AHFS Class:

• Adenosine A2A Receptor Antagonists 28:36.24

Generic Name(s):

• Istradefylline

Istradefylline, a xanthine derivative, is an adenosine receptor antagonist.1,11

Parkinsonian Syndrome

Istradefylline is used as an adjunct to levodopa-carbidopa in patients with parkinson disease experiencing “off” episodes (i.e., time when drug effect wears off and parkinsonian manifestations return).1,2,3,4,5,124

Levodopa (in combination with carbidopa) is currently the most effective drug for relieving the motor symptoms of parkinson disease.101,115,123,157 However, the effectiveness of levodopa decreases over time as the disease progresses, and most patients develop motor complications (e.g., end-of-dose failure, “on-off” phenomenon, dyskinesias) with long-term use.101,123,115,157 Strategies for reducing the risk of motor complications include adjusting the dosage of levodopa or adding other antiparkinsonian agents (e.g., istradefylline).101,115,123,124,157 (For additional information on treatment options in parkinson disease, see Uses: Parkinsonian Syndrome, in Levodopa/Carbidopa 28:36.16.)

Efficacy of istradefylline as adjunctive therapy to levodopa-carbidopa has been established in 4 multicenter, double-blind, randomized, 12-week placebo-controlled studies in patients with advanced parkinson disease (mean disease duration of 9 years) who were experiencing at least 2 hours of “off” time per day while receiving stable dosages of levodopa with or without other concomitant antiparkinsonian agents (e.g., dopamine receptor agonist, catechol- O -methyltransferase [COMT] inhibitor, monoamine oxidase-B [MAO-B] inhibitor, anticholinergic agent, amantadine); 2 of the studies were conducted in North America and 2 of the studies were conducted in Japan.1,2,3,4,5 Overall findings from these studies demonstrate that istradefylline (20 or 40 mg once daily) is effective in reducing the duration of “off” time in patients with advanced stages of parkinson disease; however, the drug's effect on dyskinesia is less clear.1,2,3,4,5,8 In the North American studies, patients receiving istradefylline experienced substantially greater reductions in the percentage of daily awake “off” time (primary efficacy end point) compared with those receiving placebo; the mean difference relative to placebo was 4.57% with istradefylline 20 mg and 6.78% with istradefylline 40 mg.1,2,3 In the Japanese studies, istradefylline substantially reduced daily “off” time (primary efficacy end point) compared with placebo; “off” time was reduced by a mean of 0.65 or 0.92 hours with istradefylline 20 or 40 mg, respectively, in one study, and by 0.76 or 0.74 hours with istradefylline 20 or 40 mg, respectively, in the other study.1,4,5 Although there was some evidence of a greater effect of the 40-mg dosage of istradefylline compared with the 20-mg dosage, a clear dose-response relationship was not demonstrated.1,4,5,6

The change from baseline in “on” time without troublesome dyskinesia was evaluated as a key secondary outcome measure in these studies.1 The reduction in “off” time observed with istradefylline was accompanied by substantial increases in “on” time without troublesome dyskinesia in 2 of the studies;1,2,5 however, dyskinesia was reported more frequently overall with istradefylline than with placebo, indicating that istradefylline may cause or worsen dyskinesia in some patients when used in combination with levodopa.1,2,3,5,6,8

The benefit of istradefylline in reducing “off” time in patients with parkinson disease appears to be similar to that of other currently available adjunctive antiparkinsonian agents.3,6,8,9

Administration

Istradefylline is administered orally once daily without regard to food.1

Dosage

Parkinsonian Syndrome

The recommended dosage of istradefylline for the adjunctive treatment of “off” episodes in adults with parkinson disease is 20 mg once daily.1 There is no need for initial dose titration; dosage may be increased based on individual patient response and tolerability up to a maximum of 40 mg once daily.1

Concomitant Use of Cytochrome P-450 (CYP) 3A4 Inhibitors or Inducers

The maximum recommended dosage of istradefylline in patients receiving concomitant therapy with a potent CYP3A4 inhibitor is 20 mg once daily.1 Concomitant use of istradefylline and potent CYP3A4 inducers should be avoided.1 (See Drug Interactions: Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes.)

