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THE IMPACT OF COMT

PHYSIOLOGY

How can you make levodopa more available where it matters?

In Parkinson's disease, two peripheral enzymes, DDC & COMT, can substantially metabolize levodopa in the periphery and limit levodopa from getting to the brain. Inhibition of DDC and COMT can optimize levodopa1-8

Graphic: Before levodopa crosses the blood-brain barrier, the COMT and DDC enzymes may metabolize levodopa. See Important Safety Information Graphic: Before levodopa crosses the blood-brain barrier, the COMT and DDC enzymes may metabolize levodopa. See Important Safety Information
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    When the DDC enzyme is inhibited by carbidopa, COMT becomes the predominant pathway for metabolizing levodopa, decreasing concentrations in the periphery2,3,6,7,9,10

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    In addition to causing lower levodopa concentrations, the metabolism of levodopa by COMT produces the metabolite 3-OMD. 3-OMD is thought to compete with levodopa for transport across the blood-brain barrier2,3,11

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    When patients on CD/LD experience "off" time, a common treatment approach is to increase the dose and/or frequency of CD/LD—leaving the COMT enzyme unchecked3,12-14

Graphic: Mechanism of Disease Video thumbnail

See the Impact of the COMT Enzyme

Learn how the COMT enzyme can make the path of levodopa to the brain more difficult.

Is COMT inhibition what your patient needs to make levodopa more available where it matters?

3-OMD=3-O-methyldopa; CD=carbidopa; COMT=catechol-O-methyltransferase; DDC=DOPA decarboxylase; LD=levodopa.

Mechanism of action

ONGENTYS is the adjunct therapy to CD/LD that may reduce "OFF" time by optimizing levodopa15-18

ONGENTYS® (opicapone) is a COMTi that offers15-17:

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Selective peripheral COMT inhibition

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Prolonged pharmacological effect due to long-lasting COMT inhibition

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Simple, once‑daily dosing

  • As carbidopa protects levodopa from the DDC enzyme, ONGENTYS protects levodopa from the COMT enzyme in the periphery15,17
    • Distinct from MAO-B inhibitors and dopamine agonists, which don't directly impact levodopa before it reaches the brain12,15,19,20
  • ONGENTYS contributed to more consistent levels of levodopa by reducing peak-trough fluctuations by 46%16
Graphic: Mechanism of Action Video thumbnail

Watch the science behind ONGENTYS

Explore the mechanism behind the selective COMT inhibition with once-daily ONGENTYS.15

Watch the MOA Video

Optimize your treatment strategy with the once-daily COMT inhibitor15

Why ONGENTYS

CD=carbidopa; COMT=catechol-O-methyltransferase; COMTi=COMT inhibitor; DDC=DOPA decarboxylase; LD=levodopa; MAO-B=monoamine oxidase-B; MOA=mechanism of action.

Important Information

INDICATION & USAGE

ONGENTYS® (opicapone) capsules is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson's disease (PD) experiencing "off" episodes.

IMPORTANT SAFETY INFORMATION

CONTRAINDICATIONS

ONGENTYS is contraindicated in patients with:

  • Concomitant use of non-selective monoamine oxidase (MAO) inhibitors.
  • Pheochromocytoma, paraganglioma, or other catecholamine secreting neoplasms.

WARNINGS & PRECAUTIONS

Cardiovascular Effects with Concomitant Use of Drugs Metabolized by Catechol-O-Methyltransferase (COMT) - Possible arrhythmias, increased heart rate, and excessive changes in blood pressure may occur with concomitant use of ONGENTYS and drugs metabolized by COMT, regardless of the route of administration (including inhalation). Monitor patients treated concomitantly with ONGENTYS and drugs metabolized by COMT.

Falling Asleep During Activities of Daily Living and Somnolence - Patients have reported falling asleep while engaged in activities of daily living, including driving, which may result in accidents. Consider discontinuing ONGENTYS or adjusting other dopaminergic/sedating medications. Advise patients to avoid driving and other potentially dangerous activities.

Hypotension/Syncope - Monitor patients for hypotension and advise patients about the risk for syncope. If necessary, consider discontinuing ONGENTYS or adjusting the dosage of other medications that can lower blood pressure.

Dyskinesia - ONGENTYS may cause or exacerbate dyskinesia. Consider levodopa or dopaminergic medication dose reduction.

Hallucinations and Psychosis - Consider stopping ONGENTYS if these occur. Patients with a major psychotic disorder should ordinarily not be treated with ONGENTYS.

Impulse Control/Compulsive Disorders - Patients may experience intense urges (eg, gambling, sexual, spending money, binge eating) and the inability to control them. It is important for prescribers to ask about the development of new or increased urges. Monitor for occurrence of intense urges and consider discontinuing ONGENTYS if they occur.

