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Tetrabenazine

FDA Drug Information • Also known as: Tetrabenazine, Xenazine

Brand Names
Tetrabenazine, Xenazine
Drug Class
Vesicular Monoamine Transporter 2 Inhibitor [EPC]
Route
ORAL
Dosage Form
TABLET
Product Type
HUMAN PRESCRIPTION DRUG

⚠ Boxed Warning (Black Box)

WARNING: DEPRESSION AND SUICIDALITY Tetrabenazine can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease. Anyone considering the use of tetrabenazine tablets must balance the risks of depression and suicidality with the clinical need for control of chorea. Close observation of patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior should accompany therapy. Patients, their caregivers, and families should be informed of the risk of depression and suicidality and should be instructed to report behaviors of concern promptly to the treating physician. Particular caution should be exercised in treating patients with a history of depression or prior suicide attempts or ideation, which are increased in frequency in Huntington’s disease. Tetrabenazine tablets are contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression [see Contraindications (4) , Warnings and Precautions (5.1) ] . 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 (5.1)
  • Balance risks of depression and suicidality with the clinical need for control of chorea when considering the use of tetrabenazine (5.2)
  • Monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior (5.1)
  • Inform patients, caregivers and families of the risk of depression and suicidality and instruct to report behaviors of concern promptly to the treating physician (5.1)
  • Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation (5.1)
  • Tetrabenazine is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression (4 , 5.1)

    • Description

    11 DESCRIPTION Tetrabenazine tablets contains tetrabenazine is a monoamine depletor for oral administration. The molecular weight of tetrabenazine is 317.42; the pKa is 6.51. Tetrabenazine is a hexahydro-dimethoxy‑benzoquinolizine derivative and has the following chemical name: cis rac –1,3,4,6,7,11b‑ hexahydro-9,10-dimethoxy-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one. The empirical formula C 19 H 27 NO 3 is represented by the following structural formula: Tetrabenazine is a white to pale yellow powder that is soluble in chloroform and sparingly soluble in methanol. Each tetrabenazine tablet contains either 12.5 or 25 mg of tetrabenazine as the active ingredient. Tetrabenazine tablets contain tetrabenazine as the active ingredient and the following inactive ingredients: lactose monohydrate, pregelatinized starch, ferric oxide yellow, talc and magnesium stearate. Tetrabenazine tablets are supplied as a light yellow to yellow, functionally scored tablet containing 25 mg of tetrabenazine or as a light yellow to yellow, non-scored tablet containing 12.5 mg of tetrabenazine. tetrabenazine-str-01.jpg

    What Is Tetrabenazine Used For?

    1 INDICATIONS AND USAGE Tetrabenazine tablets are indicated for the treatment of chorea associated with Huntington’s disease. Tetrabenazine tablets are a vesicular monoamine transporter 2 (VMAT) inhibitor indicated for the treatment of chorea associated with Huntington’s disease. (1)

    Dosage and Administration

    2 DOSAGE AND ADMINISTRATION

  • Individualization of dose with careful weekly titration is required. The 1 st week’s starting dose is 12.5 mg daily; 2nd week, 25 mg (12.5 mg twice daily); then slowly titrate at weekly intervals by 12.5 mg to a tolerated dose that reduces chorea. (2.1 , 2.2)
  • Doses of 37.5 mg and up to 50 mg per day should be administered in three divided doses per day with a maximum recommended single dose not to exceed 25 mg. (2.2)
  • Patients requiring doses above 50 mg per day should be genotyped for the drug metabolizing enzyme CYP2D6 to determine if the patient is a poor metabolizer (PM) or an extensive metabolizer (EM). (2.2 , 5.3)
  • Maximum daily dose in PMs: 50 mg with a maximum single dose of 25 mg (2.2)
  • Maximum daily dose in EMs and intermediate metabolizers (IMs): 100 mg with a maximum single dose of 37.5 mg (2.2)
  • If serious adverse reactions occur, titration should be stopped and the dose should be reduced. If the adverse reaction(s) do not resolve, consider withdrawal of tetrabenazine. (2.2) 2.1 General Dosing Considerations The chronic daily dose of tetrabenazine tablets used to treat chorea associated with Huntington’s disease (HD) is determined individually for each patient. When first prescribed, tetrabenazine tablets therapy should be titrated slowly over several weeks to identify a dose of tetrabenazine that reduces chorea and is tolerated. Tetrabenazine tablets can be administered without regard to food [see Clinical Pharmacology (12.3) ] . 2.2 Individualization of Dose The dose of tetrabenazine tablets should be individualized. Dosing Recommendations Up to 50 mg per day The starting dose should be 12.5 mg per day given once in the morning. After 1 week, the dose should be increased to 25 mg per day given as 12.5 mg twice a day. Tetrabenazine tablets 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 as akathisia, 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 tetrabenazine treatment or initiating other specific treatment (e.g., antidepressants) [see Adverse Reactions (6.1) ] . Dosing Recommendations Above 50 mg per day Patients who require doses of tetrabenazine 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 tetrabenazine tablets should then be individualized accordingly to their status as PMs or EMs [see Warnings and Precautions (5.3) , Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ] ....

