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Mechanism of Action (MOA)

Tetrabenazine works presynaptically to reduce the overall supply of monoamines, including dopamine9

The precise mechanism by which Xenazine® (tetrabenazine) exerts its antichorea effects is unknown, but it is believed to be related to its effect as a reversible depletor of monoamines from nerve terminals.9

Dialing back dopamine1

The loss of inhibitory inputs of the medium-sized projection spiny neurons in the brain striatum is believed to be the underlying cause of involuntary movement characteristic of the disease.1 Based on studies in mouse models, dialing back the dopamine input into the striatum may be a possible strategy for affecting chorea.2

Normal VMAT2 Function
  • The presynaptic release of dopamine is partially regulated by vesicular monoamine transporter 2 (VMAT2).3,4
  • VMAT2 transports and concentrates monoamines, including dopamine, in presynaptic storage vesicles.3,4
  • Dopamine stored in synaptic vesicles is protected from degradation by monoamine oxidase (MAO). Therefore, the activity of VMAT2 determines the amount of cytosolic dopamine available for synaptic release.5
Dopamine Receptor Function
  • To date, 5 dopamine receptor subtypes have been classified (D1 through D5); they are divided into 2 subclasses – namely D1-like (D1 and D5) and D2-like (D2, D3, and D4) dopamine receptors.6
  • Dopamine binds to its receptors on the postsynaptic neuron to either trigger or inhibit neuronal excitation, depending on the receptor subtypes.6,7
  • The excessive stimulation of dopamine triggers involuntary and uncontrollable body movements typical of the chorea in HD.8
Mechanism of Action of Tetrabenazine
  • Tetrabenazine reversibly binds to VMAT2 and reduces uptake of dopamine into synaptic vesicles9
  • There are no conclusive studies in humans, but it is hypothesized that tetrabenazine:
    • Provides greater selectivity for dopamine than for other monoamines11
    • Selectively reduces dopaminergic activity11
  • Tetrabenazine interacts with VMAT at a site distinct from that of substrate binding.5
  • Tetrabenazine has no affinity for the monoamine transporters on the synaptic membrane.10
  • The dopamine pool in the cytosol is rapidly metabolized and depleted from synaptic release.5
  • Tetrabenazine inhibition of VMAT2 results in an overall reduction in synaptic monoamines, including dopamine.9

Xenazine is also contraindicated in patients who have impaired hepatic function or are taking monoamine oxidase inhibitors (MAOIs) or reserpine. Xenazine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI. At least 20 days should elapse after stopping reserpine before starting Xenazine.

Xenazine® (tetrabenazine) has a
Short Half-life (t1/2)9

Tetrabenazine is hepatically metabolized and effects on monoamine
depletion are due primarily to actions of 2 major metabolites

Metabolite Half-life (t1/2)
α-HTBZ 7 hours
β-HTBZ 5 hours

α-HTBZ and β-HTBZ are metabolized principally by CYP2D6
Patients who are poor metabolizers of CYP2D6 should not be given any daily doses greater than 50 mg

HTBZ=dihydrotetrabenazine

Sources:

  1. Gil JM, Rego AC. Mechanisms of neurodegeneration in Huntington’s disease. Eur J Neurosci. 2008; 27:2803-2820.
  2. Cyr M, Sotnikova TD, Gainetdinov RR, Caron MG. Dopamine enhances motor and neuropathological consequences of polyglutamine expanded huntington. FASEBJ. 2006; 20:2541-2543.
  3. Henry JP, Sagne C, Bedet C, Gasnier B.The vesicular monoamine transporter: from chromaffin granule to brain. Neurochem Int. 1998;32:227-246.
  4. Zheng G, Dwoskin LP, Crooks PA. Vesicular monoamine transporter 2: role as a novel target for drug development. AAPS J. 2006; 8:E682-E692.
  5. Guillot TS, Miller GW. Protective actions of the vesicular monoamine transporter2 (VMAT2) in monoaminergic neurons. Mol Neurobiol. 2009;39:149-170.
  6. Werkman TR, Glennon JC, Wadman WJ, McCreary AC. Dopamine receptor pharmacology: interactions with serotonin receptors and significance for the aetiology and treatment of schizophrenia. CNS Neurol Disord Drug Targets. 2006;5:3-23.
  7. Calabresi P,Centonze D,Gubellini P,et al. Synaptic transmission in the striatum: from plasticity to neurodegeneration. Prog Neurobiol. 2000; 61:231-265.
  8. Joel D,Weiner I. The connections of the primate subthalmic nucleus: indirect pathways and the open-interconnected scheme of basal ganglia-thalamocortical circuitry. Brain Res Brain Res Rev. 1997;23:62-78.
  9. Xenazine [package insert]. Deer␣eld, IL: Lundbeck; September 2009.
  10. Rostene W, Boja JW, Scherman D, Carroll FI, Kuhar MJ. Dopamine transport: pharmacological distinction between the synaptic membrane and the vesicular transporter in rat striatum. Eur J Pharmacol. 1992; 218:175-177.
  11. Pettibone DJ, Totaro JA, Pflueger B. Tetrabenazine-induced depletion of brain monoamines: characterization and interaction with selected antidepressants. Eur J Pharmacol. 1984;102:425-430.

