Drug Interactions between Clozapine Synthon and deutetrabenazine

MONITOR CLOSELY: Tetrabenazine causes central dopamine depletion by binding reversibly to human vesicular monoamine transporter type 2 (VMAT2) and interfering with presynaptic monoamine storage mechanisms. Coadministration of tetrabenazine in combination with neuroleptic agents or other dopamine antagonists (e.g., metoclopramide) may result in severe manifestations of dopamine deficiency. Neuroleptic malignant syndrome hyperthermia, parkinsonism, dysphagia, akathisia, and other extrapyramidal disorders have been reported during tetrabenazine therapy, either alone or in combination with neuroleptic agents. The same interaction can be expected for deutetrabenazine, a deuterium-containing analog of tetrabenazine.

GENERALLY AVOID: Deutetrabenazine, as well as many neuroleptic agents (e.g., asenapine, clozapine, droperidol, haloperidol, iloperidone, paliperidone, pimozide, phenothiazines, quetiapine, risperidone, sertindole, ziprasidone) and other dopamine antagonists (e.g., domperidone) have been associated with dose-related prolongation of the QT interval. Theoretically, the use of these agents in combination may result in elevated risk of ventricular arrhythmias, including ventricular tachycardia and torsade de pointes, because of additive arrhythmogenic potential related to their effects on cardiac conduction. In healthy male and female subjects, a single 24 mg dose of deutetrabenazine increased the QTc by approximately 4.5 msec. Effects at higher exposures to deutetrabenazine or its active metabolites have not been evaluated. 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: The use of deutetrabenazine in combination with neuroleptic agents or other dopamine antagonists should preferable be avoided. When coadministration is required, patients should be instructed to notify their physician if they experience extrapyramidal symptoms such as bradykinesia, hypertonia, rigidity, restlessness, and dysphagia. Clinicians, caregivers, and family members should be apprised of the risk of neuroleptic malignant syndrome and be alert to potential signs and symptoms such as mental status changes (e.g. mutism, catatonia, stupor, coma, agitation, confusion, hallucinations, delusions), autonomic instability, restlessness, rigidity, ataxia, myoclonus, hyperreflexia, tremors, diaphoresis, elevated creatine phosphokinase levels, and hyperpyrexia. Patients should 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.