Nourianz

NOURIANZ is 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 (
  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)]

  .
  ).
• May be taken with or without food (
  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)]

  .
  ).
• 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 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)]

  .
  ,
  8.7 Hepatic Impairment

  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 Class 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 Class 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)].
  ).
• 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 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)]

  .
  ,
  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.
  ).

• 20 mg tablets: Peach-colored, pillow-shaped, film-coated tablets with "20" debossed on one side.
• 40 mg tablets: Peach-colored, almond-shaped, film-coated tablets with "40" debossed on one side.

• Pregnancy: Based on animal data, may cause fetal harm (
  8.1 Pregnancy

  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.
  ).

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

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  ).