Can memantine be used safely in a patient with acute kidney injury (creatinine clearance <30 mL/min), and what dose adjustment is recommended?

Memantine Use in Acute Kidney Injury

Memantine can be used in patients with acute kidney injury, but requires dose reduction to 5 mg twice daily (10 mg total daily) when creatinine clearance falls below 30 mL/min. 1

FDA-Approved Dosing in Renal Impairment

The FDA label provides clear guidance for memantine dosing based on renal function 1:

• Normal renal function (CrCl >30 mL/min): Standard dosing of 10 mg twice daily (20 mg/day total) is appropriate
• Severe renal impairment (CrCl 5-29 mL/min): Target dose of 5 mg twice daily (10 mg/day total) is recommended 1

The critical threshold for dose adjustment is a creatinine clearance of 30 mL/min, not 50 mL/min as with some other renally cleared medications. 1, 2

Pharmacokinetic Rationale for Dose Adjustment

Memantine is primarily cleared by the kidneys, and renal impairment significantly affects drug exposure 2, 3:

• Mild renal impairment (CrCl 50-80 mL/min): No dose adjustment needed; drug exposure increases by approximately 60% but remains within safe therapeutic range 2
• Moderate renal impairment (CrCl 30-49 mL/min): No dose adjustment needed; drug exposure increases by 60% but predicted steady-state concentrations remain acceptable at standard dosing 2
• Severe renal impairment (CrCl 5-29 mL/min): Dose reduction to 5 mg twice daily is required; drug exposure increases by 115% at standard dosing, and elimination half-life extends to approximately 124 hours 2, 3

Critical Considerations in AKI

Accurate Renal Function Assessment

The most important pitfall is using serum creatinine alone or standard eGFR equations in AKI, as these significantly overestimate actual kidney function in critically ill patients. 4, 5

• Calculate creatinine clearance using the Cockcroft-Gault equation with the most recent stable creatinine value 1
• In critically ill patients with AKI, measured 24-hour urine creatinine clearance may be more accurate than estimated values 5
• Standard GFR estimation equations based on serum creatinine have severe limitations in AKI due to non-steady-state conditions 4

Drug Interaction Risk in AKI

Avoid concurrent use of trimethoprim or other organic cation transporter-2 inhibitors with memantine in patients with renal impairment, as this combination can cause severe toxicity including myoclonus and delirium. 6

• Trimethoprim blocks renal tubular secretion of memantine, leading to drug accumulation even with appropriate dose reduction 6
• Other medications utilizing the same renal transporter (metformin, imipramine) may similarly increase memantine levels 6

Practical Dosing Algorithm for AKI

Step 1: Calculate creatinine clearance using Cockcroft-Gault equation (or measure 24-hour urine CrCl if available in ICU setting) 1, 5

Step 2: Apply dose adjustment based on CrCl 1:

• CrCl ≥30 mL/min: Continue or initiate standard dosing (10 mg twice daily)
• CrCl 5-29 mL/min: Reduce to 5 mg twice daily

Step 3: Titrate gradually if initiating therapy 1:

• Start at 5 mg once daily
• Increase by 5 mg increments weekly
• Target dose: 5 mg twice daily for severe renal impairment

Step 4: Monitor for toxicity signs 6:

• Myoclonus or involuntary movements
• Worsening confusion or delirium beyond baseline dementia
• Agitation or combativeness

Step 5: Re-evaluate renal function regularly as AKI evolves 4:

• If CrCl improves to >30 mL/min, consider uptitrating to standard dosing
• If CrCl worsens to <5 mL/min or dialysis is initiated, consult nephrology for individualized dosing

Conditions That Increase Memantine Levels

Alkaline urine pH decreases urinary elimination of memantine and increases plasma levels, requiring additional caution in AKI. 1

• Urinary alkalinization from bicarbonate therapy (common in AKI management) may further reduce memantine clearance 1
• Monitor for signs of drug accumulation if urine pH is consistently >7.0

Safety Profile

Memantine has not been systematically studied in dialysis patients, but the drug's high protein binding suggests dialysis is unlikely to significantly remove it 1. In clinical trials, seizures occurred in only 0.2% of memantine-treated patients, suggesting reasonable safety even with dose adjustment 1.