Brand Name:^1-5 Xenazine®

Generic Name:^1-5  Tetrabenazine

Manufacturer:⁵  Prestwick Pharma

Drug Class:  Benzoquinolizine^1,4, Central Nervous System Agent¹ and Monoamine Depletor^1,3,4,5  and dopamine receptor blocker¹

Uses: 

Labeled:  Treatment for: chorea due to Huntington's disease,^1,2,3,5  Huntington’s Disease ⁴

Unlabeled:⁴  Chorea, Drug-induced dyskinesia - Levodopa adverse reaction Spontaneous Dyskinesia, Gilles de la Tourette's syndrome, Tardive dyskinesia

Mechanism of Action:^1,3,4,5

Tetrabenazine’s exact mechanism is unknown.  It depletes monoamines such as dopamine, serotonin, norepinephrine, and histamine from nerve terminals. Tetrabenazine reversibly inhibits the human vesicular monoamine transporter type 2 which results in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores. 

Pharmacokinetics:   

Efficacy: 

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

Study Design:  Randomized, double blind placebo controlled trial

Description of Study: The safety, efficacy, and dose tolerability of tetrabenazine for treating chorea in Huntington disease was assessed by randomizing 84 patients with Huntington’s disease to receive tetrabenazine (n = 54) or placebo (n = 30) for 12 weeks. Tetrabenazine was increased over 7 weeks up to a maximum of 100 mg/day or until the desired antichoreic effect occurred or intolerable adverse effects took place. The primary outcome was the change from baseline in the chorea score of the Unified Huntington's Disease Rating Scale (UHDRS).  Tetrabenazine treatment resulted in a reduction of 5.0 units in chorea severity compared with a reduction of 1.5 units on placebo treatment (adjusted mean effect size = -3.5 ± 0.8 UHDRS units [mean ± SE]; 95% CI: -5.2, -1.9; p < 0.0001). There was also a significant benefit on ratings of clinical global improvement. There were five study withdrawals in the tetrabenazine group and five serious adverse events in four subjects (drowning suicide, complicated fall, restlessness/suicidal ideation, and breast cancer) compared with one withdrawal and no severe adverse events in the placebo group.  Tetrabenazine (TBZ), at adjusted dosages of up to 100 mg/day, effectively lessens chorea in patients with Huntington disease. Tetrabenazine should be dosed individually based on ongoing assessment of possible adverse side effects.

Limitations: One limitation was the duration of the study was only 12 weeks, therefore long term effects of the drug cannot be concluded from the study.  Patients were excluded if they had been treated in the past with dopamine depleting medications, dopamine D2 receptor blockers (if they had been off of them for 4 weeks), selective or nonselective monoamine oxidase  inhibitors, levodopa, dopamine agonists, amantadine or memantine.  The exclusion criteria makes the study hard to extrapolate the results to the intended population.

Conclusion: The study reduced chorea burden and appeared to be safe and generally well tolerated.  The antichoreic impact of tetrabenazazine was clinically meaningful and statistically significant.  

Citation: Ondo WG, Tintner R, Thomas M, et al: Tetrabenazine treatment for Huntington's disease-associated chorea. Clin Neuropharmacol 2002; 25(6):300-302.

Study design: Single arm, open label

Study Background: Nineteen patients, 41 to 76 years old with Huntington’s disease and disability specifically due to chorea were included in the study. Baseline videotapes were made of patients while sitting, talking, with arms forward, and walking. Tetrabenazine 12.5 mg was given twice daily and titrated by 12.5 mg weekly reaching maximum dose of 50 mg three times daily.  About 4 to 6 months later patients underwent global assessments, neurologic examinations, and videotaping. The videotapes were randomized, coded and rated using a motor subset of the Abnormal Involuntary Movement Scale (AIMS) by blinded investigators. The mean final daily dose of tetrabenazine was 62.5 mg given in 2 to 3 divided doses. Based on the motor AIMS scores, 15 patients improved with treatment, while 2 patients worsened upon treatment and 1 patient had no change (p<0.001). Overall, the mean motor AIMS score improved from 16.2 ± 4.8 to 12.8 ± 4.4. Treatment-emergent adverse events included akathisia, insomnia, constipation, depression, drooling, and subjective weakness. Most effects resolved with reduction of the dose.  In conclusion, treatment with tetrabenazine resulted in significant improvements in chorea symptoms in Huntington's disease. 

Limitations: The study was single arm, open label and the sample size was small.  The study included patients that failed other treatments; therefore the study could be biased towards more severe cases of Huntington’s disease associated chorea.  Also, the study used videotaping as a method to observe the patients movements.  The use of video makes it difficult to see subtle differences in movement.  Also, the patients knew they were being videotaped therefore they could have been more conscious about their movements showing less chorea then they normally would have.

