Amantadine

Amantadine is an N-methyl-D-aspartate receptor antagonist with dopaminergic and anticholinergic effects, used for Parkinson disease (particularly levodopa-induced dyskinesia), drug-induced extrapyramidal symptoms and, historically, influenza A. Its dose is set by kidney function, and it accumulates dangerously in renal failure.

Mechanism. Weak antagonist at N-methyl-D-aspartate receptors, increases dopamine release and blocks its reuptake, and has mild antimuscarinic action.

Pharmacokinetics. Bioavailability about 90% and half-life 10 to 14 hours in healthy adults, much longer in older adults and kidney disease (up to about 7 to 10 days in end-stage disease). About 90% is excreted unchanged in urine.

Alternative use. Parkinson disease (mild disease, and dyskinesia with levodopa), and drug-induced extrapyramidal symptoms.

• Oral amantadine for Parkinson disease: 100 mg once daily for 1 week, then 100 mg twice daily. Maximum 400 mg daily in divided doses. Give the last dose before late afternoon to avoid insomnia.

• Extended-release amantadine (where available) for dyskinesia: 137 mg once daily for 1 week, then 274 mg at bedtime.

• Influenza A: no longer used in most settings because of widespread resistance.

Kidney, liver, weight and age.

• Kidney (immediate-release): creatinine clearance 30 to 50 mL/min, 200 mg on the first day then 100 mg daily. 15 to 29 mL/min, 200 mg on the first day then 100 mg on alternate days. Under 15 mL/min or dialysis, 200 mg every 7 days.

• Liver: no adjustment.

• Older adults: start 100 mg daily and adjust to kidney function.

Contraindications. Hypersensitivity, untreated angle-closure glaucoma, severe renal impairment (creatinine clearance under 15 mL/min, except as adjusted), history of gastric ulceration in some labels, and caution in epilepsy.

Serious adverse effects. Confusion, hallucinations and psychosis, seizures, QT prolongation and arrhythmia, heart failure with oedema, urinary retention, and a neuroleptic malignant-like syndrome on abrupt withdrawal.

Common adverse effects. Livedo reticularis, ankle oedema, insomnia, vivid dreams, dry mouth, constipation, dizziness and nausea.

Interactions. Anticholinergics and memantine add confusion. Thiazides with triamterene reduce clearance. QT-prolonging drugs add arrhythmia risk. Live attenuated influenza vaccine is not given.

Common prescribing errors. Not adjusting for kidney function. Evening dosing. Abrupt withdrawal in Parkinson disease.

Special groups.

• Pregnancy: avoid unless essential.

• Breastfeeding: excreted into milk; avoid.

• Older adults: high risk of confusion; use lower doses.

Formulations. Capsules or tablets 100 mg. Syrup 50 mg/5 mL. Extended-release capsules in some markets. Take with or without food.

Monitoring.

• Baseline creatinine clearance, then at least yearly and with illness or new interacting drugs.

• Mental state, oedema, skin, dyskinesia, and ECG in cardiac disease or with QT-prolonging drugs.

Stopping. Taper over 1 to 2 weeks rather than stopping abruptly.

Referral and escalation. Refer for hallucinations, delirium, seizures or arrhythmia. Overdose needs ECG monitoring and supportive care.