What is the optimal dosing strategy for levetiracetam (Keppra) in a patient with epilepsy who is also taking Dilantin (phenytoin) and has impaired renal function?

Levetiracetam Dosing in Patients on Phenytoin with Renal Impairment

In patients with epilepsy taking phenytoin (Dilantin) who have impaired renal function, levetiracetam requires dose reduction based on creatinine clearance, but phenytoin co-administration does not necessitate additional dosage adjustments since levetiracetam has no significant pharmacokinetic interactions with phenytoin. 1

Key Pharmacokinetic Principles

Levetiracetam does not interact with phenytoin. Levetiracetam is neither an inhibitor of nor a substrate for cytochrome P450 enzymes, and it does not affect the pharmacokinetics of phenytoin. 1 This means the presence of phenytoin does not alter levetiracetam clearance or dosing requirements.

However, renal impairment is the critical factor that mandates dose adjustment, as levetiracetam is primarily eliminated renally (66% unchanged in urine). 1

Renal Dosing Algorithm

Calculate creatinine clearance first using the Cockcroft-Gault equation: CLcr = [140 - age (years)] × weight (kg) × (0.85 for females) / [72 × serum creatinine (mg/dL)]. 1

Standard Maintenance Dosing by Renal Function:

• Normal (CLcr >80 mL/min): 500-1500 mg every 12 hours 1
• Mild impairment (CLcr 50-80 mL/min): 500-1000 mg every 12 hours 1
• Moderate impairment (CLcr 30-50 mL/min): 250-750 mg every 12 hours 1
• Severe impairment (CLcr <30 mL/min): 250-500 mg every 12 hours 1
• End-stage renal disease on dialysis: 500-1000 mg every 24 hours, with a 250-500 mg supplemental dose after each dialysis session 1

Practical Dosing Strategy

Start with the lower end of the dose range for each renal function category and titrate upward based on seizure control and tolerability. 1 The typical starting dose for normal renal function is 1000 mg/day (500 mg twice daily), with increases of 1000 mg/day every 2 weeks up to a maximum of 3000 mg/day. 1

In renal impairment, total body clearance decreases proportionally: 40% reduction in mild impairment, 50% in moderate impairment, 60% in severe impairment, and 70% in end-stage renal disease. 1 The elimination half-life increases from approximately 7 hours in normal patients to significantly longer in renal dysfunction. 1

Critical Monitoring Considerations

Approximately 50% of levetiracetam is removed during a standard 4-hour hemodialysis session, necessitating supplemental dosing post-dialysis. 1 For patients on continuous renal replacement therapy (CVVH), consider 1000 mg every 12 hours as an initial regimen, with therapeutic drug monitoring to guide adjustments. 2, 3

Therapeutic drug monitoring is particularly valuable in renal impairment to ensure adequate seizure control while avoiding accumulation. Target serum concentrations are 12-46 μg/mL. 4

Common Pitfalls to Avoid

Do not reduce levetiracetam doses based on phenytoin co-administration. The two drugs do not interact pharmacokinetically, and phenytoin does not induce levetiracetam metabolism. 1 This is a critical distinction from enzyme-inducing antiepileptics like carbamazepine, which can increase levetiracetam clearance by approximately 22%. 1

Do not overlook the need for supplemental dosing after dialysis. Failure to provide post-dialysis supplementation results in subtherapeutic levels and breakthrough seizures. 1

Avoid underdosing in patients with preserved renal function. Recent evidence demonstrates that only 54% of critically ill patients achieve target levels with standard dosing, and higher doses (750-1000 mg twice daily) are more than twice as likely to achieve therapeutic levels compared to 500 mg twice daily. 4

Special Considerations

Hepatic impairment does not require dose adjustment for levetiracetam, even in severe hepatic dysfunction (Child-Pugh C), as decreased renal clearance accounts for most of the reduction in total body clearance. 1 This makes levetiracetam particularly advantageous in patients with combined hepatic and renal dysfunction.

Elderly patients require dose reduction due to age-related decline in renal function, with total body clearance decreasing by 38% and half-life increasing by 2.5 hours compared to younger adults. 1 Always calculate creatinine clearance rather than relying on serum creatinine alone in elderly patients, as serum creatinine may appear normal despite significantly reduced renal function.