Fexinidazole (Monograph)

Brand name: Fexinidazole
Drug class:

Medically reviewed by Drugs.com on Apr 10, 2024. Written by ASHP.

Introduction

Fexinidazole, a nitroimidazole derivative, is an antiprotozoal agent.

Uses for Fexinidazole

Fexinidazole has the following uses:

Treatment of first-stage (hemolymphatic) and second-stage (meningoencephalitic) human African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense in patients 6 years of age and older and weighing at least 20 kg.

For assistance with diagnosis or treatment of T. brucei gambiense trypanosomiasis in the US, clinicians can contact the CDC Parasitic Diseases Hotline at 404-718-4745 (weekdays from 8:00 a.m. to 4:00 p.m. Eastern Standard Time) or the CDC Emergency Operation Center at 770-488-7100 (after business hours and on weekends and holidays).

Fexinidazole has the following limitations of use:

Due to decreased efficacy of the drug observed in patients with severe second-stage HAT (cerebrospinal fluid white blood cell count [CSF-WBC] >100/mm³) caused by T. brucei gambiense disease, fexinidazole should only be used in such patients if there are no other available treatment options.

Fexinidazole Dosage and Administration

General

Fexinidazole is available in the following dosage form(s) and strength(s):

Tablets: 600 mg.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Pediatric Patients

Dosage and Administration

Administer fexinidazole orally once daily for a total duration of 10 days (loading doses plus maintenance doses) with food at about the same time of the day. Do not break or crush tablets.

The recommended dosage of fexinidazole for patients ≥6 years of age is based on body weight as described in Table 1 below.

Adults

Dosage and Administration

Administer fexinidazole orally once daily for a total duration of 10 days (loading doses plus maintenance doses) with food at about the same time of the day. Do not break or crush tablets.

The recommended dosage of fexinidazole for adults is based to body weight as described in Table 2 below.

Cautions for Fexinidazole

Contraindications

• Patients with known hypersensitivity to fexinidazole and/or any nitroimidazole-class drugs (e.g., metronidazole, tinidazole).

• Patients with hepatic impairment.

Warnings/Precautions

Decreased Efficacy in Severe Human African Trypanosomiasis Caused By Trypanosoma Brucei Gambiense

Decreased efficacy was observed in patients treated with fexinidazole as compared to nifurtimox-eflornithine combination therapy (NECT)-treated patients in a randomized, comparative, open-label study in the subgroup of patients with severe second-stage disease (defined by CSF-WBC >100/mm³ at baseline). The 18-month success rate in this subgroup of patients with severe second-stage disease was 86.9% with fexinidazole compared to 98.7% with NECT. Through 24 months, all-cause mortality was higher in patients with severe disease treated with fexinidazole than in those treated with NECT.

Patients with severe second-stage HAT (CSF-WBC >100 cells/mm³) due to T. brucei gambiense disease should only be treated with fexinidazole if there are no other available treatment options.

QT Interval Prolongation

Fexinidazole have been shown to prolong the QT interval in a concentration-dependent manner. Treatment with fexinidazole caused an average increase of 19 msec in the QT_cF interval. In clinical trials in HAT patients, three patients (<1%) in the fexinidazole group had a QT_cF value of >500 msec versus none in the nifurtimox-eflornithine combination therapy (NECT) group.

Avoid use of fexinidazole in patients who have:

• QT_cF interval greater than 470 msec

• A history of torsade de pointes, congenital long QT syndrome, cardiac arrhythmias, uncompensated heart failure, or family history of sudden death

• Uncorrected hypokalemia

Avoid concomitant administration of fexinidazole with other drugs that are known to prolong the QT interval, those that block cardiac potassium channels, and/or those that induce bradycardia.

Avoid concomitant administration of fexinidazole with drugs that are inducers of hepatic CYP450 as these drugs may significantly increase plasma concentrations of the active metabolites (fexinidazole sulfoxide [M1] and fexinidazole sulfone [M2]). M2 plasma concentrations have been associated with increased risk of QT prolongation.

If patients are, or need to be, treated with drugs known to prolong QT_cF interval or to induce bradycardia, either do not initiate therapy with fexinidazole until such drugs are eliminated from the body (allow a washout period of 5 half-lives for such other drugs) or do not start such drugs until fexinidazole is eliminated from the body (allow a washout period of 7 days for fexinidazole).

