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 tablets 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.

2.3 Dosage Adjustment with CYP2D6 Inhibitors

2.4 Discontinuation of Treatment

Treatment with tetrabenazine tablets can be discontinued without tapering. Re-emergence of chorea may occur within 12 to 18 hours after the last dose of tetrabenazine tablets [see Drug Abuse and Dependence (9.2)].

2.5 Resumption of Treatment

Following treatment interruption of greater than 5 days, tetrabenazine tablets therapy should be re-titrated when resumed. For short-term treatment interruption of less than 5 days, treatment can be resumed at the previous maintenance dose without titration.

5.1 Depression and Suicidality

Patients with Huntington’s disease are at increased risk for depression, suicidal ideation or behaviors (suicidality). Tetrabenazine tablets increase 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. In two open-label studies (in one study, 29 patients received tetrabenazine tablets for up to 48 weeks; in the second study, 75 patients received tetrabenazine tablets for up to 80 weeks), the rate of depression/worsening depression was 35%.

In all of the HD chorea studies of tetrabenazine tablets (n=187), one patient committed suicide, one attempted suicide, and six had suicidal ideation.

When considering the use of tetrabenazine tablets, the risk of suicidality should be balanced against the need for treatment of chorea. All patients treated with tetrabenazine tablets should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with tetrabenazine tablets.

Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with tetrabenazine tablets, and should be instructed to report behaviors of concern promptly to the treating physician. Patients with HD who express suicidal ideation should be evaluated immediately.

5.2 Clinical Worsening and Adverse Effects

Huntington’s disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time. In a 12-week controlled trial, tetrabenazine was also shown to cause slight worsening in mood, cognition, rigidity, and functional capacity. Whether these effects persist, resolve, or worsen with continued treatment is unknown.

Prescribers should periodically re-evaluate the need for tetrabenazine in their patients by assessing the effect on chorea and possible adverse effects, including depression and suicidality, cognitive decline, parkinsonism, dysphagia, sedation/somnolence, akathisia, restlessness, and disability. It may be difficult to distinguish between adverse reactions and progression of the underlying disease; decreasing the dose or stopping the drug may help the clinician distinguish between the two possibilities. In some patients, underlying chorea itself may improve over time, decreasing the need for tetrabenazine.

5.3 Laboratory Tests

Before prescribing a daily dose of tetrabenazine tablets that is greater than 50 mg/day, patients should be genotyped to determine if they express the drug metabolizing enzyme, CYP2D6. CYP2D6 testing is necessary to determine whether patients are poor metabolizers (PMs), extensive (EMs) or intermediate metabolizers (IMs) of tetrabenazine tablets.

Patients who are PMs of tetrabenazine tablets will have substantially higher levels of the primary drug metabolites (about 3-fold for α-HTBZ and 9-fold for β-HTBZ) than patients who are EMs. The dosage should be adjusted according to a patient’s CYP2D6 metabolizer status. In patients who are identified as CYP2D6 PMs, the maximum recommended total daily dose is 50 mg and the maximum recommended single dose is 25 mg [see Dosage and Administration (2.2), Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].

5.4 Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with tetrabenazine tablets and other drugs that reduce dopaminergic transmission [see Drug Interactions (7.6)]. Clinical manifestations of NMS are hyperpyrexia, muscle rigidity, altered mental status, and evidence of autonomic instability (irregular pulse or blood pressure, tachycardia, diaphoresis, and cardiac dysrhythmia). Additional signs may include elevated creatinine phosphokinase, myoglobinuria, rhabdomyolysis, and acute renal failure. The diagnosis of NMS can be complicated; other serious medical illness (e.g., pneumonia, systemic infection), and untreated or inadequately treated extrapyramidal disorders can present with similar signs and symptoms. Other important considerations in the differential diagnosis include central anticholinergic toxicity, heat stroke, drug fever, and primary central nervous system pathology.

