Austedo

1 INDICATIONS AND USAGE AUSTEDO XR ® and AUSTEDO ® are indicated in adults for the treatment of: chorea associated with Huntington’s disease [see Clinical Studies ( 14.1 )] tardive dyskinesia [see Clinical Studies ( 14.2 )] AUSTEDO XR and AUSTEDO are vesicular monoamine transporter 2 (VMAT2) inhibitors indicated in adults for the treatment of: Chorea associated with Huntington’s disease ( 1 ) Tardive dyskinesia ( 1 )

2 DOSAGE AND ADMINISTRATION AUSTEDO XR AUSTEDO Recommended Starting Dosage 12 mg once daily (12 mg per day) 6 mg twice daily (12 mg per day) Titrate at weekly intervals by 6 mg per day based on reduction of chorea or tardive dyskinesia, and tolerability, up to a maximum recommended daily dosage of 48 mg ( 2.1 ) Administer AUSTEDO XR with or without food in once-daily doses ( 2.1 ) Administer AUSTEDO with food and administer total daily dosages of 12 mg or above in two divided doses ( 2.1 ) Swallow tablets whole; do not chew, crush, or break ( 2.1 ) If switching patients from tetrabenazine, discontinue tetrabenazine and initiate AUSTEDO XR or AUSTEDO the following day. See full prescribing information for recommended conversion table ( 2.2 ) Maximum recommended dosage of AUSTEDO XR or AUSTEDO in poor CYP2D6 metabolizers is 36 mg per day ( 2.4 , 8.7 ) 2.1 Dosing Information The dose of AUSTEDO XR and AUSTEDO is determined individually for each patient based on reduction of chorea or tardive dyskinesia and tolerability. Table 1 displays the recommended dosage and important administration instructions of AUSTEDO XR and AUSTEDO when first prescribed to patients who are not being switched from tetrabenazine (a related VMAT2 inhibitor). Table 1: Recommended Dosage and Important Administration Instructions for AUSTEDO XR and AUSTEDO AUSTEDO XR extended-release tablet AUSTEDO tablet Recommended Starting Dosage 12 mg once daily (12 mg per day) 6 mg twice daily (12 mg per day) Recommended Dose Titration The dosage of AUSTEDO XR or AUSTEDO may be increased at weekly intervals in increments of 6 mg per day based on reduction of chorea or tardive dyskinesia, and tolerability, up to a maximum recommended daily dosage of 48 mg [see Clinical Trials ( 14.1 , 14.2 )] . Important Administration Instructions Administer AUSTEDO XR with or without food [see Clinical Pharmacology ( 12.3 )] . Swallow AUSTEDO XR whole. Do not chew, crush, or break tablets. Administer AUSTEDO XR once daily. Administer AUSTEDO with food [see Clinical Pharmacology ( 12.3 )] . Swallow AUSTEDO whole. Do not chew, crush, or break tablets. Administer AUSTEDO total daily dosages of 12 mg or above in two divided doses. Switching Between AUSTEDO and AUSTEDO XR When switching between AUSTEDO tablets (twice daily) and AUSTEDO XR extended-release tablets (once daily), switch to the same total daily dosage. 2.2 Switching Patients from Tetrabenazine to AUSTEDO XR or AUSTEDO Discontinue tetrabenazine and initiate AUSTEDO XR or AUSTEDO the following day. The recommended initial dosing regimen of AUSTEDO XR or AUSTEDO in patients switching from tetrabenazine to AUSTEDO XR or AUSTEDO is shown in Table 2. Table 2: Recommended Initial Dosing Regimen when Switching from Tetrabenazine to AUSTEDO XR or AUSTEDO Current tetrabenazine daily dosage Initial regimen of AUSTEDO XR extended-release tablet Initial regimen of AUSTEDO tablet 12.5 mg 6 mg once daily 6 mg once daily 25 mg 12 mg once daily 6 mg twice daily 37.5 mg 18 mg once daily 9 mg twice daily 50 mg 24 mg once daily 12 mg twice daily 62.5 mg 30 mg once daily 15 mg twice daily 75 mg 36 mg once daily 18 mg twice daily 87.5 mg 42 mg once daily 21 mg twice daily 100 mg 48 mg once daily 24 mg twice daily After patients are switched to AUSTEDO XR or AUSTEDO, the dose may be adjusted at weekly intervals [see Dosage and Administration ( 2.1 )] . 2.3 Dosage Adjustment with Strong CYP2D6 Inhibitors In patients receiving strong CYP2D6 inhibitors, the total daily dosage of AUSTEDO XR or AUSTEDO should not exceed 36 mg [see Drug Interactions ( 7.1 ) and Clinical Pharmacology ( 12.3 )] . 2.4 Dosage Adjustment in Poor CYP2D6 Metabolizers In patients who are poor CYP2D6 metabolizers, the total daily dosage of AUSTEDO XR or AUSTEDO should not exceed 36 mg [see Use in Specific Populations ( 8.7 )]. 2.5 Discontinuation and Interruption of Treatment Treatment with AUSTEDO XR or AUSTEDO can be discontinued without tapering. Following treatment interruption …

