AUSTEDO- deutetrabenazine_tablet, coated

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 (alpha-dihydrotetrabenazine [HTBZ] and beta-HTBZ) of deutetrabenazine, are reversible inhibitors of VMAT2, resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores. Cardiac Electrophysiology At the maximum recommended dose, AUSTEDO XR and AUSTEDO do not prolong the QT interval to any clinically relevant extent. An exposure-response analysis on QTc prolongation from a study in extensive or intermediate (EM) and poor CYP2D6 metabolizers (PM) showed that a clinically-relevant effect can be excluded at exposures following single doses of 24 and 48 mg of AUSTEDO. Melanin Binding Deutetrabenazine or its metabolites bind to melanin-containing tissues (i. , eye, skin, fur) in pigmented rats. After a single oral dose of radiolabeled deutetrabenazine, radioactivity was still detected in eye and fur at 35 days following dosing [see Warnings and Precautions ( 5. 9 After oral dosing, plasma concentrations of deutetrabenazine are low compared to that of the active deuterated metabolites because of the extensive hepatic metabolism of deutetrabenazine. AUSTEDO XR Systemic exposure (i. , peak plasma concentrations [C max AUSTEDO Systemic exposure (C max Absorption Following oral administration of deutetrabenazine, the extent of absorption is at least 80%. AUSTEDO XR Peak plasma concentrations (C max AUSTEDO Peak plasma concentrations (C max Effect of Food AUSTEDO XR The effects of food on the bioavailability of AUSTEDO XR were studied in subjects administered a single dose with and without food. Food had no effect on C max [see Dosage and Administration ( 2. 1 AUSTEDO The effects of food on the bioavailability of AUSTEDO were studied in subjects administered a single dose with and without food. Food had no effect on AUC of alpha-HTBZ or beta-HTBZ, although C max [see Dosage and Administration ( 2. 1 Distribution The median volume of distribution (Vc/F) of the alpha-HTBZ, and the beta-HTBZ metabolites of deutetrabenazine are approximately 500 L and 730 L, respectively. Results of PET-scan studies in humans show that following intravenous injection of 11 The protein binding of deutetrabenazine and deuterated alpha-HTBZ and beta-HTBZ in human plasma at the concentration of 0. 1 µM is 82%, 57%, and 49% respectively, with no preferential binding of drug-related total radioactivity to the cellular components of human blood. Elimination AUSTEDO XR and AUSTEDO are primarily renally eliminated in the form of metabolites. The half-life of the active deuterated alpha-HTBZ, beta-HTBZ, and total (alpha+beta)-HTBZ metabolites is approximately 12 hours, 7. 5 hours, and 9 to 11 hours, respectively. The clearance values (CL/F) of the alpha-HTBZ, and beta-HTBZ metabolites of AUSTEDO are approximately 65 L/hour and 200 L/hour, respectively, for a 70 kg HD or TD patient with functional CYP2D6 metabolism in the fed state. The elimination half-life and clearance of AUSTEDO XR are similar to that of AUSTEDO. Metabolism In vitro Excretion In a mass balance study in 6 healthy subjects, 75% to 86% of the deutetrabenazine dose was excreted in the urine, and fecal recovery accounted for 8% to 11% of the dose. Urinary excretion of the alpha-HTBZ and beta-HTBZ metabolites from deutetrabenazine each accounted for less than 10% of the administered dose. Sulfate and glucuronide conjugates of the alpha-HTBZ and beta-HTBZ metabolites of deutetrabenazine, as well as products of oxidative metabolism, accounted for the majority of metabolites in the urine. Specific Populations Male and Female Patients There is no apparent effect of gender on the pharmacokinetics of alpha-HTBZ and beta‑HTBZ of deutetrabenazine. Patients with Renal Impairment No clinical studies have been conducted to assess the effect of renal impairment on the PK of deutetrabenazine and its primary metabolites. Patients with 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 to assess the effect of hepatic impairment on the pharmacokinetics of tetrabenazine, a closely related VMAT2 inhibitor, the exposure to alpha-HTBZ and beta-HTBZ was up to 40% greater in patients with hepatic impairment, and the mean tetrabenazine C max [see Contraindications ( 4 8. 6 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 CYP2D6, it is likely that the exposure to alpha-HTBZ and beta-HTBZ would be increased similarly to taking strong CYP2D6 inhibitors (approximately 3-fold) [see Dosage and Administration ( 2. 1 Drug Interaction Studies Effect of Other Drugs on AUSTEDO/AUSTEDO XR CYP2D6 Inhibitors In vitro inf inf max [see Drug Interactions ( 7. 1 The effect of moderate or weak CYP2D6 inhibitors such as duloxetine, terbinafine, amiodarone, or sertraline on the exposure of deutetrabenazine and its metabolites has not been evaluated. Transporters In vitro Effect of AUSTEDO/AUSTEDO XR on Other Drugs CYP Enzymes In vitro Transporters In vitro Minor Metabolites The deutetrabenazine metabolites, 2-methylpropanoic acid of beta-HTBZ (M1) and monohydroxy tetrabenazine (M4), have been evaluated in a panel of in vitro.

