Tetrabenazine


Generic Medicine Info
Indications and Dosage
Oral
Tardive dyskinesia
Adult: Moderate to severe: Initially, 12.5 mg daily, subsequently titrated according to response. Discontinue treatment if there is no clear benefit or if side effects cannot be tolerated.

Oral
Movement disorders
Adult: Initially, 12.5-25 mg 1-3 times daily, may be increased in increments of 12.5-25 mg gradually every 3-4 days until optimal response is achieved and if tolerated. Dosing is individualised based on patient condition and response. Max: 200 mg daily. If no improvement at max dose for 7 days, drug is unlikely to be of benefit.
Special Patient Group
Patient taking strong CYP2D6 inhibitors (e.g. fluoxetine, paroxetine, quinidine): Max: 50 mg daily; 25 mg/dose.

Pharmacogenomics:

Tetrabenazine is rapidly and extensively metabolised in the liver by carbonyl reductase to active metabolites, α- and ß-hydroxytetrabenazine (HTBZ) which are subsequently metabolised by CYP2D6 to 9-desmethyl-α-DHTBZ (minor) and 9-desmethyl-β-DHTBZ (major), respectively.

According to the FDA-approved drug label for tetrabenazine, genotyping should be performed for patients taking doses >50 mg daily in order to determine if the patient is poor or extensive metaboliser. CYP2D6 metaboliser status may affect therapeutic response or incidence of therapy-limiting adverse effects and may be a basis for dose adjustments of tetrabenazine. US labelling recommendations on dosage adjustments are based upon pharmacokinetic data on 2 poor metaboliser patients.

CYP2D6 extensive and intermediate metabolisers
Patients who are intermediate metabolisers have less treatment response to tetrabenazine as compared to extensive metabolisers. FDA-approved drug label recommends similar dose adjustments on both intermediate and extensive metabolisers with slow up-titration at weekly intervals by 12.5 mg daily. Doses above 50 mg daily should be given in tid regimen. Max: 100 mg daily; 37.5 mg as a single dose.

CYP2D6 poor metabolisers
Patients who lack CYP2D6 enzyme activity have higher plasma concentrations of tetrabenazine and may have increased risk of adverse effects (e.g. sedation, akathisia, insomnia, suicidality). FDA-approved drug label recommends adjusting dose with a max daily dose of 50 mg and max single dose of 25 mg.
Hepatic Impairment
Mild to moderate: Half the initial dose and slower up-titration of the dose.
Administration
May be taken with or without food.
Contraindications
Patient with untreated or inadequately treated depression, actively suicidal, congenital long QT syndromes, history of cardiac arrhythmias; prolactin-dependent tumours (e.g. pituitary or breast cancer). Lactation. Concomitant use within 14 days of discontinuing MAOIs.
Special Precautions
Patient with history of depression or prior suicide attempts or ideation. Patient at risk of aspiration pneumonia. May exacerbate symptoms of parkinsonism. Hepatic impairment. Pregnancy. Patient taking strong CYP2D6 inhibitors.
Adverse Reactions
Significant: Esophageal dysmotility, dysphagia and aspiration; parkinsonism (e.g. bradykinesia, hypertonia, rigidity), akathisia, restlessness, agitation, somnolence (high dose), QTc prolongation, orthostatic hypotension, hyperprolactinaemia.
Cardiac disorders: Bradycardia.
Gastrointestinal disorders: Dysphagia, nausea, vomiting, diarrhoea, constipation, epigastric pain, dry mouth.
Nervous system disorders: Ataxia, dystonia, dizziness, amnesia, tremor, agitation.
Psychiatric disorders: Anxiety, insomnia, confusion, disorientation, nervousness.
Reproductive system and breast disorders: Irregular menstrual cycle.
Potentially Fatal: Neuroleptic malignant syndrome, suicidal ideation and behaviour.
Patient Counseling Information
This drug may cause dizziness, sedation or somnolence, if affected, do not drive or operate machinery.
MonitoringParameters
Monitor for signs or symptoms of depression or suicide ideation, parkinsonism, neuroleptic malignant syndrome, orthostatic hypotension. Perform CYP2D6 genotyping for evaluation of metabolism status (doses >50 mg/day).
Overdosage
Symptoms: Acute dystonia, oculogyric crisis, nausea, vomiting, diarrhoea, confusion, hallucinations, somnolence, sweating, hypotension, hypothermia, rubor, tremor. Management: Symptomatic and supportive treatment. Monitor cardiac rhythm and vital signs.
Drug Interactions
May enhance the adverse effects of tetrabenazine with reserpine. Increased risk of QT prolongation with antipsychotics (e.g. chlorpromazine, thioridazine), antibiotics (e.g. gatifloxacin, moxifloxacin), or class IA and III antiarrhythmics (e.g. quinidine, procainamide, amiodarone, sotalol). May diminish the effect of levodopa. Additive sedative effects with CNS depressants (e.g. neuroleptics, hypnotics, opioids). May increase risk of dopamine depletion and parkinsonism with neuroleptic agents (e.g. haloperidol, metoclopramide, chlorpromazine). May increase risk of orthostatic hypotension with antihypertensive agents (e.g. β-blockers). Increased serum concentrations of the active metabolites of tetrabenazine (α-HTBZ, β-HTBZ) with concomitant use of strong CYP2D6 inhibitors (e.g. fluoxetine, paroxetine, quinidine).
Potentially Fatal: May increase risk of adverse effects of MAOIs.
Food Interaction
Additive sedative effects with alcohol.
Action
Description: Tetrabenazine reversibly inhibits vesicular monoamine transporter 2 (VMAT2) resulting in decreased uptake of monoamines (e.g. dopamine, serotonin, norepinephrine, histamine) into synaptic vesicles and reduces monoamine stores.
Duration: 16-24 hours.
Pharmacokinetics:
Absorption: Bioavailability: Low and erratic. Time to peak plasma concentration: Within 1-1.5 hours (metabolites).
Distribution: Rapidly distributed to the brain (IV). Plasma protein binding; 82-85% (tetrabenazine); 59-68% (metabolites).
Metabolism: Rapidly and extensively metabolised in the liver by carbonyl reductase to active metabolites, α- and β-hydroxytetrabenazine (HTBZ) which are subsequently metabolised by CYP2D6 to 9-desmethyl-α-DHTBZ (minor) and 9-desmethyl-β-DHTBZ (major), respectively.
Excretion: Via urine (approx 75% as metabolites, <10% as α- and β-HTBZ); faeces (approx 7-16%). Elimination half-life: 7 hours (α-HTBZ); 5 hours (β-HTBZ); 12 hours (9-desmethyl-β-DHTBZ).
Chemical Structure

