HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. AUSTEDO tablets are available in the following strengths and packages:6 mg: round, purple-coated tablets, with SD over 6 printed in black ink on one side.Bottles of 60 tablets: NDC 68546-170-60.9 mg: round, blue-coated tablets, with SD over 9 printed in black ink on one side.Bottles of 60 tablets: NDC 68546-171-60.12 mg: round, beige-coated tablets, with SD over 12 printed in black ink on one side.Bottles of 60 tablets: NDC 68546-172-60.. 16.2 Storage. Store at 25oC (77oF); excursions permitted to 15oC to 30oC (59oF to 86oF) [see USP Controlled Room Temperature]. Protect from light and moisture.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. AUSTEDO(R) is indicated in adults for the treatment of:chorea associated with Huntingtons disease [see Clinical Studies (14.1)] tardive dyskinesia [see Clinical Studies (14.2)] chorea associated with Huntingtons disease [see Clinical Studies (14.1)] tardive dyskinesia [see Clinical Studies (14.2)] AUSTEDO is vesicular monoamine transporter (VMAT2) inhibitor indicated in adults for the treatment of:Chorea associated with Huntingtons disease (1)Tardive dyskinesia (1). Chorea associated with Huntingtons disease (1). Tardive dyskinesia (1).

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyAt the maximum recommended dose, AUSTEDO does not prolong the QT interval to any clinically relevant extent. An exposure-response analysis on QTc prolongation from study in extensive or intermediate (EM) and poor CYP2D6 metabolizers (PM) showed that clinically-relevant effect can be excluded at exposures following single doses of 24 and 48 mg of AUSTEDO.Melanin BindingDeutetrabenazine or its metabolites bind to melanin-containing tissues (i.e., eye, skin, fur) in pigmented rats. After 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)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. After oral dosing up to 25 mg, plasma concentrations of deutetrabenazine are generally below the limit of detection because of the extensive hepatic metabolism of deutetrabenazine to the active deuterated dihydro metabolites (HTBZ), -HTBZ and -HTBZ. Linear dose dependence of Cmax and AUC was observed for the active metabolites following single or multiple doses of deutetrabenazine (6 mg to 24 mg and 7.5 mg twice daily to 22.5 mg twice daily). AbsorptionFollowing oral administration of deutetrabenazine, the extent of absorption is at least 80%. Plasma concentrations of deutetrabenazine are generally below the limit of detection after oral dosing. Peak plasma concentrations (Cmax) of deuterated -HTBZ and -HTBZ are reached within to hours after dosing. Effect of FoodThe effects of food on the bioavailability of AUSTEDO were studied in subjects administered single dose with and without food. Food had no effect on the area under the plasma concentration-time curve (AUC) of -HTBZ or -HTBZ, although Cmax was increased by approximately 50% in the presence of food [see Dosage and Administration (2.1)]. DistributionThe median volume of distribution (Vc/F) of the -HTBZ, and the -HTBZ metabolites of AUSTEDO are approximately 500 and 730 L, respectively. Results of PET-scan studies in humans show that following intravenous injection of 11C-labeled tetrabenazine or -HTBZ, radioactivity is rapidly distributed to the brain, with the highest binding in the striatum and lowest binding in the cortex.The in vitro protein binding of tetrabenazine, -HTBZ, and -HTBZ was examined in human plasma for concentrations ranging from 50 to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, -HTBZ binding ranged from 60% to 68%, and -HTBZ binding ranged from 59% to 63%.EliminationAUSTEDO is primarily renally eliminated in the form of metabolites.The half-life of total (+)-HTBZ from deutetrabenazine is approximately to 10 hours.The median clearance values (CL/F) of the -HTBZ, and the -HTBZ metabolites of AUSTEDO are approximately 47 L/hour and 70 L/hour, respectively, in the Huntingtons disease patient population. MetabolismIn vitro experiments in human liver microsomes demonstrate that deutetrabenazine is extensively biotransformed, mainly by carbonyl reductase, to its major active metabolites, -HTBZ and -HTBZ, which are subsequently metabolized primarily by CYP2D6, with minor contributions of CYP1A2 and CYP3A4/5, to form several minor metabolites. ExcretionIn mass balance study in 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 -HTBZ and -HTBZ metabolites from deutetrabenazine each accounted for less than 10% of the administered dose. Sulfate and glucuronide conjugates of the -HTBZ and -HTBZ metabolites of deutetrabenazine, as well as products of oxidative metabolism, accounted for the majority of metabolites in the urine.Specific PopulationsMale and Female PatientsThere is no apparent effect of gender on the pharmacokinetics of -HTBZ and -HTBZ of deutetrabenazine.Patients with Renal ImpairmentNo clinical studies have been conducted to assess the effect of renal impairment on the PK of AUSTEDO. Patients with Hepatic ImpairmentThe effect of hepatic impairment on the pharmacokinetics of deutetrabenazine and its primary metabolites has not been studied. However, in clinical study conducted to assess the effect of hepatic impairment on the pharmacokinetics of tetrabenazine, closely related VMAT2 inhibitor, the exposure to -HTBZ and -HTBZ was up to 40% greater in patients with hepatic impairment, and the mean tetrabenazine Cmax in patients with hepatic impairment was up to 190-fold higher than in healthy subjects [see Contraindications (4), Use in Specific Populations (8.6)].Poor CYP2D6 MetabolizersAlthough 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 -HTBZ and -HTBZ would be increased similarly to taking strong CYP2D6 inhibitors (approximately 3-fold) [see Dosage and Administration (2.4), Drug Interactions (7.1)].Drug Interaction StudiesDeutetrabenazine, -HTBZ, and -HTBZ have not been evaluated in in vitro studies for induction or inhibition of CYP enzymes or interaction with P-glycoprotein. The results of in vitro studies of tetrabenazine do not suggest that tetrabenazine or its -HTBZ or -HTBZ metabolites are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. In vitro studies suggest that neither tetrabenazine nor its -HTBZ or -HTBZ metabolites are likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19. Neither tetrabenazine nor its -HTBZ or -HTBZ metabolites are likely to be substrate or inhibitor of P-glycoprotein at clinically relevant concentrations in vivo.The deutetrabenazine metabolites, 2-methylpropanoic acid of -HTBZ (M1) and monohydroxy tetrabenazine (M4), have been evaluated in panel of in vitro drug-drug interaction studies; the results indicate that M1/M4 are not expected to cause clinically relevant drug interactions.CYP2D6 InhibitorsIn vitro studies indicate that the -HTBZ and -HTBZ metabolites of deutetrabenazine are substrates for CYP2D6. The effect of CYP2D6 inhibition on the pharmacokinetics of deutetrabenazine and its metabolites was studied in 24 healthy subjects following single 22.5 mg dose of deutetrabenazine given after days of administration of the strong CYP2D6 inhibitor paroxetine 20 mg daily. In the presence of paroxetine, systemic exposure (AUCinf) of -HTBZ was 1.9-fold higher and -HTBZ was 6.5-fold higher, resulting in approximately 3-fold increase in AUCinf for total (+)-HTBZ. Paroxetine decreased the clearance of -HTBZ and -HTBZ metabolites of AUSTEDO with corresponding increases in mean half-life of approximately 1.5-fold and 2.7-fold, respectively. In the presence of paroxetine, Cmax of -HTBZ and -HTBZ were 1.2-fold and 2.2-fold higher, respectively.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.DigoxinAUSTEDO was not evaluated for interaction with digoxin. Digoxin is substrate for P-glycoprotein. study in healthy subjects showed that tetrabenazine (25 mg twice daily for days) did not affect the bioavailability of digoxin, suggesting that at this dose, tetrabenazine does not affect P-glycoprotein in the intestinal tract. In vitro studies also do not suggest that tetrabenazine or its metabolites are P-glycoprotein inhibitors.

