What is the proper way to increase Keppra (levetiracetam) levels orally?

Increasing Levetiracetam (Keppra) Levels Orally

For adults, increase levetiracetam by 1000 mg/day increments every 2 weeks, starting from 1000 mg/day (500 mg BID) up to a maximum of 3000 mg/day (1500 mg BID), as doses above 3000 mg/day have not demonstrated additional benefit. 1

Standard Dose Escalation Protocol for Adults

Initial dosing should begin at 1000 mg/day given as twice-daily dosing (500 mg BID). 1

• Increase by 1000 mg/day increments every 2 weeks until reaching the target dose 1
• The maximum recommended daily dose is 3000 mg/day (1500 mg BID) 1
• Although doses greater than 3000 mg/day have been used in open-label studies for 6+ months, there is no evidence that doses exceeding 3000 mg/day confer additional benefit 1

In clinical trials, doses of 1000 mg, 2000 mg, and 3000 mg daily all demonstrated efficacy, though a consistent dose-response relationship was not established. 1

Pediatric Dose Escalation (Ages 4-16 Years for Partial Seizures)

• Start at 20 mg/kg/day in 2 divided doses (10 mg/kg BID) 1
• Increase every 2 weeks by increments of 20 mg/kg to the recommended dose of 60 mg/kg/day (30 mg/kg BID) 1
• If 60 mg/kg/day is not tolerated, the daily dose may be reduced 1
• In clinical trials, the mean daily dose was 52 mg/kg 1

Patients weighing ≤20 kg should use oral solution, while those >20 kg can use either tablets or oral solution. 1

Special Populations Requiring Dose Adjustment

Renal Impairment

Levetiracetam dosing must be individualized based on creatinine clearance, with significant reductions required for moderate to severe renal dysfunction. 1

• Normal renal function (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
• ESRD on dialysis: 500-1000 mg every 24 hours, with a 250-500 mg supplemental dose following dialysis 1

Evidence for Higher Doses

Research demonstrates that doses from 1000-4000 mg/day are effective, with median seizure frequencies decreasing at all dose levels, though somnolence and asthenia increase with higher doses, suggesting 4000 mg/day may be the upper limit for some patients. 2

• At 1000 mg/day: 1.0 seizures/week (vs 2.06 with placebo) 2
• At 2000 mg/day: 1.5 seizures/week 2
• At 3000 mg/day: 1.0 seizures/week 2
• At 4000 mg/day: 0.75 seizures/week 2
• 22-33% of patients were seizure-free during levetiracetam treatment compared to 14% with placebo 2

Monitoring Requirements

Complete blood count monitoring is recommended when initiating levetiracetam therapy. 3

• Patients with suspected non-adherence should be considered for therapeutic level monitoring 3
• Levetiracetam can be taken with or without food 1

Common Pitfalls to Avoid

• Do not exceed 3000 mg/day in routine practice, as FDA labeling indicates no additional benefit above this dose despite use of higher doses in open-label studies 1
• Do not increase doses more frequently than every 2 weeks, as this is the established titration schedule that balances efficacy with tolerability 1
• Do not use household teaspoons or tablespoons for oral solution dosing—a calibrated measuring device must be used to ensure accurate dosing 1
• Do not forget to adjust for renal function, as levetiracetam is renally eliminated and failure to reduce doses in renal impairment can lead to toxicity 1

Tolerability Considerations

The most common adverse events are somnolence and asthenia, with frequency and severity increasing at higher doses. 2

• Extended-release formulations allow once-daily dosing, which may improve compliance and minimize concentration-related adverse effects through more constant plasma levels 4
• Levetiracetam has nearly ideal pharmacokinetics with rapid absorption, minimal protein binding, linear kinetics, no significant drug-drug interactions, and a wide therapeutic index 4