(Updated January 2023)

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)(5, 3); 

• 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, 6, 8, 9, 10, 13, 14).

• EMDrugs is currently reviewing evidence regarding LEV usage for seizure prophylaxis in traumatic brain injury and subarachnoid hemorrhage. 

Adult dose for status epilepticus (5, 8)

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

Adult dose for status epilepticus (5, 8)

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)

Pediatric dose for status epilepticus (8, 9, 10)

• 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 (15)

• 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, 14): 

  • 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 (15), in contrast with: 

  • Valproic acid and its high fetal risk with consequent contraindication in pregnancy (US-FDA Pregnancy Risk Category D)(7), and black box warning of severe hepatitis and pancreatitis (11).

  • 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 (12). These events are less frequent with its prodrug fosphenytoin, which can be administered faster. 

1. Contraindications (15)
   No contraindications besides known hypersensitivity, allergy or anaphylaxis to LEV (15).

2. Warnings and significant adverse effects (15)

• • 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. 

3. Major drug interactions (15)

• • 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 (15). 

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

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 (15). 

• AU-TGA pregnancy category: B3

• US-FDA pregnancy category: C

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. 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

5. 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)

6. 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)

7. 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)

8. 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)

9. 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

10. 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)

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

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

13. 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)

14. 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

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