Levetiracetam

Levetiracetam
Systematic (IUPAC) name
(S)-2-(2-Oxopyrrolidin-1-yl)butanamide
Clinical data
Pronunciation /lɛvᵻtɪˈræsᵻtæm/
AHFS/Drugs.com monograph
MedlinePlus a699059
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration		 Oral, intravenous
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: ℞-only
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability ~100%
Protein binding <10%
Metabolism Enzymatic hydrolysis of acetamide group
Biological half-life 6–8 hr
Excretion Urinary
Identifiers
CAS Number 102767-28-2 YesY
ATC code N03AX14 (WHO)
PubChem CID 5284583
IUPHAR/BPS 6826
DrugBank DB01202 N
ChemSpider 4447633 YesY
UNII 44YRR34555 YesY
KEGG D00709 YesY
ChEBI CHEBI:6437 N
ChEMBL CHEMBL1286 YesY
Chemical data
Formula C8H14N2O2
Molar mass 170.209 g/mol
 NYesY (what is this?)  (verify)

Levetiracetam, marketed under the trade name Keppra among others, is a medication used to treat epilepsy.[1] It is used for partial onset, myoclonic, or tonic-clonic seizures.[2] It is the S-enantiomer of etiracetam.

Levetiracetam is available by mouth in two forms: immediate release and extended release.[3] An immediate release tablet has been available as a generic in the United States since November 2008, and in the UK since 2011.[4][5] The United States patent for the extended release tablet expires September 17, 2028.[6]

Medical uses

Levetiracetam has been approved in the United States as add-on treatment for partial (focal), myoclonic, and tonic-clonic seizures.[2] 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.[7] Levetiracetam has been shown to reduce partial (focal) seizures by 50% or more as an add-on medication.[5] It is also used in veterinary medicine for similar purposes.

Levetiracetam is sometimes used off-label to treat status epilepticus[8][9] or to prevent seizures associated with subarachnoid hemorrhages.[10]

Levetiracetam has potential benefits for other psychiatric and neurologic conditions such as Tourette syndrome,[11] anxiety disorder,[12] and Alzheimer's disease.[13] However, its most serious adverse effects are behavioral, and its benefit-risk ratio in these conditions is not well understood.[12]

Levetiracetam has not been found to be useful for treatment of neuropathic pain,[14] nor for treatment of essential tremors.[15] Levetiracetam has not been found to be useful for treating autism,[16][17] but is an effective treatment for partial, myoclonic, or tonic-clonic seizures associated with autism spectrum disorder.[18]

Pregnancy

Levetiracetam is a Pregnancy Category C Drug. Studies in female pregnant rats have shown minor fetal skeletal abnormalities when given maximum recommended human doses of levetiracetam orally throughout pregnancy and lactation.[14]

Elderly

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.[16]

Children

Levetiracetam may be used in children depending on age and type of seizure. Animal studies in juvenile rats and dogs did not demonstrate a potential for age-specific toxicity.[2]

Kidney impairment

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]

Liver impairment

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

Adverse effects

The most common adverse effects of levetiracetam treatment include CNS effects such as somnolence, decreased energy, headache, dizziness, 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.[19]

A study published in 2005 suggests that the addition of pyridoxine (vitamin B6) may reduce some of the psychiatric symptoms.[20]

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.[21] The incidence of SJS following exposure to anti-epileptics such as levetiracetam is about 1 in 3,000.[22]

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]

Suicide

Levetiracetam, along with other anti-epileptic drugs, can increase the risk of suicide 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.[2]

Drug interactions

No significant pharmacokinetic interactions were observed between levetiracetam or its major metabolite and concomitant medications.[23] The pharmacokinetic profile of levetiracetam is not influenced by phenytoin, phenobarbital, primidone, carbamazepine, valproic acid, lamotrigine, gabapentin, digoxin, oral contraceptives ethinylestradiol, or warfarin.[24]

Mechanism of action

The exact mechanism by which levetiracetam acts to treat epilepsy is unknown. However, the drug binds to a synaptic vesicle glycoprotein, SV2A,[25] and inhibits presynaptic calcium channels[26] reducing neurotransmitter release and acting as a neuromodulator. This is believed to impede impulse conduction across synapses.[27]

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

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]

Available forms

Levetiracetam is available as regular and extended release oral formulations and as intravenous formulations.[3][28]

The branded version Keppra is manufactured by UCB Pharmaceuticals Inc.[29]

In 2015 Aprecia’s 3d-printed form of the drug was approved by the FDA.[30]

