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…

5 WARNINGS AND PRECAUTIONS QT Prolongation: Avoid use in patients with congenital long QT syndrome or with arrhythmias associated with a prolonged QT interval ( 5.3 ) Neuroleptic Malignant Syndrome (NMS): Discontinue if this occurs ( 5.4 ) Akathisia, agitation, restlessness, and parkinsonism: Reduce dose or discontinue if this occurs ( 5.5 , 5.6 ) Sedation/somnolence: May impair the patient’s ability to drive or operate complex machinery ( 5.7 ) 5.1 Depression and Suicidality in Patients with Huntington’s Disease Patients with Huntington’s disease are at increased risk for depression, and suicidal ideation or behaviors (suicidality). AUSTEDO XR and AUSTEDO may increase the risk for suicidality in patients with Huntington’s disease. In a 12-week, double-blind, placebo-controlled trial, suicidal ideation was reported by 2% of patients treated with AUSTEDO, compared to no patients on placebo; no suicide attempts and no completed suicides were reported. Depression was reported by 4% of patients treated with AUSTEDO. When considering the use of AUSTEDO XR or AUSTEDO, the risk of suicidality should be balanced against the need for treatment of chorea. All patients treated with AUSTEDO XR or AUSTEDO should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with AUSTEDO XR or AUSTEDO. Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with AUSTEDO XR and AUSTEDO, and should be instructed to report behaviors of concern promptly to the treating physician. Patients with Huntington’s disease who express suicidal ideation should be evaluated immediately. 5.2 Clinical Worsening and Adverse Events in Patients with Huntington’s Disease Huntington’s disease is a progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time. VMAT2 inhibitors, including AUSTEDO XR and AUSTEDO, may cause a worsening in mood, cognition, rigidity, and functional capacity. Prescribers should periodically re-evaluate the need for AUSTEDO XR or AUSTEDO in their patients by assessing the effect on chorea and possible adverse effects, including sedation/somnolence, depression and suicidality, parkinsonism, akathisia, restlessness, and cognitive decline. 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 to distinguish between the two possibilities. In some patients, the underlying chorea itself may improve over time, decreasing the need for AUSTEDO XR or AUSTEDO. 5.3 QTc Prolongation AUSTEDO XR and AUSTEDO may prolong the QT interval, but the degree of QT prolongation is not clinically significant when AUSTEDO XR or AUSTEDO is administered within the recommended dosage range [see Clinical Pharmacology (12.2)] . AUSTEDO XR and AUSTEDO should 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. 5.4 Neuroleptic Malignant Syndrome (NMS) A potentially fatal symptom complex sometimes referred to as Neuroleptic Malignant Syndrome (NMS) has been reported in association with drugs that reduce dopaminergic transmission. While NMS has not been observed in patients receiving AUSTEDO XR or AUSTEDO, it has been observed in patients receiving tetrabenazine (a closely related VMAT2 inhibitor). Clinicians should be alerted to the signs and symptoms associated with NMS. Clinical manifestations of NMS are hyperpyrexia, muscle rigidit…

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 )

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 )].

8.1 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.

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…