ADVERSE REACTIONS SECTION.

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 Huntingtons 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)] Depression and Suicidality in Patients with Huntingtons 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 Huntingtons 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 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 Huntingtons DiseaseStudy was randomized, 12-week, placebo-controlled study in patients with chorea associated with Huntingtons disease. 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 greater incidence than in patients on placebo, are summarized in Table 2.Table 2: Adverse Reactions in Patients with Huntingtons Disease (Study 1) Experienced by at Least 4% of Patients on AUSTEDO and with Greater Incidence than on PlaceboAdverse ReactionAUSTEDO(N 45)%Placebo(N 45) %Somnolence114Diarrhea90Dry mouth97Fatigue94Urinary tract infection72Insomnia74Anxiety42Constipation42Contusion42One or more adverse reactions resulted in 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 DyskinesiaThe 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 and Study 2) are summarized in Table 3.Table 3: Adverse Reactions in Placebo-Controlled Tardive Dyskinesia Studies (Study and Study 2) of 12-week Treatment on AUSTEDO Reported in at Least 2% of Patients and Greater than PlaceboPreferred TermAUSTEDO(N=279)(%)Placebo(N=131)(%)Nasopharyngitis42 Insomnia41 Depression/ Dysthymic disorder21 Akathisia/Agitation/Restlessness21One or more adverse reactions resulted in reduction of the dose of study medication in 4% of AUSTEDO-treated patients and in 2% of placebo-treated patients.

BOXED WARNING SECTION.

WARNING: DEPRESSION AND SUICIDALITY IN PATIENTS WITH HUNTINGTONS DISEASE. AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntingtons 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 history of depression or prior suicide attempts or ideation, which are increased in frequency in Huntingtons 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 HUNTINGTONS DISEASE See full prescribing information for complete boxed warning.Increases the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntingtons 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 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). Increases the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntingtons 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 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).

