Benznidazole

Benznidazole Tablets are indicated in pediatric patients 2 to 12 years of age for the treatment of Chagas disease (American trypanosomiasis) caused by

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

• Pediatric patients 2 to 12 years of age: The total daily dose is 5 mg/kg to 8 mg/kg orally administered in two divided doses separated by approximately 12 hours for a duration of 60 days (
  
  
  
  2.2 Recommended Dosage in Pediatric Patients (2 to 12 Years of Age)

  The total daily dose for pediatric patients 2 to 12 years of age is 5 mg/kg to 8 mg/kg orally administered in two divided doses separated by approximately 12 hours, for a duration of 60 days (see Table 1).

  Table 1: Recommended Dosage of Benznidazole Tablets in Pediatric Patients (2 to 12 Years of Age)

  Body Weight Range (kg)	Dose (mg)	Number of Benznidazole Tablets 12.5 mg	Number of Benznidazole Tablets 100mg	Duration and Frequency of Therapy
  Less than 15 kg	50 mg	4 tablets	½ tablet	Administered twice daily approximately 12 hours apart for 60 days.
  15 kg to less than 20 kg	62.5 mg	5 tablets
  20 kg to less than 30 kg	75 mg	6 tablets	¾ tablet
  30 kg to less than 40 kg	100 mg		1 tablet
  40 kg to less than 60 kg	150 mg		1 ½ tablets
  Greater than or equal to 60 kg	200 mg		2 tablets
  ).
  
  
• See Full Prescribing Information for important administration instructions (
  
  
  
  2.1 Important Administration Instructions

  • Benznidazole Tablets (12.5 mg and 100 mg) are for oral use and may be taken with or without food
    [see Clinical Pharmacology ]
    .
  • Benznidazole Tablets are dosed by body weight (kg)
    [see Dosage and Administration ]
    .
  • Benznidazole Tablets 100 mg are functionally scored tablets which can be split into one-half (50 mg) or one-quarter (25 mg) at the scored lines to provide doses less than 100 mg
    [see Instructions for Use]
    .
  • Benznidazole Tablets 12.5 mg and 100 mg can be made into slurry as an alternative method of administration
    [see Dosage and Administration ]
    .
  ,
  
  
  
  2.3 Assessment Prior to Initiating Benznidazole Tablets

  Obtain a pregnancy test in females of reproductive potential prior to therapy with Benznidazole Tablets

  [see Use is Specific Populations ]

  .
  ,
  
  
  
  2.4 Preparation of Slurry as an Alternative Method of Administration

  A. Preparation of Slurry Using Benznidazole Tablets 12.5 mg for the Pediatric Population with Body Weight Less Than 30 kg

  Benznidazole Tablets 12.5 mg may be made into slurry in a specified volume of water for the pediatric population with body weight less than 30 kg (see Table 2). The 12.5 mg tablet slurry is prepared by the following method:

  Table 2: Preparation and Administration of Slurry Using Benznidazole Tablets 12.5 mg for the Pediatric Population with Body Weight of Less than 30 kg

  Place the prescribed dose of Benznidazole Tablets 12.5 mg into a cup. Add the specified volume of water per number of 12.5 mg tablets as shown below.
  Body Weight Range (kg)	Dose (mg)	Number of Benznidazole Tablets 12.5 mg	Quantity of Water for Preparing the Slurry
  Less than 15 kg	50 mg	4 tablets	40 mL
  15 kg to less than 20 kg	62.5 mg	5 tablets	50 mL
  20 kg to less than 30 kg	75 mg	6 tablets	60 mL
  Allow the tablets to disintegrate in the cup over a period of approximately 1-2 minutes. Shake the contents of the cup gently to mix. Drink the contents of the cup (slurry of tablets with water) immediately. Rinse the cup with an additional 10 mL of water and drink the whole amount.

  B. Preparation of Slurry Using Benznidazole Tablets 100 mg for the Pediatric Population with Body Weight (30 kg or greater)

  Benznidazole Tablets 100 mg may be made into a slurry in a specified volume of water for the pediatric population with body weight of 30 kg or greater (see Table 3). The 100 mg tablet slurry is prepared as follows:

  Table 3: Preparation and Administration of Slurry Using Benznidazole Tablets 100 mg for the Pediatric Population with Body Weight 30 kg or greater

  Place the prescribed dose of Benznidazole Tablets 100 mg tablets into a cup. Add the specified volume of water per number of 100 mg tablets as shown below.
  Body Weight Range (kg)	Dose (mg)	Number of Benznidazole Tablets 100 mg	Quantity of Water for Preparing the Slurry
  30 kg to less than 40 kg	100 mg	1 tablet	80 mL
  40 kg to less than 60 kg	150 mg	1 ½ tablets	120 mL
  Greater than or equal to 60 kg	200 mg	2 tablets	160 mL
  Allow the tablet(s) to disintegrate in the cup over a period of approximately 1- 2 minutes. Shake the contents of the cup gently to mix. Drink the contents of the cup (slurry of tablet(s) with water) immediately. Rinse the cup by adding 80 mL of water and drink the whole amount. Repeat this rinse with 80 mL of water and drink again.
  ).
  