Conclusions: The study had many limitations such as single blinding, no power reported and small sample size; however, the study showed that tetrabenazine to be tolerable and efficacious for the symptomatic treatment of chorea in Huntington’s disease.

Citation: Paleacu D, Giladi N, Moore O, Stern A, Honigman S, Badarny S.  Tetrabenazine treatment in movement disorders.  Clin Neuropharmacol.  2004 Sep-Oct; 27 (5): 230-3.

Study Design: Retrospective chart review

Study Background: The purpose of this study was to assess the efficacy of tetrabenazine in a retrospective chart review in 3 tertiary care movement disorders centers over long-term treatment.  Of 150 patients prescribed tetrabenazine, 118 were followed up and assessed using the Clinical Global Impression of Change (CGIC), a composite grade from a patient and caregiver scale over variable periods.  The patients had an assortment of hyperkinetic movement disorders including dystonia, Huntington disease or other choreas, tardive dyskinesia or akathisia, and Tourette syndrome.  The mean follow-up time was 22 months and the mean tetrabenazine dose was 76.2±22.5 mg/day (range 25—175mg/day).  The mean CGIC score was +1 (mild improvement).  The group of patients who scored +3 on the CGIC (very good improvement) represented 18.6% of all patients.  Most of them had Huntington’s disease or other types of chorea 7.6% of all patients.  These patients had the longest treatment duration and received a mean tetrabenazine dose of 70.5mg/day for a mean of 25.4±21.3 months.  The report concludes that tetrabenazine is a moderately effective treatment of a large variety of hyperkinetic movement disorders, with excellent effects in a subgroup with chorea and facial dystonia/dyskinesias.

Limitations: A standardized scales of assessment was not used.  High doses were not achieved therefore long term severe side effects could not be assessed.  It was a retrospective non controlled trial.  Very few p values were reported.

Conclusions: The patients with very good improvement were Huntington’s disease patients and patients with other types of chorea; therefore tetrabenazine appears to be efficacious in treating Huntington’s disease associated chorea.  However, it is not known whether or not a sufficient amount of patients were studied to be able to extrapolate the study to the population.

Contraindications:  

• actively suicidal ^1,2,3,4
• concomitant use of an MAOI ^1,3,4
• concomitant use of reserpine^3,4
• depression, untreated or inadequately-treated ^1,2,3,4
• hepatic function, impaired ^1,2,4
• use of tetrabenazine within 20 days of reserpine discontinuation^3,4
• preexisting forms of neurological disease or CNS depression¹
• previous hypersensitivity to tetrabenazine or any component of the product¹ 

Precautions: 

• Patients with renal failure or any renal impairment should use caution when taking tetrabenazine because safe use of tetrabenazine in patients with renal impairment has not been evaluated. ¹
• Patients with a history of depression or suicidal thoughts or behavior should use extreme caution while on tetrabenazine because it has been shown to cause depression and suicide ideation. ^1,3,4
• Patients with alcoholism should use tetrabenazine with caution because alcohol could exacerbate the sedation side effect of tetrabenazine.¹
• Patients with cardiac disease should use tetrabenazine with caution.  Tetrabenazine may increase the risk of torsade de pointes and or sudden death.  History of cardiac arrhythmias—increased risk of QT prolongation.  Use caution when on other drugs that cause QTc prolongation. ^1,3,4
• Patients with Parkinson’s disease should use tetrabenazine with caution because it could aggravate extrapyramidal symptoms due to dopamine-receptor blockade.^1,3,4
• Patients who are going to receive general anesthesia should talk to their anesthesiologist to determine if therapy should continue due to potential CNS effects.¹
• Patients with dysphagia or other conditions causing difficulty swallowing should use tetrabenazine with caution because esophageal dysmotility and aspiration have been associated with the use of anti-dopaminergic drugs.^1,3,4  
• Use of strong CYP2D6 inhibitors, such as fluoxetine and quinidine, or patients that are CYP2D6 poor metabolizers need to have adjustments made to their dose ^1,2,3,4
• Dosing greater than 50mg should be used with caution due to risk of increased adverse events.^1,2,3,4
• Hypokalemia and hypomagnesemia along with administration of tetrabenazine may increase the risk of torsade de pointes and or sudden death⁴
• Tetrabenazine should be discontinued if irreversible tardive dyskinesia develops.⁴
• Tetrabenazine should be discontinued if neuroleptic malignant syndrome develops.^1,3,4

Adverse Effects:  

• Akathisia 8.9-20%^1,3,4,5
• Anxiety 15%^1,3,4,5
• Bronchitis 4%^3,4
• Decreased appetite 4%^3,4
• Depression 11-19%^1,3,5
• Drowsiness/Fatigue 22%^1,3,4,5
• Dysphagia 4-10%^3,4
• Dyspnea 4%^3,4
• Dysuria 4%^3,4
• Headache 4%^3,4
• Insominia 22%^1,3,4,5
• Irritability 9%^3,4,5
• Nausea 13%/vomiting 6%^1,3,4,5
• Problems with balance 9% ^2,4,5
• Pseudosparkinsonism 3-24%^1,3,4
• Solmnolence 17-57%^3,4,5
• Upper respiratory infection 11%^3,4,5