    • Side Effects (Adverse Reactions)

    6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling:

  • Depression and Suicidality [see Warnings and Precautions (5.1) ]
  • Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.4) ]
  • Akathisia, Restlessness, and Agitation [see Warnings and Precautions (5.5) ]
  • Parkinsonism [see Warnings and Precautions (5.6) ]
  • Sedation and Somnolence [see Warnings and Precautions (5.7) ]
  • QTc Prolongation [see Warnings and Precautions (5.8) ]
  • Hypotension and Orthostatic Hypotension [see Warnings and Precautions (5.9) ]
  • Hyperprolactinemia [see Warnings and Precautions (5.10) ]
  • Binding to Melanin-Containing Tissues [see Warnings and Precautions (5.11) ] Most common adverse reactions (greater than 10% and at least 5% greater than placebo) were: sedation/somnolence, fatigue, insomnia, depression, akathisia, anxiety/anxiety aggravated, nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Slate Run Pharmaceuticals, LLC at 1-888-341-9214 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. During its development, tetrabenazine tablets was administered to 773 unique subjects and patients. The conditions and duration of exposure to tetrabenazine tablets varied greatly, and included single-dose and multiple-dose clinical pharmacology studies in healthy volunteers (n=259) and open-label (n=529) and double-blind studies (n=84) in patients. In a randomized, 12-week, placebo-controlled clinical trial of HD patients, adverse reactions were more common in the tetrabenazine group than in the placebo group. Forty-nine of 54 (91%) patients who received tetrabenazine tablets experienced one or more adverse reactions at any time during the study. The most common adverse reactions (over 10%, and at least 5% greater than placebo) were sedation/somnolence, fatigue, insomnia, depression, akathisia, anxiety/anxiety aggravated, and nausea. Adverse Reactions Occurring in ≥4% of Patients The number and percentage of the most common adverse reactions that occurred at any time during the study in ≥4% of tetrabenazine tablets-treated patients, and with a greater frequency than in placebo-treated patients, are presented in Table 1. Table 1: Adverse Reactions in a 12-Week, Double-Blind, Placebo-Controlled Trial in Patients with Huntington's Disease Adverse Reaction Tetrabenazine Tablets N=54 % Placebo N=30 % Sedation/somnolence 31 3 Insomnia 22 0 Fatigue 22 13 Depression 19 0 Akathisia 19 0 Anxiety/anxiety aggravated 15 3 Fall 15 13 Nausea 13 7 Upper respiratory tract infection 11 7 Irritability 9 3 Balance difficulty 9 0 Parkinsonism/bradykinesia 9 0 Vomiting 6 3 Laceration (head) 6 0 Ecchymosis 6 0 Decreased appetite 4 0 Obsessive reaction 4 0 Dizziness 4 0 Dysarthria 4 0 Unsteady gait 4 0 Headache 4 3 Shortness of breath 4 0 Bronchitis 4 0 Dysuria 4 0 Dose escalation was discontinued or dosage of study drug was reduced because of one or more adverse reactions in 28 of 54 (52%) patients randomized to tetrabenazine tablets. These adverse reactions consisted of sedation (15), akathisia (7), parkinsonism (4), depression (3), anxiety (2), fatigue (1) and diarrhea (1). Some patients had more than one AR and are, therefore, counted more than once. Adverse Reactions Due to Extrapyramidal Symptoms Table 2 describes the incidence of events considered to be extrapyramidal adverse reactions which occurred at a greater frequency in tetrabenazine tablets-treated patients compared to placebo- treated patients. Table 2: Adverse Reactions Due to Extrapyramidal Symptoms in a 12-Week, Double- Blind, Placebo-Controlled Trial in Patients with Huntington’s Disease Tetrabenazine Tablets n = 54 % Placebo n = 30 %...

