Drug Interaction Report

ADJUST DOSE: Coadministration with potent CYP450 2D6 inhibitors may significantly increase the plasma concentrations of the pharmacologically active metabolites of tetrabenazine. In vitro studies indicate that alfa- and beta-HTBZ (dihydrotetrabenazine) are substrates for CYP450 2D6. The interaction was evaluated in 25 healthy subjects given a single 50 mg dose of tetrabenazine following 10 days of administration of the potent CYP450 2D6 inhibitor paroxetine (20 mg daily). An approximately 30% increase in peak plasma concentration (Cmax) and 3-fold increase in systemic exposure (AUC) was observed for alfa-HTBZ in the presence of paroxetine compared to tetrabenazine given alone. Likewise, the Cmax and AUC of beta-HTBZ were increased 2.4- and 9-fold, respectively, by paroxetine. The elimination half-life of alfa- and beta-HTBZ (normally 4 to 8 hours and 2 to 4 hours, respectively) was approximately 14 hours in the presence of paroxetine. 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 these metabolites. Clinically, elevated levels of alfa- and beta-HTBZ may lead to over-depletion of monoamine stores in the central nervous system and increase the risk of parkinsonism, akathisia, dysphagia, depression, and suicidality.

GENERALLY AVOID: Tetrabenazine may cause modest prolongation of the QT interval. In healthy male and female subjects, a single 25 or 50 mg dose of tetrabenazine has been shown to increase QTc by an average of approximately 8 msec. Coadministration with a potent CYP450 2D6 inhibitor may increase the plasma concentrations of the pharmacologically active metabolites of tetrabenazine. However, effects at higher exposures to either tetrabenazine or its 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). The extent of drug-induced QT prolongation is dependent on the particular drugs involved and dosages of the drugs.

MANAGEMENT: Pharmacologic response to tetrabenazine should be monitored more closely whenever a potent CYP450 2D6 inhibitor (e.g., fluoxetine, paroxetine, or quinidine) is added to or withdrawn from therapy. Tetrabenazine 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. In patients already stabilized on tetrabenazine, the daily dosage of tetrabenazine should be halved. The maximum dosage recommended is 25 mg per dose and 50 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 tetrabenazine. 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, amisulpride) 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.

GENERALLY AVOID: Tetrabenazine 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, amisulpride) 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 25 or 50 mg dose of tetrabenazine has been shown to increase QTc by an average of approximately 8 msec. Effects at higher exposures to either tetrabenazine or its 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 tetrabenazine in combination with neuroleptic agents or other dopamine antagonists should preferably 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 medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, 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.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.