Nifurtimox is an oral antiprotozoal agent used for the treatment of American trypanosomiasis (Chagas disease) caused by Trypanosoma cruzi, a disease that is rare in the US. Cases may occur in laboratory workers, immigrants, and US citizens returning from travel to Latin America. Nifurtimox is only FDA-approved in pediatric patients from birth to 17 years; however, it is used off-label in all populations. The efficacy of nifurtimox was demonstrated in pediatric patients 0 to 4 years of age in a prospective, randomized, double-blind trial based on seroconversion to negative confirmed on 3 assays (lysate ELISA, recombinant ELISA, and IHA) at 4 years post-treatment compared to untreated patients. The efficacy of nifurtimox in pediatric patients 5 to 17 years of age was extrapolated from efficacy established in the younger pediatric population as it is expected that nifurtimox would have the same effect on T. cruzi in all pediatric age groups. Supportive evidence of efficacy was provided by data on seroconversion to negative by the F29 ELISA. Of note, based on published studies, younger pediatric patients seroconvert faster. Older pediatric patients may have a longer duration of infection than younger patients, and thus the time to seroconversion is expected to be longer in these patients. It is expected that seroconversion rates would increase in older pediatric age groups over time. Nifurtimox is also used off-label for the treatment of African trypanosomiasis (sleeping sickness) due to Trypanosoma brucei gambiense with CNS involvement in combination with eflornithine.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
-If a dose is missed, take the missed dose as soon as possible together with food. However, if it is within 3 hours of the next scheduled dose, skip the missed dose, and continue treatment as prescribed. Do not take a double dose to make up for a missed dose.
-If vomiting occurs within 30 minutes after administration of the dose, repeat the same dose. If vomiting occurs 30 to 60 minutes after administration, administer half the dose. If vomiting occurs more than 60 minutes after the dose, consider that the dose has been fully absorbed.
Route-Specific Administration
Oral Administration
-Must be taken with food.
-Check body weight every 14 days during treatment to ensure the correct dosage of nifurtimox is administered. Decreased appetite and weight loss were reported in patients treated with nifurtimox in clinical trials.
Oral Solid Formulations
Instructions for splitting tablets
-Do not break tablets mechanically with a tablet splitting device. A functional score line is used to divide the tablet by hand as follows:
--To split the tablet, place the tablet on a flat surface with the score line facing up.
-With the tablet resting on the flat surface, apply enough downward pressure with the index finger centered on the top of the tablet to break it along the score line.
Extemporaneous Compounding-Oral
Preparation of a slurry
-For patients who are unable to swallow whole or half tablets, nifurtimox tablet can be dispersed in water and administered as outlined below.
--Place approximately 2.5 mL of water into a spoon.
-Place the prescribed dose into the water.
-Allow the tablet(s) to disintegrate (typically less than 30 seconds).
-A slurry (liquid suspension) is formed.
-Take the slurry immediately with food.
GI-related adverse reactions reported in pediatric patients treated with nifurtimox for 60 days in a clinical trial were vomiting (14.6%), abdominal pain (13.2%), nausea (8.2%), and diarrhea (4.6%). Decreased appetite or anorexia (10.5%) and weight loss (2.7%) were also reported. During treatment with nifurtimox, patients can lose their appetite or experience nausea/vomiting, which can result in weight loss. Check body weight every 14 days, as the dosage may have to be adjusted in these patients.
Hematologic adverse reactions reported in pediatric patients treated with nifurtimox for 60 days in a clinical trial were anemia (2.7%) and eosinophilia (2.3%). Other hematologic adverse reactions occurring in 0.1% to less than 1% of patients treated with nifurtimox for 60 days included neutropenia and leukopenia. Thrombocytopenia has been reported with nifurtimox in postmarketing surveillance.
Hypersensitivity reactions reported in pediatric patients treated with nifurtimox for 60 days in a clinical trial were rash (macular rash, maculopapular rash, morbilliform rash, and papular rash; 5.5%), urticaria (2.3%), and pruritus (0.1% to less than 1%). Fever was reported in 7.3% of patients. Serious hypersensitivity reactions, including anaphylaxis, hypotension, angioedema (including laryngeal edema or facial edema), dyspnea, drug reaction with eosinophilia and systemic symptoms (DRESS), or other severe skin reactions have been reported with nifurtimox in postmarketing surveillance. The hypersensitivity could be a reaction induced by nifurtimox or an immune response triggered by Chagas disease during treatment. Discontinue treatment with nifurtimox at the first sign of serious hypersensitivity reaction.
