此次FDA是通过加速批准程序批准Benznidazole的。加速批准通道允许FDA基于一种合理可能预测患者临床获益的代理终点而批准药物用于有未满足医疗需求的严重疾病。需要进一步的研究来验证和描述 Benznidazole 的预期临床获益。
FDA授予了Benznidazole 优先审评与孤儿药资格。这些资格的授予源于查加斯病是一种罕见疾病，到目前为止，美国还没有获批用于查加斯病的药物。随着这次的批准，Benznidazole 制造商Chemo Research被授予了一张热带疾病优先评审券，FDA此举的目的是鼓励用于预防和治疗某些热带疾病新药及生物产品的开发。
Benznidazole(Benznidazole Tablets, for Oral Use)
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
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.
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.
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.