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Class: Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors
- Adrenergic Uptake Inhibitors
- Central Monoamine-depleting Agents
- Monoamine-depleting Agents
- Monoamine Depletors
- Vesicular Monoamine Transporter 2 (VMAT2) Inhibitors
- VMAT2 Inhibitors
Chemical Name: cisrac-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one
Molecular Formula: C19H27NO3
CAS Number: 58-46-8
Brands: Xenazine

Medically reviewed by on Dec 1, 2021. Written by ASHP.


  • Tetrabenazine increases risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease; balance this risk with clinical need for treatment of chorea.

  • Closely observe all patients for emergence or clinical worsening of depression, suicidality, or unusual changes in behavior; involve family members and/or caregivers in this process. (See Risk of Depression and Suicidality under Cautions.)

  • Exercise particular caution when treating patients with a history of depression or prior suicide attempts or ideation, which are increased in frequency in Huntington's disease.

  • Tetrabenazine is contraindicated in patients who are suicidal and in patients with untreated or inadequately treated depression.


Tetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, is a monoamine-depleting agent.

Uses for Tetrabenazine

Huntington's Chorea

Symptomatic management of chorea associated with Huntington's disease in adults; designated an orphan drug by FDA for this use.

Patients receiving tetrabenazine may experience slight worsening of cognition, functional capacity, mood, or rigidity; not known whether these effects persist, worsen, or resolve over time. Periodically reevaluate long-term risks and benefits of the drug for the individual patient. (See Clinical Worsening and Adverse Events under Cautions.)

Other Hyperkinetic Movement Disorders

Has been used with some success for the symptomatic management of other hyperkinetic movement disorders (also called hyperkinesias), including hemiballismus, senile chorea, Tourette's syndrome (Gilles de la Tourette's syndrome) (see Pediatric Use under Cautions), tic disorder, and tardive dyskinesia (including severe and/or refractory cases).

Tetrabenazine Dosage and Administration


  • Allow at least 14 days to elapse between discontinuance of an MAO inhibitor and initiation of tetrabenazine; in addition, allow at least 20 days to elapse between discontinuance of reserpine and initiation of tetrabenazine. (See Specific Drugs under Interactions.)

  • Observe closely for clinical worsening or emergence of depression, suicidal thoughts or behavior (suicidality), or unusual changes in behavior. (See Boxed Warning and also see Risk of Depression and Suicidality under Cautions.)

Restricted Distribution

Available only through specialty pharmacies. Consult the Xenazine Information Center at 888-882-6013 or the manufacturer's website at [Web] for specific information.


Oral Administration

Administer orally without regard to food.

Dosages ≥37.5 mg daily: Administer in 3 divided doses.

Do not double the next dose if a dose is missed and it is time for the next dose.


If used with a potent CYP2D6 inhibitor, dosage adjustment required. (See Interactions.)

Carefully titrate dosage over several weeks to determine an individualized dosage for chronic use that reduces chorea and is well tolerated.

May discontinue treatment without tapering the dosage. Retitrate dosage if therapy is resumed following an interruption of >5 days. May resume treatment at the previous maintenance dosage (without titration) following treatment interruption of <5 days.


Huntington's Chorea

Initially, 12.5 mg given once daily in the morning. Increase dosage after one week to 12.5 mg twice daily. Adjust subsequent dosages in 12.5-mg increments at weekly intervals.

If daily dosage is ≤50 mg, the maximum recommended single dose is 25 mg.

Manufacturer recommends CYP2D6 genotype testing prior to administering dosages >50 mg daily to determine whether patient is a poor, intermediate, or extensive metabolizer of CYP2D6 substrates. (See Table 1.) However, some clinicians prefer to adjust tetrabenazine dosage based on clinical response and tolerability.

Administer dosages >50 mg daily in 3 divided doses and make dosage adjustments in 12.5-mg increments at weekly intervals.

