Vesicular Monoamine Transporter 2 Inhibitor

Tetrabenazine

Approved 4 Dec 2020OralTablet

The FDA lists this product in 21 strengths and forms.

Indications

Tetrabenazine tablets are 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 )

Contraindications

Tetrabenazine is 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 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 [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 )

Warnings and precautions

Periodically reevaluate the benefit and potential for adverse effects such as worsening mood, cognition, rigidity, and functional capacity. ( 5.2 ) Do not exceed 50 mg/day and the maximum single dose should not exceed 25 mg if administered in conjunction with a strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine). ( 5.3 , 7.1 ) Neuroleptic Malignant Syndrome (NMS): Discontinue if this occurs. ( 5.4 , 7.6 ) Restlessness, agitation, akathisia and parkinsonism: Reduce dose or discontinue if occurs.

( 5.5 , 5.6 ) Sedation/Somnolence: May impair patient’s ability to drive or operate complex machinery ( 5.7 ) QTc prolongation: Not recommended in combination with other drugs that prolong QTc ( 5.8 )

5.1 Depression and Suicidality Patients with Huntington’s disease are at increased risk for depression, suicidal ideation or behaviors (suicidality). Tetrabenazine increases the risk for suicidality in patients with HD. In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with Huntington’s disease, 10 of 54 patients (19%) treated with tetrabenazine were reported to have an adverse event of depression or worsening depression compared to none of the 30 placebo-treated patients.

At a glance

Brand name: Tetrabenazine
Pharmacologic class: Vesicular Monoamine Transporter 2 Inhibitor
Route: Oral
Dosage form: Tablet
Applicant: Ajanta Pharma LTD
Status: Discontinued
FDA approval: 4 Dec 2020
Application: ANDA213621-001

Contraindications

Warnings and precautions

Interactions

7.1Strong 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 [see Dosage and Administration ( 2.3 ), Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.7 ), Clinical Pharmacology ( 12.3 )].

7.2Reserpine

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 [see Contraindications ( 4 )].

7.3Monoamine 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 [see Contraindications ( 4 )].

7.4Alcohol or Other Sedating Drugs

Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence [see Warnings and Precautions ( 5.7 )].

7.5Drugs 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 [see Warnings and Precautions ( 5.8 ), Clinical Pharmacology ( 12.2 )].

7.6Neuroleptic 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) [see Warnings and Precautions ( 5.4 , 5.5 , 5.6 )].

7.7Concomitant Deutetrabenazine or Valbenazine

Tetrabenazine is contraindicated in patients currently taking deutetrabenazine or valbenazine.

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

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.

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/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 mg/kg/day, 15 mg/kg/day, 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 mg/kg/day 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 tetrabenazine do not produce 9-desmethyl-β-DHTBZ, a major human metabolite of tetrabenazine, the metabolite was directly administered to pregnant and lactating rats. Oral administration of 9-desmethyl-β-DHTBZ (8 mg/kg/day, 15 mg/kg/day, and 40 mg/kg/day) throughout the period of organogenesis produced increases in embryofetal mortality at 15 mg/kg/day and 40 mg/kg/day and reductions in fetal body weights at 40 mg/kg/day, which was also maternally toxic.

When 9-desmethyl-β-DHTBZ (8 mg/kg/day, 15 mg/kg/day, and 40 mg/kg/day) was orally administered to pregnant rats from the beginning of organogenesis through the lactation period, increases in gestation duration, stillbirths, and offspring postnatal mortality (40 mg/kg/day); decreases in pup weights (40 mg/kg/day); and neurobehavioral (increased activity, learning and memory deficits) and reproductive (decreased litter size) impairment (15 mg/kg/day and 40 mg/kg/day) were observed.

Maternal toxicity was seen at the highest dose. The no-effect dose for developmental toxicity in rats (8 mg/kg/day) was associated with plasma exposures (AUC) of 9-desmethyl-β-DHTBZ in pregnant rats lower than that in humans at the MRHD.

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 Ajanta Pharma USA, Inc., at 1-855-664-7744 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 was administered to 773 unique subjects and patients. The conditions and duration of exposure to tetrabenazine 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 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 greater than or equal to 4% of Patients The number and percentage of the most common adverse reactions that occurred at any time during the study in greater than or equal to 4% of tetrabenazine-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 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.

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-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 n = 54 % Placebo n = 30 % Akathisia* 19 0 Extrapyramidal event† 15 0 Any extrapyramidal event 33 0 * Patients with the following adverse event preferred terms were counted in this category: akathisia, hyperkinesia, restlessness. † Patients with the following adverse event preferred terms were counted in this category: bradykinesia, parkinsonism, extrapyramidal disorder, hypertonia.

Patients may have had events in more than one category. Dysphagia Dysphagia is a component of HD. However, drugs that reduce dopaminergic transmission have been associated with esophageal dysmotility and dysphagia. Dysphagia may be associated with aspiration pneumonia. In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with HD, dysphagia was observed in 4% of tetrabenazine-treated patients and 3% of placebo-treated patients.

In 48-week and 80-week, open-label studies, dysphagia was observed in 10% and 8% of tetrabenazine-treated patients, respectively. Some of the cases of dysphagia were associated with aspiration pneumonia. Whether these events were related to treatment is unknown.

6.2Postmarketing Experience

The following adverse reactions have been identified during post-approval use of tetrabenazine. 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

Tetrabenazine

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

Tetrabenazine

Indications

Contraindications

Warnings and precautions

At a glance

Two medicines in one question?

5.2Clinical Worsening and Adverse Effects

5.3Laboratory Tests

5.4Neuroleptic Malignant Syndrome (NMS)

5.5Akathisia, Restlessness, and Agitation

5.6Parkinsonism

5.7Sedation and Somnolence

Interactions

7.1Strong CYP2D6 Inhibitors

7.2Reserpine

7.3Monoamine Oxidase Inhibitors (MAOIs)

7.4Alcohol or Other Sedating Drugs

7.5Drugs That Cause QTc Prolongation

7.6Neuroleptic Drugs

7.7Concomitant Deutetrabenazine or Valbenazine

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary

Adverse reactions

6.1Clinical Trials Experience

6.2Postmarketing Experience

Composition

Strengths and forms

Official product information