Levetiracetam

Aka. Keppra

CLASS

• a pyrrolidine anticonvulsant

INDICATIONS

1. Seizures (primary generalised tonic-clonic, myoclonic or partial seizures as an adjunct)
2. Status epilepticus (2nd Tier)
3. Seizure prophylaxis

ADMINISTRATION / DOSING

• intravenous (IV) / oral (PO)
• Adults:
  • Initial therapeutic dose: 500 mg BD, and then increase by 500mg BD every 2-4 weeks to 1500 mg BD (max dose: 3000 mg daily)
  • Status epilepticus:
    • Load: 60 mg/kg IV over 10 min [or no more than 5 mg/kg/min] (Max dose: 4500 mg)
    • Then 20-30 mg/kg IV BD maintenance
• Children:
  • Initial therapeutic dose: 10 mg/kg (or max 500 mg BD), and then increase by 10 mg/kg BD (or max 500 mg BD) every 2-4 weeks up to a max of 30 mg/kg (max dose: 3000 mg daily)
  • Status epilepticus:
    • Load: 60 mg/kg IV over 10 min [or no more than 3 mg/kg/min] (Max dose: 4500 mg)
    • Then 20-30 mg/kg IV BD maintenance
• Caution when reducing or ceasing levetiracetam, as a rapid wean can precipitate seizures

MECHANISM OF ACTION

• Anticonvulsant — the exact mechanism is yet to be fully elucidated
• It is thought to modulate neurotransmission by binding to synaptic vesicle protein 2A which is believed to be involved with vesicle fusion and neurotransmitter exocytosis (this is proposed to be the primary anticonvulsant mechanism of action)
• Other mechanisms of action:
  • Affects intraneuronal Ca²⁺ levels by partial inhibition of N-type Ca²⁺ currents, and reducing the release of Ca²⁺ from intraneuronal stores
  • Partially reverses the reductions in GABA and glycine gated currents induced by zinc and β-carbolines

PHARMACEUTICS

• Excipients: sodium acetate trihydrate, sodium chloride, glacial acetic acid, water for injections, and nitrogen
• Store below 25^oC
• Off-white powder with a faint odour and bitter taste, very soluble in water
• IV form is usually presented as a clear and colourless aqueous solution in clear glass vials of 500 mg in 5 mL

PHARMACOKINETICS

• Absorption
  • Bioavailability is close to 100%
  • Peak plasma levels are achieved at ~1.3 hours post PO dose
• Distribution
  • <10% protein bound
  • Vd of 0.5-0.7 L/kg
• Metabolism
  • Liver, insignificant
  • Enzymatic hydrolysis is the primary pathway, 24% of the dose
• Elimination
  • Renal excretion 66% (unchanged)
  • Renal clearance: 0.6 mL/min/kg / Total body clearance: 0.96 mL/min/kg
  • Dialysable: Yes
  • T_1/2: 6-8 hours

PHARMACODYNAMICS

• CNS
  • Anticonvulsant
  • Somnolence (up to 45%)
  • Mood disturbance, suicidal intent, irritability, abnormal behaviour
  • Asthenia, dizziness, headache
• CVS
  • Angioedema (rare)
• RESP
  • Cough, nasopharyngitis
• GIT
  • Loss of appetite
  • Vomiting (15%)
  • Hepatic function derangement
• GUT
  • No significant
• OTHER
  • Decreased bone mineral density
  • Stevens-Johnson syndrome / Toxic epidermal necrolysis
  • Decreased erythrocyte production, reduced WCC, elevated eosinophil count, neutropenia, pancytopenia, thrombocytopenia

CONTRAINDICATIONS

• Relative
  • Learning disability/history of psychiatric disorders — increased risk of behavioural adverse effects
  • Japanese ancestry — may increase the risk of rhabdomyolysis

HISTORY

• If levetiracetam’s anticonvulsant mechanism is not well understood, how did we develop this fantastic anticonvulsant drug?
  • It was developed as an analogue to piracetam which was developed to improve cognitive function
  • Accidentally discovered to have anticonvulsant activity in animal models

EVIDENCE

• Use as a Tier 2 Status Epilepticus (SE) drug (refractory to benzodiazepines)
  • ESETT Trial (by NETT & PECARN groups) 2019: RCT, n=384, comparing levetiracetam (60 mg/kg), fosphenytoin (20 mg/kg) and valproate (40 mg/kg) for patients in SE after being administered benzodiazepines; no significant difference between the three, for the absence of seizures and improved responsiveness at 60 min. (The Bottom Line Summary)

References and links

LITFL

• CCC – Status epilepticus
• CCC – Post-traumatic seizures
• Toxicology Library – Newer anticonvulsants

References

• Australian Injectable Drugs Handbook, 8th Edition. (2022). Retrieved 28 August 2022, from https://aidh.hcn.com.au/
• Australian Medicines Handbook. (2022). Retrieved 28 August 2022, from https://amhonline.amh.net.au/       
• IBM Micromedex. (2022). Retrieved 28 August 2022, from https://www.micromedexsolutions.com
• Kapur J, Elm J, Chamberlain JM, Barsan W, Cloyd J, Lowenstein D, Shinnar S, Conwit R, Meinzer C, Cock H, Fountain N, Connor JT, Silbergleit R; NETT and PECARN Investigators. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. N Engl J Med. 2019 Nov 28;381(22):2103-2113. doi: 10.1056/NEJMoa1905795. PMID: 31774955; PMCID: PMC7098487. [Free full text]
• Rang, H., Dale, M., Ritter, J., & Flower, R. (2007). Rang and Dale’s pharmacology (6th ed., pp. 584, 586). Edinburgh: Churchill Livingstone Elsevier.
• Slessor, D. (2020). ESETT – The Bottom Line. Retrieved 28 August 2022, from https://www.thebottomline.org.uk/summaries/icm/esett/

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