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Warning

WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease. Anyone considering the use of AUSTEDO must balance the risks of depression and suicidality with the clinical need for treatment of chorea. Closely monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior. 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. AUSTEDO is contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression [see Contraindications (4) and Warnings and Precautions (5.1 )]. WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTON’S DISEASE See full prescribing information for complete boxed warning. Increases the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington’s disease (5.1) Balance risks of depression and suicidality with the clinical need for treatment of chorea when considering the use of AUSTEDO (5.1) Monitor patients for the emergence or worsening of depression, suicidality, or unusual changes in behavior (5.1) Inform patients, caregivers, and families of the risk of depression and suicidality and instruct to report behaviors of concern promptly to the treating physician (5.1) Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation (5.1) AUSTEDO is contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression (4, 5.1)

Recent Changes

Boxed Warning 08/2017
Indications and Usage (1) 08/2017
Dosage and Administration (2.1) 08/2017
Contraindications (4) 08/2017
Warnings and Precautions (5.1, 5.2, 5.3, 5.5, 5.7) 08/2017

Indications And Usage

AUSTEDO® is indicated for the treatment of: chorea associated with Huntington’s disease [see Clinical Studies (14.1)] tardive dyskinesia in adults [see Clinical Studies (14.2)] AUSTEDO is a vesicular monoamine transporter 2 (VMAT2) inhibitor indicated for the treatment of: Chorea associated with Huntington’s disease (1) Tardive dyskinesia in adults (1)

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Dosage And Administration

Initial Dose Recommended Dose Maximum Dose
Chorea associated with Huntington’s disease 6 mg/day 6 mg– 48 mg/day 48 mg/day
Tardive dyskinesia 12 mg/day 12 mg– 48 mg/day 48 mg/day

Dosage Forms And Strengths

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. Tablets: 6 mg, 9 mg, and 12 mg (3)

Contraindications

AUSTEDO is 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 [see Drug Interactions ( 7.3 )] . Taking monoamine oxidase inhibitors (MAOIs). AUSTEDO should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI [see Drug Interactions ( 7.4 )]. Taking tetrabenazine (XENAZINE®) or valbenazine [see Drug Interactions (7.7)]. 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 (XENAZINE®), or valbenazine (4, 7.3, 7.4, 7.7)

Warning and Cautions

QT Prolongation: May cause an increase in QT interval. 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 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, the risk of suicidality should be balanced against the need for treatment of chorea. All patients treated with AUSTEDO should be observed for new or worsening depression or suicidality. If depression or suicidality does not resolve, consider discontinuing treatment with AUSTEDO. Patients, their caregivers, and families should be informed of the risks of depression, worsening depression, and suicidality associated with 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, may cause a worsening in mood, cognition, rigidity, and functional capacity. Prescribers should periodically re-evaluate the need for 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. 5.3 QTc Prolongation Tetrabenazine, a closely related VMAT2 inhibitor, causes an increase (about 8 msec) in the corrected QT (QTc) interval. A clinically relevant QT prolongation may occur in some patients treated with AUSTEDO who are CYP2D6 poor metabolizers or are co-administered a strong CYP2D6 inhibitor [see Clinical Pharmacology ( 12.2 , 12.3 )]. For patients who are CYP2D6 poor metabolizers or are taking a strong CYP2D6 inhibitor, dose reduction may be necessary [see Dosage and Administration ( 2.3 , 2.4 )] . The use of AUSTEDO in combination with other drugs that are known to prolong QTc may result in clinically significant QT prolongations [see Drug Interactions ( 7.2 )]. For patients requiring AUSTEDO doses greater than 24 mg per day who are using AUSTEDO with other drugs known to prolong QTc, assess the QTc interval before and after increasing the dose of AUSTEDO or other medications that are known to prolong QTc. AUSTEDO 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. 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, 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 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 AUSTEDO; (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 with resumption of drug therapy. If treatment with AUSTEDO is needed after recovery from NMS, patients should be monitored for signs of recurrence. 5.5 Akathisia, Agitation, and Restlessness AUSTEDO may increase the risk of akathisia, agitation, and restlessness in patients with Huntington’s disease and tardive dyskinesia. In a 12-week, double-blind, placebo-controlled trial in Huntington’s disease patients, akathisia, agitation, or restlessness was reported by 4% of patients treated with AUSTEDO, compared to 2% of patients on placebo; in patients with tardive dyskinesia, 2% of patients treated with AUSTEDO and 1% of patients on placebo experienced these events. Patients receiving AUSTEDO should be monitored for signs and symptoms of restlessness and agitation, as these may be indicators of developing akathisia. If a patient develops akathisia during treatment with AUSTEDO, the AUSTEDO dose should be reduced; some patients may require discontinuation of therapy. 5.6 Parkinsonism in Patients with Huntington’s Disease AUSTEDO may cause parkinsonism in patients with Huntington’s disease. Because rigidity can develop as part of the underlying disease process in Huntington’s disease, it may be difficult to distinguish between this potential 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 AUSTEDO, the AUSTEDO dose should be reduced; some patients may require discontinuation of therapy. 5.7 Sedation and Somnolence Sedation is a common dose-limiting adverse reaction of AUSTEDO. In a 12-week, double-blind, placebo-controlled trial examining patients with Huntington’s disease, 11% of AUSTEDO-treated patients reported somnolence compared with 4% of patients on placebo and 9% of AUSTEDO-treated patients reported fatigue compared with 4% of placebo-treated patients. 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 AUSTEDO and know how the drug affects them. 5.8 Hyperprolactinemia Serum prolactin levels were not evaluated in the AUSTEDO development program. Tetrabenazine, a closely related VMAT2 inhibitor, elevates serum prolactin concentrations in humans. Following administration of 25 mg of tetrabenazine 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 AUSTEDO 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 AUSTEDO or tetrabenazine development programs) 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 AUSTEDO. 5.9 Binding to Melanin-Containing Tissues Since deutetrabenazine or its metabolites bind to melanin-containing tissues, it could accumulate in these tissues over time. This raises the possibility that AUSTEDO 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 deutetrabenazine’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 [see Clinical Pharmacology (12.2)].