AUSTEDO XR registered registered 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.

AUSTEDO XR AUSTEDO Recommended Starting Dosage 12 mg once daily 6 mg twice daily 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. 7 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 AUSTEDO Recommended Starting Dosage 12 mg once daily 6 mg twice daily 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. 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. 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. 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 Initial regimen of AUSTEDO XR extended-release tablet Initial regimen of 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 In patients receiving strong CYP2D6 inhibitors, the total daily dosage of AUSTEDO XR or AUSTEDO should not exceed 36 mg [see Drug Interactions ( 7. 3 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 Treatment with AUSTEDO XR or AUSTEDO can be discontinued without tapering. Following treatment interruption of greater than one week, AUSTEDO XR or AUSTEDO therapy should be re-titrated when resumed. For treatment interruption of less than one week, treatment can be resumed at the previous maintenance dose without titration.

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. gov/medwatch 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 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 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 4. Table 4: 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 Adverse Reaction AUSTEDO Placebo 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.

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. 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. 3 Taking reserpine, MAOIs, tetrabenazine, or valbenazine ( 4 7.

Pregnancy: Based on animal data, may cause fetal harm ( 8. 1 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]. 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 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. 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. 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. 8) in the flexible dose study and -0. 8 (95% CI: -3. 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; 11% vs 2%), fatigue (8% vs 3%), increased appetite (5% vs <1%), and increased weight (5% vs <1%). Juvenile Animal Toxicity Data Deutetrabenazine orally administered to juvenile rats from postnatal days 21 through 70 (at 2. 5, 5, or 10 mg/kg/day) resulted in an increased incidence of tremor, hyperactivity, and adverse increases in motor activity at >=5 mg/kg/day, and reduced body weight and food consumption at 10 mg/kg/day. There was no reproductive or early embryonic toxicity up to the highest dose. All drug-related findings were reversible after a drug-free period. The no observed adverse effect level (NOAEL) in juvenile rats was 2. 5 mg/kg/day. These drug-related findings were similar to those observed in adult rats; however, the juvenile rats were more sensitive. Clinical studies of AUSTEDO XR and 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. 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 XR or AUSTEDO in patients with hepatic impairment is contraindicated [see Contraindications ( 4 12. 3 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 alpha-HTBZ and beta-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 XR or AUSTEDO should not exceed 36 mg [see Dosage and Administration ( 2.

Concomitant use of strong CYP2D6 inhibitors: Maximum recommended dose of AUSTEDO XR or AUSTEDO is 36 mg per day ( 2. 1 Alcohol or other sedating drugs: May have additive sedation and somnolence ( 7. 5 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. , 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 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 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 The risk of parkinsonism, NMS, and akathisia may be increased by concomitant use of AUSTEDO XR or AUSTEDO with dopamine antagonists or antipsychotics. Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence [see Warnings and Precautions ( 5. 7 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.

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.
