Memantine

Memantine is an N-methyl-D-aspartate receptor antagonist used for moderate to severe Alzheimer disease, alone or added to a cholinesterase inhibitor. Benefit is modest and symptomatic. It is cleared by the kidney, so dose depends on creatinine clearance.

Mechanism. Uncompetitive, low-affinity blocker of the N-methyl-D-aspartate receptor channel, limiting pathological glutamate excitation while preserving normal synaptic transmission.

Pharmacokinetics. Bioavailability near 100% and protein binding about 45%. Half-life is 60 to 80 hours. About half is excreted unchanged in urine, and little is metabolised. Alkaline urine (pH over 8) reduces clearance.

First-line and alternative use. Moderate to severe Alzheimer disease. Treatment continues while there is clear benefit.

• Oral memantine, immediate-release: 5 mg once daily in week 1, 10 mg once daily in week 2, 15 mg once daily in week 3, then 20 mg once daily from week 4. Some labels give the target as 10 mg twice daily. Maximum 20 mg daily.

• Extended-release (where available): start 7 mg once daily and increase by 7 mg each week to 28 mg once daily.

• Combination with donepezil, rivastigmine or galantamine is used in moderate to severe disease.

Kidney, liver, weight and age.

• Kidney: creatinine clearance 30 to 49 mL/min, target 10 mg daily, increased to 20 mg daily after at least 7 days if tolerated. Creatinine clearance 5 to 29 mL/min, 10 mg daily (5 mg twice daily).

• Liver: no adjustment in mild to moderate impairment; severe impairment is not studied.

• Older adults: titrate slowly and watch for dizziness and confusion.

Contraindications. Hypersensitivity.

Serious adverse effects. Seizures, hallucinations and confusion, heart failure, hypertensive crisis (rare), and severe skin reactions (rare).

Common adverse effects. Dizziness, headache, constipation, somnolence, hypertension and balance problems.

Interactions. Avoid combining with other N-methyl-D-aspartate antagonists (amantadine, ketamine, dextromethorphan). Drugs that raise urine pH (sodium bicarbonate, carbonic anhydrase inhibitors) reduce clearance. Monitor warfarin INR. Anticholinergics and dopaminergic drugs may have altered effects.

Common prescribing errors. Not adjusting for kidney function. Fast titration. Combining with amantadine.

Special groups.

• Pregnancy: avoid unless essential.

• Breastfeeding: avoid.

• Epilepsy, recent myocardial infarction and uncontrolled hypertension: use caution.

Formulations. Tablets 10 and 20 mg. Oral solution 10 mg/mL, dispensed by pump. Extended-release capsules in some markets. Take with or without food.

Monitoring.

• Baseline creatinine clearance, blood pressure and cognition; repeat kidney function yearly and with illness.

• Review benefit and function every 6 months.

Stopping. Stop gradually where possible, over about 1 week, and monitor behaviour.

Referral and escalation. Refer for rapid decline, behavioural disturbance, seizures or when considering stopping in advanced disease.