XENAZINE® (tetrabenazine) Tablets

Indications and Usage:

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

Important Safety Information:

WARNING: DEPRESSION AND SUICIDALITY

See full prescribing information for complete boxed warning.
  • Increases the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease.
  • Balance risks of depression and suicidality with the clinical need for control of choreiform movements when considering the use of XENAZINE.
  • Monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior.
  • Inform patients, caregivers, and families of the risk of depression and suicidality and instruct to report behaviors of concern promptly to the treating physician.
  • Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation.
  • XENAZINE is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression.
  • XENAZINE is also contraindicated in patients who have impaired hepatic function or are taking monoamine oxidase inhibitors (MAOIs) or reserpine. XENAZINE should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI. At least 20 days should elapse after stopping reserpine before starting XENAZINE.
  • Prescribers should periodically re-evaluate the need for XENAZINE in their patients by assessing the beneficial effect on chorea and possible adverse effects including worsening mood, cognition, rigidity, and functional capacity. XENAZINE should be titrated slowly over several weeks for a dose that is appropriate for each patient.
  • Before a dose greater than 50 mg is administered, the patient’s CYP2D6 metabolizer status should be determined. Do not exceed 50 mg/day or 25 mg/dose if XENAZINE is administered with a strong CYP2D6 inhibitor.
  • XENAZINE therapy should be retitrated if there is a treatment interruption of greater than 5 days, or a treatment interruption occurring due to a change in the patient’s medical condition or concomitant medications.
  • A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with XENAZINE. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. The management of NMS should include immediate discontinuation of XENAZINE and other drugs not essential to concurrent therapy.
  • XENAZINE can also cause other serious side effects including: akathisia, restlessness, agitation, parkinsonism, and sedation/somnolence. These side effects may require a dose reduction or discontinuation of XENAZINE. Monitoring of vital signs on standing should be considered in patients who are vulnerable to hypotension. Dysphagia has also been reported with use of XENAZINE; some cases of dysphagia were associated with aspiration pneumonia.
  • QT prolongation–related arrhythmias have been reported with use of XENAZINE. XENAZINE should not be used in combination with drugs known to prolong QTc (which in certain circumstances can lead to torsades de pointes and/or sudden death), in patients with congenital long QT syndrome, or in patients with a history of cardiac arrhythmias. A potentially irreversible syndrome of involuntary, dyskinetic movements called tardive dyskinesia (TD) may develop in patients treated with neuroleptic drugs. If signs and symptoms of TD appear in a patient treated with XENAZINE, drug discontinuation should be considered. Adverse reactions associated with XENAZINE, such as QTc prolongation, NMS, and extrapyramidal disorders, may be exaggerated by concomitant use of dopamine antagonists.
  • XENAZINE elevates serum prolactin concentrations. XENAZINE may induce sedation/somnolence which may impair the ability to drive or operate dangerous machinery. Alcohol or other sedating drugs can worsen sedation/somnolence.
  • Some adverse events such as depression, fatigue, insomnia, sedation/somnolence, parkinsonism, and akathisia may be dose-dependent. If the adverse effect does not resolve or decrease, consideration should be given to lowering or discontinuing XENAZINE. The most commonly reported adverse events with XENAZINE compared to placebo were sedation/somnolence (31% vs 3%), fatigue (22% vs 13%), insomnia (22% vs 0%), depression (19% vs 0%), akathisia (19% vs 0%), anxiety (15% vs 3%), and nausea (13% vs 7%).

For more information, please see the full Prescribing Information, including Boxed Warning, the Medication Guide or go to www.XENAZINEusa.com.

XENAZINE is a registered trademark of Valeant International Bermuda

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