Table 1. Maximum Recommended Adult Dosage of Tetrabenazine Based on CYP2D6 Phenotype1

CYP2D6 Phenotype

Maximum Single Dose

Maximum Daily Dosage

Poor metabolizer

25 mg

50 mg

Intermediate or extensive metabolizer

37.5 mg

100 mg

Stop dosage titration and reduce daily dosage if adverse effects (e.g., excessive sedation, akathisia, restlessness, parkinsonism, depression, insomnia, anxiety) occur; consider drug discontinuance or initiation of specific treatment (e.g., antidepressant therapy) if adverse effects do not resolve.

Daily dosages >100 mg are not recommended; however, higher dosages have been used in some patients.

Other Hyperkinetic Movement Disorders†

Initial dosage of 25 mg once or twice daily has been used in clinical studies in patients with various hyperkinesias, and then increased in 25-mg daily increments every 1–3 days until optimal therapeutic response, intolerable adverse effects, or maximum dosage of 100–200 mg daily was achieved.

One non-US manufacturer recommends initial dosage of 25 mg given 3 times daily, with titration in 25-mg daily increments every 3 or 4 days until maximum tolerated dosage (not exceeding 200 mg daily) is achieved in patients with hyperkinetic movement disorders other than tardive dyskinesia. If no improvement occurs at maximum tolerated dosage within 7 days, drug is unlikely to be effective despite increase in dosage or duration of treatment.

Tardive Dyskinesia†

One non-US manufacturer recommends initial dosage of 12.5 mg daily, with subsequent dosage titration based on response; discontinue if no clear benefit or if adverse effects cannot be tolerated.

Tourette's Syndrome†

Clinical experience is limited; some clinicians recommend initial dosage of 12.5–25 mg given once daily at bedtime or twice daily, with titration to a target dosage of 25 mg given 3 times daily and a maximum dosage of 50 mg given 3 times daily.

Prescribing Limits


Huntington's Chorea

Maximum 100 mg daily.

Poor CYP2D6 metabolizer phenotype: Maximum 50 mg daily.

Other Hyperkinetic Movement Disorders†

Maximum 100–200 mg daily.

Special Populations

Hepatic Impairment

Contraindicated in hepatic impairment. (See Hepatic Impairment under Cautions; see Absorption: Special Populations, under Pharmacokinetics; and see also Elimination: Special Populations, under Pharmacokinetics.)

Renal Impairment

Manufacturer provides no specific dosage recommendations.

Geriatric Patients

Manufacturer in US provides no specific dosage recommendations. However, at least one manufacturer outside the US recommends reduced initial and maintenance dosages.

Poor CYP2D6 Metabolizers

Do not exceed 50 mg daily (maximum single dose 25 mg). (See Poor CYP2D6 Metabolizers under Cautions.)

Cautions for Tetrabenazine


  • Actively suicidal or untreated or inadequately treated depression.

  • Hepatic impairment.

  • Concomitant therapy with an MAO inhibitor. (See Specific Drugs under Interactions.)

  • Concomitant therapy with reserpine. (See Specific Drugs under Interactions.)

  • Concomitant therapy with deutetrabenazine. (See Specific Drugs under Interactions.)



Risk of Depression and Suicidality

Increased risk for depression and for suicidal ideation and behavior (suicidality) in patients with Huntington's disease. Tetrabenazine increases this risk, which may increase with higher dosages. Depression or worsening of depression reported in 19–35% of tetrabenazine-treated patients; completed suicide, attempted suicide, and suicidal ideation reported. Depression more likely to occur or worsen in patients with history of depression.

Balance potential risks of depression and suicidality with clinical need for control of chorea. Closely observe patients for emergence or worsening of depression, suicidality, or unusual changes in behavior. Inform patients, caregivers, and families of these risks and instruct them to promptly report any behaviors of concern to the treating clinician. Immediately evaluate any patient with Huntington's disease who expresses suicidal ideation. Consider drug discontinuance if depression or suicidality does not resolve.

Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation; such patients may be at an increased risk for suicidal behavior.

Contraindicated in patients who are actively suicidal or those with untreated or inadequately treated depression.

Other Warnings and Precautions

Clinical Worsening and Adverse Events

Slight worsening in mood, cognition, rigidity, and functional capacity may occur; unknown whether these effects persist, resolve, or worsen with continued treatment.

Periodically reevaluate need for continued therapy by assessing benefits on chorea and possible adverse effects (e.g., depression, cognitive decline, parkinsonism, dysphagia, sedation, somnolence, akathisia, restlessness, disability). Dosage reduction or drug discontinuance may help distinguish between drug-induced adverse effects and disease progression. Underlying chorea may improve over time, thereby possibly decreasing the need for tetrabenazine.

Determining CYP2D6 Metabolizer Status

Testing for CYP2D6 status recommended prior to administering tetrabenazine dosages >50 mg daily. Limit dosage to ≤50 mg daily and single dose to ≤25 mg for poor metabolizer phenotype. (See Dosage under Dosage and Administration and also see Absorption: Special Populations, under Pharmacokinetics.)

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome characterized by hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability, has been reported with tetrabenazine and other drugs that reduce dopaminergic transmission.

Immediately discontinue therapy and initiate supportive and symptomatic therapy if NMS occurs. Monitor for signs of recurrence if therapy is reinstituted following recovery from NMS.

Akathisia, Restlessness, and Agitation

Akathisia reported in up to 20% of tetrabenazine-treated patients.

Monitor for akathisia and symptoms of restlessness and agitation. Reduce tetrabenazine dosage if akathisia develops; drug discontinuance may be necessary in some patients.


Symptoms suggestive of parkinsonism (e.g., bradykinesia, hypertonia, rigidity) reported in 3–15% of tetrabenazine-treated patients. May be difficult to distinguish between drug-induced effect and rigidity associated with progression of Huntington's disease. For some patients, drug-induced parkinsonism may result in more functional disability than untreated chorea.

If parkinsonism develops, consider dosage reduction; some patients may require drug discontinuance.


Dysphagia, sometimes associated with aspiration pneumonia, reported in 4–10% of tetrabenazine-treated patients. Causal relationship not established; dysphagia is a manifestation of Huntington's disease and esophageal dysmotility and dysphagia also are reported with drugs that reduce dopaminergic transmission, including tetrabenazine.

Sedation and Somnolence

Sedation is the most common dose-limiting adverse effect. Sedation or somnolence reported in 17–57% of patients receiving tetrabenazine in clinical studies. Sedation was the reason for stopping upward titration of tetrabenazine dosage and/or decreasing dosage in 28% of patients in one placebo-controlled study. May occur at lower than recommended dosages in some patients. (See Dosage under Dosage and Administration and also see Advice to Patients.)

Prolongation of QT Interval

Small increase in corrected QT (QTc) interval reported. Avoid use in patients concurrently receiving other drugs known to prolong the QTc interval and in patients with congenital long QT syndrome or history of cardiac arrhythmias. (See Drugs that Prolong QT Interval under Interactions.)

Factors that may increase the risk of torsades de pointes and/or sudden death in association with drugs that prolong the QTc interval include bradycardia, hypokalemia or hypomagnesemia, concomitant use of other drugs that prolong the QTc interval, and presence of congenital QTc interval prolongation.

Hypotension and Orthostatic Hypotension

Postural dizziness, including syncope and orthostasis, and dizziness reported. Consider monitoring orthostatic vital signs in patients who are vulnerable to hypotension.


May cause elevated serum prolactin concentrations.

If contemplating tetrabenazine therapy in a patient with previously detected breast cancer, consider that approximately one-third of human breast cancers are prolactin dependent in vitro. In addition, chronic hyperprolactinemia has been associated with low estrogen concentrations and an increased risk of osteoporosis.

