Drug Interaction Report

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: Grapefruit juice may increase the plasma concentrations of orally administered drugs that are substrates of the CYP450 3A4 isoenzyme, such as cobimetinib. However, the interaction seems to affect primarily those drugs that undergo significant presystemic metabolism by CYP450 3A4 (i.e., drugs with low oral bioavailability), presumably due to the fact that grapefruit juice inhibits primarily intestinal rather than hepatic CYP450 3A4. Because pharmacokinetic interactions involving grapefruit juice are often subject to a high degree of interpatient variability, the extent to which a given patient may be affected is difficult to predict.

MANAGEMENT: Patients who regularly consume grapefruit or grapefruit juice should be monitored for adverse effects and altered plasma concentrations of cobimetinib. Grapefruit and grapefruit juice should be avoided if an interaction is suspected. Orange juice is not expected to interact with these drugs.