Levetiracetam (Keppra)
levetiracetam
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Partial-onset (focal) seizures | ≥1 month | Monotherapy or adjunctive | FDA Approved |
| Myoclonic seizures in juvenile myoclonic epilepsy | ≥12 years | Adjunctive | FDA Approved |
| Primary generalized tonic-clonic seizures | ≥6 years with idiopathic generalized epilepsy | Adjunctive | FDA Approved |
Levetiracetam is one of the most widely prescribed antiepileptic drugs globally, valued for its broad-spectrum efficacy across focal and generalized seizure types, favorable pharmacokinetic profile with negligible drug interactions, and availability of both oral and intravenous formulations. The EMA also approves levetiracetam as monotherapy for focal seizures in adults and adolescents aged 16 years and above.
Status epilepticus (IV loading) — Used as a second- or third-line agent in established status epilepticus after benzodiazepine failure. Loading doses of 40–60 mg/kg (max 4500 mg) are used in clinical practice. Evidence quality: Moderate (supported by prospective cohort data and guideline consensus, e.g., AES 2016).
Seizure prophylaxis after traumatic brain injury or neurosurgery — Commonly used for early seizure prophylaxis (first 7 days) following TBI or craniotomy. Evidence quality: Moderate (AAN guidelines; head-to-head comparison data with phenytoin).
Neonatal seizures — Increasingly used as a first- or second-line agent for neonatal seizures despite limited prospective data in this population. Evidence quality: Low (primarily retrospective cohort studies; the NEOLEV2 RCT showed non-inferiority vs phenobarbital was not met).
Dosing
Adult Dosing (16 Years and Older)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Focal epilepsy — new diagnosis, monotherapy | 500 mg BID | 500–1500 mg BID | 3000 mg/day | Titrate by 500 mg/dose every 2 weeks No evidence of benefit beyond 3000 mg/day (FDA PI) |
| Focal epilepsy — refractory, adjunctive therapy | 500 mg BID | 500–1500 mg BID | 3000 mg/day | Same titration schedule as monotherapy IV dose = oral dose (1:1 bioequivalence) |
| Juvenile myoclonic epilepsy — adjunctive | 500 mg BID | 1500 mg BID | 3000 mg/day | Target dose is 3000 mg/day Lower doses not adequately studied for JME |
| Primary generalized tonic-clonic seizures — adjunctive | 500 mg BID | 1500 mg BID | 3000 mg/day | Target dose is 3000 mg/day Lower doses not adequately studied for PGTC |
| Status epilepticus (off-label) — IV loading | 40–60 mg/kg IV | 500–1500 mg BID | 4500 mg load | Infuse over 15 minutes AES guideline; used after benzodiazepine failure |
Pediatric Dosing
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Focal seizures — infant (1 to <6 months) | 7 mg/kg BID | 21 mg/kg BID | 42 mg/kg/day | Titrate by 7 mg/kg/dose q2wk Use oral solution; calibrated device required |
| Focal seizures — young child (6 months to <4 years) | 10 mg/kg BID | 25 mg/kg BID | 50 mg/kg/day | Titrate by 10 mg/kg/dose q2wk Monitor diastolic BP in this age group |
| Focal seizures — older child (4 to <16 years) | 10 mg/kg BID | 30 mg/kg BID | 3000 mg/day | Titrate by 10 mg/kg/dose q2wk Tablets: ≤40 kg start 250 mg BID (max 1500 mg/day); >40 kg start 500 mg BID (max 3000 mg/day) |
| PGTC seizures — child (6 to <16 years, IGE) | 10 mg/kg BID | 30 mg/kg BID | 60 mg/kg/day | Titrate by 10 mg/kg/dose q2wk Lower doses not adequately studied |
Renal Impairment Dosing (Adults)
| Renal Function (CrCl mL/min/1.73m²) | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Normal (>80) | 500 mg q12h | 500–1500 mg q12h | 1500 mg q12h | No adjustment needed |
| Mild (50–80) | 500 mg q12h | 500–1000 mg q12h | 1000 mg q12h | Clearance reduced ~40% |
| Moderate (30–50) | 250 mg q12h | 250–750 mg q12h | 750 mg q12h | Clearance reduced ~50% |
| Severe (<30) | 250 mg q12h | 250–500 mg q12h | 500 mg q12h | Clearance reduced ~60% |
| ESRD on dialysis | 500 mg q24h | 500–1000 mg q24h | 1000 mg q24h | Give supplemental 250–500 mg after each dialysis session ~50% removed by standard 4-hour hemodialysis |
Levetiracetam has 1:1 bioequivalence between IV and oral formulations (same dose, same frequency). When switching between routes, no dose adjustment is needed. The IV formulation should be infused over 15 minutes. IV use beyond 4 days has not been studied in clinical trials.