Perform appropriate laboratory testing and consider drug discontinuance if symptomatic hyperprolactinemia suspected.

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary, dyskinetic movements, reported with antipsychotic agents. No clear cases reported with tetrabenazine, but other extrapyramidal adverse effects typically associated with antipsychotic agents (e.g., parkinsonism, akathisia) may occur with the drug.

Consider discontinuance of tetrabenazine if signs and symptoms of tardive dyskinesia appear.

Binding to Melanin-containing Tissues

Binds to melanin-containing tissues, possibly resulting in accumulation and toxicity with long-term use; clinical importance unknown. Ophthalmologic monitoring in clinical studies was inadequate to exclude possibility of injury after long-term drug exposure.

Although there are no specific recommendations for periodic ophthalmologic monitoring, clinicians should be aware of possible long-term ophthalmologic effects in patients receiving tetrabenazine.

Specific Populations


Category C. (See Advice to Patients.)


Not known whether tetrabenazine or its metabolites distribute into milk; however, at least one study suggests that the drug is distributed into human milk. Discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Has been effective in a limited number of pediatric patients with hyperkinetic movement disorders, including Tourette's syndrome and severe chorea, to date. May have a similar adverse effect profile in pediatric patients as in adults, possibly with fewer parkinsonian adverse effects.

Based on clinical experience, one manufacturer suggests starting tetrabenazine at approximately 50% of the adult dosage and titrating the dosage slowly according to tolerance and patient response.

Geriatric Use

Pharmacokinetics not evaluated in geriatric individuals. (See Geriatric Patients under Dosage and Administration.)

Hepatic Impairment

Decreased tetrabenazine metabolism in patients with mild to moderate hepatic impairment. Safety and efficacy of increased exposure to the drug and its metabolites unknown; dosage adjustments to ensure safe use are not possible in hepatic impairment. Use contraindicated.

Renal Impairment

Pharmacokinetics not evaluated in renal impairment.

Poor CYP2D6 Metabolizers

Increased exposure of active metabolites α-dihydrotetrabenazine (α-HTBZ) and β-dihydrotetrabenazine (β-HTBZ) expected; limit daily dosage to ≤50 mg and single doses to ≤25 mg. (See Dosage under Dosage and Administration.)

Common Adverse Effects

Sedation or somnolence, insomnia, fatigue, depression, anxiety, irritability, balance difficulties, extrapyramidal adverse effects (e.g., akathisia, bradykinesia, parkinsonism, hypertonia), nausea, vomiting, ecchymosis, falls, laceration of the head, upper respiratory tract infection.

Interactions for Tetrabenazine

Metabolized by carbonyl reductase to the active metabolites α-HTBZ and β-HTBZ, which are metabolized principally by CYP2D6.

Tetrabenazine and its α-HTBZ and β-HTBZ metabolites do not substantially inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A, nor do they substantially induce CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, or 3A4 in vitro. Neither tetrabenazine nor its α-HTBZ and β-HTBZ metabolites are substrates or inhibitors of the P-glycoprotein transport system.

Potential for tetrabenazine's 9-desmethyl-β-dihydrotetrabenazine (9-desmethyl-β-HTBZ; also known as 9-desmethyl-β-DHTBZ) metabolite to interact with other drugs not evaluated to date.

Drugs Affecting Hepatic Microsomal Enzymes

Potent CYP2D6 inhibitors: Potential pharmacokinetic interaction (increased exposure to α-HTBZ and β-HTBZ). If used concomitantly with a potent CYP2D6 inhibitor, limit tetrabenazine daily dosage to ≤50 mg and single doses to ≤25 mg. (See Specific Drugs under Interactions.)

Moderate or weak CYP2D6 inhibitors: Effects on pharmacokinetics of tetrabenazine not established.

Inducers or inhibitors of other CYP isoenzymes (1A2, 2A6, 2C9, 2C19, or 2E1): Clinically important pharmacokinetic interaction unlikely.