3 DOSAGE FORMS AND STRENGTHS AUSTEDO XR extended-release tablets are available in the following strengths: The 6 mg extended-release tablets are round, grey-coated tablets, with “Q6” printed in black ink on one side. The 12 mg extended-release tablets are round, blue-coated tablets, with “Q12” printed in black ink on one side. The 18 mg extended-release tablets are round, light grey-coated tablets, with “Q18” printed in black ink on one side. The 24 mg extended-release tablets are round, purple-coated tablets, with “Q24” printed in black ink on one side. The 30 mg extended-release tablets are round, light orange-coated tablets, with “Q30” printed in black ink on one side. The 36 mg extended-release tablets are round, light purple-coated tablets, with “Q36” printed in black ink on one side. The 42 mg extended-release tablets are round, orange-coated tablets, with “Q42” printed in black ink on one side. The 48 mg extended-release tablets are round, pink-coated tablets, with “Q48” printed in black ink on one side. AUSTEDO tablets are available in the following strengths: The 6 mg tablets are round, purple-coated tablets, with “SD” over “6” printed in black ink on one side. The 9 mg tablets are round, blue-coated tablets, with “SD” over “9” printed in black ink on one side. The 12 mg tablets are round, beige-coated tablets, with “SD” over “12” printed in black ink on one side. Extended-release tablets: 6 mg, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, and 48 mg ( 3 ) Tablets: 6 mg, 9 mg, and 12 mg ( 3 )

4 CONTRAINDICATIONS AUSTEDO XR and AUSTEDO are contraindicated in patients: With Huntington’s disease who are suicidal, or have 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 reserpine. At least 20 days should elapse after stopping reserpine before starting AUSTEDO XR or AUSTEDO [see Drug Interactions ( 7.2 )] . Taking monoamine oxidase inhibitors (MAOIs). AUSTEDO XR and AUSTEDO should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI [see Drug Interactions ( 7.3 )] . Taking tetrabenazine or valbenazine [see Drug Interactions ( 7.6 )] . Suicidal, or untreated/inadequately treated depression in patients with Huntington’s disease ( 4 , 5.1 ) Hepatic impairment ( 4 , 8.6 , 12.3 ) Taking reserpine, MAOIs, tetrabenazine, or valbenazine ( 4 , 7.2 , 7.3 , 7.6 )

