Drug Interactions between codeine / phenylephrine / promethazine and selpercatinib

MONITOR CLOSELY: Selpercatinib can cause concentration-dependent prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. Based on findings from a thorough QT study in healthy subjects, the largest mean increase in QTc is predicted to be 10.6 msec (upper 90% confidence interval: 12.1 msec) at the mean steady-state maximum concentration (Cmax) observed in patients administered selpercatinib 160 mg twice daily. In clinical trials, an increase in QTcF interval to >500 msec was measured in 6% of patients and an increase in the QTcF interval of at least 60 msec over baseline was measured in 15% of patients. Selpercatinib has not been studied in patients with clinically significant active cardiovascular disease or recent myocardial infarction. 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, hypocalcemia). Moreover, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Caution is recommended if selpercatinib is used in combination with other drugs that can prolong the QT interval. An electrocardiogram and serum electrolyte levels should be obtained prior to initiating selpercatinib therapy and periodically during treatment as appropriate based on individual risk factors including diarrhea. Correct hypokalemia, hypomagnesemia, and/or hypocalcemia before starting treatment and during treatment, as they may be risk factors for ventricular arrhythmias. Selpercatinib treatment should be discontinued, interrupted, or dosage reduced based on severity of QT prolongation and/or development of arrhythmia in accordance with the product labeling. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

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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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