Volume 15 | ORIGINALLY PUBLISHED March 2024/UPDATED JULY 2024

Classifying Tardive Dyskinesia (TD) and Drug-Induced Parkinsonism (DIP) as EPS Leads to Misdiagnosis and Inappropriate Use of Anticholinergics in TD

Treatment
AUSTEDO XR: A Once-Daily First-Line Treatment for Tardive Dyskinesia
AUSTEDO XR: A Once-Daily First-Line Treatment for Tardive Dyskinesia

All patients taking antipsychotic drugs (APD) are at a risk of developing tardive dyskinesia (TD), which can have a profound impact on many aspects of patients' lives, including psychological, social, physical, and vocational/educational effects.2-6 TD can also complicate the management of the underlying mental health disorder.7 The American Psychiatric Association (APA) guidelines recommend vesicular monoamine transport type 2 (VMAT2) inhibitors as first-line treatment for TD regardless of severity, as mild symptoms of TD can also have a substantial impact on day-to-day functioning and social functioning.1 In addition, VMAT2 inhibitors are recommended for TD without the requirement to modify the APD dose.1

AUSTEDO XR: A Once-Daily Treatment Option for TD

Once-daily AUSTEDO XR is an extended-release VMAT2 inhibitor approved in adults for the treatment of TD.8 Bioequivalence of AUSTEDO XR has been established with AUSTEDO BID based on pharmacokinetic profile studies performed across 3 phase 1 clinical trials in healthy volunteers.9 In the bioequivalence study, peak plasma concentrations (Cmax) of AUSTEDO XR were reached within approximately 3 hours followed by a sustained plateau during the majority of the 24-hour dosing interval (Figure 3.1).9

Figure 3.1: Bioequivalence of AUSTEDO XR Has Been Established With AUSTEDO BID
Figure 3.1
*Bioequivalence was determined by the plasma concentration-time curve from time 0-24h at steady state of deutetrabenazine (parent) and deuterated α-dihydrotetrabenazine and β-dihydrotetrabenazine metabolites.9

The US Food and Drug Administration (FDA) defines bioequivalence as the absence of a significant difference in the drug exposure profile of 2 drugs.10 When 2 formulations are shown to be bioequivalent, they can be considered therapeutically equivalent.10 Data support equivalence of AUSTEDO XR and AUSTEDO BID across the full clinical dosing range (12 mg QD to 48 mg QD).9

Clinical Trials for AUSTEDO

The ARM-TD, AIM-TD, and RIM-TD clinical trials were conducted to assess efficacy and safety of AUSTEDO in patients with TD. Patients in these clinical trials received the AUSTEDO BID formulation.11-13

ARM-TD: A Flexible-Dose Trial

ARM-TD was a flexible-dose clinical trial in which patients' doses were individually titrated to a level that was tolerated and reduced abnormal movements.8,11,12 Patients were randomized 1:1 to receive AUSTEDO or placebo. The starting dose of AUSTEDO was 12 mg/day, which was increased by 6 mg/day each week until satisfactory control of TD was achieved, until intolerable side effects occurred, or until a maximal dose of 48 mg/day was reached. Patients were titrated to an optimal dose over 6 weeks. The 12-week treatment period included this 6-week titration period and a 6-week maintenance period and was followed by a 1-week washout.8,12

The primary efficacy endpoint for this study was the change from baseline (defined for each patient as the value from the day 0 visit) to Week 12 in Abnormal Involuntary Movement Scale (AIMS) total score (sum of items 1 through 7) as assessed by 2 blinded central video ratings. Higher AIMS scores are indicative of more severe dyskinesia.8,9,12 Patients in the ARM-TD study showed a significant improvement in AIMS total score from baseline at Week 12 vs placebo (3.0-point reduction vs 1.6-point reduction; P=0.019).9