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Depression and Suicidality in Patients with Huntington’s disease [see Warnings and Precautions ( 5.1 )] QTc Prolongation [see Warnings and Precautions ( 5.3 )] Neuroleptic Malignant Syndrome (NMS) [see Warnings and Precautions ( 5.4 )] Akathisia, Agitation, and Restlessness [see Warnings and Precautions ( 5.5 )] Parkinsonism [see Warnings and Precautions ( 5.6 )] Sedation and Somnolence [see Warnings and Precautions ( 5.7 )] Hyperprolactinemia [see Warnings and Precautions ( 5.8 )] Binding to Melanin-Containing Tissues [see Warnings and Precautions ( 5.9 )] Most common adverse reactions (>8% of AUSTEDO-treated patients with Huntington’s disease and greater than placebo): somnolence, diarrhea, dry mouth, and fatigue ( 6.1 ) Most common adverse reactions (that occurred in 4% of AUSTEDO-treated patients with tardive dyskinesia and greater than placebo): nasopharyngitis and insomnia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 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. The studies described below were conducted with AUSTEDO tablets; adverse reactions with AUSTEDO XR extended-release tablets are expected to be similar to AUSTEDO tablets. Patients with Huntington’s Disease Study 1 [see Clinical Studies ( 14.1 )] was a randomized, 12-week, placebo-controlled study in patients with chorea associated with Huntington’s disease. A total of 45 patients received AUSTEDO, and 45 patients received placebo. Patients ranged in age between 23 and 74 years (mean 54 years); 56% were male, and 92% were Caucasian. The most common adverse reactions occurring in greater than 8% of AUSTEDO-treated patients were somnolence, diarrhea, dry mouth, and fatigue. Adverse reactions occurring in 4% or more of patients treated with AUSTEDO, and with a greater incidence than in patients on placebo, are summarized in Table 3. Table 3: Adverse Reactions in Patients with Huntington's Disease (Study 1) Experienced by at Least 4% of Patients on AUSTEDO and with a Greater Incidence than on Placebo Adverse Reaction AUSTEDO (N = 45) % Placebo (N = 45) % Somnolence 11 4 Diarrhea 9 0 Dry mouth 9 7 Fatigue 9 4 Urinary tract infection 7 2 Insomnia 7 4 Anxiety 4 2 Constipation 4 2 Contusion 4 2 One or more adverse reactions resulted in a reduction of the dose of study medication in 7% of patients in Study 1. The most common adverse reaction resulting in dose reduction in patients receiving AUSTEDO was dizziness (4%). Agitation led to discontinuation in 2% of patients treated with AUSTEDO in Study 1. Patients with Tardive Dyskinesia The data described below reflect 410 tardive dyskinesia patients participating in clinical trials. AUSTEDO was studied primarily in two 12-week, placebo-controlled trials (fixed dose, dose escalation) [see Clinical Studies ( 14.2 )] . The population was 18 to 80 years of age, and had tardive dyskinesia and had concurrent diagnoses of mood disorder (33%) or schizophrenia/schizoaffective disorder (63%). In these studies, AUSTEDO was administered in doses ranging from 12-48 mg per day. All patients continued on previous stable regimens of antipsychotics; 71% and 14% respective atypical and typical antipsychotic medications at study entry. The most common adverse reactions occurring in greater than 3% of AUSTEDO-treated patients and greater than placebo were nasopharyngitis and insomnia. The adverse reactions occurring in >2% or more patients treated with AUSTEDO (12-48 mg per day) and greater than in placebo patients in two double-blind, placebo-controlled studies in patients with …

7 DRUG INTERACTIONS Concomitant use of strong CYP2D6 inhibitors: Maximum recommended dose of AUSTEDO XR or AUSTEDO is 36 mg per day ( 2.3 , 7.1 ) Alcohol or other sedating drugs: May have additive sedation and somnolence ( 7.5 ) 7.1 Strong CYP2D6 Inhibitors A reduction in AUSTEDO XR or AUSTEDO dose may be necessary when adding a strong CYP2D6 inhibitor in patients maintained on a stable dose of AUSTEDO XR or AUSTEDO. Concomitant use of strong CYP2D6 inhibitors (e.g., paroxetine, fluoxetine, quinidine, bupropion) has been shown to increase the systemic exposure to the active dihydro-metabolites of deutetrabenazine by approximately 3-fold. The daily dose of AUSTEDO XR or AUSTEDO should not exceed 36 mg per day in patients taking strong CYP2D6 inhibitors [see Dosage and Administration ( 2.3 ) and 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 or dyskinesia to reemerge before administering AUSTEDO XR or AUSTEDO to help reduce the risk of overdosage and major depletion of serotonin and norepinephrine in the central nervous system. At least 20 days should elapse after stopping reserpine before starting AUSTEDO XR or AUSTEDO. AUSTEDO XR and AUSTEDO should not be used concomitantly with reserpine [see Contraindications ( 4 )] . 7.3 Monoamine Oxidase Inhibitors (MAOIs) AUSTEDO XR and AUSTEDO are contraindicated in patients taking MAOIs. AUSTEDO XR and AUSTEDO should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI [see Contraindications ( 4 )] . 7.4 Neuroleptic Drugs The risk of parkinsonism, NMS, and akathisia may be increased by concomitant use of AUSTEDO XR or AUSTEDO with dopamine antagonists or antipsychotics. 7.5 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 )]. 7.6 Concomitant Tetrabenazine or Valbenazine AUSTEDO XR and AUSTEDO are contraindicated in patients currently taking tetrabenazine or valbenazine. AUSTEDO XR or AUSTEDO may be initiated the day following discontinuation of tetrabenazine [see Dosage and Administration ( 2.2 )].

