Usage
- Tetrabenazine is prescribed for the treatment of chorea associated with Huntington’s disease. Huntington’s disease is a rare, inherited disease that causes the progressive breakdown of nerve cells in the brain.
- Pharmacological classification: Vesicular monoamine transporter 2 (VMAT2) inhibitor.
- Mechanism of Action: Tetrabenazine depletes monoamines, such as dopamine, serotonin, norepinephrine, and histamine, in the central nervous system by reversibly binding to VMAT2. This helps control involuntary body movements (chorea) associated with Huntington’s disease.
Alternate Names
- No alternate generic names are commonly used.
- Brand Name: Xenazine
How It Works
- Pharmacodynamics: Tetrabenazine primarily affects the central nervous system by depleting monoamines, leading to a reduction in chorea.
- Pharmacokinetics:
- Absorption: Tetrabenazine is well-absorbed orally.
- Metabolism: Extensively metabolized in the liver primarily via CYP2D6. Two active metabolites, alpha-dihydrotetrabenazine (alpha-HTBZ) and beta-dihydrotetrabenazine (beta-HTBZ), are formed.
- Elimination: Primarily via the kidneys.
- Mode of Action: Tetrabenazine reversibly binds to VMAT2, inhibiting the transport of monoamines into synaptic vesicles, thus depleting monoamine stores.
- Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: VMAT2 inhibition.
- Elimination Pathways: Primarily renal excretion of metabolites.
Dosage
Standard Dosage
Adults:
- Initial: 12.5 mg/day orally, given as a single dose in the morning.
- Titration: Increase dose by 12.5 mg every 3 or 4 days, or weekly, until the desired effect is achieved, side effects become intolerable, or the total daily dose reaches the maximum recommended dosage.
- Usual Range: 25-100 mg/day (maximum recommended dosage).
- Frequency: Doses over 37.5 mg/day should be divided into two or three doses per day; no single dose should exceed 25 mg initially.
- CYP2D6 Genotyping: Recommended for patients requiring doses greater than 50 mg/day to determine appropriate dosage adjustments.
Children:
- No established dosing guidelines for children; use with caution and under close monitoring by a specialist.
Special Cases:
- Elderly Patients: Start at a low dose and titrate cautiously.
- Patients with Renal Impairment: No dosage adjustments are formally recommended, but close monitoring for adverse effects is warranted.
- Patients with Hepatic Dysfunction: Contraindicated in patients with hepatic impairment.
- Patients with Comorbid Conditions: Use with caution in patients with depression or suicidal ideation, cardiovascular disease (especially QTc prolongation), Parkinson’s disease, or those taking drugs that prolong the QTc interval.
Clinical Use Cases
Tetrabenazine is specifically indicated for chorea associated with Huntington’s disease. It is not typically used in the clinical settings listed (intubation, surgical procedures, mechanical ventilation, ICU use, emergency situations).
Dosage Adjustments
- CYP2D6 Poor Metabolizers: Maximum single dose of 25 mg and a maximum daily dose of 50 mg.
- Concomitant CYP2D6 Inhibitors: Maximum daily dose of 50 mg and a maximum single dose not to exceed 25 mg if administered with a strong CYP2D6 inhibitor.
Side Effects
Common Side Effects
- Drowsiness, sedation, fatigue
- Insomnia
- Depression, anxiety, agitation
- Nausea, vomiting
- Akathisia, Parkinsonism
- Dizziness
Rare but Serious Side Effects
- Neuroleptic malignant syndrome (NMS)
- Suicidal ideation or behavior
- QT prolongation
- Dysphagia and risk of aspiration pneumonia
- Tardive dyskinesia
Long-Term Effects
- Tardive dyskinesia
- Worsening of underlying psychiatric conditions
Adverse Drug Reactions (ADR)
- Neuroleptic malignant syndrome (NMS)
- Suicidal ideation or behavior
- Severe dysphagia or aspiration pneumonia
- QT prolongation with risk of torsades de pointes
- Severe parkinsonism
Contraindications
- Untreated or inadequately treated depression
- Active suicidal ideation
- Hepatic impairment
- Concomitant use of MAO inhibitors or reserpine (wait at least 14 days after discontinuing MAOIs and 20 days after reserpine)
Drug Interactions
- MAO Inhibitors: Contraindicated; may cause a severe hypertensive crisis.
- Reserpine: Contraindicated; may enhance hypotensive effects.
- CYP2D6 Inhibitors (e.g., fluoxetine, paroxetine, quinidine): Significantly increase tetrabenazine levels; dosage adjustment needed.