AIM-TD: A Fixed-Dose Trial

AIM-TD was a 12-week, randomized, double-blind, placebo-controlled, fixed-dose trial in which patients were randomized 1:1:1:1 to placebo or AUSTEDO 12 mg, 24 mg, or 36 mg. 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/day and increased at weekly intervals in 6-mg/day increments to a dose target of 12, 24, or 36 mg/day.8,11 The primary efficacy endpoint was change from baseline to Week 12 in AIMS total score in the 36-mg/day group vs placebo, assessed by blinded central video rating. In AIM-TD, AUSTEDO significantly reduced AIMS total score by 3.3 points from baseline in the 36-mg/day arm (vs a reduction of 1.4 points with placebo) at Week 12 (P=0.001, treatment effect of -1.9 points).8,9,11 In an exploratory analysis, significant AIMS total score reduction was seen at 2 weeks for the 24- and 36-mg/day groups.11

AUSTEDO Safety and Tolerability Profile

The most commonly reported adverse effects by patients treated with AUSTEDO (3% and greater than placebo) in the placebo-controlled studies were nasopharyngitis and insomnia (Table 3.1).8 Discontinuation due to adverse reactions occurred in 4% of patients taking AUSTEDO vs 3% of patients taking placebo.11 Dose reduction due to adverse reactions was required in 4% of patients taking AUSTEDO vs 2% of patients taking placebo.8 Adverse reactions with AUSTEDO XR are expected to be similar to AUSTEDO BID.8 The safety profile from the RIM-TD 3-year study was comparable to the safety profiles from the 12-week clinical trials.13 There were no new safety signals identified in RIM-TD.13

Table 3.1: Placebo-Controlled TD Studies: Adverse Reactions Reported in ≥2% of Patients Treated With AUSTEDO8,9
Table 3.1
Adverse reactions with AUSTEDO XR are expected to be similar to AUSTEDO BID.8
RIM-TD: Sustained Results Through ~3 Years

RIM-TD was an open-label, long-term maintenance study in patients who successfully completed ARM-TD or AIM-TD. Patients discontinued AUSTEDO for 1 week and then started at a dose of 12 mg/day, which was titrated for up to 6 weeks. The dose was increased in a response-driven manner on a weekly basis by 6 mg/day until either the maximum allowable dose was reached, a clinically significant adverse event (AE) occurred, or adequate dyskinesia control was achieved. Patients were followed for approximately 3 years (145 weeks).13

Among the patients evaluated, 337 patients had treatment at baseline and 160 patients had treatment through the end of Week 145. During the overall treatment period, patients generally experienced an improvement in the AIMS total score. There was a gradual reduction in the mean AIMS total scores from baseline through Week 145 (Figure 3.2).13 The average dose of AUSTEDO was >36 mg/day (39.4 mg/day at Week 145).13

Figure 3.2: Rapid TD Symptom Control at 2 Weeks† With Sustained Results Observed Through ~3 Years9,13
Figure 3.2

At Week 145 in RIM-TD, 67% of patients achieved ≥50% improvement in AIMS total score.13 Clinicians and patients generally recognized improvement in TD symptoms with AUSTEDO treatment based on assessments of Clinical Global Impression of Change (CGIC) and Patient Global Impression of Change (PGIC) over time. At Week 145, a majority of patients (63%) and physicians (73%) reported symptoms as “much improved” or “very much improved.”13 Preexisting psychiatric scores remained stable throughout the treatment period and AEs were comparable to those seen in the pivotal clinical trials.9,13 The mean overall compliance rate was nearly 90% at 3 years.9

At 3 years, a mean overall compliance rate was 90% with 67% of patients achieving ≥50% improvement in AIMS score9,13
One Pill, Once Daily For All Doses

AUSTEDO XR is available in 12 mg, 18 mg, 24 mg, 30 mg, 36 mg, 42 mg, and 48 mg extended release tablets, providing flexibility for effective and tolerable symptom control.8

The recommended starting dose of AUSTEDO XR for patients with TD is 12 mg/day, which may be increased at weekly intervals by 6 mg/day until desired symptom control is tolerably achieved (Figure 3.3).8 The average daily dose in clinical trials was >36 mg/day.11-13 This average dose emphasizes the importance of titration, when appropriate, to help patients achieve desired symptom control.8,11-13 The maximum recommended daily dose of AUSTEDO XR is 48 mg/day.8

Once-daily AUSTEDO XR may be taken with or without food. AUSTEDO XR should be swallowed whole. Tablets should not be chewed, crushed, or broken.

