fexinidazole (Rx)

Brand and Other Names:
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Dosing & Uses

AdultPediatric

Dosage Forms & Strengths

tablet

  • 600mg

African Trypanosomiasis

Indicated for treatment of African trypanosomiasis (HAT; sleeping sickness) caused by Trypanosome brucei gambiense

It is indicated for stage 1 (hemolymphatic) and stage 2 (meningoencephalitic) HAT

10-Day regimen

  • Days 1-4: 1800 mg (3 tablets) PO qDay, THEN
  • Days 5-10: 1200 mg (2 tablets) PO qDay

Dosage Modifications

Renal impairment

  • Mild-to-moderate (eGFR 30 to <89 mL/min/1.73 m2): No dosage adjustment required
  • Severe (eGFR <30 mL/min/1.73 m2): Pharmacokinetics unknown; avoid use

Hepatic impairment

  • Contraindicated; pharmacokinetics unknown

Dosing Considerations

Limitations of use

  • Owing to decreased efficacy observed in patients with severe second-stage HAT (CSF-WBC >100 cells/mcL), use only if no other available treatment options exist

Monitoring

  • Evaluate liver-related laboratory tests before initiating and during treatment

Dosage Forms & Strengths

tablet

  • 600mg

African Trypanosomiasis

Indicated for treatment of human African trypanosomiasis (HAT; sleeping sickness) caused by Trypanosome brucei gambiense in children aged ≥6 years who weigh at least 20 kg

It is indicated for stage 1 (hemolymphatic) and stage 2 (meningoencephalitic) HAT

<6 years: Safety and efficacy not established

≥6 years

  • 10-Day regimen
  • ≥20 to <35 kg
    • Days 1-4: 1200 mg (2 tablets) PO qDay, THEN
    • Days 5-10: 600 mg (1 tablet) PO qDay
  • ≥35 kg
    • Days 1-4: 1800 mg (3 tablets) PO qDay, THEN
    • Days 5-10: 1200 mg (2 tablets) PO qDay

Dosage Modifications

Renal impairment

  • Mild-to-moderate (eGFR 30 to <89 mL/min/1.73 m2): No dosage adjustment required
  • Severe (eGFR <30 mL/min/1.73 m2): Pharmacokinetics unknown; avoid use

Hepatic impairment

  • Contraindicated; pharmacokinetics unknown

Dosing Considerations

Limitations of use

  • Owing to decreased efficacy observed in patients with severe second-stage HAT (CSF-WBC >100 cells/mcL), use only if no other available treatment options exist

Monitoring

  • Evaluate liver-related laboratory tests before initiating and during treatment
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Interactions

Interaction Checker

and fexinidazole

No Results

     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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            Adverse Effects

            >10%

            Aged ≥15 years

            • Headache (34.8%)
            • Vomiting (28.4%)
            • Insomnia (28%)
            • Nausea (25.8%)
            • Asthenia (22.7%)
            • Tremor (22%)
            • Decreased appetite (21.2%)
            • Dizziness (18.9%)
            • Hypocalcemia (13.6%)
            • Dyspepsia (12.9%)
            • Back pain (11.4%)
            • Upper abdominal pain (10.2%)

            1-10%

            Aged ≥15 years

            • Feeling hot (9.5%)
            • Chest pain (8.7%)
            • Hypoalbuminemia (8.7%)
            • Neck pain (8.7%)
            • Salivary hypersecretion (6.1%)
            • Neutropenia <1000 cells/mm3 (5.7%)
            • Constipation (4.9%)
            • Palpitations (4.9%)
            • Hot flush (4.9%)
            • Hypertension (4.5%)
            • Gait disturbance (4.5%)
            • Pruritus (3.8%)
            • Extrapyramidal disorder (3.4%)
            • Abdominal distension (3%)
            • Gastritis (3%)
            • Muscle spasms (2.7%)
            • Hyperhidrosis (2.7%)
            • Photophobia (2.3%)
            • Paresthesia (2.3%)
            • <2%
              • Psychiatric disorders: Hallucinations, psychotic disorder, depression, personality change, suicidal ideation
              • Laboratory investigations: Elevations of liver transaminases
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            Warnings

            Contraindications

            Hypersensitivity to fexinidazole and/or any nitroimidazole-class drug (eg, metronidazole, tinidazole)

            Hepatic impairment

            Cautions

            Adults treated with fexinidazole reported a higher percentage of CNS and psychiatric-related adverse reactions compared with nifurtimox-eflornithine combination therapy (NECT); consider alternant therapy or increase monitoring with current or history of psychiatric disorders, or if such adverse reactions occur