CNS-related adverse reactions reported in pediatric patients treated with nifurtimox for 60 days in a clinical trial were headache (12.8%) and dizziness (2.7%). Other CNS-related adverse reactions occurring in 0.1% to less than 1% of patients treated with nifurtimox for 60 days included asthenia, vertigo, paresthesias, tremor, fatigue, somnolence or drowsiness, seizures, and syncope. Amnesia and polyneuropathy have been reported with nifurtimox in postmarketing surveillance.
Psychiatric adverse reactions occurring in 0.1% to less than 1% of pediatric patients treated with nifurtimox for 60 days in a clinical trial included irritability and anxiety. Apathy, agitation, psychotic behavior, and sleep disorder have been reported with nifurtimox in postmarketing surveillance.
Musculoskeletal adverse reactions occurring in 0.1% to less than 1% of pediatric patients treated with nifurtimox for 60 days in a clinical trial included arthralgia and myalgia. Myasthenia has been reported with nifurtimox in postmarketing surveillance.
Nifurtimox is contraindicated in patients with known hypersensitivity to nifurtimox or any components of the product. Cases of hypersensitivity reactions, including anaphylaxis, hypotension, angioedema (including laryngeal or facial edema), dyspnea, pruritus, rash, or other severe skin reactions, have been reported in patients receiving therapy with nifurtimox. The hypersensitivity could be a reaction induced by nifurtimox or an immune response triggered by Chagas disease during treatment. Discontinue treatment with nifurtimox at the first sign of a serious hypersensitivity reaction.
Use nifurtimox with caution in patients with a history of neurological disease, brain injury or head trauma, seizures or seizure disorder, psychiatric disease or psychiatric event, or serious behavioral changes. These patients may experience worsening of their conditions when receiving nifurtimox. Administer nifurtimox under close medical supervision in patients who develop neurologic events or psychiatric drug reactions during treatment.
Use nifurtimox with caution in patients with porphyria. Treatment with nitrofuran derivatives, such as nifurtimox, may precipitate acute attacks of porphyria.
Ethanol ingestion or consumption of products containing alcohol is contraindicated in patients receiving nifurtimox due to the risk of undesirable effects (abdominal cramps, nausea, vomiting, headaches, and flushing) similar to other nitrofurans and nitroheterocyclic compounds. Counsel patients on the importance of avoiding alcohol.
Published postmarketing reports on nifurtimox use during human pregnancy are insufficient to inform a drug-associated risk of birth defects and miscarriage. 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. Since pregnancy findings are inconsistent, the treatment of chronic Chagas disease during pregnancy is not recommended due to the risk of embryo-fetal toxicity from nifurtimox. Acute symptomatic Chagas disease is rare in pregnant women; however, symptoms may be serious or life-threatening. If a pregnant woman presents with acute symptomatic Chagas disease, evaluate the risks versus benefits of treatment with nifurtimox to the mother and the fetus on a case-by-case basis. Advise pregnant women of the potential risk to the fetus with nifurtimox treatment. There is a pregnancy safety study for nifurtimox. If nifurtimox is administered during pregnancy, or if a patient becomes pregnant while receiving nifurtimox or within 6 months after the last dose, health care providers should report nifurtimox exposure by calling 1-888-842-2937. Based on animal findings, nifurtimox may cause fetal harm when administered to a pregnant woman. In animal reproduction studies, nifurtimox administered orally during organogenesis was associated with reduced maternal body weights in rats, and abortions, reduced maternal weight gain, and reduced numbers of live fetuses in rabbits at doses approximately equal to the maximum recommended human dose (MRHD) in rats and 2-times the MRHD in rabbits. An increased incidence of a fetal skeletal malformation (fusion of caudal vertebral bodies) occurred in rabbits at nifurtimox doses approximately 0.2 times the MRHD. In a pre-postnatal study, maternal body weights and fetal body weights of first-generation offspring were reduced at doses approximately equal to or 0.5 times the MRHD, respectively, and several male offspring in the nifurtimox treatment groups exhibited slightly small testes at doses 0.2 times or more the MRHD.
Counsel patients of appropriate age about the reproductive risk associated with nifurtimox and contraception requirements. Females of reproductive age are advised to use effective contraception during treatment and for at least 6 months after the last dose. Male patients with female partners of reproductive potential should use condoms during treatment and for 3 months after the final dose of nifurtimox. Pregnancy testing is recommended for females of reproductive age prior to treatment initiation with nifurtimox. In addition, based on animal data, nifurtimox may cause infertility in males of reproductive age; these effects on fertility were not reversible in 75% of the animals at 11 weeks after dosing.
