NJ: Exeltis USA; 2017. 2. FDA approves first U.S. treatment for Chagas disease news release. Silver Springs, MD: US Food and Drug Administration; August 29, 2017. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm573942.htm. Accessed January 12, 2018.
Indications and Usage and Important Safety Information
INDICATIONS AND USAGE
Benznidazole Tablets, a nitroimidazole antimicrobial, is indicated in pediatric patients 2 to 12 years of age for the treatment of Chagas disease (American trypanosomiasis) caused by Trypanosoma cruzi.
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 for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.