NONCLINICAL TOXICOLOGY
Carcinogenesis No carcinogenicity studies were performed with deutetrabenazine. No increase in tumors was observed in p53 +/en dash Mutagenesis Deutetrabenazine and its deuterated alpha-HTBZ and beta-HTBZ metabolites were negative in in vitro in vivo Impairment of Fertility The effects of deutetrabenazine on fertility have not been evaluated. Oral administration of deutetrabenazine (doses of 5, 10, or 30 mg/kg/day) to female rats for 3 months resulted in estrous cycle disruption at all doses; the lowest dose tested was similar to the maximum recommended human dose (48 mg/day) on a body surface area (mg/m 2 Oral administration of tetrabenazine (doses of 5, 15, or 30 mg/kg/day) to female rats prior to and throughout mating, and continuing through day 7 of gestation, resulted in disrupted estrous cyclicity at doses greater than 5 mg/kg/day. No effects on mating and fertility indices or sperm parameters (motility, count, density) were observed when males were treated orally with tetrabenazine at doses of 5, 15 or 30 mg/kg/day prior to and throughout mating with untreated females.
CLINICAL STUDIES
The studies described below establishing effectiveness for Huntington’s disease and tardive dyskinesia were conducted with AUSTEDO tablets. The efficacy of AUSTEDO XR is based on a relative bioavailability study comparing AUSTEDO XR tablets administered once daily and AUSTEDO tablets administered twice daily [see Clinical Pharmacology ( 12. 3 The efficacy of AUSTEDO as a treatment for chorea associated with Huntington''s disease was established primarily in Study 1, a randomized, double-blind, placebo-controlled, multi-center trial conducted in 90 ambulatory patients with manifest chorea associated with Huntington’s disease. The diagnosis of Huntington’s disease was based on family history, neurological exam, and genetic testing. Treatment duration was 12 weeks, including an 8-week dose titration period and a 4-week maintenance period, followed by a 1-week washout. Patients were not blinded to discontinuation. AUSTEDO was started at 6 mg per day and titrated upward, at weekly intervals, in 6 mg increments until satisfactory treatment of chorea was achieved, intolerable side effects occurred, or until a maximal dose of 48 mg per day was reached. The primary efficacy endpoint was the Total Maximal Chorea Score, an item of the Unified Huntington''s Disease Rating Scale (UHDRS). On this scale, chorea is rated from 0 to 4 (with 0 representing no chorea) for 7 different parts of the body. The total score ranges from 0 to 28. Of the 90 patients enrolled, 87 patients completed the study. The mean age was 54 (range 23 to 74). Patients were 56% male and 92% Caucasian. The mean dose after titration was 40 mg per day. Table 5 and Figure 1 summarize the effects of AUSTEDO on chorea based on the Total Maximal Chorea Score. Total Maximal Chorea Scores for patients receiving AUSTEDO improved by approximately 4. 4 units from baseline to the maintenance period (average of Week 9 and Week 12), compared to approximately 1. 9 units in the placebo group. The treatment effect of -2. 5 units was statistically significant (p<0. The Maintenance Endpoint is the mean of the Total Maximal Chorea Scores for the Week 9 and Week 12 visits. At the Week 13 follow-up visit (1 week after discontinuation of the study medication), the Total Maximal Chorea Scores of patients who had received AUSTEDO returned to baseline (Figure 1). Table 5: Change from Baseline to Maintenance Therapy in Total Maximal Chorea (TMC) * Motor Endpoint AUSTEDO Placebo p value Change in Total Chorea Score * from Baseline to Maintenance Therapy dagger -4. 0001 * dagger Figure 1: Total Maximal Chorea Score Over Time in Study 1 Figure 2: Distribution of the Change in Total Maximal Chorea Scores in Study 1 Figure 2 shows the distribution of values for the change in Total Maximal Chorea Score in Study 1. Negative values indicate a reduction in chorea and positive numbers indicate an increase in chorea. A patient-rated global impression of change assessed how patients rated their overall Huntington’s disease symptoms. Fifty-one percent of patients treated with AUSTEDO rated their symptoms as “Much Improved” or “Very Much Improved” at the end of treatment, compared to 20% of placebo-treated patients. In a physician-rated clinical global impression of change, physicians rated 42% percent of patients treated with AUSTEDO as “Much Improved” or “Very Much Improved” at the end of treatment compared to 13% of placebo-treated patients. jpg figure-02. jpg The efficacy of AUSTEDO in the treatment for tardive dyskinesia was established in two 12‑week, randomized, double-blind, placebo-controlled, multi-center