Neuropsychiatric Adverse Reactions

Adult patients treated with fexinidazole reported a higher percentage of CNS and psychiatric-related adverse reactions than those treated with nifurtimox-eflornithine combination therapy (NECT) in a clinical trial. Increased incidence in insomnia, headache, and tremor was noted in the patients treated with fexinidazole compared to NECT. In the same trial, adverse reactions representing mood changes and psychiatric disorders (e.g., agitation, anxiety, abnormal behavior, depression, nightmares, hallucination, and personality change) were more common in the patients treated with fexinidazole compared to the NECT arm. Suicidal ideation has also been observed with fexinidazole.

Healthcare providers should inform patients and their caregivers of the risk for neuropsychiatric adverse reactions during treatment with fexinidazole. In patients with current or prior history of psychiatric disorders or if such adverse reactions occur during fexinidazole therapy, healthcare providers should consider alternative therapy or increased monitoring of the patient, including hospitalization.

Neutropenia

Neutropenia (absolute neutrophil count less than 1000/mm³) has been reported in patients receiving fexinidazole. In a trial in HAT patients, this adverse reaction occurred in patients with a baseline absolute neutrophil count of less than 5000/mm³. Avoid concomitant use of drugs which may cause neutropenia and monitor leukocyte count periodically. Carefully monitor patients with neutropenia for fever or other symptoms or signs of infection and treat promptly if such symptoms or signs occur.

Potential for Hepatotoxicity

Elevations in liver aminotransferases occurred in less than 2% of patients receiving fexinidazole for the treatment of HAT. Evaluate liver-related laboratory tests at the start and during treatment with fexinidazole. Monitor patients who develop abnormal liver-related laboratory tests during fexinidazole treatment.

Risk of Disulfiram-like Reaction Due to Concomitant Use with Alcohol

Nitroimidazole-class drugs may cause a disulfiram-like reaction characterized by flushing, rash, weakness, abdominal cramps, nausea, vomiting, and headache in patients who concurrently consume alcohol. Advise patients to avoid consumption of alcohol during treatment with fexinidazole and for at least 48 hours after completing therapy.

Risk of Psychotic Reactions Due to Concomitant Use with Disulfiram

Psychotic reactions have been reported in patients who were concurrently taking disulfiram and nitroimidazole drugs. Avoid use of fexinidazole in patients who have taken disulfiram within the last 2 weeks.

Specific Populations

Pregnancy

Risk Summary: There are risks to the mother and fetus associated with untreated HAT due to T. brucei gambiense during pregnancy. Available data from clinical trials regarding use of fexinidazole in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects or miscarriage.

Clinical Considerations: Disease-associated maternal and/or embryo-fetal risk. There are adverse effects on maternal and fetal outcomes associated with untreated HAT due to T. brucei gambiense during pregnancy. Disease progression may occur during pregnancy. Pregnant women should be treated for HAT due to T. brucei gambiense during pregnancy to prevent vertical transmission. For timing of treatment during pregnancy, consider the benefits of fexinidazole to the mother and the potential risks to the fetus.

Animal Data: In embryo-fetal toxicity studies, pregnant rats were exposed from gestation day (GD) 6 through GD 17. There was no effect on prenatal development in the rat up to the daily dose of 200 mg/kg (similar to the clinical dose based on AUC comparisons). Maternal toxicity was evidenced by the significantly reduced body weight gain observed at 800 mg/kg. Delayed ossification (sternebrae, metacarpals and caudal vertebrae) and reduced fetal and placental weights were observed in the presence of maternal toxicity. In the prenatal and postnatal development study, female rats were exposed from GD 6 to lactation day 21. Lower body weights were reported in F1 pups from dams treated (approximately 1.03 times the clinical exposure based on AUC comparisons) throughout lactation. Sexual maturity showed a minimal delay for both males and females. Post-weaning development for behavior and reproductive performance did not indicate any late adverse effect on the progeny.

Lactation

Risk Summary: There are no data on the presence of fexinidazole in human milk or the effect on milk production. There are no reports of adverse effects to the breast-fed child associated with fexinidazole exposure through breast milk based on a limited number of reported cases. Fexinidazole is present in rat milk. When a drug is present in animal milk, it is likely that the drug will be present in human milk. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for fexinidazole and any potential adverse effects on the breast-fed child from fexinidazole or from the underlying maternal condition.

Data: In lactating rats given a single oral dose of 800 mg/kg of 14C-fexinidazole, the drug and/or related metabolites were detected in the milk.

Pediatric Use

The safety and effectiveness of fexinidazole for the treatment of both first-stage (hemolymphatic) and second-stage (meningoencephalitic) HAT due to T. brucei gambiense have been established in pediatric patients ≥6 years of age and weighing ≥20 kg. Use of fexinidazole for this indication is supported by evidence from an adequate and well-controlled trial in adults with additional efficacy, pharmacokinetic, and safety data in pediatric patients ≥6 years of age.

