Tetrabenazine

Tetrabenazine
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Kiran Singh, M.D. [2]

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Black Box Warning

WARNING: DEPRESSION AND SUICIDALITY See full prescribing information for complete Boxed Warning. * XENAZINE can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. Anyone considering the use of XENAZINE must balance the risks of depression and suicidality with the clinical need for control of choreiform movements. 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. XENAZINE is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression.

Overview

Tetrabenazine is a central nervous system agent that is FDA approved for the treatment of chorea associated with Huntington's disease. There is a Black Box Warning for this drug as shown here. Common adverse reactions include Sedation,somnolence, fatigue, insomnia, depression, akathisia, anxiety, nausea.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

Indications

• Treatment of chorea associated with Huntington's disease.

Dosage

General Dosing Considerations

The chronic daily dose of XENAZINE used to treat chorea associated with Huntington's disease (HD) is determined individually for each patient. When first prescribed, XENAZINE therapy should be titrated slowly over several weeks to identify a dose of XENAXINE that reduces chorea and is tolerated. XENAZINE can be administered without regard to food.

Individualization of Dose

The dose of XENAZINE 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. XENAZINE 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 events such as akathisia, restlessness, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse event does not resolve, consideration should be given to withdrawing XENAZINE 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 XENAZINE 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 XENAZINE should then be individualized accordingly to their status as PMs or EMs.

'Extensive and Intermediate CYP2D6 Metabolizers'

Genotyped patients who are identified as extensive (EMs) or intermediate metabolizers (IMs) of CYP2D6, who need doses of XENAZINE 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 events such as akathisia, parkinsonism, depression, insomnia, anxiety or sedation occur, titration should be stopped and the dose should be reduced. If the adverse event does not resolve, consideration should be given to withdrawing XENAZINE treatment or initiating other specific treatment (e.g., antidepressants).

'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.

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 XENAZINE should not exceed a maximum of 50 mg and the maximum single dose should not exceed 25 mg.

Patients with Hepatic Impairment

Because the safety and efficacy of the increased exposure to XENAZINE and other circulating metabolites are unknown, it is not possible to adjust the dosage of XENAZINE in hepatic impairment to ensure safe use. Therefore, XENAZINE is contraindicated in patients with hepatic impairment.

Discontinuation of Treatment

Treatment with XENAZINE can be discontinued without tapering. Re-emergence of chorea may occur within 12 to 18 hours after the last dose of XENAZINE.

Resumption of Treatment

Following treatment interruption of greater than five (5) days, XENAZINE 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.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Tetrabenazine in adult patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Tetrabenazine in adult patients.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

There is limited information regarding FDA-Labeled Use of Tetrabenazine in pediatric patients.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Tetrabenazine in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Tetrabenazine in pediatric patients.

Contraindications

• XENAZINE is contraindicated in patients who are actively suicidal, or in patients with untreated or inadequately treated depression.

• XENAZINE is contraindicated in patients with impaired hepatic function.

• XENAZINE is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs). XENAZINE should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI.

• XENAZINE is contraindicated in patients taking reserpine. At least 20 days should elapse after stopping reserpine before starting XENAZINE.

Warnings

WARNING: DEPRESSION AND SUICIDALITY See full prescribing information for complete Boxed Warning. * XENAZINE can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. Anyone considering the use of XENAZINE must balance the risks of depression and suicidality with the clinical need for control of choreiform movements. 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. XENAZINE is contraindicated in patients who are actively suicidal, and in patients with untreated or inadequately treated depression.

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, XENAZINE 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. Therefore, proper use of the drug requires attention to all facets of the underlying disease process over time.

Prescribers should periodically re-evaluate the need for XENAZINE in their patients by assessing the beneficial effect on chorea and possible adverse effects, including depression, cognitive decline, parkinsonism, dysphagia, sedation/somnolence, akathisia, restlessness and disability. It may be difficult to distinguish between drug-induced side-effects 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 XENAZINE.

