Chemistry:Levetiracetam

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Short description: Medication
Levetiracetam
Levetiracetam.svg Levetiracetam ball-and-stick model.png
Clinical data
Pronunciation/lɛvɪtɪˈræsɪtæm/
Trade namesKeppra, Elepsia, Spritam, others
AHFS/Drugs.comMonograph
MedlinePlusa699059
License data
Pregnancy
category
Routes of
administration		By mouth, intravenous
Drug classRacetam anticonvulsant
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability≈100%
Protein binding<10%
MetabolismEnzymatic hydrolysis of acetamide group
Elimination half-life6–8 hrs
ExcretionUrinary
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC8H14N2O2
Molar mass170.212 g·mol−1
3D model (JSmol)
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Levetiracetam, sold under the brand name Keppra among others, is a medication used to treat epilepsy.[6] 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.[6]

Common side effects of levetiracetam include sleepiness, dizziness, feeling tired, and aggression.[6] Severe side effects may include psychosis, suicide, and allergic reactions such as Stevens–Johnson syndrome or anaphylaxis.[6] Levetiracetam is the S-enantiomer of etiracetam.[7] Its mechanism of action is not yet clear.[6]

Levetiracetam was approved for medical use in the United States in 1999[6] and is available as a generic medication.[8] In 2020, it was the 92nd most commonly prescribed medication in the United States, with more than 7 million prescriptions.[9][10] It is on the World Health Organization's List of Essential Medicines.[11]

Medical uses

Focal epilepsy

Levetiracetam is effective as single-drug treatment for newly diagnosed focal epilepsy in adults.[12][13] It reduces focal seizures by 50% or more as an add-on medication.[14]

Partial-complex epilepsy

Levetiracetam is effective as add-on treatment for partial (focal) epilepsy.[15]

Generalized epilepsy

Levetiracetam is effective for treatment of generalized tonic-clonic epilepsy.[13] It has been approved in the United States as add-on treatment for myoclonic, and tonic-clonic seizures.[3] 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.[16]

Levetiracetam is sometimes used off label to treat status epilepticus.[17][18]

Prevention of seizures

Based on low-quality evidence, levetiracetam is about as effective as phenytoin for prevention of early seizures after traumatic brain injury.[19] It may be effective for prevention of seizures associated with subarachnoid hemorrhages.[20]

Other

Levetiracetam has not been found to be useful for treatment of neuropathic pain,[21] nor for treatment of essential tremors.[22] Levetiracetam has not been found to be useful for treating all developmental disorders within the autism spectrum,;[23][24] studies have only proven to be an effective treatment for partial, myoclonic, or tonic-clonic seizures associated with autism spectrum disorder.[25]

Special groups

Studies in female pregnant rats have shown minor fetal skeletal abnormalities when given maximum recommended human doses of levetiracetam orally throughout pregnancy and lactation.

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.

Adverse effects

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.[3]

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.[26]

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.[27] The incidence of SJS following exposure to anti-epileptics such as levetiracetam is about 1 in 3,000.[28]

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.[3]

In a study, the incidence of decreased bone mineral density of patients on levetiracetam was significantly higher than those for other epileptic medications.[29]

Suicide

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.[3]

Kidney and liver

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.[3]

Dose adjustment of levetiracetam is not necessary in liver impairment.[3]

Drug interactions

No significant pharmacokinetic interactions were observed between levetiracetam or its major metabolite and concomitant medications.[30] The pharmacokinetic profile of levetiracetam is not influenced by phenytoin, phenobarbital, primidone, carbamazepine, valproic acid, lamotrigine, gabapentin, digoxin, ethinylestradiol, or warfarin.[31]

Mechanism of action

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.[32] However, the drug binds to SV2A,[33] a synaptic vesicle glycoprotein, and inhibits presynaptic calcium channels,[34] reducing neurotransmitter release and acting as a neuromodulator. This is believed to impede impulse conduction across synapses.[35]

Pharmacokinetics

Absorption

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.[3]

Distribution

The volume of distribution of levetiracetam is similar to total body water. Levetiracetam modestly binds to plasma proteins (less than 10%).[3]

Metabolism

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.[3]

Excretion

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 [3] although the mean CSF half life of approx. 24 hours better reflects levels at site of action.[36]

Analogues

Brivaracetam, a chemical analogue to levetiracetam, is a racetam derivative with similar properties.

