Drug Interactions between fexinidazole and Kisqali Femara Co-Pack

GENERALLY AVOID: Fexinidazole can cause concentration-dependent prolongation of the QT interval. Coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. Based on the exposure-response relationship, treatment with fexinidazole is predicted to cause an average increase of 19 msec in the Fridericia-corrected QT interval (QTcF) at the recommended dosing regimen. In addition, drugs that are inducers of hepatic CYP450 enzymes may significantly increase the plasma concentration of fexinidazole's active metabolites, fexinidazole sulfoxide (M1) and fexinidazole sulfone (M2). The observed increase in QTcF appears to be associated with the sulfone (M2) metabolite of fexinidazole; therefore, an increase in the plasma concentration of the sulfone (M2) metabolite may increase the risk of QT prolongation. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: The concurrent use of fexinidazole with other medications that can prolong the QT interval, block cardiac potassium channels, and/or induce bradycardia should generally be avoided. If coadministration is unavoidable, treatment with fexinidazole should not be initiated until the opposing drug is eliminated from the body (allow a washout period of 5 half-lives) or do not initiate treatment with the opposing drug until fexinidazole is eliminated from the body (allow a washout period of 7 days). All QT-prolonging drugs including fexinidazole should be interrupted in patients who develop clinically significant ventricular arrhythmia or a QTcF interval greater than 500 msec confirmed by repeat ECG. Patients should be advised to seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitations, irregular heartbeat, shortness of breath, or syncope.

GENERALLY AVOID: Coadministration of fexinidazole with other immunosuppressive or myelosuppressive agents may increase the risk of neutropenia and infections. An absolute neutrophil count (ANC) of less than 1,000 cells/mm3 has been reported in patients treated with fexinidazole. In one trial, neutropenia occurred in patients with a baseline ANC of less than 5,000 cells/mm3.

MANAGEMENT: Concomitant use of fexinidazole with other agents that may cause neutropenia should generally be avoided. The manufacturer recommends monitoring leukocyte counts periodically. Patients should be advised to contact their physician if they develop signs and symptoms of infection such as fever, chills, diarrhea, sore throat, muscle aches, shortness of breath, blood in phlegm, weight loss, red or inflamed skin, body sores, and pain or burning during urination.

MONITOR: Coadministration with ribociclib may increase the plasma concentrations and pharmacologic effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to ribociclib-mediated inhibition of CYP450 3A4 metabolism. In healthy study subjects, administration of midazolam, a sensitive CYP450 3A4 substrate, with multiple 400 mg daily doses of ribociclib increased the midazolam peak plasma concentration (Cmax) and systemic exposure (AUC) by 2.1-fold and 3.8-fold, respectively, compared to midazolam administered alone. When given at a clinically relevant dose of 600 mg daily, ribociclib is predicted to increase midazolam Cmax and AUC by 2.4-fold and 5.2-fold, respectively.

MANAGEMENT: Caution is advised when ribociclib is used concomitantly with drugs that undergo metabolism by CYP450 3A4, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever ribociclib is added to or withdrawn from therapy.

GENERALLY AVOID: Coadministration with fexinidazole may increase the plasma concentrations and the risk of adverse effects of drugs that are substrates of CYP450 3A4. The proposed mechanism is decreased clearance due to fexinidazole-mediated inhibition of CYP450 3A4. Findings from a static mechanistic model-based analysis predicted that fexinidazole may significantly increase the systemic exposure (AUC) of sensitive CYP450 3A4 substrates. However, pharmacokinetic and clinical data regarding this interaction are currently lacking.

MANAGEMENT: Until more information is available, coadministration of fexinidazole with drugs that are substrates of CYP450 3A4 should generally be avoided. If concomitant use is unavoidable, clinical and laboratory monitoring may be appropriate whenever fexinidazole is added to or withdrawn from therapy with these drugs. Dosage adjustments may be considered if an interaction is suspected. Patients should be monitored for the development of adverse effects.