Xenazine

1 INDICATIONS AND USAGE 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. ( 1 )

2 DOSAGE AND ADMINISTRATION 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. ( 2.1 , 2.2 ) 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. ( 2.2 ) 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 ( 2.2 ) Maximum daily dose in EMs and intermediate metabolizers (IMs): 100 mg with a maximum single dose of 37.5 mg ( 2.2 ) 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. ( 2.2 ) 2.1 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 [see Clinical Pharmacology (12.3) ]. 2.2 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) [see Adverse Reactions (6.1)] . 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 [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 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) [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 …

3 DOSAGE FORMS AND STRENGTHS 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 ( 3 )

4 CONTRAINDICATIONS XENAZINE is contraindicated in patients: Who are actively suicidal, or in patients with untreated or inadequately treated depression [see Warnings and Precautions (5.1) ]. With hepatic impairment [see Use in Specific Populations (8.6) , Clinical Pharmacology (12.3) ]. Taking monoamine oxidase inhibitors (MAOIs). XENAZINE 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 XENAZINE [see Drug Interactions ( 7.2 )]. Taking deutetrabenazine or valbenazine [see Drug Interactions ( 7.7 )]. Actively suicidal, or who have depression which is untreated or undertreated ( 4 , 5.1 ) Hepatic impairment ( 4 , 8.6 , 12.3 ) Taking monoamine oxidase inhibitors (MAOIs) or reserpine ( 4 , 7.2 , 7.3 ) Taking deutetrabenazine or valbenazine ( 4 , 7.7 )

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Depression and Suicidality [see Warnings and Precautions (5.1) ] Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions (5.4) ] Akathisia, Restlessness, and Agitation [see Warnings and Precautions (5.5) ] Parkinsonism [see Warnings and Precautions (5.6) ] Sedation and Somnolence [see Warnings and Precautions (5.7) ] QTc Prolongation [see Warnings and Precautions (5.8) ] Hypotension and Orthostatic Hypotension [see Warnings and Precautions (5.9) ] Hyperprolactinemia [see Warnings and Precautions (5.10) ] Binding to Melanin-Containing Tissues [see Warnings and Precautions (5.11) ] Most common adverse reactions (greater than 10% and at least 5% greater than placebo) were: sedation/somnolence, fatigue, insomnia, depression, akathisia, anxiety/anxiety aggravated, nausea. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Lundbeck’s XENAZINE Information Center at 1-888-882-6013 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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, XENAZINE was administered to 773 unique subjects and patients. The conditions and duration of exposure to XENAZINE 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 XENAZINE group than in the placebo group. Forty-nine of 54 (91%) patients who received XENAZINE experienced one or more adverse reactions at any time during the study. The most common adverse reactions (over 10%, and at least 5% greater than placebo) were sedation/somnolence, fatigue, insomnia, depression, akathisia, anxiety/anxiety aggravated, and nausea. Adverse Reactions Occurring in Greater Than or Equal to 4% of Patients The number and percentage of the most common adverse reactions that occurred at any time during the study in greater than or equal to 4% of XENAZINE-treated patients, and with a greater frequency than in placebo-treated patients, are presented in Table 1. Table 1: Adverse Reactions in a 12-Week, Double-Blind, Placebo-Controlled Trial in Patients with Huntington’s Disease Adverse Reaction XENAZINE n=54 % Placebo n=30 % Sedation/somnolence 31 3 Insomnia 22 0 Fatigue 22 13 Depression 19 0 Akathisia 19 0 Anxiety/anxiety aggravated 15 3 Fall 15 13 Nausea 13 7 Upper respiratory tract infection 11 7 Irritability 9 3 Balance difficulty 9 0 Parkinsonism/bradykinesia 9 0 Vomiting 6 3 Laceration (head) 6 0 Ecchymosis 6 0 Decreased appetite 4 0 Obsessive reaction 4 0 Dizziness 4 0 Dysarthria 4 0 Unsteady gait 4 0 Headache 4 3 Shortness of breath 4 0 Bronchitis 4 0 Dysuria 4 0 Dose escalation was discontinued or dosage of study drug was reduced because of one or more adverse reactions in 28 of 54 (52%) patients randomized to XENAZINE. These adverse reactions consisted of sedation (15), akathisia (7), parkinsonism (4), depression (3), anxiety (2), fatigue (1) and diarrhea (1). Some patients had more than one AR and are, therefore, counted more than once. Adverse Reactions Due to Extrapyramidal Symptoms Table 2 describes the incidence of events considered to be extrapyramidal adverse reactions which occurred at a greater frequency in XENAZINE-treated patients compared to placebo-treated patients. Table 2: Adverse Reactions Due to Extrapyramidal Symptoms in a 12-Week, Double-Blind, Placebo-Controlled Trial in Patients with Huntington’s Disease XENAZINE n=54 % Placebo n=30 % Akathisia Patients with the following adverse event preferred terms were counted in …

