Section 03 · Monograph

Tetrabenazine

Reviewed Nov 2026FDA label

XenazineVMAT2 inhibitor

Black Box Warning

Tetrabenazine can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease.
Prescribers must balance the risks of depression and suicidality against the clinical need for control of chorea when considering use of tetrabenazine.
Patients, caregivers, and families should be informed of the risk of depression and suicidality and instructed to report behavioral changes promptly to the treating physician.
Exercise particular caution in treating patients with a history of depression or prior suicide attempts or ideation, as these are more common in the Huntington's disease population.
Tetrabenazine is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression.

Treatment of chorea associated with Huntington's disease (Xenazine and generic tetrabenazine)FDA-labeled

Tardive dyskinesia (well-documented off-label use for hyperkinetic movement disorders)Off-label
Tourette syndrome / chronic tic disordersOff-label
Other hyperkinetic movement disorders including tardive dystonia and hemiballismus (based on published literature, not an FDA-approved indication)Off-label

Reversible inhibitor of vesicular monoamine transporter type 2 (VMAT2), which depletes monoamines (dopamine, serotonin, norepinephrine, histamine) from presynaptic nerve terminals
The precise mechanism by which monoamine depletion reduces chorea is not fully established
Active circulating metabolites alpha-HTBZ and beta-HTBZ have high affinity for VMAT2 and are principally responsible for pharmacologic activity
Weak affinity for dopamine D2 receptors (Ki ≈ 2100 nM), distinct from antipsychotic dopamine-blocking mechanism, though it can still cause parkinsonism/EPS-like effects via monoamine depletion

Initiate at 12.5 mg once daily; after 1 week increase to 12.5 mg twice daily (25 mg/day)
Titrate weekly in 12.5 mg increments based on efficacy/tolerability; doses of 37.5–50 mg/day must be given three times daily; maximum single dose 25 mg
For total daily doses above 50 mg/day, CYP2D6 genotyping is required: poor metabolizers max 50 mg/day (single dose ≤25 mg); extensive/intermediate metabolizers max 100 mg/day (single dose ≤37.5 mg)
With strong CYP2D6 inhibitors, do not exceed 50 mg/day total, with single doses ≤25 mg
No tapering required on discontinuation, but chorea may re-emerge within 12–18 hours
After a treatment interruption of more than 5 days, restart with initial titration schedule; if interruption is under 5 days, prior maintenance dose may be resumed

Active suicidal ideation, or untreated/inadequately treated depression
Hepatic impairment (any degree)
Concomitant use of a monoamine oxidase inhibitor (MAOI), or use within 14 days of discontinuing an MAOI
Concomitant use with reserpine; allow at least 20 days after stopping reserpine before starting tetrabenazine
Concomitant use of deutetrabenazine or valbenazine
History of congenital long QT syndrome or history of cardiac arrhythmias associated with QTc prolongation

Strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine) markedly increase active metabolite exposure — reduce tetrabenazine dose accordingly (max 50 mg/day, single dose ≤25 mg)
MAOIs — contraindicated; requires 14-day washout before starting tetrabenazine
Reserpine — contraindicated concurrently; requires ≥20 day washout after stopping reserpine before initiating tetrabenazine
QTc-prolonging drugs (certain antipsychotics, certain antibiotics such as moxifloxacin, Class IA/III antiarrhythmics) — avoid concurrent use; tetrabenazine itself increases QTc by ~8 msec
Neuroleptic/dopamine antagonist drugs (chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone) — increased risk of parkinsonism, neuroleptic malignant syndrome, and akathisia
Alcohol and other sedating/CNS-depressant drugs — additive sedation
Deutetrabenazine or valbenazine — contraindicated concomitant use (duplicative VMAT2 inhibition)
No clinically significant effect on digoxin bioavailability (tetrabenazine does not inhibit P-glycoprotein at clinically relevant doses)

Sedation/somnolence (~31% vs 3% placebo in the pivotal 12-week trial) — dose-limiting in many patients
Insomnia (22% vs 0%)
Fatigue (22% vs 13%)
Depression (19% vs 0%)
Akathisia/restlessness/agitation (19% vs 0%)
Anxiety or aggravated anxiety (15% vs 3%)
Falls (15% vs 13%)
Nausea (13% vs 7%)
Parkinsonism/bradykinesia (9% vs 0%) and other extrapyramidal reactions (33% overall vs 0% placebo)
Dysphagia (4% in short-term trials, 8–10% in longer open-label studies; some cases associated with aspiration pneumonia)
Neuroleptic malignant syndrome (rare, potentially fatal)
QTc prolongation
Orthostatic hypotension/postural dizziness
Hyperprolactinemia
Postmarketing: tremor, confusion, worsening aggression, pneumonia, hyperhidrosis, skin rash

Screen for depression and suicidality at baseline and monitor at every visit throughout treatment (Black Box Warning)
Obtain CYP2D6 genotype before exceeding 50 mg/day
Monitor standing and supine blood pressure for orthostatic hypotension
Consider baseline ECG in patients with risk factors for QTc prolongation; avoid in congenital long QT syndrome or arrhythmia history
Watch for signs of neuroleptic malignant syndrome (hyperpyrexia, rigidity, altered mental status, autonomic instability) and discontinue immediately if suspected
Periodically reassess chorea control against emerging adverse effects (parkinsonism, sedation, akathisia, dysphagia, cognitive/mood changes)
Evaluate for symptomatic hyperprolactinemia if clinically suspected
Consider periodic ophthalmologic evaluation with long-term use given melanin-binding potential
Liver function should be normal prior to initiation (contraindicated in any hepatic impairment)

Pregnancy: no adequate data on use in pregnant women; animal studies (tetrabenazine and its major human metabolite) showed increased stillbirths, postnatal mortality, decreased growth, and neurobehavioral/reproductive impairment at clinically relevant exposures — potential for fetal harm
Lactation: no data on presence in human milk, effects on the breastfed infant, or effects on milk production; weigh developmental/health benefits of breastfeeding against the mother's clinical need for tetrabenazine and any potential infant adverse effects
Not established as safe in pediatric patients