trials conducted in 335 adult ambulatory patients with tardive dyskinesia caused by use of dopamine receptor antagonists. Patients had a history of using a dopamine receptor antagonist (antipsychotics, metoclopramide) for at least 3 months (or 1 month in patients 60 years of age and older). Concurrent diagnoses included schizophrenia/schizoaffective disorder (62%) and mood disorder (33%). With respect to concurrent antipsychotic use, 64% of patients were receiving atypical antipsychotics, 12% were receiving typical or combination antipsychotics, and 24% were not receiving antipsychotics. The Abnormal Involuntary Movement Scale (AIMS) was the primary efficacy measure for the assessment of tardive dyskinesia severity. The AIMS is a 12-item scale; items 1 to 7 assess the severity of involuntary movements across body regions and these items were used in this study. Each of the 7 items was scored on a 0 to 4 scale, rated as: 0=not present; 1=minimal, may be extreme normal (abnormal movements occur infrequently and/or are difficult to detect); 2=mild (abnormal movements occur infrequently and are easy to detect); 3=moderate (abnormal movements occur frequently and are easy to detect) or 4 =severe (abnormal movements occur almost continuously and/or of extreme intensity). The AIMS total score (sum of items 1 to 7) could thus range from 0 to 28, with a decrease in score indicating improvement. In Study 1, a 12-week, placebo-controlled, fixed-dose trial, adults with tardive dyskinesia were randomized 1:1:1:1 to 12 mg AUSTEDO, 24 mg AUSTEDO, 36 mg AUSTEDO, or placebo. Treatment duration included a 4-week dose escalation period and an 8-week maintenance period followed by a 1-week washout. The dose of AUSTEDO was started at 12 mg per day and increased at weekly intervals in 6 mg/day increments to a dose target of 12 mg, 24 mg or 36 mg per day. The population (n= 222) was 21 to 81 years old (mean 57 years), 48% male, and 79% Caucasian. In Study 1, the AIMS total score for patients receiving AUSTEDO demonstrated statistically significant improvement, from baseline to Week 12, of 3. 2 units for the 36 mg and 24 mg arms, respectively, compared with 1. 4 units in placebo (Study 1 in Table 6). The improvements on the AIMS total score over the course of the study are displayed in Figure 3. Data did not suggest substantial differences in efficacy across various demographic groups. The treatment response rate distribution, based on magnitude of AIMS total score from baseline to week 12 is displayed in Figure 4. The mean changes in the AIMS total score by visit are shown in Figure 3. In Study 2, a 12-week, placebo-controlled, flexible-dose trial, adults with tardive dyskinesia (n=113) received daily doses of placebo or AUSTEDO, starting at 12 mg per day with increases allowed in 6-mg increments at 1-week intervals until satisfactory control of dyskinesia was achieved, until intolerable side effects occurred, or until a maximal dose of 48 mg per day was reached. Treatment duration included a 6-week dose titration period and a 6-week maintenance period followed by a 1-week washout. The population was 25 to 75 years old (mean 55 years), 48% male, and 70% Caucasian. Patients were titrated to an optimal dose over 6 weeks. The average dose of AUSTEDO after treatment was 38. 3 mg per day. There was no evidence suggesting substantial differences in efficacy across various demographic groups. In Study 2, AIMS total score for patients receiving AUSTEDO demonstrated statistically significant improvement by 3. 0 units from baseline to endpoint (Week 12), compared with 1. 6 units in the placebo group with a treatment effect of -1. Table 6 summarizes the effects of AUSTEDO on tardive dyskinesia based on the AIMS. Table 6: Improvement in AIMS Total Score in Patients Treated with AUSTEDO in Study 1 and Study 2 Study Treatment Group Primary Efficacy Measure: AIMS Total Score Mean Baseline Score (SD) LS Mean Change from Baseline (SE) Treatment Effect (95% CI) Study 1 AUSTEDO 36 mg* (n= 55) 10. 79) AUSTEDO 24 mg (n= 49) 9. 63) AUSTEDO 12 mg (n= 60) 9. 42) Placebo (n= 58) 9. 41) Study 2 AUSTEDO (12-48 mg/day)* (n= 56) 9. 2) Placebo (n= 57) 9. 46) *Dose that was statistically significantly different from placebo after adjusting for multiplicity. LS Mean = Least-squares mean; SD = Standard deviation; SE = Standard error; CI = 2-sided 95% confidence interval Figure 3: Least Square Means of Change in AIMS Total Score from Baseline for AUSTEDO Compared to Placebo (Study 1) SE = Standard error Figure 4: Percent of Patients with Specified Magnitude of AIMS Total Score Improvement at the End of Week 12 (Study 1) figure-03. jpg figure-04.