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 in Patients with Huntington’s disease [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. Patients with Huntington’s Disease Study 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 2. Table 2: 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). 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 tardive dyskinesia (Study 1 and Study 2) are summarized in Table 3. Table 3: Adverse Reactions in 2 Placebo-Controlled Tardive Dyskinesia Studies (Study 1 and Study 2) of 12-week Treatment on AUSTEDO Reported in at Least 2% of Patients and Greater than Placebo Preferred Term AUSTEDO (N=279) (%) Placebo (N=131) (%) Nasopharyngitis 4 2 Insomnia 4 1 Depression/ Dysthymic disorder 2 1 Akathisia/Agitation/Restlessness 2 1 One or more adverse reactions resulted in a reduction of the dose of study medication in 4% of AUSTEDO-treated patients and in 2% of placebo-treated patients.

Drug Interactions

Concomitant use of strong CYP2D6 inhibitors: Maximum recommended dose of AUSTEDO is 36 mg per day (18 mg twice daily) (2.3, 7.1) Alcohol or other sedating drugs: May have additive sedation and somnolence (7.6) 7.1 Strong CYP2D6 Inhibitors A reduction in AUSTEDO dose may be necessary when adding a strong CYP2D6 inhibitor in patients maintained on a stable dose of 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 should not exceed 36 mg per day, and the maximum single dose of AUSTEDO should not exceed 18 mg in patients taking strong CYP2D6 inhibitors [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3)]. 7.2 Drugs that Cause QTc Prolongation Tetrabenazine, a closely related VMAT2 inhibitor, may cause an increase in the corrected QT (QTc) interval. Clinically relevant QT prolongation may also occur with AUSTEDO [see Warnings and Precautions (5.3), Clinical Pharmacology (12.2)]. For patients requiring AUSTEDO doses above 24 mg per day, who are using AUSTEDO in combination with other drugs known to prolong QTc, assess the QTc interval before and after increasing the dose of AUSTEDO or other medications that are known to prolong QTc. Drugs known to prolong QTc include 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. 7.3 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 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. AUSTEDO and reserpine should not be used concomitantly [see Contraindications (4)]. 7.4 Monoamine Oxidase Inhibitors (MAOIs) AUSTEDO is contraindicated in patients taking MAOIs. AUSTEDO should not be used in combination with an MAOI, or within 14 days of discontinuing therapy with an MAOI [see Contraindications (4)]. 7.5 Neuroleptic Drugs The risk of parkinsonism, NMS, and akathisia may be increased by concomitant use of AUSTEDO and dopamine antagonists or antipsychotics. 7.6 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)]. 7.7 Concomitant Tetrabenazine or Valbenazine AUSTEDO is contraindicated in patients currently taking tetrabenazine or valbenazine. AUSTEDO may be initiated the day following discontinuation of tetrabenazine [see Dosage and Administration (2.2)].

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 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/m2) 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 and any potential adverse effects on the breastfed infant from AUSTEDO or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of AUSTEDO did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of hepatic, renal, and cardiac dysfunction, and of concomitant disease or other drug therapy. 8.6 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of deutetrabenazine and its primary metabolites has not been studied; however, in a clinical study conducted with tetrabenazine, a closely related VMAT2 inhibitor, there was a large increase in exposure to tetrabenazine and its active metabolites in patients with hepatic impairment. The clinical significance of this increased exposure has not been assessed, but because of concerns for a greater risk for serious adverse reactions, the use of AUSTEDO in patients with hepatic impairment is contraindicated [see Contraindications (4), Clinical Pharmacology (12.3)]. 8.7 Poor CYP2D6 Metabolizers Although the pharmacokinetics of deutetrabenazine and its metabolites have not been systematically evaluated in patients who do not express the drug metabolizing enzyme, it is likely that the exposure to α-HTBZ and β-HTBZ would be increased similarly to taking a strong CYP2D6 inhibitor (approximately 3-fold). In patients who are CYP2D6 poor metabolizers, the daily dose of AUSTEDO should not exceed 36 mg (maximum single dose of 18 mg) [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3)].