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Introduction ⬇

AHFS Class:

Generic Name(s):

Chemical Name:

Molecular Formula:

Tetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, is a monoamine-depleting agent; the drug reversibly inhibits uptake of monoamines (e.g., dopamine, serotonin, norepinephrine, histamine) into synaptic vesicles and depletes monoamine stores.1,2,17,18,19,20,21,23,24,25,36,58,59

Uses ⬆ ⬇

[Section Outline]

Huntington's Chorea !!navigator!!

Tetrabenazine is used in the symptomatic management of chorea associated with Huntington's disease in adults.1,2,17,18,19,20,24,25,38,40,46 Tetrabenazine has been designated an orphan drug by the Food and Drug Administration (FDA) for the treatment of Huntington's disease.3,4,18

Safety and efficacy of tetrabenazine in the management of chorea associated with Huntington's disease have been established primarily in a randomized, double-blind, placebo-controlled study (TETRA-HD) of 12 weeks' duration in 84 ambulatory adult patients with Huntington's disease.1,2,17,19,20,24,25,46 The study included a 7-week dosage titration period followed by a 5-week maintenance period and then a 1-week washout period.1,2 Patients initially received tetrabenazine dosages of 12.5 mg daily with subsequent weekly dosage titrations in 12.5-mg increments until satisfactory control of chorea was achieved, intolerable adverse effects occurred, or a maximum dosage of 100 mg daily was reached.1,2,17,19,25 The primary measure of efficacy was the Unified Huntington's Disease Rating Scale (UHDRS) total chorea score, in a range from 0 (no impairment) to 28 (marked or prolonged impairment).1,2,7,19 The total chorea score during the maintenance period (determined by averaging the scores obtained at weeks 9 and 12) was reduced from baseline by an estimated 5 units in the tetrabenazine group compared with an estimated 1.5 units in the placebo group; these results corresponded to a treatment-related reduction in the total chorea score of 23.5% (3.5 units), which was considered by the investigators to be clinically meaningful and statistically significant.1,2,17,19,24,25 Scores on the Clinical Global Impression (CGI) Global Improvement scale also favored tetrabenazine over placebo.1,2,19,25 Measures of functional capacity and cognition generally showed no significant differences between tetrabenazine and placebo; however, one measure of functional capacity (i.e., ability to perform certain activities of daily living) suggested slight worsening of functional capacity in patients treated with tetrabenazine.1,24 In addition, a battery of cognitive assessments specifically developed to assess cognitive function in patients with Huntington's disease also showed worsening in tetrabenazine-treated patients compared with placebo recipients, but the difference was not statistically significant.1,24 The total chorea scores in the tetrabenazine-treated patients returned to pre-treatment baseline values 1 week after drug discontinuance during the washout period in this study.2,24 An open-label extension of this study demonstrated continued efficacy of tetrabenazine in suppressing chorea due to Huntington's disease for up to 80 weeks.52 Similar to the initial study, total chorea scores in tetrabenazine-treated patients returned to pre-treatment baseline values 1 week after drug discontinuance during the washout period.52

In a smaller, randomized controlled study conducted in 18 patients with Huntington's disease who had been treated with open-label tetrabenazine for at least 2 months (mean duration of treatment was 2 years), patients were randomized to continue receiving tetrabenazine in the same dosage or to receive placebo for 3 days, at which time their chorea scores were compared.1,24 Although the comparison did not reach statistical significance, tetrabenazine's treatment effect on chorea was similar to that observed in the first study (estimated reduction in total chorea score of approximately 3.5 units).1,24

Because of the possibility that patients receiving tetrabenazine may experience slight worsening of cognition, functional capacity, mood, or rigidity and because data indicating whether these effects persist, worsen, or resolve over time are lacking, clinicians who elect to use tetrabenazine for extended periods should periodically reevaluate the long-term risks and benefits of the drug for the individual patient.1,47

Other Hyperkinetic Movement Disorders !!navigator!!

Tetrabenazine has been used with some success in observational studies for the symptomatic management of other hyperkinetic movement disorders (also called hyperkinesias),22,23,30,31,32,33,35,37,38,39,40,42,47 including tic disorder†47 Tourette syndrome (Gilles de la Tourette syndrome)†,30,35,38,42,52 and tardive dyskinesia†.30,36,37,38,40,47,50,51,54 Clinical experience with tetrabenazine in tardive dyskinesia suggests that the drug is effective in the management of this condition, including in some severe and/or refractory cases.30,37,38,40 The American Psychiatric Association (APA) recommends treatment of moderate to severe or disabling tardive dyskinesia associated with antipsychotic therapy with a VMAT2 inhibitor such as tetrabenazine, deutetrabenazine, or valbenazine; such treatment may also be considered for patients with mild tardive dyskinesia based on factors such as patient preference, associated impairment, and effect on psychosocial function.62 The short elimination half-life of tetrabenazine and dose-related adverse effect profile may limit its clinical utility compared with deutetrabenazine or valbenazine, which are FDA-approved for the treatment of tardive dyskinesia and generally preferred over tetrabenazine for this indication.62

Dosage and Administration ⬆ ⬇

[Section Outline]

General !!navigator!!

