Istradefylline
Indications
Istradefylline is used for:
Parkinson Disease
Adult Dose
Parkinson Disease
Indicated as adjunctive treatment to levodopa/carbidopa in adults with Parkinson disease (PD) experiencing “OFF” episodes
20 mg PO qDay; may increase to maximum of 40 mg PO qDay
Initial dose titration not required
Hepatic impairment
Mild (Child-Pugh A): No dosage adjustment required
Moderate (Child-Pugh B): Not to exceed 20 mg PO qDay
Severe (Child-Pugh C): Avoid use
Child Dose
Renal Dose
Renal impairment
Mild, moderate, or severe (CrCl 15-89 mL/min): No dosage adjustment required
ESRD (CrCl <15 mL/min) or ESRD requiring hemodialysis: Not studied
Administration
Contra Indications
Precautions
May exacerbate psychosis; patients with major psychotic disorder should not be treated with istradefylline; consider dosage reduction or discontinuation if patient develops hallucinations or psychotic behaviors while receiving therapy
Coadministration with levodopa may cause dyskinesia or exacerbate preexisting dyskinesia; in clinical trials, dyskinesia incidence was higher in patients taking istradefylline compared with placebo
Patients treated with istradefylline and ≥1 medication(s) for PD (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; consider dose reduction or discontinuation
Pregnancy-Lactation
Pregnancy
Data are unavailable regarding use in pregnant women
Based on animal studies, may cause fetal risk
Use during pregnancy is not recommended; advise women of childbearing potential to use contraception during treatment
Animal studies
Istradefylline administered in pregnant rabbits resulted in teratogenicity (increased incidences of fetal structural abnormalities, embryofetal and offspring mortality, growth deficits) at clinically relevant exposures and in the absence of maternal toxicity
Teratogenic effects were substantially greater when administered in combination with levodopa/carbidopa than when administered alone
Lactation
There are no data on the presence in human milk, effects on breastfed infants, or effects on milk production
Present in milk of lactating rats at concentrations up to 10 times that in maternal plasma
Consider developmental and health benefits of breastfeeding along with the clinical need for istradefylline, and any potential adverse effects on breastfed infants from istradefylline or from the underlying maternal condition
Interactions
Istradefylline effect on other drugs
Istradefylline is both a weak CYP3A4 inhibitor and inducer; higher istradefylline doses (ie, 40 mg/day) may affect CYP3A4 substrates
Transporters: Istradefylline is a weak inhibitor for P-gp, BCRP, OATP1B1, OATP1B3, OAT1, OCT2, MATE1, and MATE2-K; higher istradefylline doses (ie, 40 mg/day) may affect P-gp substrates (eg, digoxin)
CYP inhibitors or inducers
Istradefylline is primarily metabolized by CYP3A4 and CYP1A1
Coadministration with strong CYP3A4 inhibitors: Not to exceed istradefylline 20 mg qDay
Strong CYP3A4 inducers: Avoid coadministration
Increase istradefylline dose with tobacco use equivalent to ≥20 cigarettes/day
Adverse Effects
Side effects of Istradefylline :
>10%
Dyskinesia (15-17%)
1-10%
Constipation (5-6%)
Nausea (4-6%)
Dizziness (3-6%)
Hallucination (2-6%)
Insomnia (1-6%)
Decreased appetite (1-3%)
Increased alkaline phosphatase (1-2%)
Increased blood glucose (1-2%)
Increased blood urea (1-2%)
Upper respiratory tract inflammation (1-2%)
Rash (1-2%)
Diarrhea (1-2%)
Mechanism of Action
Selective adenosine A2A receptor antagonist
The precise mechanism by which istradefylline exerts its therapeutic effect in PD is unknown