Entacapone

Entacapone is a peripheral catechol-O-methyltransferase inhibitor that extends the effect of each levodopa dose, and is used only with levodopa and a decarboxylase inhibitor in Parkinson disease with end-of-dose wearing-off. It does not treat Parkinson disease alone.

Mechanism. Inhibits peripheral catechol-O-methyltransferase, which reduces conversion of levodopa to 3-O-methyldopa, so more levodopa reaches the brain and plasma levels are steadier.

Pharmacokinetics. Bioavailability about 35%, protein binding about 98%, and elimination half-life about 2.4 hours. It is glucuronidated and excreted mainly in bile, so urine turns brownish-orange.

Alternative use. Adjunct to levodopa with carbidopa or benserazide for wearing-off not controlled by levodopa alone.

• Oral entacapone: 200 mg taken with each levodopa dose. Usual 4 to 8 doses daily. Maximum 2000 mg daily (10 doses).

• Combined tablets of levodopa, carbidopa and entacapone are available to reduce pill burden.

• When starting, reduce the daily levodopa dose by about 10 to 30% if dyskinesia appears, often by lengthening the dose interval.

Kidney, liver, weight and age.

• Kidney: no adjustment.

• Liver: contraindicated in hepatic impairment in many labels; use caution and consider reducing the dose.

• Older adults: no adjustment, but watch for hallucinations and dyskinesia.

Contraindications. Hepatic impairment, phaeochromocytoma, history of neuroleptic malignant syndrome or non-traumatic rhabdomyolysis, concurrent non-selective monoamine oxidase inhibitors, and hypersensitivity.

Serious adverse effects. Severe diarrhoea and colitis (may appear weeks to months after starting), worsened dyskinesia, hallucinations and psychosis, impulse control disorders, orthostatic hypotension, hepatic injury (rare), and rhabdomyolysis.

Common adverse effects. Dyskinesia, nausea, diarrhoea, abdominal pain and brownish-orange urine.

Interactions. Iron salts chelate entacapone, so separate by 2 to 3 hours. Drugs metabolised by catechol-O-methyltransferase (adrenaline, noradrenaline, dopamine, dobutamine, isoprenaline, methyldopa, apomorphine) can cause tachycardia and blood pressure changes. Monitor warfarin INR.

Common prescribing errors. Giving it without levodopa. Not reducing levodopa when dyskinesia appears. Missing late-onset diarrhoea.

Special groups.

• Pregnancy: avoid unless essential.

• Breastfeeding: avoid.

• Regional: availability is limited outside urban centres.

Formulations. Tablets 200 mg. Combined tablets of levodopa, carbidopa and entacapone in several strengths. Take with each levodopa dose, with or without food.

Monitoring.

• Motor diary, dyskinesia, weight, bowel habit and blood pressure.

• Liver function if symptoms suggest hepatic injury.

Stopping. Do not stop abruptly. The levodopa dose may need to be increased after stopping.

Referral and escalation. Refer for persistent diarrhoea, weight loss, psychosis or severe dyskinesia.