Nifurtimox

Warning

H373 (100%): May causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]

P260, P319, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 24 reports by companies from 1 notifications to the ECHA C&L Inventory.；Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown. For more detailed information, please visit ECHA C&L website.

In multiple prospective controlled trials, nifurtimox therapy was not associated with elevations in aminotransferase or bilirubin levels or with instances of clinically apparent liver injury. Since approval of nifurtimox for American trypanosomiasis, there have been no individual reports of liver injury associated with its use.；Likelihood score: E (unlikely cause of clinically apparent liver injury when given in the recommended regimens for Chagas disease).

Drug Induced Liver Injury Rank (DILIrank 2.0)

Nifurtimox

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

◉ Summary of Use during Lactation；Limited information indicates that maternal doses of nifurtimox up to 15 mg/kg daily produce do not cause any adverse serious effects in breastfed infants. Breastmilk levels and a computer simulation found that the dose that an exclusively breastfed infant would receive through breastmilk would be much less than the dose given to treat Chagas disease in newborn infants. Other authors consider that breastfeeding is not contraindicated during the use of nifurtimox.；◉ Effects in Breastfed Infants；A cohort of 33 infants who were breastfed (extent not stated) by hospitalized mothers taking nifurtimox was followed in the Democratic Republic of the Congo. Thirty mothers took a full course of 30 doses of oral nifurtimox 15 mg/kg daily and all received 14 doses of intravenous eflornithine 400 mg/kg daily for 7 days for human African trypanosomiasis. (sleeping sickness). Nursing mothers also took a median of 4 other concomitant medications, including amoxicillin, ciprofloxacin, metronidazole, trimethoprim-sulfamethoxazole, aspirin, and diclofenac (1 patient each); hydrocortisone, promethazine and quinine (2 patients each); levamisole (6 patients); sulfadoxine-pyrimethamine (8 patients); dipyrone (13 patients); acetaminophen (16 patients); and mebendazole (17 patients). No serious adverse events were reported in any of the breastfed infants.；◉ Effects on Lactation and Breastmilk；Relevant published information was not found as of the revision date.

P - Antiparasitic products, insecticides and repellents；P01 - Antiprotozoals；P01C - Agents against leishmaniasis and trypanosomiasis；P01CC - Nitrofuran derivatives；P01CC01 - Nifurtimox

QP - Antiparasitic products, insecticides and repellents；QP51 - Antiprotozoals；QP51A - Agents against protozoal diseases；QP51AC - Nitrofuran derivatives；QP51AC01 - Nifurtimox

P01CC01

Nifurtimox exerts trypanosomal activity against Trypanosoma cruzi, treating Chagas disease. One study reports that nifurtimox and other benzofuran derivatives reduce parasite dehydrogenase activity. Results of a recent phase III clinical trial have shown that a significant number of pediatric patients with acute or chronic Chagas disease treated with nifurtimox were immunoglobulin G (IgG) antibody negative and demonstrated at least a 20% decrease in optical density on two IgG antibody tests for T. cruzi antigens.

The mechanism of action of nifurtimox has not been fully elucidated, however, is believed to occur by the activation of nitroreductase enzymes that produce reactive metabolites with a series of deleterious effects on Trypanosoma cruzi, the parasite causing Chagas disease. The antiprotozoal actions of nifurtimox occur both intracellularly and extracellularly. Inhibition of parasite dehydrogenase activity is another purported mode of action of nifurtimox that warrants further research.

Nifurtimox is largely metabolized via nitroreductase enzymes. Two major inactive metabolites have been identified: M-4 and M-6. The M-4 metabolite is a cysteine conjugate of nifurtimox, while M-6 is likely formed by hydrolytic cleavage of the hydrazone moiety of nifurtimox. Other minor metabolites have also been identified in human plasma.

The average AUC of nifurtimox is estimated between 1676-2670 μg∙h/L. One pharmacokinetic study of healthy volunteers revealed an AUC of 5430 ng∙ml-1∙h. Cmax ranges between 425-568 μg/L (26–50%) after a single dose of 20 mg with food in adults. Tmax is 4 hours, ranging from 2 to 8 hours post-dose in the fed state. In a pharmacokinetic study of healthy volunteers, serum concentration was low, likely due to the first-pass effect.

In the fed state, 44% of the dose was mainly recovered in the urine as metabolites. Fecal and biliary excretion of nifurtimox have not been studied.

Nifurtimox crosses the blood-brain barrier and the placenta.

One pharmacokinetic study of nifurtimox revealed a clearance of 193.4 l∙h^-1. In patients without renal failure; clearance was 99.7 l∙h^-1.