AUSTEDO XR is a recommended first-line treatment option for adults with tardive dyskinesia1,2

Metabolic profile allows for few restrictions related to drug-
drug interactions3

No dose restrictions up to 36 mg/day for patients starting AUSTEDO XR3

  • When a drug that strongly induces or inhibits the same CYP enzyme responsible for metabolizing a
    VMAT2 inhibitor is taken concurrently, active metabolite levels are impacted4
  • ~50% of drugs are metabolized by CYP3A4/5 enzymes5,6

AUSTEDO XR is primarily metabolized
by CYP2D63*

  • ~2x fewer drugs are metabolized by CYP2D6 than by CYP3A4/55,7
Drug coadministered
with
VMAT2 inhibitor
Recommended Dosing
  AUSTEDO XR3,8,9 Valbenazine10
Strong CYP3A4/5 inducer No dose restriction Concomitant use is
not recommended
Strong CYP3A4/5 inhibitor No dose restriction 40 mg/day
lowest dose available
Strong CYP2D6 inhibitor
(or if patient is a poor
CYP2D6 metabolizer)
Up to
36 mg/day
40 mg/day
lowest dose available
P-gp substrate
(eg, calcium channel blockers, statins, antimicrobials,
and digoxin)
No dose adjustment to
P-gp substrate required
Dose adjustment
to P-gp substrate
may be required

No clinically significant QT prolongation up to the maximum recommended dose of AUSTEDO
(48 mg/day)3†

These differences should not be construed to imply difference in safety, efficacy, or clinical outcome.

Drug classes associated with CYP3A4/5, CYP2D6, and P-gp8,9,11-18

Examples of Drug Classes Associated With CYP3A4/5

Inhibitors

  • Antiarrhythmics
  • Antibiotics
  • Antidepressants
  • Antifungals
  • Antihypertensives
  • Antiretrovirals/
    antivirals

Inducers

  • Antibiotics
  • Anticonvulsants/
    sedatives
  • Antifungals
  • Antihypertensives
  • Corticosteroids
  • Wakefulness-promoting agents

Substrates

  • Antianginals
  • Antidiabetics
  • Antihistamines
  • Antihypertensives
  • Corticosteroids
  • Diuretics
  • Statins
  • Vasodilators

Examples of Drug Classes Associated With CYP2D6

Inhibitors

  • Antiarrhythmics
  • Antidepressants
  • Antifungals
  • Antihistamines
  • Antiparasitics
  • Antipsychotics
  • Calcium reducers

Inducers

Evidence suggests that, unlike most other CYP450 enzymes, CYP2D6 is not very susceptible to enzyme induction

Substrates

  • Antiarrhythmics
  • Antiemetics
  • Antihistamines
  • Antihypertensives
  • Antidepressants
  • Antipsychotics

Examples of Drug Classes Associated With P-gp

Inhibitors

  • Antiarrhythmics
  • Antidepressants
  • Antihypertensives
  • Antimicrobials
  • Statins
  • Vasodilators

Inducers

  • Antiarrhythmics
  • Anticonvulsants
  • Antidiabetics
  • Antihypertensives
  • Antimicrobials
  • Corticosteroids
  • Opioids

Substrates

  • Antimicrobials
  • Anticoagulants
  • Antiemetics
  • Anticonvulsants
  • Antihistamines
  • Antihypertensives
  • Beta blockers
  • Corticosteroids
  • Opioids
  • Statins
  • Vasodilators
  • For a list of medications that can help determine potential DDIs with your patients’ concomitant treatments, see the Flockhart TableTM
Secondary target binding3,19,20
  • Pharmacokinetic studies confirmed that VMAT2 inhibition with AUSTEDO XR is primarily driven by [+]-α-HTBZ and [+]-β-HTBZ metabolites
  • No clinically relevant implications with secondary target binding have been shown

In pharmacokinetic studies, increased plasma levels correlated with higher potential for treatment success, but not higher potential for adverse events21,22‡


Watch: Visualizing the role of metabolic pathways in DDIs

Onscreen text:

CYP enzymes mediate the breakdown of active drug to inactive metabolites for clearance.


Together, CYP3A4/5 and CYP2D6 enzymes are involved in metabolizing ~75% drugs.