Drugs Metabolized by Hepatic Microsomal Enzymes

Substrates of CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A/3A4: Clinically important pharmacokinetic interaction unlikely.

Drugs Affecting or Affected by P-Glycoprotein Transport

Clinically important interactions unlikely.

Drugs that Prolong QT Interval

Potential pharmacologic interaction (additive effect on QT-interval prolongation); avoid concomitant use of other drugs known to prolong the QTc interval. (See Prolongation of QT Interval under Cautions.)

Specific Drugs





Potential worsening of sedation and somnolence

Antiarrhythmics (class Ia and III; e.g., amiodarone, procainamide, quinidine, sotalol)

Increased risk of QT-interval prolongation

Avoid concomitant use

Antipsychotics (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone) and other dopamine antagonists

Potential increased risk of parkinsonism, NMS, and akathisia

Chlorpromazine, haloperidol, thioridazine, ziprasidone: Increased risk of QT-interval prolongation

Chlorpromazine, haloperidol, thioridazine, ziprasidone: Avoid concomitant use

CNS depressants

Potential worsening of sedation and somnolence


Possible CNS excitation and hypertension


Deutetrabenazine is a deuterium-substituted analog of tetrabenazine

Concomitant use contraindicated


Pharmacokinetic interaction unlikely


Possible increased exposure to tetrabenazine's active metabolites

Limit tetrabenazine daily dosage to ≤50 mg and single doses to ≤25 mg


Possible reduced therapeutic effects of levodopa and exacerbation of Parkinson's disease symptoms; amelioration of tetrabenazine-induced parkinsonism

MAO inhibitors

Potential for antagonistic effects and increased toxicity; possible CNS excitation and hypertension

Concomitant use contraindicated

Allow at least 14 days to elapse between discontinuance of MAO inhibitor therapy and initiation of tetrabenazine


Increased risk of QT-interval prolongation

Avoid concomitant use


Increased peak plasma concentrations, AUC, and half-lives of tetrabenazine's active metabolites

Limit tetrabenazine daily dosage to ≤50 mg and single doses to ≤25 mg


Possible increased exposure to tetrabenazine's active metabolites

Limit tetrabenazine daily dosage to ≤50 mg and single doses to ≤25 mg


Possible serotonin and norepinephrine depletion in the CNS

Concomitant use contraindicated

Wait for signs of chorea to re-emerge after discontinuing reserpine before initiating tetrabenazine therapy

Allow at least 20 days to elapse after reserpine discontinuance prior to initiating tetrabenazine therapy

Tetrabenazine Pharmacokinetics



Following oral administration, ≥75% absorbed. Because tetrabenazine is rapidly and extensively metabolized to α-HTBZ and β-HTBZ, plasma concentrations of the parent drug generally are undetectable.

Peak plasma concentrations of α-HTBZ and β-HTBZ reached within 1–1.5 hours; peak plasma concentration of 9-desmethyl-β-HTBZ (another major metabolite) is reached approximately 2 hours following a dose.


16–24 hours.


No effect on mean or peak plasma concentrations or AUC of α-HTBZ and β-HTBZ.

Special Populations

Patients with mild to moderate chronic hepatic impairment: Mean peak plasma tetrabenazine concentrations were 7- to 190-fold higher and AUCs of α-HTBZ and β-HTBZ were approximately 30–39% greater compared with values in healthy individuals.

Poor CYP2D6 metabolizers: Exposures to α-HTBZ and β-HTBZ were about threefold and ninefold higher, respectively, compared with values in extensive metabolizers.

Gender does not appear to affect pharmacokinetics of α-HTBZ and β-HTBZ.



Not known whether the drug or its metabolites are distributed into milk in humans; one study suggests that the drug is distributed into human milk and crosses the placenta.

Distributes rapidly into the CNS, with highest and lowest concentrations occurring in the striatum and cortex, respectively.

Plasma Protein Binding

Tetrabenazine: 82–85%.