Published literature demonstrates that nifurtimox is present in human breast milk with an estimated infant daily dose of less than 15% of the recommended daily dose for pediatric patients with Chagas disease. There were no reports of adverse reactions on the small number of infants who were breastfed by mothers taking nifurtimox. There is no information on the effects of nifurtimox on milk production. Monitor infants exposed to nifurtimox through breast milk for vomiting, rash, decreased appetite, fever, and irritability. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Although not reported with nifurtimox, nitrofuran agents, which are structurally similar to nifurtimox, have been reported to be carcinogenic in mice and rats. It is not known whether nifurtimox is associated with carcinogenicity in humans. Also, nifurtimox has shown mutagenic activity in humans, animal studies, and a number of in vitro assay systems. In a study evaluating the cytogenetic effect of nifurtimox in pediatric patients ranging in age from 7 months to 14 years with Chagas disease, a 13-fold increase in chromosomal aberrations was noted. Human data are not available to describe the potential for neoplastic disease secondary to nifurtimox use.
Advise patients receiving nifurtimox that if muscle weakness or tremors occur during treatment, they should avoid driving or operating machinery or other activities, such as cycling.
General dosing information:
-Check body weight every 14 days during treatment to ensure the correct dosage of nifurtimox is administered. Decreased appetite and weight loss were reported in patients treated with nifurtimox in clinical trials.
This drug may also have activity against the following microorganisms: Trypanosoma brucei gambiense, Trypanosoma cruzi
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.
For the treatment of American trypanosomiasis (Chagas disease):
Oral dosage:
Adults*: 8 to 10 mg/kg/day (Max: 900 mg/day) PO divided 3 times daily for 60 days.
Adolescents weighing 91 kg or more: 8 to 10 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 300 mg PO 3 times daily is recommended.
Adolescents weighing 71 to 90 kg: 8 to 10 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 240 mg PO 3 times daily is recommended.
Children and Adolescents weighing 51 to 70 kg: 8 to 10 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 180 mg PO 3 times daily is recommended.
Children and Adolescents weighing 41 to 50 kg: 8 to 10 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 120 mg PO 3 times daily is recommended.
Children and Adolescents weighing 35 to 40 kg: 10 to 20 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 180 mg PO 3 times daily is recommended.
Children and Adolescents weighing 27 to 34 kg: 10 to 20 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 120 mg PO 3 times daily is recommended.
Children weighing 22 to 26 kg: 10 to 20 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 90 mg PO 3 times daily is recommended.
Children weighing 18 to 21 kg: 10 to 20 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 75 mg PO 3 times daily is recommended.
Children weighing 13 to 17 kg: 10 to 20 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 60 mg PO 3 times daily is recommended.
Infants and Children weighing 9 to 12 kg: 10 to 20 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 45 mg PO 3 times daily is recommended.
Term Neonates and Infants weighing 4.6 to 8 kg: 10 to 20 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 30 mg PO 3 times daily is recommended.
Term Neonates and Infants weighing 2.5 to 4.5 kg: 10 to 20 mg/kg/day PO divided 3 times daily for 60 days; for ease of administration, a dose of 15 mg PO 3 times daily is recommended.
For the treatment of second-stage (meningoencephalitic) African trypanosomiasis (sleeping sickness)* due to T. brucei gambiense:
Oral dosage:
Adults: 5 mg/kg/dose PO every 8 hours for 10 days in combination with eflornithine (NECT).
Infants, Children, and Adolescents: 5 mg/kg/dose PO every 8 hours for 10 days in combination with eflornithine (NECT).
Maximum Dosage Limits:
-Adults
Safety and efficacy have not been established; however, doses up to 15 mg/kg/day PO have been used off-label.
-Geriatric
Safety and efficacy have not been established; however, doses up to 15 mg/kg/day PO have been used off-label.
-Adolescents
weight 41 kg or more: 10 mg/kg/day PO (Max: 900 mg/day) is FDA-approved maximum; however, doses up to 15 mg/kg/day PO have been used off-label.
weight less than 41 kg: 20 mg/kg/day PO.
-Children
weight 41 kg or more: 10 mg/kg/day PO (Max: 900 mg/day) is FDA-approved maximum; however, doses up to 15 mg/kg/day PO have been used off-label.
weight less than 41 kg: 20 mg/kg/day PO.
