Pramipexole

Pramipexole is a non-ergot dopamine agonist used for Parkinson disease and moderate to severe restless legs syndrome. It is effective and well tolerated at first, but sleepiness, impulse control disorders, hallucinations and oedema limit its use, particularly in older adults.

Mechanism. Agonist at dopamine D2 receptors, with preference for D3.

Pharmacokinetics. Bioavailability over 90%, protein binding about 15%, and half-life 8 to 12 hours. About 90% is excreted unchanged in urine, so dose depends on kidney function.

First-line use. Early Parkinson disease as monotherapy, and as adjunct to levodopa for fluctuations. Restless legs syndrome when daily symptoms need treatment.

• Parkinson disease, immediate-release tablets, doses as pramipexole salt: 0.125 mg three times daily in week 1, 0.25 mg three times daily in week 2, 0.5 mg three times daily in week 3. Then increase by up to 0.75 mg daily each week. Usual maintenance 1.5 to 4.5 mg daily in three doses. Maximum 4.5 mg daily.

• Prolonged-release tablets: start 0.375 mg once daily, increase to 0.75 mg after 5 to 7 days, then by 0.75 mg each week. Maximum 4.5 mg daily.

• Restless legs syndrome: 0.125 mg once daily 2 to 3 hours before bedtime, increased every 4 to 7 days to 0.25 mg and then 0.5 mg. Maximum 0.75 mg daily.

• Doses are given as the salt. Pramipexole 0.125 mg salt equals 0.088 mg base, and confusion between salt and base is a common error.

• When used with levodopa, reduce the levodopa dose if dyskinesia appears.

Kidney, liver, weight and age.

• Kidney: creatinine clearance over 50 mL/min, no change. 20 to 50 mL/min, start 0.125 mg twice daily, maximum 2.25 mg daily. Under 20 mL/min, 0.125 mg once daily, maximum 1.5 mg daily. Prolonged-release tablets are given every other day at 30 to 50 mL/min and are not advised under 30 mL/min.

• Liver: no adjustment.

• Older adults: start low and titrate slowly.

Contraindications. Hypersensitivity.

Serious adverse effects. Sudden sleep onset, impulse control disorders (gambling, hypersexuality, compulsive shopping, binge eating), hallucinations and psychosis, orthostatic hypotension, dyskinesia, peripheral oedema, augmentation of restless legs, and dopamine agonist withdrawal syndrome.

Common adverse effects. Nausea, somnolence, dizziness, constipation, insomnia and oedema.

Interactions. Cimetidine, amantadine, diltiazem and quinidine reduce kidney clearance and raise levels. Antipsychotics and metoclopramide antagonise the effect. Sedatives and alcohol add somnolence.

Common prescribing errors. Confusing salt and base doses. Not adjusting for kidney function. Not asking about impulse control. Advising driving without a warning about sudden sleep onset.

Special groups.

• Pregnancy: avoid unless essential.

• Breastfeeding: suppresses prolactin and lactation; avoid.

• Older adults: hallucinations and hypotension are more frequent.

Formulations. Immediate-release tablets, 0.125, 0.25, 0.5, 1 and 1.5 mg of salt (market labels differ). Prolonged-release tablets 0.375 to 4.5 mg. Swallow prolonged-release tablets whole. Take with food if nausea occurs.

Monitoring.

• Impulse control and sleepiness at each review, with carer input.

• Lying and standing blood pressure, oedema, mental state and skin examination. Kidney function at least yearly.

Stopping. Taper over 4 to 7 days or longer to limit withdrawal syndrome, unless there is a severe adverse effect.

Referral and escalation. Refer for impulse control disorders, psychosis, or motor fluctuations. Stop the drug and review for severe behavioural change.