Drug Interactions between Prozac Weekly and tetrabenazine

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.

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