The management of NMS should include (1) immediate discontinuation of tetrabenazine tablets; (2) intensive symptomatic treatment and medical monitoring; and (3) treatment of any concomitant serious medical problems for which specific treatments are available. There is no general agreement about specific pharmacological treatment regimens for NMS.

Recurrence of NMS has been reported with resumption of drug therapy. If treatment with tetrabenazine tablets is needed after recovery from NMS, patients should be monitored for signs of recurrence.

5.5 Akathisia, Restlessness, and Agitation

Tetrabenazine tablets may increase the risk of akathisia, restlessness, and agitation.

In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with HD, akathisia was observed in 10 (19%) of tetrabenazine-treated patients and 0% of placebo-treated patients. In an 80-week, open-label study, akathisia was observed in 20% of tetrabenazine-treated patients.

Patients receiving tetrabenazine tablets should be monitored for the presence of akathisia. Patients receiving tetrabenazine tablets should also be monitored for signs and symptoms of restlessness and agitation, as these may be indicators of developing akathisia. If a patient develops akathisia, the tetrabenazine tablets dose should be reduced; however, some patients may require discontinuation of therapy.

5.6 Parkinsonism

Tetrabenazine tablets can cause parkinsonism.

In a 12-week, double-blind, placebo-controlled study in patients with chorea associated with HD, symptoms suggestive of parkinsonism (i.e., bradykinesia, hypertonia and rigidity) were observed in 15% of tetrabenazine-treated patients compared to 0% of placebo-treated patients. In 48-week and 80-week, open-label studies, symptoms suggestive of parkinsonism were observed in 10% and 3% of tetrabenazine-treated patients, respectively. Because rigidity can develop as part of the underlying disease process in Huntington’s disease, it may be difficult to distinguish between this drug-induced adverse reaction and progression of the underlying disease process. Drug-induced parkinsonism has the potential to cause more functional disability than untreated chorea for some patients with Huntington’s disease. If a patient develops parkinsonism during treatment with tetrabenazine, dose reduction should be considered; in some patients, discontinuation of therapy may be necessary.

5.7 Sedation and Somnolence

Sedation is the most common dose-limiting adverse reaction of tetrabenazine. In a 12-week, double-blind, placebo-controlled trial in patients with chorea associated with HD, sedation/somnolence occurred in 17/54 (31%) of tetrabenazine-treated patients and in 1 (3%) of placebo-treated patient. Sedation was the reason upward titration of tetrabenazine tablets was stopped and/or the dose of tetrabenazine tablets was decreased in 15/54 (28%) patients. In all but one case, decreasing the dose of tetrabenazine tablets resulted in decreased sedation. In 48-week and 80-week, open-label studies, sedation/somnolence occurred in 17% and 57% of tetrabenazine-treated patients, respectively. In some patients, sedation occurred at doses that were lower than recommended doses.

Patients should not perform activities requiring mental alertness to maintain the safety of themselves or others, such as operating a motor vehicle or operating hazardous machinery, until they are on a maintenance dose of tetrabenazine tablets and know how the drug affects them.

5.8 QTc Prolongation

Tetrabenazine tablets cause a small increase (about 8 msec) in the corrected QT (QTc) interval. QT prolongation can lead to development of torsade de pointes-type ventricular tachycardia with the risk increasing as the degree of prolongation increases [see Clinical Pharmacology (12.2)]. The use of tetrabenazine tablets should be avoided in combination with other drugs that are known to prolong QTc, 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 [see Drug Interactions (7.5)].

Tetrabenazine tablets should also be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias. Certain circumstances may increase the risk of the occurrence of torsade de pointes and/or sudden death in association with the use of drugs that prolong the QTc interval, including (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 Clinical Pharmacology (12.2)].

5.9 Hypotension and Orthostatic Hypotension

Tetrabenazine tablets induced postural dizziness in healthy volunteers receiving single doses of 25 or 50 mg. One subject had syncope, and one subject with postural dizziness had documented orthostasis. Dizziness occurred in 4% of tetrabenazine-treated patients (vs. none on placebo) in the 12-week, controlled trial; however, blood pressure was not measured during these events. Monitoring of vital signs on standing should be considered in patients who are vulnerable to hypotension.