Dosing of XENAZINE

Proper dosing of XENAZINE involves titration of therapy to determine an individualized dose for each patient. When first prescribed, XENAZINE therapy should be titrated slowly over several weeks to allow the identification of a dose that both reduces chorea and is tolerated. Some adverse effects such as depression, fatigue, insomnia, sedation/somnolence, parkinsonism and akathisia may be dose-dependent and may resolve or lessen with dosage adjustment or specific treatment. If the adverse effect does not resolve or decrease, consider discontinuing XENAZINE.

Doses above 50 mg should not be given without CYP2D6 genotyping patients to determine if they are poor metabolizers.

Risk of Depression and Suicidality

Patients with Huntington's disease are at increased risk for depression, suicidal ideation or behaviors (suicidality). XENAZINE increases the risk for suicidality in patients with HD. All patients treated with XENAZINE should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with XENAZINE.

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 XENAZINE 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 XENAZINE for up to 48 weeks; in the second study, 75 patients received XENAZINE for up to 80 weeks), the rate of depression/worsening depression was 35%.

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

Clinicians should be alert to the heightened risk of suicide in patients with Huntington's disease regardless of depression indices. Reported rates of completed suicide among individuals with Huntington's disease range from 3-13% and over 25% of patients attempt suicide at some point in their illness.

Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with XENAZINE 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.

Laboratory Tests'

Before prescribing a daily dose of XENAZINE 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 XENAZINE.

Patients who are PMs of XENAZINE 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.

Risk of Neuroleptic Malignant Syndrome (NMS)

A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with XENAZINE and other drugs that reduce dopaminergic transmission. 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 XENAZINE and other drugs not essential to concurrent therapy; (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. If treatment with XENAZINE is needed after recovery from NMS, patients should be monitored for signs of recurrence.

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 XENAZINE-treated patients and 0% of placebo-treated patients. In an 80-week open-label study, akathisia was observed in 20% of XENAZINE-treated patients. Akathisia was not observed in a 48-week open-label study. Patients receiving XENAZINE should be monitored for the presence of akathisia. Patients receiving XENAZINE 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 XENAZINE dose should be reduced; however, some patients may require discontinuation of therapy.

Risk of Parkinsonism

XENAZINE 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 XENAZINE-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 XENAZINE-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 side-effect 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 XENAZINE, dose reduction should be considered; in some patients, discontinuation of therapy may be necessary.

Risk of 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 XENAZINE-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 XENAZINE-treated patients, respectively. Some of the cases of dysphagia were associated with aspiration pneumonia. Whether these events were related to treatment is unknown.

Risk of Sedation and Somnolence

Sedation is the most common dose-limiting adverse effect of XENAZINE. In a 12-week, double-blind, placebo-controlled trial in patients with chorea associated with HD, sedation/somnolence was observed in 17/54 (31%) XENAZINE-treated patients and in 1 (3%) placebo-treated patient. Sedation was the reason upward titration of XENAZINE was stopped and/or the dose of XENAZINE was decreased in 15/54 (28%) patients. In all but one case, decreasing the dose of XENAZINE resulted in decreased sedation. In 48-week and 80-week open-label studies, sedation/somnolence was observed in 17% and 57% of XENAZINE-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 XENAZINE and know how the drug affects them.

Interaction with Alcohol

Patients should be advised that the concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.

Risk of QTc Prolongation

XENAZINE 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 XENAZINE 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.

XENAZINE 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 .

Concomitant Use of Neuroleptic Drugs, Reserpine and MAOIs

Neuroleptic Drugs

Patients taking neuroleptic (antipsychotic) drugs (e.g., chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone) were excluded from clinical studies during the XENAZINE development program. Adverse reactions associated with XENAZINE, such as QTc prolongation, NMS, and extrapyramidal disorders, may be exaggerated by concomitant use of dopamine antagonists .

Reserpine

Reserpine binds irreversibly to VMAT2, and the duration of its effect is several days. The physician should wait for chorea to reemerge before administering XENAZINE to avoid overdosage and major depletion of serotonin and norepinephrine in the CNS. At least 20 days should elapse after stopping reserpine before starting XENAZINE. XENAZINE and reserpine should not be used concomitantly.

Monoamine Oxidase Inhibitors (MAOIs)

XENAZINE is contraindicated in patients taking MAOIs. XENAZINE 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) and DRUG INTERACTIONS (7.3)].