CYP enzymes play a key role in converting VMAT2 inhibitors into their active and inactive metabolites.


VMAT2, vesicular monoamine transporter 2.


Certain drugs can act as strong CYP inhibitors or inducers, affecting the metabolism of coadministered medications…


…resulting in drug-drug interactions.


Inhibited metabolism


Inhibited metabolism results in elevated levels of active metabolites.


Elevated levels of active metabolites lead to increased drug potency and potential for adverse events.


Induced metabolism


Induced metabolism results in decreased levels of active metabolites.


Decreased levels of active metabolites diminish therapeutic effect.


For VMAT2 inhibitors, drug-drug interactions are determined by:


The CYP enzymes critical in metabolizing the VMAT2 inhibitor


AND


The metabolic profiles of the medications the patient is taking concomitantly (whether they are strong inhibitors or inducers)


To avoid drug-drug interactions associated with inhibited or induced metabolism, limiting VMAT2 inhibitor dose or avoiding use with strong inhibitors and inducers may be recommended.


When choosing a VMAT2 inhibitor, considering these drug-drug interactions is key.


VMAT 2, vesicular monoamine transporter 2.


Treating TD while managing underlying conditions: Susan’s story

Onscreen text:


TREATING TD WHILE MANAGING UNDERLYING CONDITIONS


SUSAN’S STORY


Age: 62


Primary conditions: Bipolar type II, seizure disorder


Disclaimer at bottom of screen:


This was an individual patient’s experience. Results may vary.


TD, tardive dyskinesia.


Susan:


My name is Susan Wheeler.


As a person who has tardive dyskinesia, I'm passionate to tell the story because there are treatments…


Onscreen text:


When Susan sought help for involuntary movements caused by antipsychotics, her psychiatrist prescribed a VMAT2 inhibitor.


Disclaimer on bottom of screen:


VMAT2, vesicular monoamine transporter 2.


But when Susan developed a seizure disorder, her TD treatment got more complicated.


Susan:


When I first received the diagnosis of TD and went to my doctor, I was prescribed another medication, and it worked for a while. But I then got another diagnosis of seizure disorder, and when I got that diagnosis, the new medications came on board and caused a conflict with that medication.


Onscreen text:


Susan is now on AUSTEDO XR because it can be taken with her seizure medication.


Onscreen Indication and Black Box Warning:


AUSTEDO XR® and AUSTEDO® are indicated in adults for the treatment of tardive dyskinesia and for the treatment of chorea associated with Huntington's disease.


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.


Please see additional Important Safety Information at the end of this video.


Susan:


My doctor said that AUSTEDO was a good option for me, that it was a medication that would help my tardive dyskinesia but wouldn't interact with the medications I took for both my mental health and seizure disorders…


Onscreen text:


After Susan started on AUSTEDO, she noticed an improvement in her movements.


Susan:


AUSTEDO has helped me. I don't see the mouth tics anymore, which is a great relief to me, because I do a lot of public speaking, and sing with groups.


Even in retirement, you still want to feel good about yourself, and not have to deal with explaining your TD symptoms.


Onscreen text:


Learn more about how AUSTEDO XR can work with your patient’s concomitant medications at AUSTEDOhcp.com.


Disclaimer at bottom of screen:


Patient was compensated for her participation.


Onscreen ISI scroll:


INDICATIONS AND USAGE


AUSTEDO XR and AUSTEDO are indicated in adults for the treatment of tardive dyskinesia and for the treatment of chorea associated with Huntington's disease.


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 full Prescribing Information, including Boxed Warning, at AUSTEDOhcp.com.

 

Patients in the pivotal studies received the AUSTEDO BID formulation.3

*Minor contributions from the CYP3A4/5 pathways.3

Based on studies in healthy patients. For patients with congenital long QT syndrome or arrhythmias associated with prolonged QT interval, all VMAT2 inhibitors should be avoided. Caution should be used for patients taking drugs that prolong the QT interval.3,10

Treatment success defined as “much improved” or “very much improved” based on Patient Global Impression of Change (PGIC) and Clinical Global impression of Change (CGIC).21

DDI, drug-drug interaction; VMAT2, vesicular monoamine transporter 2.

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