Memantine

Indications

• FDA-approved for moderate to severe dementia of the Alzheimer type, as immediate-release tablets, oral solution, or extended-release capsules.
• Namzaric, a fixed combination of memantine extended-release with donepezil 10 mg, is approved for patients already stabilized on both drugs.
• It is not approved for mild Alzheimer disease, and trials in mild disease and in mild cognitive impairment have been negative.
• Commonly added to a cholinesterase inhibitor in moderate to severe disease, a combination supported by modest but consistent trial data.
• Used off-label for vascular dementia and for agitation in dementia, where evidence is weak and antipsychotic-sparing benefit is unproven.
• Used off-label as an augmentation strategy in obsessive-compulsive disorder, supported only by small randomized trials.

Mechanism of action

• Uncompetitive, low-affinity, voltage-dependent antagonist at the NMDA glutamate receptor channel with rapid unblocking kinetics.
• It blocks pathologic tonic glutamate signaling while still permitting the phasic bursts required for learning and memory.
• Reducing excessive calcium influx is thought to limit excitotoxic injury, though no clinical trial has shown a disease-modifying effect.
• The low affinity and fast off-rate explain why it lacks the psychotomimetic effects of high-affinity NMDA antagonists such as ketamine.
• It also has weak antagonist activity at 5-HT3 and nicotinic receptors and agonist activity at dopamine D2 receptors.

Pharmacokinetics

• Well absorbed with Tmax of 3-7 hours and bioavailability near 100 percent; food has no clinically relevant effect on absorption.
• Half-life is 60-80 hours, so steady state takes several weeks and the drug can be dosed once daily in the extended-release form.
• Undergoes minimal hepatic metabolism to inactive metabolites and is excreted 57-82 percent unchanged in urine.
• Renal elimination uses cationic transport, so alkaline urine from carbonic anhydrase inhibitors or bicarbonate reduces clearance and raises levels.
• Because clearance is renal, dose adjustment depends on creatinine clearance rather than on liver function.

Dosing

• Immediate-release: start 5 mg PO once daily and increase by 5 mg weekly to a target of 10 mg twice daily.
• Extended-release: start 7 mg PO once daily and increase by 7 mg weekly to a target of 28 mg once daily as tolerated.
• Severe renal impairment with creatinine clearance 5-29 mL/min: maximum 5 mg twice daily immediate-release or 14 mg/day extended-release.
• Switching from immediate-release 10 mg twice daily to extended-release 28 mg daily is done the day after the last immediate-release dose.
• Extended-release capsules may be opened and sprinkled on applesauce and swallowed without chewing for patients with swallowing difficulty.
• No hepatic adjustment is required in mild to moderate impairment; severe hepatic impairment has not been studied.

Adverse effects

• Dizziness in about 7 percent, headache, confusion, and constipation are the most common effects and are usually mild.
• Somnolence, fatigue, and agitation occur less often, and overall tolerability is better than with cholinesterase inhibitors.
• Blood pressure elevation and, rarely, hypertension have been reported and warrant periodic vital sign checks.
• Confusion or worsening agitation early in titration usually reflects too-rapid escalation and improves with slower titration.
• Rare hallucinations, gait disturbance, and falls occur, particularly when renal function declines and levels rise.
• It does not cause the nausea, diarrhea, bradycardia, or weight loss that limit cholinesterase inhibitor therapy.

Monitoring

• Check creatinine clearance before starting and periodically thereafter, since dosing depends on renal function rather than age alone.
• Measure blood pressure at routine visits, since hypertension has been reported during memantine treatment.
• Track cognition and function with MMSE or MoCA plus a caregiver-reported functional scale about every 6 months.
• Reassess benefit at 3 to 6 months and discuss stopping when decline continues without meaningful functional or behavioral benefit.
• Review urinary alkalinizing drugs and any new renal impairment, both of which raise memantine levels and can cause confusion.

Interactions

• Drugs that alkalinize urine, including sodium bicarbonate and carbonic anhydrase inhibitors such as acetazolamide, reduce clearance and raise levels.
• Other NMDA antagonists including amantadine, ketamine, and dextromethorphan should generally be avoided because effects are additive.
• Cimetidine, ranitidine, quinidine, nicotine, and hydrochlorothiazide share the renal cationic transport system and may alter concentrations.
• Memantine does not meaningfully inhibit or induce CYP enzymes, so it is straightforward to combine with most psychotropics.
• It can be combined safely with donepezil, and the fixed-dose combination product exists specifically for that pairing.

Special populations

• Geriatric: this is the target population, and renal function rather than chronological age determines the correct maximum dose.
• Renal impairment: reduce the dose when creatinine clearance falls below 30 mL/min; no data exist for dialysis patients.
• Hepatic impairment: no adjustment for mild or moderate disease, and severe impairment has not been studied.
• Pregnancy and lactation: human data are essentially absent, and the indication rarely applies in patients of reproductive age.
• Pediatric: not approved at any age, and trials in autism and ADHD have not demonstrated meaningful benefit.

Clinical pearls

• It is for moderate to severe disease; adding it in mild Alzheimer disease has repeatedly failed in trials.
• Dose by creatinine clearance, not by age; confusion often means renal decline, not disease progression.
• Tolerability is its strength, so it suits patients who cannot manage cholinesterase inhibitor nausea.