Society and culture

Levetiracetam is available as regular and extended release oral formulations and as intravenous formulations.[37]

The immediate release tablet has been available as a generic in the United States since 2008, and in the UK since 2011.[38][14] The patent for the extended release tablet will expire in 2028.[39]

The branded version Keppra is manufactured by UCB Pharmaceuticals S.A.[2][3][4][5]

In 2015, Aprecia's 3D-printed orally disintegrating tablet form of the drug was approved by the FDA, under the trade name Spritam.[40] Some have said that the drug has been improved by 3D printing, as the formula used now has improved disintegration properties.[41]

Legal status

Australia

Levetiracetam is a Schedule 4 substance in Australia under the Poisons Standard (February 2020).[42] 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."[42]

Japan

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.[43] Travelers who plan to bring more than a month's worth must apply for an import certificate, known as a Yakkan Shoumei (薬監証明, yakkan shōmei).[44]

Research

Levetiracetam has been studied in the past for treating symptoms of neurobiological conditions such as Tourette syndrome,[45] and anxiety disorder.[46] However, its most serious adverse effects are behavioral, and its benefit-risk ratio in these conditions is not well understood.[46]

Levetiracetam is being tested as a drug to reduce hyperactivity in the hippocampus in Alzheimer's disease.[47]

Additionally, Levetiracetam has been experimentally shown to reduce Levodopa-induced dyskinesia,[48] a type of movement disorder, or dyskinesia associated with the use of Levodopa, a medication used to treat Parkinson's disease.

Of the 10 medications evaluated in a 2023 systematic review of the literature, levetiracetam was found to be the only medication with sufficient evidence showing that it may cause seizure freedom in some infants.[49] Further, adverse effects from levetiracetam were rarely severe enough for the medication to be discontinued in this age group. Because available research included only 2 published studies reporting seizure freedom rates, however, the strength of the evidence was judged to be low.[49]

