Fexinidazole

Avoid use of herbal medicines and supplements. ( 7.1 ) See full prescribing information for complete list of clinically significant drug interactions. ( 7.2 )

7.1 Pharmacodynamic Interactions Herbal Medicines and Supplements There is a potential for pharmacodynamic interactions and/or toxicities between fexinidazole and herbal medicines and supplements. Avoid concomitant use of herbal medicines and supplements during treatment with Fexinidazole Tablets.

Drugs that May Prolong the QT Interval and/or Induce Bradycardia Coadministration of Fexinidazole Tablets with drugs known to block potassium channels (e.g., antiarrhythmics, neuroleptics, fluoroquinolones, imidazole and triazole antifungals, pentamidine) prolong the QT interval (e.g., antimalarials, phenothiazines, tricyclic antidepressants, terfenadine and astemizole, IV erythromycin, and quinolone antibacterial drugs) and/or induce bradycardia (such as β-blockers) should be avoided [see Warnings and Precautions (5.2) ] .

7.2 Pharmacokinetic Drug Interactions Table 3: Effect of Fexinidazole on other Drugs Drugs Metabolized by Cytochrome P450 (CYP) 3A4/5 Examples (not fully inclusive): Lovastatin, simvastatin, nisoldipine, saquinavir, midazolam, certain hormonal contraceptives (e.g., birth control pills, skin patches, implant) Clinical Impact Fexinidazole is considered a moderate CYP3A4/5 inducer [see Clinical Pharmacology (12.3) ] . Co-administration of Fexinidazole Tablets and CYP3A4/5 substrates may reduce the systemic exposures of CYP3A4/5 substrate drug(s), which may lead to reduced efficacy [see Clinical Pharmacology (12.3) ] . Prevention or Management Avoid concomitant use with Fexinidazole Tablets .

If coadministration cannot be avoided, monitor for lack of efficacy of sensitive substrate drugs. If concomitant use of oral contraceptives cannot be avoided, an alternative contraceptive that is not affected by enzyme inducers (e.g., intrauterine system) or additional nonhormonal contraception (e.g., condoms) is recommended during treatment with Fexinidazole Tablets and for at least 5 days after the last dose.

Drugs Metabolized by CYP1A2 or CYP2C19 Examples (not fully inclusive): CYP1A2: duloxetine, tacrine, tizanidine, theophylline CYP2C19: lansoprazole, mephenytoin, diazepam Clinical Impact Increased risk for adverse reactions associated with increased concentrations of the drug due to inhibition of either CYP1A2 or CYP2C19 by fexinidazole [see Clinical Pharmacology (12.3) ] . Prevention or Management Monitor for adverse reactions associated with these drugs when used concomitantly with Fexinidazole Tablets.

Drugs Metabolized by CYP2B6 Examples (not fully inclusive): Bupropion, efavirenz Clinical Impact Increased risk for the lack of efficacy associated with decreased plasma concentrations of the drug due to induction of CYP2B6 by fexinidazole and Metabolite M1 [see Clinical Pharmacology (12.3) ] . Prevention or Management Avoid concomitant use with Fexinidazole Tablets. If coadministration cannot be avoided, monitor for lack of efficacy of these drugs.

Drugs Metabolized by uridine 5'-diphospho--glucuronosyl transferase (UGT) Examples (not fully inclusive): Zidovudine, bictegravir, cabotegravir, dolutegravir, bexagliflozin, canagliflozin, sotagliflozin, deferasirox, lamotrigine, selexipag Clinical Impact Fexinidazole metabolites have the potential to be UGT inducers [see Clinical Pharmacology (12.3) ] . Co-administration of Fexinidazole Tablets and UGT substrates may reduce the systemic exposures of UGT substrate drug(s), which may lead to reduced efficacy. Prevention or Management When fexinidazole is concomitantly administered with UGT substrates, monitor for lack of efficacy of UGT substrate drugs.

Drugs Substrates of OCT2, OAT1, OAT3, MATE1, and MATE2-K Transporters Examples (not fully inclusive): Metformin, dofetilide, adefovir, cefaclor, furosemide Clinical Impact Increased risk for adverse reactions associated with increased concentrations of the drug due to inhibition of these transporters by fexinidazole [see Clinical Pharmacology (12.3) ] . Prevention or Management Avoid concomitant use with Fexinidazole Tablets. If coadministration cannot be avoided, monitor for adverse reactions associated with these drugs. Table 4: Effect of other Drugs on Fexinidazole CYP450 Inducers Examples (not fully inclusive): Rifampin, phenytoin, St.

John's wort, carbamazepine Clinical Impact Increased risk for adverse reactions associated with increased systemic exposure to the M1 and M2 metabolites of fexinidazole. M2 plasma concentrations have been associated with the increased risk of QT interval prolongation. Prevention or Management Avoid concomitant use with Fexinidazole Tablets [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.3) ]. CYP450 Inhibitors Examples (not fully inclusive): Clarithromycin, itraconazole, voriconazole, erythromycin, fluconazole Clinical Impact Multiple CYP450 enzymes are involved in the metabolism of fexinidazole to its pharmacologically active M1 and M2 metabolites.

Although no clinical drug interaction studies were performed with CYP450 inhibitors, the formation of the M1 and M2 metabolites may be decreased. Prevention or Management Avoid concomitant use with Fexinidazole Tablets. If coadministration cannot be avoided, monitor for lack of efficacy of fexinidazole due to potential for decreased plasma concentrations of the M1 and M2 metabolites [see Clinical Pharmacology (12.3) ] .

8.1 Pregnancy Risk Summary There are risks to the mother and fetus associated with untreated HAT due to T. brucei gambiense during pregnancy (see Clinical Considerations ) . 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. There were no effects on prenatal development in embryo-fetal studies where pregnant rats were administered oral fexinidazole during organogenesis at a dose similar to the clinical dose based on AUC comparisons. Effects of fexinidazole on embryo-fetal development were observed in the rat and in the rabbit at doses harmful to the dams only.

Exposure of fexinidazole and its metabolites at those maternal toxic doses in rats and rabbits were 2 times and less than 0.02 times the clinical exposure, respectively. In the prenatal and postnatal development study, administration of oral fexinidazole to pregnant rats during organogenesis and through lactation resulted in lower body weights in first generation offspring from dams treated at approximately 1.03 times the clinical exposure based on AUC comparisons. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. 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 in 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 Tablets to the mother and the potential risks to the fetus.

Data Animal data In the 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 rabbit…