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There is more to the Parkinson’s disease (PD) picture than just dopamine¹

The addition of NOURIANZ^® (istradefylline) offers a balanced approach to PD^2,3

Just like a car needs a gas and brake pedal, people need to have dopamine and adenosine working together to help them move the way they want to.

In PD, motor dysfunction occurs when there is a deficiency of dopamine and an overactivation of adenosine A_2A receptors.¹ Levodopa/carbidopa acts on the gas but not on the brake.^2,4

Understanding the go (direct) and no go (indirect) pathways in PD

Imbalance among these pathways contributes to motor dysfunction.⁵

Dopamine works in both go and no go pathways, while adenosine works in the no go pathway only⁵
Adenosine is a product of cellular metabolism that is present in both non-PD and PD brains^5,6
In normal movement, balance between the pathways facilitates movement signals from the basal ganglia, enabling motor activity²
In patients with PD, dopamine levels are decreased, reducing the activity of the go pathway and increasing the activity of the no go pathway^1,5
As PD progresses, adenosine A_2A receptor concentration increases and the effect of adenosine on the no go pathway becomes more prominent^1,5

Human brain PET image by A_2A receptor tracer⁷

The density of adenosine A_2A receptors is identified by ¹¹C-TMSX PET imaging⁷

A: The normal subject is a healthy, 56-year-old man.

B: The newly diagnosed patient with Parkinson’s disease is a 56-year-old man with left-dominant parkinsonism. The distribution volume ratio (DVR) of ¹¹C-TMSX was smaller in the right putamen than in the left.

C: The patient with mild dyskinesia and Parkinson’s disease is a 66-year-old woman with left-dominant parkinsonism. Compared with the normal subject and newly diagnosed patient, the DVR of ¹¹C-TMSX in the striata was increased in the patient with dyskinesia.

DVR, distribution volume ratio; PET, positron emission tomography.

NOURIANZ works differently to lift the brake of adenosine in PD^2,3

NOURIANZ is a first-of-its-kind adenosine A_2A receptor antagonist indicated as adjunctive treatment to levodopa/carbidopa in adults for reducing “off” time in PD^3,8

The precise mechanism by which NOURIANZ exerts its therapeutic effect in PD is unknown.³

In in vitro studies and in vivo animal studies, NOURIANZ was demonstrated to be an adenosine A_2A receptor antagonist.³

“In PD, non-dopaminergic approaches can be useful in the clinical management of patients with “off” episodes. Istradefylline is the only adenosine A_2A antagonist to reach clinical practice.”⁸

- Drs Stuart H. Isaacson,
Sagari Betté, and Rajesh Pahwa

With a novel mechanism of action (MOA), NOURIANZ works differently than other adjunctive treatments for “off” episodes in PD⁸

The precise MOA by which NOURIANZ exerts its therapeutic effect in PD is unknown.³

NOURIANZ blocks A_2A receptors.³

DRUG CLASS^3,9-15	DOPAMINERGIC ACTIVITY	A_2A RECEPTOR ACTIVITY
A_2A receptor antagonist
Levodopa/carbidopa
COMT inhibitor
Dopamine agonist
MAO-B inhibitor
Other^a

^aIncludes other classes of medication for PD, like anticholinergics and N-methyl-D-aspartate (NMDA) receptor antagonists, including amantadine, which may have effects on dopamine neurons.^13-15
COMT, catechol-o-methyltransferase; MAO-B, monoamine oxidase B.

Dopaminergic treatments affect dopamine receptors in the striatum and in other areas of the brain and peripheral system^16,17
NOURIANZ is highly selective for adenosine A_2A receptors¹⁸
In in vitro studies and in vivo animal studies, NOURIANZ was demonstrated to be an adenosine A_2A receptor antagonist³

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Explore clinical study results Efficacy

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Important Safety Information

Warnings and Precautions

Dyskinesia: NOURIANZ in combination with levodopa may cause dyskinesia or exacerbate pre-existing dyskinesia. In clinical trials, 1% of patients treated with either NOURIANZ 20 mg or 40 mg discontinued treatment because of dyskinesia, compared to 0% for placebo.

