NOURIANZ Film-coated tablet Ref.[10315] Active ingredients:

Cardiac Electrophysiology

The effect of NOURIANZ (40 mg or 160 mg [4 times the maximum recommended dosage] once daily for 14 days) on the QTc interval was evaluated in a randomized, placebo and moxifloxacin-controlled, multiple-dose, blinded, parallel group study. There was no clinically significant prolongation of QTc interval or relationship between changes in QTc and concentrations of istradefylline.

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 ¹⁴C-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 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 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.

Carcinogenesis

In lifetime oral carcinogenicity studies, there was no evidence of carcinogenicity in mouse (0, 25, 125, or 250 mg/kg) or rat (0, 30, 100, or 320 mg/kg). Plasma exposures (AUC) at the highest doses tested were approximately 20 (mouse) and 10 (rat) times that in humans at the maximum recommended human dose (MRHD) of 40 mg/day.

Mutagenesis

Istradefylline was negative in in vitro (bacterial reverse mutation assay, chromosomal aberration in mammalian cells) and in vivo (mouse bone marrow micronucleus) assays.

Impairment of Fertility

Oral administration of istradefylline (0, 160, 360, or 800 mg/kg/day) to male and female rats prior to and during mating and continuing in females to gestation day 7 resulted in a decrease in fertility at the highest dose tested and an increase in preimplantation loss at the mid and high doses. Sperm motility was reduced at the highest dose tested. Plasma exposure (AUC) at the no-effect dose (160 mg/kg for adverse effects on reproductive function is approximately 3 times that in humans at the MRHD.

Oral administration of istradefylline (0, 30, 100, or 320 mg/kg/day) to rats for two years resulted in an increase in the incidence and severity of vascular mineralization in the brain (including in the caudate/putamen, globus pallidus, thalamus, and nucleus accumbens) at all doses tested. The vascular mineralization was composed of calcium and phosphorus and, at higher doses, were reported to partially or completely occlude the blood vessels. There was no evidence of neuronal degeneration, inflammation, or glial response associated with the foci of mineralization.

Brain mineralization was not detected in mice administered istradefylline (0, 25, 125, or 250 mg/kg/day) orally for two years or in dogs administered istradefylline (0, 10, 30, or 100 mg/kg/day) orally for 52 weeks.

The efficacy of NOURIANZ for the adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes was shown in four randomized, multicenter, double-blind, 12-week, placebo-controlled studies (Study 1, NCT00456586; Study 2, NCT00199407; Study 3, NCT00455507; and Study 4, NCT00955526). The studies enrolled patients with a mean duration of Parkinson’s disease of 9 years (range: 1 month to 37 years) that were Hoehn and Yahr Stage II to IV, experiencing at least 2 hours (mean approximately 6 hours) of “off” time per day, and were treated with levodopa for at least one year, with stable dosage for at least 4 weeks before screening (mean total daily dosage range: 416 to 785 mg). Patients continued levodopa treatment with or without concomitant PD medications, including dopamine agonists (85%), COMT inhibitors (38%), MAO-B inhibitors (40%), anticholinergics (13%), and/or amantadine (33%), provided the medications were stable for at least 4 weeks before screening and throughout the study period. The studies excluded patients who had received a neurosurgical treatment for PD (e.g., pallidotomy, thalamotomy, deep brain stimulation).

The primary efficacy endpoint was the change from baseline in the daily awake percentage of “off” time, or the change from baseline in total daily “off” time, based on 24-hour diaries completed by patients. A change from baseline in “on” time without troublesome dyskinesia (i.e., “on” time without dyskinesia plus “on” time with non-troublesome dyskinesia) was a secondary efficacy endpoint.

Study 1 was conducted in the U.S. and Canada, and Study 2 was conducted in the U.S. In these studies, patients were randomized to once-daily treatment with NOURIANZ 20 mg, 40 mg, or placebo. Patients treated with NOURIANZ 20 mg or NOURIANZ 40 mg once daily experienced a statistically significant decrease from baseline in percentage of daily awake “off” time, compared with patients on placebo, as summarized in Table 2.

Table 2. Studies 1 and 2: Change From Baseline in Daily Awake OFF Time:

SD: Standard Deviation
* LSMD: Least squares mean difference; a negative value indicates a greater reduction from baseline in Percentage Daily Awake “off” time for NOURIANZ, relative to placebo.

Compared with patients on placebo, patients treated with NOURIANZ experienced an additional increase from baseline in “on” time without troublesome dyskinesia of 0.96 hours (nominal p=0.026) in Study 1, and of 0.55 hours (nominal p=0.135) in Study 2.

Study 3 and Study 4 were conducted in Japan. In these studies, patients were randomized equally to treatment with NOURIANZ 20 mg, 40 mg, or placebo. Patients treated with NOURIANZ 20 mg or NOURIANZ 40 mg once daily experienced a statistically significant decrease from baseline in “off” time compared with patients on placebo, as summarized in Table 3.

Table 3. Studies 3 and 4: Change From Baseline in Daily OFF Time:

SD: Standard Deviation
* LSMD: Least squares mean difference; a negative value indicates a greater reduction from baseline in “off” time for NOURIANZ, relative to placebo.

In Study 3, compared with placebo, an additional increase from baseline in “on” time without troublesome dyskinesia of 0.57 hours (nominal p=0.085) and of 0.65 hours (nominal p=0.048), respectively, were observed in patients treated with NOURIANZ 20 mg or NOURIANZ 40 mg. In Study 4, the corresponding increases in “on” time without troublesome dyskinesia were 0.83 hours (nominal p=0.008) for NOURIANZ 20 mg and 0.81 hours (nominal p=0.008) for NOURIANZ 40 mg.