Brand Name:  Xenazine

 

Generic Name:  Tetrabenazine

Manufacturer: Prestwick Pharmaceuticals, Inc

Drug Class:  Central Monoamine-Depleting Agent1

Uses: 

            Labeled: Chorea associated with Huntington’s disease1

            Unlabeled: Tourette’s Syndrome, Tardive dyskinesia3

 

Mechanism of Action:  

Tetrabenazine inhibits vesicular monoamine transporter 2, which selectively, reversibly and centrally depletes dopamine and other monoamines.  It works by depleting presynaptic dopamine, norepinephrine, histamine and serotonin while antagonizing postsynaptic dopamine receptors.2,3

 

Pharmacokinetics:

 

Tmax

1-1.5 hours 1

Vd

N/A

T1/2

5.5 hours4 and Alpha-HTBZ: 4-8 hours; Beta-HTBZ: 2-4 hours 1

Clearance

Urine (75% as metabolites, <10% as alpha and beta HTBZ); feces (7% to 16%)1

Protein Binding

82% to 85%; Metabolites: 59% to 681

Bioavailability

75%3

 

Metabolism:  Tetrabenazine is rapidly metabolized hepatically primarily by CYP2D6. Active metabolites of tetrabenazine are alpha- hydroxytetrabenazine, beta-hydroxytetrabenazine and O-dealkylated-hydroxytetrabenazine3

Elimination:   Tetrabenazine is mostly excreted in the urine in the form of metabolites (75%).  About 7%-16% is excreted through the fecal route.1

 

Efficacy:

 

Kenney C, Hunter C, Jankovic J.  Long-Term Tolerability of Tetrabenazine in the Treatment of Hyperkinetics Movement Disorders.  Movement Disorders.  2007;22(2):193-197.

 

Study Design:  A retrospective, cohort chart review study was completed to evaluate the long-term tolerability of tetrabenazine.  Patients involved in this study received tetrabenazine from a clinic between 1997 and 2004, but were excluded if they initiated treatment after 2002.  The efficacy of the medication was also evaluated, but was not the main purpose of the study.

Description of study:  The most common adverse effects associated with tetrabenazine treatment were drowsiness(25%), Parkinsonism(15.4%), depression(7.6%), akathisia(7.6%), nausea/vomiting(5.6%), nervousness/anxiety(5.1%), and insomnia(4.9%).  46.2% of the patients who received tetrabenazine did not report any adverse events.  Most of the people who were treated for tardive dyskinesia or chorea with tetrabenazine remained on treatment.  The main reasons for discontinuation of the medication were intolerability of adverse effects (17%), lack of efficacy (8.5%) and travel/financial difficulties (7.6%).  Over 80% of the patients in the clinic had major improvements in their chorea.

Limitations:  This was a retrospective and open-label study.  There was no placebo in the study making it impossible to compare the adverse effects with anything.  Analyses for this study were based on patient charts, and the authors of the study did not talk to the patients.

Conclusion:  There are side effects associated with this medication, but the benefits may outweigh the disabling effects of the disease.  Another benefit to tetrabenazine is that it doesn’t cause tardive dyskinesia like many of the other medications used to control chorea.

Although efficacy was not a primary outcome for this study, tetrabenazine can be an effective treatment for chorea and other hyperkinetic movement disorders.  Not all patients are cured by this medication, but it helped the majority of patients studied. 

 

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

 

Study Design:  This study was done to examine the safety, efficacy, and dose tolerability of tetrabenazine for treating chorea in Huntington’s disease.  This was a multicenter, prospective, double blind, randomized, placebo-controlled dose-finding study.  There were a total of 84 participants in the study with 30 in the placebo group and 54 in the tetrabenazine group.  Patients were treated for 12 weeks, taken off tetrabenazine/placebo for one week, and then evaluated.   Dosing was individualized to achieve desired antichoreic effects or until intolerable side effects occurred.

Description of study:  The primary outcome was to measure the total maximal chorea score on the UHDRS scale. 69% of patients had a decrease in chorea symptoms of at least 3 units compared to 20% in the placebo group.  Tetrabenazine was also superior to placebo on the CGI Global Improvement Scale, but the other secondary outcomes did not show a significant benefit with tetrabenazine.  The main adverse events were drowsiness, insomnia, depressed mood, parkinsonism and akathisia, but adverse effects were usually fixed with dosage adjustments.  Four patients did experience severe adverse events during the study, one being suicide.  The authors concluded that tetrabenzaprine significantly reduced chorea burden, improved global outcome and was generally safe and well tolerated. 