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisNo carcinogenicity studies were performed with deutetrabenazine. No increase in tumors was observed in p53+/- transgenic mice treated orally with tetrabenazine at doses of 0, 5, 15, and 30 mg/kg/day for 26 weeks.MutagenesisDeutetrabenazine and its deuterated -HTBZ and -HTBZ metabolites were negative in in vitro (bacterial reverse mutation and chromosome aberration in human peripheral blood lymphocytes) assays in the presence or absence of metabolic activation and in the in vivo micronucleus assay in mice.Impairment of FertilityThe 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 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 body surface area (mg/m2) basis. 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 of gestation, resulted in disrupted estrous cyclicity at doses greater than 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 PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 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 Huntingtons disease is unknown but is believed to be related to its effect as reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals. The major circulating metabolites (-dihydrotetrabenazine [HTBZ] and -HTBZ) of deutetrabenazine, are reversible inhibitors of VMAT2, resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyAt the maximum recommended dose, AUSTEDO does not prolong the QT interval to any clinically relevant extent. An exposure-response analysis on QTc prolongation from study in extensive or intermediate (EM) and poor CYP2D6 metabolizers (PM) showed that clinically-relevant effect can be excluded at exposures following single doses of 24 and 48 mg of AUSTEDO.Melanin BindingDeutetrabenazine or its metabolites bind to melanin-containing tissues (i.e., eye, skin, fur) in pigmented rats. After 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)]. 12.3 Pharmacokinetics. After oral dosing up to 25 mg, plasma concentrations of deutetrabenazine are generally below the limit of detection because of the extensive hepatic metabolism of deutetrabenazine to the active deuterated dihydro metabolites (HTBZ), -HTBZ and -HTBZ. Linear dose dependence of Cmax and AUC was observed for the active metabolites following single or multiple doses of deutetrabenazine (6 mg to 24 mg and 7.5 mg twice daily to 22.5 mg twice daily). AbsorptionFollowing oral administration of deutetrabenazine, the extent of absorption is at least 80%. Plasma concentrations of deutetrabenazine are generally below the limit of detection after oral dosing. Peak plasma concentrations (Cmax) of deuterated -HTBZ and -HTBZ are reached within to hours after dosing. Effect of FoodThe effects of food on the bioavailability of AUSTEDO were studied in subjects administered single dose with and without food. Food had no effect on the area under the plasma concentration-time curve (AUC) of -HTBZ or -HTBZ, although Cmax was increased by approximately 50% in the presence of food [see Dosage and Administration (2.1)]. DistributionThe median volume of distribution (Vc/F) of the -HTBZ, and the -HTBZ metabolites of AUSTEDO are approximately 500 and 730 L, respectively. Results of PET-scan studies in humans show that following intravenous injection of 11C-labeled tetrabenazine or -HTBZ, radioactivity is rapidly distributed to the brain, with the highest binding in the striatum and lowest binding in the cortex.The in vitro protein binding of tetrabenazine, -HTBZ, and -HTBZ was examined in human plasma for concentrations ranging from 50 to 200 ng/mL. Tetrabenazine binding ranged from 82% to 85%, -HTBZ binding ranged from 60% to 68%, and -HTBZ binding ranged from 59% to 63%.EliminationAUSTEDO is primarily renally eliminated in the form of metabolites.The half-life of total (+)-HTBZ from deutetrabenazine is approximately to 10 hours.The median clearance values (CL/F) of the -HTBZ, and the -HTBZ metabolites of AUSTEDO are approximately 47 L/hour and 70 L/hour, respectively, in the Huntingtons disease patient population. MetabolismIn vitro experiments in human liver microsomes demonstrate that deutetrabenazine is extensively biotransformed, mainly by carbonyl reductase, to its major active metabolites, -HTBZ and -HTBZ, which are subsequently metabolized primarily by CYP2D6, with minor contributions of CYP1A2 and CYP3A4/5, to form several minor metabolites. ExcretionIn mass balance study in 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 -HTBZ and -HTBZ metabolites from deutetrabenazine each accounted for less than 10% of the administered dose. Sulfate and glucuronide conjugates of the -HTBZ and -HTBZ metabolites of deutetrabenazine, as well as products of oxidative metabolism, accounted for the majority of metabolites in the urine.Specific PopulationsMale and Female PatientsThere is no apparent effect of gender on the pharmacokinetics of -HTBZ and -HTBZ of deutetrabenazine.Patients with Renal ImpairmentNo clinical studies have been conducted to assess the effect of renal impairment on the PK of AUSTEDO. Patients with Hepatic ImpairmentThe effect of hepatic impairment on the pharmacokinetics of deutetrabenazine and its primary metabolites has not been studied. However, in clinical study conducted to assess the effect of hepatic impairment on the pharmacokinetics of tetrabenazine, closely related VMAT2 inhibitor, the exposure to -HTBZ and -HTBZ was up to 40% greater in patients with hepatic impairment, and the mean tetrabenazine Cmax in patients with hepatic impairment was up to 190-fold higher than in healthy subjects [see Contraindications (4), Use in Specific Populations (8.6)].Poor CYP2D6 MetabolizersAlthough 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 -HTBZ and -HTBZ would be increased similarly to taking strong CYP2D6 inhibitors (approximately 3-fold) [see Dosage and Administration (2.4), Drug Interactions (7.1)].Drug Interaction StudiesDeutetrabenazine, -HTBZ, and -HTBZ have not been evaluated in in vitro studies for induction or inhibition of CYP enzymes or interaction with P-glycoprotein. The results of in vitro studies of tetrabenazine do not suggest that tetrabenazine or its -HTBZ or -HTBZ metabolites are likely to result in clinically significant inhibition of CYP2D6, CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, or CYP3A. In vitro studies suggest that neither tetrabenazine nor its -HTBZ or -HTBZ metabolites are likely to result in clinically significant induction of CYP1A2, CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19. Neither tetrabenazine nor its -HTBZ or -HTBZ metabolites are likely to be substrate or inhibitor of P-glycoprotein at clinically relevant concentrations in vivo.The deutetrabenazine metabolites, 2-methylpropanoic acid of -HTBZ (M1) and monohydroxy tetrabenazine (M4), have been evaluated in panel of in vitro drug-drug interaction studies; the results indicate that M1/M4 are not expected to cause clinically relevant drug interactions.CYP2D6 InhibitorsIn vitro studies indicate that the -HTBZ and -HTBZ metabolites of deutetrabenazine are substrates for CYP2D6. The effect of CYP2D6 inhibition on the pharmacokinetics of deutetrabenazine and its metabolites was studied in 24 healthy subjects following single 22.5 mg dose of deutetrabenazine given after days of administration of the strong CYP2D6 inhibitor paroxetine 20 mg daily. In the presence of paroxetine, systemic exposure (AUCinf) of -HTBZ was 1.9-fold higher and -HTBZ was 6.5-fold higher, resulting in approximately 3-fold increase in AUCinf for total (+)-HTBZ. Paroxetine decreased the clearance of -HTBZ and -HTBZ metabolites of AUSTEDO with corresponding increases in mean half-life of approximately 1.5-fold and 2.7-fold, respectively. In the presence of paroxetine, Cmax of -HTBZ and -HTBZ were 1.2-fold and 2.2-fold higher, respectively.