Data from FDA - Curated by EPG Health - Last updated 09 February 2018

Indication(s)

1 INDICATIONS AND USAGE Tetrabenazine tablet is indicated for the treatment of chorea associated with Huntington's disease. TETRABENAZINE is a vesicular monoamine transporter 2 (VMAT) inhibitor indicated for the treatment of chorea associated with Huntington's disease ( 1)

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Advisory information

contraindications
4 CONTRAINDICATIONS Tetrabenazine tablet is contraindicated in patients: Who are actively suicidal, or in patients with untreated or inadequately treated depression [see Warnings and Precautions (5.2)]. With hepatic impairment [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)]. Taking monoamine oxidase inhibitors (MAOIs). Tetrabenazine tablet 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 tablet [see Drug Interactions (7.2)]. Actively suicidal, or who have depression which is untreated or undertreated ( 4, 5.2) Hepatic impairment ( 4, 8.6, 12.3) Taking MAOIs or reserpine ( 4, 7.2, 7.3)
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 (5.2)] Akathisia, restlessness, and agitation [see Warnings and Precautions (5.5)] Parkinsonism [see Warnings and Precautions (5.6)] Dysphagia [see Warnings and Precautions (5.7)] Sedation and somnolence [see Warnings and Precautions (5.8)] Most common adverse reactions (>10% and at least 5% greater than placebo) were: Sedation/somnolence, fatigue, insomnia, depression, akathisia, anxiety, nausea ( 6.1) To report SUSPECTED ADVERSE REACTIONS, contact AvKARE, Inc. at 1-855-361-3993 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 tablet was administered to 773 unique subjects and patients. The conditions and duration of exposure to Tetrabenazine tablet varied greatly, and included single 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 subjects, adverse reactions were more common in the Tetrabenazine tablet group than in the placebo group. Forty-nine of 54 (91%) patients who received Tetrabenazine tablet 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 and nausea. Adverse Reactions Occurring in ≥4% Patients The number and percentage of the most common adverse reactions that occurred at any time during the study in ≥4% of Tetrabenazine tablet-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 tablet n = 54 (%) Placebo n = 30 (%) Sedation/somnolence 31 3 Insomnia 22 0 Depression 19 0 Anxiety/anxiety aggravated 15 3 Irritability 9 3 Decreased appetite 4 0 Obsessive reaction 4 0 Akathisia 19 0 Balance difficulty 9 0 Parkinsonism/bradykinesia 9 0 Dizziness 4 0 Dysarthria 4 0 Unsteady gait 4 0 Headache 4 3 Nausea 13 7 Vomiting 6 3 Fatigue 22 13 Fall 15 13 Laceration (head) 6 0 Ecchymosis 6 0 Upper respiratory tract infection 11 7 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 tablet. 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 adverse reaction 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 tablet –treated patients compared to placebo-treated patients. Table 2. Adverse Reactions Due to Extrapyramidal Symptons in a 12-Week, Double-Blind, Placebo-Controlled Trial with Huntington's disease. Tetrabenazine tablet n = 54 Placebo n = 30 % Akathisia Patients with the following adverse event preferred terms were counted in this category: akathisia, hyperkinesia, restlessness. 19 0 Extrapyramidal event Patients with the following adverse event preferred terms were counted in this category: bradykinesia, parkinsonism, extrapyramidal disorder, hypertonia. 15 0 Any extrapyramidal event 33 0 Patients may have had events in more than one category 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of Tetrabenazine tablet. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Nervous system disorders: tremor Psychiatric disorders: confusion, worsening aggression Respiratory, thoracic and mediastinal disorders: pneumonia Skin and subcutaneous tissue disorders: hyperhidrosis, skin rash To report SUSPECTED ADVERSE REACTIONS contact AvKARE, Inc. at 1-855-361-3993; email [email protected]; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Usage information

