NOURIANZ

1 INDICATIONS AND USAGE NOURIANZ is indicated as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson's disease (PD) experiencing "off" episodes. NOURIANZ is an adenosine receptor antagonist indicated as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson's disease (PD) experiencing "off" episodes ( 1 ).

2 DOSAGE AND ADMINISTRATION The recommended dosage is 20 mg orally once daily. The dosage may be increased to a maximum of 40 mg once daily ( 2.1 ). May be taken with or without food ( 2.1 ). Patients with hepatic impairment: Maximum recommended dosage with moderate hepatic impairment is 20 mg once daily; use of NOURIANZ in patients with severe hepatic impairment should be avoided ( 2.4 , 8.7 ). Patients who smoke 20 or more cigarettes per day (or the equivalent of another tobacco product): Recommended dosage is 40 mg once daily ( 2.5 , 8.8 ). 2.1 Dosing Information The recommended dosage of NOURIANZ is 20 mg administered orally once daily. The dosage may be increased to a maximum of 40 mg once daily, based on individual need and tolerability. Initial dose titration is not required. NOURIANZ can be taken with or without food [see Clinical Pharmacology (12.3) ] . 2.2 Dosage Adjustment with Strong CYP3A4 Inhibitors The maximum recommended dosage of NOURIANZ with concomitant use of strong CYP3A4 inhibitors is 20 mg once daily [see Drug Interactions (7.1) ] . 2.3 Dosing with Strong CYP3A4 Inducers Avoid use of NOURIANZ with strong CYP3A4 inducers [see Drug Interactions (7.1) ] . 2.4 Dosage Adjustment in Patients with Hepatic Impairment The maximum recommended dosage of NOURIANZ in patients with moderate hepatic impairment (Child-Pugh Class B) is 20 mg once daily. Closely monitor patients with moderate hepatic impairment for adverse reactions when on NOURIANZ treatment [see Adverse Reactions (6.1) ] . Avoid use of NOURIANZ in patients with severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.7) ] . 2.5 Dosage Adjustment for Tobacco Smokers The recommended dosage of NOURIANZ in patients who use tobacco in amounts of 20 or more cigarettes per day (or the equivalent of another tobacco product) is 40 mg once daily [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.3) ] .

3 DOSAGE FORMS AND STRENGTHS 20 mg tablets: Peach-colored, pillow-shaped, film-coated tablets with "20" debossed on one side. 40 mg tablets: Peach-colored, almond-shaped, film-coated tablets with "40" debossed on one side. Tablets: 20 mg and 40 mg ( 3 ).

4 CONTRAINDICATIONS None. None ( 4 ).

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Dyskinesia [see Warnings and Precautions (5.1) ] Hallucinations / Psychotic Behavior [see Warnings and Precautions (5.2) ] Impulse Control / Compulsive Behaviors [see Warnings and Precautions (5.3) ] The most common adverse reactions (at least 5% and more frequent than placebo) were dyskinesia, dizziness, constipation, nausea, hallucination, and insomnia ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Kyowa Kirin Inc. at 1-844-768-3544 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of NOURIANZ was evaluated in 734 patients with Parkinson's disease (PD) taking a stable dose of levodopa and a DOPA decarboxylase inhibitor, with or without other PD medications, in four randomized, multicenter, double-blind, placebo-controlled trials 12 weeks in duration (Studies 1, 2, 3 and 4) [see Clinical Studies (14) ] . Of the patient population exposed to NOURIANZ, 50% were male, 32% White, 67% Asian, and the mean age was 65 years (range: 33 to 84 years). Of these patients, 356 received NOURIANZ 20 mg and 378 received NOURIANZ 40 mg. Adverse Reactions Leading to Discontinuation of Treatment The incidence of patients discontinuing for any adverse reaction was 5% for NOURIANZ 20 mg, 6% for NOURIANZ 40 mg, and 5% for placebo. The most frequently reported adverse reaction causing study discontinuation was dyskinesia [see Warnings and Precautions (5.1) ] . Common Adverse Reactions in Pooled Placebo-Controlled Trials Table 1 shows adverse reactions with a frequency of at least 2% in patients treated with NOURIANZ 20 mg or 40 mg once daily. The most common adverse reactions in which the frequency for NOURIANZ was at least 5%, and greater than the incidence on placebo, were dyskinesia, dizziness, constipation, nausea, hallucination, and insomnia. Table 1: Adverse Reactions with an Incidence of at Least 2% in Patients Treated with NOURIANZ, and Greater than on Placebo, in Pooled Studies 1, 2, 3, and 4 Adverse Reactions NOURIANZ 20 mg/day (N=356) % NOURIANZ 40 mg/day (N=378) % Placebo N=426 (%) Nervous system disorders Dyskinesia 15 17 8 Dizziness 3 6 4 Gastrointestinal disorders Constipation 5 6 3 Nausea 4 6 5 Diarrhea 1 2 1 Psychiatric disorders Hallucination Includes hallucinations, hallucinations visual, hallucinations olfactory, hallucinations somatic, hallucinations auditory. 2 6 3 Insomnia 1 6 4 Metabolism and nutrition disorders Decreased appetite 1 3 1 Investigations Blood alkaline phosphatase increased 1 2 1 Blood glucose increased 1 2 0 Blood urea increased 1 2 0 Respiratory, thoracic and mediastinal disorders Upper Respiratory Tract Inflammation 1 2 0 Skin and subcutaneous tissue disorders Rash 1 2 1 6.2 Postmarketing Experience The following adverse reaction has been identified during post approval use of istradefylline outside of the United States. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: increased libido.