Pretreatment Screening

Patient Monitoring

Other General Considerations

Administration !!navigator!!

Tetrabenazine tablets are administered orally without regard to food.1,18,24,28 If a dose of tetrabenazine is missed, the prescribed dose should be taken at the next scheduled time; an additional dose should not be administered to replace the missed dose.1

Store tetrabenazine tablets at 25°C; excursions permitted between 15-30°C.1

Dosage !!navigator!!

Huntington's Chorea

For the management of chorea associated with Huntington's disease, dosage of tetrabenazine should be titrated over several weeks to determine an individualized dosage for chronic use based on reduction of chorea and tolerability.1,28

The recommended initial oral dosage of tetrabenazine in adults is 12.5 mg given once daily in the morning.1 After one week, dosage should be increased to 12.5 mg twice daily.1 Subsequent dosage adjustments should be made slowly in 12.5-mg increments at weekly intervals to allow identification of a dosage that reduces chorea and is tolerated.1 Daily dosages of 37.5 mg or greater should be given in 3 divided doses.1 In patients receiving a daily dosage of 50 mg or less, the maximum recommended single dose of tetrabenazine is 25 mg.1 Tetrabenazine dosage titration should be stopped and the daily dosage reduced if adverse effects (e.g., excessive sedation, akathisia, restlessness, parkinsonism, depression, insomnia, anxiety) occur; consideration should be given to discontinuing the drug or initiating specific treatment (e.g., antidepressant therapy) if adverse effects do not resolve.1

The manufacturer recommends that patients requiring tetrabenazine dosages exceeding 50 mg daily undergo cytochrome P-450 (CYP) isoenzyme 2D6 genotype testing prior to receiving such higher dosages in order to determine whether they are poor, intermediate, or extensive metabolizers of CYP2D6 substrates.1 However, such testing can be expensive and some clinicians prefer to adjust tetrabenazine dosage based on clinical response and tolerability.47 Although the manufacturer states that daily dosages exceeding 100 mg are not recommended for any patient,1 higher dosages have reportedly been used in some patients.22,28,39,40

In patients who are poor metabolizers of CYP2D6 substrates (patients who do not express CYP2D6), the manufacturer states that the maximum recommended daily dosage of tetrabenazine is 50 mg and the maximum recommended single dose is 25 mg.1

In patients who are intermediate or extensive metabolizers of CYP2D6 substrates (patients who express CYP2D6), the maximum recommended daily dosage of tetrabenazine is 100 mg and the maximum recommended single dose is 37.5 mg.1 In these patients, dosages exceeding 50 mg daily should be given in 3 divided doses, and dosage adjustments should be made in 12.5-mg increments at weekly intervals.1 Tetrabenazine dosage titration should be stopped and the daily dosage reduced if adverse effects occur; consideration should be given to discontinuing the drug or initiating other specific treatment (e.g., antidepressant therapy) if adverse effects do not resolve.1

If tetrabenazine is used concurrently with strong CYP2D6 inhibitors (e.g., fluoxetine, paroxetine, quinidine), the maximum recommended daily dosage of tetrabenazine is 50 mg and the maximum recommended single dose is 25 mg.1

Treatment with tetrabenazine may be discontinued without tapering the dosage.1 Although the manufacturer states that re-emergence of chorea may occur within 12-18 hours after the last dose of the drug, earlier re-emergence of chorea (within 5.5 hours) following a single dose of tetrabenazine has been reported in one study.1,20,45

If tetrabenazine therapy will be resumed following a treatment interruption of more than 5 days, the drug should be retitrated.1 Following treatment interruptions of less than 5 days, treatment can be resumed at the previous maintenance dosage without titration.1

Other Hyperkinetic Movement Disorders

When tetrabenazine has been used for the treatment of other hyperkinetic movement disorders† in adults, the dosage generally has been individualized and titrated slowly based on the clinical response of the individual patient.38,39,40 In several clinical studies, initial tetrabenazine dosages of 25 mg given once or twice daily have been given for the treatment of other hyperkinetic movement disorders, and then increased in 25-mg daily dosage increments every 1-3 days until optimal therapeutic response, intolerable adverse effects, or a maximum dosage of 100-200 mg daily has been achieved.38,39,40

Current APA guidelines for the treatment of tardive dyskinesia associated with antipsychotic therapy† recommend an initial tetrabenazine dosage of 25-50 mg daily given in divided doses and increased in 12.5-mg daily increments every week to a maximum of 150-200 mg daily.62

Clinical experience with tetrabenazine in the treatment of Tourette syndrome† is limited; some clinicians recommend an initial tetrabenazine dosage of 12.5-25 mg given once daily at bedtime or twice daily in adults, with titration up to a target dosage of 25 mg given 3 times daily and a maximum recommended dosage of 50 mg given 3 times daily.35,42 Dosage adjustment may be necessary if used in pediatric patients.42

Special Populations !!navigator!!