Special Populations

Hepatic Impairment

No dosage adjustment is necessary in patients with mild hepatic impairment (Child-Pugh class A).1 In patients with moderate hepatic impairment (Child-Pugh class B), the maximum recommended dosage of istradefylline is 20 mg once daily; such patients should be closely monitored for adverse effects during therapy.1 Istradefylline is not recommended in patients with severe hepatic impairment (Child-Pugh class C).1

Renal Impairment

No dosage adjustment is necessary in patients with mild (creatinine clearance of 60-89 mL/minute), moderate (creatinine clearance of 30-59 mL/minute), or severe (creatinine clearance of 15-29 mL/minute) renal impairment.1 Istradefylline has not been evaluated in patients with end-stage renal disease (creatinine clearance less than 15 mL/minute), including those undergoing hemodialysis.1

Geriatric Patients

No dosage adjustment is necessary based solely on age in geriatric patients.1

Tobacco Smokers

In patients who use 20 or more cigarettes a day (or the equivalent of another tobacco product), the recommended dosage of istradefylline is 40 mg once daily.1

Contraindications

There are no contraindications to the use of istradefylline.1

Warnings/Precautions

Dyskinesia

Istradefylline may cause or exacerbate preexisting dyskinesia in patients receiving concomitant levodopa therapy.1 Dyskinesia was the most frequent adverse effect of istradefylline in clinical studies,2,3,4,5 occurring in 15-17% of patients receiving the drug in combination with levodopa compared with 8% of those receiving placebo in combination with levodopa.1 Most cases were mild to moderate in severity.2,5 Patients should be monitored for dyskinesias while receiving istradefylline.1

Hallucinations/Psychotic Behavior

In the principal efficacy studies evaluating adjunctive use of istradefylline, hallucinations were reported in 2% of patients receiving the 20-mg dosage and 6% of patients receiving the 40-mg dosage of the drug compared with 3% of those receiving placebo.1 Adverse effects related to abnormal thinking and behavior (e.g., paranoid ideation, delusions, confusion, mania, disorientation, aggressive behavior, agitation, delirium) were reported in about 1-2% of patients receiving istradefylline.1 Other drugs used in the treatment of parkinson disease, particularly dopaminergic agents, can produce similar effects on thinking and behavior.6

Because of the risk of exacerbating psychosis, istradefylline should not be used in patients with major psychotic disorders.1 If a patient develops hallucinations or other psychotic behaviors during istradefylline therapy, consideration should be given to reducing the dosage or discontinuing treatment.1

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 the inability to control these urges have been reported in patients receiving istradefylline and other antiparkinsonian agents, including levodopa.1,6 These urges stopped in some cases when dosage was reduced or the drug was discontinued.1 In the principal efficacy studies, impulse control disorder was reported in one patient who received istradefylline 40 mg daily.1

Because patients may not recognize such behaviors as abnormal, clinicians should specifically ask patients or caregivers whether any new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges have developed during treatment with istradefylline.1 If a patient develops any such behaviors while receiving istradefylline, consideration should be given to reducing the dosage or discontinuing therapy.1 (See Advice to Patients.)

Specific Populations

Pregnancy

There are no adequate data in pregnant women to determine whether istradefylline is associated with a risk of adverse developmental outcomes; based on animal findings, the drug may cause fetal harm.1 In animal reproduction studies, teratogenic effects (e.g., fetal structural abnormalities, growth deficits, embryofetal and offspring mortality) were observed when istradefylline was administered orally to pregnant rats and rabbits during organogenesis at clinically relevant doses not associated with maternal toxicity.1 The teratogenic effects of istradefylline in pregnant rabbits were increased when the drug was administered in combination with levodopa-carbidopa.1

Use of istradefylline is not recommended in pregnant women.1 Women of childbearing potential should use effective contraception during treatment with the drug.1

Lactation

Istradefylline is distributed into milk in rats at concentrations up to 10 times those in maternal plasma.1 It is not known whether istradefylline is distributed into human milk; the effects of istradefylline on the breast-fed infant or on milk production also are not known.1

The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for istradefylline, and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Pediatric Use

Safety and efficacy of istradefylline have not been established in pediatric patients.1

