Tetrabenazine

Tetrabenazine is a Central Monoamine-Depleting Agent belonging to Vesicular Monoamine Transporter 2 (VMAT2) Inhibitor class.

Tetrabenazine is a vesicular monoamine transporter 2 (VMAT) inhibitor used for the management of chorea associated with Huntington's Disease.

Its bioavailability is low and erratic (due to extensive first-pass effects), Time taken to reach peak plasma concentration is within 1 to 1.5 hours. Tetrabenazine is Rapidly distributed to the brain (IV), and it has Plasma protein binding of approximately 82-85%. Tetrabenazine is Rapidly and extensively metabolized in the liver by carbonyl reductase to active metabolites, α- and β-hydroxy tetrabenazine (HTBZ) which are subsequently metabolized by CYP2D6 to 9-desmethyl-α-DHTBZ (minor) and 9-desmethyl-β-DHTBZ (major), respectively. Tetrabenazine is mainly excreted Via urine (approximately 75% as metabolites, <10% as α- and β-HTBZ) and faeces (approximately 7-16%).

Tetrabenazine shows side effects like Nausea, diarrhoea, vomiting, decreased appetite, headache, pain or burning upon urination, bruising, difficulty speaking or being understood, etc.

Tetrabenazine is available in the form of an Oral Tablet.

Tetrabenazine is available in India, US, Australia, Denmark, France, Germany, Ireland, Israel, Italy, New Zealand, Portugal, Spain, Switzerland and the United Kingdom.

Tetrabenazine belongs to Vesicular Monoamine Transporter 2 (VMAT2) Inhibitor class and acts as Central Monoamine-Depleting Agent.

The 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) (Ki≈ 100 nM), resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores.

The Onset of action of Tetrabenazine is not clinically established.

The Duration of action of Tetrabenazine is about 16-24 hours.

The Time to peak plasma concentration of Tetrabenazine is approximately 1-1.5 hours.

Tetrabenazine is available in the form of an Oral Tablet.

Tetrabenazine tablet is taken orally usually in divided dose.

Tetrabenazine is used in the treatment of chorea (abnormal, jerky, or involuntary movements) associated with Huntington’s disease, an inherited condition in which the nerve cells in the brain become damaged. Tetrabenazine works by reducing the level of certain chemicals that cause abnormal movements.

Tetrabenazine is a Central Monoamine-Depleting Agent belonging to Vesicular Monoamine Transporter 2 (VMAT2) Inhibitor class.

Tetrabenazine acts as a reversible inhibitor of the human vesicular monoamine transporter type 2 (VMAT-2) and thereby decreases the uptake of monoamines (including dopamine, serotonin, norepinephrine, and histamine) into synaptic vesicles and depletes the monoamine stores; hydroxy tetrabenazine (HTBZ) also inhibits VMAT-2; weak binding affinity for dopamine D₂ receptors.

Tetrabenazine is approved for use in the following clinical indications

• Huntington disease–associated chorea
• Tardive dyskinesia
• Tourette syndrome

• Huntington disease–associated chorea

Oral: 12.5 mg once daily in the morning; may increase to 12.5 mg twice daily after 1 week. May increase daily dosage by 12.5 mg increments at weekly intervals up to 50 mg/day; divide daily doses >37.5 mg into 3 doses (maximum single dose: 25 mg).

• Tardive dyskinesia

Oral: Initial: 50 mg/day in divided doses; may increase daily dose by 50 mg increments every 2 weeks up to maximum of 150 mg/day in divided doses.

• Tourette syndrome

Oral: 12.5 mg 2 to 3 times daily; may increase daily dose by 12.5 mg increments at weekly intervals. Usual maximum tolerated dosage: 25 mg 3 times daily; maximum recommended dose: 200 mg/day.

Tetrabenazine is available in various strengths as 12.5 mg and 25 mg.

Tetrabenazine is available in the form of an Oral Tablet.

Tetrabenazine is contraindicated in patients with

• Who are actively suicidal, or in patients with untreated or inadequately treated depression.
• With hepatic impairment.
• Taking monoamine oxidase inhibitors (MAOIs). Tetrabenazine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI
• Taking reserpine. At least 20 days should elapse after stopping reserpine before starting Tetrabenazine.
• Taking deutetrabenazine or valbenazine.

• CNS depression

May cause CNS depression, which may impair physical or mental abilities; patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving). If sedation occurs during treatment, dosage reduction or discontinuation may be necessary.

