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DRUG RECORD

 

TETRABENAZINE

OVERVIEW
Tetrabenazine

 

Introduction

Tetrabenazine is a potent, selective inhibitor of the monoamine transporter 2 that causes a depletion of neuroactive peptides in nerve terminals and is used to treat chorea associated with Huntington disease.  Tetrabenazine has not been associated with serum enzyme elevations during therapy or linked to instances of clinically apparent liver injury.

 

Background

Tetrabenazine (tet" ra ben' a zeen) is an inhibitor of the synaptic vesicular monoamine transporter 2 (VMAT2), the inhibition of which causes a depletion of neuroactive monoamines (serotonin, norepinephrine and particularly dopamine) in nerve terminals.  The reduction in these active neurotransmitters results in a decrease in spontaneous jerk-like movements of the extremities, trunk, face and neck (chorea) that are typical of patients with degenerative neurologic conditions such as Huntington disease.  Tetrabenazine, however, does not prevent the progression or alter the outcome of these diseases.  Tetrabenazine was approved by the FDA in 2008 as an orphan disease agent for treatment of the chorea associated with Huntington disease.  While it is used off-label to treat other forms of chorea, tetrabenazine is not formally approved for those indications.  Tetrabenazine is available as tablets of 12.5 and 25 mg generically and under the brand name Xenazine.  The recommended initial dose is 12.5 mg once daily, with subsequent careful increase to a maximum of 25 mg twice daily.  Because of the variable metabolism of tetrabenazine (by CYP 2D6), the maintenance dose varies by individual, and inducers or inhibitors of CYP 2D6 should be avoided.  Common side effects include fatigue, sedation, somnolence, insomnia, depression, restlessness (akathisia), agitation, and nausea.  Less common, but potentially serious adverse events include severe depression, suicidality, symptomatic hypotension and neuroleptic malignant syndrome.


Hepatotoxicity

Tetrabenazine has not been associated with serum enzyme elevations greater than occurs with placebo therapy, but information on liver test results during therapy is limited and occasional instances of asymptomatic ALT elevations leading to drug discontinuation or dose modification have been reported.  In prelicensure pivotal registration trials in several hundred patients, tetrabenazine was not associated with cases of jaundice or hepatitis.  Since licensure, there have been no published reports of clinically apparent liver injury, jaundice or hepatitis attributed to tetrabenazine.  Thus, clinically apparent liver injury with jaundice due to tetrabenazine must be very rare, if it occurs at all.

Likelihood score: E (unlikely cause of clinically apparent liver injury).

 

Mechanism of Injury

The mechanism by which tetrabenazine might cause liver injury is not known.  Tetrabenazine undergoes hepatic metabolism largely by CYP 2D6 and is susceptible to drug-drug interactions with agents that induce or inhibit this enzyme.

 

Drug Class:  Genetic Disorder Agents, Huntington Disease Agents

 

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PRODUCT INFORMATION
Tetrabenazine

 

REPRESENTATIVE TRADE NAMES
Tetrabenazine – Generic, Xenazine®

 

DRUG CLASS
Huntington Disease Agents

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

 

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DRUG CAS REGISTRY NO. MOLECULAR FORMULA STRUCTURE
Tetrabenazine 58-46-8 C19-H27-N-O3 Tetrabenazine Chemical Structure

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REFERENCES
Tetrabenazine

 

References updated:  15 December 2016

  1. Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999.  (Expert review of hepatotoxicity published in 1999 does not discuss tetrabenazine).

  2. Molinoff PB. Neurotransmission and the central nervous system. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 363-95.  (Textbook of pharmacology and therapeutics).

  3. Standaert DG, Roberson ED. Huntington's disease. Treatment of central nervous system degenerative diseases. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman's the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 622-4-95.  (Textbook of pharmacology and therapeutics).

  4. Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology 2006; 66: 366-72. PubMed Citation  (Among 84 patients with Huntington disease and chorea treated with tetrabenazine or placebo for 12 weeks, chorea scores were less with tetrabenazine, but adverse events included restlessness, agitation, depression and suicidality; 3 patients developed ALT elevations, but without symptoms or jaundice and 2 resolved without and one with dose adjustment).

