​

Chris: Treating TD in a Patient at Risk of DDIs

Photo of “Chris,” a TD patient with drug-drug interactions

Chris, 55 Years

Chris, 55, is a twice-divorced stockbroker.

Medical History

  • Bipolar disorder
  • Rheumatoid arthritis

Current Medications

  • Carbamazepine extended-release after nonresponse to lithium and atypical APDs
  • Glucocorticoids

Current Presentation

  • Concerned about excessive blinking and twitching in his fingers, jaw, and lips
  • Chris has been distracted at work and has trouble staying focused on his stock trades, which has been noticed by his colleagues

Assessment

  • Recognizing that Chris had previous exposure to APDs, which increased his risk of TD, his psychiatrist performed an Abnormal Involuntary Movement Scale (AIMS) examination

Not an actual patient. Image is for illustrative purposes only.

Chris’ AIMS Exam Confirms TD

MOVEMENT RATINGS SCORE
Facial & Oral
Movements		 1.

Muscles of facial expression

 01234
2.

Lips and perioral area

 01234
3.

Jaw

 01234
4.

Tongue

 01234
Extremity
Movements		 5.

Upper (arms, wrists, hands, fingers)

 01234
6.

Lower (legs, knees, ankles, toes)

 01234
Trunk Movements 7.

Neck, shoulders, hips

 01234
Global Judgments 8.

Severity of abnormal movements overall

 01234
9.

Incapacitation due to abnormal movements

 01234
10.

Patient awareness of abnormal movements

 01234
Dental Status 11.

Current problems with teeth/dentures?

 NOYES
12.

Are dentures usually worn?

 NOYES
Total AIMS Score = 7

Diagnosis

  • Score of at least 2 on the AIMS and affecting at least 1 body part
  • Movements were choreoathetoid in nature and primarily affected the orofacial region
  • TD, based on visual assessment with the AIMS and DSM-5-TR criteria

Treatment Decisions: Considering Drug-Drug Interactions

Clinical Considerations

  • The American Psychiatric Association (APA) recommends treatment with a VMAT2 inhibitor for TD that has an impact on the patient, as is the case with Chris
  • Cannot modify underlying medical regimen (previously did not respond to lithium and atypical APDs)
  • Carbamazepine extended-release and glucocorticoids are strong CYP3A4 inducers
  • DDIs

~75%

of drugs are metabolized through the CYP3A4/5 or CYP2D6 pathways,
increasing the risk of DDIs

Icon of blue pill bottle with blue cap and first-aid cross in a blue circle with white background

Treatment With AUSTEDO® Resulted in Statistically Significant TD Symptom Control in the AIM-TD Trial

In the Addressing Involuntary Movements in Tardive Dyskinesia (AIM-TD) trial

  • Placebo: 1.4-point reduction vs baseline
  • 36 mg/day: 3.3-point reduction vs baseline
  • −1.9-point treatment effect vs placebo (P=0.001)


Patients in the AIM-TD clinical trial received the AUSTEDO BID formulation.

In the AIM-TD study, a 12-week, placebo-controlled, fixed-dose trial, adults with TD, ages 21 to 81 years, were randomized 1:1:1:1 to 12 mg of AUSTEDO, 24 mg of AUSTEDO, 36 mg of AUSTEDO, or placebo. 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 mg/day, 24 mg/day, or 36 mg/day. 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 the phase 3 trials for AUSTEDO, the most common adverse events (AEs) were nasopharyngitis and insomnia
  • Of patients taking AUSTEDO:
  • Discontinuation due to AEs occurred in 4% of patients vs 3% of patients on placebo
  • Dose reduction due to AEs was required in 4% of patients vs 2% of patients taking placebo
  • Adverse reactions with AUSTEDO XR® are expected to be similar to AUSTEDO BID

The Only VMAT2 Inhibitor Indicated for TD With No Recommendations Against Concomitant Use With CYP3A4/5 Inducers or Inhibitors

Table comparing DDI dose restrictions with AUSTEDO and Ingrezza

No trials comparing AUSTEDO XR and Ingrezza® have been conducted.

