NOURIANZ istradefylline 20 mg Tablet, Film Coated, 7-count

5 WARNINGS AND PRECAUTIONS Dyskinesia: Monitor patients for dyskinesia or exacerbation of existing dyskinesia ( 5.1 ). Hallucinations / Psychotic Behavior: Consider dosage reduction or stopping NOURIANZ if occurs ( 5.2 ). Impulse Control / Compulsive Behaviors: Consider dosage reduction or stopping NOURIANZ if occurs ( 5.3 ).

5.1Dyskinesia NOURIANZ in combination with levodopa may cause dyskinesia or exacerbate pre-existing dyskinesia. In controlled clinical trials (Studies 1, 2, 3, and 4) [see Clinical Studies (14) ] , the incidence of dyskinesia was 15% for NOURIANZ 20 mg, 17% for NOURIANZ 40 mg, and 8% for placebo, in combination with levodopa. One percent of patients treated with either NOURIANZ 20 mg or 40 mg discontinued treatment because of dyskinesia, compared to 0% for placebo.

5.2Hallucinations / 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. In controlled clinical trials (Studies 1, 2, 3, and 4) [see Clinical Studies (14) ] , the incidence of hallucinations was 2% for NOURIANZ 20 mg, 6% for NOURIANZ 40 mg, and 3% for placebo.

In patients treated with NOURIANZ 40 mg, 1% discontinued because of hallucinations, compared to 0% for placebo and 0% for patients treated with NOURIANZ 20 mg. The incidence of "abnormal thinking and behavior" (paranoid ideation, delusions, confusion, mania, disorientation, aggressive behavior, agitation, or delirium) reported as an adverse reaction was 1% for NOURIANZ 20 mg, 2% for NOURIANZ 40 mg, and 1% for placebo.

5.3Impulse 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 controlled clinical trials (Studies 1, 2, 3 and 4) [see Clinical Studies (14) ] , one patient treated with NOURIANZ 40 mg was reported to have impulse control disorder, compared to no patient on placebo or NOURIANZ 20 mg.

In some postmarketing cases, these urges were reported to have stopped when the dose was reduced, or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with NOURIANZ. Consider dose reduction or discontinuation if a patient develops such urges while taking NOURIANZ [see Adverse Reactions (6.2) ] .

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.

6.1Clinical 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

6.2Postmarketing 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 ).

7.1Effect 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) ].

7.2Effect 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.