Hallucinations / Psychotic Behavior: Because of the potential risk of exacerbating psychosis, patients with a major psychotic disorder should not be treated with NOURIANZ. Consider dosage reduction or discontinuation if a patient develops hallucinations or psychotic behaviors while taking NOURIANZ.

Impulse Control / Compulsive Behaviors: Patients treated with NOURIANZ and one or more medication(s) for the treatment of Parkinson’s disease (including levodopa) may experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge or compulsive eating, and/or other intense urges, and the inability to control these urges. In clinical trials, 1 patient treated with NOURIANZ 40 mg was reported to have impulse control disorder, compared to no patient on NOURIANZ 20 mg or placebo.

Drug Interactions

The maximum recommended dosage in patients taking strong CYP3A4 inhibitors is 20 mg once daily. Avoid use of NOURIANZ with strong CYP3A4 inducers.

Specific Populations

Pregnancy: Based on animal data, may cause fetal harm.

Hepatic impairment: The maximum recommended dosage of NOURIANZ in patients with moderate hepatic impairment is 20 mg once daily. Avoid use in patients with severe hepatic impairment.

Adverse Reactions

The most common adverse reactions with an incidence ≥5% and occurring more frequently than with placebo were dyskinesia (15%, 17%, and 8%), dizziness (3%, 6%, and 4%), constipation (5%, 6%, and 3%), nausea (4%, 6%, and 5%), hallucination (2%, 6%, and 3%), and insomnia (1%, 6%, and 4%) for NOURIANZ 20 mg, 40 mg, and placebo, respectively.

Indication

NOURIANZ^® (istradefylline) is an adenosine receptor antagonist indicated as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson’s disease (PD) experiencing “off” episodes.

You are encouraged to report suspected adverse reactions to Kyowa Kirin, Inc. at 1-844-768-3544 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Please see full Prescribing Information for NOURIANZ.

References: 1. NOURIANZ [package insert]. Kyowa Kirin, Inc., Princeton, NJ 08540. 2. Chen J-F, Cunha RA. The belated US FDA approval of the adenosine A_2A receptor antagonist istradefylline for treatment of Parkinson’s disease. Purinergic Signal. 2020;16(2):167-174. 3. Isaacson SH, Betté S, Pahwa R. Istradefylline for OFF episodes in Parkinson’s disease: a US perspective of common clinical scenarios. Degener Neurol Neuromuscul Dis. 2022;12:97-109.

References: 1. Parkinson’s disease. National Institutes of Health. Updated June 26, 2023. Accessed April 9, 2024. https://www.nih.gov/research-training/accelerating-medicines-partnership-amp/parkinsons-disease 2. Olanow CW, Poewe W, Rascol O, Stocchi F. From OFF to ON—treating OFF episodes in Parkinson’s disease. US Neurol. 2020;16(suppl 1):2-10.

