Xenazine (tetrabenazine) is a monoamine depletor for oral administration. The precise mechanism by which tetrabenazine exerts its anti-chorea effects is unknown, but is believed to be related to its effect as a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals.

Xenazine is specifically indicated for the treatment of chorea associated with Huntington’s disease.

Xenazine is supplied as a tablet, in 25 mg and 125 mg strengths, designed for oral administration. It is recommended that dosing of Xenazine involve careful titration of therapy to determine an individualized dose for each patient.

Dosing Recommendations up to 50 mg per day
The starting dose should be 12.5 mg per day given once in the morning. After one week, the dose should be increased to 25 mg per day given as 12.5 mg twice a day. Xenazine should be titrated up slowly at weekly intervals by 12.5 mg, to allow the identification of a dose that reduces chorea and is well tolerated. If a dose of 37.5 to 50 mg per day is needed, it should be given in a three times a day regimen. The maximum recommended single dose is 25 mg. If adverse events occur, titration should be stopped and the dose should be reduced. If the adverse event does not resolve, consideration should be given to withdrawing Xenazine treatment or initiating other specific treatment.

Dosing Recommendations above 50 mg per day
Patients who appear to require doses greater than 50 mg per day should be genotyped for CYP2D6.
For CYP2D6 Extensive and Intermediate Metabolizers (patients who express CYP2D6)
At doses above 50 mg per day, Xenazine should be titrated up slowly at weekly intervals by 12.5 mg, to allow the identification of a dose that reduces chorea and is well tolerated. Doses above 50 mg per day should be given in a three times a day regimen. The maximum recommended daily dose is 100 mg and the maximum recommended single dose is 37.5 mg. If the adverse event does not resolve, consideration should be given to withdrawing Xenazine treatment or initiating other specific treatment.
For CYP2D6 Poor Metabolizers (patients who do not express CYP2D6)
Dosing is similar to EMs except that the recommended maximum single dose is 25 mg, and the maximum recommended daily dose is 50 mg.

Resumption of Treatment
Following treatment interruption of greater than five days or a treatment interruption occurring due to a change in the patient’s medical condition or concomitant medications, Xenazine should be retitrated when resumed. For short-term treatment interruption of less than five days, treatment can be resumed at the previous maintenance dose without titration.

Xenazine is contraindicated in patients who are actively suicidal, or in those with untreated or inadequately treated depression, as tetrabenazine can increase the risk of depression and suicidal thoughts.

FDA Approvl
FDA approval of Xenazine was based on the results of two clinical studies.

Study One
This randomized, double-blind, placebo-controlled multi-center study enrolled 84 ambulatory subjects. The subjects received Xenazine starting at 12.5 mg/day and titrated upward at weekly intervals in 12.5 mg increments until satisfactory control of chorea was achieved, until intolerable side effects occurred, or until a maximal dose of 100 mg per day was reached. Treatment duration was 12 weeks, including a 7-week dose titration period and a 5 week maintenance period followed by a 1-week washout. The primary efficacy endpoint was the Total Chorea Score, an item of the Unified Huntington’s Disease Rating Scale (UHDRS). Total Chorea Scores for subjects in the drug group declined by an estimated 5.0 units during maintenance therapy (average of Week 9 and Week 12 scores versus baseline), compared to an estimated 1.5 units in the placebo group. The treatment effect of 3.5 units was highly statistically significant. At the Week 13 follow-up in Study 1 (1 week after discontinuation of the study medication), the Total Chorea Scores of subjects receiving Xenazine returned to baseline. A Physician-rated Clinical Global Impression (CGI) statistically favored Xenazine.

Study Two
This controlled study was conducted in subjects who had been treated with open-label Xenazine for at least 2 months (mean duration of treatment was 2 years). They were randomized to continuation of tetrabenazine at the same dose (n=12) or to placebo (n=6) for three days, at which time their chorea scores were compared. Although the comparison did not reach statistical significance (p=0.1), the estimate of the treatment effect was similar to that seen in Study 1 (about 3.5 units).

Ongoing Study Commitments

• Prestwick Pharma has agreed to complete the ongoing 2-year carcinogenicity study in male rats to identify the unexpected serious risk of carcinogenicity.
  Final Report Submission: by March 2009
• Prestwick Pharma has agreed to conduct a 2-year carcinogenicity study in female rats to identify the unexpected serious risk of carcinogenicity.
  Protocol Submission: September 2009
  Study Start Date: January 2010
  Final Report Submission: January 2013
• Prestwick Pharma has agreed to conduct a nonclinical toxicity study of fertility and early embryonic development (to implantation) to identify the unexpected serious risk of adverse effects on reproduction.
  Protocol Submission: September 2008
  Study Start Date: January 2009
  Final Report Submission: September 2009
• Prestwick Pharma has agreed to submit in vivo metabolism data in the animal species used in the nonclinical studies of tetrabenazine, particularly the reproductive toxicology and the carcinogenicity studies.
  Final Report Submission: October 2008
• Prestwick Pharma has agreed to conduct a neurotoxicity study of tetrabenazine using methodology and a multiple dose regimen similar to Satou T et al. Exp Toxicol Pathol 53(4):303-308, 2001. Consideration should be given to including a group in which tetrabenazine is administered i.p. as in Satou et al. (2001) in order to facilitate comparisons between studies. Ideally, tetrabenazine should be tested at several dose levels with the high dose being a maximum tolerated dose.
  Protocol Submission: September 2008
  Study Start Date: January 2009
  Final Report Submission: January 2010
• Prestwick Pharma has agreed to conduct an in vitro metabolism study to characterize the potential serious safety risk of the inhibitory effect of tetrabenazine, a-HTBZ, and ß-HTBZ on CYP2B6.
  Protocol Submission: September 2008
  Study Start Date: January 2009
  Final Report Submission: April 2009

Adverse events associated with the use of Xenazine may include, but are not limited to, the following:

• sedation/somnolence
• fatigue
• insomnia
• depression
• akathisia
• nausea
• anxiety
• upper respiratory tract infection
• irritability
• balance difficulty
• brachykinesia

Xenazine (tetrabenazine) is a monoamine depletor for oral administration. The precise mechanism by which tetrabenazine exerts its anti-chorea effects is unknown, but is believed to be related to its effect as a reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals. Tetrabenazine reversibly inhibits the human vesicular monoamine transporter type 2 (VMAT2), resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores.

Frank S, Ondo W, Fahn S, Hunter C, Oakes D, Plumb S, Marshall F, Shoulson I, Eberly S, Walker F, Factor S, Hunt V, Shinaman A, Jankovic J A study of chorea after tetrabenazine withdrawal in patients with Huntington disease. Clinical Neuropharmacology 2008 May-Jun;31(3):127-33

Savani AA, Login IS Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology 2007 Mar 6;68(10):797

Huntington Study Group Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial. Neurology 2006 Feb 14;66(3):366-72

Ondo WG, Tintner R, Thomas M, Jankovic J Tetrabenazine treatment for Huntington's disease-associated chorea. Clinical Neuropharmacology 2002 Nov-Dec;25(6):300-2

For additional information regarding Huntington's disease or Xenazine, please visit the Xenazine web page.