Xenazine - Drug Monograph

Introduction

Xenazine (tetrabenazine) is a vesicular monoamine transporter 2 (VMAT2) inhibitor approved for the treatment of chorea associated with Huntington's disease. It is the first FDA-approved medication specifically indicated for this purpose. Xenazine works by depleting monoamine neurotransmitters, particularly dopamine, in the central nervous system, which helps reduce the involuntary movements characteristic of Huntington's chorea.

Mechanism of Action

Xenazine exerts its therapeutic effects through reversible inhibition of vesicular monoamine transporter 2 (VMAT2). This inhibition prevents the uptake of monoamines (dopamine, serotonin, norepinephrine, and histamine) into synaptic vesicles, leading to:

• Depletion of monoamine stores in nerve terminals
• Reduced dopamine neurotransmission in the basal ganglia
• Diminished hyperkinetic movements associated with Huntington's disease

The drug is a reversible, high-affinity VMAT2 inhibitor with weak dopamine D2 receptor antagonism.

Indications

FDA-approved indications:

• Treatment of chorea associated with Huntington's disease

Off-label uses (not FDA-approved):

• Tardive dyskinesia
• Tourette syndrome
• Other hyperkinetic movement disorders

Dosage and Administration

• 12.5 mg once daily
• May increase to 12.5 mg twice daily after one week

• Increase dosage at weekly intervals by 12.5 mg per day
• Maximum single dose: 25 mg
• Maximum daily dose: 100 mg (divided into three doses)

• Hepatic impairment: Use contraindicated in patients with impaired hepatic function
• Renal impairment: No dosage adjustment necessary
• Elderly: Use caution due to increased risk of sedation and parkinsonism
• Pediatrics: Safety and effectiveness not established

• Oral administration with or without food
• Tablets should be swallowed whole

Pharmacokinetics

• Rapidly absorbed after oral administration
• Time to peak concentration: 1-1.5 hours
• Bioavailability: Approximately 75%

• Volume of distribution: 1.2 L/kg
• Protein binding: 82-85%
• Crosses blood-brain barrier

• Extensive hepatic metabolism via carbonyl reductase
• Forms active metabolites: α-dihydrotetrabenazine and β-dihydrotetrabenazine
• CYP2D6 contributes to secondary metabolism

• Half-life: 4-8 hours (parent compound)
• Half-life of active metabolites: 4-8 hours
• Excretion: Primarily renal (75%), fecal (7-16%)

Contraindications

• Hepatic impairment
• Hypersensitivity to tetrabenazine or any component of the formulation
• Concomitant use with monoamine oxidase inhibitors (MAOIs) or within 14 days of MAOI use
• Patients with untreated or inadequately treated depression
• Suicidal ideation

Warnings and Precautions

• Depression and suicidal ideation: Xenazine can increase the risk of depression and suicidal thoughts and behavior

• Neuroleptic malignant syndrome: Rare cases reported
• Akathisia, restlessness, and agitation
• Parkinsonism: May exacerbate or cause parkinsonian symptoms
• Sedation and somnolence: May impair ability to operate machinery
• QTc prolongation: Use with caution in patients at risk
• Hyperprolactinemia: May occur due to dopamine depletion

Drug Interactions

• MAO inhibitors: Contraindicated (risk of serotonin syndrome)
• Reserpine: Avoid concomitant use (additive effects)
• Dopamine antagonists: Increased risk of parkinsonism
• Alcohol: Enhanced sedative effects
• CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine): May increase tetrabenazine levels

• Other CNS depressants: Additive sedation
• Levodopa: May diminish effectiveness

Adverse Effects

• Sedation/somnolence (31%)
• Fatigue (22%)
• Insomnia (22%)
• Depression (19%)
• Akathisia (19%)
• Nausea (13%)

• Depression with suicidal ideation
• Neuroleptic malignant syndrome
• Severe parkinsonism
• QTc prolongation
• Syncope

Monitoring Parameters

• Comprehensive psychiatric evaluation
• Hepatic function tests
• ECG (if risk factors for QTc prolongation)
• Movement disorder assessment
• Pregnancy test if applicable

• Weekly monitoring for depression and suicidal ideation for first month
• Monthly monitoring for depression thereafter
• Regular assessment of chorea symptoms
• Monitoring for parkinsonian symptoms
• Assessment of sedation and functional impairment
• Periodic hepatic function monitoring

Patient Education

• Take medication exactly as prescribed
• Do not abruptly discontinue medication
• Report any thoughts of depression or suicide immediately
• Avoid alcohol and other CNS depressants
• Be cautious when driving or operating machinery
• Inform all healthcare providers about Xenazine use
• Report any unusual movements or restlessness
• Use reliable contraception during treatment
• Keep medication out of reach of children

References

1. FDA Prescribing Information: Xenazine (tetrabenazine) tablets 2. Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology. 2006;66(3):366-372. 3. Kenney C, Jankovic J. Tetrabenazine in the treatment of hyperkinetic movement disorders. Expert Rev Neurother. 2006;6(1):7-17. 4. Jankovic J, Beach J. Long-term effects of tetrabenazine in hyperkinetic movement disorders. Neurology. 1997;48(2):358-362. 5. Armstrong MJ, Miyasaki JM. Evidence-based guideline: pharmacologic treatment of chorea in Huntington disease. Neurology. 2012;79(6):597-603. 6. Clinical Pharmacology [Internet]. Tampa (FL): Gold Standard, Inc.; 2023 [cited 2023 Nov 15].