Dosing 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; 2 nd 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 37.5mg ( 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 tablet ( 2.2) 2.1 General Dosing Considerations The chronic daily dose of Tetrabenazine tablet used to treat chorea associated with Huntington's disease (HD) is determined individually for each patient. When first prescribed, Tetrabenazine tablet therapy should be titrated slowly over several weeks to identify a dose of Tetrabenazine tablet that reduces chorea and is tolerated. Tetrabenazine tablet can be administered without regard to food [see Clinical Pharmacology (12.3)] . 2.2 Individualization of Dose The dose of Tetrabenazine tablet 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 one week, the dose should be increased to 25 mg per day given as 12.5 mg twice a day. Tetrabenazine tablet 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 tablet 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 tablet 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 tablet 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)]. Extensive and Intermediate CYP2D6 Metabolizers Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of CYP2D6, who need doses of Tetrabenazine tablet 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 Tetrabenazine tablet treatment or initiating other specific treatment (e.g, antidepressants) [see Warnings and Precautions (5.3), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. Poor CYP2D6 Metabolizers In PMs, the initial dose and titration is similar to EMs except that the recommended maximum single dose is 25 mg , and the recommended daily dose should not exceed a maximum of 50 mg [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. 2.3 Dosage Adjustments with CYP2D6 Inhibitors Strong CYP2D6 Inhibitors Medications that are strong CYP2D6 inhibitors such as quinidine or antidepressants (e.g, fluoxetine, paroxetine) significantly increase the exposure to α-HTBZ and β-HTBZ, therefore, the total dose of Tetrabenazine tablet should not exceed a maximum of 50 mg and the maximum single dose should not exceed 25 mg [see Warnings and Precautions (5.3), Drug Interactions (7.1), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)]. 2.4 Discontinuation of Treatment Treatment with Tetrabenazine tablet can be discontinued without tapering. Re-emergence of chorea may occur within 12 to 18 hours after the last dose of Tetrabenazine tablet [see Drug Abuse and Dependence (9.2)]. 2.5 Resumption of Treatment Following treatment interruption of greater than five (5) days, Tetrabenazine tablet therapy should be re-titrated when resumed. For short-term treatment interruption of less than five (5) days, treatment can be resumed at the previous maintenance dose without titration.
Use in special populations
8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, tetrabenazine may cause fetal harm. ( 8.1) 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. Tetrabenazine tablet should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Tetrabenazine had no clear effects on embryo-fetal 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/day on a mg/m 2 basis). Tetrabenazine had no effects on embryo-fetal 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). Because neither rat nor rabbit dosed with tetrabenazine produce 9-desmethyl-beta-DHTBZ, a major human metabolite, these studies may not have adequately addressed the potential effects of tetrabenazine on embryo-fetal development in humans. When tetrabenazine was administered to female rats (doses of 5, 15, and 30 mg/kg/day) 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. The no-effect dose for stillbirths and postnatal mortality was 0.5 times the MRHD on a mg/m 2 basis. Because rats dosed with tetrabenazine do not produce 9-desmethyl-beta-DHTBZ, a major human metabolite, this study may not have adequately assessed the potential effects of tetrabenazine on the offspring of women exposed in utero and via lactation. 8.2 Labor and Delivery The effect of Tetrabenazine tablet on labor and delivery in humans is unknown. 8.3 Nursing Mothers It is not known whether TETRABENAZINE 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 Tetrabenazine tablet, a decision should be made whether to discontinue nursing or to discontinue Tetrabenazine tablet, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and efficacy of Tetrabenazine tablet in pediatric patients have not been established. 8.5 Geriatric Use The pharmacokinetics of Tetrabenazine tablet and its primary metabolites have not been formally studied in geriatric subjects. 8.6 Hepatic Impairment Because the safety and efficacy of the increased exposure to Tetrabenazine tablet and other circulating metabolites are unknown, it is not possible to adjust the dosage of Tetrabenazine tablet in hepatic impairment to ensure safe use. The use of Tetrabenazine tablet in patients with hepatic impairment is contraindicated [see Contraindications (4), Clinical Pharmacology (12.3)]. 8.7 Pooror Extensive CYP2D6 Metabolizers Patients who require doses of Tetrabenazine tablet greater than 50 mg per day, should be first tested and genotyped to determine if they are poor (PMs) or extensive metabolizers (EMs) by their ability to express the drug metabolizing enzyme, CYP2D6. The dose of Tetrabenazine tablet should then be individualized accordingly to their status as either poor (PMs) or extensive metabolizers (EMs) [see Dosage and Administration (2.2), Warnings and Precautions (5.3), Clinical Pharmacology (12.3)]. Poor Metabolizers Poor CYP2D6 metabolizers (PMs) will have substantially higher levels of exposure to the primary metabolites (about 3-fold for α-HTBZ and 9-fold for β-HTBZ) compared to EMs. The dosage should, therefore, be adjusted according to a patient's CYP2D6 metabolizer status by limiting a single dose to a maximum of 25 mg and the recommended daily dose to not exceed a maximum of 50 mg/day in patients who are CYP2D6 PMs [see Dosage and Administration (2.2), Warnings and Precautions (5.3), Clinical Pharmacology (12.3)]. Extensive/Intermediate Metabolizers In extensive (EMs) or intermediate metabolizers (IMs), the dosage of Tetrabenazine tablet can be titrated to a maximum single dose of 37.5 mg and a recommended maximum daily dose of 100 mg [see Dosage and Administration (2.2), Drug Interactions (7.1), Clinical Pharmacology (12.3)].
Pregnancy and lactation
8.3 Nursing Mothers It is not known whether TETRABENAZINE 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 Tetrabenazine tablet, a decision should be made whether to discontinue nursing or to discontinue Tetrabenazine tablet, taking into account the importance of the drug to the mother.