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.DigoxinAUSTEDO was not evaluated for interaction with digoxin. Digoxin is substrate for P-glycoprotein. study in healthy subjects showed that tetrabenazine (25 mg twice daily for days) did not affect the bioavailability of digoxin, suggesting that at this dose, tetrabenazine does not affect P-glycoprotein in the intestinal tract. In vitro studies also do not suggest that tetrabenazine or its metabolites are P-glycoprotein inhibitors.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Chorea Associated with Huntingtons Disease. Double-Blind, Placebo-Controlled StudyThe efficacy of AUSTEDO as treatment for chorea associated with Huntingtons disease was established primarily in Study 1, randomized, double-blind, placebo-controlled, multi-center trial conducted in 90 ambulatory patients with manifest chorea associated with Huntingtons disease. The diagnosis of Huntingtons disease was based on family history, neurological exam, and genetic testing. Treatment duration was 12 weeks, including an 8-week dose titration period and 4-week maintenance period, followed by 1-week washout. Patients were not blinded to discontinuation. AUSTEDO was started at mg per day and titrated upward, at weekly intervals, in mg increments until satisfactory treatment of chorea was achieved, intolerable side effects occurred, or until maximal dose of 48 mg per day was reached. The primary efficacy endpoint was the Total Maximal Chorea Score, an text of the Unified Huntingtons Disease Rating Scale (UHDRS). On this scale, chorea is rated from to (with representing no chorea) for different parts of the body. The total score ranges from 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 and Figure 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 and Week 12), compared to approximately 1.9 units in the placebo group. The treatment effect of -2.5 units was statistically significant (p<0.0001). The Maintenance Endpoint is the mean of the Total Maximal Chorea Scores for the Week 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 4: Change from Baseline to Maintenance Therapy in Total Maximal Chorea (TMC) Score in Patients with Huntingtons Disease Treated with AUSTEDO in Study 1Motor EndpointAUSTEDON 45Placebo = 45p valueChange in Total Chorea Score from Baseline to Maintenance Therapy+ -4.4-1.9<0.0001TMC is subscale of the Unified Huntingtons Disease Rating Scale (UHDRS)+Primary efficacy endpoint Figure 1: Total Maximal Chorea Score Over Time in Study Figure 2: Distribution of the Change in Total Maximal Chorea Scores in Study 1Figure shows the distribution of values for the change in Total Maximal Chorea Score in Study 1. Negative values indicate reduction in chorea and positive numbers indicate an increase in chorea.A patient-rated global impression of change assessed how patients rated their overall Huntingtons 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 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.. figure-01.jpg. figure-02.jpg. 14.2 Tardive Dyskinesia. 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 history of using dopamine receptor antagonist (antipsychotics, metoclopramide) for at least months (or 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 12-text scale; texts to assess the severity of involuntary movements across body regions and these texts were used in this study. Each of the texts was scored on 0 to 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 =severe (abnormal movements occur almost continuously and/or of extreme intensity). The AIMS total score (sum of texts to 7) could thus range from to 28, with decrease in score indicating improvement. In Study 1, 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 4-week dose escalation period and an 8-week maintenance period followed by 1-week washout. The dose of AUSTEDO was started at 12 mg per day and increased at weekly intervals in mg/day increments to 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 3.3 and 3.2 units for the 36 mg and 24 mg arms, respectively, compared with 1.4 units in placebo (Study in Table 5). 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, 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 maximal dose of 48 mg per day was reached. Treatment duration included 6-week dose titration period and 6-week maintenance period followed by 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 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 treatment effect of -1.4 units. Table summarizes the effects of AUSTEDO on tardive dyskinesia based on the AIMS. Table 5: Improvement in AIMS Total Score in Patients Treated with AUSTEDO in Study and Study 2StudyTreatment GroupPrimary Efficacy Measure: AIMS Total ScoreMean Baseline Score (SD)LS Mean Change from Baseline (SE)Treatment Effect (95% CI)Study AUSTEDO 36 mg (n= 55)10.1 (3.21)-3.3 (0.42)-1.9 (-3.09, -0.79)AUSTEDO 24 mg (n= 49)9.4 (2.93)-3.2 (0.45)-1.8 (-3.00, -0.63)AUSTEDO 12 mg (n= 60)9.6 (2.40)-2.1 (0.42)-0.7 (-1.84, 0.42)Placebo (n= 58)9.5 (2.71)-1.4 (0.41)Study 2AUSTEDO (12-48 mg/day) (n= 56)9.7 (4.14)-3.0 (0.45)-1.4 (-2.6, -0.2)Placebo (n= 57)9.6 (3.78)-1.6 (0.46)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 errorFigure 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.jpg.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. AUSTEDO is contraindicated in patients:With Huntingtons 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 (7.2 )].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 (7.3 )].Taking tetrabenazine (XENAZINE(R)) or valbenazine [see Drug Interactions (7.6)].. With Huntingtons 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 (7.2 )].. 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 (7.3 )].. Taking tetrabenazine (XENAZINE(R)) or valbenazine [see Drug Interactions (7.6)].. Suicidal, or untreated/inadequately treated depression in patients with Huntingtons disease (4, 5.1)Hepatic impairment (4, 8.6, 12.3)Taking reserpine, MAOIs, tetrabenazine (XENAZINE(R)), or valbenazine (4, 7.2, 7.3, 7.6). Suicidal, or untreated/inadequately treated depression in patients with Huntingtons disease (4, 5.1). Hepatic impairment (4, 8.6, 12.3). Taking reserpine, MAOIs, tetrabenazine (XENAZINE(R)), or valbenazine (4, 7.2, 7.3, 7.6).