Hepatic Impairment

Tetrabenazine is contraindicated in patients with hepatic impairment.1,18

Renal Impairment

The manufacturer provides no specific dosage recommendations for patients with renal impairment.1

Geriatric Patients

The manufacturer provides no specific dosage recommendations for tetrabenazine in geriatric patients.1

Poor CYP2D6 Metabolizers

Do not exceed 50 mg daily (maximum single dose 25 mg).1

Extensive and Intermediate CYP2D6 Metabolizers

Do not exceed 100 mg daily (maximum single dose 37.5 mg).1

Cautions ⬆ ⬇

[Section Outline]

Contraindications !!navigator!!

Patients who are actively suicidal or patients with untreated or inadequately treated depression.1,18

Hepatic impairment.1,18

Concomitant therapy with a monoamine oxidase (MAO) inhibitor.1,17,18 At least 14 days should elapse between discontinuance of an MAO inhibitor and initiation of tetrabenazine.1

Concomitant therapy with reserpine.1,18 At least 20 days should elapse between discontinuance of reserpine and initiation of tetrabenazine therapy.1,17,18

Concomitant therapy with deutetrabenazine or valbenazine.1

Warnings/Precautions !!navigator!!

Warnings

Risk of Depression and Suicidality

A boxed warning about the risk of depression and suicidality is included in the prescribing information for tetrabenazine.1 Patients with Huntington's disease are at an increased risk for depression and suicidal ideation and behavior (suicidality).1,2 Tetrabenazine increases this risk, which may increase with higher dosages of the drug.1,18,19,24,49 In clinical studies evaluating tetrabenazine in Huntington's disease, depression or worsening of depression was reported in 19-35% of the tetrabenazine-treated patients.1 In these studies, 1 completed suicide, 1 attempted suicide, and 6 cases of suicidal ideation were reported in 187 tetrabenazine recipients.1 Depression appears more likely to occur or worsen in tetrabenazine-treated patients with a preexisting history of depression.49

Anyone considering the use of tetrabenazine must balance the potential risks of depression and suicidality with the clinical need for control of chorea.1 Clinicians should be aware of a heightened risk of suicide in patients with Huntington's disease.1 Patients receiving tetrabenazine should be closely observed for the emergence or worsening of depression, suicidality, or unusual changes in behavior.1 Clinicians should inform patients, their caregivers, and families of the risk of depression, worsening of depression, and suicidality associated with tetrabenazine and instruct them to promptly report any behaviors of concern to their treating clinician.1 Any patient with Huntington's disease who expresses suicidal ideation should be evaluated immediately.1 If depression or suicidality does not resolve, discontinuance of tetrabenazine should be considered.1

Caution should be exercised in treating patients with tetrabenazine who have a history of depression or prior suicide attempts or ideation since these patients may be at an increased risk for suicidal behavior.1 Patients who are actively suicidal or those with untreated or inadequately treated depression should not be treated with the drug.1

Other Warnings and Precautions

Clinical Worsening and Adverse Events

Huntington's disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time.1,2 Although tetrabenazine decreased chorea associated with Huntington's disease in a 12-week, controlled trial, the drug also was shown to cause slight worsening in mood, cognition, rigidity, and functional capacity;1,2,47 it remains unknown whether these effects persist, resolve, or worsen with continued treatment.1

Clinicians should periodically reevaluate the need for tetrabenazine in individual patients by assessing the beneficial effect on chorea and possible adverse effects, including depression, cognitive decline, parkinsonism, dysphagia, sedation or somnolence, akathisia, restlessness, and disability.1,47 Distinguishing between drug-induced adverse effects and progression of the underlying disease may be difficult; decreasing the dosage or discontinuing the drug may help the clinician to distinguish between these two possibilities.1 Underlying chorea also may improve over time in some patients, which may decrease the need for tetrabenazine.1

Determining CYP2D6 Metabolizer Status

Prior to administering tetrabenazine dosages exceeding 50 mg daily, the manufacturer recommends patients be tested to determine their cytochrome P-450 (CYP) isoenzyme 2D6 status (i.e., poor metabolizers, extensive metabolizers, intermediate metabolizers).1 Drug exposure will be substantially higher (about threefold for α-dihydrotetrabenazine [α-HTBZ] and ninefold for β-dihydrotetrabenazine [β-HTBZ], both active metabolites) when a dose is given to a poor metabolizer than when given to an extensive metabolizer.1 The manufacturer recommends limiting the dosage of tetrabenazine to 50 mg daily and single doses of the drug to 25 mg in patients who are poor CYP2D6 metabolizers.1

Neuroleptic Malignant Syndrome

Neuroleptic malignant syndrome (NMS), a potentially fatal syndrome, has been reported in patients receiving tetrabenazine and other drugs that reduce dopaminergic transmission.1,16,17,24,25,26,27 Clinicians should be aware of the manifestations of NMS, including hyperpyrexia, muscle rigidity, altered mental status, and autonomic instability (e.g., irregular heart rate, labile blood pressure, tachycardia, diaphoresis, cardiac arrhythmias).1 Other signs may include increased serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations, myoglobinuria, rhabdomyolysis, and acute renal failure.1 Management of NMS should include immediate discontinuance of tetrabenazine, intensive symptomatic treatment and medical monitoring, and treatment of any concomitant serious medical conditions for which specific treatments are available.1 Recurrence of NMS has been reported; if tetrabenazine is required following recovery from NMS, the patient should be monitored for signs of recurrence.1

