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Tetrabenazine

Pronunciation

(tet ra BEN a zeen)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Xenazine: 12.5 mg

Xenazine: 25 mg [scored]

Generic: 12.5 mg, 25 mg

Brand Names: U.S.

  • Xenazine

Pharmacologic Category

  • Central Monoamine-Depleting Agent

Pharmacology

Acts as a reversible inhibitor of the human vesicular monamine transporter type 2 (VMAT-2) and thereby decreases the uptake of monoamines (including dopamine, serotonin, norepinephrine, and histamine) into synaptic vesicles and depletes the monoamine stores; hydroxytetrabenazine (HTBZ) also inhibits VMAT-2; weak binding affinity for dopamine D2 receptors.

Metabolism

Hepatic (rapid and extensive), to active metabolites: Alpha and beta hydroxytetrabenazine (HTBZ) via CYP2D6 (primary active moiety)

Excretion

Urine (75% as metabolites, <10% as alpha and beta HTBZ); feces (7% to 16%)

Time to Peak

Metabolites: Within 1 to 1.5 hours

Duration of Action

16 to 24 hours (at steady-state); chorea may recur within 12 to 18 hours after discontinuation

Half-Life Elimination

Alpha-HTBZ: 7 hours; 10 hours (hepatic impairment); Beta-HTBZ: 5 hours, 8 hours (hepatic impairment); Terabenazine: ~17.5 hours (hepatic impairment)

Protein Binding

82% to 85%; Metabolites: 59% to 68%

Special Populations: Hepatic Function Impairment

Metabolism of tetrabenazine is decreased in patients with hepatic function impairment and the Cmax is 7- to 190-fold higher compared with healthy subjects.

Use: Labeled Indications

Chorea associated with Huntington disease: Treatment of chorea associated with Huntington disease

Canadian labeling: Treatment of hyperkinetic movement disorders, including Huntington chorea, hemiballismus, senile chorea, Tourette syndrome, and tardive dyskinesia

Contraindications

Hepatic impairment; patients who are actively suicidal or who have untreated or inadequately treated depression; coadministration of monoamine oxidase inhibitors (MAOIs) or use of tetrabenazine within 2 weeks of discontinuation of MAOI therapy; coadministration with reserpine, ≥20 days should pass after discontinuing reserpine before initiating tetrabenazine therapy

Canadian labeling: Hypersensitivity to tetrabenazine or any component of the formulation; history or current episode of clinical depression

Dosage

Oral: Dose should be individualized; titrate slowly

Chorea associated with Huntington disease: Adults:

Initial: 12.5 mg once daily in the morning, may increase to 12.5 mg twice daily after 1 week. Dosage may be increased by 12.5 mg daily at weekly intervals; daily doses >37.5 mg should be divided into 3 doses (maximum single dose: 25 mg)

Patients requiring doses >50 mg/day: Genotype for CYP2D6:

Extensive/intermediate metabolizers: Maximum: 100 mg/day; 37.5 mg/dose

Poor metabolizers: Maximum: 50 mg/day; 25 mg/dose

Concomitant use with strong CYP2D6 inhibitors (eg, fluoxetine, paroxetine, quinidine): Maximum: 50 mg/day; 25 mg dose

Note: If treatment is interrupted for >5 days, retitration is recommended. If treatment is interrupted for <5 days resume at previous maintenance dose.

Canadian labeling: Hyperkinetic movement disorders:

Adults: Initial: 12.5 mg 2 to 3 times daily; may be increased by 12.5 mg daily at weekly intervals; should be titrated slowly to maximal tolerated and effective dose (dose is individualized)

Usual maximum tolerated dosage: 25 mg 3 times daily; maximum recommended daily dose: 200 mg

Note: If there is no improvement at the maximum tolerated dose after 7 days, improvement is unlikely.

Elderly and/or debilitated patients: Consider initiation at lower doses; must be titrated slowly to individualize dosage

Dosage adjustment for toxicity: For toxicity/adverse reaction, including akathisia, restlessness, parkinsonism, insomnia, depression, suicidality, anxiety, sedation (intolerable): Suspend upward dosage titration and reduce dose; consider discontinuing if adverse reaction does not resolve (may be discontinued without tapering).