DESCRIPTION SECTION.

11 DESCRIPTION. AUSTEDO (deutetrabenazine) is vesicular monoamine transporter (VMAT2) inhibitor for oral administration. The molecular weight of deutetrabenazine is 323.46; the pKa is 6.31. Deutetrabenazine is hexahydro-dimethoxybenzoquinolizine derivative and has the following chemical name: (RR, SS)-1, 3, 4, 6, 7, 11b-hexahydro-9, 10-di(methoxy-d3)-3-(2-methylpropyl)-2H-benzo[a]quinolizin-2-one.The molecular formula for deutetrabenazine is C19H21D6NO3. Deutetrabenazine is racemic mixture containing the following structures:Deutetrabenazine is white to slightly yellow crystalline powder that is sparingly soluble in water and soluble in ethanol.AUSTEDO tablets contain mg, mg, or 12 mg deutetrabenazine, and the following inactive ingredients: ammonium hydroxide, black iron oxide, n-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 lake. The mg tablets also contain FD&C red 40 lake. The 12 mg tablets also contain FD&C yellow lake.. chemical-structure.jpg.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Initial DoseRecommended DoseMaximum DoseChorea associated with Huntingtons disease6 mg/day6 mg 48 mg/day48 mg/dayTardive dyskinesia12 mg/day12 mg 48 mg/day48 mg/dayTitrate at weekly intervals by mg per day based on reduction of chorea or tardive dyskinesia, and tolerability, up to maximum recommended daily dosage of 48 mg (24 mg twice daily) (2.1)Administer total daily dosages of 12 mg or above in two divided doses (2.1) Administer with food (2.1)Swallow tablets whole; do not chew, crush, or break (2.1)If switching patients from tetrabenazine, discontinue tetrabenazine and initiate AUSTEDO the following day. See full prescribing information for recommended conversion table (2.2)Maximum recommended dosage of AUSTEDO in poor CYP2D6 metabolizers is 36 mg per day (i.e., 18 mg twice daily) (2.4, 8.7). Titrate at weekly intervals by mg per day based on reduction of chorea or tardive dyskinesia, and tolerability, up to maximum recommended daily dosage of 48 mg (24 mg twice daily) (2.1). Administer total daily dosages of 12 mg or above in two divided doses (2.1) Administer with food (2.1). Swallow tablets whole; do not chew, crush, or break (2.1). If switching patients from tetrabenazine, discontinue tetrabenazine and initiate AUSTEDO the following day. See full prescribing information for recommended conversion table (2.2). Maximum recommended dosage of AUSTEDO in poor CYP2D6 metabolizers is 36 mg per day (i.e., 18 mg twice daily) (2.4, 8.7). 2.1 Dosing Information. The dose of AUSTEDO is determined individually for each patient based on reduction of chorea or tardive dyskinesia and tolerability. When first prescribed to patients who are not being switched from tetrabenazine (a related VMAT2 inhibitor), the recommended starting dose of AUSTEDO is mg administered orally once daily for patients with Huntingtons disease and 12 mg per day (6 mg twice daily) for patients with tardive dyskinesia.The dose of AUSTEDO may be increased at weekly intervals in increments of mg per day to maximum recommended daily dosage of 48 mg.Administer total daily dosages of 12 mg or above in two divided doses. Administer AUSTEDO with food [see Clinical Pharmacology (12.3)]. Swallow AUSTEDO whole. Do not chew, crush, or break tablets. The dose of AUSTEDO may be increased at weekly intervals in increments of mg per day to maximum recommended daily dosage of 48 mg.. Administer total daily dosages of 12 mg or above in two divided doses. Administer AUSTEDO with food [see Clinical Pharmacology (12.3)]. Swallow AUSTEDO whole. Do not chew, crush, or break tablets.. 2.2 Switching Patients from Tetrabenazine (XENAZINE(R)) to AUSTEDO. Discontinue tetrabenazine (XENAZINE(R)) and initiate AUSTEDO the following day. The recommended initial dosing regimen of AUSTEDO in patients switching from tetrabenazine (XENAZINE(R)) to AUSTEDO is shown in Table 1.Table 1: Recommended Initial Dosing Regimen when Switching from Tetrabenazine (XENAZINE(R)) to AUSTEDOCurrent tetrabenazine daily dosageInitial regimen ofAUSTEDO12.5 mg6 mg once daily25 mg6 mg twice daily37.5 mg9 mg twice daily50 mg12 mg twice daily62.5 mg15 mg twice daily75 mg18 mg twice daily87.5 mg21 mg twice daily100 mg24 mg twice dailyAfter patients are switched to 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 (e.g., quinidine, antidepressants such as paroxetine, fluoxetine, and bupropion), the total daily dosage of AUSTEDO should not exceed 36 mg (maximum single dose of 18 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 should not exceed 36 mg (maximum single dose of 18 mg) [see Use in Specific Populations (8.7)]. 2.5 Discontinuation and Interruption of Treatment. Treatment with AUSTEDO can be discontinued without tapering. Following treatment interruption of greater than one week, 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. AUSTEDO tablets are available in the following strengths:The mg tablets are round, purple-coated tablets, with SD over 6 printed in black ink on one side.The 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.. The mg tablets are round, purple-coated tablets, with SD over 6 printed in black ink on one side.. The 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: mg, mg, and 12 mg (3).

DRUG INTERACTIONS SECTION.

7 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 (7.5). 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 (7.5). 7.1 Strong CYP2D6 Inhibitors. reduction in AUSTEDO dose may be necessary when adding strong CYP2D6 inhibitor in patients maintained on 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 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)].. 7.3 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)].. 7.4 Neuroleptic Drugs. The risk of parkinsonism, NMS, and akathisia may be increased by concomitant use of AUSTEDO and 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 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)].

GERIATRIC USE SECTION.

