Drug Interactions between dextromethorphan / promethazine and Gilenya

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.

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MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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