Withdrawal-Emergent Hyperpyrexia and Confusion - A symptom complex resembling neuroleptic malignant syndrome can develop with rapid dose reduction or withdrawal of drugs that increase central dopaminergic tone. When discontinuing ONGENTYS, monitor patients and consider adjustment of dopaminergic therapies as needed.

ADVERSE REACTIONS

The most common adverse reactions (incidence at least 4% and greater than placebo) were dyskinesia, constipation, blood creatine kinase increased, hypotension/syncope, and weight decreased.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit MedWatch at www.fda.gov/medwatch or call 1-800-FDA-1088.

Please see ONGENTYS full Prescribing Information.

References:

  1. Goodall M, Alton H. Metabolism of 3,4-dihydroxyphenylalanine (L-dopa) in human subjects. Biochem Pharmacol. 1972;21(17):2401-2408.
  2. Männistö PT, Kaakkola S. Catechol-O-methyltransferase (COMT): biochemistry, molecular biology, pharmacology, and clinical efficacy of the new selective COMT inhibitors. Pharmacol Rev. 1999;51(4):593-628.
  3. Reilly DK, Rivera-Calimlim L, Van Dyke D. Catechol-O-methyltransferase activity: a determinant of levodopa response. Clin Pharmacol Ther. 1980;28(2):278-286.
  4. Cedarbaum JM. Clinical pharmacokinetics of antiparkinsonian drugs. Clin Pharmacokinet. 1987;13(3):141-178.
  5. Andersson I, Granerus AK, Jagenburg R, Svanborg A. Intestinal decarboxylation of orally administered L-dopa: influence of pharmacological preparation, dose magnitude, dose sequence and food intake. Acta Med Scand. 1975;198(5):415-420.
  6. Kuruma I, Bartholini G, Tissot R, Pletscher A. Comparative investigation of inhibitors of extracerebral dopa decarboxylase in man and rats. J Pharm Pharmacol. 1972;24(4):289-294.
  7. Reilly DK, Rivera-Calimlim L. Red blood cell catechol-O-methyl transferase, plasma 3-O-methyldopa and dyskinesias [abstract 57]. Pharmacologist. 1978;20:156.
  8. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA. 2014;311(16):1670-1683.
  9. Rivera-Calimlim L, Tandon D, Anderson F, Joynt R. The clinical picture and plasma levodopa metabolite profile of parkinsonian nonresponders: treatment with levodopa and decarboxylase inhibitor. Arch Neurol. 1977;34(4):228-232.
  10. Dingemanse J, Kleinbloesem CH, Zürcher G, Wood ND, Crevoisier C. Pharmacodynamics of benserazide assessed by its effects on endogenous and exogenous levodopa pharmacokinetics. Br J Clin Pharmacol. 1997;44(1):41-48.
  11. Wade LA, Katzman R. 3-O-methyldopa uptake and inhibition of L-dopa at the blood-brain barrier. Life Sci. 1975;17(1):131-136.
  12. Fabbri M, Rosa MM, Ferreira JJ. Adjunctive therapies in Parkinson's disease: how to choose the best treatment strategy approach. Drugs Aging. 2018;35(12):1041-1054.
  13. Ondo WG. Motor complications in Parkinson's disease. Int J Neurosci. 2011;121(suppl 2):37-44.
  14. Olanow CW, Stern MB, Sethi K. The scientific and clinical basis for the treatment of Parkinson's disease (2009). Neurology. 2009;72(21)(suppl 4):S1-S136.
  15. ONGENTYS [package insert]. Bridgewater, NJ: Amneal Pharmaceuticals LLC; 2023.
  16. Data on file. Amneal Pharmaceuticals LLC.
  17. Rocha J-F, Falcão A, Santos A, et al. Effect of opicapone and entacapone upon levodopa pharmacokinetics during three daily levodopa administrations. Eur J Clin Pharmacol. 2014;70(9):1059-1071.
  18. Rocha JF, Ebersbach G, Lees A, et al. The added benefit of opicapone when used in Parkinson's disease patients with levodopa-induced motor fluctuations: a post-hoc analysis of BIPARK-I and -II. Front Neurol. 2021;12:754016.
  19. Dézsi L, Vécsei L. Monoamine oxidase B inhibitors in Parkinson's disease. CNS Neurol Discord Drug Targets. 2017;16(4):425-439.
  20. Stocchi F, Torti M, Fossati C. Advances in dopamine receptor agonists for the treatment of Parkinson's disease. Expert Opin Pharmacother. 2016;17(14):1889-1902.