            Neutropenia reported; avoid concomitant use with drugs that cause neutropenia; monitor for neutropenia, fever, or signs of infection; treat promptly if symptoms occur

            Monitor for elevated liver transaminases

            Severe second-stage HAT

            • Decreased efficacy observed in patients treated with fexinidazole compared with NECT-treated patients in a randomized, comparative open-label study in the subgroup of patients with severe second-stage disease (CSF-WBC >100 cells/mcL at baseline)
            • For severe second-stage HAT, consider fexinidazole only if there are no other available treatment options

            QT prolongation

            • Shown to prolong the QT interval in a concentration-dependent manner (QTcF interval average increase of 19 msec)
            • Avoid coadministration with other drugs known to prolong QT interval or drugs that increase systemic exposure of fexinidazole’s active metabolite
            • Avoid use in
              • QTcF interval >470 msec
              • History of torsade de pointes, congenital long QT syndrome, cardiac arrhythmias, uncompensated heart failure, or family history of sudden death
              • Uncorrected hypokalemia

            Drug interaction overview

            • Inhibits CYP isoenzymes 3A4, 1A2, and 2C19
            • Induces CYP2B6
            • Inhibits transporters OCT2, OAT1, OAT3, MATE1, and MATE2-K
            • Substrate of multiple CYP450 enzymes; these enzymes are involved in the metabolism of fexinidazole to its pharmacologically active M1 and M2 metabolites
            • CYP450 inducers
              • Avoid coadministration with drugs that are CYP450 inducers
              • These drugs may significantly increase plasma concentrations of fexinidazole’s active metabolites: fexinidazole sulfoxide (M1) and fexinidazole sulfone (M2)
              • M2 plasma concentrations associated with increased QT prolongation risks
            • CYP450 inhibitors
              • Avoid coadministration; if unavoidable, monitor for lack of efficacy of fexinidazole owing to potential for decreased plasma concentrations of active metabolites
              • Multiple CYP450 enzymes are involved in fexinidazole metabolism to its pharmacologically active metabolites
            • Drugs that prolong QT interval and/or induce bradycardia
              • Avoid coadministration with other drugs known to prolong QT interval, those that block cardiac potassium channels, and/or those that induce bradycardia
              • If treated with or need to on drugs known to prolong QTcF interval or to induce bradycardia, either do not initiate therapy with fexinidazole until such drugs are eliminated from the body (allow washout period of 5 half-lives) or do not start such drugs until fexinidazole is eliminated (allow washout period of 7 days)
            • Alcohol
              • Avoid alcohol consumption during treatment and for at least 48 hr after last dose
              • Nitroimidazole-class drugs may cause a disulfiramlike reaction characterized by flushing, rash, weakness, abdominal cramps, nausea, vomiting, and headache when coadministered with alcohol
            • Disulfiram
              • Avoid use in patients who have taken disulfiram within the last 2 weeks
              • Psychotic reactions reported in patients who were concurrently taking disulfiram and nitroimidazole drugs
            • Substrates of CYP3A4
              • Avoid coadministration
              • May increase risk for adverse effects by increasing concentration of CYP3A4 substrates owing to fexinidazole inhibiting CYP3A4
            • Substrates of CYP1A2 or CYP2C19
              • Monitor for adverse effects of CYP1A2/CYP2C19 substrates
              • Increased risk for adverse reactions with substrates owing to CYP1A2/CYP2C19 inhibition by fexinidazole
            • Substrates of CYP2B6
              • Avoid coadministration; if unavoidable, monitor for lack of efficacy
              • May decrease plasma concentrations of CYP2B6 substrates owing to fexinidazole inducing CYP2B6
            • Substrates of OAT2, OAT1, OAT3, MATE1, and MATE2-K transporters
              • Avoid coadministration; if unavoidable, monitor for adverse reactions
              • Increased risk for adverse reactions associated with increased concentrations of transporter substrates owing to inhibition of these transporters by fexinidazole
            • Herbals and supplements
              • Avoid concomitant use of herbal medicines and supplements during treatment
              • Potential for pharmacodynamic interactions and/or toxicities between fexinidazole and herbal medicines and supplements
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            Pregnancy & Lactation

            Pregnancy

            Available data from clinical trials with fexinidazole use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects or miscarriage