Risk of Hypotension and Orthostatic Hypotension

XENAZINE 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 XENAZINE-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.

Risk of Hyperprolactinemia

XENAZINE elevates 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 XENAZINE is 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 XENAZINE 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 XENAZINE.

Risk of Tardive Dyskinesia (TD)

A potentially irreversible syndrome of involuntary, dyskinetic movements may develop in patients treated with neuroleptic drugs. In an animal model of orofacial dyskinesias, acute administration of reserpine, a monoamine depletor, has been shown to produce vacuous chewing in rats. Although the pathophysiology of tardive dyskinesia remains incompletely understood, the most commonly accepted hypothesis of the mechanism is that prolonged post-synaptic dopamine receptor blockade leads to supersensitivity to dopamine. Neither reserpine nor XENAZINE, which are dopamine depletors, have been reported to cause clear tardive dyskinesia in humans, but as pre-synaptic dopamine depletion could theoretically lead to supersensitivity to dopamine, and XENAZINE can cause the extrapyramidal symptoms also known to be associated with neuroleptics (e.g., parkinsonism and akathisia), physicians should be aware of the possible risk of tardive dyskinesia. If signs and symptoms of TD appear in a patient treated with XENAZINE, drug discontinuation should be considered.

Use in Patients with Concomitant Illnesses

Clinical experience with XENAZINE in patients with systemic illnesses is limited.

Depression and Suicidality

XENAZINE may increase the risk for depression or suicidality in patients with a history of depression or suicidal behavior or in patients with diseases, conditions, or treatments that cause depression or suicidality. XENAZINE is contraindicated in patients with untreated or inadequately treated depression or who are actively suicidal.

Hepatic Disease

XENAZINE is contraindicated in patients with hepatic impairment.

Heart Disease

XENAZINE has not been evaluated in patients with a recent history of myocardial infarction or unstable heart disease. Patients with these diagnoses were excluded from premarketing clinical trials.

Binding to Melanin-Containing Tissues

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

The clinical relevance of XENAZINE'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

Adverse Reactions

Clinical Trials Experience

The following risks are discussed in greater detail in other sections of the labeling:

• Depression and suicidality
• Akathisia, restlessness and agitation
• Parkinsonism
• Dysphagia
• Sedation and somnolence

Commonly Observed Adverse Reactions in Controlled Clinical Trials

The most common adverse reactions from Table 1 occurring in over 10% of XENAZINE-treated patients, and at least 5% greater than placebo, were sedation/somnolence (31%), fatigue (22%), insomnia (22%), depression (19%), akathisia (19%), and nausea (13%).

Clinical Studies 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, XENAZINE was administered to 773 unique subjects and patients. The conditions and duration of exposure to XENAZINE 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 (ARs) were more common in the XENAZINE group than in the placebo group. Forty-nine of 54 (91%) patients who received XENAZINE experienced one or more ARs at any time during the study. The ARs most commonly reported (over 10%, and at least 5% greater than placebo) were sedation/somnolence (31% vs. 3% on placebo), fatigue (22% vs. 13% on placebo), insomnia (22% vs. 0% on placebo), depression (19% vs. 0% on placebo), akathisia (19% vs. 0% on placebo), and nausea (13% vs. 7% on placebo).

Adverse Reactions Occurring in ≥4% Patients

The number and percentage of the most commonly reported AEs that occurred at any time during the study in ≥4% of XENAZINE-treated patients, and with a greater frequency than in placebo-treated patients, are presented in Table 1 in decreasing order of frequency within body systems for the XENAZINE group.

This image is provided by the National Library of Medicine.

Dose escalation was discontinued or dosage of study drug was reduced because of one or more ARs in 28 of 54 (52%) patients randomized to XENAZINE. These ARs 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 (EPS)

The following table describes the incidence of events considered to be extrapyramidal adverse reactions.

This image is provided by the National Library of Medicine.

Patients may have had events in more than one category.

Laboratory Tests

No clinically significant changes in laboratory parameters were reported in clinical trials with XENAZINE. In controlled clinical trials, XENAZINE caused a small mean increase in alanine aminotransferase (ALT) and aspartate aminotransferase (AST), laboratory values as compared to placebo.