Drug Interactions:^1,3,4  

• Alcohol—additive CNS depressant effect
• Antipsychotics:  Tetrabenazine may enhance the adverse/toxic effects of antipsychotics
• Ciprofloxacin, Gadobutrol, Nilotinib, Arsenic Trioxide and QTc-prolonging agents:  Tetrabenazine may enhance the QTc-prolonging effect
• CNS depressants:  Tetrabenazine may enhance the adverse toxic effect of CNS depressants
• CYP2D6 Inhibitors:  may decrease the metabolism of CYP2D6 substrates (moderate inhibitors); may increase the concentration of tetrabenazine (dose of tetrabenazine should be reduced)(major inhibitors)
• MAO Inhibitors:  tetrabenzine may enhance the adverse/toxic effect of MAOIs
• Reserpine: Reserpine may enhance the adverse effects of tetrabenazine
• Avoid valerian, St Johns wort, kava kava, gotu kola because they may all increase CNS depression.

Dosing/Administration:^1,2,3,4,5  

Huntington's Chorea:

• Adults should initially start at 12.5 mg each morning and after one week increase to 12.5 mg twice daily.  The dose may be increased by 12.5 mg each week.
• The dose must be individualized and titrated slowly.  
• Patients that require doses greater than 50 mg per day should be genotyped for CYP2D6 expression.    Those requiring doses greater than 50 mg per day should get three doses per day.
• Patients that are poor CYP2D6 metabolizers may require a daily dose of 37.5—50 mg, administer in 1 divided doses3 or 25 mg twice daily. 
• The daily dose of tetrabenazine should be halved in patients receiving strong CYP2D6 inhibitors such as fluoxetine, paroxetine, or quinidine. 
• Tetrabenazine may be abruptly discontinued, but chorea may occur 12—18 hours after the last dose. 
• If tetrabenazine therapy is interrupted for greater than 5 days, retitration of the dose is advised. If the therapy is interrupted for less than 5 days then the previous dose can be
• Maximum Adult Dosage is 100 mg/day in patients who express CYP2D6 and 50 mg/day in patients who do not express CYP2D6.
• Maximum Geriatric Dosage is 100 mg/day in patients who express CYP2D6 and 50 mg/day in patients who do not express CYP2D6.
• Safe and effective use has not been established in adolescents and children.
• Tetrabenazine is contraindicated in patients with hepatic impairment.
• Specific guidelines renal adjustments are not available.

Use in special circumstances:

• Pregnancy
• FDA pregnancy risk category C^1,2,4
• Animal studies have shown adverse events on the fetus and no controlled studies have been completed in women^1,4
• Effects of labor and delivery are unknown^1,4
• Lactation
• Unknown if tetrabenazine is excreted into human breast milk.^1,4

Conclusion:  Tetrabenazine is effectively used to treat chorea due to Huntington’s disease.  It should not be used in patients with severe depression, hepatic disease or actively suicidal.  The dose should be individualized and titrated weekly to get the appropriate therapeutic outcome without severe adverse events.  Other therapy for chorea due to Huntington’s disease is supportive care.  Although chorea due to Huntington’s disease is not very common the approval of tetrabenazine is a great advancement for its therapy.

Recommended References:

1. Tetrabenazine.  Clinical Pharmacology [Internet database].  Gold Standard, Inc., 2008.  Available at:  http://www.clinicalpharmacology.com  Accessed:  January 13, 2008.
2. Facts and comparisons
3. Lexi-Comp
4. Tetrabenazine.  In:  DRUGDEX® Evaluations System [Internet database].  Greenwood Village, Colo:  Thomson MicroMedex.  Updated periodically.  Accessed September 13, 2008.
5. Drugs approved by the FDA [updated September 8, 2008].  Thomson CenterWatch.  Available at:  http://www.centerwatch.com/patient/drugs/dru972.html.  Accessed on September 12, 2008.
6. Huntington Study Group.  Tetrabenazine as antichorea therapy in Huntington disease: a randomized controlled trial.  Neurology. 2006 Feb 14;66(3):366-72.
7. Ondo WG, Tintner R, Thomas M, et al: Tetrabenazine treatment for Huntington's disease-associated chorea. Clin Neuropharmacol 2002; 25(6):300-302.
8. Paleacu D, Giladi N, Moore O, Stern A, Honigman S, Badarny S.  Tetrabenazine treatment in movement disorders.  Clin Neuropharmacol.  2004 Sep-Oct; 27 (5): 230-3.

Prepared by: Ashley Corcoran, Doctor of Pharmacy Candidate.