Drug Interactions between letrozole / ribociclib and ponesimod

GENERALLY AVOID: Due to its significant bradycardic effects, the risk of QT prolongation and torsade de pointes arrhythmia may be increased during initiation of ponesimod treatment in patients receiving drugs that prolong the QT interval. Ponesimod can cause a transient decrease in heart rate during initiation of therapy that is usually apparent within an hour of the first dose and reaches its nadir within 2 to 4 hours. The heart rate typically recovers to baseline levels 4 to 5 hours after administration, and the effect diminishes with repeated dosing on subsequent days, indicating tolerance. In an active-controlled clinical study, bradycardia at treatment initiation and sinus bradycardia on ECG (defined as heart rate less than 50 bpm) occurred in 5.8% of ponesimod-treated patients compared to 1.6% of patients receiving teriflunomide. The mean decrease in heart rate on day 1 of ponesimod dosing was 6 bpm. Following day 1, decreases in heart rate were less pronounced. Post-dose heart rates below or equal to 40 bpm were rarely observed. However, decreases in heart rate induced by ponesimod can be reversed by atropine if necessary. Initiation of ponesimod treatment has also resulted in transient AV conduction delays that follow a similar temporal pattern as that observed for decreases in heart rate during dose titration. In the same study, first-degree AV block (prolonged PR interval on ECG) occurred in 3.4% of ponesimod-treated patients and 1.2% of patients receiving teriflunomide. Second- and third-degree AV blocks were not reported in patients treated with ponesimod. Overall, bradycardia and conduction abnormalities were usually transient and asymptomatic, and resolved within the first 24 hours without intervention or discontinuation of ponesimod treatment. In a study evaluating the effect on QT interval of ponesimod 40 mg and 100 mg (respectively 2- and 5-fold the recommended maintenance dose) administered until steady-state, ponesimod treatment resulted in maximum mean prolongations of the QTcF of 11.8 ms (40 mg) and 16.2 ms (100 mg). No subject had absolute QTcF greater than 480 ms or change in QTcF from baseline greater than 90 ms following ponesimod treatment. 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: Ponesimod has not been studied in patients receiving drugs that can prolong the QT interval. Because bradycardia and AV block are recognized risk factors for QT prolongation and torsade de pointes arrhythmia, treatment with ponesimod should generally not be initiated in patients who are concurrently treated with QT prolonging drugs with known arrhythmogenic properties. Advice from a cardiologist should be sought if treatment with ponesimod is considered in patients on concurrent therapy with QT prolonging drugs with a known risk of torsades de pointes or drugs that slow heart rate or AV conduction.

MONITOR CLOSELY: Coadministration of ponesimod with antineoplastic, immunosuppressive, or other immune-modulating therapies may increase the risk of unintended additive immunosuppressive effects. Ponesimod causes reversible sequestration of lymphocytes in lymphoid tissues. When administered daily, ponesimod produces a dose-dependent reduction in peripheral lymphocyte count to 30% to 40% of baseline values, which may increase the risk of infections. Life-threatening and rare fatal infections have been reported in association with sphingosine 1-phosphate (S1P) receptor modulators. Decreased lymphocyte counts persist during chronic daily dosing and generally return to normal within 1 week after stopping the medication. Because residual pharmacodynamic effects, such as decreased peripheral lymphocytes, may persist for 1 to 2 weeks after the last dose, use of immunosuppressants during this time may also lead to additive immune effects.

MANAGEMENT: The safety and efficacy of ponesimod in combination with antineoplastic, immunosuppressive, or immune-modulating agents have not been evaluated. Caution is advised during coadministration and for 1 to 2 weeks after the last dose of ponesimod. When switching from drugs with prolonged immune effects to ponesimod, the half-life and mode of action of these drugs must be considered to avoid unintended additive immunosuppressive effects while at the same time minimizing risk of disease reactivation.

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.