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 C 19 H 27 NO 3 is represented by the following structural formula: 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) tablets are supplied as a yellowish-buff, scored tablet containing 25 mg of tetrabenazine or as a white, non-scored tablet containing 12.5 mg of tetrabenazine. Chemical Structure

XENAZINE is indicated for the treatment of chorea associated with Huntington’s disease. XENAZINE is a vesicular monoamine transporter 2 (VMAT) inhibitor indicated for the treatment of chorea associated with Huntington’s disease.

XENAZINE tablets are available in the following strengths and packages: The 12.5 mg XENAZINE tablets are white, cylindrical, biplanar tablets with beveled edges, non-scored, embossed on one side with “CL” and “12.5.” The 25 mg XENAZINE tablets are yellowish-buff, cylindrical, biplanar tablets with beveled edges, scored, embossed on one side with “CL” and “25.” Tablets: 12.5 mg non-scored and 25 mg scored

Individualization of dose with careful weekly titration is required. The 1 st week’s starting dose is 12.5 mg daily; 2 nd week, 25 mg (12.5 mg twice daily); then slowly titrate at weekly intervals by 12.5 mg to a tolerated dose that reduces chorea. Doses of 37.5 mg and up to 50 mg/day should be administered in three divided doses per day with a maximum recommended single dose not to exceed 25 mg. Patients requiring doses above 50 mg/day should be genotyped for the drug metabolizing enzyme CYP2D6 to determine if the patient is a poor metabolizer (PM) or an extensive metabolizer (EM). ( 2.2 , 5.3) Maximum daily dose in PMs: 50 mg with a maximum single dose of 25 mg Maximum daily dose in EMs and intermediate metabolizers (IMs): 100 mg with a maximum single dose of 37.5 mg If serious adverse reactions occur, titration should be stopped and the dose should be reduced. If the adverse reaction(s) do not resolve, consider withdrawal of XENAZINE

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 XENAZINE 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/day The starting dose should be 12.5 mg/day given once in the morning. After 1 week, the dose should be increased to 25 mg/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/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 XENAZINE treatment or initiating other specific treatment (e.g., antidepressants) . Dosing Recommendations Above 50 mg/day Patients who require doses of XENAZINE greater than 50 mg/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/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/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 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

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

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 5 days, XENAZINE 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.

Periodically reevaluate the benefit and potential for adverse effects such as worsening mood, cognition, rigidity, and functional capacity. Do not exceed 50 mg/day and the maximum single dose should not exceed 25 mg if administered in conjunction with a strong CYP2D6 inhibitor (e.g., fluoxetine, paroxetine). (5.3, 7.1 ) Neuroleptic Malignant Syndrome (NMS): Discontinue if this occurs. Restlessness, agitation, akathisia and parkinsonism: Reduce dose or discontinue if occurs. Sedation/Somnolence: May impair patient’s ability to drive or operate complex machinery QTc prolongation: Not recommended in combination with other drugs that prolong QTc 5.1 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. 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. When considering the use of XENAZINE, the risk of suicidality should be balanced against the need for treatment of chorea. 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. 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

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. Prescribers should periodically re-evaluate the need for XENAZINE 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 XENAZINE

Laboratory Tests Before prescribing a daily dose of XENAZINE 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 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

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 immediate discontinuation of XENAZINE; intensive symptomatic treatment and medical monitoring; and 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 XENAZINE is needed after recovery from NMS, patients should be monitored for signs of recurrence

Akathisia, Restlessness, and Agitation XENAZINE 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 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. 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

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

Sedation and Somnolence Sedation is the most common dose-limiting adverse reaction of XENAZINE. In a 12-week, double-blind, placebo-controlled trial in patients with chorea associated with HD, sedation/somnolence occurred in 17/54 (31%) of XENAZINE-treated patients and in 1 (3%) of 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 occurred 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

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 . 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 bradycardia; hypokalemia or hypomagnesemia; concomitant use of other drugs that prolong the QTc interval; and presence of congenital prolongation of the QT interval

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

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

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 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 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 .

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 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/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 re-emerge 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 or Other Sedating Drugs Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence

Drugs That Cause QTc Prolongation XENAZINE causes a small prolongation of QTc (about 8 msec), concomitant use with other drugs that are known to cause QTc prolongation should be avoided, these including antipsychotic medications (e.g., chlorpromazine, haloperidol, thioridazine, ziprasidone), antibiotics (e.g., moxifloxacin), Class 1A (e.g., quinidine, procainamide) and Class III (e.g., amiodarone, sotalol) antiarrhythmic medications or any other medications known to prolong the QTc interval. XENAZINE 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 bradycardia; hypokalemia or hypomagnesemia; concomitant use of other drugs that prolong the QTc interval; and presence of congenital prolongation of the QT interval

Neuroleptic Drugs The risk for Parkinsonism, NMS, and akathisia may be increased by concomitant use of XENAZINE and dopamine antagonists or antipsychotics (e.g., chlorpromazine, haloperidol, olanzapine, risperidone, thioridazine, ziprasidone)

Concomitant Deutetrabenazine or Valbenazine XENAZINE is contraindicated in patients currently taking deutetrabenazine or valbenazine.