Safety & Tolerability

Polypharmacy

Treat with AUSTEDO XR while maintaining your patient’s current regimen^1,2

AUSTEDO XR is the only once-daily VMAT2 inhibitor with no restrictions or recommendations against use with strong CYP3A4/5 inducers or inhibitors^1,3

~75% of drugs are metabolized through the CYP3A4/5 or CYP2D6 pathways, which may increase the likelihood of drug-drug interactions (DDIs) with subsequent medications in the treatment plan^4-6

Now Available One Pill, Once-Daily AUSTEDO XR

Coadministration per Pathway	Recommended Maximum Therapeutic Dose
	AUSTEDO XR¹	Ingrezza® (valbenazine) and Ingrezza® sprinkle (valbenazine)³
Strong CYP3A4/5 inducer	No dose restriction	Concomitant use is not recommended
Strong CYP3A4/5 inhibitor	No dose restriction	40 mg/day
Strong CYP2D6 inhibitor	36 mg/day	40 mg/day
Poor CYP2D6 metabolizer	36 mg/day	40 mg/day

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

Drug classes with significant interactions related to CYP3A4/5 and CYP2D6, as seen in clinical practice of psychiatric and diverse medical conditions

For a list of medications that can help determine potential drug-drug interactions with your patients’ concomitant treatments, see the Flockhart^TM Table

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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.

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.

VMAT2, vesicular monoamine transporter 2.

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Patients in the pivotal study received the AUSTEDO BID formulation.¹

AUSTEDO XR is metabolized primarily through CYP2D6, with minor contributions from CYP3A4/5.¹

VMAT2, vesicular monoamine transporter 2.

The brands listed are registered trademarks of their respective owners.

REFERENCES: 1. AUSTEDO^® XR (deutetrabenazine) extended-release tablets and AUSTEDO^® current Prescribing Information. Parsippany, NJ: Teva Neuroscience, Inc. 2. Data on file. Parsippany, NJ: Teva Neuroscience, Inc. 3. Ingrezza^® (valbenazine) capsules. Prescribing Information. San Diego, CA: Neurocrine Biosciences, Inc. 4. Lee S-J, Goldstein JA. Comparison of CYP3A4 and CYP3A5: the effects of cytochrome b5 and NADPH-cytochrome P450 reductase on testosterone hydroxylation activities. Drug Metab Pharmacokinet. 2012;27(6):663-667. 5. Basheer L, Kerem Z. Interactions between CYP3A4 and dietary polyphenols. Oxid Med Cell Longev. 2015;2015:854015. 6. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part I. Clin Pharmacokinet. 2009;48(11):689-723. 7. NIH National Library of Medicine. Drugs, herbs and supplements. MedlinePlus. Updated April 28, 2015. Accessed June 9, 2022. https://medlineplus.gov/druginformation.html 8. Horn JR, Hansten PD. Get to know an enzyme: CYP3A4. Pharm Times. September 1, 2008. Accessed November 12, 2022. https://www.pharmacytimes.com/view/2008-09-8687 9. US Food and Drug Administration. Drug development and drug interactions: table of substrates, inhibitors and inducers. US Food and Drug Administration. Updated March 10, 2020. Accessed November 12, 2022. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers 10. PubChem Compound Database. National Center for Biotechnology Information. Accessed November 12, 2022. https://pubchem.ncbi.nlm.nih.gov 11. PubMed Central. National Center for Biotechnology Information. Accessed November 12, 2022. https://www.ncbi.nlm.nih.gov/pmc 12. Horn JR, Hansten PD. Get to know an enzyme: CYP2D6. Pharm Times. July 1, 2008. Accessed November 12, 2022. https://www.pharmacytimes.com/view/2008-07-8624

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.

Treat with AUSTEDO XR while maintaining your patient’s current regimen^1,2

Examples of Drug Classes Associated With CYP3A4/5

Inhibitors

Inducers

Substrates

Examples of Drug Classes Associated With CYP2D6

Inhibitors

Inducers

Substrates

Watch: Visualizing the role of metabolic pathways in DDIs

Treat with AUSTEDO XR while maintaining your patient’s current regimen1,2

Examples of Drug Classes Associated With CYP3A4/5

Inhibitors

Inducers

Substrates

Examples of Drug Classes Associated With CYP2D6

Inhibitors

Inducers

Substrates

Watch: Visualizing the role of metabolic pathways in DDIs

Treat with AUSTEDO XR while maintaining your patient’s current regimen^1,2