  

Benznidazole Tablets are available as 100 mg and 12.5 mg tablets.

The 100 mg white tablets are round and functionally scored twice as a cross on both sides, debossed with “E” on one side of each quarter portion.

The 12.5 mg white tablets are round and unscored, debossed with “E” on one side.

Lactation: Breastfeeding is not recommended (

• Potential Risk for Genotoxicity and Carcinogenicity (
  
  5.1 Potential for Genotoxicity and Carcinogenicity

  Genotoxicity

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

  [see Nonclinical Toxicology ]

  .

  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 2-fold compared to pre-dose values. In the same study, the mean incidence of chromosomal aberrations in 10 patients also increased 2-fold compared to pre-dose values.

  Carcinogenicity

  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

  [see Nonclinical Toxicology ]

  . It is not known whether benznidazole is associated with carcinogenicity in humans.
  ).
  
• Embryo-Fetal Toxicity: Can cause fetal harm. Pregnancy testing is recommended for females of reproductive potential. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception (
  
  2.3 Assessment Prior to Initiating Benznidazole Tablets

  Obtain a pregnancy test in females of reproductive potential prior to therapy with Benznidazole Tablets

  [see Use is Specific Populations ]

  .
  ,
  
  5.2 Embryo-Fetal Toxicity

  Based on findings from animal studies, Benznidazole Tablets can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, benznidazole administered orally to pregnant rats and rabbits during organogenesis was associated with fetal malformations at doses approximately 1-3 times the maximum recommended human dose (MRHD) in rats (anasarca, anophthalmia, and/or microphthalmia) and doses approximately 0.3-1 times the MRHD in rabbits (ventricular septal defect). In rats, reduced maternal weights and smaller litter sizes occurred at a dose approximately 3 times the MRHD. In rabbits, reduced maternal weight gain, and abortions in 2/20 females occurred at a dose approximately equal to the MHRD

  [see Use in Specific Populations ]

  . Advise pregnant women of the potential risk to a fetus. Pregnancy testing is recommended for females of reproductive potential

  [see Dosage and Administration ]

  . Advise females of reproductive potential to use effective contraception during treatment with Benznidazole Tablets and for 5 days after the last dose

  [see Use in Specific Populations and Clinical Pharmacology ]

  .
  ,
  
  8.1 Pregnancy

  Risk Summary

  Based on findings from animal studies, Benznidazole Tablets may cause fetal harm when administered to a pregnant woman. Published postmarketing reports on benznidazole use during pregnancy are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes. There are risks to the fetus associated with Chagas Disease

  (see Clinical Considerations)

  . In embryo-fetal development studies, benznidazole administered orally to pregnant rats and rabbits during organogenesis was associated with fetal malformations at doses approximately 1-3 times the MRHD in rats (anasarca, anophthalmia, and/or microphthalmia) and doses approximately 0.3-1.0 times the MRHD in rabbits (ventricular septal defect). In pregnant rats administered benznidazole during gestation and through lactation, effects in first generation offspring included reduced fertility in individual males and reduced numbers of live embryos and fetuses in pregnant females at a maternal dose equivalent to approximately 1.5 times the MRHD

  (see Data)

  . Advise pregnant women of the potential risk to a fetus.

  The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

  Clinical Considerations

  Disease-associated Maternal and/or Embryo/Fetal Risk

  Published data from case-control and observational studies on chronic Chagas disease during pregnancy are inconsistent in their findings. Some studies showed an increased risk of pregnancy loss, prematurity and neonatal mortality in pregnant women who have chronic Chagas disease while other studies did not demonstrate these findings. Chronic Chagas disease is usually not life-threatening. Since pregnancy findings are inconsistent, treatment of chronic Chagas disease during pregnancy is not recommended due to risk of embryo-fetal toxicity from Benznidazole Tablets.

  Acute symptomatic Chagas disease is rare in pregnant women; however, symptoms may be serious or life-threatening. There have been reports of pregnant women with life-threatening symptoms associated with acute Chagas disease who were treated with benznidazole. If a pregnant woman presents with acute symptomatic Chagas disease, the risks versus benefits of treatment with Benznidazole Tablets to the mother and the fetus should be evaluated on a case-by-case basis.

