Section 03 · Monograph

Istradefylline

Reviewed Nov 2026FDA label

NourianzAdenosine A2A antagonist

Indications

Adjunctive treatment to levodopa/carbidopa in adult patients with Parkinson's disease experiencing 'off' episodesFDA-labeled

Selective adenosine A2A receptor antagonist; the precise mechanism by which this produces benefit in Parkinson's disease is unknown
Blockade of A2A receptors, which are densely expressed in the striatum, is thought to modulate GABAergic output from the indirect pathway and reduce 'off' time without directly affecting dopaminergic transmission

Starting dose: 20 mg orally once daily
May increase to a maximum of 40 mg once daily based on tolerability and efficacy
Can be taken without regard to food
With strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin): limit dose to 20 mg once daily
With strong CYP3A4 inducers (e.g., rifampin, carbamazepine, phenytoin, St. John's wort): avoid use
Heavy smokers (≥20 cigarettes/day): may need to increase to 40 mg once daily, as smoking decreases istradefylline exposure by 38–54%

Moderate hepatic impairment (Child-Pugh Class B): maximum dose 20 mg once daily, with close monitoring for adverse effects
Severe hepatic impairment (Child-Pugh Class C): avoid use (predicted steady-state exposure ~3.3-fold higher than healthy subjects)

Strong CYP3A4 inhibitors (ketoconazole) increased istradefylline AUC by 2.5-fold — cap dose at 20 mg/day
Strong CYP3A4 inducers (rifampin) decreased istradefylline Cmax by 45% and AUC by 81% — avoid coadministration
At the 40 mg dose, istradefylline increased atorvastatin (a CYP3A4 substrate) Cmax and AUC by 1.5-fold — monitor for statin-related adverse effects
At the 40 mg dose, istradefylline increased digoxin (a P-glycoprotein substrate) Cmax by 33% and AUC by 21% — monitor P-gp substrate levels/effects
No pharmacokinetic interaction observed with carbidopa/levodopa
No significant effect on midazolam exposure at the 20 mg dose

Dyskinesia — most common adverse reaction, 15% (20 mg) and 17% (40 mg) vs. 8% placebo; leading cause of discontinuation
Dizziness (3% at 20 mg, 6% at 40 mg, vs. 4% placebo)
Constipation (5% at 20 mg, 6% at 40 mg, vs. 3% placebo)
Nausea (4% at 20 mg, 6% at 40 mg, vs. 5% placebo)
Hallucinations (2% at 20 mg, 6% at 40 mg, vs. 3% placebo) — dose-dependent
Insomnia (1% at 20 mg, 6% at 40 mg, vs. 4% placebo) — dose-dependent
Abnormal thinking/behavior including paranoia, delusions, confusion, mania, disorientation, aggression, agitation, delirium (1–2% vs. 1% placebo)
Decreased appetite and diarrhea reported at low rates
Postmarketing reports of increased libido

Dyskinesia — monitor for new or worsening involuntary movements, especially after dose increase to 40 mg
Psychiatric status — screen for hallucinations, paranoia, delusions, confusion, aggression, particularly at the 40 mg dose
Impulse control/compulsive behaviors (gambling, hypersexuality, spending, binge/compulsive eating) via direct questioning
Hepatic function — closely monitor patients with moderate hepatic impairment
Full medication list for strong CYP3A4 inhibitors/inducers and P-glycoprotein substrates
Smoking status/cigarette consumption to determine whether dose adjustment to 40 mg is warranted

Use of istradefylline during pregnancy is not recommended — animal data demonstrated teratogenicity at clinically relevant exposures, with more severe effects when combined with levodopa/carbidopa
Rabbit studies showed fetal malformations at all doses tested with no identified safe dose; rat studies identified a no-effect dose at an exposure approximately 4 times the maximum recommended human dose
Women of childbearing potential should use effective contraception during treatment
No human data on presence of istradefylline in breast milk; animal studies showed drug concentrations in milk up to 10 times maternal plasma levels
Weigh the developmental and health benefits of breastfeeding against the mother's clinical need for istradefylline and any potential adverse effects on the breastfed infant