MEDICATION GUIDE
MEDICATION GUIDE AUSTEDO XR registered aw-STED-oh XR (deutetrabenazine) extended-release tablets, for oral use AUSTEDO registered aw-STED-oh (deutetrabenazine) tablets, for oral use What is the most important information I should know about AUSTEDO XR and AUSTEDO? AUSTEDO XR and AUSTEDO can cause serious side effects in people with Huntington’s disease, including: depression suicidal thoughts suicidal actions Do not start taking AUSTEDO XR or AUSTEDO if you have Huntington’s disease and are depressed (have untreated depression or depression that is not well controlled by medicine) or Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is especially important when AUSTEDO XR or AUSTEDO is started and when the dose is changed. Call your healthcare provider right away if you become depressed or have any of the following symptoms, especially if they are new, worse, or worry you: feel sad or have crying spells lose interest in seeing your friends or doing things you used to enjoy sleep a lot more or a lot less than usual feel unimportant feel guilty feel hopeless or helpless feel more irritable, angry, or aggressive than usual feel more or less hungry than usual or notice a big change in your body weight have trouble paying attention feel tired or sleepy all the time have thoughts about hurting yourself or ending your life What are AUSTEDO XR and AUSTEDO? AUSTEDO XR and AUSTEDO are prescription medicines that are used to treat: the involuntary movements (chorea) of Huntington’s disease. AUSTEDO XR and AUSTEDO do not cure the cause of the involuntary movements, and it does not treat other symptoms of Huntington’s disease, such as problems with thinking or emotions. movements in the face, tongue, or other body parts that cannot be controlled (tardive dyskinesia). It is not known if AUSTEDO XR and AUSTEDO are safe and effective in children. Who should not take AUSTEDO XR or AUSTEDO? Do not take AUSTEDO XR or AUSTEDO if you: have Huntington’s disease and are depressed or have thoughts of suicide. See “ What is the most important information I should know about AUSTEDO XR and AUSTEDO? have liver problems. are taking reserpine. Do not are taking a monoamine oxidase inhibitor (MAOI) medicine. Do not Do not are taking tetrabenazine. If your healthcare provider plans to switch you from tetrabenazine to AUSTEDO XR or AUSTEDO, take your first dose of AUSTEDO XR or AUSTEDO on the day after your last dose of tetrabenazine. are taking valbenazine. Before taking AUSTEDO XR or AUSTEDO, tell your healthcare provider about all of your medical conditions, including if you: have emotional or mental problems (for example, depression, nervousness, anxiety, anger, agitation, psychosis, previous suicidal thoughts or suicide attempts). have liver disease. have an irregular heart rhythm or heartbeat (QT prolongation, cardiac arrhythmia) or a heart problem called congenital long QT syndrome. have low levels of potassium or magnesium in your blood (hypokalemia or hypomagnesemia). have breast cancer or a history of breast cancer. are pregnant or plan to become pregnant. It is not known if AUSTEDO XR or AUSTEDO can harm your unborn baby. are breastfeeding or plan to breastfeed. It is not known if AUSTEDO XR or AUSTEDO passes into breast milk. Tell your healthcare provider about all of the medicines you take Taking AUSTEDO XR or AUSTEDO with certain other medicines may cause side effects. Do not start any new medicines while taking AUSTEDO XR or AUSTEDO without talking to your healthcare provider first. How should I take AUSTEDO XR or AUSTEDO? Take AUSTEDO XR or AUSTEDO exactly as your healthcare provider tells you to take it. If you take AUSTEDO XR, take your dose by mouth one time each day, with or without food. If