Drug Interactions between deutetrabenazine and PC-CAP

GENERALLY AVOID: Deutetrabenazine has been associated with modest QT interval prolongation. A single 24 mg dose has been shown to increase the QTc by approximately 4.5 msec in a study in healthy male and female subjects. The risk of clinically significant QT prolongation may be increased in patients treated in combination with a strong CYP450 2D6 inhibitor or in patients who are poor metabolizers of CYP450 2D6 (approximately 7% of Caucasians and 2% of Asians and those of African descent). However, data evaluating the effects at higher exposures to deutetrabenazine or its active metabolites are lacking. 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 drugs involved and dosages of the drugs. In addition, central nervous system (CNS)-depressant effects may be additively or synergistically increased in patients taking deutetrabenazine with certain other drugs that cause these effects, especially in elderly or debilitated patients.

MANAGEMENT: Coadministration of deutetrabenazine with other drugs that can prolong the QT interval should generally be avoided. Deutetrabenazine is not recommended for use in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval. If concomitant use is required, assessment of baseline QT interval and periodic monitoring during therapy may be considered. In addition, dosage reduction may be considered in patients on concurrent therapy with a strong CYP450 2D6 inhibitor, or in patients who are poor metabolizers of CYP450 2D6. The maximum recommended dosage of deutetrabenazine is 18 mg per dose and 36 mg per day during coadministration with a potent CYP450 2D6 inhibitor or in patients who are poor metabolizers of CYP450 2D6. Patients and their caregivers should be advised to notify their physician if they experience new or worsening depression, suicidal thoughts, parkinsonism, restlessness, agitation, dysphagia, and/or excessive sedation while taking deutetrabenazine. Patients should also 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. 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 doctor if they experience excessive or prolonged CNS effects that interfere with their normal activities.

One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.