Istradefylline

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) ] .

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.

12.3 Pharmacokinetics Istradefylline exhibits dose-proportional pharmacokinetics after multiple oral doses from 20 mg to 80 mg (2 times the maximum recommended dosage). Steady-state was reached within 2 weeks of once-daily dosing. The pharmacokinetics of istradefylline were similar in PD patients and healthy subjects. Absorption The median time to reach the maximum concentration (T max ) for istradefylline was about 4 hours under fasted dosing conditions. Effect of Food Istradefylline exposure, represented by the area under the curve over time to infinity (AUC inf ), increased 1.25-fold when NOURIANZ was coadministered with a standard high-fat meal, compared with administration in a fasted state. Istradefylline maximum plasma concentrations (C max ) increased by 1.64-fold and T max was shortened by 1 hour when NOURIANZ was administered with a high-fat meal. These differences in pharmacokinetic parameters are not expected to be clinically significant [see Dosage and Administration (2.1) ]. Distribution The plasma protein binding of istradefylline was approximately 98%. The apparent volume of distribution (V d /F) of istradefylline is approximately 557 liters. Elimination The total clearance of istradefylline is approximately 4.6 L/hour. The mean terminal half-life (t 1/2 ) for istradefylline at steady-state is approximately 83 hours. Metabolism In humans, istradefylline is exclusively eliminated via metabolism. In vitro studies indicate that istradefylline is primarily metabolized via CYP1A1 and CYP3A4, with minor contribution from CYP1A2, 2B6, 2C8, CYP2C9, CYP2C18, and 2D6. Six metabolites have been identified in human plasma. These metabolites each account for less than 10% of the exposure of the parent drug. Excretion Approximately 48% of a 40-mg oral dose of 14 C-istradefylline was eliminated in feces, and 39% in urine. Unchanged istradefylline was not detected in urine. Specific Populations In patients with moderate hepatic impairment (Child-Pugh Class B), the steady-state exposure (AUC 0-24 ) of istradefylline is predicted to be 3.3-fold higher relative to healthy subjects, based on the estimated mean terminal half-life [see Use in Specific Populations (8.7) ]. Based on population pharmacokinetic analyses, no clinically relevant changes in the pharmacokinetics of istradefylline were observed based on age, sex, weight, or race. No clinically relevant changes in istradefylline exposure were observed in patients with severe renal impairment (CrCL 15-29 mL/min) or mild hepatic impairment. NOURIANZ has not been studied in patients with ESRD (CrCL < 15 mL/min), ESRD patients requiring hemodialysis, or severe hepatic impairment (Child-Pugh Class C) [see Use in Specific Populations (8.6 , 8.7) ] . Steady-state systemic exposure to istradefylline (40 mg) is 38% to 54% lower in tobacco smokers (who smoke 20 or more cigarettes per day) when compared with non-smokers matched for age, gender, and body weight [see Specific Populations (8.8) ] . Drug Interaction Studies In Vitro Assessment of Drug Interactions Drug-Metabolizing Enzyme Inhibition Istradefylline is a weak inhibitor of CYP3A4, but not an inhibitor of CYP1A2, 2B6, 2C9, 2C19, or 2D6 in vitro . Drug-Metabolizing Enzyme Induction Istradefylline was a weak inducer of CYP3A4 but not an inducer of CYP1A2 and 2B6 when tested in vitro . However, clinical drug-drug interaction studies with a CYP3A4 substrate (i.e., midazolam) showed no induction of CYP3A4. Transporters Istradefylline was not a substrate for drug transporters P-gp, BCRP, OATP1B1, or OATP1B3 when tested in vitro . Istradefylline was a weak inhibitor for P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OCT2, MATE1, and MATE2-K, but not an inhibitor of OAT3 when tested in vitro . In Vivo Assessment of Drug Interactions Effect of Other Drugs on Istradefylline Strong CYP3A4 Inhibitors Coadministration of ketoconazole (200 mg twice daily for 4 days) with a single dose of istradefylline (40 mg) increased the AUC inf of istradefylline by 2.5-fold, but had no effect on C max [see Drug Interactions (7.1) ] . Strong CYP3A4 Inducers Coadministration of rifampin (600 mg daily for 20 days) with a single dose of istradefylline (40 mg) reduced the C max and AUC inf of istradefylline by 45% and 81% respectively, when compared with istradefylline administered alone [see Drug Interactions (7.1) ] . Effect of Istradefylline on Other Drugs CYP3A4 Substrates Coadministration of istradefylline at higher than the recommended doses (80 mg for 14 days) with a single dose of midazolam (10 mg) increased midazolam AUC inf 2.4-fold, and C max by 1.6-fold, when compared with midazolam administered alone. Coadministration of lower doses of istradefylline (5 mg and 20 mg) with midazolam (7.5 mg) did not have these effects [see Drug Interactions (7.2) ] . Coadministration of istradefylline (40 mg daily for 17 days) with a single dose of atorvastatin (40 mg) increased the C max and AUC inf of atorvastatin by 1.5-fold, compared with atorvastatin alone [see Drug Interactions (7.2) ] . P-glycoprotein Substrates Coadministration of istradefylline (40 mg daily for 21 days) with a single dose of digoxin (0.4 mg) increased the C max and AUC inf of digoxin by 33% and 21%, respectively, when compared with digoxin alone [see Drug Interactions (7.2) ] . Carbidopa/Levodopa Coadministration of istradefylline (80 mg [two times the recommended maximum dosage] daily for 14 days) with a single dose of carbidopa/levodopa (50/200 mg) did not affect the pharmacokinetics of carbidopa/levodopa. Also, coadministration of istradefylline (20 mg or 40 mg daily for 14 days) with carbidopa/levodopa (25/100 mg three times a day for 14 days) did not affect the systemic exposure of carbidopa/levodopa.