Pharmacology
Mechanism of Action
Levetiracetam exerts its antiepileptic effect through a mechanism distinct from all other available antiepileptic drugs. It binds selectively to synaptic vesicle protein 2A (SV2A), a transmembrane glycoprotein present on synaptic vesicles throughout the brain. SV2A is involved in regulating vesicle fusion and neurotransmitter release at presynaptic terminals. By modulating SV2A function, levetiracetam is thought to reduce excessive synchronised neuronal firing without affecting normal synaptic transmission. Notably, the binding affinity of levetiracetam analogs to SV2A correlates with their anticonvulsant potency in animal models. Levetiracetam does not block voltage-gated sodium or calcium channels at therapeutic concentrations, and it does not directly modulate GABA or glutamate receptor activity, which distinguishes it pharmacologically from conventional antiepileptic agents.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Bioavailability ~100%; Tmax ~1 h fasted; food delays Tmax by 1.5 h but does not reduce extent | Rapid onset; can be taken with or without food; dose equivalence between oral and IV |
| Distribution | Vd 0.5–0.7 L/kg; protein binding <10%; crosses placenta and enters breast milk | Distributes into total body water; negligible protein-binding displacement interactions; monitor levels in pregnancy |
| Metabolism | Enzymatic hydrolysis of acetamide group (24% of dose) by type B esterases in blood; no CYP450 involvement; inactive metabolite ucb L057 | No hepatic enzyme induction or inhibition; no significant drug-drug interactions via CYP pathway; no hepatic dose adjustment needed |
| Elimination | t½ 7 ± 1 h (adults); 66% excreted unchanged in urine; renal clearance 0.6 mL/min/kg; total clearance 0.96 mL/min/kg; dialysable (~50% in 4 h) | Predominantly renal elimination; dose adjustment required in renal impairment; supplemental dose needed post-dialysis |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Somnolence | 15% (vs 8% placebo) | Dose-related; ~45% at 4000 mg/day without titration; typically self-limiting within 4 weeks |
| Asthenia / fatigue | 15% (vs 9% placebo) | Peaks during first 4 weeks of treatment; usually improves with continued therapy |
| Headache | 14% (vs 13% placebo) | Only marginally above placebo rate; rarely requires discontinuation |
| Infection (non-specific) | 13% (vs 8% placebo) | Predominantly nasopharyngitis and upper respiratory infections |
| Behavioral symptoms (pediatric 4–16 yr) | 38% (vs 19% placebo) | Includes aggression, irritability, agitation, anxiety, hostility; specific concern in pediatric populations |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Dizziness | 9% (vs 4% placebo) | Peaks in first 4 weeks; advise caution with driving |
| Pharyngitis | 6% (vs 4% placebo) | Usually mild and self-resolving |
| Depression | 4% (vs 2% placebo) | Monitor; consider alternative AED if clinically significant |
| Nervousness | 4% (vs 2% placebo) | May overlap with irritability spectrum |
| Anorexia / decreased appetite | 3% (vs 2% placebo) | More prominent in pediatric populations (~8%) |
| Ataxia | 3% (vs 1% placebo) | Includes abnormal gait and incoordination; onset within first 4 weeks |
| Vertigo | 3% (vs 1% placebo) | Assess fall risk, especially in elderly |
| Diplopia | 2% (vs 1% placebo) | May indicate supratherapeutic levels or pharmacodynamic interaction with concomitant AEDs |
| Emotional lability | 2% (vs 0% placebo) | Part of the behavioral adverse effect spectrum; monitor mood closely |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Psychiatric / behavioral disturbances (psychosis, suicidal ideation) | 1% adults; 2% pediatric | First 1–4 weeks | Assess severity; dose reduction or discontinuation; psychiatric referral if warranted |
| Anaphylaxis / angioedema | Rare (postmarketing) | Any time (including first dose) | Discontinue immediately; emergency management; permanent discontinuation |
| Stevens-Johnson syndrome / TEN | Very rare (postmarketing) | Median 14–17 days | Discontinue at first sign of rash unless clearly not drug-related; do not rechallenge |
| DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) | Very rare (FDA alert Nov 2023) | 2–8 weeks after initiation | Discontinue if no alternative etiology; presents with fever, rash, lymphadenopathy, organ involvement |
| Suicidality (AED class effect) | 0.43% (vs 0.24% placebo) | As early as 1 week | Monitor for emergence of depression, mood changes, suicidal thoughts; risk-benefit assessment |
| Hematologic abnormalities (leukopenia, pancytopenia, agranulocytosis) | Rare (postmarketing); WBC decrease ~3.2% in trials | Variable | CBC if significant weakness, recurrent infections, or pyrexia; most WBC decreases resolve without discontinuation |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Somnolence | 3–4% | Most common reason in adults; risk mitigated by slow titration |
| Behavioral adverse effects | 1.7% (vs 0.2% placebo) | Includes aggression, irritability, hostility; higher risk in pediatric and psychiatric comorbidity populations |
| Dizziness | 1% (vs 0% placebo) | Generally transient with continued therapy |
| Asthenia | 0.8% (vs 0.5% placebo) | Usually resolves after first month |
Behavioral adverse effects (irritability, aggression, mood changes) are the most clinically significant tolerability concern with levetiracetam, particularly in pediatric patients and those with pre-existing psychiatric conditions. A gradual dose reduction or trial of pyridoxine supplementation (50–200 mg/day) has been used in clinical practice, though evidence for pyridoxine benefit remains limited. If severe behavioral disturbances develop, switching to brivaracetam (which also targets SV2A but has a lower reported incidence of psychiatric adverse effects) may be considered.