Geriatric Use

Among patients who received istradefylline in clinical trials, 53% were 65 years of age or older and 13% were 75 years of age or older.1 No overall differences in response were observed between these patients and younger patients.1 No clinically important changes in the pharmacokinetics of istradefylline have been observed based on age.1

Hepatic Impairment

Population pharmacokinetic studies indicate that systemic exposure of istradefylline is not substantially altered in patients with mild hepatic impairment (Child-Pugh class A).1 In patients with moderate hepatic impairment (Child-Pugh class B), systemic exposure is expected to be 3.3-fold higher than in healthy individuals; therefore, dosage adjustments are necessary and patients should be monitored for adverse effects during therapy.1 (See Hepatic Impairment under Dosage and Administration: Special Populations.) Istradefylline has not been evaluated and should not be used in patients with severe hepatic impairment (Child-Pugh class C).1

Renal Impairment

Population pharmacokinetic studies indicate that systemic exposure of istradefylline is not substantially altered in patients with severe renal impairment (creatinine clearance of 15-29 mL/minute); therefore, no dosage adjustments are necessary in patients with any degree of renal impairment.1 However, istradefylline has not been evaluated in patients with end-stage renal disease (creatinine clearance less than 15 mL/minute), including those undergoing hemodialysis.1

Tobacco Smokers

Compared with nonsmokers, systemic exposure of istradefylline is reduced by 38-54% in tobacco smokers (defined as those who smoke 20 or more cigarettes a day); such decreased exposure may decrease efficacy of the drug.1,10 (See Tobacco Smokers under Dosage and Administration.)

Common Adverse Effects

The most common adverse effects of istradefylline (reported at an incidence of at least 5% and more frequently than placebo) include dyskinesia, dizziness, constipation, nausea, hallucination, and insomnia.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

In vitro studies indicate that istradefylline is metabolized principally by cytochrome P-450 (CYP) isoenzymes 1A1 and 3A4, and to a lesser extent by CYP1A2, 2B6, 2C8, 2C9, 2C18, and 2D6.1 In vitro studies also indicate that istradefylline is a weak inhibitor of CYP3A4, but does not inhibit CYP1A2, 2B6, 2C9, 2C19, or 2D6.1 In vitro studies demonstrated some potential for istradefylline to weakly induce CYP3A4; however, this has not been confirmed in clinical drug interaction studies.1 Istradefylline does not appear to induce CYP1A2 or 2B6.1

Potent CYP3A4 Inhibitors

Potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, clarithromycin) may substantially increase systemic exposure to istradefylline; therefore, the recommended maximum dosage of istradefylline should be reduced to 20 mg once daily during concomitant use.1,10 (See Drug Interactions: Ketoconazole.)

Potent CYP3A4 Inducers

Potent CYP3A4 inducers (e.g., carbamazepine, rifampin, phenytoin, St. John's wort) may substantially decrease plasma concentrations and exposure of istradefylline; therefore, concomitant use should be avoided.1,13 (See Drug Interactions: Rifampin.)

CYP3A4 Substrates

Istradefylline can potentially increase concentrations and adverse effects of CYP3A4 substrates (e.g., atorvastatin, midazolam).1 In drug interaction studies using the CYP3A4 substrates midazolam and atorvastatin, istradefylline increased systemic exposure of the substrate drug in a dose-dependent manner.1 (See Drug Interactions: Atorvastatin and also see Drug Interactions: Midazolam.) Based on these findings, the manufacturer recommends that patients receiving istradefylline 40 mg and a CYP3A4 substrate concomitantly should be monitored for increased adverse effects of the substrate drug.1

Drugs Affecting Transporters

In vitro studies indicate that istradefylline is not a substrate for P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or organic anion transport proteins (OATP) 1B1 or 1B3.1 When tested in vitro, istradefylline exhibited 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 did not inhibit OAT3.1

P-glycoprotein Substrates

Istradefylline can potentially increase plasma concentrations and adverse effects of P-gp substrates.1 (See Drug Interactions: Digoxin.) Patients should be monitored for increased adverse effects of the P-gp substrate during concomitant use.1

