(June 22, 2023)

Executive Summary

Levetiracetam (LEV) is a second generation antiepileptic drug (AED) that has gained popularity in the ED for the treatment of status epilepticus (with a conjunction of benzodiazepines, usually IV lorazepam or IM midazolam)(3, 7); 

• It modulates neuronal activity through GABA and high-voltage-dependent calcium channels, by unknown molecular mechanisms (2).

• In children and adults, compared with other AED, LEV has a similar efficacy treating SE, with an excellent safety profile (most studies comparing it with phenytoin)(1, 9, 12, 13, 14, 19, 20).

• EMDrugs is currently reviewing the evidence regarding the usage of LEV for seizure prophylaxis in subarachnoid hemorrhage.
  
  

Adult dose for status epilepticus (7, 12)

• Loading dose of 60mg/kg IV (max 4,500mg) in 15 minutes. 

• Maintenance dose of 1gr every 12 hours IV or PO (up to a maximum of 3gr/day)
  
  

Adult dose for post-traumatic seizure prophylaxis in severe TBI (4, 22)

• Loading dose of 1000 mg IV.

• Maintenance of 500 to 1000 mg every 12 hours (IV or PO).

Adult dose for status epilepticus (7, 12)

• Loading dose of 60mg/kg IV (max 4,500mg) in 15 minutes. 

• Maintenance dose of 1gr every 12 hours IV or PO (up to a maximum of 3gr/day).
  
  

Adult dose for post-traumatic seizure prophylaxis in severe TBI (4, 22)

• Loading dose of 1000 mg IV.

• Maintenance of 500 to 1000 mg every 12 hours (IV or PO)*.
  
  

*The dosing strategy may be discussed with the consulting neurologist considering the age and weight of the patient.

Pediatric dose for status epilepticus (12, 13, 14)

• Loading dose of 40-60 mg/kg IV (max 4,500mg) in 15 minutes

• Maintenance dose of 20mg/kg/day divided every 12 hours IV or PO, initiated 12 hours after loading dose.

US FDA-Labeled (21)

• Partial-Onset Seizures

• Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy

• Primary Generalized Tonic-Clonic Seizures

Off-label

• Status epilepticus

• Subarachnoid hemorrhage (short-term seizure prophylaxis)

• Complicated traumatic brain injury (short-term seizure prophylaxis)

• LEV has a long-standing clinical experience in adults and children, with a straightforward pharmacokinetic profile (1, 20): 

  • No protein binding

  • No potential or significant drug interactions

  • No hepatic metabolization

  • Linear kinetics and no active metabolites

• The election of an AED remains based on an individual basis but levetiracetam is usually elected to start in the ED because it has fewer adverse events and an absence of contraindications (21), in contrast with: 

  • Valproic acid and its high fetal risk with consequent contraindication in pregnancy (US-FDA Pregnancy Risk Category D)(10), and black box warning of severe hepatitis and pancreatitis (15).

  • Phenytoin has an association to serious cardiovascular events, and is more frequently observed on rapid infusions that are thought to be caused by sodium channel blockage effects. Phenytoin also has various drug interactions (16). These events are less frequent with its prodrug fosphenytoin, which can be administered faster. 

Post-traumatic seizures (PTS)

• In severe TBI, clinical seizures occur in up to 12% of patients, while subclinical seizures occur in 20% to 25% (23). 

• Post-traumatic seizures (PTS) are classified as either early (0-7 days after the injury), or late (>7 days after the injury). Early PTS can contribute to secondary brain injury by increasing metabolic demand, intracranial pressure, and excitotoxicity.
  
  

Standard of care and the use of LEV

• Early PTS prophylaxis is considered a standard of care for all patients with severe TBI (8, 23). Phenytoin has been shown to be effective and is the most studied agent to this indication. Studies have shown similar efficacy when comparing phenytoin with LEV (4, 6, among others). In practice, there has been a tendency over the years to prefer LEV over phenytoin because of its safer pharmacological profile and the absence of a need for monitoring blood levels.

• Adult and pediatric guidelines have not yet included levetiracetam as the drug of choice for PTS (8, 11). A systematic review and meta-analysis conducted in 2022, analyzing the use of levetiracetam for seizure prophylaxis in intracerebral hemorrhage, TBI, and subarachnoid hemorrhage, did not find sufficient evidence to support or discourage its use for those indications (18).
  