Chemical Structure Image
Tetrabenazine

Source: National Center for Biotechnology Information. PubChem Database. Tetrabenazine, CID=6018, https://pubchem.ncbi.nlm.nih.gov/compound/Tetrabenazine (accessed on Jan. 23, 2020)

Storage
Store at 25°C.
References
Mehanna R, Hunter C, Davidson A et al. Analysis of CYP2D6 genotype and response to tetrabenazine. Movement Disorders: Official Journal of the Movement Disorder Society. 2013 Feb;28(2):210-215. doi: 10.1002/mds.25278. Accessed 05/11/2019. PMID: 23280482

Annotation of FDA Label for Tetrabenazine and CYP2D6. Pharmacogenomics Knowledgebase (PharmGKB). https://www.pharmgkb.org/. Accessed 05/11/2019.

Anon. CYP2D6 - Tetrabenazine (Pharmacogenomics). Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 05/11/2019.

Anon. Tetrabenazine. Lexicomp Online. Hudson, Ohio. Wolters Kluwer Clinical Drug Information, Inc. https://online.lexi.com. Accessed 05/11/2019.

Buckingham R (ed). Tetrabenazine. Martindale: The Complete Drug Reference [online]. London. Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 05/11/2019.

Joint Formulary Committee. Tetrabenazine. British National Formulary [online]. London. BMJ Group and Pharmaceutical Press. https://www.medicinescomplete.com. Accessed 20/11/2019.

Tetrabenazine Tablet (Dr. Reddys Laboratories Inc). DailyMed. Source: U.S. National Library of Medicine. https://dailymed.nlm.nih.gov/dailymed/. Accessed 05/11/2019.

Xenazine Tablets (Valeant Pharmaceuticals North America LLC). U.S. FDA. https://www.fda.gov/. Accessed 05/11/2019.

Disclaimer: This information is independently developed by MIMS based on Tetrabenazine from various references and is provided for your reference only. Therapeutic uses, prescribing information and product availability may vary between countries. Please refer to MIMS Product Monographs for specific and locally approved prescribing information. Although great effort has been made to ensure content accuracy, MIMS shall not be held responsible or liable for any claims or damages arising from the use or misuse of the information contained herein, its contents or omissions, or otherwise. Copyright © 2021 MIMS. All rights reserved. Powered by MIMS.com
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