• Depression/suicidal ideation

Use can increase risk for depression and suicidal thoughts and behavior in patients with Huntington disease. Dosage reduction, treatment of depression, or discontinuation may be necessary.

• Esophageal dysmotility/aspiration

Use has been associated with esophageal dysmotility, dysphagia, and aspiration; use with caution in patients at risk of aspiration pneumonia.

• Neuroleptic malignant syndrome

Use may be associated with neuroleptic malignant syndrome (NMS). Discontinue with confirmed NMS; may recur with reintroduction of treatment; monitor carefully.

• Ophthalmic effects

Binds to melanin-containing tissues in animal studies; may result in accumulation and toxicity with extended use and long-term ophthalmic effects. Clinical relevance and monitoring recommendations are unknown.

• Orthostatic hypotension

May cause orthostatic hypotension; monitor patients at risk closely.

• Parkinsonism

May cause parkinsonism symptoms (ie, bradykinesia, hypertonia, rigidity). Dose reduction, treatment of parkinsonism, or discontinuation of therapy may be necessary.

• Psychomotor stimulation

Use has been associated with akathisia, restless, and agitation. Dosage reduction, treatment of psychomotor effects, or discontinuation may be necessary.

• QT prolongation

Has been shown to prolong the QT interval alone (minimal) and with other drugs with comparable effects on the QT interval (additive). Avoid use in patients with congenital QT prolongation, a history of cardiac arrhythmias, or concomitant drugs known to cause QT prolongation.

• Tardive dyskinesia

May cause dyskinetic movements; discontinue use if signs and symptoms of tardive dyskinesia occur.

• Prolactin-dependent tumors

Elevates prolactin levels; use with caution in patients with breast cancer or other prolactin-dependent tumors; dose discontinuation may be considered.

• CYP2D6 poor metabolizers

CYP2D6 poor metabolizers have increased levels of primary drug metabolites. Patients should be tested for the CYP2D6 gene prior to initiating doses >50 mg/day.

• Huntington disease

May worsen mood, cognition, rigidity, and functional capacity in patients with Huntington disease, which can be difficult to differentiate from progression of the underlying disease. Underlying chorea may improve over time in some patients, thereby decreasing the need for therapy. Re-evaluate patients need for treatment by periodically assessing the effect on chorea and possible adverse effects. Dose reduction or discontinuation of therapy may be necessary.

Consumption of alcohol is not recommended during treatment with Tetrabenazine due to the increased risk of side effects.

There is no data on the presence of tetrabenazine or its metabolites in human milk, the effects on the breastfed infant, or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Tetrabenazine and any potential adverse effects on the breastfed infant from Tetrabenazine or from the underlying maternal condition.

Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risks.

Common

Drowsiness, sedation, depression, extrapyramidal reaction, fatigue, insomnia, akathisia, anxiety, falling, Gastrointestinal: Nausea, Upper respiratory tract infection Drug-induced Parkinson's disease, equilibrium disturbance, irritability, abnormal gait, dizziness, dysarthria, headache, obsessive rumination, Dysphagia, vomiting, decreased appetite, diarrhea, Dysuria, Bruise, Bradykinesia, Bronchitis, dyspnea, Laceration.

Rare

Aggressive behavior (worsening), aspiration pneumonia, confusion, hyperhidrosis, hyperprolactinemia, increased serum transaminases, orthostatic dizziness, orthostatic hypotension, neuroleptic malignant syndrome, pneumonia, prolonged QT interval on ECG, restlessness, skin rash, suicidal ideation, syncope, tremor.

• Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants.
• Cannabinoid-Containing Products: CNS Depressants may enhance the CNS depressant effect of Cannabinoid-Containing Products.
• Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used.
• Strong CYP2D6 Inhibitors: In vitro studies indicate that α-HTBZ and β-HTBZ are substrates for CYP2D6. Strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine) markedly increase exposure to these metabolites. A reduction in Tetrabenazine dose may be necessary when adding a strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine, quinidine) in patients maintained on a stable dose of Tetrabenazine. The daily dose of Tetrabenazine should not exceed 50 mg per day and the maximum single dose of Tetrabenazine should not exceed 25 mg in patients taking strong CYP2D6 inhibitors.
• Reserpine: Reserpine binds irreversibly to VMAT2, and the duration of its effect is several days. Prescribers should wait for chorea to re-emerge before administering Tetrabenazine to avoid overdosage and major depletion of serotonin and norepinephrine in the CNS. At least 20 days should elapse after stopping reserpine before starting Tetrabenazine. Tetrabenazine and reserpine should not be used concomitantly.
• Monoamine Oxidase Inhibitors (MAOIs): Tetrabenazine is contraindicated in patients taking MAOIs. Tetrabenazine should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI.
• Alcohol or Other Sedating Drugs: Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.
• Drugs That Cause QTc Prolongation: Tetrabenazine causes a small prolongation of QTc (about 8 msec), concomitant use with other drugs that are known to cause QTc prolongation should be avoided, these including antipsychotic medications (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications or any other medications known to prolong the QTc interval. Tetrabenazine should be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain conditions may increase the risk for torsade de pointes or sudden death such as (1) bradycardia; (2) hypokalemia or hypomagnesemia; (3) concomitant use of other drugs that prolong the QTc interval; and (4) presence of congenital prolongation of the QT interval.
• Neuroleptic Drugs: The risk for Parkinsonism, NMS, and akathisia may be increased by concomitant use of Tetrabenazine and dopamine antagonists or antipsychotics (e.g., chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone).
• Concomitant Deutetrabenazine or Valbenazine: Tetrabenazine is contraindicated in patients currently taking deutetrabenazine or valbenazine.

The common side effects of Tetrabenazine include the following

Common side effects

Nausea, diarrhea, vomiting, decreased appetite, headache, pain or burning upon urination, bruising, difficulty speaking or being understood.

Rare side effects

Fever, sweating, confusion, fast or irregular heartbeat, and severe muscle stiffness, difficulty moving, or keeping your balance, muscle stiffness, irregular heartbeat, shortness of breath, restlessness.

• Pregnancy

Pregnancy Category C

There are no adequate data on the developmental risk associated with the use of Tetrabenazine in pregnant women. Administration of tetrabenazine to rats throughout pregnancy and lactation resulted in an increase in stillbirths and postnatal offspring mortality. Administration of a major human metabolite of tetrabenazine to rats during pregnancy or during pregnancy and lactation produced adverse effects on the developing fetus and offspring (increased mortality, decreased growth, and neurobehavioral and reproductive impairment). The adverse developmental effects of tetrabenazine and a major human metabolite of tetrabenazine in rats occurred at clinically relevant doses [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

• Nursing Mothers

There is no data on the presence of tetrabenazine or its metabolites in human milk, the effects on the breast-fed infant, or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Tetrabenazine and any potential adverse effects on the breastfed infant from Tetrabenazine or from the underlying maternal condition.

• Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

• Geriatric Use

The pharmacokinetics of Tetrabenazine and its primary metabolites have not been formally studied in geriatric subjects.

Symptoms: Acute dystonia, oculogyric crisis, nausea, vomiting, diarrhea, confusion, hallucinations, somnolence, sweating, hypotension, hypothermia, rubor, tremor. Management: Symptomatic and supportive treatment. Monitor cardiac rhythm and vital signs.

• Pharmacodynamic

Prolongation of the QTc interval has been observed at doses of 50 mg. In rats, it has been observed that tetrabenazine or its metabolites bind to melanin-containing tissues such as the eyes and skin. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing.

• Pharmacokinetics

Absorption

Its bioavailability is low and erratic (due to extensive first-pass effects),Time taken to reach peak plasma concentration is within 1 to 1.5 hours

Distribution

Tetrabenazine is Rapidly distributed to the brain (IV) and it has Plasma protein binding of approximately 82-85%.

Metabolism and Excretion

Tetrabenazine is Rapidly and extensively metabolized in the liver by carbonyl reductase to active metabolites, α- and β-hydroxy tetrabenazine (HTBZ) which are subsequently metabolized by CYP2D6 to 9-desmethyl-α-DHTBZ (minor) and 9-desmethyl-β-DHTBZ (major), respectively. Tetrabenazine is mainly excreted Via urine (approximately 75% as metabolites, <10% as α- and β-HTBZ) and faeces (approximately 7-16%).

• https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021894s013lbl.pdf
• https://go.drugbank.com/drugs/DB04844
• https://www.uptodate.com/contents/tetrabenazine-drug-information?search=tetrabenazine&source=panel_search_result&selectedTitle=1~21&usage_type=panel&kp_tab=drug_general&display_rank=1
• https://www.drugs.com/pregnancy/tetrabenazine.html
• https://medlineplus.gov/druginfo/meds/a618009.html#:~:text=Tetrabenazine is used to treat,transporter 2 (VMAT2) inhibitors.