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Impact of COMT

MOD

Is your levodopa/CARBIDOPA strategy missing something?

In PD, peripheral enzymes can limit levodopa from getting to the brain1-3

Before levodopa can get to the brain, 2 major enzymes may metabolize it substantially: DDC & COMT1,2,4-8

Before levodopa crosses the blood-brain barrier, the COMT and DDC enzymes may metabolize levodopa. See Important Safety Information. 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 peripheral metabolic pathway for levodopa2,3,6,7,9,10

  • Brain icon

    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 levodopa/carbidopa experience off time, a common treatment approach is to increase the dose and/or frequency of levodopa/carbidopa—leaving the COMT enzyme unchecked3,12-14

Mechanism of Disease Video Thumbnail

See the Impact of the COMT Enzyme

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

Watch the MOD Video >

Is the COMT enzyme metabolizing the levodopa your patients need?

3-OMD=3-O-methyldopa; COMT=catechol-O-methyltransferase; DDC=dopa decarboxylase; PD=Parkinson’s disease.

MOA

the early levodopa/carbidopa partner for off time that optimizes levodopa15,16

A unique molecule in COMT inhibition, ONGENTYS has15,17

Brain icon

High COMT-binding affinity

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Prolonged pharmacologic effect

Capsule icon

Once-daily dosing

  • As carbidopa protects levodopa from the DDC enzyme, ONGENTYS® (opicapone) capsules 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 brain12,15,18,19
  • Increased levodopa exposure by up to 74%, helping more levodopa be available to reach the brain15,16

COMT=catechol-O-methyltransferase; DDC=dopa decarboxylase; MAO=monoamine oxidase.

Mechanism of Action Video Thumbnail

Watch the science behind ONGENTYS

Explore the science behind the first and only once-daily COMT inhibitor15

Watch the MOA Video >

Optimize your treatment with the first and only once-daily COMT inhibitor15

Why ONGENTYS

VIEW FULL IMPORTANT SAFETY INFORMATION

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:

footnotes

  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 anti-parkinsonian drugs. Clin Pharmacokinet. 1987;13(3):141-178.
  5. Andersson I, Granerus A-K, 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 disease (2009). Neurology. 2009;72(21)(suppl 4):S1-S136.
  15. ONGENTYS [package insert]. San Diego, CA: Neurocrine Biosciences, Inc; 2020.
  16. Data on file. Neurocrine Biosciences, Inc.
  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. Dézsi L, Vécsei L. Monoamine oxidase B inhibitors in Parkinson’s disease. CNS Neurol Disord Drug Targets. 2017;16(4):425-439.
  19. 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.