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 AUSTEDO XR or AUSTEDO in pregnant women. Administration of deutetrabenazine to rats during organogenesis produced no clear adverse effect on embryofetal development. However, administration of tetrabenazine to rats throughout pregnancy and lactation resulted in an increase in stillbirths and postnatal offspring mortality [see Data]. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Oral administration of deutetrabenazine (5, 10, or 30 mg/kg/day) or tetrabenazine (30 mg/kg/day) to pregnant rats during organogenesis had no clear effect on embryofetal development. The highest dose tested was 6 times the maximum recommended human dose of 48 mg/day, on a body surface area (mg/m 2 ) basis. The effects of deutetrabenazine when administered during organogenesis to rabbits or during pregnancy and lactation to rats have not been assessed. 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. 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. 8.2 Lactation Risk Summary There are no data on the presence of deutetrabenazine 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 AUSTEDO XR or AUSTEDO and any potential adverse effects on the breastfed infant from AUSTEDO XR or AUSTEDO or from the underlying maternal condition. 8.4 Pediatric Use Chorea associated with Huntington’s Disease and Tardive Dyskinesia The safety and effectiveness of AUSTEDO XR and AUSTEDO have not been established in pediatric patients for the treatment of chorea associated with Huntington’s disease or for the treatment of tardive dyskinesia. Tourette Syndrome The safety and effectiveness of AUSTEDO XR and AUSTEDO have not been established in pediatric patients for the treatment of Tourette syndrome. Efficacy was not demonstrated in two randomized, double-blind, placebo-controlled studies in pediatric patients aged 6 to 16 years with Tourette syndrome. One study evaluated fixed doses of deutetrabenazine over 8 weeks (NCT03571256); the other evaluated flexible doses of deutetrabenazine over 12 weeks (NCT03452943). The studies included a total of 274 pediatric patients who received at least one dose of deutetrabenazine or placebo. The primary efficacy endpoint in both studies was the change from baseline to end-of-treatment on the Yale Global Tic Severity Scale Total Tic Score (YGTSS-TTS). The estimated treatment effect of deutetrabenazine on the YGTSS-TTS was not statistically significantly different from placebo in either study. The placebo subtracted least squares means difference in YGTSS-TTS from baseline to end-of-treatment was -0.7 (95% CI: -4.1, 2.8) in the flexible dose study and -0.8 (95% CI: -3.9, 2.3) for the primary analysis in the fixed dose study. The following adverse reactions were reported in frequencies of at least 5% of pediatric patients treated with AUSTEDO and with a greater incidence than in pediatric patients receiving placebo (AUSTEDO vs placebo): headache (includes: migraine, migraine with aura, and headache; 13% vs 9%), somnolence (includes: sedation, hypersomnia, and somnolence …

12.1 Mechanism of Action The precise mechanism by which deutetrabenazine exerts its effects in the treatment of tardive dyskinesia and chorea in patients with Huntington’s disease 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. The major circulating metabolites (α-dihydrotetrabenazine [HTBZ] and β-HTBZ) of deutetrabenazine, are reversible inhibitors of VMAT2, resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores.