Dosage adjustment in renal impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosage adjustment in hepatic impairment: Use is contraindicated

Administration

May administer without regard to meals.

Dietary Considerations

May be taken without regard to meals.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Alcohol (Ethyl): CNS Depressants may enhance the CNS depressant effect of Alcohol (Ethyl). Monitor therapy

Antipsychotic Agents: Tetrabenazine may enhance the adverse/toxic effect of Antipsychotic Agents. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Exceptions: Levocabastine (Nasal). Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Strong): May increase the serum concentration of Tetrabenazine. Specifically, concentrations of the active alpha- and beta-dihydrotetrabenazine metabolites may be increased. Management: Tetrabenazine adult dose should be reduced by 50% when starting a strong CYP2D6 inhibitor. Maximum tetrabenazine adult dose is 50 mg/day when used with a strong CYP2D6 inhibitor. Consider therapy modification

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Highest Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of other Highest Risk QTc-Prolonging Agents. Avoid combination

Hydrocodone: CNS Depressants may enhance the CNS depressant effect of Hydrocodone. Management: Consider starting with a 20% to 30% lower hydrocodone dose when using together with any other CNS depressant. Dose reductions in the other CNS depressant may also be warranted. Consider therapy modification

Ivabradine: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

MAO Inhibitors: Tetrabenazine may enhance the adverse/toxic effect of MAO Inhibitors. Avoid combination

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

Metoclopramide: May enhance the adverse/toxic effect of Tetrabenazine. Avoid combination

Metyrosine: May enhance the adverse/toxic effect of Tetrabenazine. Monitor therapy

Mifepristone: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Minocycline: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Moderate Risk QTc-Prolonging Agents: May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Avoid combination

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

QTc-Prolonging Agents (Indeterminate Risk and Risk Modifying): May enhance the QTc-prolonging effect of Highest Risk QTc-Prolonging Agents. Management: Avoid such combinations when possible. Use should be accompanied by close monitoring for evidence of QT prolongation or other alterations of cardiac rhythm. Consider therapy modification

Reserpine: May enhance the adverse/toxic effect of Tetrabenazine. Avoid combination

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Start tapentadol at a dose of one-third to one-half of the normal dose if being initiated in a patient who is taking another drug with CNS depressant effects. Monitor closely for evidence of excessive CNS depression. Consider therapy modification

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

Note: Many adverse effects are dose-related and may resolve at lower dosages. Adverse effects reported for adults with chorea associated with Huntington’s disease.

>10%:

Central nervous system: Drowsiness (≤17% to ≤57%), sedation (≤17% to ≤57%), depression (19% to 35%), extrapyramidal reaction (15% to 33%), fatigue (22%), insomnia (22%), akathisia (19% to 20%), anxiety (15%), falling (15%)

Gastrointestinal: Nausea (13%)

Respiratory: Upper respiratory tract infection (11%)

1% to 10%:

Central nervous system: Drug-induced Parkinson's disease (3% to 10%), equilibrium disturbance (9%), irritability (9%), abnormal gait (4%), dizziness (4%), dysarthria (4%), headache (4%), obsessive rumination (4%)

Gastrointestinal: Dysphagia (4% to 10%), vomiting (6%), decreased appetite (4%), diarrhea (2%)

Genitourinary: Dysuria (4%)

Hematologic & oncologic: Bruise (6%)

Neuromuscular & skeletal: Bradykinesia (9%)

Respiratory: Bronchitis (4%), dyspnea (4%)

Miscellaneous: Laceration (6%, head)

<1% (Limited to important or life-threatening): Aggressive behavior (worsening), aspiration pneumonia, confusion, hyperhidrosis, hyperprolactinemia, increased serum transaminases, orthostatic dizziness, orthostatic hypotension, neuroleptic malignant syndrome, pneumonia, prolonged QT interval on ECG, restlessness, skin rash, suicidal ideation, syncope, tremor

ALERT: U.S. Boxed Warning

Depression and suicidality:

Tetrabenazine can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington disease. Anyone considering the use of tetrabenazine must balance the risks of depression and suicidality with the clinical need for control of chorea. Close observation of patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior should accompany therapy. Patients, their caregivers, and families should be informed of the risk of depression and suicidality, and should be instructed to report behaviors of concern promptly to the treating physician.

