Drug Interactions between deutetrabenazine and fluoxetine / olanzapine

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more closely whenever a strong CYP450 2D6 inhibitor (e.g.,fluoxetine, paroxetine, or quinidine) is added to or withdrawn from therapy.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.

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.

MONITOR: It is uncertain whether olanzapine causes clinically significant prolongation of the QT interval. In pooled studies of adults as well as pooled studies of adolescents, there were no significant differences between olanzapine and placebo in the proportion of patients experiencing potentially important changes in ECG parameters, including QT, QTcF (Fridericia-corrected), and PR intervals. In clinical trials, clinically meaningful QTc prolongations (QTcF >=500 msec at any time post-baseline in patients with baseline QTcF <500 msec) occurred in 0.1% to 1% of patients treated with olanzapine, with no significant differences in associated cardiac events compared to placebo. Published studies have generally reported no significant effect of olanzapine on QTc interval, although both QTc prolongation and QTc shortening have also been reported. There have been a few isolated case reports of QT prolongation in patients receiving olanzapine. However, causality is difficult to establish due to confounding factors such as concomitant use of drugs that cause QT prolongation and underlying conditions that may predispose to QT prolongation (e.g., hypokalemia, congenital long QT syndrome, preexisting conduction abnormalities).

MANAGEMENT: Some authorities recommend caution when olanzapine is used with drugs that are known to cause QT prolongation. ECG monitoring may be advisable in some cases, such as in patients with a history of cardiac arrhythmias or congenital or family history of long QT syndrome. 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.