Drug Interactions between Budeprion SR and deutetrabenazine

ADJUST DOSE: Coadministration with a strong CYP450 2D6 inhibitor may increase the plasma concentrations of the pharmacologically active dihydro-metabolites of deutetrabenazine, alfa- and beta-HTBZ (dihydrotetrabenazine), which may increase the risk of adverse effects, including somnolence, clinically relevant QT interval prolongation, parkinsonism, akathisia, neuroleptic malignant syndrome, depression, and suicidality. 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. Data are not available on the effect of moderate or weak CYP450 2D6 inhibitors on the exposure of deutetrabenazine and its metabolites.

GENERALLY AVOID: Deutetrabenazine has been associated with modest QT 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. Coadministration with a strong CYP450 2D6 inhibitor may increase the plasma concentrations of the pharmacologically active metabolites of deutetrabenazine. 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.

MANAGEMENT: Pharmacologic response to deutetrabenazine should be monitored more closely whenever a strong CYP450 2D6 inhibitor (e.g.,fluoxetine, paroxetine, or quinidine) is added to or withdrawn from therapy. Deutetrabenazine is not recommended for use in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval. Assessment of baseline QT interval and periodic monitoring during therapy may be considered. 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.