Tetrabenazina

Uses

Tetrabenazina is used for the treatment of chorea associated with Huntington's disease.

Tetrabenazina is also used to associated treatment for these conditions: Gilles de la Tourette's Syndrome, Hemiballismus, Huntington's Disease (HD), Tardive Dyskinesia (TD), Senile chorea

How Tetrabenazina works

Tetrabenazina is a reversible human vesicular monoamine transporter type 2 inhibitor (Ki = 100 nM). It acts within the basal ganglia and promotes depletion of monoamine neurotransmitters serotonin, norepinephrine, and dopamine from stores. It also decreases uptake into synaptic vesicles. Dopamine is required for fine motor movement, so the inhibition of its transmission is efficacious for hyperkinetic movement. Tetrabenazina exhibits weak in vitro binding affinity at the dopamine D2 receptor (Ki = 2100 nM).

Dosage

Tetrabenazina dosage

General Dosing Considerations:

The chronic daily dose of Tetrabenazina used to treat chorea associated with Huntington's disease (HD) is determined individually for each patient. When first prescribed, Tetrabenazina therapy should be titrated slowly over several weeks to identify a dose of XENAXINE that reduces chorea and is tolerated. Tetrabenazina can be administered without regard to food.

Individualization Of Dose:

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. Tetrabenazina should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces chorea. 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 reactions such asakathisia, restlessness,parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse reaction does not resolve, consideration should be given to withdrawing Tetrabenazina treatment or initiating other specific treatment (e.g.,antidepressants).

Dosing Recommendations Above 50 mg per day: Patients who require doses of Tetrabenazina greater than 50 mg per day should be first tested and genotyped to determine if they are poor metabolizers (PMs) or extensive metabolizers (EMs) by their ability to express the drug metabolizing enzyme, CYP2D6. The dose of Tetrabenazina should then be individualized accordingly to their status as PMs or EMs

Extensive and Intermediate CYP2D6 Metabolizers:

Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of CYP2D6, who need doses of Tetrabenazina above 50 mg per day, should be titrated up slowly at weekly intervals by 12.5 mg daily, to allow the identification of a tolerated dose that reduces chorea. 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 adverse reactions such as akathisia, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse reaction does not resolve, consideration should be given to withdrawing Tetrabenazina treatment or initiating other specific treatment (e.g., antidepressants)

Side Effects

The following serious adverse reactions are Depression, Suicidality Akathisia, restlessness, and agitation, Parkinsonism, Dysphagia, Sedation and somnolence

Toxicity

Dose-limiting adverse effects are sedation, parkinsonism, akathsia, and depression. LD50 oral, mouse: 550 mg/kg

Precaution

May exacerbate symptoms of parkinsonism. Caution to be exercised when driving or performing skilled tasks. Pregnancy.

Interaction

Tetrabenazina should not be given with or within 14 days of discontinuation of MAOI therapy. Blocks action of reserpine. Decreases effects of levodopa and worsen parkinsonism. Increased risk of extrapyramidal side effects when given with amantadine, metoclopramide, antipsychotics.

Food Interaction

• Avoid alcohol. Ingesting alcohol may increase the drowsiness caused by tetrabenazine.
• Take with or without food.

[Moderate] GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents.

Use in combination may result in additive central nervous system depression and
MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol.

Ambulatory patients should be counseled to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

Tetrabenazina Drug Interaction

Major: escitalopramModerate: fluticasone / salmeterol, lorazepam, benztropine, clonazepam, lamotrigine, pregabalin, polyethylene glycol 3350, topiramate, diazepam, ondansetron, sertralineUnknown: amphetamine / dextroamphetamine, fexofenadine, ferrous sulfate, methylphenidate, levothyroxine, cyanocobalamin, ascorbic acid, cholecalciferol

Tetrabenazina Disease Interaction

Major: cardiac arrhythmias, depression, hepatic impairment, Huntington's diseaseModerate: dysphagia, hyperprolactinemia, hypotension

Volume of Distribution

Steady State, IV, in HD or tardive dyskinesia patients: 385L. Tetrabenazina is rapidly distributed to the brain following IV injection. The site with the highest binding is the striatum, while the lowest binding was observed in the cortex.

Elimination Route

Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine. Food does not affect the absorption of tetrabenazine. Cmax, oral = 4.8 ng/mL in HD or tardive dyskinesia patients;
Tmax, oral = 69 min in HD or tardive dyskinesia patients

Half Life

α-HTBZ = 7 hours; β-HTBZ = 5 hours; 9-desmethyl-β-DHTBZ = 12 hours.

Clearance

IV, 1.67 L/min in HD or tardive dyskinesia patients

Elimination Route

After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated (75%). Tetrabenazina is also cleared fecally (7% to 16%). Unchanged tetrabenazine has not been found in human urine. Urinary excretion of α-HTBZ or β-HTBZ (the major metabolites) accounted for less than 10% of the administered dose.

Pregnancy & Breastfeeding use

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. Tetrabenazina should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: It is not known whether Tetrabenazina or its metabolites are excreted in human milk. Since many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Tetrabenazina, a decision should be made whether to discontinue nursing or to discontinue Tetrabenazina, taking into account the importance of the drug to the mother.

Contraindication

Tetrabenazina is contraindicated in patients:

• Who are actively suicidal, or in patients with untreated or inadequately treated depression
• With hepatic impairment
• Taking monoamine oxidase inhibitors (MAOIs). XENAZINE should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI

Special Warning

Pediatric Use: The safety and efficacy of Tetrabenazina in pediatric patients have not been established.

Geriatric Use: The pharmacokinetics of Tetrabenazina and its primary metabolites have not been formally studied in geriatric subjects.

Hepatic Impairment: Because the safety and efficacy of the increased exposure to Tetrabenazina and other circulating metabolites are unknown, it is not possible to adjust the dosage of Tetrabenazina in hepatic impairment to ensure safe use. The use of Tetrabenazina in patients with hepatic impairment is contraindicated

Acute Overdose

Three episodes of overdose occurred in the open-label trials performed in support of registration. Eight cases of overdose with Tetrabenazina have been reported in the literature. The dose of Tetrabenazina in these patients ranged from 100 mg to 1g. Adverse reactions associated with Tetrabenazina overdose include acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor.

Treatment should consist of those general measures employed in the management of overdosage with any CNS-active drug. General supportive and symptomatic measures are recommended. Cardiac rhythm and vital signs should be monitored. In managing overdosage, the possibility of multiple drug involvement should always be considered. The physician should consider contacting a poison control center on the treatment of any overdose.

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