Drug Interactions between deutetrabenazine and Quinora

GENERALLY AVOID: Coadministration with quinidine may significantly increase the plasma concentrations of the pharmacologically active dihydro-metabolites of deutetrabenazine, alfa- and beta-dihydrotetrabenazine (alfa- and beta-HTBZ). The proposed mechanism is inhibition of CYP450 2D6-mediated metabolism by quinidine. The interaction was evaluated in 25 healthy subjects given a single 22.5 mg dose of deutetrabenazine following 8 days of administration of the strong CYP450 2D6 inhibitor paroxetine (20 mg daily). An approximately 3-fold increase in systemic exposure for total (alfa and beta)-HTBZ was observed in the presence of paroxetine compared to deutetrabenazine given alone. Poor CYP450 2D6 metabolizer status (approximately 7% of Caucasians and 2% of Asians and those of African descent) is also predicted to increase exposure to alfa- and beta-HTBZ to a similar extent. High plasma levels of these metabolites may increase the risk of adverse effects of deutetrabenazine such as somnolence, QT interval prolongation, parkinsonism, akathisia, neuroleptic malignant syndrome, depression, and suicidality. Pharmacodynamically, deutetrabenazine and quinidine, a class IA antiarrhythmic, may also have additive effects on the QT interval. A single 24 mg dose of deutetrabenazine has been shown to increase the QTc interval by approximately 4.5 msec in a study in healthy male and female subjects. However, data evaluating the effects at higher exposures to deutetrabenazine and 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 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 drugs involved and dosages of the drugs.

MANAGEMENT: Due to increased risk of QT prolongation and torsade de pointes arrhythmia, concomitant use of deutetrabenazine with quinidine should generally be avoided. If coadministration is required, the dosage of deutetrabenazine should be reduced. 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 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.

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