-Infants
20 mg/kg/day PO.
-Neonates
weight 2.5 kg or more: 20 mg/kg/day PO.
weight less than 2.5 kg: Safety and efficacy have not been established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; administer nifurtimox under close medical supervision in patients with hepatic impairment.
Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment are not available. Published data suggest that blood concentrations of nifurtimox were increased in patients with end-stage renal disease requiring hemodialysis; administer nifurtimox under close medical supervision in patients with renal impairment.
*non-FDA-approved indication
Ethanol: (Contraindicated) Nifurtimox is contraindicated in patients who consume alcohol during treatment. Concomitant use of nifurtimox with alcohol may increase the incidence and severity of undesirable effects (i.e., abdominal cramps, nausea, vomiting, headaches, and flushing) similar to other nitrofurans and nitroheterocyclic compounds. (Moderate) Although the injection of alcohol used for therapeutic procedures is not expected to produce significant systemic effects of ethanol, use caution with concomitant use of nifurtimox. Disulfiram-like side effects, including nausea, vomiting, tachycardia, headache, flushing, and abdominal cramps, may occur.
The mechanism of action of nifurtimox is not fully understood. Studies suggest that nifurtimox is metabolized/activated by Type I (oxygen insensitive) and Type II (oxygen-sensitive) nitoreductases (NTR), leading to the production of toxic intermediate metabolites and/or reactive oxygen species that induce DNA damage and cell death of both intracellular and extracellular forms of T. cruzi. Nifurtimox is active against all three stages, trypomastigotes, amastigotes, and epimastigotes, of T. cruzi. However, the sensitivity of T. cruzi strains to nifurtimox, from different geographic regions, may vary.
In vitro studies suggest the potential for the development of resistance in T. cruzi against nifurtimox. The mechanism of resistance to nifurtimox appears to be multifactorial. Trypanosomal nitroreductase is defined as a key resistance determinate. Either loss of gene copy, mutation of gene, or down-regulation of gene expression are sufficient to cause decreased susceptibility of T. cruzi against nitroheterocyclic drugs like nifurtimox. In addition, other mechanisms of resistance like lower drug influx or higher drug efflux are described. However, the clinical relevance of these findings is unknown.
Nonclinical studies suggest cross-resistance between nifurtimox and benznidazole. This appears to be due to downregulation of Type I NTR localized in the mitochondria.
Nifurtimox is administered orally. Nifurtimox passes the blood-brain barrier as well as the placental barrier. The plasma protein binding of nifurtimox is 42%. Metabolism of nifurtimox is primarily mediated via nitroreductases. Analyses identified 2 major pharmacologically inactive metabolites (M-4, M-6) and several other minor metabolites in pooled human plasma. M-4 is a rearranged cysteine conjugate of nifurtimox with a half-life of approximately 28 hours, and M-6 is postulated to be formed by hydrolytic cleavage of the hydrazone moiety with a half-life of approximately 10 hours. After the administration of nifurtimox under fed and fasted conditions, approximately 44% and 27% of the dose was recovered in the urine mainly as metabolites, respectively. Biliary and fecal elimination of nifurtimox and its metabolites has not been evaluated. The mean (%CV) estimates for elimination half-life of nifurtimox ranged between 2.4 to 3.6 hours (12% to 37%).
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Oral Route
The mean (%CV) nifurtimox AUC estimates ranged between 1,676 to 2,670 mcg x hour/L (19% to 32%) and Cmax estimates ranged between 425 to 568 mcg/L (26% to 50%) after administration of a single oral dose of 120 mg nifurtimox with food in adult Chagas patients. No clinically significant differences in nifurtimox AUC or Cmax at the 120 mg dose were observed when using 2 tablet strengths (30 and 120 mg) or administered as whole or dissolved tablets under fed conditions. The median time to reach maximum concentration (Tmax) of nifurtimox under fed conditions was 4 hours (range: 2 to 8 hours).
Effect of food
After administration of a single oral dose of 120 mg nifurtimox in adult Chagas patients, nifurtimox Cmax increased 68%, AUC increased 71%, and Tmax increased by 1 hour with a high-fat meal (800 to 1,000 calorie, approximately 60% fat) compared to fasted conditions.
-Special Populations
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of nifurtimox is unknown.
Renal Impairment
The effect of renal impairment on the pharmacokinetics of nifurtimox is unknown. Blood concentrations of nifurtimox were increased in patients with end-stage renal disease requiring hemodialysis.