Limitations:  Some of the authors in this study were from the manufacturer of Xenazine.  The recommended titration for tetrabenazine is to start with one tablet daily for one week and then increase to twice daily after that.  This study only did one day of the once daily 12.5mg tablet.  Also, participants were allowed to stop taking the medication for 7 days, and they were not retitrated after restarting the medication.  For patients that dropped out, the last available score was carried forward.  The treatment for this study was only 12 weeks long which limited the ability to determine the long term efficacy and safety of tetrabenazine.

Conclusion:  Tetrabenazine did show an improvement the UHDRS total maximum chorea score and CGI Global Improvement score.  Other than the 4 serious adverse events, side effects seemed relatively minor.  Since one suicide did occur during the study, and depression is a side effect of tetrabenazine, depression symptoms and suicidal ideation should be monitored while on the medication.  Dosing is highly individualized, therefore chorea symptoms and adverse events should be closely monitored while titrating medicine to correct dose.

 

Fasano A, Caddeddu F, Guidubaldi A, Piano C, Soleti F,Zinzi P, Bentivoglio A.  The Long-term Effect of Tetrabenazine in the Management of Huntington Disease.  Clinical Neuropharmacology.  2008;31(6):313-318.

 

Study Design:  68 patients with Huntington disease that were treated with tetrabenazine were retrospectively analyzed by reviewing clinical charts.  The objective of the study was to enhance the knowledge on the long-term efficacy and safety of tetrabenazine in managing chorea.

Description of Study:  Baseline analyses were conducted followed by two visits.  The first follow-up which was 9.7±7.8 months after the initial evaluation showed a reduction in chorea subscore of 21%, a reduction in the mean dystonia subscore of 25%(not statistically significant) and no mean change in UHDRS motor score.  At the last follow-up which was conducted 34.4±25.2 months after baseline visit, there was an increase of the mean UHDRS motor score and the mean score of the dystonia section increased 37% and the mean score of the chorea section decreased by 9%.  Only 5 patients did not see any improvement from treatment with tetrabenazine.  The only predictor of better outcomes with tetrabenazine was an older age at onset of Huntington disease.  Half of the patients in the study experienced at least one adverse effect with complaints of drowsiness, depression, gut disturbances, parkinsonism, xerostomia, and hypotension.  Only two patients withdrew from the medication due to intolerable side effects.

Limitations:  This was a retrospective study.  It was also an open-label study, without a placebo control.  There was also no control of what other medications the patients in the study were taking, therefore concomitant medications could have helped or worsened motor functioning or side effects. 

Conclusion:  The study showed that patients had better results at the beginning of treatment.  As the study progressed dosages were increased due to worsening symptoms.  Side effects were manageable since only 2 patients withdrew from treatment due to side effects.  Side effects that occurred with the patients in the study were usually controlled by decreasing the dose and/or by adding antidepressant or antiparkinsonian medications.  This study showed that tetrabenazine was effective for the treatment of Huntington Disease, but since patients were allowed to use other medications while in the study it is difficult to determine the true efficacy of tetrabenazine.

 

Contraindications:

Hepatic disease, MAOI therapy and torsade de pointes2, suicidal ideation*, use of reserpine within twenty days and depression*3

*There is a black box warning for depression and suicidal ideation

 

Precautions:

Alcoholism, bradycardia, breast cancer, breast-feeding, cardiac arrhythmias, cardiac disease, children, CNS depression, coma, dehydration, depression, driving or operating machinery, dysphagia, elderly, fever, hyperprolactinemia, hypokalemia, hypomagnesemia, hypotension, hypovolemia, infants, infertility, myocardial infarction, neurological disease, orthostatic hypotension, Parkinson’s disease, pregnancy, QT prolongation, renal disease, renal failure, renal impairment, suicidal ideation, surgery and tardive dyskinesia.2

 

Adverse Effects:2

Extrapyramidal symptoms (15-33%)

Sedation (31%)

Somnolence (31%)

Fatigue (22%)

Insomnia (22%)

Akathisia (19%)

Depression (19%)

Anxiety (15%)

Nausea (13%)

Falls (15%)

Upper respiratory tract infection (11%)

Parkinsonism (3-10%)

Irritability (9%)

Dizziness (4%)

Headache (4%)

Obsessive reaction (4%)

Bruising (6%)

Dysphagis (4%-10%)

Vomiting (6%)

Decreased appetite (4%)

Diarrhea (2%)

Dysuria (4%)

Balance difficulty (9%)

Bradykinesia (9%)

Dysarthria (4%)

Gait disturbance (4%)

Bronchitis (4%)

Dyspnea (4%)

Hyperprolactinemia

Orthostatic hypotension 

Neuroleptic malignant syndrome

QT prolongation

Suicidal ideation

 

