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

5.1 Dyskinesia

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.

5.2 Hallucinations / 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.

5.3 Impulse 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)].

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)]

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:

* Includes hallucinations, hallucinations visual, hallucinations olfactory, hallucinations somatic, hallucinations auditory.

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.

7.1 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.

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.

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 present in the milk of lactating rats at concentrations up to 10 times that in maternal plasma.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for NOURIANZ, and any potential adverse effects on the breastfed infant from NOURIANZ or from the underlying maternal condition.

Contraception

Use of NOURIANZ during pregnancy is not recommended. Women of childbearing potential should be advised to use contraception during treatment with NOURIANZ [see Use in Specific Populations (8.1)].

Safety and effectiveness in pediatric patients have not been established.

No adjustment of NOURIANZ dosage is recommended on the basis of age. Of the total number of PD patients who received NOURIANZ in clinical trials, 53% were ≥65 years and 13% were ≥75 years of age. No overall differences in effectiveness were observed between these patients and younger patients.

No adjustment of NOURIANZ dosage is needed in patients with mild renal impairment (estimated creatinine clearance (CrCL) by Cockcroft-Gault equation: 60-89 mL/min), moderate renal impairment (CrCL 30-59 mL/min), or severe renal impairment (CrCL 15-29 mL/min). NOURIANZ has not been evaluated in patients with end-stage renal disease (ESRD) (CrCL <15 mL/min) or ESRD requiring hemodialysis [see Clinical Pharmacology (12.3)].

No adjustment of NOURIANZ dosage is needed in patients with mild hepatic impairment (Child-Pugh Class A).

In patients with moderate hepatic impairment (Child-Pugh B), the steady-state exposures (AUC_0-24h) were predicted to be 3.3-fold higher than in healthy subjects, based on the estimated mean terminal half-life. Therefore, the maximum recommended dosage of NOURIANZ in patients with moderate hepatic impairment (Child-Pugh B) is 20 mg once daily [see Clinical Pharmacology (12.3)]. Closely monitor patients with moderate hepatic impairment for adverse events when on NOURIANZ treatment [see Adverse Reactions (6.1)].

NOURIANZ has not been studied in patients with severe hepatic impairment (Child-Pugh Class C). Avoid use of NOURIANZ in patients with severe hepatic impairment [see Clinical Pharmacology (12.3)].

8.8 Tobacco Smokers

Tobacco smoking decreased NOURIANZ steady-state systemic exposures by 38% to 54% [see Clinical Pharmacology (12.3)], which may decrease efficacy. Therefore, the recommended NOURIANZ dosage in patients who smoke 20 or more cigarettes per day (or the equivalent amount of another tobacco product) is 40 mg once daily.