Istradefylline

Approved Indications:

• Parkinson’s Disease (PD):
  Used as an adjunctive treatment to levodopa/carbidopa in adult patients experiencing “off” episodes (i.e., periods when other Parkinson’s medications are not working well, resulting in increased symptoms).

Off-Label / Clinically Accepted Uses:

• Levodopa-induced dyskinesia management (limited evidence).
• Adjunct therapy in advanced PD with motor fluctuations (clinical support, not FDA-approved).

General Dosing (Adults):

• Initial Dose: 20 mg orally once daily.
• Maximum Dose: 40 mg once daily.
• Dosage Adjustment: If patient tolerates 20 mg/day without adverse effects, may increase to 40 mg/day based on clinical response.

Special Populations:

• Renal Impairment:
  No dosage adjustment required in mild to moderate renal impairment. Avoid in severe renal impairment or end-stage renal disease (ESRD) due to lack of data.
• Hepatic Impairment:
  Avoid in severe hepatic impairment. Use with caution in moderate hepatic impairment.
• Elderly:
  No dosage adjustment required solely based on age; monitor for increased sensitivity.

Administration:

• Oral administration once daily, with or without food.
• Tablets should be swallowed whole.

Istradefylline is a selective adenosine A2A receptor antagonist. In Parkinson’s disease, the overactivation of A2A receptors in the basal ganglia is thought to inhibit dopaminergic activity, contributing to motor symptoms. By blocking these A2A receptors, istradefylline enhances dopaminergic neurotransmission, thereby improving motor function and reducing “off” episodes in patients already receiving dopaminergic therapy such as levodopa. This mechanism operates independently of dopamine receptors, making it complementary to dopaminergic agents.

• Absorption:
  Rapidly absorbed after oral administration. Peak plasma concentration (Tmax) occurs within 4 hours post-dose.
• Bioavailability:
  Absolute bioavailability is approximately 100%.
• Distribution:
  Volume of distribution: ~557 L. Highly protein bound (>98%).
• Metabolism:
  Metabolized primarily by CYP3A4 isoenzyme.
• Elimination Half-life:
  Approximately 83 hours, supporting once-daily dosing.
• Excretion:
  Eliminated mainly via feces (~68%) and urine (~12%).

• Pregnancy:
  No FDA pregnancy category assigned. Animal studies showed adverse fetal effects (decreased fetal weight, delayed ossification), but no adequate human data. Use only if potential benefits outweigh risks.
• Lactation:
  Unknown whether istradefylline is excreted in human breast milk. Based on its long half-life and pharmacologic activity, breastfeeding is not recommended during treatment and for several days after discontinuation.

• Primary Class: Antiparkinsonian Agent
• Subclass: Adenosine A2A Receptor Antagonist (Non-dopaminergic PD adjunct)

• Known hypersensitivity to istradefylline or any excipients in the formulation.
• Severe hepatic impairment (Child-Pugh Class C) – use is contraindicated due to increased exposure risk.
• Severe renal impairment/ESRD – lack of safety data.

• Impulse Control Disorders (ICDs):
  May increase risk of compulsive behaviors (e.g., gambling, binge eating, hypersexuality). Monitor closely.
• Psychosis or Hallucinations:
  Use cautiously in patients with a history of psychotic disorders; may exacerbate symptoms.
• Severe Hepatic or Renal Dysfunction:
  Avoid use; elevated drug exposure may increase adverse effects.
• Drug Interactions:
  Use with strong CYP3A4 inducers may reduce efficacy; avoid co-administration.
• Driving & Machinery:
  May cause drowsiness or dizziness; caution advised during activities requiring alertness.

Common Adverse Effects (≥5%):

• Dyskinesia
• Dizziness
• Constipation
• Hallucinations
• Insomnia
• Nausea

Less Common:

• Anxiety
• Dry mouth
• Decreased appetite

Serious/Rare Adverse Events:

• Psychotic episodes (hallucinations, delusions)
• Impulse control disorders (pathologic gambling, hypersexuality)
• Suicidal ideation (rare, monitor in patients with psychiatric history)

Timing:
Adverse effects typically occur within the first few weeks of therapy initiation or after dose escalation.

• CYP3A4 Inducers (e.g., rifampin, carbamazepine):
  May significantly reduce istradefylline plasma concentration – avoid use.
• CYP3A4 Inhibitors (e.g., ketoconazole, clarithromycin):
  May increase istradefylline exposure. If co-administered, limit dose to 20 mg/day.
• Levodopa and other dopaminergic agents:
  Increased dopaminergic adverse effects (e.g., dyskinesia, hallucinations) possible.
• Alcohol:
  May enhance CNS side effects such as dizziness and sedation.

Note:
Istradefylline does not inhibit or induce CYP enzymes significantly on its own.

• FDA Approval:
  Approved by the U.S. FDA in August 2019 for adjunctive treatment in PD patients with “off” episodes.
• Recent Clinical Guideline Updates:
  Recognized in 2022 Movement Disorder Society guidelines as an option for adjunctive therapy in advanced PD.
• No recent label changes or black box warnings as of 2025.

• Temperature:
  Store at 20°C to 25°C (68°F to 77°F). Excursions permitted between 15°C and 30°C.
• Humidity/Light:
  Store in a dry place, away from excessive moisture. Protect from direct light.
• Handling Precautions:
  Keep in original packaging until use. Do not crush or split tablets.
• Reconstitution/Refrigeration:
  Not applicable. No special reconstitution or refrigeration required.