Atorvastatin

Concomitant administration of a single dose of atorvastatin 40 mg with istradefylline (40 mg daily for 17 days) increased systemic exposure and peak plasma concentrations of atorvastatin by 1.5-fold.1,12 Patients should be monitored for increased adverse effects of atorvastatin when the drug is used concomitantly with istradefylline 40 mg daily.1

Digoxin

Concomitant administration of digoxin and istradefylline increased peak plasma concentrations and systemic exposure of digoxin by 33 and 21%, respectively.1 Patients should be monitored for increased adverse effects of digoxin during concomitant use of istradefylline.1

Levodopa-Carbidopa

The pharmacokinetics of levodopa-carbidopa were not affected when istradefylline was administered concomitantly at various dosages ranging from 20 to 80 mg daily.1

Midazolam

Concomitant administration of a single dose of midazolam 10 mg with istradefylline (at a higher than recommended dosage of 80 mg daily for 14 days) increased systemic exposure of midazolam by 2.4-fold and peak plasma concentrations of the drug by 1.6-fold.1 However, these effects were not observed when lower doses of istradefylline (e.g., 5 or 20 mg) were administered concomitantly with midazolam 7.5 mg.1 Patients should be monitored for increased adverse effects of midazolam when the drug is used concomitantly with istradefylline 40 mg daily.1

Ketoconazole

When administered concomitantly, ketoconazole (a potent CYP3A4 inhibitor) increased systemic exposure of istradefylline by 2.5-fold, but did not affect peak plasma concentrations of the drug.1 A maximum istradefylline dosage of 20 mg once daily should not be exceeded during concomitant use of ketoconazole.1

Rifampin

When administered concomitantly, rifampin (a potent CYP3A4 inducer) decreased peak plasma concentrations and systemic exposure of istradefylline by 45 and 81%, respectively.1,13 Concomitant use of these drugs should be avoided.1

Description

Istradefylline, a xanthine derivative, is a selective adenosine A_2A receptor antagonist.1,8,11 The drug is considered a nondopaminergic antiparkinsonian agent because of its lack of effects on dopamine receptors and dopamine-metabolizing enzymes.5,9 The precise mechanism by which istradefylline exerts its therapeutic effect in parkinson disease is unknown, but is thought to involve the restoration of balance in the overactive striatopallidal output pathway.1,9,10,11 In humans, A_2A receptors are predominately located in the striatum on medium spiny neurons that produce GABA and enkephalin; these neurons form the indirect output pathway from the striatum to the globus pallidus.8,9,11 The indirect pathway is known to be overactive in patients with parkinson disease due to the lack of normal inhibition of the nigrostriatal pathway as a result of dopaminergic cell degeneration.9,11 It is thought that blockade of A_2A receptors by istradefylline reduces the excitability of this indirect pathway, resulting in an improvement of parkinsonian symptoms.9,10,11 There is some evidence that A_2A receptor levels are increased in patients with dyskinesia, although the clinical importance of these findings has not been determined.8

Istradefylline exhibits dose-proportional pharmacokinetics over the dosage range of 20-80 mg daily.1 Following oral administration under fasted conditions, peak plasma concentrations of the drug are achieved in approximately 4 hours and steady-state is reached within 2 weeks of repeated dosing.1 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 was delayed by 1 hour compared with administration in the fasted state; however, these changes are not expected to be clinically important.1 Istradefylline is extensively distributed in the body, but is highly bound (approximately 98%) to plasma proteins.1,13 The drug is primarily metabolized by oxidative metabolism via cytochrome P-450 (CYP) isoenzymes 1A1 and CYP3A4, and to a lesser extent by CYP1A2, 2B6, 2C8, 2C9, 2C18, and 2D6.1,13 Approximately 48% of a dose is eliminated in feces and 39% in the urine.1 The mean terminal half-life of the drug is 83 hours.1

Advice to Patients

Importance of advising patients to read the manufacturer's patient labeling (patient information).1

Importance of advising patients that istradefylline may cause or exacerbate dyskinesia.1

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.1

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.1

Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and herbal supplements, as well as any concomitant illnesses.1 Advise patients to also inform their healthcare provider about their smoking status.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1

Importance of informing patients of other important precautionary information.1 (See Cautions.)

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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