Akathisia, Restlessness, and Agitation

Tetrabenazine may increase the risk of akathisia, restlessness, and agitation.1 Akathisia was reported in up to 20% of tetrabenazine-treated patients in clinical studies.1 Patients receiving the drug should be monitored for the presence of akathisia as well as for signs and symptoms of restlessness and agitation, since they may indicate developing akathisia.1 If a patient develops akathisia, the dosage of tetrabenazine should be reduced; discontinuance of the drug may be necessary in some patients.1

Parkinsonism

Parkinsonism has been reported in patients receiving tetrabenazine.1 Symptoms suggestive of parkinsonism (e.g., bradykinesia, hypertonia, rigidity) were reported in 3-15% of patients in several clinical studies.1 Because rigidity can develop as part of the underlying disease process in Huntington's disease, it may be difficult to distinguish between this drug-induced adverse effect and possible disease progression.1 Drug-induced parkinsonism potentially can cause more functional disability than untreated chorea for some patients with Huntington's disease.1 If parkinsonism develops during tetrabenazine therapy, reduction of the tetrabenazine dosage should be considered; drug discontinuance may be necessary in some patients.1

Sedation and Somnolence

Sedation is the most common dose-limiting adverse effect of tetrabenazine.1 Sedation or somnolence was reported in 17-57% of patients receiving the drug in several controlled and uncontrolled clinical studies.1 Sedation was the reason for stopping upward titration of tetrabenazine dosage and/or decreasing dosage of the drug in 28% of patients in one placebo-controlled study.1 In some patients, sedation occurred at dosages that were lower than recommended dosages.1 Tetrabenazine may impair cognitive and/or motor skills required to perform tasks such as driving or operating complex machinery.1 These tasks should be avoided until the patient is on a maintenance dose of tetrabenazine and knows how the drug affects them.1

Prolongation of QT Interval

Tetrabenazine causes a small increase (mean increase of approximately 8 msec) in the corrected QT (QTc) interval.1 The risk of torsades de pointes in association with drugs that prolong the QTc interval may be increased in patients with bradycardia, hypokalemia, or hypomagnesemia; patients receiving other drugs that prolong the QTc interval; and in those with congenital prolongation of the QT interval.1 Therefore, the manufacturer states that tetrabenazine should be avoided in patients concurrently receiving other drugs known to prolong the QTc interval, patients with congenital long QT syndrome, and those with a history of cardiac arrhythmias.1,18

Hypotension and Orthostatic Hypotension

Postural dizziness, including one case of syncope and one case of documented orthostasis, has been reported in healthy individuals receiving single doses of tetrabenazine.1 Dizziness was reported in 4% of tetrabenazine-treated patients in a 12-week controlled study; however, blood pressure was not measured during these events.1,2 Consideration should be given to monitoring orthostatic vital signs in patients who are vulnerable to hypotension.1

Hyperprolactinemia

Elevated prolactin concentrations have been reported; peak plasma prolactin concentrations increased four- to fivefold following a single 25-mg tetrabenazine dose in healthy individuals.1 Although amenorrhea, galactorrhea, gynecomastia, and impotence have been associated with elevated prolactin concentrations, the clinical significance of such elevations for most patients is unknown.1 If tetrabenazine therapy is considered for a patient with previously detected breast cancer, clinicians should consider that approximately one-third of human breast cancers are prolactin-dependent in vitro.1 In addition, chronic hyperprolactinemia (although not evaluated in the tetrabenazine clinical development program) has been associated with low estrogen concentrations and an increased risk of osteoporosis.1 If symptomatic hyperprolactinemia is suspected, appropriate laboratory testing should be performed and discontinuance of tetrabenazine should be considered.1

Binding to Melanin-containing Tissues

Tetrabenazine and/or its metabolites bind to melanin-containing tissues, which may result in accumulation and possible toxicity with long-term use.1,18 Ophthalmologic monitoring in clinical studies was inadequate to exclude the possibility of injury after long-term drug exposure,1,18 and the clinical importance of the drug's binding to melanin-containing tissues is unknown.1 Although the manufacturer does not make specific recommendations for periodic ophthalmologic monitoring during tetrabenazine therapy, the manufacturer states that clinicians should be aware of possible long-term ophthalmologic effects in patients receiving the drug.1

Specific Populations

Pregnancy

May cause fetal harm based on animal studies.1 There are no adequate and well-controlled studies of tetrabenazine in pregnant women.1 Reproduction studies in animals revealed no clear effects on embryofetal development when tetrabenazine was administered orally during the period of organogenesis at dosages up to 3 and 12 times the maximum recommended human dosage in rats and rabbits, respectively.1 However, when the drug was administered to rats during pregnancy and lactation, increased stillbirths, reduced pup survival, and delayed pup maturation were observed.1 Rats dosed orally with tetrabenazine do not produce 9-desmethyl-β-dihydrotetrabenazine (DHTBZ), a major human metabolite of the drug.1 Oral administration of 9-desmethyl-β-DHTBZ to rats at clinically relevant doses during the period of organogenesis or throughout pregnancy and lactation increased embryofetal and offspring postnatal mortality, decreased growth, and produced neurobehavioral and reproductive impairment in offspring.1 Maternal toxicity was also observed.1