            Clinical considerations

            • There are risks to the mother and fetus associated with untreated HAT due to T brucei gambiense during pregnancy
            • Disease progression may occur during pregnancy
            • Pregnant women should be treated for HAT during pregnancy to prevent vertical transmission
            • For timing of treatment during pregnancy, consider the benefits to the mother and the potential risks to the fetus

            Animal studies

            • There were no effects on prenatal development in embryofetal studies where pregnant rats were administered fexinidazole during organogenesis in a similar human dosage based on AUC comparisons
            • Effects of fexinidazole on embryofetal development observed in rats and rabbits at doses harmful to dams only
            • Exposure of fexinidazole and its metabolites at those maternal toxic doses in rats and rabbits were 2 times and <0.02 times the clinical exposure, respectively
            • In the prenatal and postnatal development study, administration to pregnant rats during organogenesis and through lactation resulted in lower body weights in first-generation offspring from dams treated at ~1.03 times the clinical exposure based on AUC comparisons

            Lactation

            Data are unavailable on presence in human milk or the effect on milk production

            There are no reports of adverse effects to breastfed children associated with fexinidazole exposure through breastmilk 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 to be present in human milk

            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.

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            Pharmacology

            Mechanism of Action

            Nitroimidazole antiprotozoal drug

            Mechanism of action not yet elucidated, but likely involves bioreductive activation related to fexinidazole and the sulfoxide and sulfone metabolites

            Absorption

            Food: AUC of fexinidazole, M1, and M2 were ~4- to 5-fold higher after administration with food compared with fasting

            Peak plasma time, Day 4

            • Fexinidazole: 4 hr
            • M1: 4 hr
            • M2: 6 hr

            Peak plasma concentration

            • Fexinidazole
              • Day 1: 1.6 mcg/mL
              • Day 4: 0.8 mcg/mL
              • Day 10: 0.5 mcg/mL
            • M1
              • Day 1: 8.1 mcg/mL
              • Day 4: 8 mcg/mL
              • Day 10: 5.9 mcg/mL
            • M2
              • Day 1: 7.5 mcg/mL
              • Day 4: 19.6 mcg/mL
              • Day 10: 12.5 mcg/mL

            AUC

            • AUC0-24 of M1 and M2 are 11- and 34-fold higher, respectively, than fexinidazole
            • Fexinidazole
              • Day 1: 14.3 mcgh/mL
              • Day 4: 11.6 mcgh/mL
              • Day 10: 7 mcgh/mL
            • M1
              • Day 1: 102.3 mcgh/mL
              • Day 4: 127.9 mcgh/mL
              • Day 10: 84.2 mcgh/mL
            • M2
              • Day 1: 110.1 mcgh/mL
              • Day 4: 391.5 mcgh/mL
              • Day 10: 252.4 mcgh/mL

            Distribution

            Vd Day 4, fexinidazole: 3222 L

            Protein bound

            • Fexinidazole: 98%
            • M1: 41%
            • M2: 57%

            Mean CSF concentrations

            • 24 hr after last dose on Day 10
            • M1: 1.39 mcg/mL
            • M2: 6.45 mcg/mL

            Metabolism

            Fexinidazole: Metabolized to pharmacologically active M1 (sulfoxide) metabolite by several CYP450 enzymes, including CYP3A4 and flavin monooxygenases

            Active metabolites

            • Several CYP450 enzymes, including CYP3A4 and flavin monooxygenases, are involved in the metabolism of M1 to M2 (sulfone)
            • M2 is not further metabolized

            Elimination

            Excretion: Urine <3.2%, primarily as metabolites

            Clearance, Day 4 (fexinidazole): 161 L/hr

            Half-life, Day 10

            • Fexinidazole: 15 hr
            • M1: 16 hr
            • M2: 23 hr
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            Administration

            Oral Administration

            Administer with food at about the same time each day

            Do not break or crush tablet

            Avoid consuming alcohol during treatment and for at least 48 hr after last dose

            Vomited dose

            • First vomiting event: Do not take an additional dose that day; administer next dose on the following day as scheduled
            • Second vomiting event following administration of any other dose: Instruct patient to contact their healthcare provider immediately

            Missed dose

            • If dose is missed on assigned day, resume normal dosing the following day until the full course (10 days) of treatment is completed
            • Clinical consequences of multiple missed doses are unknown

            Storage

            Store at <30ºC (86ºF) in original package to protect from light and moisture

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
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            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
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            Code Definition
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            Medscape prescription drug monographs are based on FDA-approved labeling information, unless otherwise noted, combined with additional data derived from primary medical literature.