What is the recommended treatment and dosage for epilepsy using Levetiracetam (Keppra)?

Levetiracetam (Keppra) for Epilepsy: Treatment and Dosing

Levetiracetam is indicated as adjunctive therapy for partial-onset seizures, myoclonic seizures in juvenile myoclonic epilepsy, and primary generalized tonic-clonic seizures, with standard maintenance dosing starting at 1000 mg/day (500 mg BID) in adults and titrating up to 3000 mg/day based on response. 1

FDA-Approved Indications

Levetiracetam has three primary approved uses:

• Partial-onset seizures: Adjunctive treatment in adults and children ≥4 years old 1
• Myoclonic seizures: Adjunctive therapy in patients ≥12 years with juvenile myoclonic epilepsy 1
• Primary generalized tonic-clonic seizures: Adjunctive therapy in adults and children ≥6 years with idiopathic generalized epilepsy 1

Standard Maintenance Dosing for Chronic Epilepsy

Adults (≥16 years) - Partial-Onset Seizures

Start with 1000 mg/day divided as 500 mg twice daily, then increase by 1000 mg/day increments every 2 weeks to a maximum of 3000 mg/day. 1

• Daily doses of 1000 mg, 2000 mg, and 3000 mg have all demonstrated efficacy 1
• No consistent evidence that doses >3000 mg/day provide additional benefit 1
• Can be taken with or without food 1

Pediatric Patients (4 to <16 years) - Partial-Onset Seizures

Begin at 20 mg/kg/day in two divided doses (10 mg/kg BID), increase every 2 weeks by 20 mg/kg increments to the recommended dose of 60 mg/kg/day (30 mg/kg BID). 1

• If 60 mg/kg/day is not tolerated, the dose may be reduced 1
• Patients ≤20 kg should use oral solution; those >20 kg can use tablets or solution 1
• Mean effective dose in clinical trials was 52 mg/kg/day 1

Myoclonic Seizures (≥12 years)

Start at 1000 mg/day (500 mg BID), increase by 1000 mg/day every 2 weeks to the recommended dose of 3000 mg/day. 1

• Efficacy of doses <3000 mg/day has not been established for this indication 1

Primary Generalized Tonic-Clonic Seizures

Adults (≥16 years): Start at 1000 mg/day (500 mg BID), increase by 1000 mg/day every 2 weeks to 3000 mg/day 1

Pediatric (6 to <16 years): Start at 20 mg/kg/day (10 mg/kg BID), increase every 2 weeks by 20 mg/kg to 60 mg/kg/day (30 mg/kg BID) 1

Acute/Emergency Dosing for Status Epilepticus

Second-Line Agent (After Benzodiazepines)

Administer 30 mg/kg IV over 5 minutes for benzodiazepine-refractory status epilepticus, with demonstrated efficacy of 68-73%. 2, 3

• Alternative studied dosing: 1500-2500 mg IV over 5 minutes 2
• Avoid lower doses of 20 mg/kg, which show reduced efficacy (38-67%) 2, 4
• Levetiracetam has similar efficacy to valproate (73% vs 68% seizure cessation) when both used at 30 mg/kg IV 2

Maintenance After Status Epilepticus Resolution

• Convulsive status epilepticus: 30 mg/kg IV every 12 hours OR increase prophylaxis dose by 10 mg/kg (to 20 mg/kg) IV every 12 hours (maximum 1500 mg) 3
• Non-convulsive status epilepticus: 15 mg/kg (maximum 1500 mg) IV every 12 hours 3

ED Loading for Known Seizure Patients

For patients with known epilepsy requiring loading, administer 1500 mg oral or rapid IV. 5

• Rapid IV loading up to 60 mg/kg has been well tolerated in studies 5, 4
• 89% of patients denied adverse effects with oral loading 4
• No seizures occurred within 24 hours of loading, with discharge possible within 3-30 hours 4

Safety Profile and Adverse Effects

Common Adverse Effects

Levetiracetam is generally well tolerated with minimal serious adverse effects:

