Benazin

Approved Indications:

• Chorea associated with Huntington’s disease (FDA approved)
• Tardive dyskinesia (in select countries, off-label use in some regions)
• Tourette syndrome (off-label use in refractory cases)
• Hemiballismus (off-label)
• Dystonia (including idiopathic and secondary dystonias, off-label)
• Tics and tic disorders in children/adolescents (off-label and investigational use)
• Ballism or hyperkinetic movement disorders due to various neurodegenerative or post-encephalitic etiologies (off-label)

General Administration:

• Oral route only. May be taken with or without food.
• Tablets should be swallowed whole and not crushed.

Adults:

• Chorea associated with Huntington’s disease:
• Initial: 12.5 mg once daily.
• After 1 week: Increase to 12.5 mg twice daily.
• Titrate weekly by 12.5 mg/day.
• Maximum dose: 100 mg/day in divided doses (typically TID).
• If daily dose >50 mg: Assess CYP2D6 metabolizer status and consider dose adjustment.

Pediatrics (off-label use):

• Tourette’s syndrome/tics:
• Start at 0.25 mg/kg/day or 6.25 mg once daily.
• Titrate based on response and tolerability.
• Max dose: 100 mg/day or per clinical judgment.

Geriatrics:

• Start at lower doses due to decreased hepatic metabolism.
• Close monitoring required.

Hepatic impairment:

• Contraindicated in severe hepatic dysfunction.
• Use with caution in mild to moderate impairment; slower titration recommended.

Renal impairment:

• No formal guidelines, but caution is advised due to limited data.

Missed dose:

• If a dose is missed, skip and resume at next scheduled time. Do not double dose.

Tetrabenazine is a reversible inhibitor of vesicular monoamine transporter 2 (VMAT2). It depletes presynaptic dopamine by preventing its storage and transport into synaptic vesicles, leading to functional reduction of dopaminergic neurotransmission in the CNS. This reduction in dopamine activity helps suppress hyperkinetic movements such as chorea, tics, or dystonia. It may also mildly affect serotonin and norepinephrine storage at higher doses.

• Absorption: Rapid oral absorption; bioavailability ~5–10% due to first-pass metabolism.
• Distribution: Widely distributed; moderate plasma protein binding (~80%).
• Metabolism: Extensively metabolized in the liver via carbonyl reductase to active metabolites: α-dihydrotetrabenazine and β-dihydrotetrabenazine. Further metabolized via CYP2D6.
• Half-life: Parent compound: ~6 hours; active metabolites: 4–8 hours.
• Excretion: Primarily renal (urine); minor via feces.
• Time to peak concentration (Tmax): ~1–1.5 hours.

• Pregnancy: Not assigned a formal FDA pregnancy category. Animal studies show potential fetal harm at high doses. Human data are limited; use only if potential benefit justifies the risk.
• Lactation: Unknown whether tetrabenazine is excreted in human milk. Due to the potential for serious adverse reactions in nursing infants, a risk-benefit decision should be made. Breastfeeding is generally not recommended during treatment.

• Primary class: Vesicular Monoamine Transporter 2 (VMAT2) Inhibitor
• Subclass: Antichorea/Antidyskinetic agent

• Known hypersensitivity to tetrabenazine or any component of the formulation
• Actively suicidal or untreated/undertreated depression
• Hepatic impairment (severe)
• Concomitant use with MAO inhibitors (within 14 days)
• Use with reserpine (within 20 days)
• Prolonged QT interval or history of arrhythmia (relative contraindication)

• Suicidality and depression: Increased risk of depression and suicidal ideation; monitor mood and behavior frequently, especially during dose titration.
• Parkinsonism: May induce or worsen parkinsonian symptoms.
• QT prolongation: Caution in patients with congenital long QT syndrome or taking QT-prolonging agents.
• Neuroleptic malignant syndrome (NMS): Rare but serious; discontinue if suspected.
• Akathisia/restlessness: Monitor and manage accordingly.
• CYP2D6 poor metabolizers: Risk of increased exposure to active metabolites; genetic testing may guide dosing if >50 mg/day is used.
• Hypotension: Risk of orthostatic hypotension, especially in elderly.

Common:

• CNS: Somnolence, insomnia, depression, anxiety, fatigue, akathisia
• GI: Nausea, dry mouth
• Neurological: Dizziness, parkinsonism, tremor

Serious:

• Suicidal ideation or behavior
• Neuroleptic malignant syndrome
• Severe depression
• Prolonged QT interval
• Extrapyramidal symptoms (e.g., dystonia, bradykinesia)

Rare:

• Seizures
• Hepatotoxicity
• Blood dyscrasias (very rare)

Side effects often dose-dependent and may resolve with dose reduction or discontinuation.

• MAO inhibitors: Contraindicated; may lead to hypertensive crisis.
• Reserpine: Avoid use within 20 days due to additive dopaminergic depletion.
• CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine): Increase tetrabenazine exposure; dose adjustment required.
• Alcohol: May enhance CNS depressive effects; avoid or limit use.
• Antipsychotics: Additive risk of extrapyramidal symptoms.
• QT-prolonging agents: Additive risk; monitor ECG if used concurrently.

• Revised labeling now recommends CYP2D6 genotyping for patients exceeding 50 mg/day dosing to avoid toxicity.
• Guidance from movement disorder societies supports its use in off-label indications such as tardive dyskinesia when other options fail.
• No major regulatory changes in EMA/FDA guidance since the last update, but emphasis on suicide risk monitoring has increased in recent clinical guidance.

• Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C.
• Protect from moisture and light.
• Do not refrigerate or freeze.
• Keep in tightly closed container.
• Keep out of reach of children.