Vital Signs

In controlled clinical trials, XENAZINE did not affect blood pressure, pulse, and body weight. Orthostatic blood pressure was not consistently measured in the XENAZINE clinical trials.

Postmarketing Experience

There is limited information regarding Postmarketing Experience of Tetrabenazine in the drug label.

Drug Interactions

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 XENAZINE dose may be necessary when adding a strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine, quinidine) in patients maintained on a stable dose of XENAZINE. The daily dose of XENAZINE should not exceed 50 mg per day and the maximum single dose of XENAZINE should not exceed 25 mg in patients taking strong CYP2D6 inhibitors.

Reserpine

Reserpine binds irreversibly to VMAT2 and the duration of its effect is several days. Prescribers should wait for chorea to reemerge before administering XENAZINE to avoid overdosage and major depletion of serotonin and norepinephrine in the CNS. At least 20 days should elapse after stopping reserpine before starting XENAZINE. XENAZINE and reserpine should not be used concomitantly.

Monoamine Oxidase Inhibitors (MAOIs)

XENAZINE is contraindicated in patients taking MAOIs. XENAZINE should not be used in combination with an MAOI, or within a minimum of 14 days of discontinuing therapy with an MAOI .

Alcohol

Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.

Drugs that Cause QTc Prolongation

Since XENAZINE causes a small increase in QTc prolongation (about 8 msec), the concomitant use with other drugs that are known to cause QTc prolongation should be avoided 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. XENAZINE 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.

Neuroleptic Drugs

Adverse reactions associated with XENAZINE, such as QTc prolongation, NMS, and extrapyramidal disorders, may be exaggerated by concomitant use of dopamine antagonists, including antipsychotics (e.g., chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone).

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA): Pregnancy Category C

• There are no adequate and well-controlled studies in pregnant women. XENAZINE 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/m2 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/m2 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/m2 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.

Pregnancy Category (AUS): There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Tetrabenazine in women who are pregnant.

Labor and Delivery

• The effect of XENAZINE on labor and delivery in humans is unknown.

Nursing Mothers

• It is not known whether XENAZINE 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 XENAZINE, a decision should be made whether to discontinue nursing or to discontinue XENAZINE, taking into account the importance of the drug to the mother.

Pediatric Use

• The safety and efficacy of XENAZINE in children have not been established.

Geriatic Use

• The pharmacokinetics of XENAZINE and its primary metabolites have not been formally studied in geriatric subjects.

Gender

• There is no apparent effect of gender on the pharmacokinetics of α-HTBZ or β-HTBZ.

Race

There is no FDA guidance on the use of Tetrabenazine with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Tetrabenazine in patients with renal impairment.

Hepatic Impairment

• The use of XENAZINE in patients with liver disease is contraindicated.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Tetrabenazine in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Tetrabenazine in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

Monitoring

There is limited information regarding Monitoring of Tetrabenazine in the drug label.

IV Compatibility

There is limited information regarding IV Compatibility of Tetrabenazine in the drug label.

Overdosage

Human Experience

Three episodes of overdose occurred in the open-label trials performed in support of registration. Eight cases of overdose with XENAZINE have been reported in the literature. The dose of XENAZINE in these patients ranged from 100 mg to 1 g. Adverse reactions associated with XENAZINE overdose included acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor.

Management of Overdose

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. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference® (PDR®).

Pharmacology

1 : 1 mixture (racemate)Tetrabenazine
Systematic (IUPAC) name
(SS,RR)-3-Isobutyl-9,10-dimethoxy-1,3,4,6,7,11b-hexahydro-pyrido[2,1-a]isoquinolin-2-one
Identifiers
CAS number	58-46-8
ATC code	N07XX06
PubChem	6018
DrugBank	DB04844
Chemical data
Formula	Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox
Mol. mass	317.427 g/mol
SMILES	eMolecules & PubChem
Synonyms	Ro-1-9569
Pharmacokinetic data
Bioavailability	Low, extensive first pass effect
Protein binding	82–85%
Metabolism	Hepatic (CYP2D6-mediated)
Half life	?
Excretion	Renal and fecal
Therapeutic considerations
Pregnancy cat.	C
Legal status	℞-only (US)
Routes	Oral (tablets, 25 mg)

Mechanism of Action

• The precise mechanism by which XENAZINE (tetrabenazine) exerts 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).

