Levetiracetam, sold under the brand name Keppra among others, is a medication used to treat epilepsy. It is used for partial-onset, myoclonic, or tonic–clonic seizures and is taken either by mouth as an immediate or extended release formulation or by injection into a vein.
|Trade names||Keppra, Elepsia, Spritam, others|
|By mouth, intravenous|
|Drug class||Racetam anticonvulsant|
|Metabolism||Enzymatic hydrolysis of acetamide group|
|Elimination half-life||6–8 hrs|
|Chemical and physical data|
|Molar mass||170.212 g·mol−1|
|3D model (JSmol)|
|(what is this?)|
Common side effects of levetiracetam include sleepiness, dizziness, feeling tired, and aggression. Severe side effects may include psychosis, suicide, and allergic reactions such as Stevens–Johnson syndrome or anaphylaxis. It is unclear if levetiracetam is safe for use during pregnancy, but it appears safe for use while breastfeeding. Levetiracetam is the S-enantiomer of etiracetam. Its mechanism of action is not yet clear.
Levetiracetam was approved for medical use in the United States in 1999 and is available as a generic medication. In 2018, it was the 97th most commonly prescribed medication in the United States, with more than 7 million prescriptions.
Levetiracetam is effective for treatment of generalized tonic-clonic epilepsy. It has been approved in the United States as add-on treatment for myoclonic, and tonic-clonic seizures. Levetiracetam has been approved in the European Union as a monotherapy treatment for epilepsy in the case of partial seizures or as an adjunctive therapy for partial, myoclonic, and tonic-clonic seizures.
Prevention of seizuresEdit
Based on low-quality evidence, levetiracetam is about as effective as phenytoin for prevention of early seizures after traumatic brain injury. It may be effective for prevention of seizures associated with subarachnoid hemorrhages.
Levetiracetam has not been found to be useful for treatment of neuropathic pain, nor for treatment of essential tremors. Levetiracetam has not been found to be useful for treating autism, but is an effective treatment for partial, myoclonic, or tonic-clonic seizures associated with autism spectrum disorder.
Levetiracetam is categorized as a pregnancy category C drug in the US. Studies in female pregnant rats have shown minor fetal skeletal abnormalities when given maximum recommended human doses of levetiracetam orally throughout pregnancy and lactation.[medical citation needed]
Studies were conducted to look for increased adverse effects in the elderly population as compared to younger patients. One such study published in Epilepsy Research showed no significant increase in incidence of adverse symptoms experienced by young or elderly patients with central nervous system (CNS) disorders.[medical citation needed]
Levetiracetam may be safely used with caution in children over the age of four. However, it has not been determined whether it can be safely given to children under the age of four.
The most common adverse effects of levetiracetam treatment include CNS effects such as somnolence, decreased energy, headache, dizziness, mood swings and coordination difficulties. These adverse effects are most pronounced in the first month of therapy. About 4% of patients dropped out of pre-approval clinical trials due to these side effects.
About 13% of people taking levetiracetam experience adverse neuropsychiatric symptoms, which are usually mild. These include agitation, hostility, apathy, anxiety, emotional lability, and depression. Serious psychiatric adverse side effects that are reversed by drug discontinuation occur in about 1%. These include hallucinations, suicidal thoughts, or psychosis. These occurred mostly within the first month of therapy, but they could develop at any time during treatment.
Although rare, Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), which appears as a painful spreading rash with redness and blistering and/or peeling skin, have been reported in patients treated with levetiracetam. The incidence of SJS following exposure to anti-epileptics such as levetiracetam is about 1 in 3,000.
Levetiracetam should not be used in people who have previously shown hypersensitivity to levetiracetam or any of the inactive ingredients in the tablet or oral solution. Such hypersensitivity reactions include, but are not limited to, unexplained rash with redness or blistered skin, difficulty breathing, and tightness in the chest or airways.
In a study, the incidence of decreased bone mineral density of patients on levetiracetam was significantly higher than those for other epileptic medications.
Levetiracetam, along with other anti-epileptic drugs, can increase the risk of suicidal behavior or thoughts. People taking levetiracetam should be monitored closely for signs of worsening depression, suicidal thoughts or tendencies, or any altered emotional or behavioral states.
Kidney and liverEdit
Kidney impairment decreases the rate of elimination of levetiracetam from the body. Individuals with reduced kidney function may require dose adjustments. Kidney function can be estimated from the rate of creatinine clearance.
Dose adjustment of levetiracetam is not necessary in liver impairment.
