Drug Interactions between Adapin and valbenazine

MONITOR: Valbenazine may cause modest 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. In healthy volunteers, an 80 mg dose of valbenazine has been shown to increase the QTc by an average of 6.7 msec. This increase is not considered clinically significant at the concentrations expected with the manufacturer-recommended dosing regimen. However, analysis of clinical data from two studies in healthy volunteers showed increased QTc intervals at higher plasma concentrations of the active metabolite of valbenazine, (+)-alfa-dihydrotetrabenazine. Metabolism by CYP450 3A4 and 2D6 are the primary pathways for elimination of valbenazine and (+)-alfa-dihydrotetrabenazine. Therefore, strong inhibitors of these isoenzymes or poor metabolizers of CYP450 2D6 (approximately 7% of Caucasians and 2% of Asians and those of African descent) may lead to increased exposure to valbenazine and (+)-alfa-dihydrotetrabenazine. Based on an 80 mg dose of valbenazine, patients with increased exposure to (+)-alfa-dihydrotetrabenazine may show QTc prolongation of an average of 11.7 msec. 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 drugs involved and the dosages of the drugs.

MONITOR: Central nervous system (CNS)-depressant effects may be additively or synergistically increased in patients taking valbenazine with certain other drugs that cause these effects, especially in elderly or debilitated patients.

MANAGEMENT: Caution and clinical monitoring are recommended if concomitant use of valbenazine with other drugs that can prolong the QT interval is required. Valbenazine is not recommended for use in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval. In patients with other risk factors for QT prolongation, the QT interval should be assessed before increasing the dose of valbenazine. The manufacturer recommends that valbenazine dosage be reduced to 40 mg once daily in patients on concomitant therapy with a strong CYP450 3A4 inhibitor (e.g., itraconazole, ketoconazole, clarithromycin). Valbenazine dose reduction should also be considered in patients on concurrent therapy with a strong CYP450 2D6 inhibitor (e.g., paroxetine, fluoxetine, quinidine), or in patients who are poor metabolizers of CYP450 2D6. In addition, 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. When valbenazine is used in combination with other drugs that cause CNS depression, patients should be monitored for potentially excessive or prolonged CNS depression. 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.

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