References: 1. Kalia LV, Brotchie JM, Fox SH. Novel nondopaminergic targets for motor features of Parkinson's disease: review of recent trials. Mov Disord. 2013;28(2):131-144. 2. Mori A. Mode of action of adenosine A_2A receptor antagonists as symptomatic treatment for Parkinson’s disease. Int Rev Neurobiol. 2014;119:87-116. 3. Varani K, Vincenzi F, Tosi A, et al. A_2A adenosine receptor overexpression and functionality, as well as TNF-α levels, correlate with motor symptoms in Parkinson’s disease. FASEB J. 2010;24(2):587-598. doi:10.1096/fj.09-141044. 4. Fuxe K, Marcellino D, Genedani S, Agnati L. Adenosine A_2A receptors, dopamine D₂ receptors and their interactions in Parkinson's disease. Mov Disord. 2007;22(14):1990-2017. doi: 10.1002/mds.21440. 5. Morelli M, Di Paolo T, Wardas J, Calon F, Xiao D, Schwarzschild MA. Role of adenosine A_2A receptors in parkinsonian motor impairment and L-DOPA-induced motor complications. Prog Neurobiol. 2007;83(5):293-309. 6. Morelli M, Blandini F, Simola N, Hauser RA. A_2A receptor antagonism and dyskinesia in Parkinson's disease. Parkinsons Dis. 2012;2012:489853. doi: 10.1155/2012/489853. 7. Mishina M, Ishiwata K. Adenosine receptor PET imaging in human brain. Int Rev Neurobiol. 2014;119:51-69. doi:10.1016/B978-0-12-801022-8.00002-7. 8. The voice of the patient: Parkinson’s disease. Silver Spring, MD: US Food and Drug Administration; April 2016. https://www.fda.gov/media/124392/download. Accessed June 11, 2019. 9. Hickey P, Stacy M. Available and emerging treatments for Parkinson’s disease: a review. Drug Des Devel Ther. 2011;5:241-254. 10. Stocchi F, Antonini A, Barone P, et al. Early DEtection of wEaring off in Parkinson disease: the DEEP study. Parkinsonism Relat Disord. 2014;20(2):204-211.

References: 1. Kulisevsky J, Poyurovsky M. Adenosine A_2A-receptor antagonism and pathophysiology of Parkinson’s disease and drug-induced movement disorders. Eur Neurol. 2012;67(1):4-11. 2. Mori A. Mode of action of adenosine A_2A receptor antagonists as symptomatic treatment for Parkinson’s disease. Int Rev Neurobiol. 2014;119:87-116. 3. NOURIANZ [package insert]. Kyowa Kirin, Inc., Princeton, NJ 08540. 4. DHIVY [package insert]. Alpharetta, GA: Avion Pharmaceuticals, LLC; 2021. 5. Morelli M, Blandini F, Simola N, Hauser RA. A_2A receptor antagonism and dyskinesia in Parkinson’s disease. Parkinsons Dis. 2012;2012:489853. 6. Liu Y-J, Chen J, Li X, et al. Research progress on adenosine in central nervous system diseases. CNS Neurosci Ther. 2019;25(9):899-910. 7. Mishina M, Ishiwata K. Adenosine receptor PET imaging in human brain. Int Rev Neurobiol. 2014;119:51-69. 8. Isaacson SH, Betté S, Pahwa R. Istradefylline for OFF episodes in Parkinson’s disease: a US perspective of common clinical scenarios. Degener Neurol Neuromuscul Dis. 2022;12:97-109. 9. Chen J-F, Cunha RA. The belated US FDA approval of the adenosine A_2A receptor antagonist istradefylline for treatment of Parkinson’s disease. Purinergic Signal. 2020;16(2):167-174. 10. Brichta L, Greengard P, Flajolet M. Advances in the pharmacological treatment of Parkinson’s disease: targeting neurotransmitter systems. Trends Neurosci. 2013;36(9):543-554. 11. Kaakkola S, Wurtman RJ. Effects of COMT inhibitors on striatal dopamine metabolism: a microdialysis study. Brain Res.1992;587(2):241-249. 12. Kong P, Zhang B, Lei P, et al. Neuroprotection of MAO-B inhibitor and dopamine agonist in Parkinson disease. Int J Clin Exp Med. 2015;8(1):431-439. 13. Barrett MJ, Sargent L, Nawaz H, Weintraub D, Price ET, Willis AW. Antimuscarinic anticholinergic medications in Parkinson disease: to prescribe or deprescribe? Mov Disord Clin Pract. 2021;8(8):1181-1188. 14. Vanle B, Olcott W, Jimenez J, Bashmi L, Danovitch I, IsHak WW. NMDA antagonists for treating the non-motor symptoms in Parkinson’s disease. Transl Psychiatry. 2018;8(1):117. 15. Rascol O, Fabbri M, Poewe W. Amantadine in the treatment of Parkinson’s disease and other movement disorders. Lancet Neurol. 2021;20:1048-1056. 16. Rubí B, Maechler P. Minireview: new roles for peripheral dopamine on metabolic control and tumor growth: let’s seek the balance. Endocrinology. 2010;151(12):5570-5581. 17. Gerlach M, Double K, Arzberger T, Leblhuber F, Tatschner T, Riederer P. Dopamine receptor agonists in current clinical use: comparative dopamine receptor binding profiles defined in the human striatum. J Neural Transm (Vienna). 2003;110(10):1119-1127. 18. Jenner P. Istradefylline, a novel adenosine A_2A receptor antagonist, for the treatment of Parkinson’s disease. Expert Opin Investig Drugs. 2005;14(6):729-738. 19. Ishibashi K, Miura Y, Wagatsuma K, Toyohara J, Ishiwata K, Ishii K. Occupancy of adenosine A_2A receptors by istradefylline in patients with Parkinson’s disease using ¹¹C-preladenant PET. Neuropharmacology. 2018;143:106-112.