References

  1. ↑ "Levetiracetam Use During Pregnancy". https://www.drugs.com/pregnancy/levetiracetam.html. 
  2. ↑ 2.0 2.1 "Keppra 100 mg/ml concentrate for solution for infusion - Summary of Product Characteristics (SmPC)". https://www.medicines.org.uk/emc/product/2296/smpc. 
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 "Keppra- levetiracetam tablet, film coated Keppra- levetiracetam solution". 5 November 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=3ca9df05-a506-4ec8-a4fe-320f1219ab21. 
  4. ↑ 4.0 4.1 "Keppra XR- levetiracetam tablet, film coated, extended release". 4 November 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2919e43b-69a8-434c-a2d2-1f3ecd7554c0. 
  5. ↑ 5.0 5.1 "Keppra- levetiracetam injection, solution, concentrate". 4 November 2019. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c6d5784d-abf9-45fe-ac5a-d5c53bd50f7e. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 6.5 "Levetiracetam Monograph for Professionals" (in en). AHFS. https://www.drugs.com/monograph/levetiracetam.html. 
  7. ↑ Behavioural Neurology of Anti-Epileptic Drugs: A Practical Guide. Oxford University Press. 2018. p. 17. ISBN 9780198791577. https://books.google.com/books?id=QVZYDwAAQBAJ&pg=PA17. 
  8. ↑ British national formulary: BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 319. ISBN 9780857113382. 
  9. ↑ "The Top 300 of 2020". https://clincalc.com/DrugStats/Top300Drugs.aspx. 
  10. ↑ "Levetiracetam - Drug Usage Statistics". https://clincalc.com/DrugStats/Drugs/Levetiracetam. 
  11. ↑ The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. 2023. WHO/MHP/HPS/EML/2023.02. 
  12. ↑ "Antiepileptic monotherapy in newly diagnosed focal epilepsy. A network meta-analysis". Acta Neurologica Scandinavica 139 (1): 33–41. January 2019. doi:10.1111/ane.13025. PMID 30194755. 
  13. ↑ 13.0 13.1 "Antiepileptic drug monotherapy for epilepsy: a network meta-analysis of individual participant data". The Cochrane Database of Systematic Reviews 2022 (4): CD011412. April 2022. doi:10.1002/14651858.CD011412.pub4. PMID 35363878. 
  14. ↑ 14.0 14.1 "Levetiracetam add-on for drug-resistant focal epilepsy: an updated Cochrane Review". The Cochrane Database of Systematic Reviews 2012 (9): CD001901. September 2012. doi:10.1002/14651858.cd001901.pub2. PMID 22972056. 
  15. ↑ "Efficacy of antiepileptic drugs in the adjunctive treatment of refractory partial-onset seizures: Meta-analysis of pivotal trials". Epilepsy Research 143: 120–129. July 2018. doi:10.1016/j.eplepsyres.2017.10.004. PMID 29784458. 
  16. ↑ BNF 59. BMA & RPSGB. 2010. 
  17. ↑ "Guidelines for the evaluation and management of status epilepticus". Neurocritical Care 17 (1): 3–23. August 2012. doi:10.1007/s12028-012-9695-z. PMID 22528274. 
  18. ↑ "EFNS guideline on the management of status epilepticus in adults". European Journal of Neurology 17 (3): 348–355. March 2010. doi:10.1111/j.1468-1331.2009.02917.x. PMID 20050893. 
  19. ↑ "Should Levetiracetam or Phenytoin Be Used for Posttraumatic Seizure Prophylaxis? A Systematic Review of the Literature and Meta-analysis". Neurosurgery 79 (6): 775–782. December 2016. doi:10.1227/NEU.0000000000001445. PMID 27749510. 
  20. ↑ "Utility of levetiracetam in patients with subarachnoid hemorrhage". Seizure 18 (10): 676–679. December 2009. doi:10.1016/j.seizure.2009.09.003. PMID 19864168. 
  21. ↑ "The Role of Levetiracetam in Treating Chronic Neuropathic Pain Symptoms". American Family Physician 92 (1): 23–24. July 2015. PMID 26132123. http://www.aafp.org/link_out?pmid=26132123. Retrieved 1 September 2017. 
  22. ↑ "Evidence-based guideline update: treatment of essential tremor: report of the Quality Standards subcommittee of the American Academy of Neurology". Neurology 77 (19): 1752–1755. November 2011. doi:10.1212/WNL.0b013e318236f0fd. PMID 22013182. 
  23. ↑ "Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder". Journal of the American Academy of Child and Adolescent Psychiatry 53 (2): 237–257. February 2014. doi:10.1016/j.jaac.2013.10.013. PMID 24472258. 
  24. ↑ "Antiepileptic medications in autism spectrum disorder: a systematic review and meta-analysis". Journal of Autism and Developmental Disorders 44 (4): 948–957. April 2014. doi:10.1007/s10803-013-1952-2. PMID 24077782. 
  25. ↑ "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. September 2013. doi:10.3389/fpubh.2013.00031. PMID 24350200. 
  26. ↑ "Monotherapy for partial epilepsy: focus on levetiracetam". Neuropsychiatric Disease and Treatment 4 (1): 33–38. February 2008. doi:10.2147/NDT.S1655. PMID 18728811. 
