No dose restrictions up to 36 mg/day for patients starting AUSTEDO XR1
AUSTEDO XR is primarily metabolized
by CYP2D61*
| Drug coadministered with VMAT2 inhibitor |
Recommended Dosing | |
|---|---|---|
| AUSTEDO XR1,6,7 | Valbenazine8 | |
| 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.
Evidence suggests that, unlike most other CYP450 enzymes, CYP2D6 is not very susceptible to enzyme induction
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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.
Patients in the pivotal studies received the AUSTEDO BID formulation.1
*Minor contributions from the CYP3A4/5 pathways.1
†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.1,8
DDI, drug-drug interaction; VMAT2, vesicular monoamine transporter 2.
REFERENCES: 1. AUSTEDO XR® (deutetrabenazine) extended-release tablets and AUSTEDO® current Prescribing Information. Parsippany, NJ: Teva Neuroscience, Inc. 2. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005;352(21):2211-2221. 3. Basheer L, Kerem Z. Interactions between CYP3A4 and dietary polyphenols. Oxid Med Cell Longev. 2015;2015:854015. 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. Zhou SF. Polymorphism of human cytochrome P450 2D6 and its clinical significance: part I. Clin Pharmacokinet. 2009;48(11):689-723. 6. Zhou SF. Structure, function and regulation of P-glycoprotein and its clinical relevance in drug disposition. Xenobiotica. 2008;38(7-8):802-832. 7. Ahmed Juvale II, Abdul Hamid AA, Abd Halim KB, Che Has AT. P-glycoprotein: new insights into structure, physiological function, regulation and alterations in disease. Heliyon. 2022;8(6):e09777. 8. Ingrezza® (valbenazine) capsules. Prescribing Information. San Diego, CA: Neurocrine Biosciences, Inc. 9. NIH National Library of Medicine. Drugs, herbs and supplements. MedlinePlus. Updated April 28, 2015. Accessed March 26, 2025. https://medlineplus.gov/druginformation.html 10. Horn JR, Hansten PD. Get to know an enzyme: CYP3A4. Pharm Times. September 1, 2008. Accessed March 26, 2025. https://www.pharmacytimes.com/view/2008-09-8687 11. US Food and Drug Administration. Drug development and drug interactions: Table of substrates, inhibitors and inducers. US Food and Drug Administration. Updated June 5, 2023. Accessed March 26, 2025. https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers 12. PubChem Compound Database. National Center for Biotechnology Information. Accessed March 26, 2025. https://pubchem.ncbi.nlm.nih.gov 13. PubMed Central. National Center for Biotechnology Information. Accessed March 26, 2025. https://www.ncbi.nlm.nih.gov/pmc 14. Horn JR, Hansten PD. Get to know an enzyme: CYP2D6. Pharm Times. July 1, 2008. Accessed March 26, 2025. https://www.pharmacytimes.com/view/2008-07-8624 15. Grymonprez M, Vanspranghe K, Capiau A, Boussery K, Steurbaut S, Lahousse L. Impact of P-glycoprotein and/or CYP3A4-interacting drugs on effectiveness and safety of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: a meta-analysis. Br J Clin Pharmacol. 2022;88(7):3039-3051. 16. Agrawal A, Kerndt CC, Manna B. Apixaban. [Updated 2024 Feb 22]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; January 2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK507910. 17. Stahl SM. Comparing pharmacologic mechanism of action for the vesicular monoamine transporter 2 (VMAT2) inhibitors valbenazine and deutetrabenazine in treating tardive dyskinesia: does one have advantages over the other? CNS Spectr. 2018;23(4):239-247. 18. Broner NB, et al. Potency and specificity of deutetrabenazine deuterated metabolites for VMAT2 as confirmed by binding affinity and functional activity studies. Poster presented at: NEI Spring Congress; May 8-10, 2025; Philadelphia, PA.
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