Tetrabenazine: Package Insert and Label Information

TETRABENAZINE- tetrabenazine tablet
Slate Run Pharmaceuticals, LLC

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)].

1 INDICATIONS AND USAGE

Tetrabenazine tablets are indicated for the treatment of chorea associated with Huntington’s disease.

2 DOSAGE AND ADMINISTRATION

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)].

Extensive and Intermediate CYP2D6 Metabolizers

Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of CYP2D6, who need doses of tetrabenazine tablets 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 tablets 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 Adjustment 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 tablets 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 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 five (5) days, tetrabenazine tablets 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.

3 DOSAGE FORMS AND STRENGTHS

Tetrabenazine tablets are available in the following strengths and packages:

The 12.5 mg Tetrabenazine Tablets are light yellow to yellow, round shaped, flat, beveled edge tablets, debossed with

“T”

12.5 on one side and plain on other side.

The 25 mg Tetrabenazine Tablets are light yellow to yellow, round shaped, flat beveled edge tablets, debossed with “T 25” on one side and functional scoreline on other side.

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)].

5 WARNINGS AND PRECAUTIONS

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 tablets 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 (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 tablets 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 tablets 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 tablets.

5.3 Laboratory Tests

Before prescribing a daily dose of tetrabenazine tablets that is greater than 50 mg per 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 tablets-treated patients and 0% of placebo-treated patients. In an 80-week, open-label study, akathisia was observed in 20% of tetrabenazine tablets-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 tablets-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 tablets-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 tablets, 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 tablets. 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 tablets-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 and know how the drug affects them.

5.8 QTc Prolongation

Tetrabenazine tablets causes 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)].

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