7 DRUG INTERACTIONS Strong CYP3A4 inhibitors: Recommended maximum dosage with concomitant use is 20 mg once daily ( 2.2 , 7.1 ). Strong CYP3A4 inducers: Avoid use ( 2.3 , 7.1 ). 7.1 Effect of Other Drugs on NOURIANZ Strong CYP3A4 Inhibitors Coadministration of NOURIANZ with a strong CYP3A4 inhibitor (ketoconazole) increased istradefylline AUC inf by 2.5-fold [see Clinical Pharmacology (12.3) ] . Therefore, the recommended maximum dosage of NOURIANZ in patients concomitantly using strong CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, clarithromycin) is 20 mg once daily [see Dosage and Administration (2.2) ]. Strong CYP3A4 Inducers Coadministration of NOURIANZ with a strong CYP3A4 inducer (rifampin) decreased istradefylline C max and AUC inf by 45% and 81%, respectively [see Clinical Pharmacology (12.3) ] . Therefore, it is recommended to avoid use of NOURIANZ with strong CYP3A4 inducers (e.g., carbamazepine, rifampin, phenytoin, St. John's wort) [see Dosage and Administration (2.3) ]. 7.2 Effect of NOURIANZ on Other Drugs CYP3A4 Substrates Coadministration of NOURIANZ 20 mg with a CYP3A4 substrate (midazolam) did not affect the CYP3A4 substrate exposure, while concomitant administration of NOURIANZ 40 mg increased the CYP3A4 substrate (atorvastatin) C max and AUC inf by 1.5-fold [see Clinical Pharmacology (12.3) ] . Monitor for an increase in adverse reactions of concomitant drugs that are CYP3A4 substrates when coadministering with NOURIANZ 40 mg. P-glycoprotein (P-gp) Substrates Coadministration of NOURIANZ with a P-gp substrate (digoxin) increased the P-gp substrate C max and AUC inf by 33% and 21%, respectively [see Clinical Pharmacology (12.3) ] . Monitor for an increase in adverse reactions of concomitant drugs that are P-gp substrates when coadministering with NOURIANZ.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm ( 8.1 ). 8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of NOURIANZ in pregnant women. In animal studies ( see Data ), oral administration of istradefylline during pregnancy resulted in teratogenicity (increased incidences of fetal structural abnormalities, embryofetal and offspring mortality and growth deficits) at clinically relevant exposures and in the absence of maternal toxicity. The teratogenic effects of istradefylline in pregnant rabbits were substantially greater when administered in combination with levodopa/carbidopa than when administered alone. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2-4% and 15-20%, respectively. Data Animal Data Oral administration of istradefylline (0, 40, 200, or 1000 mg/kg/day) to pregnant rats throughout organogenesis resulted in decreased fetal body weight and increased fetal skeletal and visceral variations at the highest dose tested. Plasma exposure (AUC) at the no-effect dose for adverse effects on embryofetal development in rats (200 mg/kg/day) is approximately 4 times that in humans at the maximum recommended human dose (MRHD) of 40 mg. Oral administration of istradefylline (0, 50, 200, or 800 mg/kg/day) to pregnant rabbits throughout organogenesis resulted in increased embryofetal mortality at the mid and high doses, increased fetal malformations (external, visceral, skeletal) at all doses, and reduced fetal body weight at the highest dose tested. A no-effect dose for adverse effects on embryofetal development in rabbits was not identified. Plasma exposure (AUC) at the lowest dose tested (50 mg/kg/day) is less than that in humans at the MRHD. In pregnant rabbits, oral administration of istradefylline (0, 50, 200, or 400 mg/kg/day) alone or in combination with oral levodopa/carbidopa (80/20 mg/kg/day) throughout the period of organogenesis resulted in an increase in embryofetal mortality and an increase (marked at the high dose) in malformations (including limb reduction, craniofacial, and cardiovascular) in fetuses from rats administered istradefylline at all doses in combination with levodopa/carbidopa. Istradefylline alone resulted in an increase in embryofetal mortality and visceral malformations; no increase in fetal malformations was observed with levodopa/carbidopa alone. Fetal body weight was reduced by istradefylline alone (400 mg/kg/day) and in combination (200 and 400 mg/kg/day) with levodopa/carbidopa. A no-effect dose for adverse effects on embryofetal development in rabbits when istradefylline was administered in combination with levodopa/carbidopa was not identified. Plasma exposure (AUC) at the lowest dose of istradefylline tested (50 mg/kg/day) in combination with levodopa/carbidopa is less than that in humans at the MRHD. Oral administration of istradefylline (0, 6, 25, 100, or 400 mg/kg/day) to female rats throughout gestation and lactation resulted in decreased pup survival and reduced pup body weight (which persisted into adulthood) at all but the lowest dose tested. Exposure to drug in the milk may have contributed to these effects, as demonstrated in pups of untreated (control) dams reared by dams receiving istradefylline (400 mg/kg/day). No adverse effects were observed on physical or neurobehavioral development, or reproductive function. Plasma exposure at the no-effect dose for adverse effects on pre- and postnatal development in rats (6 mg/kg/day) is less than that in humans at the MRHD. 8.2 Lactation Risk Summary There are no data on the presence of istradefylline in human milk, the effects of istradefylline on the breastfed infant, or the effects of istradefylline on milk production. Istradefylline was presen …

