Keppra (Levetiracetam): Proper Usage and Dosage
Primary Indications
Levetiracetam is FDA-approved as adjunctive therapy for partial onset seizures (ages ≥4 years), myoclonic seizures in juvenile myoclonic epilepsy (ages ≥12 years), and primary generalized tonic-clonic seizures (ages ≥6 years). 1
Standard Maintenance Dosing for Chronic Seizure Management
Adults (≥16 years) with Partial Onset Seizures
- Initial dose: 1000 mg/day divided as 500 mg twice daily 1
- Titration: Increase by 1000 mg/day every 2 weeks as needed 1
- Target dose: 3000 mg/day (1500 mg twice daily) 1
- Maximum studied dose: 3000 mg/day; higher doses show no additional benefit 1
Pediatric Patients (4-15 years) with Partial Onset Seizures
- Initial dose: 20 mg/kg/day divided twice daily (10 mg/kg BID) 1
- Titration: Increase by 20 mg/kg every 2 weeks 1
- Target dose: 60 mg/kg/day (30 mg/kg BID) 1
- If intolerant: May reduce from 60 mg/kg/day target; mean effective dose in trials was 52 mg/kg 1
- Weight-based guidance: Patients ≤20 kg require oral solution; >20 kg can use tablets or solution 1
Myoclonic Seizures (≥12 years with Juvenile Myoclonic Epilepsy)
- Initial dose: 1000 mg/day (500 mg BID) 1
- Titration: Increase by 1000 mg/day every 2 weeks 1
- Target dose: 3000 mg/day (1500 mg BID) 1
- Note: Efficacy of doses <3000 mg/day not established 1
Primary Generalized Tonic-Clonic Seizures
Adults (≥16 years):
- Same dosing as partial onset seizures: start 1000 mg/day, titrate to 3000 mg/day 1
Pediatric (6-15 years):
- Same weight-based dosing as partial onset seizures: start 20 mg/kg/day, titrate to 60 mg/kg/day 1
Emergency Dosing for Status Epilepticus
Second-Line Agent (After Benzodiazepines)
Levetiracetam is a Level A recommendation as second-line therapy for benzodiazepine-refractory status epilepticus, with equivalent efficacy to fosphenytoin and valproate (approximately 47% seizure cessation). 2
Adult loading dose:
- 30 mg/kg IV over 5 minutes (typical fixed dose: 1500-3000 mg) 3, 4
- Maximum infusion rate: 100 mg/min 4
- Efficacy: 68-73% seizure control when used after benzodiazepine failure 3, 5
Pediatric loading dose:
- 20-30 mg/kg IV (maximum 1000 mg per dose) over 10-20 minutes 4
- For convulsive status epilepticus: 40 mg/kg (maximum 2500 mg) IV bolus 4
Key advantage: No cardiac monitoring required, unlike fosphenytoin which carries 12% hypotension risk 3
Maintenance After Status Epilepticus Resolution
Adults:
- 30 mg/kg IV every 12 hours OR increase prophylaxis dose by 10 mg/kg (to 20 mg/kg) every 12 hours (maximum 1500 mg) 3
Pediatric:
- Convulsive status: 30 mg/kg IV every 12 hours 4
- Non-convulsive status: 15 mg/kg (maximum 1500 mg) IV every 12 hours 4
Administration Considerations
Route and Timing
- Oral administration: Can be taken with or without food 1
- IV formulation: Bioavailability equivalent to oral, allowing use in emergencies 6
- Extended-release formulation: Once-daily dosing available for patients ≥16 years, may improve compliance 7
Measuring Devices
- Household teaspoons/tablespoons are inadequate for oral solution 1
- Use calibrated measuring device that delivers prescribed dose accurately 1
Pharmacokinetic Advantages
Levetiracetam has nearly ideal pharmacokinetics that distinguish it from older anticonvulsants:
- Rapid, complete absorption after oral ingestion 7
- <10% protein binding 7
- Linear kinetics across dose ranges 7
- Minimal metabolism via non-cytochrome P450 pathway 7, 6
- No significant drug-drug interactions 7, 8
- Wide therapeutic index 7
This profile makes levetiracetam particularly valuable for brain tumor patients on chemotherapy or other P450-inducing drugs 6
Efficacy Data
Adjunctive Therapy for Refractory Partial Seizures
