Istradefylline (Monograph)

Brand name: Nourianz
Drug class: Central Nervous System Agents, Miscellaneous
- Antiparkinsonian Agents
Chemical name: 8-[(E)-2-(3,4-dimethoxyphenyl)ethenyl]-1,3-diethyl-7-methylpurine-2,6-dione
Molecular formula: C₂₀H₂₄N₄O₄
CAS number: 155270-99-8

Medically reviewed by Drugs.com on Sep 25, 2023. Written by ASHP.

Introduction

Adenosine receptor antagonist; xanthine derivative.

Uses for Istradefylline

Parkinsonian Syndrome

Adjunct to levodopa-carbidopa in patients with parkinson disease experiencing “off” episodes.

Reduces duration of “off” time in patients with advanced parkinson disease; however, effect on dyskinesia is less clear. May cause or worsen dyskinesia in some patients.

Observed benefit appears similar to other currently available adjunctive antiparkinsonian agents.

Levodopa is currently the most effective drug for relieving motor symptoms of parkinson disease; however, long-term use associated with motor complications. Strategies to reduce these complications include adjusting dosage of levodopa or adding other antiparkinsonian agents (e.g., istradefylline).

Istradefylline Dosage and Administration

Administration

Oral Administration

Administer orally once daily without regard to food.

Dosage

Adults

Parkinsonian Syndrome

Oral

Recommended dosage is 20 mg once daily as adjunctive therapy to levodopa-carbidopa. No need for initial dose titration.

May increase dosage based on individual patient response and tolerability up to a maximum of 40 mg once daily (or 20 mg once daily in patients with moderate hepatic impairment or receiving a potent CYP3A4 inhibitor concomitantly). (See Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes under Interactions.)

Prescribing Limits

Adults

Parkinsonian Syndrome

Oral

Maximum 40 mg once daily (or 20 mg once daily in patients with moderate hepatic impairment or receiving a potent CYP3A4 inhibitor).

Special Populations

Hepatic Impairment

Parkinsonian Syndrome

Oral

Mild hepatic impairment (Child-Pugh class A): No dosage adjustment necessary.

Moderate hepatic impairment (Child-Pugh class B): Maximum 20 mg once daily; monitor patients closely for adverse effects.

Severe hepatic impairment (Child-Pugh class C): Not recommended.

Renal Impairment

Parkinsonian Syndrome

Oral

Mild renal impairment (Cl_cr 60–89 mL/minute): No dosage adjustment necessary.

Moderate renal impairment (Cl_cr 30–59 mL/minute): No dosage adjustment necessary.

Severe renal impairment (Cl_cr 15–29 mL/minute): No dosage adjustment necessary.

End-stage renal disease (Cl_cr <15 mL/minute), including those undergoing hemodialysis: Not evaluated.

Geriatric Patients

No dosage adjustment necessary based solely on age.

Tobacco Smokers

In patients who smoke 20 or more cigarettes a day (or the equivalent of another tobacco product), recommended dosage is 40 mg once daily.

Cautions for Istradefylline

Contraindications

• None.

Warnings/Precautions

Dyskinesia

May cause or exacerbate preexisting dyskinesia in patients receiving concomitant levodopa. Monitor patients for dyskinesias.

Hallucinations/Psychotic Behavior

Hallucinations reported. Abnormal thinking and behavior (e.g., paranoid ideation, delusions, confusion, mania, disorientation, aggressive behavior, agitation, delirium) also observed. Other antiparkinsonian drugs can produce similar effects on thinking and behavior.

Because of risk of exacerbating psychosis, avoid use in patients with major psychotic disorders. If hallucinations or other psychotic behaviors occur during therapy, consider reducing dosage or discontinuing therapy.

Impulse Control/Compulsive Behaviors

Intense urges and compulsive behaviors (e.g., urge to gamble, increased sexual urges, binge eating, uncontrolled spending, other intense urges) and inability to control these urges reported with istradefylline and other antiparkinsonian agents. In some cases, urges stopped when dosage was reduced or drug was discontinued.

Because patients may not recognize such behaviors as abnormal, specifically ask patients whether they have developed any new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while receiving istradefylline. Consider reducing dosage or discontinuing therapy if a patient develops such behaviors. (See Advice to Patients.)

Specific Populations

Pregnancy

No adequate data in pregnant women; based on animal findings, the drug may cause fetal harm. In animal reproduction studies, teratogenic effects (e.g., fetal structural abnormalities, growth deficits, embryofetal and offspring mortality) observed.

Use not recommended in pregnant women. Women of childbearing potential should use effective contraception during treatment.

Lactation

Distributed into milk in rats. Not known whether distributed into human milk, affects the breast-fed infant, or affects milk production.

Consider developmental and health benefits of breast-feeding along with mother's clinical need for istradefylline, and any potential adverse effects on breast-fed infant from the drug or underlying maternal condition.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

No overall differences in response observed between geriatric and younger patients. No clinically important pharmacokinetic changes observed based on age.

Hepatic Impairment

In patients with moderate hepatic impairment (Child-Pugh class B), increased systemic exposure expected; dosage adjustments necessary. (See Hepatic Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Not evaluated in patients with severe hepatic impairment (Child-Pugh class C); avoid use.

