Drug Interactions between Triavil and valbenazine

MONITOR: Coadministration of a phenothiazine with a tricyclic antidepressant (TCA) may result in elevated plasma concentrations of one or both drugs as well as additive adverse effects. Most phenothiazines and TCAs have been found to undergo metabolism by CYP450 2D6, thus competitive inhibition of the enzyme may occur when more than one of these agents are administered. Although these drugs have been used together clinically, the possibility of increased risk of serious adverse effects such as central nervous system depression, tardive dyskinesia, hypotension, and prolongation of the QT interval should be considered, as many of these agents alone can and have produced these effects. In addition, excessive anticholinergic effects may occur in combination use, which can result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of anticholinergic intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures.

MANAGEMENT: Concurrent use of phenothiazines and TCAs should be approached with caution, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication (e.g., abdominal pain, fever, heat intolerance, blurred vision, confusion, hallucinations) or cardiovascular toxicity (e.g., dizziness, palpitations, arrhythmias, syncope). Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A dosage reduction in one or both drugs may be necessary if excessive adverse effects develop.

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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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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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