Structure

• XENAZINE (tetrabenazine) is a monoamine depletor for oral administration. The molecular weight of tetrabenazine is 317.43; 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 C19H27NO3 is represented by the following structural formula:

This image is provided by the National Library of Medicine.

• Tetrabenazine is a white to slightly yellow crystalline powder that is sparingly soluble in water and soluble in ethanol.

• Each XENAZINE (tetrabenazine) Tablet contains either 12.5 or 25 mg of tetrabenazine as the active ingredient.

• XENAZINE (tetrabenazine) Tablets contain tetrabenazine as the active ingredient and the following inactive ingredients: lactose, magnesium stearate, maize starch, and talc. The 25 mg strength tablet also contains yellow iron oxide as an inactive ingredient.

• XENAZINE (tetrabenazine) is supplied as a yellowish-buff scored tablet containing 25 mg of XENAZINE or as a white non-scored tablet containing 12.5 mg of XENAZINE.

Pharmacodynamics

QTc Prolongation

The effect of a single 25 or 50 mg dose of XENAZINE on the QT interval was studied in a randomized, double-blind, placebo controlled crossover study in healthy male and female subjects with moxifloxacin as a positive control. At 50 mg, XENAZINE caused an approximately 8 msec mean increase in QTc (90% CI: 5.0, 10.4 msec). Additional data suggest that inhibition of CYP2D6 in healthy subjects given a single 50 mg dose of XENAZINE does not further increase the effect on the QTc interval. Effects at higher exposures to either XENAZINE or its metabolites have not been evaluated.

Melanin Binding

Tetrabenazine or its metabolites bind to melanin-containing tissues (i.e., eye, skin, fur) in pigmented rats. After a single oral dose of radiolabeled tetrabenazine, radioactivity was still detected in eye and fur at 21 days post dosing.

Pharmacokinetics

Absorption

• Following oral administration of tetrabenazine, the extent of absorption is at least 75%. After single oral doses ranging from 12.5 to 50 mg, plasma concentrations of tetrabenazine are generally below the limit of detection because of the rapid and extensive hepatic metabolism of tetrabenazine by carbonyl reductase to the active metabolites α-HTBZ and β-HTBZ. α-HTBZ and β-HTBZ are metabolized principally by CYP2D6. Peak plasma concentrations (Cmax) of α-HTBZ and β-HTBZ are reached within 1 to 1½ hours post-dosing. α-HTBZ is subsequently metabolized to a minor metabolite, 9-desmethyl-α-DHTBZ. β-HTBZ is subsequently, metabolized to another major circulating metabolite, 9-desmethyl-β-DHTBZ, for which Cmax is reached approximately 2 hours post-dosing.

Food Effects

• The effects of food on the bioavailability of XENAZINE were studied in subjects administered a single dose with and without food. Food had no effect on mean plasma concentrations, Cmax, or the area under the concentration time course (AUC) of α-HTBZ or β-HTBZ. XENAZINE can, therefore, be administered without regard to meals.

Distribution

• Results of PET-scan studies in humans show that radioactivity is rapidly distributed to the brain following intravenous injection of 11C-labeled tetrabenazine or α-HTBZ, with the highest binding in the striatum and lowest binding in the cortex.

• The in vitro protein binding of tetrabenazine, α-HTBZ, and β-HTBZ was examined in human plasma for concentrations ranging from 50 to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, α-HTBZ binding ranged from 60% to 68%, and β-HTBZ binding ranged from 59% to 63%.

Metabolism

• After oral administration in humans, at least 19 metabolites of tetrabenazine have been identified. α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ, are the major circulating metabolites, and they are, subsequently, metabolized to sulfate or glucuronide conjugates. α-HTBZ and β-HTBZ are formed by carbonyl reductase that occurs mainly in the liver. α-HTBZ is O-dealkylated by CYP450 enzymes, principally CYP2D6, with some contribution of CYP1A2 to form 9-desmethyl-α-DHTBZ, a minor metabolite. β-HTBZ is O-dealkylated principally by CYP2D6 to form 9-desmethyl-β-DHTBZ.

