Levetiracetam (Keppra)

• Workhorse ASM: Broad-spectrum antiseizure medication for new-onset seizures, status epilepticus adjunct, and post-neurosurgery/ICH/TBI prophylaxis
• IV/PO Equivalence: IV and PO have essentially 1:1 equivalence; easy to transition from IV → PO when enteral route available
• Common ICU Dosing: Loading 60 mg/kg IV (max 4,500 mg) for status epilepticus (many centers 40–60 mg/kg), then 1,000–1,500 mg IV/PO q12h for maintenance
• Renal Clearance: Renally cleared → dose-reduce in CKD; minimal hepatic metabolism and very few drug–drug interactions compared with older agents
• Major Downside: Behavioral/psychiatric effects (agitation, irritability, mood change, psychosis) and somnolence; watch closely in delirious or brain-injured patients
• Key Advantage: Generally hemodynamically stable, non-sedating at typical doses, and safe in hepatic dysfunction, which is why neuro/ICU teams love it

• Generic Name: Levetiracetam
• Brand Names: Keppra, Keppra XR, generics

Antiseizure medication (ASM); pyrrolidone derivative; SV2A modulator

Mechanism of Action:

• Binds to synaptic vesicle protein 2A (SV2A), a presynaptic protein involved in neurotransmitter release; modulation of SV2A is thought to reduce neuronal excitability and seizure propagation
• Also may inhibit N-type calcium channels and modulate GABA and glycine–gated currents in some models, but the exact antiseizure mechanism is not fully defined
• Does not act via classic sodium channel blockade like phenytoin/carbamazepine, which may contribute to its more favorable interaction profile

Pharmacokinetics:

• Bioavailability: Oral ≈ 100%; IV and PO are interchangeable 1:1 on a mg-per-mg basis
• Onset: Peak concentration ~1 hour after PO; IV administration achieves peak at end of infusion (commonly 15 minutes)
• Distribution: Low protein binding (<10%); volume of distribution ~0.5–0.7 L/kg; good CNS penetration
• Metabolism: Minimal hepatic metabolism (non–CYP mediated hydrolysis)
• Elimination: ~66% excreted unchanged in urine; elimination half-life ~6–8 hours in normal renal function, prolonged in CKD
• Special Considerations: Dose adjustment is required in reduced creatinine clearance; not significantly affected by hepatic impairment alone

• Acute treatment of status epilepticus (after benzodiazepine) as part of first- or second-line ASM therapy
• New-onset focal or generalized seizures in ED/ICU when long-term ASM is likely
• Seizure prophylaxis in selected patients: TBI, subarachnoid hemorrhage, intracerebral hemorrhage, post–brain tumor resection (per neurosurgery/neurocritical care protocols)
• Conversion from older ASMs (e.g., phenytoin) in critically ill patients when interaction or toxicity concerns arise

Available Forms:

• IV solution: 100 mg/mL (e.g., 500 mg/5 mL, 1,000 mg/10 mL, etc.) for dilution in compatible fluids
• Immediate-release tablets: 250 mg, 500 mg, 750 mg, 1,000 mg
• Oral solution: 100 mg/mL (varies by manufacturer)
• Extended-release (XR) tablets: typically once-daily dosing, more outpatient than ICU

Adult Dosing (IV/PO):

Contraindications:

• Known hypersensitivity to levetiracetam or other pyrrolidone derivatives
• History of serious hypersensitivity reaction (e.g., anaphylaxis, angioedema) to the drug

Major Precautions:

• Behavioral and psychiatric effects: irritability, agitation, mood lability, depression, and psychosis can occur—monitor closely, especially in patients with prior psychiatric disease or delirium
• Somnolence and fatigue: generally less sedating than many ASMs, but can still contribute to decreased alertness, especially at high doses or with other CNS depressants
• Renal impairment: accumulation increases risk of adverse effects; adjust dose based on creatinine clearance
• Gradual taper is recommended when discontinuing chronic therapy to avoid increased seizure risk
• Use caution in pregnancy; levetiracetam is often preferred over older agents but still requires risk–benefit discussion and folate supplementation

Common:

• Somnolence, fatigue
• Dizziness, incoordination
• Headache
• Nausea, vomiting, decreased appetite
• Irritability, agitation, anxiety

Serious:

• Behavioral disturbances: severe agitation, aggression, psychosis, suicidal ideation
• Serious hypersensitivity reactions including Stevens–Johnson syndrome (rare)
• Blood dyscrasias (e.g., neutropenia, pancytopenia) – rare but reported
• Increased seizure frequency with abrupt withdrawal or nonadherence

Elderly Patients:

• Often have reduced renal function; adjust dose accordingly
• Start at lower end of dosing range
• Monitor for somnolence and falls risk

Renal Impairment:

• Dose adjustment essential based on CrCl (see dosing table)
• Consider 50% loading dose reduction in severe CKD
• Post-dialysis supplemental doses required

Hepatic Impairment:

• No dose adjustment required for hepatic impairment alone
• Advantage over older ASMs with hepatic metabolism

Pregnancy:

• Often preferred over older ASMs (less teratogenic)
• Still requires risk-benefit discussion
• Folate supplementation recommended
• Levels may decrease in pregnancy; monitor clinical response

Lactation:

• Excreted in breast milk
• Monitor infant for sedation, poor feeding

Clinical Monitoring:

• Clinical seizure control: frequency, duration, and electrographic seizures if on continuous EEG
• Mental status and behavior for signs of agitation, mood change, or psychosis—especially after initiation or dose escalation
• Renal function (SCr, CrCl) regularly in critically ill patients to guide dosing
• CBC periodically with prolonged use, particularly if infection, bruising, or fatigue occurs
• Adherence and timing of doses when transitioning IV → PO and at ICU-to-floor or floor-to-home handoffs

• 1. Lexicomp. (2024). Levetiracetam: Drug information. Wolters Kluwer.
• 2. Glauser, T., Shinnar, S., Gloss, D., et al. (2016). Evidence-based guideline: Treatment of convulsive status epilepticus in children and adults. Epilepsy Currents, 16(1), 48–61. https://doi.org/10.5698/1535-7597-16.1.48
• 3. Brophy, G. M., Bell, R., Claassen, J., et al. (2012). Guidelines for the evaluation and management of status epilepticus. Neurocritical Care, 17(1), 3–23. https://doi.org/10.1007/s12028-012-9695-z
• 4. Patsalos, P. N. (2000). Pharmacokinetic profile of levetiracetam: Toward ideal characteristics. Pharmacology & Therapeutics, 85(2), 77–85. https://doi.org/10.1016/S0163-7258(99)00052-2
• 5. Kapur, J., Elm, J., Chamberlain, J. M., et al. (2019). Randomized trial of three anticonvulsant medications for status epilepticus. New England Journal of Medicine, 381(22), 2103–2113. https://doi.org/10.1056/NEJMoa1905795