How should a 60-year-old man with end-stage renal disease (ESRD) on hemodialysis and a levetiracetam (Keppra) concentration of 97 µg/mL be managed?

Management of Elevated Levetiracetam Level in ESRD Patient on Hemodialysis

Immediate Action Required

This patient has a toxic levetiracetam level of 97 µg/mL (therapeutic range 12-46 µg/mL) and requires urgent hemodialysis to remove the drug, as standard hemodialysis procedures result in approximately 50% clearance of levetiracetam in 4 hours. 1

Clinical Assessment

• Evaluate immediately for signs of levetiracetam toxicity: somnolence, agitation, aggression, depressed level of consciousness, respiratory depression, and coma 1
• Monitor vital signs closely and assess the patient's clinical status, as these toxic levels can cause severe neurological impairment 1, 2
• Document any recent falls or trauma, as supratherapeutic levels commonly cause fatigue and somnolence leading to injury 2

Acute Management

Hemodialysis for Drug Removal

• Perform hemodialysis urgently if the patient is symptomatic or has significantly elevated levels, as this is the definitive treatment for levetiracetam overdose 1
• Hemodialysis achieves approximately 50% drug clearance in a 4-hour session and should be considered the primary intervention in cases of overdose or significant renal impairment 1

Supportive Care

• Provide general supportive care including airway protection if consciousness is depressed 1
• Contact a Certified Poison Control Center for up-to-date management guidance 1
• Hold all levetiracetam doses until levels normalize and the patient is clinically stable 2

Root Cause Analysis

Likely Causes of Toxicity

• Inappropriate dosing for ESRD: The standard recommendation for ESRD patients is a 50% dose reduction (250-750 mg every 12 hours), but even this may be insufficient 2
• Prolonged half-life in dialysis patients: Levetiracetam half-life increases from 7 hours in normal patients to 18.4 hours in peritoneal dialysis patients, suggesting similar prolongation in hemodialysis patients 2
• Inadequate supplementation timing: If post-dialysis doses were missed or given at incorrect times, drug accumulation occurs between sessions 3, 4

Long-Term Dosing Strategy

Recommended Regimen

After levels normalize, restart levetiracetam using a twice-daily (BID) dosing regimen rather than daily dosing, as BID achieves significantly higher and more stable therapeutic levels with better recovery to predialysis concentrations. 3

Specific Dosing Protocol

• Initial dose: 500 mg twice daily (reduced from standard dosing) 3
• Timing: Administer one dose after each hemodialysis session on dialysis days, following the general principle for ESRD medications to avoid premature drug removal 5, 6, 7
• Non-dialysis days: Continue twice-daily dosing at 12-hour intervals 3

Rationale for BID Over Daily Dosing

• BID dosing achieves mean predialysis levels of 43.1 µg/mL versus 21.1 µg/mL with daily dosing 3
• Post-HD dose levels recover to 81.4% of predialysis levels with BID versus only 65.7% with daily dosing (p=0.045) 3
• More consistent therapeutic levels reduce risk of breakthrough seizures between dialysis sessions 3, 4

Monitoring Requirements

Therapeutic Drug Monitoring

• Obtain levetiracetam levels regularly to avoid supratherapeutic concentrations that can lead to severe sequelae 2
• Check pre-dialysis and post-dialysis levels initially to establish the patient's individual pharmacokinetic profile 3
• Target therapeutic range: 12-46 µg/mL 2

Clinical Monitoring

• Monitor for seizure activity closely, as hemodialysis significantly reduces serum levels and can induce breakthrough seizures if dosing is inadequate 4
• Assess for adverse effects including somnolence, fatigue, and cognitive impairment at each visit 2
• Evaluate medication adherence after dialysis sessions, as poor adherence to post-HD doses results in fluctuating plasma levels 3

Critical Pitfalls to Avoid

• Do not use daily dosing regimens in hemodialysis patients, as they result in subtherapeutic levels and inadequate seizure control 3
• Never give levetiracetam before dialysis on dialysis days, as this leads to premature drug removal and therapeutic failure 5, 4
• Do not assume standard ESRD dosing is adequate without therapeutic drug monitoring, as individual pharmacokinetic variability is substantial 2, 8
• Avoid high loading doses (>2000 mg) as levetiracetam can cause acute kidney injury, especially in patients with compromised renal function 9