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.

The recommended dosage is 20 mg orally once daily. The dosage may be increased to a maximum of 40 mg once daily. May be taken with or without food. 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 ).

2.1Dosing 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 .

2.2Dosage Adjustment with Strong CYP3A4 Inhibitors

The maximum recommended dosage of NOURIANZ with concomitant use of strong CYP3A4 inhibitors is 20 mg once daily .

2.3Dosing with Strong CYP3A4 Inducers Avoid

use of NOURIANZ with strong CYP3A4 inducers .

2.4Dosage 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 . Avoid use of NOURIANZ in patients with severe hepatic impairment (Child-Pugh Class C) .

2.5Dosage 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 .

Dyskinesia: Monitor patients for dyskinesia or exacerbation of existing dyskinesia. Hallucinations / Psychotic Behavior: Consider dosage reduction or stopping NOURIANZ if occurs. Impulse Control / Compulsive Behaviors: Consider dosage reduction or stopping NOURIANZ if occurs.

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) , 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) , 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) , 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 .

None. None.

8.1Pregnancy Risk Summary There

are no adequate data on the developmental risk associated with the use of NOURIANZ in pregnant women. In animal studies , 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.

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Dyskinesia Hallucinations / Psychotic Behavior Impulse Control / Compulsive Behaviors The most common adverse reactions (at least 5% and more frequent than placebo) were dyskinesia, dizziness, constipation, nausea, hallucination, and insomnia. 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) . 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 . 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.