DRUG INTERACTIONS 

1.Disulfiram Psychotic reactions have been reported in patients who are concurrently taking disulfiram and nitroimidazole agents (structurally related to benznidazole, but not with benznidazole).

Benznidazole Tablets should not be given to patients who have taken disulfiram within the last two weeks [see Contraindications (4.2)].

2. Alcohol and Products Containing Propylene Glycol-                                     Abdominal cramps, nausea, omiting, headaches, and flushing may occur if alcoholic beverages or products containing propylene glycol are consumed during or following therapy with nitroimidazole agents which are structurally related to benznidazole. 

Although no similar reactions have been reported with benznidazole, discontinue alcoholic beverage or products containing propylene glycol during and for at least 3 days after therapy with Benznidazole Tablets 

U.S. FDA APPROVED  DRUGS DURING 2017

ADVERSE REACTIONS

Most common adverse reactions observed were -

abdominal pain, rash, decreased weight, headache, nausea, vomiting, neutropenia, urticaria, pruritus, eosinophilia, decreased appetite 

WARNINGS AND PRECAUTIONS

­ • Potential Risk for Genotoxicity and Carcinogenicity 

. • 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 

• 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

. • 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 

• There have been hematological manifestations of bone marrow depression, such as neutropenia, thrombocytopenia, anemia, and leukopenia 

 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Instructions for Use).

Embryo-Fetal Toxicity -                                                                                             Advise pregnant women and females of reproductive potential that exposure to Benznidazole Tablets during pregnancy can result in fetal harm.                               

Advise females to inform their healthcare provider of a known or suspected pregnancy

Advise females of reproductive potential to use effective contraception while taking Benznidazole Tablets and for 5 days after the last dose

 Lactation-                                                                                                                   Advise women not to breastfeed during treatment with Benznidazole Tablets   

Infertility-                                                                                                                   Advise males of reproductive potential that Benznidazole Tablets may impair fertility

Important Administration Instructions-                                                            -         Advise patients and parents/caregivers of pediatric patients taking Benznidazole Tablets that:                                                                                                                                      • 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.                                                                                                                                • Benznidazole Tablets 12.5 mg and 100 mg (whole or split) can be made into a slurry in a specified volume of water for the pediatric population .

Hypersensitivity Skin Reactions-                                                                             Advise patients that serious skin reactions can occur with Benznidazole Tablets. In case of skin reactions, presenting with additional symptoms of systemic involvement such as lymphadenopathy, fever and/or purpura, discontinuation of treatment is necessary.

Central and Peripheral Nervous System Effects-                                                  Advise patients that treatment can potentially cause paresthesia or symptoms of peripheral neuropathy. In cases where neurological symptoms occur, immediate discontinuation of treatment is recommended.

Hematological Manifestations of Bone Marrow Depression-                                 Advise patients that there have been hematological manifestations of bone marrow depression, such as anemia and leukopenia, which are reversible, and normalized after treatment discontinuation.

Interaction with Alcohol-                                                                                             Advise patients to discontinue consumption of alcoholic beverages or products containing propylene glycol while taking Benznidazole Tablets and for at least three days afterward because abdominal cramps, nausea, vomiting, headaches, and flushing may occur.

Manufactured for Chemo Research, S.L. Madrid, Spain

Manufactured by Laboratorios Liconsa S.A. Guadalajara, Spain Distributed by: Exeltis USA, Inc. Florham Pa

 CLINICAL PHARMACOLOGY

1. Mechanism of Action

Benznidazole is a nitroimidazole antimicrobial drug 

2. Pharmacodynamics-                                                                                                 The pharmacodynamics of benznidazole is unknown.

3.Pharmacokinetics-

Absorption-                                                                                                                      The absorption of benznidazole from three different 100 mg benznidazole preparations was comparable when administered as a single dose under fasting conditions in adult healthy volunteers

Effect of Food-                                                                                                  Benznidazole Cmax and AUC were not affected by the administration of Benznidazole 100 mg tablet with a high-fat, high-caloric meal (approximately 1034 total kcal, 67 kcal from fat, 42 kcal from carbohydrates, 59 kcal from protein) compared with fasted conditions in adult healthy volunteers.

Serum concentrations of benznidazole reached peak levels at 3.2 hours (1-10 hours) after administration of Benznidazole Tablets 100 mg tablet after a high-fat, high-caloric meal, and at 2.0 hours (0.5-4 hours) in fasted conditions

 Distribution-                                                                                                                Protein binding is reported to be approximately 44 to 60 %.

Elimination-                                                                                                                    The elimination half-life of benznidazole is approximately 13 hours in healthy volunteers following single dose.

Metabolism-                                                                                                    Benznidazole metabolism pathway is unknown.

Excretion-                                                                                                         Benznidazole and unknown metabolites are reported to be excreted in the urine and feces

 Specific Populations-                                                                                                   The effect of sex, race, renal impairment, or hepatic impairment on the pharmacokinetics of benznidazole is unknown.

Drug Interaction Studies-                                                                                                In vitro studies showed that benznidazole is a P-gp substrate and does not notably induce Cytochrome P450 enzymes 1A2, 2B6, and 3A4 at concentrations up to 100 uM. 

 USE IN SPECIFIC POPULATIONS

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).

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 2-4% and 15-20%, 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 embryofetal toxicity from Benznidazole Tablets.

 2.Lactation Risk Summary-                                                                                    Limited published literature based on breast milk sampling reports that benznidazole is present in human milk at infant doses of 5.5 to 17% of the maternal weight-adjusted dosage and a milk/plasma ratio ranging between 0.3­ 2.79.

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.

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 . 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 rodents, Benznidazole Tablets may impair fertility in males of reproductive potential. It is not known whether effects on fertility are reversible 

4.Pediatric Use                                                                                                              The safety and effectiveness of Benznidazole Tablets have been established in pediatric patients 2 to 12 years of age for the treatment of Chagas disease.

Use in pediatric patients 2 to 12 years of age was established in two adequate and well-controlled trials in pediatric patients 6 to 12 years old with additional safety and pharmacokinetic data from pediatric patients 2 to 6 years of age.

 Safety and effectiveness in pediatric patients below the age of 2 years and above the age of 12 years have not been established.

5.Hepatic Impairment-                                                                                                  Use of Benznidazole Tablets has not been evaluated in patients with hepatic impairment.

6. Renal Impairment-                                                                                                      Use of Benznidazole Tablets has not been evaluated in patients with renal impairment.