NOURIANZ- istradefylline tablet, film coated

United States - English - NLM (National Library of Medicine)

Buy It Now

Active ingredient:
istradefylline (UNII: 2GZ0LIK7T4) (istradefylline - UNII:2GZ0LIK7T4)
Available from:
Kyowa Kirin, Inc.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
NOURIANZ is indicated as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson's disease (PD) experiencing "off" episodes. None. 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%, respe
Product summary:
NOURIANZ (istradefylline) tablets are available as: 20 mg Tablets: Peach-colored, pillow-shaped, film-coated tablets with "20" debossed on one side. Bottle of 90: NDC 42747-602-90 40 mg Tablets: Peach-colored, almond-shaped, film-coated tablets with "40" debossed on one side. Bottle of 90: NDC 42747-604-90 Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C (59°F to 86°F) [see USP Controlled Room Temperature].
Authorization status:
New Drug Application
Authorization number:
42747-602-07, 42747-602-90, 42747-604-07, 42747-604-90

NOURIANZ- istradefylline tablet, film coated

Kyowa Kirin, Inc.

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use NOURIANZ safely and effectively. See full

prescribing information for NOURIANZ.

NOURIANZ™ (istradefylline) tablets, for oral use

Initial U.S. Approval: 2019

INDICATIONS AND USAGE

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).

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).

DOSAGE FORMS AND STRENGTHS

Tablets: 20 mg and 40 mg (3).

CONTRAINDICATIONS

None (4).

WARNINGS AND PRECAUTIONS

Dyskinesia: Monitor patients for dyskinesia or exacerbation of existing dyskinesia (5.1).

Hallucinations / Psychotic Behavior: Consider dosage reduction or stopping NOURIANZ if occurs (5.2).

Impulse Control / Compulsive Behaviors: Consider dosage reduction or stopping NOURIANZ if occurs (5.3).

ADVERSE REACTIONS

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.

DRUG INTERACTIONS

Strong CYP 3A4 inhibitors: Recommended maximum dosage with concomitant use is 20 mg once daily (2.2, 7.1).

Strong CYP 3A4 inducers: Avoid use (2.3, 7.1).

USE IN SPECIFIC POPULATIONS

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

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 8/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Dosing Information

2.2 Dosage Adjustment with Strong CYP 3A4 Inhibitors

2.3 Dosing with Strong CYP 3A4 Inducers

2.4 Dosage Adjustment in Patients with Hepatic Impairment

2.4 Dosage Adjustment in Patients with Hepatic Impairment

2.5 Dosage Adjustment for Tobacco Smokers

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Dyskinesia

5.2 Hallucinations / Psychotic Behavior

5.3 Impulse Control / Compulsive Behaviors

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Effect of Other Drugs on NOURIANZ

7.2 Effect of NOURIANZ on Other Drugs

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

8.8 Tobacco Smokers

10 OVERDOSAGE

10.1 Human Experience

10.2 Management of Overdose

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage and Handling

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

NOURIANZ is indicated as adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson's

disease (PD) experiencing "off" episodes.

2 DOSAGE AND ADMINISTRATION

Sections or subsections omitted from the full prescribing information are not listed.

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 CYP 3A4 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 CYP 3A4 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 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 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)].

3 DOSAGE FORMS AND STRENGTHS

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.

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

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)].

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)]

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

Dizziness

Gastrointestinal disorders

Constipation

Nausea

Diarrhea

Psychiatric disorders

Hallucination

Insomnia

Metabolism and nutrition disorders

Decreased appetite

Inves tigations

Blood alkaline phosphatase increased

Blood glucose increased

Blood urea increased

Respiratory, thoracic and mediastinal

dis orders

Upper Respiratory Tract Inflammation

Skin and subcutaneous tissue

dis orders

Rash

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.

7 DRUG INTERACTIONS

7.1 Effect of Other Drugs on NOURIANZ

Strong CYP3A4 Inhibitors

Coadministration of NOURIANZ with a strong CYP3A4 inhibitor (ketoconazole) increased

istradefylline AUC

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

and AUC

by 45% and 81%, respectively [see Clinical Pharmacology (12.3)]. Therefore, it is

Includes hallucinations, hallucinations visual, hallucinations olfactory, hallucinations somatic, hallucinations

auditory.

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

and AUC

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

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.

8 USE IN SPECIFIC POPULATIONS

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.

8.2 Lactation

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.

8.3 Females and Males of Reproductive Potential

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)].

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

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.

8.6 Renal Impairment

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)].

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 B), the steady-state exposures (AUC

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.

10 OVERDOSAGE

10.1 Human Experience

There is limited clinical experience regarding human overdosage with NOURIANZ. In clinical trials,

one patient took 6 tablets (120 mg, 3 times the maximum recommended dosage) of istradefylline with

alcoholic beverages and developed hallucinations, agitation, and worsening dyskinesia.

10.2 Management of Overdose

There are no known specific antidotes for NOURIANZ nor any specific treatment for istradefylline

overdose. If an overdose occurs, NOURIANZ treatment should be discontinued and supportive

treatment should be administered as clinically indicated. Consider the long terminal half-life of

istradefylline (about 83 hours) and the possibility of multiple drug involvement.

Consult a Certified Poison Control Center for up-to-date guidance and advice.

11 DESCRIPTION

NOURIANZ contains istradefylline, an adenosine receptor antagonist, which has a xanthine derivative

structure. The chemical name is (E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methyl-3,7-dihydro-1H-

purine-2,6-dione. Its molecular formula is C

H N O . The molecular weight is 384.43.

Istradefylline has the following structural formula:

Istradefylline is a light yellow-green crystalline powder. Istradefylline has a dissociation constant (pK )

of 0.78. The aqueous solubility of istradefylline is ~0.5 µg/mL across the physiological pH range and

0.6 µg/mL in water.

NOURIANZ tablets are intended for oral administration only. Each tablet contains 20 mg or 40 mg of

0-24h

istradefylline and the following inactive ingredients: crospovidone, lactose monohydrate, magnesium

stearate, microcrystalline cellulose, and polyvinyl alcohol. The film coating contains hypromellose,

lactose monohydrate, polyethylene glycol 3350, titanium dioxide, triacetin, and the following dyes: iron

oxide red and iron oxide yellow. Carnauba wax is used for polishing.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The precise mechanism by which istradefylline exerts its therapeutic effect in Parkinson disease is

unknown. In in vitro studies and in in vivo animal studies, istradefylline was demonstrated to be an

adenosine A

receptor antagonist.

12.2 Pharmacodynamics

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.

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

) 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

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

) increased by

1.64-fold and T

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 /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

) 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

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 B), the steady-state exposure (AUC

) 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

of istradefylline by 2.5-fold, but had no effect on C

[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

and AUC

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

2.4-fold, and C

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)

0-24

Similar products

Search alerts related to this product

View documents history

Share this information