Levetiracetam

Aka: Levetiracetam, Keppra, Spiritam

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II. Indications

  1. Status Epilepticus
    1. Off-FDA label, but first-line agent after Benzodiazepines
  2. Seizure Prophylaxis
    1. Partial Seizures or Focal onset Seizures (FDA Approved for adjunctive therapy)
    2. Juvenile Myoclonic Epilepsy (FDA approved for ages >12 years for adjunctive therapy)
    3. Primary Generalized Tonic Clonic Seizures (FDA approved for ages >6 years for adjunctive therapy)
  3. Myoclonus (adults, off label)

III. Mechanism

  1. Broad spectrum Pyrrolidine Anticonvulsant
    1. Activity isolated to the synaptic plasma membrane of CNS Neurons
    2. Binds Glycoprotein 2A at the synaptic Vesicle and may alter Vesicle fusion
    3. May also affect Gamma-Aminobutyric Acid (GABA)
    4. May effect Calcium-dependent Neurotransmitter release
  2. Modulates Neurotransmitter release and Neuron excitability
    1. Decreases burst Neuron firing (and decreased Seizure propagation)

IV. Dosing: Status Epilepticus

  1. Dose: 40-60 mg/kg IV (up to 4500 mg maximum)
    1. Adult typical dose: 2000 to 4500 mg over 5 to 15 min for single dose

V. Dosing: Seizure Prophylaxis in Adults

  1. Target serum concentration: 12 to 46 mcg/ml
  2. Immediate Release (Levetiracetam, Spiritam)
    1. Start: 500 mg orally or IV twice daily
    2. Titrate every 2 weeks, increasing by 500-1000 mg/day divided twice daily
    3. Typical target dose: 1000-3000 mg/day (or 80 mg/kg/day) divided twice daily
    4. Maximum: 3000 mg/day (higher doses do not increase efficacy)
  3. Extended Release (Levetiracetam XR for Partial Seizures)
    1. Start 1000 mg orally daily
    2. Titrate every 2 weeks, increasing by 1000 mg/day
      1. Rapid titration is associated with increased adverse effects
      2. Typical target dose: 1000-3000 mg/day (or 80 mg/kg/day)
    3. Maximum: 3000 mg/day
      1. Higher doses do not increase efficacy, but increase adverse effects
  4. Intravenous infusion dose is bioequivalent to oral dose
    1. Load: 20-30 mg/kg IV at 5 mg/kg/min

VI. Dosing: Seizure Prophylaxis in Children

  1. Age 1 to 6 months (Levetiracetam Solution, oral dosing only)
    1. Start 14 mg/kg/day divided orally twice daily
    2. Increase every 2 weeks by 14 mg/kg/day divided twice daily
    3. Target dose: 42 mg/kg/day divided twice daily
  2. Age 6 months to 4 years (Levetiracetam Solution, oral dosing only)
    1. Start 20 mg/kg/day divided orally twice daily
    2. Increase every 2 weeks by 20 mg/kg/day divided twice daily
    3. Target dose: 50 mg/kg/day divided twice daily
  3. Age 4 to 16 years (oral dosing only)
    1. Levetiracetam Solution
      1. Start 20 mg/kg/day divided orally twice daily
      2. Increase every 2 weeks by 20 mg/kg/day divided twice daily
      3. Target dose: 60 mg/kg/day divided twice daily
    2. Levetiracetam tablets: Weight 20 to 40 kg
      1. Start: 250 mg orally twice daily
      2. Titrate every 2 weeks, increasing by 500 mg/day divided twice daily
      3. Typical target dose: 1500 mg/day divided twice daily
      4. Maximum: 1500 mg/day
    3. Levetiracetam tablets: Weight >40 kg
      1. Start: 500 mg orally twice daily
      2. Titrate every 2 weeks, increasing by 1000 mg/day divided twice daily
      3. Typical target dose: 3000 mg/day divided twice daily
      4. Maximum: 3000 mg/day (higher doses do not increase efficacy)
  4. Age >16 years
    1. Use adult dosing (IV or oral)

VII. Pharmacokinetics

  1. Protein binding <10%
  2. Renal Excretion: 66% is excreted unchanged in the urine
    1. Adjust dosing in renal Impairment
  3. Oral
    1. Bioavailability: Approaches 100%
    2. Onset: 1-2 hours
    3. Peak: 1-1.3 hours
    4. Steady-State: 48 hours
  4. IV
    1. Peak: 5-15 minutes

VIII. Adverse Effects

  1. Most common
    1. Fatigue or Weakness
    2. Somnolence
    3. Dizziness or Vertigo
  2. Psychiatric symptoms or Behavioral Changes (common, may limit usage)
    1. Agitation, irritability or hostility
    2. Emotional lability
    3. Anxiety
    4. Depressed mood
    5. Rare case reports of Psychosis, severe behavioral disturbance, Suicidality
  3. Other symptoms
    1. Irritability
    2. Rash
  4. Serious (rare)
    1. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS Syndrome)
      1. FDA warning issued 2023
      2. Presents with fever, Lymphadenopathy, rash at 2-8 weeks after medication start
    2. Overdose
      1. Somnolence, Dizziness and Agitation are more common
      2. Severe cases may be associated with respiratory depression and coma
      3. Recovery for most patients with supportive care
      4. Consider Hemodialysis in severe toxicity or Renal Insufficiency

IX. Safety

  1. Safe in children
  2. Unknown safety in Lactation
  3. Pregnancy Category C
    1. Considered among the safer Anticonvulsants in pregnancy based on registry data
    2. Lower risk of congenital malformation than older Anticonvulsants

X. Metabolism

  1. Rapid oral absorption
  2. Renal Excretion
    1. Decrease dose in renal Impairment

XI. Drug Interactions

  1. May result in toxicity if used with carbamezepine
  2. Low risk for other Drug Interactions

XII. Resources

  1. Levetiracetam (DailyMed)
    1. https://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f65ec19d-b90e-452e-b761-c68b1cf2c892
  2. Levetiracetam (StatPearls)
    1. https://www.ncbi.nlm.nih.gov/books/NBK499890/

XIII. References

  1. LoVecchio and Pringle (2026) Crit Dec Emerg Med 40(7): 36
  2. LoVecchio and Pringle (2018) Crit Dec Emerg Med 32(12): 28
  3. (2022) Presc Lett, Resource #361206, Antiseizure Medications
  4. Olson (2020) Clinical Pharmacology, Medmaster Miami, p. 56-7
  5. Hamilton (2020) Tarascon Pocket Pharmacopoeia
  6. Liu (2017) Am Fam Physician 96(2): 87-96 [PubMed]

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