Drug Interactions between fingolimod and midostaurin

MONITOR CLOSELY: Coadministration of fingolimod with antineoplastic, immunosuppressive, or other immune-modulating therapies may increase the risk of infections. Fingolimod causes reversible sequestration of lymphocytes in lymphoid tissues. When administered daily, fingolimod produces a dose-dependent reduction in peripheral lymphocyte count to 20% to 30% of baseline values, which may increase the risk of infections. A small study consisting of 12 subjects receiving fingolimod 0.5 mg daily found that lymphocyte count decreased to approximately 60% of baseline within 4 to 6 hours after the first dose and continued to decrease over a 2-week period, reaching a nadir count of approximately 500 cells/mcL, or 30% of baseline. In a placebo-controlled study of 1272 multiple sclerosis patients, 18% of patients on fingolimod 0.5 mg daily reached a nadir of less than 200 cells/mcL on at least one occasion, compared to no patient on placebo. Decreased lymphocyte counts persist during daily dosing and generally return to baseline within 1 to 2 months after stopping the medication. In addition, a mild decrease in the neutrophil count to approximately 80% of baseline occurs during chronic therapy. Serious infections requiring admission to hospital have been reported.

MANAGEMENT: The safety and efficacy of fingolimod in combination with antineoplastic, immunosuppressive, or immune-modulating agents have not been evaluated. Caution is advised during coadministration. A complete blood count is recommended prior to starting fingolimod if a recent one (i.e., within last 6 months) is not available. Treatment suspension should be considered in patients who develop a serious infection, and the benefits and risks reassessed prior to restarting treatment. Because fingolimod remains in the blood for up to two months after the last dose, continued monitoring is recommended throughout this period, and initiating other drugs during this period warrants the same considerations needed for concomitant administration.

MONITOR CLOSELY: Due to its significant bradycardic effects, the risk of QT prolongation and torsade de pointes arrhythmia may be increased during initiation of fingolimod treatment in patients receiving drugs that prolong the QT interval. Fingolimod can cause a decrease in heart rate during initiation of therapy that is apparent within an hour of the first dose and maximal at approximately 6 hours post-dose in most cases, but occasionally up to 20 hours after the first dose. Further, but smaller decreases in heart rate may occur after the second dose, although heart rate eventually returns to baseline within one month of chronic treatment. The mean decrease in heart rate in patients receiving fingolimod 0.5 mg at 6 hours after the first dose was approximately 13 beats per minute (bpm). Heart rates below 40 bpm and AV block were rarely observed. In a study evaluating the effect on QT interval of fingolimod 1.25 or 2.5 mg at steady-state, when a negative chronotropic effect of the drug was still present, fingolimod treatment resulted in a prolongation of the QTc, with an upper bound of the 90% confidence interval of 14.0 msec. There was no consistent signal of increased incidence of QTc outliers, either absolute or change from baseline, associated with fingolimod treatment. In clinical studies, investigators did not observed meaningful prolongation of the QT interval during fingolimod use, but patients at risk for QT prolongation were excluded. 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: Fingolimod 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, close monitoring is recommended during initiation of fingolimod treatment in patients receiving concomitant drugs that can prolong the QT interval, patients with significant QT prolongation (QTc >470 msec in females or >450 msec in males), or patients with relevant risk factors for QT prolongation (e.g., hypokalemia, hypomagnesemia, congenital QT prolongation). Overnight continuous ECG monitoring after the first dose is recommended in accordance with the product labeling. Fingolimod should not be given if baseline QTc interval is 500 msec or greater. The same precautions are applicable if, after the first month of treatment, fingolimod is discontinued for more than two weeks and then restarted, since the effects on heart rate and AV conduction may recur on reintroduction of fingolimod. Within the first 2 weeks of treatment, first-dose procedures are also recommended after interruption of one day or more; during week 3 and 4 of treatment, first-dose procedures are recommended after treatment interruption of more than 7 days.