you take AUSTEDO, take your dose by mouth and with food. If your dose of AUSTEDO is 12 mg or more each day, take AUSTEDO tablets 2 times a day in equal doses. Swallow AUSTEDO XR or AUSTEDO tablets whole with water. Do not chew, crush, or break AUSTEDO XR or AUSTEDO tablets before swallowing. If you cannot swallow AUSTEDO XR or AUSTEDO tablets whole, tell your healthcare provider. You may need a different medicine. The AUSTEDO XR tablet shell does not dissolve completely in the body after all the medicine has been released. Sometimes the tablet shell may be seen in your stool. This is normal. Your healthcare provider may increase your dose of AUSTEDO XR or AUSTEDO each week for several weeks, until you and your healthcare provider find the right dose for you. Tell your healthcare provider if you stop taking AUSTEDO XR or AUSTEDO for more than 1 week. Do not take another dose until you talk to your healthcare provider. What should I avoid while taking AUSTEDO XR or AUSTEDO? Sleepiness (sedation) is a common side effect of AUSTEDO XR and AUSTEDO. While taking AUSTEDO XR or AUSTEDO, do not drive a car or operate dangerous machinery until you know how AUSTEDO XR or AUSTEDO affects you. Drinking alcohol and taking other drugs that may also cause sleepiness while you are taking AUSTEDO XR or AUSTEDO may increase any sleepiness caused by AUSTEDO XR and AUSTEDO. What are the possible side effects of AUSTEDO XR and AUSTEDO? AUSTEDO XR and AUSTEDO can cause serious side effects, including: Depression and suicidal thoughts or actions in people with Huntington’s disease. What is the most important information I should know about AUSTEDO XR and AUSTEDO? Irregular heartbeat (QT prolongation). Neuroleptic Malignant Syndrome (NMS). high fever problems thinking increased sweating stiff muscles very fast or uneven heartbeat Restlessness. Parkinsonism. The most common side effects of AUSTEDO in people with Huntington’s disease include: sleepiness (sedation) diarrhea tiredness dry mouth The most common side effects of AUSTEDO in people with tardive dyskinesia include: inflammation of the nose and throat (nasopharyngitis) problems sleeping (insomnia) The most common side effects of AUSTEDO XR are expected to be similar to AUSTEDO in people with Huntington''s disease or tardive dyskinesia. These are not all the possible side effects of AUSTEDO XR or AUSTEDO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store AUSTEDO XR and AUSTEDO? Store AUSTEDO XR and AUSTEDO tablets at room temperature between 68°F to 77°F (20°C to 25°C). Keep the bottle tightly closed to protect AUSTEDO XR and AUSTEDO from light and moisture. Do not throw away the desiccant canister in the bottle until the last dose of AUSTEDO XR or AUSTEDO is taken. Keep AUSTEDO XR and AUSTEDO and all medicines out of the reach of children. General information about the safe and effective use of AUSTEDO XR and AUSTEDO. Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use AUSTEDO XR or AUSTEDO for a condition for which it was not prescribed. Do not give AUSTEDO XR or AUSTEDO to other people, even if they have the same symptoms you have. It may harm them. You can ask your pharmacist or healthcare provider for information about AUSTEDO XR and AUSTEDO that is written for health professionals. What are the ingredients in AUSTEDO XR and AUSTEDO? AUSTEDO XR: Active ingredient: Inactive ingredients: AUSTEDO: Active ingredient: Inactive ingredients: Manufactured for: Teva Neuroscience, Inc. copyright AUSMG-011 For more information, go to www.AUSTEDO.com or call 1-888-483-8279. This Medication Guide has been approved by the U.S. Food and Drug Administration. Revised: February 2025

AUSTEDO- deutetrabenazine

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