Drug Interactions
Levetiracetam has an exceptionally clean drug interaction profile. It is not metabolised by cytochrome P450 enzymes, does not inhibit or induce CYP isoforms, and has negligible protein binding (<10%). Formal pharmacokinetic studies have confirmed no interactions with phenytoin, valproate, warfarin, digoxin, or oral contraceptives (FDA PI). However, pharmacodynamic interactions (additive CNS depression, additive neurotoxicity) can occur.
Monitoring
-
Renal Function
Baseline, then annually
Routine Serum creatinine and estimated CrCl. Levetiracetam clearance is directly correlated with creatinine clearance; dose adjustments are required at all levels of renal impairment. Reassess more frequently in elderly patients or those with changing renal status. -
Behavioral / Psychiatric Status
Each visit; first 4 weeks closely
Routine Screen for new or worsening irritability, aggression, depression, suicidal ideation, and psychotic symptoms. Particularly important in pediatric patients where non-psychotic behavioral symptoms affect up to 38% of treated children (FDA PI). -
Complete Blood Count
If symptomatic
Trigger-based Obtain CBC if patient develops significant weakness, recurrent infections, pyrexia, or signs of coagulation disorder. Minor decreases in WBC and RBC counts occur in clinical trials but rarely require intervention. -
Blood Pressure
Each visit (infants)
Routine Monitor diastolic blood pressure in patients aged 1 month to <4 years; 17% of treated infants developed increased diastolic BP vs 2% on placebo. Not observed in older children or adults. -
Levetiracetam Levels
Pregnancy; suspected non-adherence
Trigger-based Therapeutic drug monitoring is not routinely indicated due to the wide therapeutic index. However, plasma levels may decrease significantly during pregnancy (especially third trimester) and should be monitored to guide dose adjustments. Suggested reference range: 12–46 mcg/mL. -
Skin / Hypersensitivity
First 3 months especially
Trigger-based Educate patients to report any rash immediately. Discontinue levetiracetam at the first sign of rash unless clearly unrelated. Assess for SJS/TEN (median onset 14–17 days) and DRESS (fever, rash, lymphadenopathy, organ involvement).
Contraindications & Cautions
Absolute Contraindications
- Known hypersensitivity to levetiracetam — prior anaphylaxis or angioedema to levetiracetam or any component of the formulation
Relative Contraindications (Specialist Input Recommended)
- Active major depression or suicidal ideation — AEDs as a class are associated with increased suicidality risk (0.43% vs 0.24% placebo); levetiracetam also causes depression in ~4% of adults. If prescribing in patients with active psychiatric illness, ensure close psychiatric monitoring and documented risk-benefit discussion.
- Pre-existing significant behavioral disturbance (especially in children) — Given up to 38% non-psychotic behavioral symptom rate in pediatric patients, prescribing in children with pre-existing aggression or severe behavioral disorders should involve specialist co-management.
- End-stage renal disease without dialysis access — Accumulation risk without appropriate dose reduction and supplemental dosing post-dialysis.
Use with Caution
- Renal impairment (any degree) — dose reduction required; see Renal Impairment Dosing table.
- Elderly patients — higher risk of falls from somnolence and dizziness; typically have reduced renal clearance (half-life extends to 10–11 hours).
- Pregnancy — plasma levels may decrease significantly, particularly in the third trimester; monitor levels and adjust dose accordingly. Available registry data have not identified a clear drug-associated risk of major birth defects.
- History of bone marrow suppression — rare postmarketing cases of agranulocytosis and pancytopenia have been reported.