Interactions

7 DRUG INTERACTIONS 7.1 Strong CYP2D6 Inhibitors In vitro studies indicate that α-HTBZ and β-HTBZ are substrates for CYP2D6. Strong CYPD6 inhibitors (e.g., paroxetine, fluoxetine, quinidine) markedly increase exposure to these metabolites. A reduction in Tetrabenazine tablet dose may be necessary when adding a strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine, quinidine) in patients maintained on a stable dose of Tetrabenazine tablet. The daily dose of Tetrabenazine tablet should not exceed 50 mg per day and the maximum single dose of Tetrabenazine tablet 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 Population (8.7), Clinical Pharmacology (12.2)] . 7.2 Reserpine Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days. Prescribers should wait for chorea to reemerge before administering Tetrabenazine tablet 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 tablet. Tetrabenazine tablet and reserpine should not be used concomitantly [see Contraindications (4), Warnings and Precautions (5.12)]. 7.3 Monoamine Oxidase Inhibitors (MAOIs ) Tetrabenazine tablet is contraindicated in patients taking MAOIs. Tetrabenazine tablet 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), Warnings and Precautions (5.12)]. 7.4 Alcohol Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence. 7.5 Drugs that Cause QTc Prolongation Tetrabenazine tablet 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 tablet 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 (5.9), Clinical Pharmacology (12.2) ]. 7.6 Neuroleptic Drugs The risk for Parkinsonism, NMS, and akathisia may be increased by concomitant use of Tetrabenazine tablet and dopamine antagonists or antipsychotics (e.g.chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone).

More information

Category Value
Authorisation number ANDA207682
Agency product number Z9O08YRN8O
Orphan designation No
Product NDC 42291-806,42291-807
Date Last Revised 30-01-2018
Type HUMAN PRESCRIPTION DRUG
Storage and handling 16.2 Storage Store at 25°C (77° F); excursions permitted to 15-30 °C (59-86°F) [see USP Controlled Room Temperature].
Marketing authorisation holder AvKARE, Inc.
Warnings WARNING: DEPRESSION AND SUICIDALITY Tetrabenazine tablet can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. Anyone considering the use of Tetrabenazine tablet 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 behavio rs 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 tablet is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression [see Contraindications (4), Warnings and Precautions (5.2)] . 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 ( 5.2). Balance risks of depression and suicidality with the clinical need for control of chorea when considering the use of Tetrabenazine tablet (5.1) Monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior ( 5.2). Inform patients, caregivers and families of the risk of depression and suicidality and instruct to report behaviors of concern promptly to the treating physician ( 5.2). Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation ( 5.2). Tetrabenazine tablet is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression ( 4, 5.2).