Levetiracetam - Drug Monograph

Introduction

Levetiracetam is a second-generation antiepileptic drug (AED) belonging to the racetam class. First approved by the FDA in 1999, it has become one of the most widely prescribed antiepileptic medications worldwide due to its favorable pharmacokinetic profile, broad spectrum of activity, and generally good tolerability. Levetiracetam is available under the brand name Keppra® and various generic formulations.

Mechanism of Action

Levetiracetam's exact mechanism of action differs from traditional antiepileptic drugs. Its primary mechanism involves binding to synaptic vesicle protein 2A (SV2A), which is involved in vesicle exocytosis and neurotransmitter release. This binding is thought to modulate synaptic neurotransmission and stabilize neuronal membranes. Unlike many AEDs, levetiracetam does not primarily act on sodium channels, GABA receptors, or glutamate receptors. It demonstrates inhibitory effects on high-voltage-activated calcium currents and may reduce neuronal hypersynchronization.

Indications

• FDA-approved indications:

- Monotherapy or adjunctive therapy for partial-onset seizures in patients 1 month and older with epilepsy - Adjunctive therapy for myoclonic seizures in patients 12 years and older with juvenile myoclonic epilepsy - Adjunctive therapy for primary generalized tonic-clonic seizures in patients 6 years and older with idiopathic generalized epilepsy

• Off-label uses:

- Neuropathic pain - Migraine prophylaxis - Bipolar disorder augmentation - Anxiety disorders - Seizure prophylaxis following traumatic brain injury

Dosage and Administration

• Initial dose: 500 mg twice daily
• May increase by 500 mg twice daily every 2 weeks
• Maintenance dose: 1000-1500 mg twice daily (maximum 3000 mg/day)

• 1 month to <6 years: 10-20 mg/kg/day in 2 divided doses
• 6 to <16 years: 10-20 mg/kg/day in 2 divided doses (max 60 mg/kg/day)

• Renal impairment: Dose adjustment required based on creatinine clearance
• Hepatic impairment: No adjustment needed (renally eliminated)
• Elderly: Consider reduced dosing due to potential decreased renal function
• Pregnancy: Category C - use only if potential benefit justifies potential risk

• Tablets: 250 mg, 500 mg, 750 mg, 1000 mg
• Oral solution: 100 mg/mL
• Extended-release tablets: 500 mg, 750 mg
• Intravenous injection: 100 mg/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 hepatically metabolized (24% via enzymatic hydrolysis)
• Elimination: Primarily renal excretion (66% unchanged); half-life 6-8 hours
• Steady state: Achieved within 2 days with twice-daily dosing

Contraindications

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

Warnings and Precautions

• Psychiatric effects: May cause psychiatric symptoms including depression, psychosis, aggression, and suicidal ideation
• Somnolence and fatigue: May impair mental and physical abilities required for hazardous tasks
• Withdrawal seizures: Abrupt discontinuation may increase seizure frequency
• Hematologic effects: Rare reports of pancytopenia and leukopenia
• Coagulation disorders: Isolated cases of altered coagulation parameters

Drug Interactions

• Minimal cytochrome P450 interactions
• Moderate interactions:

- May enhance CNS depression when combined with other CNS depressants (alcohol, benzodiazepines, opioids) - Oral contraceptives: No significant interaction observed - Carbamazepine, phenytoin, phenobarbital: May slightly decrease levetiracetam concentrations

• Laboratory interactions: May cause false-positive pregnancy tests

Adverse Effects

• Somnolence (15%)
• Asthenia (15%)
• Dizziness (9-15%)
• Infection (13%)

• Behavioral abnormalities (agitation, anxiety, depression)
• Coordination difficulties
• Gastrointestinal disturbances
• Rhinitis

• Suicidal ideation and behavior
• Severe psychiatric reactions
• Hematologic abnormalities
• Stevens-Johnson syndrome (rare)
• Anaphylaxis (rare)

Monitoring Parameters

• Baseline:

- Complete blood count - Renal function (BUN, creatinine, creatinine clearance) - Psychiatric assessment - Seizure frequency and characteristics

• Ongoing:

- Seizure frequency and severity - Behavioral and mood changes - Signs of infection or bleeding - Renal function (annually or with clinical changes) - Therapeutic drug monitoring not routinely required

Patient Education

• Take medication exactly as prescribed; do not stop abruptly
• May cause drowsiness or dizziness - avoid driving or operating machinery until effects are known
• Report any mood changes, depression, or suicidal thoughts immediately
• Inform all healthcare providers about levetiracetam use
• Use effective contraception if of childbearing potential
• Store at room temperature; oral solution should be used within 6 weeks of opening
• Extended-release tablets should be swallowed whole, not crushed or chewed

References

1. Patsalos PN. The pharmacokinetic characteristics of levetiracetam. Methods Find Exp Clin Pharmacol. 2003;25(2):123-129. 2. Lyseng-Williamson KA. Levetiracetam: a review of its use in epilepsy. Drugs. 2011;71(4):489-514. 3. Keppra® (levetiracetam) prescribing information. UCB, Inc. 2021. 4. 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. 2006;47(7):1094-1120. 5. French JA, Pedley TA. Initial management of epilepsy. N Engl J Med. 2008;359(2):166-176. 6. Zaccara G, Gangemi P, Cincotta M. Central nervous system adverse effects of new antiepileptic drugs: a meta-analysis of placebo-controlled studies. Seizure. 2008;17(5):405-421.