  

LEV dosing for PTS

• Studies have used different dosing of LEV for PTS prophylaxis. A 2022 study compared different dosing strategies and did not find a significant difference in the cumulative incidence of early PTS between dosing strategies (≤1000 mg/day, 1500 mg/day, and ≥2000 mg/day)(22). 

• Most experts recommend a dosing range of 500 to 1000 mg every 12 hours if no seizure activity has been detected.

• Contraindications (21)
  No contraindications besides known hypersensitivity, allergy or anaphylaxis to LEV.
  
  

• Warnings and significant adverse effects (21) 

  • Most common adverse effects that lead to discontinuation of therapy are somnolence (11-15%) and fatigue (10-11%).

  • Coordination Difficulties: Monitor for ataxia (3%), abnormal gait, and incoordination.

  • Behavioral abnormalities including psychotic symptoms, suicidal ideation (1%), irritability, depression (2-5%) and aggressive behavior have been observed; monitor patients for psychiatric signs and symptoms.

  • Abrupt cessation of LEV in a long term user can precipitate seizures.
    
    

• Major drug interactions (21)

  • In vitro data on metabolic interactions indicate that levetiracetam is unlikely to produce, or be subject to, pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above Cmax levels achieved within the therapeutic dose range, are neither inhibitors of, nor high affinity substrates for, human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes (21). 

  • Monitor concomitant usage of other central nervous system depressants, as it thought it could lead to oversedation in a LEV user.

Pregnancy

Prolonged experience with levetiracetam in pregnant women has not identified a drug-associated risk of major birth defects or miscarriage, based on published literature, which includes data from pregnancy registries, and reflects experience over two decades (21). 

• AU-TGA pregnancy category: B3

• US-FDA pregnancy category: C

Lactation

• Label information (21)

  • Levetiracetam is excreted in human milk. There is no data on the effects of Keppra (levetiracetam) on the breastfed infant, or the effects on milk production.

  • The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for levetiracetam and any potential adverse effects on the breastfed infant from Keppra levetiracetam or from the underlying maternal condition.
    
    

• Levetiracetam is considered a drug with low risk during breast-feeding (possibly safe. Probably compatible. Mild risk possible. Follow up recommended)(17).

  • Infant plasma levels are very low or undetectable.

  • No problems have been observed in infants whose mothers took it, except for hypotonia in a 7-day-old preterm, somnolence in three fully breastfed infants and sedation and vomiting in a 25-day-old infant. 

  • Seizures such as neonatal withdrawal syndrome have been described in a non-breastfed newborn whose mother took Levetiracetam and phenobarbital during pregnancy. Symptoms disappeared when breastfeeding began.

  • Various experts consider the use of this medication compatible or very likely compatible during breastfeeding.

  • It is recommended to observe for sedation of infants. The transitional shift to partial breastfeeding can solve this problem.

1. van Rijckevorsel K, Boon PA. The 'number needed to treat' with Levetiracetam (LEV): comparison with the other new antiepileptic drugs (AEDs). Seizure. 2001;10(3):235-236. doi:10.1053/seiz.2001.0497
   Pubmed

2. Surges R, Volynski KE, Walker MC. Is levetiracetam different from other antiepileptic drugs? Levetiracetam and its cellular mechanism of action in epilepsy revisited [published correction appears in Ther Adv Neurol Disord. 2008 Sep;1(2):79]. Ther Adv Neurol Disord. 2008;1(1):13-24. doi:10.1177/1756285608094212
   Pubmed

3. Cook AM, Castle A, Green A, et al. Practice variations in the management of status epilepticus. Neurocrit Care. 2012;17(1):24-30. doi:10.1007/s12028-012-9711-3
   Pubmed

4. Inaba K, Menaker J, Branco BC, et al. A prospective multicenter comparison of levetiracetam versus phenytoin for early posttraumatic seizure prophylaxis. J Trauma Acute Care Surg. 2013;74(3):766-773. doi:10.1097/TA.0b013e3182826e84
   Pubmed

5. Kruer RM, Harris LH, Goodwin H, et al. Changing trends in the use of seizure prophylaxis after traumatic brain injury: a shift from phenytoin to levetiracetam. J Crit Care. 2013;28(5):883.e9-883.e8.83E13. doi:10.1016/j.jcrc.2012.11.020
   Pubmed

6. Khan SA, Bhatti SN, Khan AA, et al. Comparison Of Efficacy Of Phenytoin And Levetiracetam For Prevention Of Early Post Traumatic Seizures. J Ayub Med Coll Abbottabad. 2016;28(3):455-460.
   JAMC (Open Access)

