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levetiracetam (Keppra, Etiracetam, Spritam)

Tradename: Keppra. Indications: 1) adjunctive agent for partial seizures 2) adjunctive agent for generalized seizures [4] 3) useful agent for Asians with HLA-B*1502 allele [5] 4) effective for myoclonic seizures, myoclonic epilepsy [5] 5) may improve cognition in Alzheimer's disease with epileptiform activity [10] 6) bipolar disorder (unlabeled use) 7) neuropathic pain (unlabeled use) 8) may be preferred choice of anticonvulsant during pregnancy [7] Contraindications: - avoid in patients with mood disorders [5] * Pregnancy category: C Dosage: 1) start 500 mg PO BID 2) may increase every 3 days 3) maximum 3000 mg/day 4) pediatrics: start 10 mg/kg/day; maximum 30 mg/kg/day Tabs: - 250, 500, 750 (tablets may be crushed) - Spritam (3D-printed) up to 1000 mg.tab [8] Solution: 100 mg/mL (480 mL) * dosage adjustment in patients with severe liver failure [5] Dosage adjustment in renal failure: 1) creatinine clearance 50-80 mL/min: 500-1000 mg BID 2) creatinine clearance 30-50 mL/min: 250-750 mg BID 3) creatinine clearance < 30 mL/min: 250-500 mg BID 4) ESRD: 500-1000 mg/day, supplemental dose of 250-500 mg after dialysis Pharmacokinetics: 1) bioavailability 100%, food may delay absorption 2) peak effect 1 hour 3) protein binding < 10% 4) elimination 1/2life 608 hours 5) excreted in urine 66% as unchanged drug Adverse effects: 1) common (> 10%) a) behavioral symptoms (13% {adults}, 38% {children}) b) somnolence (15-23%) c) headache (14%) d) vomiting (15%), anorexia (13%) e) weakness (9-15%) f) cough (2-11%) g) irritability h) depression i) sedation [5] 2) less common (1-10%) - facial edema, nervousness, dizziness, ataxia, vertigo, confusion, psychosis, paresthesia, diplopia, conjunctivitis, pharyngitis, asthma, leukopenia (neutropenia), albuminuria 3) uncommon (< 1%) a) alopecia, thrombocytopenia, pancytopenia b) 3-fold increased risk of suicide [6] 4) well-tolerated in the elderly [5] 5) in utero effect less than valproate [7] - does not seem to affect language or developmental scores 6) acute interstitial nephritis, acute renal failure [9] 7) osteopenia & osteoporosis < carbamazepine, phenytoin, valproate [5] 8) increased risk of Parkinson's disease (RR~1.8) [11] Drug interactions: - few drug interactions [5] - none with other anticonvulsants Mechanism of action: 1) inhibition of votage-dependent N-type Ca+2 channels 2) inhibition of inhibitory GABA-ergic activity 3) diminishes delayed rectifier K+ current 4) binds synaptic proteins which modulate neurotransmitter release (SV2A)

Interactions

drug interactions drug adverse effects of anticonvulsants monitor with anticonvulsants

Related

seizure; epileptic seizure synaptic vesicle glycoprotein 2A (SV2A, KIAA0736, PSEC0174)

General

anticonvulsant

Database Correlations

PUBCHEM correlations

References

  1. Prescriber's Letter 7(5):28, May 2000
  2. Kaiser Permanente Northern California, Drug update, 9/2000
  3. Lexi-Comp, Drug Information 2005
  4. Berkovic SF et al, Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Neurology 2007, 69:1751 PMID: 17625106
  5. Medical Knowledge Self Assessment Program (MKSAP) 15, 16, 17, 18. American College of Physicians, Philadelphia 2009, 2012, 2015, 2018.
  6. Andersohn F et al, Use of antiepileptic drugs in epilepsy and the risk of self-harm or suicidal behavior Neurology 2010;75:335-340 PMID: 20660863 http://www.neurology.org/cgi/content/abstract/75/4/335
  7. Shallcross R et al In utero exposure to levetiracetam vs valproate. Development and language at 3 years of age. Neurology. Jan 8, 2014 PMID: 24401687 http://www.neurology.org/content/early/2014/01/08/WNL.0000000000000030.short - Klein P, Mathews GC Antiepileptic drugs and neurocognitive development. Neurology. Jan 8, 2014 PMID: 24401684 http://www.neurology.org/content/early/2014/01/08/WNL.0000000000000044.extract
  8. Aprecia News Release. Aug 3, 2015 FDA APPROVES THE FIRST 3D PRINTED DRUG PRODUCT Aprecia Introduces its First Product Using the ZipDose Formulation Platform for the Treatment of Epilepsy. https://www.aprecia.com/pdf/2015_08_03_Spritam_FDA_Approval_Press_Release.pdf
  9. Lowes R New FDA Watch List Flags More Drugs Medscape Internal Medicine. July 3, 2017 http://www.medscape.com/viewarticle/882425
  10. Vossel K, Ranasinghe KG, Beagle AJ et al Effect of Levetiracetam on Cognition in Patients With Alzheimer Disease With and Without Epileptiform Activity. A Randomized Clinical Trial. JAMA Neurol. Published online September 27, 2021 PMID: 34570177 https://jamanetwork.com/journals/jamaneurology/fullarticle/2784539
  11. Kneisel K Epilepsy Drugs May Up Risk of Parkinson's. Strongest association seen for sodium valproate. MedPage Today December 27, 2022 https://www.medpagetoday.com/neurology/seizures/102398 - Belete D, Jacobs BM, Simonet C et al Association Between Antiepileptic Drugs and Incident Parkinson Disease in the UK Biobank. JAMA Neurol. Published online December 27, 2022. PMID: 36574240 https://jamanetwork.com/journals/jamaneurology/fullarticle/2799620