5.10 Hyperprolactinemia

Tetrabenazine tablets elevate serum prolactin concentrations in humans. Following administration of 25 mg to healthy volunteers, peak plasma prolactin levels increased 4- to 5-fold. Tissue culture experiments indicate that approximately one third of human breast cancers are prolactin-dependent in vitro, a factor of potential importance if tetrabenazine tablets are being considered for a patient with previously detected breast cancer. Although amenorrhea, galactorrhea, gynecomastia, and impotence can be caused by elevated serum prolactin concentrations, the clinical significance of elevated serum prolactin concentrations for most patients is unknown. Chronic increase in serum prolactin levels (although not evaluated in the tetrabenazine development program) has been associated with low levels of estrogen and increased risk of osteoporosis. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of tetrabenazine tablets.

5.11 Binding to Melanin-Containing Tissues

Since tetrabenazine or its metabolites bind to melanin-containing tissues, it could accumulate in these tissues over time. This raises the possibility that tetrabenazine may cause toxicity in these tissues after extended use. Neither ophthalmologic nor microscopic examination of the eye has been conducted in the chronic toxicity studies in a pigmented species, such as dogs. Ophthalmologic monitoring in humans was inadequate to exclude the possibility of injury occurring after long-term exposure.

The clinical relevance of tetrabenazine’s binding to melanin-containing tissues is unknown. Although there are no specific recommendations for periodic ophthalmologic monitoring, prescribers should be aware of the possibility of long-term ophthalmologic effects [see Clinical Pharmacology (12.2)].

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 were 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 tablets 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.

6.2 Postmarketing Experience

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

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 tablets 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 should not exceed 50 mg/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 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)].

7.5 Drugs That Cause QTc Prolongation

Tetrabenazine tablets cause 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 tablets 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, 5.6)].

7.7 Concomitant Deutetrabenazine or Valbenazine

Tetrabenazine tablets are contraindicated in patients currently taking deutetrabenazine or valbenazine.

8.1 Pregnancy

8.2 Lactation

Risk Summary

There are 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 tablets or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

The pharmacokinetics of tetrabenazine tablets 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 tablets and other circulating metabolites are unknown, it is not possible to adjust the dosage of tetrabenazine tablets in hepatic impairment to ensure safe use. The use of tetrabenazine tablets in patients with hepatic impairment is contraindicated [see Contraindications (4), Clinical Pharmacology (12.3)].

8.7 Poor or Extensive CYP2D6 Metabolizers

Patients who require doses of tetrabenazine tablets greater than 50 mg/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 tablets 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 tablets 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)].

9.1 Controlled Substance

Tetrabenazine tablets are not a controlled substance.

9.2 Abuse

Clinical trials did not reveal patients developed drug seeking behaviors, though these observations were not systematic. Abuse has not been reported from the postmarketing experience in countries where tetrabenazine has been marketed.

As with any CNS-active drug, prescribers should carefully evaluate patients for a history of drug abuse and follow such patients closely, observing them for signs of tetrabenazine misuse or abuse (such as development of tolerance, increasing dose requirements, drug-seeking behavior).

Abrupt discontinuation of tetrabenazine tablets from patients did not produce symptoms of withdrawal or a discontinuation syndrome; only symptoms of the original disease were observed to re-emerge [see Dosage and Administration (2.4)].

12.1 Mechanism of Action

The precise mechanism by which tetrabenazine tablets exert 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. Human VMAT2 is also inhibited by dihydrotetrabenazine (HTBZ), a mixture of α-HTBZ and β-HTBZ. α- and β-HTBZ, major circulating metabolites in humans, exhibit high in vitro binding affinity to bovine VMAT2. Tetrabenazine exhibits weak in vitro binding affinity at the dopamine D2 receptor (Ki = 2100 nM).