  27. ↑ "Stevens-Johnson syndrome induced by levetiracetam". Seizure 21 (10): 823–825. December 2012. doi:10.1016/j.seizure.2012.09.005. PMID 23036769. 
  28. ↑ "Acute management of hypersensitivity reactions and seizures". Epilepsia 39 (Suppl 7): S17–S21. 1998. doi:10.1111/j.1528-1157.1998.tb01680.x. PMID 9798757. 
  29. ↑ "Bone mineral density in adult patients treated with various antiepileptic drugs". Seizure 21 (6): 471–472. July 2012. doi:10.1016/j.seizure.2012.04.002. PMID 22541979. 
  30. ↑ "Absence of pharmacokinetic drug interaction of levetiracetam with phenytoin in patients with epilepsy determined by new technique". Journal of Clinical Pharmacology 40 (6): 590–595. June 2000. doi:10.1002/j.1552-4604.2000.tb05984.x. PMID 10868309. 
  31. ↑ "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. 2005. doi:10.1016/j.eplepsyres.2005.01.005. PMID 15823510. 
  32. ↑ "Mechanisms of levetiracetam in the control of status epilepticus and epilepsy". Frontiers in Neurology 5: 11. 2014. doi:10.3389/fneur.2014.00011. PMID 24550884. 
  33. ↑ "The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam". Proceedings of the National Academy of Sciences of the United States of America 101 (26): 9861–9866. June 2004. doi:10.1073/pnas.0308208101. PMID 15210974. Bibcode: 2004PNAS..101.9861L. 
  34. ↑ "The synaptic vesicle glycoprotein 2A ligand levetiracetam inhibits presynaptic Ca2+ channels through an intracellular pathway". Molecular Pharmacology 82 (2): 199–208. August 2012. doi:10.1124/mol.111.076687. PMID 22554805. 
  35. ↑ "Diverse mechanisms of antiepileptic drugs in the development pipeline". Epilepsy Research 69 (3): 273–294. June 2006. doi:10.1016/j.eplepsyres.2006.02.004. PMID 16621450. 
  36. ↑ "Levetiracetam and brivaracetam: a review of evidence from clinical trials and clinical experience". Therapeutic Advances in Neurological Disorders 12: 1756286419873518. January 2019. doi:10.1177/1756286419873518. PMID 31523280. 
  37. ↑ "Levetiracetam Injection Prescribing Information". http://www.sagentpharma.com/wp-content/uploads/2015/05/Levetiracetam-Injection_PI.pdf. 
  38. ↑ Branch Website Management. "Patent Terms Extended Under 35 USC §156". http://www.uspto.gov/patent/laws-and-regulations/patent-term-extension/patent-terms-extended-under-35-usc-156. 
  39. ↑ "FDA Access Data". Department of Health and Human Services. 12 September 2011. http://www.accessdata.fda.gov/drugsatfda_docs/appletter/2011/091291s000ltr.pdf. 
  40. ↑ "FDA approves the first 3D-printed drug product". 13 October 2015. http://www.kurzweilai.net/fda-approves-the-first-3d-printed-drug-product. 
  41. ↑ "3D Printing in medicine: Technology overview and drug delivery applications" (in en). Annals of 3D Printed Medicine. 3D-Printed Medicine: From today's accomplishments to tomorrow's promises 4: 100037. 2021-12-01. doi:10.1016/j.stlm.2021.100037. ISSN 2666-9641. 
  42. ↑ 42.0 42.1 Poisons Standard February 2020 . comlaw.gov.au
  43. ↑ "Information for those who are bringing medicines for personal use into Japan". Japanese Ministry of Health, Labour and Welfare. https://www.mhlw.go.jp/english/policy/health-medical/pharmaceuticals/01.html. 
  44. ↑ "Q&A for those who are importing medicines into Japan". https://www.mhlw.go.jp/english/policy/health-medical/pharmaceuticals/dl/qa1.pdf. 
  45. ↑ "Levetiracetam as an alternative therapy for Tourette syndrome". Neuropsychiatric Disease and Treatment 6: 309–316. June 2010. doi:10.2147/ndt.s6371. PMID 20628631. 
  46. ↑ 46.0 46.1 "Levetiracetam for managing neurologic and psychiatric disorders". American Journal of Health-System Pharmacy 66 (6): 541–561. March 2009. doi:10.2146/ajhp070607. PMID 19265183. 
  47. ↑ "Targeting Neural Hyperactivity as a Treatment to Stem Progression of Late-Onset Alzheimer's Disease". Neurotherapeutics 14 (3): 662–676. July 2017. doi:10.1007/s13311-017-0541-z. PMID 28560709. 
  48. ↑ "Levetiracetam Ameliorates L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats Inducing Critical Molecular Changes in the Striatum". Parkinson's Disease (London, England, United Kingdom: Hindawi Publishing Corporation) 2015 (1): 253878. 27 January 2015. doi:10.1155/2015/253878. PMID 25692070. 
  49. ↑ 49.0 49.1 Management of Infantile Epilepsies (Report). Rockville (MD): Agency for Healthcare Research and Quality (AHRQ) (US). October 2022. doi:10.23970/ahrqepccer252. 22(23)-EHC004 Report No.: 2021-SR-01. PMID 36383706. https://effectivehealthcare.ahrq.gov/products/management-infantile-epilepsy/research. 



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