No significant pharmacokinetic interactions were observed between levetiracetam or its major metabolite and concomitant medications. The pharmacokinetic profile of levetiracetam is not influenced by phenytoin, phenobarbital, primidone, carbamazepine, valproic acid, lamotrigine, gabapentin, digoxin, ethinylestradiol, or warfarin.
Mechanism of actionEdit
The exact mechanism by which levetiracetam acts to treat epilepsy is unknown. Levetiracetam does not exhibit pharmacologic actions similar to that of classical anticonvulsants. It does not inhibit voltage-dependent Na+ channels, does not affect GABAergic transmission, and does not bind to GABAergic or glutamatergic receptors. However, the drug binds to SV2A, a synaptic vesicle glycoprotein, and inhibits presynaptic calcium channels, reducing neurotransmitter release and acting as a neuromodulator. This is believed to impede impulse conduction across synapses.
The absorption of levetiracetam tablets and oral solution is rapid and essentially complete. The bioavailability of levetiracetam is close to 100 percent, and the effect of food on absorption is minor.
The volume of distribution of levetiracetam is similar to total body water. Levetiracetam modestly binds to plasma proteins (less than 10%).
Levetiracetam does not undergo extensive metabolism, and the metabolites formed are not active and do not exert pharmacological activity. Metabolism of levetiracetam is not by liver cytochrome P450 enzymes, but through other metabolic pathways such as hydrolysis and hydroxylation.
In persons with normal kidney function, levetiracetam is eliminated from the body primarily by the kidneys with about 66 percent of the original drug passed unchanged into urine. The plasma half-life of levetiracetam in adults is about 6 to 8 hours.
Society and cultureEdit
Levetiracetam is available as regular and extended release oral formulations and as intravenous formulations.
Levetiracetam is a Schedule 4 substance in Australia under the Poisons Standard (February 2020). A Schedule 4 substance is classified as "Prescription Only Medicine, or Prescription Animal Remedy – Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription."
Under Japanese law, levetiracetam and other racetams cannot be brought into the country except for personal use by a traveler for whom it has been prescribed. Travelers who plan to bring more than a month's worth must apply for an import certificate.
Levetiracetam is being looked at in psychiatric and neurologic conditions such as Tourette syndrome, and anxiety disorder. However, its most serious adverse effects are behavioral, and its benefit-risk ratio in these conditions is not well understood.
- "Levetiracetam Use During Pregnancy". Drugs.com. Retrieved 5 March 2019.
- "Keppra 100 mg/ml concentrate for solution for infusion - Summary of Product Characteristics (SmPC)". (emc). Retrieved 9 September 2020.
- "Keppra- levetiracetam tablet, film coated Keppra- levetiracetam solution". DailyMed. 5 November 2019. Retrieved 9 September 2020.
- "Keppra XR- levetiracetam tablet, film coated, extended release". DailyMed. 4 November 2019. Retrieved 9 September 2020.
- "Keppra- levetiracetam injection, solution, concentrate". DailyMed. 4 November 2019. Retrieved 9 September 2020.
- "Levetiracetam Monograph for Professionals". Drugs.com. AHFS. Retrieved 14 January 2019.
- Cavanna, Andrea E. (2018). Behavioural Neurology of Anti-Epileptic Drugs: A Practical Guide. Oxford University Press. p. 17. ISBN 9780198791577.
- British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. p. 319. ISBN 9780857113382.
- "The Top 300 of 2021". ClinCalc. Retrieved 18 February 2021.
- "Levetiracetam - Drug Usage Statistics". ClinCalc. Retrieved 18 February 2021.
- Lattanzi S, Zaccara G, Giovannelli F, Grillo E, Nardone R, Silvestrini M, Trinka E, Brigo F (January 2019). "Antiepileptic monotherapy in newly diagnosed focal epilepsy. A network meta-analysis". Acta Neurol. Scand. 139 (1): 33–41. doi:10.1111/ane.13025. PMID 30194755. S2CID 52174058.
- Mbizvo, Gashirai K; Dixon, Pete; Hutton, Jane L; Marson, Anthony G (2012). "Levetiracetam add-on for drug-resistant focal epilepsy: An updated Cochrane Review". Cochrane Database of Systematic Reviews (9): CD001901. doi:10.1002/14651858.cd001901.pub2. PMC 7061650. PMID 22972056.
- Slater J, Chung S, Huynh L, Duh MS, Gorin B, McMicken C, Ziemann A, Isojarvi J (July 2018). "Efficacy of antiepileptic drugs in the adjunctive treatment of refractory partial-onset seizures: Meta-analysis of pivotal trials". Epilepsy Res. 143: 120–129. doi:10.1016/j.eplepsyres.2017.10.004. PMID 29784458.