Pediatric patients may be more sensitive to vomiting. The safety profile for fexinidazole in pediatric patients was generally similar to that of adult patients, with the exception of more frequent vomiting within 2 hours of administration of fexinidazole. Vomiting did not result in permanent treatment discontinuation.

The safety and efficacy of fexinidazole have not been established in pediatric patients <6 years old and/or weighing <20 kg.

Geriatric Use

Of the 619 patients in 3 clinical trials who received fexinidazole for the treatment of HAT, there were 11 who were ≥65 years of age; none were >75 years of age. The number of geriatric patients in clinical trials was insufficient to detect differences in safety and/or effectiveness between elderly and younger adults.

Renal Impairment

No dosage adjustment is needed for patients with mild to moderate renal impairment with estimated glomerular filtration rates (eGFR) from 30 mL/minute per 1.73 m² up to 89 mL/minute per 1.73 m².

Avoid the use of fexinidazole in patients with severe renal impairment (eGFR <30 mL/min per 1.73 m²). The pharmacokinetics of the drug in patients with severe renal impairment is unknown.

Hepatic Impairment

The pharmacokinetics of fexinidazole in patients with hepatic impairment is unknown. Since fexinidazole is extensively metabolized by the liver, the drug is contraindicated in patients with hepatic impairment.

Common Adverse Effects

Most common adverse reactions (incidence >10%) are headache, vomiting, insomnia, nausea, asthenia, tremor, decreased appetite, dizziness, hypocalcemia, dyspepsia, back pain, upper abdominal pain, and hyperkalemia.

Drug Interactions

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

• Avoid use of herbal medicines and supplements.

• See full prescribing information for complete list of clinically significant drug interactions.

Actions and Spectrum

Mechanism of Action

Fexinidazole is a nitroimidazole derivative with antitrypanosomal activity.

Studies with Trypanosoma brucei and other protozoans suggest that, like for other nitro-containing drugs, the nitroreductase (NTR) enzyme in susceptible organisms plays an important role in the bioactivation of fexinidazole, resulting in generation of reactive amines and damage to DNA and proteins. The activity of fexinidazole and its metabolites (M1 and M2) is trypanocidal and appears to be concentration and time dependent. However, the precise mechanism by which fexinidazole and the two metabolites exhibit activity against T. brucei is not known..

Spectrum

Fexinidazole and its two metabolites, M1 and M2, are active against T. brucei gambiense.

Resistance

In vitro studies suggest a potential for development of resistance to fexinidazole in T. brucei.

The mechanism of resistance appears to be similar to other nitro-containing drugs, such as nifurtimox, and includes down-regulation of Type 1 NTR. However, the clinical relevance of these findings is not known.

Nonclinical studies suggest cross-resistance between fexinidazole and other nitro-containing drugs such as nifurtimox. This appears to be due to down-regulation of Type I NTR. Although the clinical relevance of these findings is not known, the potential for the development of resistance to fexinidazole in patients previously treated with nifurtimox-eflornithine combination therapy (NECT) cannot be discounted.

Advice to Patients

• Advise patients that fexinidazole tablets must be taken with food once daily at about the same time of the day (e.g., during or immediately after the main meal of the day), to make sure it is adequately absorbed.

• Advise patients not to consume alcoholic beverages during treatment with fexinidazole and for at least 48 hours after completing fexinidazole therapy.

• Advise the patient not to administer an additional dose if vomiting occurs after administration of a dose of fexinidazole; continue with the next scheduled dose on the following day. If a second event of vomiting occurs after administration of any other dose of fexinidazole, counsel the patient on the importance of contacting the healthcare provider immediately.

• Advise patients that if a scheduled dose is missed (not taken on the assigned day), normal dosing should resume the following day until the full course (10 days) of treatment has been completed. Counsel the patient on the importance of contacting the healthcare provider immediately if a second scheduled dose is missed.

• Counsel patients and their caregivers of the risk for neuropsychiatric adverse reactions, such as insomnia, headache, tremor, mood changes, psychiatric disorders (e.g., agitation, anxiety, abnormal behavior, depression, nightmares, hallucination, and personality change) and suicidal ideation. If such adverse reactions occur, advise the patients and their caregivers to contact their healthcare provider immediately.

• Counsel patients that they should not drive or use machines if they feel tired or dizzy. Dizziness, fatigue, asthenia, and somnolence have been reported following treatment with fexinidazole.

• Advise patients to disclose to their healthcare provider all other medications, including herbal medicines, the patient is currently taking while being treated with fexinidazole.

Additional Information

AHFSfirstRelease^™. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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