Pharmacology Update

Tetrabenazine Tablets (Xenazine®)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD. Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; and Assistant Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Drs. Chan and Elliott report no financial relationship to this field of study.

The FDA has approved the first drug for the treatment of Huntington's disease. Tetrabenazine selectively binds to central nervous system vesicular monoamine transporter sites (VMAT2), resulting in depletion of serotonin and monoamine from nerve terminals. The drug is marketed by Prestwick Pharmaceuticals, Inc., as Xenazine®.

Indication

Tetrabenazine is indicated for the treatment of chorea associated with Huntington's disease.1

Dosage

Tetrabenazine is available as 12.5 mg and 25 mg tablets. The recommended starting dose is 12.5 mg taken in the morning. The dose may be increased to 25 mg daily (12.5 mg twice daily) after one week. Titration may continue at weekly intervals at 12.5 mg increments. Doses of 37.5-50 mg should be broken into three times daily dosing with no single dose greater than 25 mg. If further titration > 50 mg daily is indicated, the increment is 25 mg daily. Doses greater than 50 mg should not be given without CYP2D6 genotyping. The maximum dose is 100 mg daily (37.5 mg three times daily). For patients who are poor metabolizers (i.e., do express CYP2D6), the maximum dose is 50 mg daily.1

Potential Advantages

Tetrabenazine showed statistically significant improvement in chorea burden as well as improved clinical global improvement.1,2

Potential Disadvantages

Tetrabenazine produces dose-dependent adverse events that include depression, fatigue, insomnia, sedation/somnolence, akathisea, restlessness, and disability.1 It can increase the risk of suicidal thought and behavior. Most frequent adverse events compared to placebo are akathisia (19% vs 0%), sedation/somnolence (31% vs 3%), and Parkinson symptoms (15% vs 0%). Other adverse events include dysphagia, hypotension, hyperprolactinemia, small QTc prolongation, and neuroleptic malignant syndrome. Tetrabenazine should be avoided in patients at risk for cardiac arrhythmias, or patients who are taking a drug that may prolong QTc.

Comments

Tetrabenazine selectively and reversibly binds to VMAT2, resulting in depletion of monoamines in the CNS. The drug has been available since the 1950s and was initially studied as an antipsychotic but more recently for hyperkinetic movement disorders such as chorea, tics, and tardive dyskinesia.3 The antichorea effectiveness of tetrabenazine was shown in a randomized controlled trial in 84 ambulatory patients with Huntington's disease.1,2 Patients were independently ambulatory, with a screening total functional capacity greater than 5, and total maximum chorea score of 10 or greater (i.e., sum of the maximal chorea scores for face, buccal-oral-lingual, truncal, and each extremity from the motor subscale of the Unified Huntington's Disease Rating Scale [UHDRS]). Patients were randomized to tetrabenazine or placebo. The study duration was 12 weeks with a 7-week titration period, 5-week maintenance period, and a 1-week washout period. Tetrabenazine was started at 12.5 mg, and increased 12.5 mg weekly until the desired antichorea effect was achieved, 100 mg daily, or tolerability. The primary outcome was a reduction in the total maximal chorea score of the UHDRS. The secondary outcome was clinical global improvement. Tetrabenazine produced a reduction of 5 units compared to 1.5 units for placebo. The adjusted mean affect size (-3.5 units) represented a 23.5% reduction in chorea severity. There was also a statistical improvement in clinical global improvement. Five patients withdrew from the study group (9.3%) compared to none in the placebo group. Two occurrences of suicide or suicide ideation occurred in the study group and none in the control group. During the washout period, the mean total chorea score returned to baseline.

Clinical Implications

Huntington's disease is an inherited autosomal dominant disease with about 250,000 individuals in the United States affected or at risk of inheriting this fatal disease.4 This disease is characterized by progressive motor, cognitive, and behavioral symptoms.1,4,5 Antipsychotics, NMDA-antagonists, and other drugs have been used to treat chorea with limited success. Tetrabenazine showed improvement in chorea in a small randomized placebo-controlled study. However, benefit may be limited as functional capacity worsens, chorea lessens, and dystonia intensifies.6 Tetrabenazine does not appear to improve other symptoms and may increase the risk of depression and suicidal thoughts. Depression is the most frequent psychiatric symptom in Huntington's disease.

References

1. Xenazine Product Information. Washington, DC: Prestwick Pharmaceuticals; August 2008.

2. Huntington Study Group. Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial. Neurology 2006;66:366-372.

3. Kenney C, et al. Long-term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders. Mov Disord 2007;22:193-197.

4. Stack EC, Ferrante RJ. Huntington's disease: Progress and potential in the field. Expert Opin Investig Drugs 2007;16:1933-1953.

5. Bonelli RM, Hofmann P. A systematic review of the treatment studies in Huntington's disease since 1990. Expert Opin Pharmacother 2007;8:141-153.

6. Louis ED, et al. Dystonia in Huntington's disease: Prevalence and clinical characteristics. Mov Disord 1999;14:95-101.