7. Glauser T, Shinnar S, Gloss D, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016;16(1):48-61. doi:10.5698/1535-7597-16.1.48
   American Epilepsy Society (Open Access)

8. Carney N, Totten AM, O'Reilly C, et al. Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition. Neurosurgery. 2017;80(1):6-15. doi:10.1227/NEU.0000000000001432
   Pubmed

9. Nakamura K, Inokuchi R, Daidoji H, et al. Efficacy of levetiracetam versus fosphenytoin for the recurrence of seizures after status epilepticus. Medicine (Baltimore). 2017;96(25):e7206. doi:10.1097/MD.0000000000007206
   Pubmed Central (Open Access)

10. US-FDA (United States Food and Drug Administration), FDA Drug Safety Communication: Children born to mothers who took Valproate products while pregnant may have impaired cognitive development, 2018. Accessed 17 January 2023.
    US-FDA (Open Access)

11. Kochanek PM, Tasker RC, Carney N, et al. Guidelines for the Management of Pediatric Severe Traumatic Brain Injury, Third Edition: Update of the Brain Trauma Foundation Guidelines, Executive Summary. Neurosurgery. 2019;84(6):1169-1178. doi:10.1093/neuros/nyz051
    Pubmed

12. ESSET - Kapur J, Elm J, Chamberlain JM, et al. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. N Engl J Med. 2019;381(22):2103-2113. doi:10.1056/NEJMoa1905795
    NEJM (Open Access)

13. ConSEPT - Dalziel SR, Borland ML, Furyk J, et al. Levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children (ConSEPT): an open-label, multicentre, randomised controlled trial. Lancet. 2019;393(10186):2135-2145. doi:10.1016/S0140-6736(19)30722-6
    Pubmed

14. EcLiPSE - Appleton RE, Rainford NE, Gamble C, et al. Levetiracetam as an alternative to phenytoin for second-line emergency treatment of children with convulsive status epilepticus: the EcLiPSE RCT. Health Technol Assess. 2020;24(58):1-96. doi:10.3310/hta24580
    Pubmed Central (Open Access)

15. NIH-NLM (National Institutes of Health - National Library of Medicine). DailyMed. Label: Valproic acid solution. Updated in January 2021.
    DailyMed

16. NIH-NLM (National Institutes of Health - National Library of Medicine). DailyMed. Label: Phenytoin sodium injection. Updated in February 2021.
    DailyMed

17. APILAM (Association for promotion of and cultural and scientific research into breastfeeding). e-lactancia. Levetiracetam. Updated July 16, 2022. Accessed June 20, 2023.
    E-lactancia (Open Access)

18. Fang T, Valdes E, Frontera JA. Levetiracetam for Seizure Prophylaxis in Neurocritical Care: A Systematic Review and Meta-analysis. Neurocrit Care. 2022;36(1):248-258. doi:10.1007/s12028-021-01296-z
    Pubmed

19. Webb CA, Wanbon R, Otto ED. Levetiracetam for Status Epilepticus in Adults: A Systematic Review. Can J Hosp Pharm. 2022;75(1):46-53. doi:10.4212/cjhp.v75i1.3254
    Pubmed Central (Open Access)

20. Trinka E, Leitinger M. Management of Status Epilepticus, Refractory Status Epilepticus, and Super-refractory Status Epilepticus. Continuum (Minneap Minn). 2022;28(2):559-602. doi:10.1212/CON.0000000000001103
    Pubmed

21. NIH-NLM (National Institutes of Health - National Library of Medicine). DailyMed. Label: Keppra - levetiracetam injection, solution, concentrate. Updated in September 2022.
    DailyMed

22. Ohman K, Kram B, Schultheis J, Sigmon J, Kaleem S, Yang Z, Lee HJ, Vatsaas C, Komisarow J. Evaluation of Levetiracetam Dosing Strategies for Seizure Prophylaxis Following Traumatic Brain Injury. Neurocrit Care. 2023 Apr;38(2):345-355. doi: 10.1007/s12028-022-01599-9. Epub 2022 Sep 27. PMID: 36167949; PMCID: PMC10040473.
    Pubmed Central (Open Access)

23. Salasky VR, Chang WW. Neurotrauma Update. Emerg Med Clin North Am. 2023;41(1):19-33. doi:10.1016/j.emc.2022.09.014
    Pubmed