Tetrabenazine

Trade Names:
Xenazine
- Tablets, oral 12.5 mg
- Tablets, oral 25 mg

Pharmacology

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Precise mechanism of action is unknown; however, reversible depletion of monoamines, such as dopamine, serotonin, norepinephrine, and histamine, from nerve terminals may be involved.

Pharmacokinetics

Absorption

Following oral administration, absorption is at least 75%. T _max is approximately 1 to 1.5 h.

Distribution

Protein binding ranges from 82% to 85%.

Metabolism

At least 19 metabolites have been identified. The 2 major metabolites are formed by carbonyl reductase in the liver.

Elimination

Elimination half-life of the major circulating metabolites is 2 to 8 h. Elimination is primarily by the kidney (approximately 75%) and about 7% to 16% in the feces.

Special Populations

Pharmacokinetics have not be studied.

Metabolism of tetrabenazine is decreased in patients with hepatic function impairment and the C _max is 7- to 190-fold higher compared with healthy subjects. The elimination half-life in patients with hepatic function impairment is 17.5 h.

Indications and Usage

Treatment of chorea associated with Huntington disease.

Contraindications

Patients who are actively suicidal; untreated or inadequately treated depression; hepatic function impairment; MAOI therapy, reserpine therapy, and for at least 20 days after stopping reserpine.

Dosage and Administration

The daily dose of tetrabenazine should be reduced by 50%.

Initiate tetrabenazine using the dosing recommendations for CYP2D6 poor metabolizers.

PO Start with 12.5 mg once daily in the morning. Increase the dosage to 12.5 mg twice daily after 1 wk. Titrate the dose slowly at weekly intervals by increments of 12.5 mg daily. If akathisia, anxiety, insomnia, depression, intolerable sedation, parkinsonism, or restlessness occur, stop titration and reduce the dose. If the adverse reaction does not resolve, consider discontinuing tetrabenazine or administering another treatment (eg, antidepressants).

May require doses higher than 50 mg/day. Titrate doses higher than 50 mg/day slowly at weekly intervals by increments of 12.5 mg daily to a max of 100 mg daily. If akathisia, anxiety, depression, insomnia, intolerable sedation, parkinsonism, or restlessness occur, stop titration and reduce the dose. If the adverse reaction does not resolve, consider discontinuing tetrabenazine or administering another treatment (eg, antidepressants).

Dosing is similar to extensive metabolizers, except the max single dose is 25 mg and max daily dose is 50 mg.

General Advice

• May be given without regard to meals.
• Careful titration over several weeks of therapy is necessary for proper tetrabenazine dosing.
• Daily doses of 37.5 mg or more should be given in 3 divided doses.
• Max recommended single dose is 25 mg, except in extensive or intermediate CYP2D6 metabolizers, in which instance the max recommended single dose is 37.5 mg.
• Patients who appear to require doses higher than 50 mg/day should be genotyped for CYP2D6.
• Treatment may be discontinued without tapering.
• Following treatment interruption of more than 5 days or interruption because of a change in the patient's condition or concurrent drug treatment, retitrate tetrabenazine when treatment is resumed.
• Doses above 100 mg/day are not recommended for any patient.

Storage/Stability

Store at 59° to 86°F.

Drug Interactions

CNS depressant effects may be enhanced.

Risk of life-threatening cardiac arrhythmias may be increased; avoid coadministration with tetrabenazine.

Use with caution; effects have not been evaluated.

Tetrabenazine adverse reactions (eg, extrapyramidal effects, NMS, QTc prolongation) may be exaggerated.

To avoid overdosage and major depletion of serotonin and norepinephrine in the CNS when switching a patient from reserpine to tetrabenazine, allow chorea to reemerge before starting tetrabenazine. Allow at least 20 days to elapse after stopping reserpine before starting tetrabenazine.

Tetrabenazine plasma levels may be elevated; reduce tetrabenazine dosage by half.

Laboratory Test Interactions

None well documented.

Adverse Reactions

CNS

Any extrapyramidal event (33%); sedation/somnolence (31%); fatigue, insomnia (22%); akathisia, depression (19%); anxiety or aggravated anxiety (15%); balance difficulty, bradykinesia/parkinsonism, irritability (9%); decreased appetite, dizziness, dysarthria, headache, obsessive reaction, unsteady gait (4%).

GI

Nausea (13%); dysphagia (10%); vomiting (6%).

Genitourinary

Dysuria (4%).

Hematologic-Lymphatic

Ecchymosis (6%).

Respiratory

Upper respiratory tract infection (11%); bronchitis, shortness of breath (4%).

Miscellaneous

Falling (15%); head laceration (6%).

Precautions

Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established.

Special Risk Patients

Use with caution in patients with a history of depression or suicidality, or with conditions, diseases, or treatments that could cause depression or suicidality.

Dysphagia

Dysphagia is a component of Huntington disease and has been associated with drugs that reduce dopaminergic transmission, such as tetrabenazine; therefore, use with caution in patients at risk of aspiration pneumonia.

Hyperprolactinemia

Elevated serum prolactin concentrations may occur.

Hypotension/Orthostatic hypotension

Has been reported.

Melanin-containing tissue

Since tetrabenazine or its metabolites bind to melanin-containing tissue, toxicity in these tissues over time is a possibility.

NMS

Potentially life-threatening NMS has been reported.

Parkinsonism

May occur.

QTc prolongation

Small increases in the QTc interval may occur, increasing the risk of life-threatening arrhythmias, including torsades de pointes. Avoid use in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.

Sedation/Somnolence

Caution patients about operating potentially hazardous machinery (eg, driving) until they know whether the drug impairs their ability.

Tardive dyskinesia

A potentially irreversible syndrome of involuntary, dyskinetic movements may occur in patients receiving neuroleptic agents.

Overdosage

Symptoms

Acute dystonia, confusion, diarrhea, hallucinations, hypotension, nausea, oculogyric crisis, rubor, sedation, sweating, tremor, vomiting.

Patient Information

• Advise patient to read the Medication Guide that comes with the product before starting use and again with each refill.
• Inform patients of the risk of depression and suicidality, and instruct them to report behaviors of concern promptly to treating health care provider.
• Caution patients about operating potentially hazardous machinery (eg, driving) until they know whether the drug impairs their ability.
• Instruct patients to report symptoms of agitation, anxiety, hostility, insomnia, irritability, panic attacks, psychomotor restlessness, sadness, or worsening depression promptly to health care provider.
• Advise patients that while the dose of tetrabenazine is being titrated, symptoms such as akathisia, depression, difficulty in swallowing, parkinsonism, or sedation should be reported promptly to health care provider because dose reduction may be necessary.
• Advise patients that alcohol may potentiate tetrabenazine sedation.

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