nifurtimox (Rx)

>10%

Vomiting (14.6%)

Abdominal pain (13.2%)

Headache (12.8%)

Decreased appetite (10.5%)

1-10%

Nausea (8.2%)

Pyrexia (7.3%)

Rash (5.5%)

Diarrhea (4.6%)

Decreased weight (2.7%)

Dizziness (2.7%)

Anemia (2.7%)

Urticaria (2.3%)

Eosinophilia (2.3%)

<1%

Vertigo

Arthralgia

Myalgia

Paresthesia

Tremor

Irritability

Anxiety

Pruritus

Fatigue

Somnolence

Seizure

Syncope

Neutropenia

Leukopenia

Postmarketing Reports

Hypersensitivity reactions, including anaphylaxis

Vertigo

Angioedema

Drug reaction with eosinophilia and systemic symptoms (DRESS)

Muscle weakness

Amnesia

Polyneuropathy

Apathy

Agitation

Psychotic behavior

Sleep disorder

Thrombocytopenia

Contraindications

Hypersensitivity to nifurtimox or any of the excipients

Alcohol consumption during treatment

Cautions

Genotoxicity has been demonstrated in humans, in vitro in several bacterial species and mammalian cell systems, and in vivo in rodents; a study in treated children with Chagas disease aged 7 months to 14 years demonstrated a 13-fold increase in chromosomal aberrations

Carcinogenicity has been observed in mice and rats treated chronically with nitrofuran agents which are structurally similar to nifurtimoximilar data have not been reported; association with carcinogenicity is unknown

May cause fetal harm when administered to pregnant females

May worsen conditions in patients with history of brain injury, seizures, psychiatric disease, or serious behavioral alterations; closely monitor these patients and in patients who develop neurological disturbances or psychiatric drug reactions during treatment

Cases of hypersensitivity reported; reaction may be induced by nifurtimox or an immune response triggered by Chagas disease during treatment; at first sign of serious hypersensitivity, discontinue treatment

Decreased appetite and weight loss were reported; patients can lose their appetite or experience nausea/vomiting which can result in weight loss; check body weight every 14 days and adjust dose accordingly

Nitrofuran derivatives may precipitate acute attacks of porphyria; administer tablets under close medical supervision in patients with porphyria

Drug interaction overview

• Alcohol

  • Alcohol consumption during treatment is contraindicated
  • Alcohol may increase the incidence and severity of undesirable effects similar to other nitrofurans and nitroheterocyclic compounds

Pregnancy

Based on animal studies, may cause fetal harm when administered to pregnant females

Published postmarketing reports on use during pregnancy are insufficient to inform a drug-associated risk of birth defects and miscarriage

Pregnancy test recommended before initiating treatment

Report drug exposure

• If administered during pregnancy
• If patient becomes pregnant during treatment or within 6 months following last dose
• Report exposure by calling 1-888-842-2937

Animal data

• Administered orally during organogenesis was associated with reduced fetal body weights in mice, reduced maternal and fetal body weights in rats
• Treatment with nifurtimox did not produce fetal toxicity and no nifurtimox-related fetal malformations were observed
• Abortions, reduced maternal weight gain, and reduced numbers of live fetuses in rabbits when orally administered during organogenesis at doses approximately equal to the MRHD in rodents 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 ~0.2x the MRHD
• Advise pregnant women of the potential risk to a fetus

Disease-associated maternal and/or embryo/fetal risk

• Published data from studies on chronic Chagas disease during pregnancy are inconsistent
• Treatment of chronic Chagas disease during pregnancy is not recommended
• Acute symptomatic Chagas disease is rare in pregnant females; however, symptoms may be serious or life-threatening
• If a pregnant female presents with acute symptomatic Chagas disease, evaluate the risks versus benefits of treatment to the mother and the fetus

Contraception

• Females of reproductive potential: Use effective contraception during treatment and for 6 months after final dose
• Males with female partners of reproductive potential: Use condoms during treatment and for 3 months after final dose

Infertility

• May impair fertility in males of reproductive potential
• Effects were not reversible in 75% of animals at 11 weeks after dosing

Lactation

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

No adverse effects reported on the small number of infants who were breastfed by treated mothers

There is no information on the effects of nifurtimox on milk production

Monitor infants for vomiting, rash, decreased appetite, pyrexia and irritability if exposed to drug

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Antiprotozoal agent

Mechanism of action is not fully understood

May react with the nucleic acids of the parasite and inhibits trypanothione reductase, a parasite-specific antioxidant defense enzyme

Absorption

Peak plasma time: 4 hr

Peak plasma concentration: 425-568 mcg/L (single 120-mg dose)

AUC: 1676-2670 mcg⋅hr/L (single 120-mg dose)

Effects of food

• Following a single 120-mg dose in adults, peak plasma concentration increased 68%, AUC increased 71%, and peak plasma time increased by 1 hr with a high-fat meal (800–1000 calorie, ~60% fat) compared to fasted conditions

Distribution

Passes blood brain barrier and placental barrier

Protein bound: 42%

Metabolism

Primarily mediated via nitroreductases

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

Elimination

Half-life: 2.4-3.6 hr

Excretion H4

Urine: ~44% (fed state); ~27% (fasted state); recovered mainly as metabolites

Oral Administration

Administer with food

Tablets are functionally scored; may be split into one-half (eg, 15 mg and 60 mg respectively) at scored lines by hand; do not break tablets mechanically with a tablet splitting device

Unable to swallow whole or half tablets

• Prepare a slurry as an alternate method of administration
• Disperse prescribed dose in ~2.5 mL of water into a spoon
• Allow tablet(s) to disintegrate (typically less than 30 seconds; forms a slurry (liquid suspension)
• Administer slurry immediately with food

Missed dose

• >3 hr of next scheduled dose: Take as soon possible
• ≤3 hr of next scheduled dose: Skip missed dose and continue treatment as prescribed; do not take a double dose to make up for a missed dose

Storage

Store at controlled room temperature 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF)

Store tablets in the original bottle with child-resistant closures and do not remove the desiccant

Keep bottle with tightly closed and protect from moisture