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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient or caregiver to read the FDA-approved patient labeling (Medication Guide). Administration InstructionsAdvise patients to take AUSTEDO with food. AUSTEDO tablets should be swallowed whole and not chewed, crushed, or broken [see Dosage and Administration (2.1)].Risk of Depression and Suicide in Patients with Huntingtons DiseaseAdvise patients, their caregivers, and families that AUSTEDO may increase the risk of depression, worsening depression, and suicidality, and to immediately report any symptoms to healthcare provider [see Contraindications (4), Warnings and Precautions (5.2)].Prolongation of the QTc IntervalInform patients to consult their physician immediately if they feel faint, lose consciousness, or have heart palpitations [see Warnings and Precautions (5.3)]. Advise patients to inform physicians that they are taking AUSTEDO before any new drug is taken.Parkinsonism Inform patients that AUSTEDO may cause Parkinson-like symptoms, which could be severe. Advise patients to consult their healthcare provider if they experience slight shaking, body stiffness, trouble moving, trouble keeping their balance, or falls [see Warnings and Precautions (5.6)]. Risk of Sedation and SomnolenceAdvise patients that AUSTEDO may cause sedation and somnolence and may impair the ability to perform tasks that require complex motor and mental skills. Until they learn how they respond to stable dose of AUSTEDO, patients should be careful doing activities that require them to be alert, such as driving car or operating machinery [see Warnings and Precautions (5.7)].Interaction with Alcohol or Other Sedating DrugsAdvise patients that alcohol or other drugs that cause sleepiness will worsen somnolence [see Drug Interactions (7.5)].Concomitant MedicationsAdvise patients to notify their physician of all medications they are taking and to consult with their healthcare provider before starting any new medications because of potential for interactions [see Contraindications (4) and Drug Interactions (7.1, 7.4)]. Distributed by: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054(C)2020 Teva Neuroscience, Inc.AUS-006U.S. Patent Nos: 8,524,733; 9,233,959; 9,296,739; 9,550,780; 9,814,708; 10,959,996XENAZINE(R) is trademark of Valeant Pharmaceuticals Luxembourg S.A.R.L.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 mothers clinical need for AUSTEDO and any potential adverse effects on the breastfed infant from AUSTEDO or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

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 Huntingtons disease is unknown but is believed to be related to its effect as reversible depletor of monoamines (such as dopamine, serotonin, norepinephrine, and histamine) from nerve terminals. The major circulating metabolites (-dihydrotetrabenazine [HTBZ] and -HTBZ) of deutetrabenazine, are reversible inhibitors of VMAT2, resulting in decreased uptake of monoamines into synaptic vesicles and depletion of monoamine stores.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisNo carcinogenicity studies were performed with deutetrabenazine. No increase in tumors was observed in p53+/- transgenic mice treated orally with tetrabenazine at doses of 0, 5, 15, and 30 mg/kg/day for 26 weeks.MutagenesisDeutetrabenazine and its deuterated -HTBZ and -HTBZ metabolites were negative in in vitro (bacterial reverse mutation and chromosome aberration in human peripheral blood lymphocytes) assays in the presence or absence of metabolic activation and in the in vivo micronucleus assay in mice.Impairment of FertilityThe 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 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 body surface area (mg/m2) basis. 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 of gestation, resulted in disrupted estrous cyclicity at doses greater than 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.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Overdoses ranging from 100 mg to g have been reported in the literature with tetrabenazine, 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 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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Package/Label Display Panel. NDC 68546-170-60 Austedo(R) (deutetrabenazine) tablets mg 60 tablets Medication Guide Required: Each time AUSTEDO is dispensed, give the patient Medication Guide.. image.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Tourette syndrome The safety and effectiveness of 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 to 16 years with Tourette syndrome. One study evaluated fixed doses of deutetrabenazine over weeks (NCT03571256); the other evaluated flexible doses of deutetrabenazine over 12 weeks (NCT03452943). The studies included 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 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%).Chorea associated with Huntingtons disease and Tardive dyskinesia The safety and effectiveness of AUSTEDO have not been established in pediatric patients for the treatment of chorea associated with Huntingtons disease or for the treatment of tardive dyskinesia.Juvenile Animal Toxicity DataDeutetrabenazine 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 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere 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. DataAnimal DataOral 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 times the maximum recommended human dose of 48 mg/day, on 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.

RECENT MAJOR CHANGES SECTION.

RECENT MAJOR CHANGES. Dosage and Administration (2.1) RemovedWarnings and Precautions (5.3)12/202012/2020.

SPL MEDGUIDE SECTION.