See also

References

  1. ↑ Abou-Khalil B (June 2008). "Levetiracetam in the treatment of epilepsy". Neuropsychiatr Dis Treat 4 (3): 507–23. doi:10.2147/NDT.S2937. PMC 2526377. PMID 18830435.
  2. 1 2 3 4 "DailyMed - KEPPRA- levetiracetam tablet". dailymed.nlm.nih.gov. Retrieved 2015-11-04.
  3. 1 2 3 4 5 6 7 8 9 10 "Keppra (levetiracetam) Prescribing Information" (PDF).
  4. ↑ Branch Website Management. "Patent Terms Extended Under 35 USC §156". www.uspto.gov. Retrieved 2015-11-05.
  5. 1 2 Mbizvo, Gashirai K; Dixon, Pete; Hutton, Jane L; Marson, Anthony G (2012-09-12). Levetiracetam add-on for drug-resistant focal epilepsy: an updated Cochrane Review. John Wiley & Sons, Ltd. doi:10.1002/14651858.cd001901.pub2/full. ISSN 1465-1858.
  6. ↑ Webber, Keith (September 12, 2011). "FDA Access Data" (PDF). ANDA 091291. Department of Health and Human Services. Retrieved November 4, 2015.
  7. ↑ BNF 59. BMA & RPSGB. 2010.
  8. ↑ Brophy, Gretchen (April 24, 2012). "Guidelines for the Evaluation and Management of Status Epilepticus" (PDF). Neurocritical Care Society. doi:10.1007/s12028-012-9695-z. Retrieved November 11, 2015.
  9. ↑ Meierkord, H.; Boon, P.; Engelsen, B.; Göcke, K.; Shorvon, S.; Tinuper, P.; Holtkamp, M. (2010-03-01). "EFNS guideline on the management of status epilepticus in adults". European Journal of Neurology: The Official Journal of the European Federation of Neurological Societies 17 (3): 348–355. doi:10.1111/j.1468-1331.2009.02917.x. ISSN 1468-1331. PMID 20050893.
  10. ↑ Shah, Dharmen; Husain, Aatif M. (2009-12-01). "Utility of levetiracetam in patients with subarachnoid hemorrhage". Seizure 18 (10): 676–679. doi:10.1016/j.seizure.2009.09.003.
  11. ↑ Martínez-Granero, MA; García-Pérez, A; Montañes, F (2010-01-01). "Levetiracetam as an alternative therapy for Tourette syndrome". Neuropsychiatric Disease and Treatment 6: 309–316. ISSN 1176-6328. PMC 2898169. PMID 20628631.
  12. 1 2 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.
  13. ↑ Sanchez, Pascal; Zhu, Verret; Vossel, Orr; Cirrito, Devidze; Ho, Yu; Palop, Mucke (August 6, 2012). "Levetiracetam suppresses neuronal network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer's disease model". PNAS 109 (42): E2895–903. doi:10.1073/pnas.1121081109. PMC 3479491. PMID 22869752.
  14. ↑ "Cochrane for Clinicians: The Role of Levetiracetam in Treating Chronic Neuropathic Pain Symptoms - American Family Physician". www.aafp.org. Retrieved 2015-11-12.
  15. ↑ Zesiewicz, TA; Elble, RJ; Louis, ED; Gronseth, GS; Ondo, WG; Dewey, RB, Jr; Okun, MS; Sullivan, KL; Weiner, WJ (Nov 8, 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.
  16. ↑ "Practice Parameter for the Assessment and Treatment of Children and Adolescents With Autism Spectrum Disorder - Journal of the American Academy of Child & Adolescent Psychiatry". www.jaacap.com. Retrieved 2015-11-12.
  17. ↑ Hirota, Tomoya; Veenstra-Vanderweele, Jeremy; Hollander, Eric; Kishi, Taro (2014-04-01). "Antiepileptic medications in autism spectrum disorder: a systematic review and meta-analysis". Journal of Autism and Developmental Disorders 44 (4): 948–957. doi:10.1007/s10803-013-1952-2. ISSN 1573-3432. PMID 24077782.
  18. ↑ Frye, Richard E.; Rossignol, Daniel; Casanova, Manuel F.; Brown, Gregory L.; Martin, Victoria; Edelson, Stephen; Coben, Robert; Lewine, Jeffrey; Slattery, John C. (2013-01-01). "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. ISSN 2296-2565. PMC 3859980. PMID 24350200.
  19. ↑ Gambardella A, Labate A, Colosimo E, Ambrosio R, Quattrone A (February 2008). "Monotherapy for partial epilepsy: focus on levetiracetam". Neuropsychiatr Dis Treat 4 (1): 33–8. doi:10.2147/NDT.S1655. PMC 2515905. PMID 18728811.
  20. ↑ "Clinical Epilepsy: Pediatrics". Epilepsia 46 (s8): 142–67. 2005. doi:10.1111/j.1528-1167.2005.460801_16.x.
  21. ↑ Zou, Li-Ping; Ding, Chang-Hong; Song, Zhen-Jiang; Li, Xiao-Feng (2012-12-01). "Stevens–Johnson syndrome induced by levetiracetam". Seizure 21 (10): 823–825. doi:10.1016/j.seizure.2012.09.005.
  22. ↑ Griebel ML. Acute management of hypersensitivity reactions and seizures. Epilepsia. 1998;39(7):S17–S21
  23. ↑ Browne TR, Szabo GK, Leppik IE, et al. Absence of pharmacokinetic drug interaction of levetiracetam with phenytoin in patients with epilepsy determined by new technique. J Clin Pharmacol. 2000;40:590–5.
  24. ↑ Gidal BE, Baltès E, Otoul C, et al. Effect of levetiracetam on the pharmacokinetics of adjunctive antiepileptic drugs: a pooled analysis of data from randomized clinical trials. Epilepsy Res.2005;64:1–11.
  25. ↑ 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. doi:10.1073/pnas.0308208101. PMC 470764. PMID 15210974.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ "Levetiracetam Injection Prescribing Information" (PDF).
  29. ↑ "Products | UCB". www.ucb-usa.com. Retrieved 2015-11-05.
  30. ↑ "FDA approves the first 3D-printed drug product | KurzweilAI". www.kurzweilai.net. October 13, 2015. Retrieved 2015-10-14.

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