Lactation

It is not known whether tetrabenazine or its metabolites distribute into milk;1,18 one study suggests that the drug does distribute into human milk.54,57 The effects of tetrabenazine on breastfed infants or on the production of milk are unknown.1 Consider the developmental and health benefits of breastfeeding along with the mother's clinical need for tetrabenazine and any potential adverse effects on the breastfed infant from the drug or from the underlying maternal condition.1

Pediatric Use

The manufacturer states that safety and efficacy of tetrabenazine have not been established in pediatric patients.1,18,28

Although controlled clinical trials have not been conducted to date, tetrabenazine has been effective in a limited number of pediatric patients with hyperkinetic movement disorders, including Tourette syndrome† and severe chorea†.33,35,42,54,55 Limited experience suggests that the drug may have a similar adverse effect profile in pediatric patients as in adults, possibly with fewer parkinsonian adverse effects.33

Geriatric Use

Pharmacokinetics of tetrabenazine and its principal metabolites have not been evaluated in geriatric individuals.1

Renal Impairment

Pharmacokinetics of tetrabenazine and its principal metabolites have not been evaluated in patients with renal impairment.1

Hepatic Impairment

In a single-dose study, mean peak plasma tetrabenazine concentrations were 7- to 190-fold higher in patients with mild to moderate chronic hepatic impairment (Child-Pugh score: 5-9) compared with those in healthy individuals.1 The elimination half-lives of tetrabenazine and its active metabolites, α- and β-HTBZ, also were prolonged in hepatically impaired patients.1 Because safety and efficacy of this increased exposure to tetrabenazine and its metabolites are unknown, it is not possible to adjust the dosage of tetrabenazine in patients with hepatic impairment to ensure its safe use.1 Therefore, the manufacturer states that tetrabenazine is contraindicated in patients with hepatic impairment.1,18

Poor CYP2D6 Metabolizers

Although the pharmacokinetics of tetrabenazine and its principal metabolites have not been evaluated in patients who are poor metabolizers of CYP2D6 substrates, three- and ninefold increased exposure of tetrabenazine's active metabolites, α-HTBZ and β-HTBZ, respectively, are expected; in such patients the maximum recommended daily dosage of tetrabenazine is 50 mg and the maximum recommended single dose is 25 mg.1

Common Adverse Effects !!navigator!!

Adverse effects reported in ≥5% of patients with Huntington's chorea receiving tetrabenazine and at an incidence greater than that reported with placebo include 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, and upper respiratory tract infection.1,2,18,21,22,25,38,47

Drug Interactions ⬆ ⬇

[Section Outline]

Tetrabenazine and its α-dihydrotetrabenazine (α-HTBZ), β-dihydrotetrabenazine (β-HTBZ), and 9-desmethyl-β-dihydrotetrabenazine (DHTBZ) metabolites do not substantially inhibit cytochrome P-450 (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.1 Neither tetrabenazine nor its α-HTBZ, β-HTBZ, or 9-desmethyl-β-DHTBZ metabolites are likely to be substrates or inhibitors of P-glycoprotein (P-gp) at clinically relevant concentrations in vivo.1

Tetrabenazine's active metabolites α-HTBZ and β-HTBZ are substrates of CYP2D6.1

Drugs Affecting Hepatic Microsomal Enzymes !!navigator!!

Potential pharmacokinetic interaction when tetrabenazine is given concomitantly with strong CYP2D6 inhibitors (increased exposure, peak plasma concentrations, and half-lives of tetrabenazine metabolites).1,7,18 When the strong CYP2D6 inhibitor paroxetine (20 mg daily for 10 days) was administered concomitantly with tetrabenazine (single 50-mg dose) in healthy individuals, peak plasma concentrations of α-HTBZ and β-HTBZ increased 1.3- and 2.4-fold, respectively, and area under the plasma concentration-time curve (AUC) increased three- and ninefold, respectively; half-life of both α-HTBZ and β-HTBZ was approximately 14 hours.1

Dosage reduction of tetrabenazine may be required if a strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine, quinidine) is used in patients already receiving a stable dosage of tetrabenazine.1,17 If tetrabenazine is used concurrently with strong CYP2D6 inhibitors, the maximum recommended daily dosage of tetrabenazine is 50 mg and the maximum recommended single dose is 25 mg.1 Effect of moderate or weak CYP2D6 inhibitors (e.g., amiodarone, duloxetine, sertraline, terbinafine) on the pharmacokinetics of tetrabenazine has not been evaluated.1,18

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

Drugs Affecting or Affected by P-Glycoprotein Transport !!navigator!!

At clinically relevant concentrations, neither tetrabenazine nor its α-HTBZ, β-HTBZ, or 9-desmethyl-β-DHTBZ metabolites are likely to be substrates of or inhibitors of P-glycoprotein; clinically important interactions unlikely.1

Drugs that Prolong QT Interval !!navigator!!

Potential pharmacologic interaction (additive effect on QT-interval prolongation); concomitant use of other drugs known to prolong the QTc interval (e.g., amiodarone, procainamide, sotalol, quinidine, other Class Ia and III antiarrhythmics, chlorpromazine, haloperidol, thioridazine, ziprasidone, moxifloxacin) should be avoided.1,18

Alcohol and other CNS Depressants !!navigator!!