7 DRUG INTERACTIONS 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 [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 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 [see Contraindications (4) ]. 7.3 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) ]. 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 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 (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 XENAZINE 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 XENAZINE is contraindicated in patients currently taking deutetrabenazine or valbenazine.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm. ( 8.1 ) 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of XENAZINE in pregnant women. Administration of tetrabenazine to rats throughout pregnancy and lactation resulted in an increase in stillbirths and postnatal offspring mortality. Administration of a major human metabolite of tetrabenazine to rats during pregnancy or during pregnancy and lactation produced adverse effects on the developing fetus and offspring (increased mortality, decreased growth, and neurobehavioral and reproductive impairment). The adverse developmental effects of tetrabenazine and a major human metabolite of tetrabenazine in rats occurred at clinically relevant doses [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Tetrabenazine had no clear effects on embryofetal development when administered to pregnant rats throughout the period of organogenesis at oral doses up to 30 mg/kg/day (or 3 times the maximum recommended human dose [MRHD] of 100 mg/day on a mg/m 2 basis). Tetrabenazine had no effects on embryofetal development when administered to pregnant rabbits during the period of organogenesis at oral doses up to 60 mg/kg/day (or 12 times the MRHD on a mg/m 2 basis). When tetrabenazine (5, 15, and 30 mg/kg/day) was orally administered to pregnant rats from the beginning of organogenesis through the lactation period, an increase in stillbirths and offspring postnatal mortality was observed at 15 and 30 mg/kg/day and delayed pup maturation was observed at all doses. A no-effect dose for pre- and postnatal developmental toxicity in rats was not identified. The lowest dose tested (5 mg/kg/day) was less than the MRHD on a mg/m 2 basis. Because rats dosed orally with tetrabenazine do not produce 9-desmethyl-β-DHTBZ, a major human metabolite of tetrabenazine, the metabolite was directly administered to pregnant and lactating rats. Oral administration of 9-desmethyl-β-DHTBZ (8, 15, and 40 mg/kg/day) throughout the period of organogenesis produced increases in embryofetal mortality at 15 and 40 mg/kg/day and reductions in fetal body weights at 40 mg/kg/day, which was also maternally toxic. When 9-desmethyl-β-DHTBZ (8, 15, and 40 mg/kg/day) was orally administered to pregnant rats from the beginning of organogenesis through the lactation period, increases in gestation duration, stillbirths, and offspring postnatal mortality (40 mg/kg/day); decreases in pup weights (40 mg/kg/day); and neurobehavioral (increased activity, learning and memory deficits) and reproductive (decreased litter size) impairment (15 and 40 mg/kg/day) were observed. Maternal toxicity was seen at the highest dose. The no-effect dose for developmental toxicity in rats (8 mg/kg/day) was associated with plasma exposures (AUC) of 9-desmethyl-β-DHTBZ in pregnant rats lower than that in humans at the MRHD. 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 XENAZINE and any potential adverse effects on the breastfed infant from XENAZINE 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 XENAZINE 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 XENAZINE and other circulating metabolites are unknown, it is not po …

12.1 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) (K i ≈ 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 (K i = 2100 nM).

11 DESCRIPTION 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

10 OVERDOSAGE 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 include acute dystonia, oculogyric crisis, nausea and vomiting, sweating, sedation, hypotension, confusion, diarrhea, hallucinations, rubor, and tremor. 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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied XENAZINE ® (tetrabenazine) 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”. NDC 67386-421-01 12.5 mg 112-count bottle The 25 mg XENAZINE tablets are yellowish-buff, cylindrical, biplanar tablets with beveled edges, scored, embossed on one side with “CL” and “25”. NDC 67386-422-01 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].