- Nevitt SJ, Sudell M, Weston J, Tudur Smith C, Marson AG (December 2017). "Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data". Cochrane Database Syst Rev. 12: CD011412. doi:10.1002/14651858.CD011412.pub3. PMC 6486134. PMID 29243813.
- BNF 59. BMA & RPSGB. 2010.
- Brophy, Gretchen M.; Bell, Rodney; Claassen, Jan; Alldredge, Brian; Bleck, Thomas P.; Glauser, Tracy; Laroche, Suzette M.; Riviello, James J.; Shutter, Lori; Sperling, Michael R.; Treiman, David M.; Vespa, Paul M.; Neurocritical Care Society Status Epilepticus Guideline Writing Committee (2012). "Guidelines for the Evaluation and Management of Status Epilepticus". Neurocritical Care. 17 (1): 3–23. doi:10.1007/s12028-012-9695-z. PMID 22528274. S2CID 4675838.
- Meierkord, H.; Boon, P.; Engelsen, B.; Göcke, K.; Shorvon, S.; Tinuper, P.; Holtkamp, M. (2010). "EFNS guideline on the management of status epilepticus in adults". European Journal of Neurology. 17 (3): 348–55. doi:10.1111/j.1468-1331.2009.02917.x. PMID 20050893. S2CID 1032139.
- Khan NR, VanLandingham MA, Fierst TM, Hymel C, Hoes K, Evans LT, Mayer R, Barker F, Klimo P (December 2016). "Should Levetiracetam or Phenytoin Be Used for Posttraumatic Seizure Prophylaxis? A Systematic Review of the Literature and Meta-analysis". Neurosurgery. 79 (6): 775–782. doi:10.1227/NEU.0000000000001445. PMID 27749510.
- Shah, Dharmen; Husain, Aatif M. (2009). "Utility of levetiracetam in patients with subarachnoid hemorrhage". Seizure. 18 (10): 676–9. doi:10.1016/j.seizure.2009.09.003. PMID 19864168. S2CID 7555384.
- Crawford-Faucher, A; Huijon, R. M. (2015). "The Role of Levetiracetam in Treating Chronic Neuropathic Pain Symptoms". American Family Physician. 92 (1): 23–4. PMID 26132123.
- Zesiewicz, T. A.; Elble, R. J.; Louis, E. D.; Gronseth, G. S.; Ondo, W. G.; Dewey, R. B.; Okun, M. S.; Sullivan, K. L.; Weiner, W. J. (2011). "Evidence-based guideline update: Treatment of essential tremor: Report of the Quality Standards Subcommittee of the American Academy of Neurology". Neurology. 77 (19): 1752–5. doi:10.1212/WNL.0b013e318236f0fd. PMC 3208950. PMID 22013182.
- Volkmar, Fred; Siegel, Matthew; Woodbury-Smith, Marc; King, Bryan; McCracken, James; State, Matthew (2014). "Practice Parameter for the Assessment and Treatment of Children and Adolescents with Autism Spectrum Disorder". Journal of the American Academy of Child & Adolescent Psychiatry. 53 (2): 237–57. doi:10.1016/j.jaac.2013.10.013. PMID 24472258.
- Hirota, Tomoya; Veenstra-Vanderweele, Jeremy; Hollander, Eric; Kishi, Taro (2013). "Antiepileptic Medications in Autism Spectrum Disorder: A Systematic Review and Meta-Analysis". Journal of Autism and Developmental Disorders. 44 (4): 948–57. doi:10.1007/s10803-013-1952-2. PMID 24077782. S2CID 36509998.
- Frye, Richard; Rossignol, Daniel; Casanova, Manuel F.; Brown, Gregory L.; Martin, Victoria; Edelson, Stephen; Coben, Robert; Lewine, Jeffrey; Slattery, John C. (2013). "A review of traditional and novel treatments for seizures in autism spectrum disorder: Findings from a systematic review and expert panel". Frontiers in Public Health. 1: 31. doi:10.3389/fpubh.2013.00031. PMC 3859980. PMID 24350200.
- Leeman BA, Cole AJ (February 2008). "Advancements in the treatment of epilepsy" (PDF). Annu. Rev. Med. 59: 503–23. doi:10.1146/annurev.med.58.071105.110848. PMID 17883367.
- Gambardella, Antonio (2008). "Monotherapy for partial epilepsy: Focus on levetiracetam". Neuropsychiatric Disease and Treatment. 4 (1): 33–8. doi:10.2147/NDT.S1655. PMC 2515905. PMID 18728811.