Potential pharmacologic interaction (worsening of sedation and somnolence) with alcohol and other CNS depressants.1,18

Antipsychotic Agents and Other Dopamine Antagonists !!navigator!!

The manufacturer states that the risk of certain adverse effects associated with tetrabenazine (e.g., QTc prolongation, parkinsonism, akathisia, neuroleptic malignant syndrome [NMS]) may be increased with concomitant use of tetrabenazine and dopamine antagonists, including antipsychotic agents.1

Digoxin !!navigator!!

In a study conducted in healthy volunteers, tetrabenazine (25 mg twice daily for 3 days) did not affect the bioavailability of digoxin.1,7 Digoxin is a substrate for P-glycoprotein, which suggests that at this dosage, tetrabenazine does not affect P-glycoprotein in the intestinal tract.1,7

Levodopa !!navigator!!

Potential pharmacologic interaction (possible reduced therapeutic effects of levodopa and exacerbation of Parkinson's disease symptoms; amelioration of tetrabenazine-induced parkinsonism).34

Monoamine Oxidase Inhibitors !!navigator!!

Because of the potential for antagonistic effects and increased toxicity, concomitant use of tetrabenazine with a monoamine oxidase (MAO) inhibitor is contraindicated.1,17,18 Since the effects of an MAO inhibitor may persist for up to 3 weeks after discontinuance, caution also is advised when initiating tetrabenazine therapy following MAO inhibitor discontinuance.15 The manufacturer states that at least 14 days should elapse between discontinuance of MAO inhibitor therapy and initiation of tetrabenazine.1

VMAT2 Inhibitors !!navigator!!

Concomitant use of tetrabenazine and other VMAT2 inhibitors (i.e., deutetrabenazine, valbenazine) is contraindicated.1

Reserpine !!navigator!!

Potential pharmacologic interaction (serotonin and norepinephrine depletion in the CNS).1 Concomitant therapy is contraindicated.1,17 Clinicians should wait for signs of chorea to re-emerge after discontinuing reserpine before initiating tetrabenazine therapy.1 At least 20 days should elapse after reserpine discontinuance prior to initiating tetrabenazine therapy.1,17,18

Other Information ⬆ ⬇

Description

Tetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor, is a monoamine-depleting agent.1,2,17,18,19,20,21,23,24,25,36 The drug reversibly inhibits uptake of monoamines (e.g., dopamine, norepinephrine, serotonin, histamine) into synaptic vesicles and depletes monoamine stores from nerve terminals.1,2,7,8,17,18,19,20,21,23,24,25

Patients with Huntington's disease appear to exhibit oversensitivity to dopamine stimulation, resulting in choreic movements.7 Although the precise mechanism of tetrabenazine's antichorea effects has not been established, it appears to be related to the drug's ability to reversibly and selectively inhibit VMAT2 in the CNS, thereby decreasing the uptake of monoamines into synaptic vesicles and depleting monoamine stores from nerve terminals.1,2,7,8,17,18,19,20,21,23,24,25 In contrast, reserpine binds to both VMAT type 1 (VMAT1), which is expressed primarily in peripheral tissues (e.g., adrenal medulla, enterochromaffin cells), and VMAT2; because reserpine binds irreversibly to the transporter protein, monoamine depletion is long lasting.2,7,12,14,47

Tetrabenazine and its metabolites preferentially deplete dopamine; the dose of tetrabenazine required to deplete norepinephrine or serotonin is approximately fivefold higher than that required to deplete dopamine.2,7,17,21,23 The preferential depletion of dopamine in the striatum is thought to contribute to the drug's antichorea effects.4,18,22,58 Tetrabenazine exhibits weak in vitro binding affinity for dopamine type 2 (D2) receptors.1,21,23 The drug does not possess binding affinity for γ-aminobutyric acid (GABA), glutamate, glycine, histamine, or norepinephrine receptors or ion channels.7

The duration of tetrabenazine's action reportedly ranges from 16 to 24 hours.38 Following oral administration, tetrabenazine is rapidly and extensively metabolized in the liver, primarily by carbonyl reductase, to form 2 major active metabolites (α- and β-dihydrotetrabenazine [HTBZ]), which are subsequently metabolized primarily by cytochrome P-450 (CYP) isoenzyme 2D6 to form 9-desmethyl-α-dihydrotetrabenazine (a minor metabolite) and 9-desmethyl-β-dihydrotetrabenazine (a major metabolite).1,7,12,18 Plasma concentrations of the parent drug are generally undetectable.1 Peak plasma concentrations of α-HTBZ and β-HTBZ occur 1-1.5 hours following oral administration of the drug; administration with food has no effect on peak plasma concentrations or area under the plasma concentration-time curve (AUC) of these metabolites.1 The drug and α-HTBZ distribute rapidly into the CNS, with the highest and lowest concentrations occurring in the striatum and cortex, respectively.1 At least 19 metabolites of the drug have been identified.1 Approximately 75% of an oral dose of tetrabenazine is eliminated in urine as metabolites, and fecal excretion accounts for 7-16% of the dose.1,18

Advice to Patients

Inform patients of other important precautionary information.1,28 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations ⬆ ⬇

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.