• The results of in vitro studies do not suggest that tetrabenazine, α-HTBZ, or β-HTBZ are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. In vitro studies suggest that neither tetrabenazine nor its α- or β-HTBZ metabolites are likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19.

• Neither tetrabenazine nor its α- or β-HTBZ metabolites is likely to be a substrate or inhibitor of P-glycoprotein at clinically relevant concentrations in vivo.

• No in vitro metabolism studies have been conducted to evaluate the potential of the 9-desmethyl-β-DHTBZ metabolite to interact with other drugs. The activity of this metabolite relative to the parent drug is unknown.

Elimination

• After oral administration, tetrabenazine is extensively hepatically metabolized, and the metabolites are primarily renally eliminated. α-HTBZ, β-HTBZ and 9-desmethyl-β-DHTBZ have half-lives of 7 hours, 5 hours and 12 hours respectively. In a mass balance study in 6 healthy volunteers, approximately 75% of the dose was excreted in the urine and fecal recovery accounted for approximately 7-16% of the dose. Unchanged tetrabenazine has not been found in human urine. Urinary excretion of α-HTBZ or β-HTBZ accounted for less than 10% of the administered dose. Circulating metabolites, including sulfate and glucuronide conjugates of HTBZ metabolites as well as products of oxidative metabolism, account for the majority of metabolites in the urine.

'Specific Populations''

Pediatric Patient

The pharmacokinetics of XENAZINE and its primary metabolites have not been studied in pediatric subjects.

Geriatric Patient

The pharmacokinetics of XENAZINE and its primary metabolites have not been formally studied in geriatric subjects.

Gender

There is no apparent effect of gender on the pharmacokinetics of α-HTBZ or β-HTBZ.

Race

Racial differences in the pharmacokinetics of XENAZINE and its primary metabolites have not been formally studied.

Patients with Renal Impairment

The effect of renal insufficiency on the pharmacokinetics of XENAZINE and its primary metabolites has not been studied.

Patients with Hepatic Impairment

The disposition of tetrabenazine was compared in 12 patients with mild to moderate chronic liver impairment (Child-Pugh scores of 5-9) and 12 age- and gender-matched subjects with normal hepatic function who received a single 25 mg dose of tetrabenazine. In patients with hepatic impairment, tetrabenazine plasma concentrations were similar to or higher than concentrations of α-HTBZ, reflecting the markedly decreased metabolism of tetrabenazine to α-HTBZ. The mean tetrabenazine Cmax in hepatically impaired subjects was approximately 7- to 190-fold higher than the detectable peak concentrations in healthy subjects. The elimination half-life of tetrabenazine in subjects with hepatic impairment was approximately 17.5 hours. The time to peak concentrations (tmax) of α-HTBZ and β-HTBZ was slightly delayed in subjects with hepatic impairment compared to age-matched controls (1.75 hrs vs. 1.0 hrs), and the elimination half lives of the α-HTBZ and β-HTBZ were prolonged to approximately 10 and 8 hours, respectively. The exposure to α-HTBZ and β-HTBZ was approximately 30-39% greater in patients with liver impairment than in age-matched controls. The safety and efficacy of this increased exposure to tetrabenazine and other circulating metabolites are unknown so that it is not possible to adjust the dosage of tetrabenazine in hepatic impairment to ensure safe use. Therefore, tetrabenazine is contraindicated in patients with hepatic impairment.

Patients Who Are Poor or Extensive CYP2D6 Metabolizers

Patients should be genotyped for drug metabolizing enzyme, CYP2D6, prior to treatment with daily doses of XENAZINE over 50 mg.

Poor Metabolizers

Although the pharmacokinetics of XENAZINE and its metabolites in subjects who do not express the drug metabolizing enzyme, CYP2D6, poor metabolizers, (PMs), have not been systematically evaluated, it is likely that the exposure to α-HTBZ and β-HTBZ would be increased similar to that observed in patients taking strong CYP2D6 inhibitors (3- and 9-fold, respectively). Patients who are PMs should not be given doses greater than 50 mg per day and the maximum recommended single dose is 25 mg.