Figure 3.3: One Pill, Once Daily For All Doses8,13
Figure 3.3
The average daily dose in clinical trials was >36 mg/day11-13
Getting New Patients Started on AUSTEDO XR

To get new patients started on AUSTEDO XR, a 4-week Titration Kit is available through sample or prescription. For continuing patients, write once-daily AUSTEDO XR for the next refill at the same total daily dose as AUSTEDO BID.9

Figure 3.4: Starting Patients on AUSTEDO XR9
Figure 3.4
Summary

To summarize, the APA guidelines recommend VMAT2 inhibitors as first-line treatment for TD.1 Once-daily AUSTEDO XR is an extended-release VMAT2 inhibitor approved in adults for the treatment of TD.8 The bioequivalence of AUSTEDO XR has been established with AUSTEDO BID based on pharmacokinetic profile studies performed across 3 phase 1 clinical trials in healthy volunteers.9 The efficacy and safety of AUSTEDO BID in patients with TD was demonstrated in 3 clinical trials (ARM-TD, AIM-TD, and RIM-TD).11-13 Adverse reactions with AUSTEDO XR are expected to be similar to AUSTEDO BID.8 In the RIM-TD study, patients exhibited sustained results through 3 years.13 AUSTEDO XR is available as one pill, once daily for all doses. The recommended starting dose of AUSTEDO XR for patients with TD is 12 mg/day and may be increased at weekly intervals by 6 mg/day until desired symptom control is tolerably achieved.8,9

References
1. American Psychiatric Association. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. 3rd ed. American Psychiatric Association; 2021. 2. Hauser RA, Meyer JM, Factor SA, et al. Differentiating tardive dyskinesia: a video-based review of antipsychotic-induced movement disorders in clinical practice. CNS Spectr. 2022;27(2):208-217. 3. Fahn S, Jankovic J, Hallett M, eds. Principles and Practice of Movement Disorders. 2nd ed. Elsevier Saunders; 2011. 4. Zutshi D, Cloud LJ, Factor SA. Tardive syndromes are rarely reversible after discontinuing dopamine receptor blocking agents: experience from a university-based movement disorder clinic. Tremor Other Hyperkinet Mov (N Y). 2014;4:266. 5. Caroff SN, Citrome L, Meyer J, et al. A modified Delphi consensus study of the screening, diagnosis, and treatment of tardive dyskinesia. J Clin Psychiatry. 2020;81(2):19cs12983. 6. Jackson R, Brams MN, Citrome L. Assessment of the impact of tardive dyskinesia in clinical practice: consensus panel recommendations. Neuropsychiatr Dis Treat. 2021;17:1589-1597. 7. Jain R, Ayyagari R, Goldschmidt D, Zhou M, Finkbeiner S, Leo S. Impact of tardive dyskinesia on physical, psychological, social, and professional domains of patient lives: a survey of patients in the United States. J Clin Psychiatry. 2023;84(3):22m14694. 8. AUSTEDO® XR (deutetrabenazine) extended-release tablets/AUSTEDO® current Prescribing Information. Parsippany, NJ: Teva Neuroscience, Inc. 9. Data on file. Teva Neuroscience, Inc. 10. Chow SC. Bioavailability and bioequivalence in drug development. Wiley Interdiscip Rev Comput Stat. 2014;6(4):304-312. 11. Anderson KE, Stamler D, Davis MD, et al. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Psychiatry. 2017;4(8):595-604. 12. Fernandez HH, Factor SA, Hauser RA, et al. Randomized controlled trial of deutetrabenazine for tardive dyskinesia: the ARM-TD study. Neurology. 2017;88(21):2003-2010. 13. Hauser RA, Barkay H, Fernandez HH, et al. Long-term deutetrabenazine treatment for tardive dyskinesia is associated with sustained benefits and safety: a 3-year, open-label extension study. Front Neurol. 2022;13:773999.
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Past Volumes
Volume 14
Understanding the Long-Term Nature of TD and Its Impact on the Underlying Mental Health Condition
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Volume 13
Exploring the Nurse Practitioner's Role in the Screening and Assessment of Patients for Tardive Dyskinesia
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Volume 11
The Critical Need to Accurately Differentiate Tardive Dyskinesia Versus Drug-Induced Parkinsonism
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Volume 10
Screening and Assessment of TD With a Focus on the Virtual Visit
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IMPORTANT SAFETY INFORMATION
Depression and Suicidality in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. 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. Inform patients, their caregivers, and families of the risk of
IMPORTANT SAFETY INFORMATION
Depression and Suicidality in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO can increase the risk of depression
INDICATIONS AND USAGE