• Most common: Somnolence, asthenia, headache, dizziness 6
• Status epilepticus loading: Fatigue, dizziness, rarely nausea or transient transaminitis 2
• Behavioral effects: Transient irritability, imbalance, tiredness, or lightheadedness reported in 11% of patients 4
• Overall adverse event incidence similar to placebo in clinical trials 7, 8

Cardiovascular Safety

Levetiracetam has minimal cardiovascular effects, making it safer than phenytoin/fosphenytoin in acute settings. 2, 3

• Low incidence of hypotension (1.7-3.2%) and bradycardia (3.5-7.8%) with rapid IV administration 4
• No significant blood pressure changes, local infusion site reactions, or ECG abnormalities in pediatric IV loading studies 4
• Does not require cardiac monitoring during administration, unlike phenytoin 3

Cognitive and Quality of Life Effects

• Not associated with cognitive impairment or weight gain 7, 8
• Positive effects on cognition and quality of life measures compared to placebo 9

Pharmacokinetic Advantages

Levetiracetam has several properties that make it clinically favorable:

• Rapid and complete absorption with high oral bioavailability 7, 8
• Minimal metabolism via hydrolysis of acetamide group, primarily renal elimination 7, 8
• No cytochrome P450 enzyme induction 7, 8
• No clinically significant drug interactions with other antiepileptic drugs, digoxin, warfarin, probenecid, or oral contraceptives 7, 8, 6

Clinical Efficacy Data

Adjunctive Therapy for Partial-Onset Seizures

• Approximately 15% of patients on 1000 mg/day and 20-30% on 3000 mg/day achieve ≥50% reduction in seizure frequency 9
• Clear dose-response relationship with increasing efficacy at higher doses 9
• Efficacy demonstrated in both pediatric and adult populations 7, 8

Monotherapy

• Non-inferior to carbamazepine controlled-release for newly diagnosed partial-onset seizures 7, 8

Status Epilepticus

• 44-73% efficacy when used after benzodiazepine failure 2
• Comparable to valproate as second-line agent 2, 3

Critical Clinical Pitfalls to Avoid

Dosing Errors in Status Epilepticus

Do not use 20 mg/kg doses for status epilepticus—this shows significantly reduced efficacy (38-67%). 2, 4

• The evidence-based dose is 30 mg/kg IV 2, 3
• Lower doses were studied but demonstrated inferior outcomes 2

Inappropriate Use as Third-Line Agent

Evidence for levetiracetam as third-line therapy (after benzodiazepines AND phenytoin/valproate) is less clear. 2

• Levetiracetam is best positioned as a second-line agent after benzodiazepine failure 2, 3

Inadequate Titration in Chronic Management

Do not add a second antiepileptic drug before optimizing levetiracetam to maximum tolerated dose (up to 3000 mg/day in adults). 3

• Ensure compliance before escalating treatment, as non-compliance is a common cause of breakthrough seizures 3
• Search for precipitating factors (sleep deprivation, alcohol, medication non-compliance, intercurrent illness) 3
• Consider obtaining serum levels to assess compliance and adequate dosing 3

Measurement Device for Pediatric Oral Solution

A household teaspoon or tablespoon is not adequate for measuring oral solution. 1

• Use a calibrated measuring device that can accurately deliver the prescribed dose 1

Special Populations

Renal Dysfunction

Both levetiracetam and valproate require dose adjustments in renal impairment 3

Women of Childbearing Potential

When combining with valproate, avoid valproate in women of childbearing potential due to significantly increased risks of fetal malformations and neurodevelopmental delay. 3

• Levetiracetam is preferred in this population 3

Elderly Patients

• 1500 mg IV in ≤15 minutes showed 89% reduction in seizures in patients ≥65 years 4
• Valproate protein binding is reduced in elderly, increasing free fraction 3

Combination Therapy Considerations

When to Add Valproate to Levetiracetam

For patients with inadequate seizure control on optimized levetiracetam monotherapy, adding sodium valproate is a reasonable combination strategy. 3

• Both agents have similar efficacy (46-47% seizure control) as second-line monotherapy 3
• No significant pharmacokinetic interactions between levetiracetam and valproate 3
• Monitor liver function tests due to valproate's hepatotoxicity risk 3