MEDICATION GUIDE. MEDICATION GUIDE AUSTEDO(R) (aw-STED-oh) (deutetrabenazine) tablets, for oral use What is the most important information should know about AUSTEDO AUSTEDO can cause serious side effects in people with Huntingtons disease, including:depressionsuicidal thoughtssuicidal actions Do not start taking AUSTEDO if you have Huntingtons disease and are depressed (have untreated depression or depression that is not well controlled by medicine) or have suicidal thoughts. Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is especially important when 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 spellslose interest in seeing your friends or doing things you used to enjoysleep lot more or lot less than usualfeel unimportantfeel guiltyfeel hopeless or helplessfeel more irritable, angry, or aggressive than usualfeel more or less hungry than usual or notice big change in your body weighthave trouble paying attentionfeel tired or sleepy all the timehave thoughts about hurting yourself or ending your life What is AUSTEDO AUSTEDO is prescription medicine that is used to treat: the involuntary movements (chorea) of Huntingtons disease. AUSTEDO does not cure the cause of the involuntary movements, and it does not treat other symptoms of Huntingtons 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 is safe and effective in children. Who should not take AUSTEDO Do not take AUSTEDO if you: have Huntingtons disease and are depressed or have thoughts of suicide. See What is the most important information should know about AUSTEDOhave liver problems.are taking monoamine oxidase inhibitor (MAOI) medicine. Do not take an MAOI within 14 days after you stop taking AUSTEDO. Do not start AUSTEDO if you stopped taking an MAOI in the last 14 days. Ask your healthcare provider or pharmacist if you are not sure.are taking reserpine. Do not take medicines that contain reserpine (such as Serpalan and Renese-R) with AUSTEDO. If your healthcare provider plans to switch you from taking reserpine to AUSTEDO, you must wait at least 20 days after your last dose of reserpine before you start taking AUSTEDO.are taking tetrabenazine (Xenazine). If your healthcare provider plans to switch you from tetrabenazine (Xenazine) to AUSTEDO, take your first dose of AUSTEDO on the day after your last dose of tetrabenazine (Xenazine).are taking valbenazine (Ingrezza). Before taking 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 heart problem called congenital long QT syndrome.have low levels of potassium or magnesium in your blood (hypokalemia or hypomagnesemia).have breast cancer or history of breast cancer.are pregnant or plan to become pregnant. It is not known if AUSTEDO can harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if AUSTEDO passes into breast milk. Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking AUSTEDO with certain other medicines may cause side effects. Do not start any new medicines while taking AUSTEDO without talking to your healthcare provider first. How should take AUSTEDO Take AUSTEDO exactly as your healthcare provider tells you to take it.Take AUSTEDO by mouth and with food.Swallow AUSTEDO tablets whole with water. Do not chew, crush, or break AUSTEDO tablets before swallowing. If you cannot swallow AUSTEDO tablets whole, tell your healthcare provider. You may need different medicine.If your dose of AUSTEDO is 12 mg or more each day, take AUSTEDO tablets times day in equal doses with food.Your healthcare provider will increase your dose of 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 for more than week. Do not take another dose until you talk to your healthcare provider. What should avoid while taking AUSTEDO Sleepiness (sedation) is common side effect of AUSTEDO. While taking AUSTEDO, do not drive car or operate dangerous machinery until you know how AUSTEDO affects you. Drinking alcohol and taking other drugs that may also cause sleepiness while you are taking AUSTEDO may increase any sleepiness caused by AUSTEDO. What are the possible side effects of AUSTEDO AUSTEDO can cause serious side effects, including: Depression and suicidal thoughts or actions in people with Huntingtons disease. See What is the most important information should know about AUSTEDO Irregular heartbeat (QT prolongation). AUSTEDO increases your chance of having certain changes in the electrical activity in your heart. These changes can lead to dangerous abnormal heartbeat. Taking AUSTEDO with certain medicines may increase this chance. Neuroleptic Malignant Syndrome (NMS). Call your healthcare provider right away and go to the nearest emergency room if you develop these signs and symptoms that do not have another obvious cause:high fever problems thinking increased sweatingstiff musclesvery fast or uneven heartbeat Restlessness. You may get condition where you feel strong urge to move. This is called akathisia.Parkinsonism. Symptoms of parkinsonism include: slight shaking, body stiffness, trouble moving, trouble keeping your balance, or falls. The most common side effects of AUSTEDO in people with Huntingtons disease include: sleepiness (sedation) diarrheatirednessdry mouth The most common side effects of AUSTEDO in people with tardive dyskinesia include: inflammation of the nose and throat (nasopharyngitis)problems sleeping (insomnia) These are not all the possible side effects of AUSTEDO. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store AUSTEDO Store AUSTEDO tablets at room temperature, between 68F to 77F (20C to 25C).Keep the bottle tightly closed to protect AUSTEDO from light and moisture. Keep AUSTEDO tablets and all medications out of reach of children. General information about the safe and effective use of AUSTEDO. Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. Do not use AUSTEDO for condition for which it was not prescribed. Do not give 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 that is written for health professionals. What are the ingredients in AUSTEDO Active ingredient: deutetrabenazine Inactive ingredients: ammonium hydroxide, black iron oxide, n-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 lake. The mg tablets also contain FD&C red 40 lake. The 12 mg tablets also contain FD&C yellow lake. Distributed by: Teva Pharmaceuticals USA, Inc.Parsippany, NJ 07054 (C)2020 Teva Neuroscience, Inc. AUSMG-005 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: December 2020. AUSTEDO can cause serious side effects in people with Huntingtons disease, including:depressionsuicidal thoughtssuicidal actions depression. suicidal thoughts. suicidal actions. Do not start taking AUSTEDO if you have Huntingtons disease and are depressed (have untreated depression or depression that is not well controlled by medicine) or have suicidal thoughts.. Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is especially important when AUSTEDO is started and when the dose is changed. feel sad or have crying spells. lose interest in seeing your friends or doing things you used to enjoy. sleep lot more or 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 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. the involuntary movements (chorea) of Huntingtons disease. AUSTEDO does not cure the cause of the involuntary movements, and it does not treat other symptoms of Huntingtons disease, such as problems with thinking or emotions.. movements in the face, tongue, or other body parts that cannot be controlled (tardive dyskinesia).. have Huntingtons disease and are depressed or have thoughts of suicide. See What is the most important information should know about AUSTEDO. have liver problems.. are taking monoamine oxidase inhibitor (MAOI) medicine. Do not take an MAOI within 14 days after you stop taking AUSTEDO. Do not start AUSTEDO if you stopped taking an MAOI in the last 14 days. Ask your healthcare provider or pharmacist if you are not sure.. are taking reserpine. Do not take medicines that contain reserpine (such as Serpalan and Renese-R) with AUSTEDO. If your healthcare provider plans to switch you from taking reserpine to AUSTEDO, you must wait at least 20 days after your last dose of reserpine before you start taking AUSTEDO.. are taking tetrabenazine (Xenazine). If your healthcare provider plans to switch you from tetrabenazine (Xenazine) to AUSTEDO, take your first dose of AUSTEDO on the day after your last dose of tetrabenazine (Xenazine).. are taking valbenazine (Ingrezza).. 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 heart problem called congenital long QT syndrome.. have low levels of potassium or magnesium in your blood (hypokalemia or hypomagnesemia).. have breast cancer or history of breast cancer.. are pregnant or plan to become pregnant. It is not known if AUSTEDO can harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if AUSTEDO passes into breast milk.. Take AUSTEDO exactly as your healthcare provider tells you to take it.. Take AUSTEDO by mouth and with food.. Swallow AUSTEDO tablets whole with water. Do not chew, crush, or break AUSTEDO tablets before swallowing. If you cannot swallow AUSTEDO tablets whole, tell your healthcare provider. You may need different medicine.. If your dose of AUSTEDO is 12 mg or more each day, take AUSTEDO tablets times day in equal doses with food.. Your healthcare provider will increase your dose of 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 for more than week. Do not take another dose until you talk to your healthcare provider.. Depression and suicidal thoughts or actions in people with Huntingtons disease. See What is the most important information should know about AUSTEDO. Irregular heartbeat (QT prolongation). AUSTEDO increases your chance of having certain changes in the electrical activity in your heart. These changes can lead to dangerous abnormal heartbeat. Taking AUSTEDO with certain medicines may increase this chance.. Neuroleptic Malignant Syndrome (NMS). Call your healthcare provider right away and go to the nearest emergency room if you develop these signs and symptoms that do not have another obvious cause:high fever problems thinking increased sweatingstiff musclesvery fast or uneven heartbeat. high fever problems thinking increased sweating. stiff muscles. very fast or uneven heartbeat. Restlessness. You may get condition where you feel strong urge to move. This is called akathisia.. Parkinsonism. Symptoms of parkinsonism include: slight shaking, body stiffness, trouble moving, trouble keeping your balance, or falls. sleepiness (sedation) diarrhea. tiredness. dry mouth. inflammation of the nose and throat (nasopharyngitis). problems sleeping (insomnia). Store AUSTEDO tablets at room temperature, between 68F to 77F (20C to 25C).. Keep the bottle tightly closed to protect AUSTEDO from light and moisture.