  Data

  Animal Data

  In an embryo-fetal toxicity study in pregnant rats, benznidazole was administered in oral doses of 15, 50, and 150 mg/kg/day during organogenesis (days 6-17 of gestation), and the high dose was associated with maternal weight loss, reduced fetal weights, and smaller litter sizes. Benznidazole was also associated with a low incidence of fetal malformations including anasarca in one fetus at a dose of 50 mg/kg/day and anasarca and eye abnormalities (anophthalmia and microphthalmia) in 5 fetuses in 5 litters at a high dose of 150 mg/kg/day (approximately equivalent to 1 and 3 times, respectively, the MRHD based on whole body surface area comparisons). No maternal toxicity was observed at a benznidazole dose of 50 mg/kg/day (approximately equal to the MRHD based on body surface area comparison), and no fetal toxicity was observed at a dose of 15 mg/kg/day (approximately equivalent to 0.3 times the MRHD based on whole body surface area comparison).

  In an embryo-fetal study in pregnant rabbits benznidazole administered by oral (gavage) in doses of 2.5, 7.5, and 25 mg/kg/day during organogenesis (days 6 to 19 of gestation) was associated with maternal toxicity at the high dose, including reduced weight gain and food consumption and abortions in 2/20 females. Benznidazole was also associated with a low incidence of fetal abnormalities including ventricular septal defect in 2 fetuses in 2 litters at a dose of 7.5 mg/kg/day and in 1 fetus at a dose of 25 mg/kg/day (approximately equivalent to 0.3 and 1 times respectively the MRHD based on whole body surface area comparison).The benznidazole doses that were not associated with maternal and fetal toxicity in this study were 7.5 and 2.5 mg/kg/day respectively, which are respectively equivalent to approximately 0.3 and 0.1 times the MRHD based on whole body surface area comparison.

  In a pre-postnatal study in rats, first generation (F₁) pups born to dams administered 15, 50, and 75 mg/kg/day benznidazole from day 6 of gestation to day 20 of lactation demonstrated normal pre-weaning behavior, physical and functional development, neurological findings, and reproductive parameters. However, cesarean section data for the pregnant first generation (F₁) females in the high-dose group included significantly higher pre-implantation loss and significantly lower mean values for corpora lutea counts, number of implantations, and number of live embryos. Also, small testes and/or epididymides were observed in 1/20 and 2/20 first generation males in the mid- and high-dose groups respectively, and two of the affected animals failed to mate or induce pregnancy. However, the mean values for mating performance, fertility index, testes weight, testes and epididymides sperm counts, and epididymal sperm motility and progression were not altered in any of the F₁males in benznidazole treatment groups. The number of live second generation (F₂) fetuses born to F₁dams was reduced in the high-dose group. The benznidazole dose that was not associated with adverse effects was considered to be 50 mg/kg/day which is approximately equal to the MRHD based on whole body surface area comparison.
  ,
  
  8.3 Females and Males of Reproductive Potential

  Pregnancy Testing

  Pregnancy testing is recommended for females of reproductive potential.

  Contraception

  Females

  Benznidazole Tablets can cause fetal harm when administered to a pregnant woman

  [see Use in Specific Populations ]

  . Advise females of reproductive potential to use effective contraception during treatment with Benznidazole Tablets and for 5 days after the final dose.

  Infertility

  Males

  Based on findings in rats, Benznidazole Tablets may impair fertility in males of reproductive potential. In rats, the effects on fertility were reversible 22 weeks after dosing; however, the effects in humans are unknown

  [see Nonclinical Toxicology ]

  .
  ).
  
• Hypersensitivity skin reactions have been reported with benznidazole. In case of skin reactions, presenting with additional symptoms of systemic involvement such as lymphadenopathy, fever and/or purpura, discontinuation of treatment is recommended (
  
  5.3 Hypersensitivity Skin Reactions

  Serious skin and subcutaneous disorders including acute generalized exanthematous pustulosis (AGEP), toxic epidermal necrolysis (TEN), erythema multiforme, and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported with benznidazole. Discontinue treatment at the first evidence of these serious cutaneous reactions

  [see Adverse Reactions ]

  .

  Extensive skin reactions, such as rash (maculopapular, pruritic macules, eczema, pustules, erythematous, generalized, and allergic dermatitis, exfoliative dermatitis) 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.
  ).
  
• Treatment with Benznidazole Tablets can potentially cause paresthesia or symptoms of peripheral neuropathy. In cases where neurological symptoms occur, immediate discontinuation of treatment is recommended (
  
  5.4 Central and Peripheral Nervous System Effects

  Treatment with 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.
  ).
  
• There have been hematological manifestations of bone marrow depression, such as neutropenia, thrombocytopenia, anemia, and leukopenia (
  
  5.5 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

  [see Adverse Reactions ]

  . 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.
  ).