Drug Interactions:

Arsenic Trioxide, Astemizole, Bepridil, Chloroquine, Clarithromycin, Daunorubicin, Doxorubicin, Erythromycin, Grepafloxacin, Halofantrine, Levomethadyl, Maprotiline, Mefloquine, Moxifloxacin, Pentamidine, Probucol, Sparfloxacin, Terfenadine 

Aripirazole, Cloazpine, Droperidol, Haloperidol, Olanzapine, Paliperidone, Phenothiazines, Pimozide, Quetiapine, Risperdone, Ziprasidone 

Buprenorphine, Butorphanol, Dronabinol, Ethanol, Nabilone, Nalbuphine, Opiate Agaonists, Pentazocine, Tramadol, Trazodone 

Monoamine oxidase inhibitors- Enhanced adverse and toxic effects of MOAI1

Reserpine- Enhanced adverse and toxic effects of MOAI due to similar mechanism of action.1

Amoxapine- Increased risk of QT prolongation, drowsiness, sedation, orthostatic hypotension and dizziness2

Fluoxetine- Fluoxetine is a CYP2D6 inhibitor therefore dose of tetrabenazine should be halved. 2

Loxapine-  Increased risk of drowsiness, sedation, orthostatic hypotension, dizziness, neuroleptic malignant syndrome, and extrapyramidal symptoms2

Molindone-  Increased risk of drowsiness, sedation, orthostatic hypotension, dizziness, neuroleptic malignant syndrome, and extrapyramidal symptoms2

Nilotinib- Increased risk of QT prolongation and nilotinib is a CYP2D6 inhibitor increasing the side effects of tetrabenazine2

Paroxetine- Paroxetine is a CYP2D6 inhibitor therefore dose of tetrabenazine should be halved. 2

Quinidine- Increased risk of QT prolongation and quinidine is a CYP 2D6 inhibitor therefore decreasing elimination of tetrabenazine. 2

Thiothixene- Increased risk of drowsiness, sedation, orthostatic hypotension, dizziness, neuroleptic malignant syndrome, and extrapyramidal symptoms2

Tricyclic antidepressants- Increased risk of QT prolongation, drowsiness, sedation, orthostatic hypotension, dizziness2

Troleandomycin- Increased risk of QT prolongation and Torsade de pointes2

Antihypertensive Agents- Increased hypotensive effects such as orthostatic hypotension.2

Anxiolytics, sedatives, hypnotics- Increased intensity of dizziness, drowsiness, orthostatic hypotension and sedation. 2

Gonadotropin-Releasing Hormone (GnRH) Analogs- Increased risk of hyperprolactinemia       

Methadone- Increased risk of QT prolongation, drowsiness, sedation, orthostatic hypotension and dizziness2           

 

Dosing/Administration:

            Usual dose:

Tetrabenazine should be titrated up to the necessary dose starting with 12.5mg every morning, then increasing to 12.5mg twice daily.  Dose should be titrated in one week intervals as necessary.  If greater than 50mgs per day is necessary for symptoms to resolve, the patient should be tested for expression of CYP2D6.  If the patient does not express CYP2D6 then the maximum dose is 50mg per day with a maximum single dose of 25mg.  If the patient expresses CYP2D6 the maximum daily dose is 100mg with a maximum single dose of  37.5mg. 2

Renal Impairment dose: Not necessary2

Hepatic Impairment dose:  Use is contraindicated with hepatic impairment2

 

Use in Special Circumstances:

Pregnancy:  Category Risk C based on insufficient evidence.  Recommend use when benefits outweigh risks. 2

Lactation:  Recommended to use when benefits outweigh risks. 2

           

Conclusion:

Tetrabenazine has been found beneficial for the treatment of chorea associated with Huntinton’s disease in many patients.  Treatment for chorea associated with Huntington’s Disease can be necessary due to quality of life. Tetrabenazine has been used for chorea associated with Huntington’s disease in the past, but was  only recently FDA approved in the United States.  An advantage of tetrabenazine over both typical and atypical neuroleptics is that these agents can cause tardive dyskinesia.  Tetrabenazine has not been found to be effective in helping with chorea in all patients, but did help most patients in trials.  Side effects associated with tetrabenazine are drowsiness, parkinsonism, depression, akathisia, nausea/vomiting, nervousness/anxiety, insomnia, salivation, and dizziness.  Tetrabenazine has a black box warning for depression, therefore mood symptoms and signs of suicide should be monitored closely.  The potential benefits of tetrabenazine may outweigh the side effects associated with the medication.

 

Recommended References:

 

Prepared by:  Ashlee Weitzman, Doctor of Pharmacy Candidate