Dosing and uses of Xenazine (tetrabenazine)
Adult dosage forms and strengths
tablet
- 12.5mg
- 25mg
Huntington Disease
Indicated for treatment of chorea associated with Huntington’s disease
Individualize and slowly titrate dosage over several weeks to identify a dose that reduces chorea and is well tolerated
Total daily dose up to 50 mg/day
- 12.5 mg PO qDay initially; after 1 week, the dose should be increased to 12.5 mg q12hr
- Maintenance: Titrate slowly by weekly intervals of 12.5 mg/day to identify dose that reduces chorea and is tolerated
- If daily dose is 37.5 to 50 mg/day, administer in divided doses q8hr
- Not to exceed 25 mg per single dose for total daily dosage between 37.5-50 mg/day
Total Daily dose >50 mg/day
- If >50 mg/day is required, test and genotype to determine if poor or extensive metabolizers of CYP2D6; not to exceed 100 mg/day or 37.5 mg/dose
- Dose maintenance requirements are dependent on CYP2D6 genotype (see Dosage modifications)
Dosage modifications
CYP2D6 extensive/intermediate metabolizers
- Extensive metabolizers may require dose >50 mg/day
- If total daily dose >50 mg/day, administer in divided doses q8hr
- Titrate slowly by 12.5 mg/day qWeek to identify dose that reduces chorea and is tolerated
- If >50 mg/day is required, do not to exceed 37.5 mg per single dose or a total daily dose of 100 mg/day
CYP2D6 poor metabolizers
- Not to exceed 25 mg per single dose or a total daily dose of 50 mg/day
Hepatic impairment
- Contraindicated; it is not possible to adjust the dose to ensure safe use
Dosing Considerations
May take with or without food
Dosage interruption >5 days: Retitrate dose when treatment resumed
Dosage interruption <5 days: May resume at previous maintenance dose without titration
Suspend upward dosage titration and reduce dose; discontinue if adverse reaction (intolerable effects such as: akathisia, restlessness, parkinsonism, insomnia, depression, suicidality, anxiety, sedation) does not resolve (may stop without taper)
Treatment discontinuation
- May discontinue without tapering
- Chorea may re-emerge within 12-18 hr after last dose
Tardive Dyskinesia (Off-label)
Investigational (see www.clinicaltrials.gov)
Pediatric dosage forms and strengths
Safety and efficacy not established
Xenazine (tetrabenazine) adverse (side) effects
>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
Warnings
Black box warnings
Increased risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease
Balance risks of depression and suicidality with the clinical need for control of choreiform movements when considering the use of tetrabenazine
Monitor for emergence or worsening of depression, suicidality, or unusual changes in behavior
Inform patients, caregivers and families of the risk of depression and suicidality and instruct to report behaviors of concern promptly to the treating physician
Caution in patients with a history of depression or prior suicide attempts or ideation
Contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression
Contraindications
Hypersensitivity
Hepatic impairment
Patients who are actively suicidal, or who have untreated or inadequately treated depression (see Black box warnings)
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; 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 and lactation
Pregnancy category: C
Lactation: Unknown whether distributed in breast milk
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.
Pharmacology of Xenazine (tetrabenazine)
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
