Generic Name

Austedo

Mechanism

• Peripheral COMT inhibition: Tolcapone blocks the COMT enzyme that catalyzes the methylation of levodopa and other catecholamine substrates.
• Extended levodopa half‑life: By reducing peripheral levodopa clearance, serum levodopa concentrations remain higher for longer periods, decreasing motor fluctuations.
• No direct CNS effect: Tolcapone’s brain penetration is limited; its therapeutic benefit is largely from systemic action.

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Pharmacokinetics

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Indications

• Parkinson’s disease – adjunctive therapy for levodopa/carbidopa in patients with motor complications or fluctuating response.
• Management of levodopa “OFF” periods – improves ON time and reduces OFF time.

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Contraindications

• Hepatotoxicity – contraindicated in patients with active liver disease, baseline alanine aminotransferase (ALT) ≥3× ULN or alkaline phosphatase ≥2× ULN.
• Known hypersensitivity – to tolcapone or any excipient.
• Pregnancy & Lactation – Classified as pregnancy category C; avoid use unless benefits outweigh risks.
• Drug–Drug Interaction – Avoid concomitant use with strong CYP2C19 inhibitors/inducers that may alter tolcapone levels.
• CYP2C19 Loss‑of‑Function Genotype – Extra caution; high systemic exposure may increase hepatotoxic risk.

Warning: Routine liver‑function monitoring is mandatory. The FDA recommends weekly ALT/AST levels during the first 3 months, then quarterly thereafter.

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Dosing

• Initial dose: 200 mg BID (morning and evening).
• Maintenance: 200–400 mg BID, titrated to clinical response and tolerability (max 400 mg BID).
• Co‑administration: Must be taken with levodopa/carbidopa the same time.
• Administration instructions: Take with food to improve absorption and reduce GI upset.

Special Populations
• Renal impairment: No dose adjustment required.
• Hepatic impairment (Child‑Pugh B/C): Use with caution; monitor LFTs closely, consider dose reduction.
• Elderly: Dose may be reduced if significant hepatic dysfunction.

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Adverse Effects

• Hepatotoxicity – The most significant risk; approximately 10–20 % of users may develop elevated liver enzymes, with an incidence of 1–2 % for clinically significant hepatotoxicity.

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Monitoring

• Liver Function Tests (LFTs)
• ALT, AST, ALP, bilirubin: weekly for first 3 months, then quarterly.
• Discontinue if ALT/AST >3× ULN or ALT >5× ULN in absence of other causes.
• Blood Pressure & Orthostatic Measurements – Monitor for hypotension or dizziness.
• Levodopa/Tolcapone Symptom Diary – Document ON/OFF periods, falls, dyskinesia.
• Crystallographic Imaging – Not required but can help adjust dosing if OFF periods persist.

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Clinical Pearls

• Why Tolcapone, Not Entacapone?
• Tolcapone’s powerful COMT inhibition extends levo‑dopamine action longer than the more commonly used entacapone, but at the cost of higher hepatotoxicity risk; choose based on patient liver function.
• Role of CYP2C19 Genotyping
• Patients with loss‐of‑function CYP2C19 polymorphisms may have markedly higher exposure; consider dose reductions or intensive monitoring in these individuals.
• Use in “ON/Off” Management
• Tolcapone proves especially useful for patients experiencing abrupt OFF periods after levodopa ingestion; by maintaining plasma levodopa levels, it smooths dopamine delivery.
• Safety Net: “Check LFTs Daily” for the First 3 Weeks
• For patients with borderline liver enzymes at baseline, checking LFTs twice weekly during the first month may pre‑empt severe hepatotoxicity.
• Avoid Over‑Timing with Other COMT Inhibitors
• Concomitant use of other COMT inhibitors (e.g., entacapone) is contraindicated to prevent additive hepatotoxicity.
• Potential for “Post‑Dose” Dyskinesia
• In early titration, be vigilant for increased dyskinesias; may require levodopa dose adjustment or a slower ramp.
• Patient Counseling
• Emphasize routine liver function checks, report dark urine or yellowing promptly, and adhere to prescribed dosing schedule to avoid missed doses that might precipitate OFF flares.

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• Bottom line: Austedo is a powerful adjunct to levodopa therapy, but its clinical benefit is tightly balanced against hepatotoxicity risk. Regular monitoring, judicious patient selection, and genotype‑aware dosing are essential for safe and effective use in Parkinson’s disease management.