Extensive or Intermediate CYP2D6 Metabolizers

In patients who express the enzyme, CYP2D6, (extensive [EMs] or intermediate [IMs] metabolizers), the maximum recommended daily dose is 100 mg per day, with a maximum recommended single dose of 37.5 mg.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

• No increase in tumors was observed in p53+/- transgenic mice treated orally with tetrabenazine at doses of 0, 5, 15 and 30 mg/kg/day for 26 weeks. When compared to humans receiving a 50 mg dose of XENAZINE, mice dosed with a 30 mg/kg dose of tetrabenazine produce about one sixth the levels of 9-desmethyl-beta-DHTBZ, a major human metabolite. Therefore, this study may not have adequately characterized the potential of tetrabenazine to be carcinogenic in people.

Mutagenesis

• Tetrabenazine and metabolites α-HTBZ and β-HTBZ were negative in the in vitro bacterial reverse mutation assay. Tetrabenazine was clastogenic in the in vitro chromosome aberration assay in Chinese hamster ovary cells in the presence of metabolic activation. α-HTBZ and β-HTBZ were clastogenic in the in vitro chromosome aberration assay in Chinese hamster lung cells in the presence and absence of metabolic activation. In vivo micronucleus tests were conducted in male and female rats and male mice. Tetrabenazine was negative in male mice and rats but produced an equivocal response in female rats.

• Because the bioactivation system used in the in vitro studies was hepatic S9 fraction prepared from rat, a species that, when dosed with tetrabenazine, does not produce 9-desmethyl-beta-DHTBZ, a major human metabolite, these studies may not have adequately assessed the potential of XENAZINE to be mutagenic in humans. Furthermore, since the mouse produces very low levels of this metabolite when dosed with tetrabenazine, the in vivo study may not have adequately assessed the potential of XENAZINE to be mutagenic in humans.

Impairment of Fertility

• Oral administration of tetrabenazine (doses of 5, 15, or 30 mg/kg/day) to female rats prior to and throughout mating, and continuing through day 7 of gestation resulted in disrupted estrous cyclicity at doses greater than 5 mg/kg/day (less than the MRHD on a mg/m2 basis).

• No effects on mating and fertility indices or sperm parameters (motility, count, density) were observed when males were treated orally with tetrabenazine (doses of 5, 15 or 30 mg/kg/day; up to 3 times the MRHD on a mg/m2 basis) prior to and throughout mating with untreated females.

• Because rats dosed with tetrabenazine do not produce 9-desmethyl-beta-DHTBZ, a major human metabolite, these studies may not have adequately assessed the potential of XENAZINE to impair fertility in humans.

Clinical Studies

Study 1

• The efficacy of XENAZINE 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. The dose of XENAZINE was started at 12.5 mg per day and titrated upward at weekly intervals in 12.5 mg increments until satisfactory control of chorea was achieved, until intolerable side effects occurred, or until a maximal dose of 100 mg per 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 subjects 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 subjects receiving XENAZINE returned to baseline.

This image is provided by the National Library of Medicine.

• Figure 2 illustrates the cumulative percentages of patients from the XENAZINE 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 XENAZINE-treated patients indicates that these patients were more likely to have any given degree of improvement in chorea score. Thus, for example, about 7% of placebo patients had a 6-point or greater improvement compared to 50% of XENAZINE-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.

This image is provided by the National Library of Medicine.

• 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%.

Study 2

• A second controlled study was performed in patients who had been treated with open-label XENAZINE for at least 2 months (mean duration of treatment was 2 years). They were randomized to continuation of XENAZINE 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).

A Physician-rated Clinical Global Impression (CGI) favored XENAZINE statistically. In general, measures of functional capacity and cognition showed no difference between XENAZINE 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 XENAZINE 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 XENAZINE compared to placebo, but the difference was not statistically significant.

How Supplied

Storage

There is limited information regarding Tetrabenazine Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Tetrabenazine in the drug label.

Precautions with Alcohol

• Alcohol-Tetrabenazine interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

There is limited information regarding Tetrabenazine Brand Names in the drug label.

Look-Alike Drug Names

There is limited information regarding Tetrabenazine Look-Alike Drug Names in the drug label.

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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