12.1 Mechanism of Action The precise mechanism by which istradefylline exerts its therapeutic effect in Parkinson’s disease is unknown. In in vitro studies and in in vivo animal studies, istradefylline was demonstrated to be an adenosine A 2A receptor antagonist.

11 DESCRIPTION NOURIANZ contains istradefylline, an adenosine receptor antagonist, which has a xanthine derivative structure. The chemical name is ( E )-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methyl-3,7-dihydro-1 H -purine-2,6-dione. Its molecular formula is C 20 H 24 N 4 O 4 . The molecular weight is 384.43. Istradefylline has the following structural formula: Istradefylline is a light yellow-green crystalline powder. Istradefylline has a dissociation constant (p K a ) of 0.78. The aqueous solubility of istradefylline is ~0.5 μg/mL across the physiological pH range and 0.6 μg/mL in water. NOURIANZ tablets are intended for oral administration only. Each tablet contains 20 mg or 40 mg of istradefylline and the following inactive ingredients: crospovidone, lactose monohydrate, magnesium stearate, microcrystalline cellulose, and polyvinyl alcohol. The film coating contains hypromellose, lactose monohydrate, polyethylene glycol 3350, titanium dioxide, triacetin, and the following dyes: iron oxide red and iron oxide yellow. Carnauba wax is used for polishing. Chemical Structure

10 OVERDOSAGE 10.1 Human Experience There is limited clinical experience regarding human overdosage with NOURIANZ. In clinical trials, one patient took 6 tablets (120 mg, 3 times the maximum recommended dosage) of istradefylline with alcoholic beverages and developed hallucinations, agitation, and worsening dyskinesia. 10.2 Management of Overdose There are no known specific antidotes for NOURIANZ nor any specific treatment for istradefylline overdose. If an overdose occurs, NOURIANZ treatment should be discontinued and supportive treatment should be administered as clinically indicated. Consider the long terminal half-life of istradefylline (about 83 hours) and the possibility of multiple drug involvement. Consult a Certified Poison Control Center for up-to-date guidance and advice.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied NOURIANZ (istradefylline) tablets are available as: 20 mg Tablets: Peach-colored, pillow-shaped, film-coated tablets with "20" debossed on one side. Bottle of 90: NDC 42747-602-90 40 mg Tablets: Peach-colored, almond-shaped, film-coated tablets with "40" debossed on one side. Bottle of 90: NDC 42747-604-90 16.2 Storage and Handling Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F) [see USP Controlled Room Temperature].