SPL UNCLASSIFIED SECTION.

2.1 Dosing Information. The dose of AUSTEDO is determined individually for each patient based on reduction of chorea or tardive dyskinesia and tolerability. When first prescribed to patients who are not being switched from tetrabenazine (a related VMAT2 inhibitor), the recommended starting dose of AUSTEDO is mg administered orally once daily for patients with Huntingtons disease and 12 mg per day (6 mg twice daily) for patients with tardive dyskinesia.The dose of AUSTEDO may be increased at weekly intervals in increments of mg per day to maximum recommended daily dosage of 48 mg.Administer total daily dosages of 12 mg or above in two divided doses. Administer AUSTEDO with food [see Clinical Pharmacology (12.3)]. Swallow AUSTEDO whole. Do not chew, crush, or break tablets. The dose of AUSTEDO may be increased at weekly intervals in increments of mg per day to maximum recommended daily dosage of 48 mg.. Administer total daily dosages of 12 mg or above in two divided doses. Administer AUSTEDO with food [see Clinical Pharmacology (12.3)]. Swallow AUSTEDO whole. Do not chew, crush, or break tablets.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm (8.1). 8.1 Pregnancy. Risk SummaryThere 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. DataAnimal DataOral 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 times the maximum recommended human dose of 48 mg/day, on 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 SummaryThere 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 mothers 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. Tourette syndrome The safety and effectiveness of 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 to 16 years with Tourette syndrome. One study evaluated fixed doses of deutetrabenazine over weeks (NCT03571256); the other evaluated flexible doses of deutetrabenazine over 12 weeks (NCT03452943). The studies included 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 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%).Chorea associated with Huntingtons disease and Tardive dyskinesia The safety and effectiveness of AUSTEDO have not been established in pediatric patients for the treatment of chorea associated with Huntingtons disease or for the treatment of tardive dyskinesia.Juvenile Animal Toxicity DataDeutetrabenazine 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 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.. 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 clinical study conducted with tetrabenazine, closely related VMAT2 inhibitor, there was 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 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 -HTBZ and -HTBZ would be increased similarly to taking 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)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. QT Prolongation: Avoid use in patients with congenital long QT syndrome or with arrhythmias associated with 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 patients ability to drive or operate complex machinery (5.7). QT Prolongation: Avoid use in patients with congenital long QT syndrome or with arrhythmias associated with 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 patients ability to drive or operate complex machinery (5.7). 5.1 Depression and Suicidality in Patients with Huntingtons Disease. Patients with Huntingtons disease are at increased risk for depression, and suicidal ideation or behaviors (suicidality). AUSTEDO may increase the risk for suicidality in patients with Huntingtons disease. In 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 Huntingtons disease who express suicidal ideation should be evaluated immediately.. 5.2 Clinical Worsening and Adverse Events in Patients with Huntingtons Disease. Huntingtons disease is progressive disorder characterized by changes in mood, cognition, chorea, rigidity, and functional capacity over time. VMAT2 inhibitors, including AUSTEDO, may cause 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. AUSTEDO may prolong the QT interval, but the degree of QT prolongation is not clinically significant when AUSTEDO is administered within the recommended dosage range [see Clinical Pharmacology (12.2)].AUSTEDO should be avoided in patients with congenital long QT syndrome and in patients with 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). 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 Huntingtons disease and tardive dyskinesia. In 12-week, double-blind, placebo-controlled trial in Huntingtons 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 patient develops akathisia during treatment with AUSTEDO, the AUSTEDO dose should be reduced; some patients may require discontinuation of therapy.. 5.6 Parkinsonism. AUSTEDO may cause parkinsonism in patients with Huntingtons disease or tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors.Because rigidity can develop as part of the underlying disease process in Huntingtons disease, it may be difficult to distinguish between potential drug-induced parkinsonism and progression of underlying Huntingtons disease. Drug-induced parkinsonism has the potential to cause more functional disability than untreated chorea for some patients with Huntingtons disease. Postmarketing cases of parkinsonism in patients treated with AUSTEDO for tardive dyskinesia have been reported. Signs and symptoms in reported cases have included bradykinesia, gait disturbances, which led to falls in some cases, and the emergence or worsening of tremor. In most cases, the development of parkinsonism occurred within the first two weeks after starting or increasing the dose of AUSTEDO. In cases in which follow-up clinical information was available, parkinsonism was reported to resolve following discontinuation of AUSTEDO therapy.If 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 common dose-limiting adverse reaction of AUSTEDO. In 12-week, double-blind, placebo-controlled trial examining patients with Huntingtons 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 motor vehicle or operating hazardous machinery, until they are on 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, 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, factor of potential importance if AUSTEDO is being considered for 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 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 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 deutetrabenazines 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)].