- 1000 mg/day: Approximately 15% achieve ≥50% seizure reduction 9
- 3000 mg/day: 20-30% achieve ≥50% seizure reduction 9
- Overall responder rate: Odds ratio 3.81 (95% CI: 2.78-5.22) compared to placebo 9
- Dose-response relationship: Clear evidence of increasing efficacy with higher doses 9
Status Epilepticus (Second-Line)
- After benzodiazepine failure: 68-73% efficacy at 30 mg/kg dose 3, 5
- Lower doses (20 mg/kg): Reduced efficacy of 38-67%, not recommended 5
- Comparable to alternatives: Similar efficacy to valproate (73% vs 68%) and fosphenytoin (47% vs 45%) 2, 5
Adverse Effects and Safety Profile
Common Adverse Events
Most frequently reported (generally mild):
- Somnolence 7, 8
- Dizziness (OR 2.36 vs placebo) 9
- Asthenia 8
- Headache 8
- Infection (OR 1.82 vs placebo) 9
- Irritability 7
- Nausea 7
Notably, accidental injury was significantly associated with placebo (OR 0.55), not levetiracetam 9
Serious but Rare Neuropsychiatric Effects
- Behavioral abnormalities 10
- Psychosis (uncommon) 10
- Delirium: First case reported in 2014; symptoms resolved within 24 hours of discontinuation 10
Critical pitfall: In elderly patients presenting with acute confusion after levetiracetam initiation, consider drug-induced delirium and discontinue the medication 10
Status Epilepticus Safety Profile
- Hypotension: 0.7% (vs 3.2% fosphenytoin, 1.6% valproate) 2
- Cardiac arrhythmias: 0.7% 2
- Endotracheal intubation: 20% (vs 26.4% fosphenytoin, 16.8% valproate) 2
- No cardiac monitoring required during administration 3
Clinical Pearls and Quality of Life
Cognitive and Quality of Life Effects
Levetiracetam demonstrates positive effects on cognition and quality of life aspects, distinguishing it from many older anticonvulsants. 9
Drug Interaction Profile
- No interactions with: Digoxin, warfarin, probenecid 8
- Oral contraceptives: Protective efficacy not affected 8
- Other anticonvulsants: No clinically relevant interactions 8
Special Populations
Brain tumor patients:
- Particularly advantageous due to lack of P450 induction 6
- Can be used prophylactically perioperatively 6
- Emerging evidence suggests increased temozolomide sensitivity 6
Critical Pitfalls to Avoid
Dosing Errors
- Do not use inadequate loading doses in status epilepticus: 20 mg/kg shows only 38% efficacy; use 30 mg/kg 5
- Do not exceed 100 mg/min infusion rate to minimize adverse effects 4
- Do not assume doses >3000 mg/day provide additional benefit in chronic management 1
Treatment Algorithm Errors
- Never use as first-line for active seizures: Benzodiazepines remain Level A first-line treatment 3
- Do not skip second-line agents: Levetiracetam is second-line after benzodiazepines, not third-line 3, 5
- Do not use neuromuscular blockers alone: They mask seizure activity while allowing continued brain injury 3
Monitoring Failures
- In breakthrough seizures on levetiracetam: Check serum levels to assess compliance before adding second agent 3
- Search for precipitating factors: Sleep deprivation, alcohol, medication non-compliance, intercurrent illness 3
- Consider EEG: To distinguish true epileptic seizures from psychogenic seizures or detect subclinical activity 3
Combination Therapy Considerations
When to Add Second Agent
Optimize levetiracetam to maximum tolerated dose (up to 3000 mg/day in adults, 60 mg/kg/day in children) before adding second anticonvulsant. 3, 1
Reasonable Combinations
- Levetiracetam + valproate: Safe combination without significant pharmacokinetic interactions; both demonstrated 46-47% efficacy as monotherapy in status epilepticus 3
- Monitor liver function tests when adding valproate due to hepatotoxicity risk 3