  5. 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 Citation  (Among 75 patients with Huntington disease who completed a 12 week controlled trial and were continued on tetrabenazine for up to 2 years, side effects included sedation, depression, anxiety, insomnia and akathisia; 3 patients had ALT elevations, but all resolved or improved despite continued therapy).

  6. Tetrabenazine (Xenazine) for Huntington's chorea. Med Lett Drugs Ther 2009; 51 (1304): 7-8. PubMed Citation  (Concise summary of the mechanism of action, clinical efficacy, side effects and costs of tetrabenazine, a drug available for several decades that had been recently approved for use in the US, mentions side effects of depression and suicidality, but does not mention ALT elevations or hepatotoxicity).

  7. Frank S. Tetrabenazine: the first approved drug for the treatment of chorea in US patients with Huntington disease. Neuropsychiatr Dis Treat 2010; 6 :657-65. PubMed Citation  (Summary of the clinical features and course of Huntington disease and its management including use of the recently approved tetrabenazine; no discussion of hepatic adverse events).

  8. Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. PubMed Citation    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, but none to tetrabenazine).

  9. Leung JG, Breden EL. Tetrabenazine for the treatment of tardive dyskinesia. Ann Pharmacother 2011; 45: 525-31. PubMed Citation  (Systematic review of the literature on use of tetrabenazine for the chorea of tardive dyskinesia; mentions side effects of drowsiness, Parkinsonism and depression, but does not mention ALT elevations or hepatotoxicity).

  10. Chen JJ, Ondo WG, Dashtipour K, Swope DM. Tetrabenazine for the treatment of hyperkinetic movement disorders: a review of the literature. Clin Ther 2012; 34: 1487-504. PubMed Citation  (Review of the mechanism of action, clinical efficacy and safety of tetrabenazine for treatment of hyperkinetic disorders; mentions that it is "well tolerated, although fatalities and severe reactions have been reported"; no mention of ALT elevations or hepatotoxicity).

  11. Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. PubMed Citation  (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none were attributed to tetrabenazine).

  12. Shen V, Clarence-Smith K, Hunter C, Jankovic J. Safety and Efficacy of Tetrabenazine and Use of concomitant medications during long-term, open-label treatment of chorea associated with Huntington's and other diseases. Tremor Other Hyperkinet Mov (N Y) 2013; 3. PubMed Citation  (Among 98 patients with Huntington disease and 47 with other conditions and chorea who were treated with tetrabenazine [12.5 to 300 mg daily] for up to 11 years, 75% had a very good response at the optimal dose, and side effects included somnolence [45%], insomnia [28%], depression [27%], weight loss [14%], restlessness [12%], anxiety [10%], diarrhea and nausea [9%]; no mention of ALT elevations).

  13. Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America: an analysis of published reports. Ann Hepatol 2014; 13: 231-9. PubMed Citation  (Among 176 reports of drug induced liver injury from Latin America published between 1996 and 2012, none were attributed to tetrabenazine).

  14. Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study. Gastroenterology 2015; 148: 1340-52. PubMed Citation  (Among 899 cases of drug induced liver injury seen over a ten year period at 8 US medical centers, none were attributed to tetrabenazine).

  15. Huntington Study Group. Effect of deutetrabenazine on chorea among patients with Huntington disease: a randomized clinical trial. JAMA 2016; 316: 40-50. PubMed Citation  (Among 90 adults with Huntington disease and chorea treated with deutetrabenazine [tetrabenazine with deuterium which decreases CYP 2D6 activity and prolongs its half-life] or placebo for 12 weeks, chorea was improved with the active drug and changes in scores for side effects [depression, somnolence] and laboratory values were similar in the two groups).

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OTHER REFERENCE LINKS
Tetrabenazine
  1. PubMed logoRecent References on Tetrabenazine

  2. Clinical Trials logoTrials on Tetrabenazine

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