- Drugs that prolong the QTc interval (e.g., antipsychotics, certain antibiotics, Class IA and III antiarrhythmics): Increased risk of QT prolongation and torsades de pointes.
- Alcohol: May potentiate sedative effects.
- Levodopa: Tetrabenazine may decrease its effectiveness.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: C (Animal studies have shown adverse effects, but adequate studies in pregnant women have not been conducted.)
- Fetal Risks: Potential for fetal harm based on animal data.
- Breastfeeding: Tetrabenazine is excreted in breast milk; breastfeeding is not recommended.
Drug Profile Summary
- Mechanism of Action: VMAT2 inhibitor, depletes monoamines in the CNS.
- Side Effects: Drowsiness, fatigue, insomnia, depression, akathisia, nausea, NMS, suicidal ideation, QT prolongation, dysphagia, tardive dyskinesia.
- Contraindications: Depression, suicidal ideation, hepatic impairment, MAOI or reserpine use.
- Drug Interactions: MAOIs, reserpine, CYP2D6 inhibitors, drugs that prolong the QTc interval, alcohol, levodopa.
- Pregnancy & Breastfeeding: Not recommended during pregnancy or breastfeeding.
- Dosage: Start at 12.5 mg/day, titrate up to 100 mg/day (divided doses). Adjust dosage for CYP2D6 inhibitors or poor metabolizers.
- Monitoring Parameters: Chorea severity, psychiatric status (especially for depression and suicidality), ECG (QTc interval), extrapyramidal symptoms, swallowing function, liver function tests (periodically).
Popular Combinations
No specific drug combinations are routinely recommended with tetrabenazine for Huntington’s disease. Treatment is individualized based on the patient’s specific needs and comorbidities.
Precautions
- General Precautions: Screen for depression, suicidality, hepatic dysfunction, and cardiac conditions (especially QTc prolongation) before initiating therapy.
- Pregnant Women: Avoid use unless the benefits clearly outweigh the risks.
- Breastfeeding Mothers: Do not breastfeed while taking tetrabenazine.
- Children & Elderly: Use cautiously in both groups; start with a low dose and titrate slowly.
- Lifestyle Considerations: Avoid alcohol. Driving or operating machinery should be avoided until the effects of the medication are known, as it can cause drowsiness and impaired cognition.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Tetrabenazine?
A: Initial dose is 12.5 mg/day, titrated up to a maximum of 100 mg/day as tolerated and needed to control symptoms. Doses above 37.5 mg/day should be divided.
Q2: What are the most common side effects of Tetrabenazine?
A: Drowsiness, fatigue, insomnia, depression, anxiety, nausea, akathisia, and parkinsonism.
Q3: Can Tetrabenazine be used in patients with depression?
A: Tetrabenazine can exacerbate depression and increase the risk of suicidality. It is contraindicated in patients with untreated or inadequately treated depression and should be used with extreme caution in those with a history of depression.
A: Neuroleptic malignant syndrome (NMS), new or worsening depression or suicidal ideation, QT prolongation, severe dysphagia, and tardive dyskinesia.
Q5: What are the drug interactions to be aware of with Tetrabenazine?
A: MAO inhibitors (contraindicated), reserpine (contraindicated), CYP2D6 inhibitors (require dosage adjustment), drugs that prolong the QTc interval (use with caution), levodopa (may reduce efficacy), and alcohol (increases sedation).
Q6: Can Tetrabenazine be used during pregnancy or breastfeeding?
A: Tetrabenazine is generally not recommended during pregnancy due to potential fetal harm. It should not be used during breastfeeding as it is excreted in breast milk.
Q7: What should be monitored in patients taking Tetrabenazine?
A: Chorea severity, psychiatric status, ECG for QTc interval, extrapyramidal symptoms, swallowing function, and periodically, liver function tests.
Q8: What is the mechanism of action of Tetrabenazine?
A: Tetrabenazine is a reversible inhibitor of VMAT2, reducing monoamine stores in the central nervous system, thereby alleviating chorea.
Q9: How should Tetrabenazine be discontinued?
A: It should be tapered gradually to minimize the risk of symptom recurrence or withdrawal effects.
A: Tetrabenazine is primarily metabolized by CYP2D6. Patients with poor CYP2D6 metabolism or taking concomitant CYP2D6 inhibitors require lower doses of tetrabenazine. Genotyping is recommended for patients needing doses above 50 mg/day.
