Drug Interaction Report

GENERALLY AVOID: Pimavanserin may cause dose-related prolongation of the QT interval. Tramadol may also prolong the QT interval, and theoretically, coadministration of multiple 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. In a thorough QTc study conducted in 252 healthy subjects, the maximum mean change in QTc interval from baseline was 13.5 msec at twice the therapeutic pimavanserin dosage given to steady state. In 6-week premarketing placebo-controlled effectiveness studies, mean increases in QTc interval were approximately 5 to 8 msec in patients receiving the recommended pimavanserin dosage of 34 mg once daily. Sporadic Fridericia-corrected QT interval (QTcF) values of 500 msec or greater and change from baseline values of 60 msec or greater were observed in subjects treated with pimavanserin, although the incidence was generally similar to that reported for placebo groups. There were no reports of torsade de pointes arrhythmia or differences from placebo in any other adverse reactions associated with delayed ventricular repolarization due to pimavanserin. The effect of tramadol on the QT interval was evaluated in a randomized, double-blind, 4-way crossover, placebo- and positive-controlled, multiple-dose ECG study of 62 healthy subjects. The maximum placebo-adjusted mean change from baseline in QTcF was 5.5 msec in the 400 mg/day treatment arm (100 mg every 6 hours on days 1 through 3 with a single 100 mg dose on day 4) and 6.5 msec in the 600 mg/day treatment arm (150 mg every 6 hours on days 1 through 3 with a single 150 mg dose on day 4), both occurring at the 8-hour time point. 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). The extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

GENERALLY AVOID: Concomitant use of opioids such as tramadol with other central nervous system (CNS) depressants such as pimavanserin may result in hypotension, profound sedation, respiratory depression, coma, and death.

MANAGEMENT: Coadministration of pimavanserin with tramadol should generally be avoided. If coadministration is necessary, the dosage and duration of each drug should be limited to the minimum required to achieve the desired clinical effect. Patients should have regular ECGs and be monitored for arrhythmias when the QT interval is prolonged. Persistent QTc measurements exceeding 500 msec will require suspension of pimavanserin therapy and immediate action to correct any concomitant risk factors before resuming treatment. Particular care should be exercised in patients suspected to be at an increased risk of torsade de pointes. 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. In addition, patients should be monitored closely for signs and symptoms of respiratory depression and sedation, and advised to avoid driving or operating hazardous machinery until they know how these medications affect them.

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GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete 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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