What are the uses and dosing recommendations for Levetiracetam (Keppra)?

Levetiracetam: Uses and Dosing

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), with emerging evidence supporting its use as a second-line agent for status epilepticus refractory to benzodiazepines. 1

FDA-Approved Indications and Standard Dosing

Partial-Onset Seizures

Adults (≥16 years):

• Initial dose: 1000 mg/day divided as 500 mg twice daily 1
• Titration: Increase by 1000 mg/day every 2 weeks as needed 1
• Maximum recommended dose: 3000 mg/day (1500 mg twice daily) 1
• Doses above 3000 mg/day have been studied but show no additional benefit 1

Pediatric patients (4 to <16 years):

• Initial dose: 20 mg/kg/day divided as 10 mg/kg twice daily 1
• Titration: Increase by 20 mg/kg every 2 weeks 1
• Target dose: 60 mg/kg/day (30 mg/kg twice daily) 1
• If 60 mg/kg/day is not tolerated, the dose may be reduced; mean effective dose in trials was 52 mg/kg/day 1
• Patients ≤20 kg should use oral solution; those >20 kg can use tablets or solution 1

Myoclonic Seizures (Juvenile Myoclonic Epilepsy)

Patients ≥12 years:

• Initial dose: 1000 mg/day (500 mg twice daily) 1
• Titration: Increase by 1000 mg/day every 2 weeks 1
• Recommended dose: 3000 mg/day 1
• Efficacy of doses <3000 mg/day has not been established 1

Primary Generalized Tonic-Clonic Seizures

Adults (≥16 years):

• Initial dose: 1000 mg/day (500 mg twice daily) 1
• Titration: Increase by 1000 mg/day every 2 weeks 1
• Recommended dose: 3000 mg/day 1

Pediatric patients (6 to <16 years):

• Initial dose: 20 mg/kg/day (10 mg/kg twice daily) 1
• Titration: Increase by 20 mg/kg every 2 weeks 1
• Recommended dose: 60 mg/kg/day (30 mg/kg twice daily) 1

Status Epilepticus (Off-Label but Guideline-Supported)

Levetiracetam is recommended by the American Academy of Emergency Medicine as a second-line agent for status epilepticus refractory to benzodiazepines, with efficacy comparable to valproate (73% vs 68% seizure cessation). 2, 3

Dosing for Status Epilepticus:

• Loading dose: 30 mg/kg IV at 5 mg/kg/minute 2
• Alternative dosing studied: 1500-2500 mg IV over 5 minutes 2
• Lower doses (20 mg/kg) showed reduced efficacy (38% within 30 minutes) 2
• For ED loading in known seizure patients: 1500 mg oral or rapid IV loading (up to 60 mg/kg has been well tolerated) 2

Efficacy Data:

• Studies show 44-73% efficacy when used after benzodiazepine failure 2
• Similar efficacy to valproate when both used at 30 mg/kg IV 2
• Adverse effects are minimal: fatigue, dizziness, rarely nausea or transient transaminitis 2

Key Pharmacokinetic Advantages

Levetiracetam has several therapeutic advantages that make it particularly useful in clinical practice:

• Excellent oral bioavailability with rapid absorption 4, 5
• Linear pharmacokinetics with minimal protein binding 4
• No hepatic metabolism (hydrolysis of acetamide group only) 5, 6
• Primarily renal elimination 5
• No clinically significant drug interactions with other antiepileptic drugs, digoxin, warfarin, probenecid, or oral contraceptives 7, 6
• Rapid achievement of steady-state concentrations 4

Administration Considerations

• Can be given with or without food 1
• IV and oral formulations can be used interchangeably 5
• Extended-release once-daily formulation available 5
• For pediatric oral solution, use calibrated measuring device (not household spoons) 1

Common Adverse Effects

Most adverse effects are mild to moderate and CNS-related, occurring predominantly during the first 4 weeks of treatment:

• Somnolence, asthenia, headache, and dizziness 7, 8, 6
• No dose-relationship apparent within recommended range (1000-3000 mg/day) 8
• Behavioral adverse effects reported in some patients 6
• Not associated with cognitive impairment or weight gain 6
• Overall tolerability similar to placebo in controlled trials 8

Clinical Pitfalls to Avoid

• Do not use household measuring devices for oral solution in pediatric patients 1
• Doses >3000 mg/day in adults provide no additional benefit 1
• For status epilepticus, doses <20 mg/kg IV show significantly reduced efficacy 2
• While effective as second-line for status epilepticus, evidence for use as third-line (after benzodiazepines AND phenytoin/valproate) is less clear 2