Safety & Tolerability

Polypharmacy

Only VMAT2 inhibitor indicated for TD with no dose restrictions for—or recommendations against—use in patients taking strong CYP3A4/5 inducers or inhibitors³

Patients with TD take a variety of concomitant medications—it is important to consider metabolic pathways in the treatment of tardive dyskinesia (TD)^3,4

~50% of drugs are metabolized through the CYP3A4/5 pathway, which may increase the likelihood of drug-drug interactions with subsequent medications in the treatment plan^4,5
AUSTEDO^® (deutetrabenazine) tablets are metabolized primarily through CYP2D6—with minor contributions of CYP3A4/5 and other enzymes to form several minor metabolites³

Coadministration per Pathway	Recommended Maximum Therapeutic Dose
	AUSTEDO³	Ingrezza® (valbenazine)⁶
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.

In patients who are poor CYP2D6 metabolizers or are taking strong CYP2D6 inhibitors, the total dosage of AUSTEDO should not exceed 36 mg/day (maximum single dose of 18 mg).³

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

In the pivotal studies, most patients taking AUSTEDO were able to stay on their concomitant psychiatric medications¹³

Learn more: dosing options

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Rakesh Jain discuss drug metabolism as a crucial consideration for TD treatment

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AUSTEDO.

For more TD Talks videos, visit the
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AUSTEDO.

VMAT2, vesicular monoamine transporter 2.

REFERENCES: 1. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Schizophrenia. 3rd ed. American Psychiatric Association; 2021. 2. Bhidayasiri R, Jitkritsadakul O, Friedman JH, Fahn S. Updating the recommendations for treatment of tardive syndromes: a systematic review of new evidence and practical treatment algorithm. J Neurol Sci. 2018;389:67-75. 3. AUSTEDO^® (deutetrabenazine) tablets current Prescribing Information. Parsippany, NJ: Teva Neuroscience, Inc. 4. Lynch T, Price A. The effect of cytochrome P450 metabolism on drug response, interactions, and adverse effects. Am Fam Physician. 2007;76(3):391-396. 5. 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. 6. INGREZZA^® (valbenazine) capsules Prescribing Information. San Diego, CA: Neurocrine Biosciences, Inc.; April 2021. 7. 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. Pharmacy Times. September 1, 2008. Accessed June 9, 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 June 9, 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 June 9, 2022. https://pubchem.ncbi.nlm.nih.gov 11. PubMed Central. National Center for Biotechnology Information. Accessed June 9, 2022. https://www.ncbi.nlm.nih.gov/pmc 12. Horn JR, Hansten PD. Get to know an enzyme: CYP2D6. Pharmacy Times. July 1, 2008. Accessed June 9, 2022. https://www.pharmacytimes.com/view/2008-07-8624 13. Data on file. Parsippany, NJ: Teva Neuroscience, Inc.

Important safety information

Depression and Suicidality in Patients with Huntington’s Disease: 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 is contraindicated in patients who are suicidal, and in patients with untreated or inadequately treated depression.

Contraindications: AUSTEDO is contraindicated in patients with Huntington’s disease who are suicidal, or have untreated or inadequately treated depression. AUSTEDO is 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 (Xenazine^®) or valbenazine (Ingrezza^®).

Clinical Worsening and Adverse Events in Patients with Huntington’s Disease: AUSTEDO may cause a 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.

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. 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; intensive symptomatic treatment and medical monitoring; and treatment of any concomitant serious medical problems.

Akathisia, Agitation, and Restlessness: 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 dose should be reduced; some patients may require discontinuation of therapy.

Parkinsonism: 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 dose should be reduced; some patients may require discontinuation of therapy.

Sedation and Somnolence: Sedation is a common dose-limiting adverse reaction of 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 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.

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.

Please see full Prescribing Information, including Boxed Warning.

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Only VMAT2 inhibitor indicated for TD with no dose restrictions for—or recommendations against—use in patients taking strong CYP3A4/5 inducers or inhibitors³

Examples of Drug Classes Associated With CYP3A4/5

Inhibitors

Inducers

Substrates

Examples of Drug Classes Associated With CYP2D6

Inhibitors

Inducers

Substrates

Watch Dr.
Rakesh Jain discuss drug metabolism as a crucial consideration for TD treatment

Only VMAT2 inhibitor indicated for TD with no dose restrictions for—or recommendations against—use in patients taking strong CYP3A4/5 inducers or inhibitors3

Examples of Drug Classes Associated With CYP3A4/5

Inhibitors

Inducers

Substrates

Examples of Drug Classes Associated With CYP2D6

Inhibitors

Inducers

Substrates

Watch Dr. Rakesh Jain discuss drug metabolism as a crucial consideration for TD treatment

Only VMAT2 inhibitor indicated for TD with no dose restrictions for—or recommendations against—use in patients taking strong CYP3A4/5 inducers or inhibitors³

Watch Dr.
Rakesh Jain discuss drug metabolism as a crucial consideration for TD treatment