Tolcapone

Tolcapone is a catechol-O-methyltransferase inhibitor acting peripherally and centrally, and is reserved for Parkinson disease with fluctuations that have failed another inhibitor of the same class. It carries a risk of fatal acute liver failure, so it requires strict liver monitoring and specialist supervision.

Mechanism. Inhibits catechol-O-methyltransferase, increasing the amount and duration of levodopa reaching the brain.

Pharmacokinetics. Bioavailability about 65%, protein binding over 99.9%, and half-life 2 to 3 hours. It is extensively glucuronidated and excreted in urine and faeces.

Specialist use. Adjunct to levodopa with a decarboxylase inhibitor in Parkinson disease when entacapone has failed or is unsuitable.

• Oral tolcapone: 100 mg three times daily, with the first dose of the day taken with levodopa and later doses about 6 hours apart. A dose of 200 mg three times daily is used only if the extra benefit justifies the liver risk. Maximum 600 mg daily.

• Stop if there is no clear benefit within 3 weeks.

• The levodopa dose often needs to be reduced by about 30% at the start because of dyskinesia.

Kidney, liver, weight and age.

• Kidney: no adjustment in mild to moderate impairment; use caution in severe impairment.

• Liver: contraindicated in liver disease or raised transaminases.

• Older adults: no adjustment.

Contraindications. Liver disease or raised transaminases, previous tolcapone-induced hepatitis, previous neuroleptic malignant syndrome, non-traumatic rhabdomyolysis or hyperpyrexia, phaeochromocytoma, concurrent non-selective monoamine oxidase inhibitors, and hypersensitivity.

Serious adverse effects. Fulminant hepatic failure, severe diarrhoea, worsened dyskinesia, hallucinations, orthostatic hypotension, rhabdomyolysis and neuroleptic malignant-like reactions.

Common adverse effects. Dyskinesia, nausea, diarrhoea, insomnia, vivid dreams, orange urine and abdominal pain.

Interactions. Catechol-O-methyltransferase substrates (adrenaline, noradrenaline, dopamine, dobutamine, isoprenaline, methyldopa, apomorphine) can cause tachycardia or hypertension. Warfarin INR may rise. Non-selective monoamine oxidase inhibitors are contraindicated.

Common prescribing errors. Starting without baseline liver tests. Missing scheduled liver tests. Continuing despite no benefit at 3 weeks. Starting it before trying entacapone.

Special groups.

• Pregnancy: avoid unless essential.

• Breastfeeding: avoid.

• Regional: seldom available, so confirm supply and monitoring capacity before starting.

Formulations. Tablets 100 mg. Take three times daily, with or without food.

Monitoring.

• Liver function (alanine and aspartate aminotransferases) before starting, then every 2 weeks for the first year, every 4 weeks for the next 6 months, and every 8 weeks after that. Restart the schedule after a dose increase to 200 mg three times daily.

• Stop at once if transaminases exceed the upper limit of normal or if jaundice, dark urine, abdominal pain or fatigue appear.

Stopping. Stop at once for liver injury. Otherwise taper under supervision and adjust levodopa.

Referral and escalation. Start only under a specialist Parkinson disease service. Refer urgently for any liver symptoms.