AUSTEDO XR® (deutetrabenazine) extended-release tablets and AUSTEDO® (deutetrabenazine) tablets are indicated in adults for the treatment of chorea associated with Huntington's disease and for the treatment of tardive dyskinesia.

IMPORTANT SAFETY INFORMATION
Depression and Suicidality in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. 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. Inform patients, their caregivers, and families of the risk of depression and suicidality and instruct them to report behaviors of concern promptly to the treating physician. Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation. AUSTEDO XR and AUSTEDO are contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression.
Contraindications AUSTEDO XR and AUSTEDO are contraindicated in patients with Huntington's disease who are suicidal, or have untreated or inadequately treated depression. AUSTEDO XR and AUSTEDO are also contraindicated in: patients with hepatic impairment; patients taking reserpine or within 20 days of discontinuing reserpine; patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing MAOI therapy; and patients taking tetrabenazine or valbenazine.
Clinical Worsening and Adverse Events in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO may cause a worsening in mood, cognition, rigidity, and functional capacity. Prescribers should periodically re-evaluate the need for AUSTEDO XR or AUSTEDO in their patients by assessing the effect on chorea and possible adverse effects.
QTc Prolongation: AUSTEDO XR and AUSTEDO may prolong the QT interval, but the degree of QT prolongation is not clinically significant when AUSTEDO XR or AUSTEDO is administered within the recommended dosage range. AUSTEDO XR and AUSTEDO should be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.
Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex reported in association with drugs that reduce dopaminergic transmission, has been observed in patients receiving tetrabenazine. The risk may be increased by concomitant use of dopamine antagonists or antipsychotics. The management of NMS should include immediate discontinuation of AUSTEDO XR and AUSTEDO; intensive symptomatic treatment and medical monitoring; and treatment of any concomitant serious medical problems.
Akathisia, Agitation, and Restlessness: AUSTEDO XR and AUSTEDO may increase the risk of akathisia, agitation, and restlessness. The risk of akathisia may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops akathisia, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy.
Parkinsonism: AUSTEDO XR and AUSTEDO may cause parkinsonism in patients with Huntington's disease or tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors. The risk of parkinsonism may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops parkinsonism, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy.
Sedation and Somnolence: Sedation is a common dose-limiting adverse reaction of AUSTEDO XR and AUSTEDO. Patients should not perform activities requiring mental alertness, such as operating a motor vehicle or hazardous machinery, until they are on a maintenance dose of AUSTEDO XR or AUSTEDO and know how the drug affects them. Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.
Hyperprolactinemia: Tetrabenazine elevates serum prolactin concentrations in humans. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of AUSTEDO XR and AUSTEDO.
Binding to Melanin-Containing Tissues: Deutetrabenazine or its metabolites bind to melanin-containing tissues and could accumulate in these tissues over time. Prescribers should be aware of the possibility of long-term ophthalmologic effects.
Common Adverse Reactions: The most common adverse reactions for AUSTEDO (>8% and greater than placebo) in a controlled clinical study in patients with Huntington's disease were somnolence, diarrhea, dry mouth, and fatigue. The most common adverse reactions for AUSTEDO (4% and greater than placebo) in controlled clinical studies in patients with tardive dyskinesia were nasopharyngitis and insomnia. Adverse reactions with AUSTEDO XR extended-release tablets are expected to be similar to AUSTEDO tablets.
Please see accompanying full Prescribing Information, including Boxed Warning.
INDICATIONS AND USAGE

AUSTEDO XR® (deutetrabenazine) extended-release tablets and AUSTEDO® (deutetrabenazine) tablets are indicated in adults for the treatment of chorea associated with Huntington's disease and for the treatment of tardive dyskinesia.

