tetrabenazine (Rx)

>10%

Sedation/somnolence (31%)

Fatigue (22%)

Insomnia (22%)

Depression (19%)

Akathisia (19%)

Extrapyramidal event (15%)

Anxiety (15%)

Nausea (13%)

1-10%

Irritability (9%)

Bruising (6%)

Vomiting (6%)

Decreased appetite (4%)

Dysuria (4%)

Obsessive reaction (4%)

Imbalance (9%)

Parkinsonism/bradykinesia (9%)

Dizziness (4%)

Dysarthria (4%)

Unsteady gait (4%)

Headache (4%)

Frequency Not Defined

QTc prolongation

Neuroleptic malignant syndrome

Orthostatic Hypotension

Restlessness and agitation

Dysphagia

Depression and suicidality

Postmarketing Reports

Nervous system disorders: Tremor

Psychiatric disorders: Confusion, worsening aggression, depression/suicidality

Respiratory, thoracic and mediastinal disorders: Pneumonia

Skin and subcutaneous tissue disorders: Hyperhidrosis, skin rash

Endocrine system: Hyperprolactinemia

Contraindications

Hypersensitivity

Hepatic impairment

Patients who are actively suicidal, or who have untreated or inadequately treated depression (see Black Box Warnings)

Coadministration with deutetrabenazine or valbenazine

Concomitant MAO inhibitor or within 14 days of discontinuing MAO inhibitor

Reserpine

• Do not use tetrabenazine and reserpine concomitantly
• Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days
• Caution when switching from reserpine to tetrabenazine; wait for chorea to re-emerge before administering tetrabenazine to avoid overdosage and major CNS depletion of serotonin and norepinephrine
• At least 20 days should elapse after stopping reserpine before starting tetrabenazine

Cautions

Not indicated for treatment of levodopa-induced dyskinetic movements

Should only be used by physicians experienced with treatment of hyperkinetic disorders

May cause depression; consider risk of suicidality; should be balanced against need for treatment of chorea; discontinue at first sign

May induce symptoms of Parkinsonism, including symptoms of tardive dyskinesia; akathisia, restlessness, and agitation may occur; reduce dose or discontinue

Dysphagia, a component of Huntington chorea, may also be caused by dopamine antagonists such as tetrabenazine

Neuroleptic malignant syndrome (NMS) reported; clinical manifestations include hyperpyrexia, muscle rigidity, altered mental status and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia); additional signs include elevated creatinine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure

May cause sedation/somnolence; avoid alcohol and other sedative drugs

May prolong QTc interval

May cause orthostatic hypotension

Concomitant use of neuroleptics (eg, haloperidol, chlorpromazine, risperidone, olanzapine) may cause additive effects of QTc prolongation, NMS, and extrapyramidal disorders

Caution with poor CYP2D6 metabolizers or drugs that inhibit CYP2D6 (eg, fluoxetine, paroxetine, quinidine); may markedly increase exposure to tetrabenazine active metabolites (alpha- and beta-HTBZ)

Hyperprolactinemia has resulted from dopaminergic antagonists

Pregnancy

There are no adequate data on the developmental risk associated with therapy in pregnant women; administration of tetrabenazine to rats throughout pregnancy and lactation resulted in an increase in stillbirths and postnatal offspring mortality

Lactation

There are no data on presence of tetrabenazine or metabolites in human milk, effects on breastfed infant, or on milk production; developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and potential adverse effects on breastfed infant or underlying maternal condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Reversibly inhibits human vesicular monoamine transporter type 2 (VMAT2), resulting in decreased uptake of monoamines (eg, dopamine, serotonin, norepinephrine, histamine) into synaptic vesicles and depletion of monoamine stores from nerve terminals

This effect is similar to reserpine, but with less peripheral activity and is shorter-acting

Absorption

Extent of absorption is at least 75%

Distribution

Protein Bound: 82-85%; 59-68% (metabolites)

Parent drug and metabolites bind to melanin-containing tissues (ie, eye, skin)

Rapidly distributed in brain (highest binding in striatum, lowest binding in cortex)

Metabolism

Rapid and extensively metabolized in liver by carbonyl reductase to active metabolites

Metabolites (active): alpha-hydroxytetrabenazine, beta-hydroxytetrabenazine

Active metabolites are predominantly metabolized by CYP2D6

Elimination

Half-Life: 7 hr (alpha-hydroxytetrabenazine); 5 hr (beta-hydroxytetrabenazine)

Excretion: 75% urine; 7-16% feces; excreted mostly as metabolites