Drug Interactions between Cardioquin and tetrabenazine

GENERALLY AVOID: Coadministration with quinidine 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 proposed mechanism is inhibition of CYP450 2D6-mediated metabolism by quinidine. The interaction was evaluated with potent CYP450 2D6 inhibitor, paroxetine. In 25 healthy subjects given a single 50 mg dose of tetrabenazine following 10 days of administration of 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 alfa- and beta- HTBZ by 3-fold and 9-fold, respectively, compared to extensive CYP450 2D6 metabolizers. High plasma levels of these metabolites may increase the risk of adverse effects such as somnolence, QT interval prolongation, parkinsonism, akathisia, neuroleptic malignant syndrome, depression, and suicidality. Pharmacodynamically, tetrabenazine and quinidine, a class IA antiarrhythmic, may also have additive effects on the QT interval. In healthy male and female subjects, a single 25 mg or 50 mg dose of tetrabenazine has been shown to increase QTc by an average of approximately 8 msec. However, data evaluating the effects at higher exposures to tetrabenazine and 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 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: Due to increased risk of QT prolongation and torsade de pointes arrhythmia, concomitant use of tetrabenazine with quinidine should generally be avoided. If coadministration is required, the dosage of tetrabenazine should be reduced. 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. 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 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.

Switch to consumer interaction data