IMPORTANT SAFETY INFORMATION
Depression and Suicidality in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO can increase the risk of depression and suicidal thoughts and behavior (suicidality) in patients with Huntington's disease. 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. Inform patients, their caregivers, and families of the risk of depression and suicidality and instruct them to report behaviors of concern promptly to the treating physician. Exercise caution when treating patients with a history of depression or prior suicide attempts or ideation. AUSTEDO XR and AUSTEDO are contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression.
Contraindications AUSTEDO XR and AUSTEDO are contraindicated in patients with Huntington's disease who are suicidal, or have untreated or inadequately treated depression. AUSTEDO XR and AUSTEDO are also contraindicated in: patients with hepatic impairment; patients taking reserpine or within 20 days of discontinuing reserpine; patients taking monoamine oxidase inhibitors (MAOIs), or within 14 days of discontinuing MAOI therapy; and patients taking tetrabenazine or valbenazine.
Clinical Worsening and Adverse Events in Patients with Huntington's Disease: AUSTEDO XR and AUSTEDO may cause a worsening in mood, cognition, rigidity, and functional capacity. Prescribers should periodically re-evaluate the need for AUSTEDO XR or AUSTEDO in their patients by assessing the effect on chorea and possible adverse effects.
QTc Prolongation: AUSTEDO XR and AUSTEDO may prolong the QT interval, but the degree of QT prolongation is not clinically significant when AUSTEDO XR or AUSTEDO is administered within the recommended dosage range. AUSTEDO XR and AUSTEDO should be avoided in patients with congenital long QT syndrome and in patients with a history of cardiac arrhythmias.
Neuroleptic Malignant Syndrome (NMS), a potentially fatal symptom complex reported in association with drugs that reduce dopaminergic transmission, has been observed in patients receiving tetrabenazine. The risk may be increased by concomitant use of dopamine antagonists or antipsychotics. The management of NMS should include immediate discontinuation of AUSTEDO XR and AUSTEDO; intensive symptomatic treatment and medical monitoring; and treatment of any concomitant serious medical problems.
Akathisia, Agitation, and Restlessness: AUSTEDO XR and AUSTEDO may increase the risk of akathisia, agitation, and restlessness. The risk of akathisia may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops akathisia, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy.
Parkinsonism: AUSTEDO XR and AUSTEDO may cause parkinsonism in patients with Huntington's disease or tardive dyskinesia. Parkinsonism has also been observed with other VMAT2 inhibitors. The risk of parkinsonism may be increased by concomitant use of dopamine antagonists or antipsychotics. If a patient develops parkinsonism, the AUSTEDO XR or AUSTEDO dose should be reduced; some patients may require discontinuation of therapy.
Sedation and Somnolence: Sedation is a common dose-limiting adverse reaction of AUSTEDO XR and AUSTEDO. Patients should not perform activities requiring mental alertness, such as operating a motor vehicle or hazardous machinery, until they are on a maintenance dose of AUSTEDO XR or AUSTEDO and know how the drug affects them. Concomitant use of alcohol or other sedating drugs may have additive effects and worsen sedation and somnolence.
Hyperprolactinemia: Tetrabenazine elevates serum prolactin concentrations in humans. If there is a clinical suspicion of symptomatic hyperprolactinemia, appropriate laboratory testing should be done and consideration should be given to discontinuation of AUSTEDO XR and AUSTEDO.
Binding to Melanin-Containing Tissues: Deutetrabenazine or its metabolites bind to melanin-containing tissues and could accumulate in these tissues over time. Prescribers should be aware of the possibility of long-term ophthalmologic effects.
Common Adverse Reactions: The most common adverse reactions for AUSTEDO (>8% and greater than placebo) in a controlled clinical study in patients with Huntington's disease were somnolence, diarrhea, dry mouth, and fatigue. The most common adverse reactions for AUSTEDO (4% and greater than placebo) in controlled clinical studies in patients with tardive dyskinesia were nasopharyngitis and insomnia. Adverse reactions with AUSTEDO XR extended-release tablets are expected to be similar to AUSTEDO tablets.
Please see accompanying full Prescribing Information, including Boxed Warning.