- Zou, Li-Ping; Ding, Chang-Hong; Song, Zhen-Jiang; Li, Xiao-Feng (2012). "Stevens–Johnson syndrome induced by levetiracetam". Seizure. 21 (10): 823–5. doi:10.1016/j.seizure.2012.09.005. PMID 23036769.
- Griebel, May L. (1998). "Acute Management of Hypersensitivity Reactions and Seizures". Epilepsia. 39: S17–21. doi:10.1111/j.1528-1157.1998.tb01680.x. PMID 9798757. S2CID 10305861.
- Beniczky, Simona Alexandra; Viken, Janina; Jensen, Lars Thorbjørn; Andersen, Noémi Becser (2012). "Bone mineral density in adult patients treated with various antiepileptic drugs". Seizure. 21 (6): 471–2. doi:10.1016/j.seizure.2012.04.002. PMID 22541979.
- Browne, T. R.; Szabo, G. K.; Leppik, I. E.; Josephs, E.; Paz, J.; Baltes, E.; Jensen, C. M. (2000). "Absence of Pharmacokinetic Drug Interaction of Levetiracetam with Phenytoin in Patients with Epilepsy Determined by New Technique". The Journal of Clinical Pharmacology. 40 (6): 590–5. doi:10.1002/j.1552-4604.2000.tb05984.x. PMID 10868309. S2CID 35576679.
- Gidal, Barry E.; Baltès, Eugène; Otoul, Christian; Perucca, Emilio (2005). "Effect of levetiracetam on the pharmacokinetics of adjunctive antiepileptic drugs: A pooled analysis of data from randomized clinical trials". Epilepsy Research. 64 (1–2): 1–11. doi:10.1016/j.eplepsyres.2005.01.005. PMID 15823510. S2CID 13555324.
- Deshpande LS, Delorenzo RJ (2014). "Mechanisms of levetiracetam in the control of status epilepticus and epilepsy". Front Neurol. 5: 11. doi:10.3389/fneur.2014.00011. PMC 3907711. PMID 24550884.
- Lynch BA, Lambeng N, Nocka K, et al. (June 2004). "The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam". Proc Natl Acad Sci USA. 101 (26): 9861–6. Bibcode:2004PNAS..101.9861L. doi:10.1073/pnas.0308208101. PMC 470764. PMID 15210974.
- Vogl C, Mochida S, Wolff C, et al. (August 2012). "The Synaptic Vesicle Glycoprotein 2A Ligand Levetiracetam Inhibits Presynaptic Ca2+ Channels through an Intracellular Pathway". Mol. Pharmacol. 82 (2): 199–208. doi:10.1124/mol.111.076687. PMID 22554805. S2CID 8333373.
- Rogawski, MA (June 2006). "Diverse mechanisms of antiepileptic drugs in the development pipeline". Epilepsy Research. 69 (3): 273–94. doi:10.1016/j.eplepsyres.2006.02.004. PMC 1562526. PMID 16621450.
- "Levetiracetam Injection Prescribing Information" (PDF).
- Branch Website Management. "Patent Terms Extended Under 35 USC §156". www.uspto.gov. Retrieved 5 November 2015.
- Webber, Keith (12 September 2011). "FDA Access Data" (PDF). ANDA 091291. Department of Health and Human Services. Retrieved 4 November 2015.
- "FDA approves the first 3D-printed drug product". KurzweilAI. 13 October 2015. Retrieved 14 October 2015.
- Poisons Standard February 2020. comlaw.gov.au
- "Ministry of Health, Labour and Welfare: Information for those who are bringing medicines for personal use into Japan". www.mhlw.go.jp. Retrieved 10 November 2020.
- (PDF) https://www.mhlw.go.jp/english/policy/health-medical/pharmaceuticals/dl/qa1.pdf. Retrieved 10 November 2020. Missing or empty
- Martínez-Granero, M. A.; García-Pérez, A; Montañes, F (2010). "Levetiracetam as an alternative therapy for Tourette syndrome". Neuropsychiatric Disease and Treatment. 6: 309–16. doi:10.2147/ndt.s6371. PMC 2898169. PMID 20628631.
- Farooq MU, Bhatt A, Majid A, Gupta R, Khasnis A, Kassab MY (2009). "Levetiracetam for managing neurologic and psychiatric disorders". Am J Health Syst Pharm. 66 (6): 541–61. doi:10.2146/ajhp070607. PMID 19265183.CS1 maint: uses authors parameter (link)
- Haberman, RP; Branch, A; Gallagher, M (July 2017). "Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer's Disease". Neurotherapeutics. 14 (3): 662–676. doi:10.1007/s13311-017-0541-z. PMC 5509635. PMID 28560709.
- "Levetiracetam". Drug Information Portal. U.S. National Library of Medicine.