11 DESCRIPTION AUSTEDO XR extended-release tablets and AUSTEDO tablets are formulated with deutetrabenazine, a vesicular monoamine transporter 2 (VMAT2) inhibitor for oral administration. The molecular weight of deutetrabenazine is 323.46; the pKa is 6.31. Deutetrabenazine is a hexahydro-dimethoxybenzoquinolizine derivative and has the following chemical name: ( RR, SS )-1, 3, 4, 6, 7, 11b-hexahydro-9, 10-di(methoxy-d 3 )-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one. The molecular formula for deutetrabenazine is C 19 H 21 D 6 NO 3 . Deutetrabenazine is a racemic mixture containing the following structures: Deutetrabenazine is a white to slightly yellow crystalline powder that is sparingly soluble in water and soluble in ethanol. AUSTEDO XR AUSTEDO XR extended-release tablets contain 6 mg, 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, or 48 mg deutetrabenazine, and the following inactive ingredients: ammonium hydroxide, black iron oxide, butyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, cellulose acetate, hydroxypropyl cellulose, hypromellose, isopropyl alcohol, magnesium stearate, polyethylene glycol, polyethylene glycol 3350, polyethylene oxide, polyvinyl alcohol, propylene glycol, shellac, sodium chloride, talc, titanium dioxide, and FD&C red #40 lake. The 6 mg, 12 mg, 18 mg, 30 mg, 36 mg, and 42 mg extended-release tablets also contain FD&C yellow #6 lake. The 6 mg, 12 mg, 24 mg, and 36 mg extended-release tablets also contain FD&C blue #2 lake. The 18 mg extended-release tablets also contain carmine. AUSTEDO XR Delivery System Components and Performance AUSTEDO XR uses osmotic pressure to deliver deutetrabenazine at a controlled rate. The delivery system, which resembles a round tablet in appearance, consists of a bilayer core tablet that contains deutetrabenazine along with other excipients. The biologically inert components of the tablet remain intact during gastrointestinal transit and are eliminated in the stool. AUSTEDO AUSTEDO tablets contain 6 mg, 9 mg, or 12 mg deutetrabenazine, and the following inactive ingredients: ammonium hydroxide, black iron oxide, butyl alcohol, butylated hydroxyanisole, butylated hydroxytoluene, magnesium stearate, mannitol, microcrystalline cellulose, polyethylene glycol, polyethylene oxide, polysorbate 80, polyvinyl alcohol, povidone, propylene glycol, shellac, talc, titanium dioxide, and FD&C blue #2 lake. The 6 mg tablets also contain FD&C red #40 lake. The 12 mg tablets also contain FD&C yellow #6 lake. chemical-structure.jpg

10 OVERDOSAGE Overdoses ranging from 100 mg to 1 g have been reported in the literature with tetrabenazine, a closely related VMAT2 inhibitor. The following adverse reactions occurred with overdosing: 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 central nervous system-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 on the American Association of Poison Control Centers website www.aapcc.org.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied AUSTEDO XR extended-release tablets are supplied in the following configurations: Strength Description Package Configuration NDC Code 6 mg Round, grey-coated tablets, with “Q6” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-470-56 12 mg Round, blue-coated tablets, with “Q12” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-471-56 18 mg Round, light grey-coated tablets, with “Q18” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-479-56 24 mg Round, purple-coated tablets, with “Q24” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-472-56 30 mg Round, light orange-coated tablets, with “Q30” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-473-56 36 mg Round, light purple-coated tablets, with “Q36” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-474-56 42 mg Round, orange-coated tablets, with “Q42” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-475-56 48 mg Round, pink-coated tablets, with “Q48” printed in black ink on one side Bottle with child-resistant cap / 30 count 68546-476-56 AUSTEDO XR Patient Titration Kits are supplied in the following configuration: Strength Description Package Configuration NDC Code 4-Week Patient Titration Kit 12 mg Round, blue-coated tablets, with “Q12” printed in black ink on one side Titration Kit / 28 count Each Titration Kit contains 1 child-resistant blister pack, containing one foil card with extended-release tablets in the following configuration: Seven 12 mg tablets taken during Week 1; seven 18 mg tablets taken during Week 2; seven 24 mg tablets taken during Week 3; and seven 30 mg tablets taken during Week 4. 68546-477-29 18 mg Round, light grey-coated tablets, with “Q18” printed in black ink on one side 24 mg Round, purple-coated tablets, with “Q24” printed in black ink on one side 30 mg Round, light orange-coated tablets, with “Q30” printed in black ink on one side AUSTEDO tablets are supplied in the following configurations: Strength Description Package Configuration NDC Code 6 mg Round, purple-coated tablets, with “SD” over “6” printed in black ink on one side Bottle with child-resistant cap / 60 count 68546-170-60 9 mg Round, blue-coated tablets, with “SD” over “9” printed in black ink on one side Bottle with child-resistant cap / 60 count 68546-171-60 12 mg Round, beige-coated tablets, with “SD” over “12” printed in black ink on one side Bottle with child-resistant cap / 60 count 68546-172-60 16.2 Storage Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature] . Protect from light and moisture. Dispense in original containers or in tight containers as defined in USP.