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Study 1

The efficacy of tetrabenazine tablets as a treatment for the chorea of Huntington’s disease was established primarily in a randomized, double-blind, placebo-controlled multi-center trial (Study 1) conducted in ambulatory patients with a diagnosis of HD. The diagnosis of HD was based on family history, neurological exam, and genetic testing. Treatment duration was 12 weeks, including a 7-week dose titration period and a 5-week maintenance period followed by a 1-week washout. Tetrabenazine tablets were started at a dose of 12.5 mg/day, followed by upward titration at weekly intervals, in 12.5 mg increments until satisfactory control of chorea was achieved, intolerable side effects occurred, or until a maximal dose of 100 mg/day was reached.

The primary efficacy endpoint was the Total Chorea Score, an item of the Unified Huntington’s Disease Rating Scale (UHDRS). On this scale, chorea is rated from 0 to 4 (with 0 representing no chorea) for 7 different parts of the body. The total score ranges from 0 to 28.

As shown in Figure 1, Total Chorea Scores for patients in the drug group declined by an estimated 5.0 units during maintenance therapy (average of Week 9 and Week 12 scores versus baseline), compared to an estimated 1.5 units in the placebo group. The treatment effect of 3.5 units was statistically significant. At the Week 13 follow-up in Study 1 (1 week after discontinuation of the study medication), the Total Chorea Scores of patients receiving tetrabenazine tablets returned to baseline.

Figure 1: Mean ± s.e.m. Changes from Baseline in Total Chorea Score in 84 HD Patients Treated with Tetrabenazine Tablets (n=54) or Placebo (n=30)

(error bars are ± s.e.m.)            

*p is less than 0.05

Figure 2 illustrates the cumulative percentages of patients from the tetrabenazine tablets and placebo treatment groups who achieved the level of reduction in the Total Chorea Score shown on the X axis. The left-ward shift of the curve (toward greater improvement) for the tetrabenazine tablet-treated patients indicates that these patients were more likely to have any given degree of improvement in chorea score. For example, about 7% of placebo patients had a 6-point or greater improvement compared to 50% of tetrabenazine-treated patients. The percentage of patients achieving reductions of at least 10, 6, and 3 points from baseline to Week 12 are shown in the inset table.

Figure 2: Cumulative Percentage of Patients with Specified Changes from Baseline in Total Chorea Score. The Percentages of Randomized Patients Within Each Treatment Group Who Completed Study 1 Were: Placebo 97%, Tetrabenazine 91%

A Physician-rated Clinical Global Impression (CGI) favored tetrabenazine tablets statistically. In general, measures of functional capacity and cognition showed no difference between tetrabenazine tablets and placebo. However, one functional measure (Part 4 of the UHDRS), a 25-item scale assessing the capacity for patients to perform certain activities of daily living, showed a decrement for patients treated with tetrabenazine tablets compared to placebo, a difference that was nominally statistically significant. A 3-item cognitive battery specifically developed to assess cognitive function in patients with HD (Part 2 of the UHDRS) also showed a decrement for patients treated with tetrabenazine tablets compared to placebo, but the difference was not statistically significant.

Study 2

A second controlled study was performed in patients who had been treated with open-label tetrabenazine tablets for at least 2 months (mean duration of treatment was 2 years). They were randomized to continuation of tetrabenazine tablets at the same dose (n=12) or to placebo (n=6) for three days, at which time their chorea scores were compared. Although the comparison did not reach statistical significance (p=0.1), the estimate of the treatment effect was similar to that seen in Study 1 (about 3.5 units).

16.1 How Supplied

Tetrabenazine tablets are available in the following strengths and packages:

The 12.5 mg tetrabenazine tablets are white, cylindrical, biplanar tablets with beveled edges, non-scored, embossed on one side with “CL” and “12.5”.

NDC 68682-421-12 12.5 mg 112-count bottle

The 25 mg tetrabenazine tablets are yellowish-buff, cylindrical, biplanar tablets with beveled edges, scored, embossed on one side with “CL” and “25”.

NDC 68682-422-25 25 mg 112-count bottle

16.2 Storage

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].