Drug Interactions between asciminib and siponimod

MONITOR CLOSELY: Coadministration of siponimod with antineoplastic, immunosuppressive, or other immune-modulating therapies may result in additive immune system effects and increased risk of infections. Siponimod causes reversible sequestration of lymphocytes in lymphoid tissues. When administered daily, siponimod produces a dose-dependent reduction in peripheral lymphocyte count to 20% to 30% of baseline values, which may increase the risk of infections. Life-threatening and rare fatal infections have occurred in association with siponimod. Decreased lymphocyte counts persist during chronic daily dosing and generally return to normal within 10 days after stopping the medication. However, residual pharmacodynamic effects, such as decreased peripheral lymphocytes, may persist for up to 3 to 4 weeks after the last dose. Use of other myelo- or immunosuppressive drugs during this time may lead to unintended additive effects on the immune system.

MANAGEMENT: The safety and efficacy of siponimod in combination with antineoplastic, immunosuppressive, or other immune-modulating agents have not been evaluated. Close monitoring for signs and symptoms of infection is advised during coadministration and for 3 to 4 weeks after the last dose of siponimod. When switching from drugs with prolonged immune effects to siponimod, 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 CLOSELY: Coadministration with asciminib may increase the plasma concentrations of siponimod, which is primarily metabolized by CYP450 2C9 (79.3%) and CYP450 3A4 (18.5%). Pharmacokinetic studies with probe substrates have shown asciminib to be a weak CYP450 2C9 inhibitor at lower recommended dosages (i.e., 40 mg twice daily or 80 mg once daily) and a moderate CYP450 2C9 inhibitor at the highest recommended dosage (i.e., 200 mg twice daily) as well as a weak CYP450 3A4 inhibitor across the recommended dosage range. The effects of asciminib on the pharmacokinetics of siponimod have not been evaluated, but the interaction has been studied with fluconazole, a moderate CYP450 2C9 and 3A4 dual inhibitor. When a single 4 mg dose of siponimod was administered to healthy CYP450 2C9*1/*1 genotype volunteers (i.e., extensive metabolizers of CYP450 2C9) receiving fluconazole 200 mg daily to steady-state, mean siponimod systemic exposure (AUC) increased by 2-fold and terminal half-life increased by 50%. According to in silico (computer-based) evaluation, use of fluconazole resulted in a 2- to 4-fold increase in the steady-state AUC of siponimod across different CYP450 2C9 genotypes. The CYP450 2C9 genotype influences the fractional contributions of CYP450 2C9 and 3A4 to overall elimination. If the metabolic activity of CYP450 2C9 is decreased, a larger contribution of CYP450 3A4 can be anticipated. Metabolism of siponimod may be particularly impacted when both pathways are inhibited.

MANAGEMENT: Caution is advised when siponimod is used with drugs that can inhibit CYP450 2C9 and/or 3A4 such as asciminib. Patients should be closely monitored for adverse effects such as infections, macular edema, bradycardia, hypertension, peripheral edema, hepatotoxicity, and cutaneous malignancies including basal cell carcinoma, squamous cell carcinoma, and melanoma. Consider alternatives to siponimod in patients receiving asciminib at the maximum recommended dosage of 200 mg twice daily, particularly in conjunction with medications that are potent or moderate inhibitors of CYP450 3A4 (e.g., amprenavir, aprepitant, atazanavir, berotralstat, boceprevir, ceritinib, chloramphenicol, ciprofloxacin, clarithromycin, cobicistat, conivaptan, crizotinib, dalfopristin-quinupristin, darunavir, delavirdine, diltiazem, dronedarone, duvelisib, erythromycin, fedratinib, fexinidazole, fluconazole, fluvoxamine, fosamprenavir, fosaprepitant, fosnetupitant, fusidic acid, idelalisib, imatinib, indinavir, isavuconazole, itraconazole, ketoconazole, lefamulin (oral), letermovir, levoketoconazole, lonafarnib, mifepristone, nefazodone, nelfinavir, netupitant, posaconazole, ribociclib, ritonavir, saquinavir, stiripentol, telaprevir, telithromycin, tucatinib, verapamil, voriconazole, voxelotor).