  • AUSTEDO XR has a range of dosing options for your patients on concomitant medications
  • AUSTEDO XR is metabolized primarily through CYP2D6, with minor contribution of CYP3A4/5 and other enzymes to form several minor metabolites
  • No dose reduction required for patients taking digoxin

Consider drug-drug interactions when choosing a treatment
for TD

Blue circle with blue half brain connected to blue half gear with cogs

A retrospective real-world analysis (July 2019 to June 2022) was conducted to estimate the proportion of patients with newly diagnosed TD not currently taking a VMAT2 inhibitor at risk of DDIs

Inclusion Criteria*

  • ≥18 years of age
  • ≥1 claim for an APD at any time
  • Continuous enrollment in the analysis for ≥3 months before and ≥12 months after TD diagnosis
  • Identified by ≥1 medial/pharmacy claim(s) ≥3 months prior to and ≥12 months after TD diagnosis
  • No VMAT2 inhibitor claims ≥3 months before and ≥12 months after TD diagnosis

Included patients (N=14,264)

A bar chart with 4 values: 20.8, 4.5, 4.2, 0.2 showing concomitant medication in possible DDI patients

*Patients were identified from the Symphony Health Solutions database, a US-based medical, hospital, and pharmacy claims database.

AUSTEDO XR: The Right Choice for Chris

Photo of Chris, jacket and open shirt, holding papers

Chris

Decision Made: Initiate
AUSTEDO XR

  • Based on efficacy and safety results of AUSTEDO BID in placebo-controlled clinical trials
  • AUSTEDO XR has no dose restrictions for or recommendations against use in patients taking strong CYP3A4/5 inducers or inhibitors
  • According to its product label, valbenazine is not recommended for use with strong CYP3A4 inducers
  • Chris was given a 4-week Titration Kit of AUSTEDO XR
  • He was instructed to call the office in 2 weeks to check in and schedule a follow-up visit in 4 weeks

Case Study: Treatment Outcome

Photo of Chris looking into distance, jacket on shoulder

Chris

Outcome

  • After 2 weeks on once-daily AUSTEDO XR, Chris called his doctor and reported that he had noticeable improvements in his jaw clenching and finger movements
  • At his 4-week follow-up appointment, there was a reduction in the AIMS score from 7 to 4
  • The eye blinking persisted—Chris was referred to a rheumatologist for further evaluation, since dry eyes could be a symptom of RA
  • Chris was instructed to schedule another follow-up visit in 4 weeks

Not an actual patient. Image is for illustrative purposes only.

​

Thank you for completing

Case Studies: Chapter 3 — Drug-Drug Interactions

Patient Case: Chris

Orange clipboard with checkmarks next to 3 lines, surrounded by an orange circle.

Summary:

Patients with TD often have comorbid conditions and concomitant medications, as seen in Chris’ case. With 75% of drugs metabolized through the CYP3A4/5 or CYP2D6 pathways, healthcare professionals should always be watchful for potential DDIs.

Explore the Next Chapter
Eva

Chapter 3 References:

American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed, Text Revision. Washington, DC: American Psychiatric Association; 2022.

American Psychiatric Association. The American Psychiatric Association Practice Guideline for the Treatment of Patients With Schizophrenia. 3rd ed. Washington, DC:

American Psychiatric Association; 2021.

Anderson KE et al. Lancet Psychiatry. 2017;4:595-604.

AUSTEDO XR® (deutetrabenazine) extended-release tablets/AUSTEDO® current Prescribing Information. Parsippany, NJ: Teva Neuroscience, Inc.

Data on file. Teva Neuroscience, Inc. Parsippany, NJ.

Flockhart DA et al. Division of Clinical Pharmacology, Indiana University School of Medicine. The Flockhart Cytochrome P450 Drug-Drug Interaction Table.
Accessed July 1, 2024. https://medicine.iu.edu/internal-medicine/specialties/clinical-pharmacology/drug-interaction-flockhart-table

Ingrezza® (valbenazine) capsules. Prescribing Information. San Diego, CA: Neurocrine Biosciences, Inc.

Mychaskiw M et al. Poster presented at: Annual Psych Congress Elevate; June 1-4, 2023; Las Vegas, Nevada.

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.