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Breast Feeding; Lactation; Milk, Human; Anti-Infective Agents; Antiprotozoal Agents; Nitroimidazoles

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Medicines for the treatment of 1st stage African trypanosomiasis

Warning

H302 (100%): Harmful if swallowed [Warning Acute toxicity, oral]

P261, P264, P270, P271, P280, P301+P317, P302+P352, P304+P340, P317, P321, P330, P362+P364, and P501 (click each P-code to see the statement)

The GHS information provided by 1 company from 1 notification to the ECHA C&L Inventory.

Fexinidazole therapy was not associated with elevations in aminotransferase or bilirubin levels or with clinically apparent liver injury during the ten day regimens used to treat African trypanosomiasis. However, evaluation of longer courses of therapy and use of higher doses in Chagas disease caused by Trypanosoma cruzi demonstrated several instances of ALT or AST elevations above 3 times the upper limit of normal (ULN), which persisted for as long as 3 months after stopping fexinidazole. The enzyme elevations were usually hepatocellular and arose after 2 weeks of therapy. The liver injury was asymptomatic and not associated with jaundice or with rash, fever or other signs of hypersensitivity. Nevertheless, the hepatic injury as well as delayed neutropenia led to discontinuation of the clinical trials of fexinidazole in high doses in Chagas disease. Since approval of fexinidazole for African trypanosomiasis, there have been no individual reports of liver injury associated with its use.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Fexinidazole

Ambiguous-DILI-concern

3

Warnings & precautions

DOI:10.1016/j.drudis.2016.02.015

P - Antiparasitic products, insecticides and repellents

P01CA03

Fexinidazole is a 2-substituted 5-nitroimidazole that is likely activated by parasitic nitroreductases to highly reactive species, leading to DNA and protein damage and eventual parasite death. The dosing schedule is designed to ensure a high enough concentration of fexinidazole and its reactive metabolites for at least 48 hours, which from _in vitro_ studies was shown to be the minimum exposure time that was effectively trypanocidal. Although fexinidazole is effective in late-stage _T. brucei gambiense_ HAT, it is less effective than NECT therapy in patients with severe (cerebrospinal fluid white blood cell count (CSF-WBC) >100 cells/μL at baseline) disease. It should only be used in these patients if there are no other available treatment options. Fexinidazole has been shown to prolong the QT interval in a dose-dependent manner and was also associated with a higher incidence of insomnia, headache, tremors, psychiatric disorders, and suicidal ideation in clinical trials; patients with pre-existing conditions or concomitant medications that could aggravate any of these effects should be treated with caution. In addition, fexinidazole has been associated with neutropenia and elevations in liver transaminases, which should be monitored. Nitroimidazoles like fexinidazole have been associated with a disulfiram-like reaction when used concomitantly with alcohol and psychotic reactions when taken with [disulfiram] itself; patients should avoid alcohol and [disulfiram] when taking fexinidazole.

Human African trypanosomiasis (HAT) is caused by two subspecies of _Trypanosoma brucei_, _T. brucei gambiense_ and _T. brucei rhodesiense_, with _T. brucei gambiense_ HAT accounting for ~97% of the total disease burden. Transmitted by the bite of an infected tsetse fly, HAT begins as a local infection at the bite site before disseminating throughout the blood and reticuloendothelial system (first or hemolymphatic stage) and eventually crossing the blood-brain barrier (second or meningoencephalitic stage). First stage _T. brucei gambiense_ HAT is characterized by fever, headache, swollen lymph nodes, pruritus, and other non-specific symptoms. Progression to the second stage results in progressive deterioration of neurological function, including sleep disturbances (HAT is also referred to as sleeping sickness), tremors, ataxia, abnormal behaviour, confusion, and coma; myocarditis and endocrine hypothalamic-hypophyseal dysfunction may also be present. If left untreated, HAT is fatal. Fexinidazole is the first all-oral treatment for _T. brucei gambiense_ HAT. Both fexinidazole and its two main metabolites, a sulfoxide (M1) and sulfone (M2) metabolite, possess _in vitro_ activity against _T. brucei gambiense_, _T. brucei rhodesiense_, and _T. brucei brucei_ in the 0.2-0.9 μg/mL range. Further studies revealed _in vivo_ efficacy in HAT animal models and acceptable toxicity profiles, both in animal and human subjects. Crucially, fexinidazole was shown to be non-inferior to existing [nifurtimox]/[eflornithine] combination therapy (NECT) in late-stage _T. brucei gambiense_ infection. The precise mechanism of action of fexinidazole remains unknown. However, it is suggested that bacterial-like nitroreductases encoded by trypanosomes activate fexinidazole and its M1/M2 metabolites through reduction to form reactive intermediates capable of damaging DNA and proteins. Whole-body autoradiography of [14C]-labelled fexinidazole in rats revealed broad distribution into all tissues, including an observed brain-to-blood concentration ratio of 0.4-0.6. Therefore, fexinidazole is capable of direct toxicity against trypanosomes throughout the body and in the brain, which is consistent with its efficacy against both early and late-stage infections.