References: 1. NOURIANZ [package insert]. Kyowa Kirin, Inc., Princeton, NJ 08540. 2. Isaacson SH, Betté S, Pahwa R. Istradefylline for OFF episodes in Parkinson’s disease: a US perspective of common clinical scenarios. Degener Neurol Neuromuscul Dis. 2022;12:97-109. 3. Mori A. Mode of action of adenosine A_2A receptor antagonists as symptomatic treatment for Parkinson’s disease. Int Rev Neurobiol. 2014;119:87-116. 4. Data on file. Kyowa Kirin Pharmaceutical Development, Inc., Princeton, NJ.

References: 1. NOURIANZ [package insert]. Kyowa Kirin, Inc. Princeton, NJ 08540. 2. Data on file. Kyowa Kirin Pharmaceutical Development, Inc., Princeton, NJ. 3. Wadhwa RR, Cascella M. Steady state concentration. StatPearls Publishing; 2023.

References: 1. NOURIANZ [package insert]. Kyowa Kirin, Inc. Princeton, NJ 08540. 2. Data on file. Kyowa Kirin Pharmaceutical Development, Inc., Princeton, NJ. 3. Hauser RA, Hattori N, Fernandez H, et al. Efficacy of istradefylline, an adenosine A_2A receptor antagonist, as adjunctive therapy to levodopa in Parkinson’s disease: a pooled analysis of 8 phase 2b/3 trials. J Park Dis. 2021;11:1663-1675.

Reference: 1. NOURIANZ [package insert]. Kyowa Kirin, Inc., Princeton, NJ 08540.

References: 1. NOURIANZ [package insert]. Kyowa Kirin, Inc., Princeton, NJ 08540. 2. Isaacson SH, Betté S, Pahwa R. Istradefylline for OFF episodes in Parkinson’s disease: a US perspective of common clinical scenarios. Degener Neurol Neuromuscul Dis. 2022;12:97-109. 3. Kulisevsky J, Poyurovsky M. Adenosine A_2A-receptor antagonism and pathophysiology of Parkinson’s disease and drug-induced movement disorders. Eur Neurol. 2012;67(1):4-11. 4. Mori A. Mode of action of adenosine A_2A receptor antagonists as symptomatic treatment for Parkinson’s disease. Int Rev Neurobiol. 2014;119:87-116. 5. DHIVY [package insert]. Alpharetta, GA: Avion Pharmaceuticals, LLC; 2021. 6. Olanow CW, Poewe W, Rascol O, Stocchi F. From OFF to ON—treating OFF episodes in Parkinson’s disease. US Neurol. 2020;16(suppl 1):2-10. 7. Chou KL, Stacy M, Simuni T, et al. The spectrum of “off” in Parkinson’s disease: what have we learned over 40 years? Parkinsonism Relat Disord. 2018;51:9-16.

Reference: 1. NOURIANZ. Prescribing Information. Kyowa Kirin, Inc; 2020. Accessed April 1, 2021. https://www.nourianzhcp.com/assets/pdf/nourianz-full-prescribing-information.pdf