α-HTBZ: 60–68%.

β-HTBZ: 59–63%.



Rapidly and extensively metabolized mainly in the liver by carbonyl reductase to active metabolites α-HTBZ and β-HTBZ, which are further O-dealkylated, principally by CYP2D6, to 9-desmethyl-α-HTBZ and 9-desmethyl-β-HTBZ.

Elimination Route

Eliminated in urine (about 75%) and feces (7–16%). In urine, <10% eliminated as α-HTBZ or β-HTBZ.


α-HTBZ: 7 hours.

β-HTBZ: 5 hours.

9-Desmethyl-β-HTBZ: 12 hours.

Special Populations

Patients with hepatic impairment: Elimination half-lives prolonged to approximately 17.5 hours for tetrabenazine, 10 hours for α-HTBZ, and 8 hours for β-HTBZ.





25°C (may be exposed to 15–30°C).


  • Reversibly inhibits uptake of monoamines (e.g., dopamine, norepinephrine, serotonin, histamine) into synaptic vesicles and depletes monoamine stores from nerve terminals.

  • Precise mechanism of antichorea effects not established, but appears to be related to drug's ability to reversibly and selectively inhibit vesicular monoamine transporter type 2 (VMAT2) in CNS, thereby decreasing uptake of monoamines into synaptic vesicles and depleting monoamine stores from nerve terminals.

  • Preferentially depletes dopamine; dose required to deplete norepinephrine or serotonin is approximately fivefold higher than that required to deplete dopamine. Preferential depletion of dopamine in striatum may contribute to antichorea effects.

  • Exhibits weak in vitro binding affinity for dopamine type 2 (D2) receptors. Does not possess binding affinity for GABA, glutamate, glycine, histamine, or norepinephrine receptors or ion channels.

Advice to Patients

  • Importance of patient and caregiver reading the medication guide prior to initiation of tetrabenazine therapy and each time the prescription is refilled.

  • Risk of new or worsening depression and suicidality; importance of patients or their families being alert to and immediately reporting emergence of suicidality, new or worsening depression, or other unusual changes in behavior.

  • Importance of informing patients that tetrabenazine is used to treat the involuntary movements (chorea) of Huntington's disease and that the drug does not cure the cause of the involuntary movements and does not treat other symptoms of Huntington's disease (e.g., problems with thinking and emotions).

  • Importance of informing patients and their families that the dosage of tetrabenazine will be gradually increased to reach the optimal dosage. Importance of being alert to possible development of adverse effects (e.g., sedation, akathisia, parkinsonism, depression, difficulty swallowing, fatigue, insomnia) that may require a dosage reduction or tetrabenazine discontinuance.

  • Importance of informing patients not to take a double dose of the drug if a dose of tetrabenazine is missed and it is time for the next dose.

  • Importance of informing patients that involuntary movements may return or worsen within 12–18 hours after the last dose if therapy is discontinued or a dose is missed. Importance of patients informing clinicians if tetrabenazine has been discontinued for >5 days and importance of patients not taking additional doses of the drug until they notify their clinician.

  • Risk of sedation and somnolence; importance of advising patients to exercise caution or avoid engaging in activities requiring mental alertness and coordination such as operating a motor vehicle or other dangerous machinery until the effects of the drug on the individual are known.

  • Importance of informing patients that concomitant use of alcohol or other CNS depressants may worsen the sedative effects of tetrabenazine.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary and herbal supplements, as well as any concomitant illnesses (e.g., depression or other psychiatric disorders, liver disease).

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing patients of other important precautionary information. (See Cautions.)


Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of tetrabenazine is restricted. (See Restricted Distribution under Dosage and Administration.)

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name



Dosage Forms


Brand Names




12.5 mg*

Tetrabenazine Tablets



25 mg*

Tetrabenazine Tablets (scored)

Xenazine (scored)


AHFS DI Essentials™. © Copyright 2022, Selected Revisions December 11, 2017. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

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