Tetrabenazine is available only through a specialty pharmacy network.61 Patients and clinicians may consult the Xenazine® Information Center at 888-882-6013 or consult the Xenazine® website at [Web] for specific availability information.61

Tetrabenazine

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

12.5 mg*

Tetrabenazine Tablets

Xenazine®

Lundbeck

25 mg*

Tetrabenazine Tablets (scored)

Xenazine® (scored)

Lundbeck

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

Copyright ⬆ ⬇

AHFS® Drug Information. © Copyright, 1959-2024, Selected Revisions May 25, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.

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

References ⬆

1. Lundbeck Inc. Xenazine® (tetrabenazine) tablets prescribing information. Deerfield, IL.; 2019 Nov.

2. . Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology . 2006; 66:366-72. [PubMed 16476934]

3. Food and Drug Administration. Orphan designations pursuant to Section 526 of the Federal Food and Cosmetic Act as amended by the Orphan Drug Act (P.L. 97 414). Rockville, MD. From FDA website. Accessed 2008 Sep 12. [Web]

4. Food and Drug Administration: FDA News: FDA approves first drug for treatment of chorea in Huntington's disease. Rockville, MD; 2008 Aug 15. From FDA website. [Web]

7. Prestwick Pharmaceuticals. Peripheral and central nervous system advisory committee briefing document on tetrabenazine. December 6, 2007. From FDA website. [Web]

8. Tang TS, Chen X, Liu J et al. Dopaminergic signaling and striatal neurodegeneration in Huntington's disease. J Neurosci . 2007; 27:7899-910. [PubMed 17652581][PubMedCentral]

12. Zheng G, Dwoskin LP, Crooks PA. Vesicular monoamine transporter 2: role as a novel target for drug development. AAPS J . 2006; 8:E682-92. [PubMed 17233532][PubMedCentral]

14. Gonzalez AM, Walther D, Pazos A et al. Synaptic vesicular monoamine transporter expression: distribution and pharmacologic profile. Brain Res Mol Brain Res . 1994; 22:219-26. [PubMed 7912402]

15. Potter WZ, Hollister LE. Antidepressant agents. In: Katzung BG (ed): Basic and Clinical Pharmacology 10th ed. McGraw-Hill's Access Medicine, 2007.

16. Mateo D, Muñoz-Blanco JL, Giménez-Roldán S. Neuroleptic malignant syndrome related to tetrabenazine introduction and haloperidol discontinuation in Huntington's disease. Clin Neuropharmacol . 1992; 15:63-8. [PubMed 1533561]

17. Anon. Tetrabenazine (Xenazine) for Huntington's chorea. Med Lett Drugs Ther . 2009; 51:7-8. [PubMed 19172140]

18. Hussar DA. New drugs: clevidipine butyrate, difluprednate, and tetrabenazine. J Am Pharm Assoc . 2008; 48:815-7, 819, 821.

19. Hayden MR, Leavitt BR, Yasothan U et al. Tetrabenazine. Nat Rev Drug Discov . 2009; 8:17-8. [PubMed 19116624]

20. Frank S, Ondo W, Fahn S et al. A study of chorea after tetrabenazine withdrawal in patients with Huntington disease. Clin Neuropharmacol . 2008 May-Jun; 31:127-33.

21. Fasano A, Cadeddu F, Guidubaldi A et al. The long-term effect of tetrabenazine in the management of Huntington disease. Clin Neuropharmacol . 2008 Nov-Dec; 31:313-8.

22. Toglia JU, McGlamery M, Sambandham RR. Tetrabenazine in the treatment of Huntington's chorea and other hyperkinetic movement disorders. J Clin Psychiatry . 1978; 39:81-7. [PubMed 147268]

23. Paleacu D, Giladi N, Moore O et al. Tetrabenazine treatment in movement disorders. Clin Neuropharmacol . 2004 Sep-Oct; 27:230-3.

24. Morrow T. Gene therapy offers HD patients relief from some symptoms: tetrabenazine inhibits the transport of a molecule called vesicular monoamine transporter type 2 or VMAT2. Manag Care . 2008; 17:46-7. [PubMed 19052001]

25. Bonelli RM, Hofmann P. A systematic review of the treatment studies in Huntington's disease since 1990. Expert Opin Pharmacother . 2007; 8:141-53. [PubMed 17257085]

26. Ossemann M, Sindic CJ, Laterre C. Tetrabenazine as a cause of neuroleptic malignant syndrome. Mov Disord . 1996; 11:95. [PubMed 8771075]

27. Petzinger GM, Bressman SB. A case of tetrabenazine-induced neuroleptic malignant syndrome after prolonged treatment. Mov Disord . 1997; 12:246-8. [PubMed 9087987]

28. Lundbeck Inc. Xenazine® (tetrabenazine) tablets medication guide. Deerfield, IL.; 2019 Nov.

30. Kenney C, Jankovic J. Tetrabenazine in the treatment of hyperkinetic movement disorders. Expert Rev Neurother . 2006; 6:7-17. [PubMed 16466307]

31. Porta M, Sassi M, Cavallazzi M et al. Tourette's syndrome and role of tetrabenazine: review and personal experience. Clin Drug Invest . 2008; 28:443-59.

