Keppra - Drug Monograph

Introduction

Keppra (levetiracetam) is an antiepileptic drug (AED) approved by the FDA in 1999 for the treatment of seizures. It belongs to the racetam class of medications and has become one of the most widely prescribed antiepileptic drugs due to its favorable safety profile, predictable pharmacokinetics, and broad spectrum of efficacy across multiple seizure types.

Mechanism of Action

Levetiracetam's exact mechanism of action remains incompletely understood but differs from traditional antiepileptic drugs. It binds selectively to synaptic vesicle protein 2A (SV2A), which is involved in neurotransmitter release. This binding is thought to modulate presynaptic calcium channels, reducing neurotransmitter release and stabilizing neuronal hyperexcitability. Unlike many AEDs, it does not primarily act on sodium or calcium channels, GABA receptors, or glutamatergic transmission.

Indications

• FDA-approved indications:

- Monotherapy or adjunctive therapy for partial-onset seizures in patients ≥4 years - Adjunctive therapy for myoclonic seizures in patients ≥12 years with juvenile myoclonic epilepsy - Adjunctive therapy for primary generalized tonic-clonic seizures in patients ≥6 years - Adjunctive therapy for partial-onset seizures in infants and children 1 month to <4 years

• Off-label uses:

- Status epilepticus (IV formulation) - Epilepsy prophylaxis in traumatic brain injury - Migraine prophylaxis - Bipolar disorder maintenance therapy

Dosage and Administration

• Initial dose: 500 mg twice daily (1000 mg/day)
• May increase by 1000 mg/day every 2 weeks
• Maximum recommended dose: 3000 mg/day

• Children 4-15 years: 10 mg/kg twice daily
• Children 1 month to <4 years: 10-20 mg/kg twice daily
• Dose adjustments based on weight and clinical response

• Renal impairment: Dose adjustment required based on creatinine clearance

- CrCl 50-80 mL/min: 500-1000 mg every 12 hours - CrCl 30-50 mL/min: 250-750 mg every 12 hours - CrCl <30 mL/min: 250-500 mg every 12 hours

• Hepatic impairment: No dosage adjustment needed (renally eliminated)
• Elderly: Adjust based on renal function
• Dialysis: Supplemental dose required after dialysis

• Tablets: 250, 500, 750, 1000 mg
• Oral solution: 100 mg/mL
• Extended-release tablets: 500, 750 mg
• IV injection: 500 mg/5 mL

Pharmacokinetics

• Absorption: Rapid and almost complete (>95%) with no food effect
• Distribution: Volume of distribution ~0.5-0.7 L/kg; minimal protein binding (<10%)
• Metabolism: Not extensively metabolized (24% via enzymatic hydrolysis); no cytochrome P450 involvement
• Elimination: Renal excretion (66% unchanged); half-life 6-8 hours (adults), 5-7 hours (children)
• Steady-state: Reached within 2 days of initiation

Contraindications

• Hypersensitivity to levetiracetam, other racetam derivatives, or any component of the formulation

Warnings and Precautions

• Neuropsychiatric effects: May cause psychiatric symptoms including psychosis, hallucinations, aggression, anxiety, and depression
• Suicidal ideation: AEDs increase risk of suicidal thoughts and behavior
• Somnolence and fatigue: May impair ability to drive or operate machinery
• Withdrawal seizures: Avoid abrupt discontinuation (taper gradually)
• Hematologic effects: Rare cases of pancytopenia and leukopenia reported
• Renal impairment: Requires dosage adjustment

Drug Interactions

• Minimal drug interactions due to lack of CYP450 metabolism
• Moderate interactions:

- May potentiate effects of other CNS depressants (alcohol, benzodiazepines, opioids) - Carbamazepine may decrease levetiracetam concentrations - Not affected by enzyme-inducing AEDs to clinically significant degree

• Laboratory interactions: May cause false-positive pregnancy tests

Adverse Effects

• Somnolence (15%)
• Asthenia (15%)
• Dizziness (9%)
• Infection (13%)
• Behavioral symptoms (irritability, aggression, anxiety)

• Stevens-Johnson syndrome
• Toxic epidermal necrolysis
• Pancreatitis
• Severe psychiatric reactions
• Hematologic abnormalities
• Anaphylaxis

Monitoring Parameters

• Baseline:

- Complete blood count - Renal function tests - Liver function tests - Psychiatric assessment - Seizure frequency and characteristics

• Ongoing:

- Seizure frequency diary - Behavioral and mood changes - Somnolence and cognitive effects - Renal function (annually or with clinical changes) - Therapeutic drug monitoring not routinely required

Patient Education

• Take as prescribed; do not stop abruptly
• May cause drowsiness - avoid driving until effects known
• Report any mood changes, depression, or suicidal thoughts
• Inform healthcare providers of all medications being taken
• Oral solution: Use measuring device provided; refrigerate after opening
• Extended-release tablets: Swallow whole; do not crush or chew
• Pregnancy considerations: Register with AED Pregnancy Registry if pregnant

References

1. Patsalos PN. Levetiracetam: commentary on efficacy and tolerability. Expert Opin Pharmacother. 2021;22(11):1365-1379. 2. Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatment guidelines: evidence-based analysis of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54(3):551-563. 3. Keppra® [package insert]. UCB, Inc.; 2021. 4. French JA, Kanner AM, Bautista J, et al. Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy. Neurology. 2004;62(8):1252-1260. 5. Lyseng-Williamson KA. Levetiracetam: a review of its use in epilepsy. Drugs. 2011;71(4):489-514. 6. National Institute for Health and Care Excellence (NICE). Epilepsies: diagnosis and management. Clinical guideline [CG137]. 2021.