Particular caution should be exercised in treating patients with a history of depression or prior suicide attempts or ideation, which are increased in frequency in Huntington disease. Tetrabenazine is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression.

Warnings/Precautions

Concerns related to adverse effects:

• Akathisia: Use has been associated with akathisia; monitor for signs and symptoms of restlessness and agitation. Dosage reduction or discontinuation may be necessary.

• Depression/suicidal ideation: [US Boxed Warning]: Use can increase risk for depression and suicidal thoughts and behavior; closely monitor for emergence or worsening of depression, suicidality, or unusual behavioral changes. Use with caution in patients with a history of depression or prior suicide attempts or ideation; monitor patients closely for new or worsening signs or symptoms of depression. Use is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression. Consider discontinuing use if depression/suicidal ideation does not resolve.

• Esophageal dysmotility/aspiration: Use has been associated with esophageal dysmotility, dysphagia, and aspiration; use with caution in patients at risk of aspiration pneumonia.

• Neuroleptic malignant syndrome (NMS): Use may be associated with NMS; monitor for mental status changes, fever, muscle rigidity and/or autonomic instability. Discontinue with confirmed NMS; may recur with reintroduction of treatment; monitor carefully.

• Ophthalmic effects: Binds to melanin-containing tissues in animal studies; may result in accumulation and toxicity with extended use and long-term ophthalmic effects. Clinical relevance and monitoring recommendations are unknown.

• Orthostatic hypotension: May cause orthostatic hypotension; monitor patients at risk closely.

• QT prolongation: Has been shown to prolong the QT interval alone (minimal) and with other drugs with comparable effects on the QT interval (additive). Avoid use in patients with congenital QT prolongation, a history of cardiac arrhythmias, or concomitant drugs known to cause QT prolongation.

• Sedation: Most common dose-limiting adverse effect; sedation has occurred at lower than recommended doses. Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Dose reduction or discontinuation of therapy may be necessary.

• Tardive dyskinesia: May cause dyskinetic movements; discontinue use if signs and symptoms of tardive dyskinesia occur.

Disease-related concerns:

• Parkinsonism: May cause parkinsonism symptoms (ie, bradykinesia, hypertonia, rigidity). Dose reduction or discontinuation of therapy may be necessary.

• Prolactin-dependent tumors: Elevates prolactin levels; use with caution in patients with breast cancer or other prolactin; dose discontinuation may be considered.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• CYP2D6 poor metabolizers: CYP2D6 poor metabolizers have increased levels of primary drug metabolites. Patients should be tested for the CYP2D6 gene prior to initiating doses >50 mg/day; maximum dosage should not exceed 50 mg/day in poor metabolizers.

Other warnings/precautions:

• Appropriate use: Should not be used to treat levodopa-induced dyskinesia.

Monitoring Parameters

Improvement in movement disorder; signs and/or symptoms of depression or suicide ideation; signs and/or symptoms of NMS; orthostatic blood pressure. Due to the possibility of comorbid psychiatric disorders, and potential psychiatric adverse effects, patients should be carefully monitored for potential changes in psychiatric status during therapy. CYP2D6 genotyping for evaluation of metabolizer status (for patients requiring >50 mg/day).

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Limited information related to the use of tetrabenazine in pregnancy has been located (Lubbe, 1983).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience fatigue, fasciculations, bradykinesia, anxiety, nausea, or insomnia. Have patient report immediately to prescriber tachycardia, arrhythmia, severe dizziness, syncope, dysphagia, signs of neuroleptic malignant syndrome, ot signs of tardive dyskinesia (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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