32. Jankovic J, Beach J. Long-term effects of tetrabenazine in hyperkinetic movement disorders. Neurology . 1997; 48:358-62. [PubMed 9040721]

33. Jain S, Greene PE, Frucht SJ. Tetrabenazine therapy of pediatric hyperkinetic movement disorders. Mov Disord . 2006; 21:1966-72. [PubMed 16958131]

34. Giladi N, Melamed E. Levodopa therapy can ameliorate tetrabenazine-induced parkinsonism. Mov Disord . 1999; 14:158-9. [PubMed 9918362]

35. Kenney C, Kuo S-H, Jimenez-Shahed J. Tourette's syndrome. Am Fam Physician . 2008; 77:651-60. [PubMed 18350763]

36. Ondo WG, Hanna PA, Jankovic J. Tetrabenazine treatment for tardive dyskinesia: assessment by randomized videotape protocol. Am J Psychiatry . 1999; 156:1279-81. [PubMed 10450276]

37. Koch HJ, Szecsey A, Vogel M et al. Successful therapy of tardive dyskinesia in a 71-year-old woman with a combination of tetrabenazine, olanzapine and tiapride. Int J Clin Pract . 2003; 57:147-9. [PubMed 12661802]

38. Jankovic J, Orman J. Tetrabenazine therapy of dystonia, chorea, tics, and other dyskinesias. Neurology . 1988; 38:391-4. [PubMed 3279337]

39. Jankovic J. Treatment of hyperkinetic movement disorders with tetrabenazine: a double-blind crossover study. Ann Neurol . 1982; 11:41-7. [PubMed 6460467]

40. Asher SW, Aminoff MJ. Tetrabenazine and movement disorders. Neurology . 1981; 31:1051-4. [PubMed 6455607]

41. Lundbeck Inc. Xenazine® healthcare professionals information. From Lundbeck Inc.'s website for Xenazine® ([Web]). Accessed 2009 Apr 8.

42. Jankovic J. Tourette's syndrome. N Engl J Med . 2001; 345:1184-92. [PubMed 11642235]

45. Kenney C, Hunter C, Davidson A et al. Short-term effects of tetrabenazine on chorea associated with Huntington's disease. Mov Disord . 2007; 22:10-3. [PubMed 17078062]

46. Mestre T, Ferreira J, Coelho MM et al. Therapeutic interventions for symptomatic treatment in Huntington's disease. Cochrane Database Syst Rev . 2009; :CD006456.

47. Jankovic J. Treatment of hyperkinetic movement disorders. Lancet Neurol . 2009; 8:844-56. [PubMed 19679276]

49. Kenney C, Hunter C, Mejia N et al. Is history of depression a contraindication to treatment with tetrabenazine?. Clin Neuropharmacol . 2006; 29:259-64. [PubMed 16960470]

50. Rauchverger B, Isakov V, Jabarin M. Olanzapine-induced tardive dystonia successfully treated by tetrabenazine. J Neuropsychiatry Clin Neurosci . 2007; 19:484-5. [PubMed 18070868]

51. Sharma H. Treatment of Tardive Dyskinesia by tetrabenazine, clonazepam and vitamin E. Indian J Psychiatry . 2009; 51:162-3. [PubMed 19823645][PubMedCentral]

52. Frank S. Tetrabenazine as anti-chorea therapy in Huntington disease: an open-label continuation study. Huntington Study Group/TETRA-HD Investigators. BMC Neurol . 2009; 9:62. [PubMed 20021666][PubMedCentral]

54. Fasano A, Bentivoglio AR. Tetrabenazine. Expert Opin Pharmacother . 2009; 10:2883-96. [PubMed 19929707]

55. Chatterjee A, Frucht SJ. Tetrabenazine in the treatment of severe pediatric chorea. Mov Disord . 2003; 18:703-6. [PubMed 12784277]

56. Mehvar R, Jamali F, Watson MWB et al. Pharmacokinetics of tetrabenazine and its major metabolite in man and rat. Drug Metab Dispos. 1986; 15:250-5.

57. Roberts MS, McLean S, Millingen KS et al. The pharmacokinetics of tetrabenazine and its hydroxy metabolite in patients treated for involuntary movement disorders. Eur J Clin Pharmacol 1986; 29:703-8. [PubMed 3709613]

58. Jankovic J. Dopamine depleters in the treatment of hyperkinetic movement disorders. Expert Opin Pharmacother . 2016; 17:2461-70. [PubMed 27819145]

59. Kaur N, Kumar P, Jamwal S et al. Tetrabenazine: Spotlight on Drug Review. Ann Neurosci . 2016; 23:176-85. [PubMed 27721587][PubMedCentral]

61. Lundbeck. Xenazine® (tetrabenazine) Treatment Form. From Xenazine® website. Accessed 2022 Nov 16. [Web]

62. American Psychiatric Association. Practice guideline for the treatment of patients with schizophrenia. 3rd ed. American Psychiatric Association Publishing. Washington, DC; 2021.