    • Drug Interactions

    7 DRUG INTERACTIONS 7.1 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 tablets. The daily dose of tetrabenazine tablets should not exceed 50 mg per day and the maximum single dose of tetrabenazine tablets should not exceed 25 mg in patients taking strong CYP2D6 inhibitors [see Dosage and Administration (2.3) , Warnings and Precautions (5.3) , Use in Specific Populations (8.7) , Clinical Pharmacology (12.3) ] . 7.2 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 tablets 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 tablets. Tetrabenazine tablets and reserpine should not be used concomitantly [see Contraindications (4) ] . 7.3 Monoamine Oxidase Inhibitors (MAOIs) Tetrabenazine tablets are contraindicated in patients taking MAOIs. Tetrabenazine tablets should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI [see Contraindications (4) ] . 7.4 Alcohol or Other Sedation Drugs Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence [see Warnings and Precautions (5.7) ]. 7.5 Drugs That Cause QTc Prolongation Tetrabenazine tablets 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 [see Warnings and Precautions (5.8) , Clinical Pharmacology (12.2) ] . 7.6 Neuroleptic Drugs The risk for Parkinsonism, NMS, and akathisia may be increased by concomitant use of tetrabenazine tablets and dopamine antagonists or antipsychotics (e.g., chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone) [see Warnings and Precautions (5.4 , 5.5 ,...

    Contraindications

    4 CONTRAINDICATIONS Tetrabenazine tablets are contraindicated in patients:

  • Who are actively suicidal, or in patients with untreated or inadequately treated depression [see Warnings and Precautions (5.1) ] .
  • With hepatic impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ] .
  • Taking monoamine oxidase inhibitors (MAOIs). Tetrabenazine tablets should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI [see Drug Interactions (7.3) ] .
  • Taking reserpine. At least 20 days should elapse after stopping reserpine before starting tetrabenazine tablets [see Drug Interactions (7.2) ] .
  • Taking deutetrabenazine or valbenazine [see Drug Interactions (7.7) ].
  • Actively suicidal, or who have depression which is untreated or undertreated (4 , 5.1)
  • Hepatic impairment (4 , 8.6 , 12.3)
  • Taking monoamine oxidase inhibitors (MAOIs) or reserpine (4 , 7.2 , 7.3)
  • Taking deutetrabenazine or valbenazine (4 , 7.7)

    • Pregnancy and Breastfeeding

    8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of tetrabenazine tablets 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. Data Animal Data Tetrabenazine had no clear effects on embryofetal development when administered to pregnant rats throughout the period of organogenesis at oral doses up to 30 mg/kg/day (or 3 times the maximum recommended human dose [MRHD] of 100 mg per day on a mg/m 2 basis). Tetrabenazine had no effects on embryofetal development when administered to pregnant rabbits during the period of organogenesis at oral doses up to 60 mg/kg/day (or 12 times the MRHD on a mg/m 2 basis). When tetrabenazine (5, 15, and 30 mg/kg/day) was orally administered to pregnant rats from the beginning of organogenesis through the lactation period, an increase in stillbirths and offspring postnatal mortality was observed at 15 and 30 mg/kg/day and delayed pup maturation was observed at all doses. A no-effect dose for pre- and postnatal developmental toxicity in rats was not identified. The lowest dose tested (5 mg/kg/day) was less than the MRHD on a mg/m 2 basis. Because rats dosed orally with...

    Overdosage

    10 OVERDOSAGE Three episodes of overdose occurred in the open-label trials performed in support of registration. Eight cases of overdose with tetrabenazine tablets have been reported in the literature. The dose of tetrabenazine tablets in these patients ranged from 100 mg to 1 g. Adverse reactions associated with tetrabenazine tablets 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.

    How Supplied

    16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Tetrabenazine tablets are available in the following strengths and packages: Tetrabenazine tablets 12.5 mg are formulated as light yellow to yellow, round shaped, flat, beveled edge tablets, debossed with “T” 12.5 on one side and plain on other side. Bottles of 112: NDC 70436-101-09 Tetrabenazine tablets 25 mg are formulated as light yellow to yellow, round shaped, flat, beveled edge tablets, debossed “T 25” on one side and functional scoreline on other side. Bottles of 112: NDC 70436-102-09 16.2 Storage Store at 25º C (77º F); excursions permitted to 15° to 30ºC (59° to 86º F) [see USP Controlled Room Temperature].

    About This Information

    This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.

    What are side effects?

    Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.

    What are drug interactions?

    Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.