Ovation

Monoamine depletor

Tetrabenazine 12.5mg; 25mg+ (+scored); tabs.

Huntington's chorea.

Huntington's disease is a progressive neurodegenerative disorder characterized by chorea (involuntary movements), rigidity, and changes in mood, cognition, and functional capacity over time.

Tetrabenazine is a reversible depletor of monoamines (eg, dopamine, serotonin, norepinephrine) from nerve terminals. It works by inhibiting the activity of human vesicular monoamine transporter type 2, reducing the uptake of these neurotransmitters into synaptic vesicles and depleting monoamine stores. It has been shown to improve chorea associated with Huntington's disease, but it may worsen the emotional and mood aspects, particularly depression.

Tetrabenazine is metabolized by the liver into two major metabolites which also have activity as monoamine depletors.

A randomized, double-blind, placebo-controlled trial was conducted in 84 ambulatory patients with Huntington's chorea. The trial included a 7-week dose titration period followed by a 5-week maintenance period and a 1-week washout period. The primary endpoint was the Total Chorea Score, which rates the chorea on a scale from 0 to 4 in seven different parts of the body. Total scores range from 0 to 28. During maintenance therapy, the Total Chorea Scores in the drug treatment group declined by about 5 units compared to 1.5 units in the placebo group, a significant effect. One week after discontinuing the study medication, the Total Chorea Scores returned to baseline. Patients given tetrabenazine were more likely to experience an improvement in chorea scores. A Physician-rated Global Impression favored tetrabenazine statistically. In general, measures of functional capacity and cognition showed no difference between tetrabenazine and placebo.

Individualize. Initially 12.5mg once daily in the AM, then 12.5mg twice daily after one week. Titrate slowly at weekly intervals by 12.5mg. Doses of 37.5–50mg/day should be given in a 3 times/day regimen, max 25mg/dose. Do not exceed 50mg/day before genotyping for CYP2D6 activity; see literature. Poor metabolizers (CYP2D6): max 25mg/dose and 50mg/day; extensive metabolizers: max 37.5mg/dose and 100mg/day. Concomitant strong CYP2D6 inhibitors (eg, paroxetine, fluoxetine, quinidine): reduce tetrabenazine dose by 1/2; moderate to weak CYP2D6 inhibitors: not evaluated. Retitrate if therapy interrupted for more than 5 days.

Not recommended.

Depression. Suicidal ideation. Hepatic impairment. Concomitant monoamine oxidase inhibitors (MAOIs). During or within 20 days of stopping reserpine.

Avoid in congenital long QT syndrome or history of cardiac arrhythmias. Bradycardia. Hypokalemia. Hypomagnesemia. Recent MI. Unstable heart disease. Cardiovascular disease. History of depression, suicidal ideation, or breast cancer. Monitor for depression, emotional lability, akathisia. Poor metabolizers (CYP2D6). Reevaluate periodically. Pregnancy (Cat.C). Nursing mothers: not recommended.

See Contraindications. Avoid other drugs that can cause QT prolongation (eg, chlorpromazine, thioridazine, ziprasidone, moxifloxacin, quinidine, procainamide, amiodarone, sotalol). Potentiated by CYP2D6 inhibitors (eg, paroxetine, fluoxetine). Increased risk of neuroleptic malignant syndrome, extrapyramidal syndrome with neuroleptics, dopamine antagonists. Additive CNS depression with alcohol, other CNS depressants.

Sedation, fatigue, insomnia, depression, dysphagia, akathisia, nausea, parkinsonism, QTc prolongation, orthostatic hypotension, elevated serum prolactin; rarely: neuroleptic malignant syndrome, tardive dyskinesia, extrapyramidal effects.

Tabs- 112

November 26, 2008