Renal Impairment

Systemic exposure not substantially altered in patients with severe renal impairment (Cl_cr 15–29 mL/minute); therefore, no dosage adjustments necessary in patients with any degree of renal impairment. However, not evaluated in patients with end-stage renal disease (Cl_cr <15 mL/minute), including those undergoing hemodialysis.

Tobacco Smokers

Systemic exposure is reduced in tobacco smokers (defined as those who smoke ≥20 cigarettes a day). Such decreased exposure may decrease efficacy of the drug; increased dosage required. (See Tobacco Smokers under Dosage and Administration and also see Special Populations under Pharmacokinetics.)

Common Adverse Effects

Dyskinesia, dizziness, constipation, nausea, hallucinations, insomnia.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Metabolized principally by CYP1A1 and 3A4, and to a lesser extent by CYP1A2, 2B6, 2C8, 2C9, 2C18, and 2D6.

Weak inhibitor of CYP3A4, but does not inhibit CYP1A2, 2B6, 2C9, 2C19, or 2D6. In vitro studies demonstrate potential to weakly induce CYP3A4, but not confirmed in clinical drug interaction studies.

Does not appear to induce CYP1A2 or 2B6.

Potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, clarithromycin) may substantially increase systemic exposure to istradefylline; recommended maximum dosage of istradefylline is 20 mg once daily during concomitant use. (See Specific Drugs under Interactions.)

Potent CYP3A4 inducers (e.g., carbamazepine, rifampin, phenytoin, St. John's wort) may substantially decrease plasma concentrations and exposure to istradefylline; avoid concomitant use. (See Specific Drugs under Interactions.)

Istradefylline can potentially increase concentrations and adverse effects of CYP3A4 substrates. In drug interaction studies using CYP3A4 substrates (midazolam and atorvastatin), istradefylline increased systemic exposure to the substrate drug in a dose-dependent manner.

Monitor patients receiving istradefylline 40 mg and a CYP3A4 substrate concomitantly for increased adverse effects of the substrate drug.

Drugs Affecting Transporters

Not a substrate for P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or organic anion transport proteins (OATP) 1B1 or 1B3. Exhibits weak inhibition of P-gp, BCRP, OATP1B1, OATP1B3, organic anion transporter (OAT)1, organic cation transporter (OCT)2, multidrug and toxin extrusion (MATE)1 and MATE2-K, but does not inhibit OAT3.

Istradefylline can potentially increase plasma concentrations and adverse effects of P-gp substrates (e.g., digoxin). (See Specific Drugs under Interactions.)

Monitor patients for increased adverse effects of the P-gp substrate during concomitant use.

Specific Drugs

Istradefylline Pharmacokinetics

Absorption

Bioavailability

Exhibits dose-proportional pharmacokinetics over the dosage range of 20–80 mg daily.

Food

When administered with a high-fat meal, exposure to istradefylline increased by about 25%, peak plasma concentrations increased by 64%, and time to reach peak plasma concentrations were delayed by 1 hour; however, these changes not expected to be clinically important.

Plasma Concentrations

Following oral administration under fasted conditions, peak plasma concentrations achieved in approximately 4 hours and steady-state reached within 2 weeks of repeated dosing.

Special Populations

Patients with mild hepatic impairment (Child-Pugh class A): Systemic exposure not substantially altered.

Patients with moderate hepatic impairment (Child-Pugh class B): Systemic exposure expected to be 3.3-fold higher. (See Hepatic Impairment under Cautions.)

Patients with severe hepatic impairment (Child-Pugh class C): Not evaluated.

Patients with severe renal impairment (Cl_cr 15–29 mL/minute): Systemic exposure not substantially altered. (See Renal Impairment under Cautions.)

Tobacco smokers: Compared with nonsmokers, systemic exposure of istradefylline is reduced by 38–54% in tobacco smokers (defined as those who smoke ≥20 cigarettes a day). (See Tobacco Smokers under Cautions.)

Distribution

Extent

Extensively distributed.

Plasma Protein Binding

Highly bound (approximately 98%) to plasma proteins.

Elimination

Metabolism

Primarily metabolized by oxidative metabolism via CYP1A1 and CYP3A4.

Elimination Route

Approximately 48% of a dose is eliminated in feces and 39% in the urine, mostly as metabolites.

Half-life

Mean terminal half-life is 83 hours.

Stability

Storage

Oral

Tablets

20–25°C (may be exposed to 15–30°C).

Actions

• Selective adenosine A_2A receptor antagonist with a xanthine-derived structure.

• Considered a nondopaminergic antiparkinsonian agent because of lack of effects on dopamine receptors and dopamine-metabolizing enzymes.

• Precise mechanism in parkinson disease unknown, but thought to involve restoration of balance in the overactive striatopallidal output pathway.

Advice to Patients

• Importance of advising patients to read the manufacturer's patient labeling (patient information).

• Importance of advising patients that istradefylline may cause or exacerbate dyskinesia.

• Importance of advising patients that istradefylline may cause hallucinations or psychotic behavior and that they should report any of these adverse effects to their clinician.

• Importance of asking patients whether they have developed any new or increased urges or compulsive behaviors (e.g., gambling urges, sexual urges, uncontrolled spending, binge eating) while receiving istradefylline and of advising them of the importance of reporting such urges.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses. Advise patients to also inform their healthcare provider about their smoking status.

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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