- Patients requiring abrupt discontinuation — withdrawal seizures and status epilepticus may occur; taper gradually when possible.
A pooled analysis of 199 placebo-controlled trials of 11 AEDs (including levetiracetam) demonstrated an approximately 2-fold increased risk of suicidal thinking or behavior in AED-treated patients compared with placebo (adjusted relative risk 1.8; 95% CI 1.2–2.7). The risk was observed as early as one week after initiation and persisted throughout treatment. Patients should be monitored for emergence or worsening of depression, suicidal thoughts, and any unusual changes in mood or behavior.
Patient Counselling
Purpose of Therapy
Levetiracetam helps prevent seizures by reducing abnormal electrical activity in the brain. It does not cure epilepsy, but taking it regularly as prescribed significantly reduces the frequency and severity of seizures. It may be used alone or alongside other seizure medications depending on the type and severity of epilepsy.
How to Take
Levetiracetam tablets should be swallowed whole (not crushed or chewed) and can be taken with or without food. The medicine is taken twice daily, approximately 12 hours apart. An oral solution is available for children or patients who cannot swallow tablets. The dose will typically start low and increase every two weeks to reach the target dose. Missing a dose increases the risk of breakthrough seizures. If a dose is missed, it should be taken as soon as remembered, but two doses should never be taken at the same time.
Sources
- UCB, Inc. KEPPRA (levetiracetam) prescribing information. Revised 03/2024. FDA Label Primary regulatory source for all approved indications, dosing, adverse reactions, pharmacokinetics, and contraindications cited in this monograph.
- UCB Pharma. KEPPRA XR (levetiracetam) extended-release tablets prescribing information. Revised 03/2024. FDA Label Extended-release formulation PI; approved only for partial-onset seizures in patients 12 years and older.
- FDA Drug Safety Communication. Antiseizure Medicines Levetiracetam and Clobazam: Risk of DRESS. November 28, 2023. FDA Safety Communication Prompted the labeling update (Section 5.6) adding DRESS as a recognized serious adverse reaction.
- Shorvon SD, Lowenthal A, Janz D, et al. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. Epilepsia. 2000;41(9):1179–1186. DOI European pivotal trial (Study 2 in FDA PI) demonstrating efficacy of 1000 mg/day and 2000 mg/day for refractory focal seizures.
- Cereghino JJ, Biton V, Abou-Khalil B, et al. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology. 2000;55(2):236–242. DOI US pivotal trial (Study 1 in FDA PI) demonstrating efficacy at 1000 mg/day and 3000 mg/day.
- Noachtar S, Andermann E, Meencke HJ, et al. Levetiracetam for the treatment of idiopathic generalized epilepsy with myoclonic seizures. Neurology. 2008;70(8):607–616. DOI Pivotal trial (Study 6) establishing adjunctive efficacy for myoclonic seizures in JME at 3000 mg/day.
- Berkovic SF, Knowlton RC, Leroy RF, et al. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology. 2007;69(18):1751–1760. DOI Pivotal trial (Study 7) demonstrating adjunctive efficacy for primary generalized tonic-clonic seizures.
- Glauser T, Ben-Menachem E, Bourgeois B, et al. Updated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes. Epilepsia. 2013;54(3):551–563. DOI ILAE guideline review supporting levetiracetam as an option for initial monotherapy in focal seizures.
- Glauser T, Shinnar S, Gloss D, et al. Evidence-based guideline: treatment of convulsive status epilepticus in children and adults. Epilepsy Curr. 2016;16(1):48–61. DOI AES guideline supporting levetiracetam as a treatment option for established status epilepticus.
- Lynch BA, Lambeng N, Bhatt K, et al. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A. 2004;101(26):9861–9866. DOI Landmark study identifying SV2A as the binding target for levetiracetam, establishing its unique mechanism of action.
- Patsalos PN. Clinical pharmacokinetics of levetiracetam. Clin Pharmacokinet. 2004;43(11):707–724. DOI Comprehensive PK review covering absorption, distribution, metabolism, elimination, and special population pharmacokinetics.
- Wright C, Downing J, Mungall D, et al. Clinical pharmacology and pharmacokinetics of levetiracetam. Front Neurol. 2013;4:192. DOI Review of IV levetiracetam pharmacokinetics including neonatal data and critically ill populations.
- Verrotti A, Prezioso G, Di Sabatino F, et al. The adverse event profile of levetiracetam: a meta-analysis on children and adults. Epilepsy Behav. 2015;49:49–54. DOI Meta-analysis of 26 RCTs (2832 patients) confirming nasopharyngitis, somnolence, dizziness, irritability, and asthenia as statistically significant LEV-associated adverse events.