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Levetiracetam

Levetiracetam (INN)
Systematic (IUPAC) name
(S)-2-(2-Oxopyrrolidin-1-yl)butanamide
Clinical data
Pronunciation
AHFS/Drugs.com
MedlinePlus
Licence data US FDA:
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
Oral, intravenous
Pharmacokinetic data
Bioavailability ~100%
Protein binding <10%
Metabolism Enzymatic hydrolysis of acetamide group
Biological half-life 6 - 8 hr
Excretion Urinary
Identifiers
CAS Registry Number  Y
ATC code N03
PubChem CID:
IUPHAR/BPS
DrugBank  N
ChemSpider  Y
UNII  Y
KEGG  Y
ChEBI  N
ChEMBL  Y
Chemical data
Formula C8H14N2O2
Molecular mass 170.209 g/mol
 N   

Levetiracetam is an anticonvulsant medication used to treat epilepsy.[1] It is the S-enantiomer of etiracetam, structurally similar to the prototypical nootropic drug piracetam.

Levetiracetam is marketed under the trade name Keppra. Keppra is manufactured by UCB Pharmaceuticals Inc. Since November 2008, the drug is available as a generic brand in the United States and the United Kingdom.

Contents

  • Medical uses 1
  • Adverse effects 2
    • Drug interactions 2.1
    • Special populations 2.2
      • Pregnancy 2.2.1
      • Elderly 2.2.2
  • Measurement in bodily fluids 3
    • Assay of levetiracetam 3.1
  • Mechanism of action 4
  • Available forms 5
  • See also 6
  • References 7
  • External links 8

Medical uses

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.[2] It is also used in veterinary medicine for similar purposes.

Levetiracetam has potential benefits for other psychiatric and neurologic conditions such as Tourette syndrome, autism, and anxiety disorder,[3] as well as Alzheimer's disease.[4] However, its most serious adverse effects are behavioral, and its benefit-risk ratio in these conditions is not well understood.[3]

Along with other anticonvulsants like gabapentin, it is also sometimes used to treat neuropathic pain. It has not been found to be useful for essential tremors.[5]

Adverse effects

The most common adverse effects of levetiracetam treatment include CNS effects such as somnolence, infection, asthenia, headache, dizziness, and ataxia. 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 including 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 ideations, or psychosis. These occurred mostly within the first month of therapy, but they could develop at any time during treatment.[6]

A study published in 2005 suggests that the addition of pyridoxine (vitamin B6) may curtail some of the psychiatric symptoms.[7]

Although rare, Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with levetiracetam. Recommendations are to discontinue leviteracetam upon signs of unexplained rash. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. The incidence of SJS following exposure to anti-epileptics such as Levetiracetam is about 1 in 3,000[8]

Drug interactions

No significant pharmacokinetic interactions were observed between levetiracetam or its major metabolite and concomitant medications.[9] The pharmacokinetic profile of Keppra is not influenced by phenytoin, phenobarbital, primidone, carbamazepine, valproic acid, lamotrigine, gabapentin, digoxin, oral contraceptives ethinylestradiol, and warfarin.[10]

Special populations

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 Keppra orally throughout pregnancy and lactation.[11]

A study in the Journal Neurology retrospectively looked at 671 human pregnancies with known maternal exposure to levetiracetam and found that the rate of Major congenital malformations (MCM) was not significantly higher when levetiracetam was used as a monotherapy. However, the majority of the patients were also exposed to other anti-epileptic drugs as a combination therapy and found increases in Major Congential Malformations when combined with valproate and carbamazepine. The paper concluded that the data suggests levetiracetam monotherapy to be a suitable regimen if anti-epileptic medication is needed during pregnancy.[12] A British study in 2014, conducted by Dr. Rebekah Shallcross of the University of Liverpool in England, in a news release from the American Academy of Neurology, examined its safety in pregnancy regarding thinking, movement, and language, suggesting that it might be usable as monotherapy in pregnant epileptics who had previously been taking a decidedly more risky anticonvulsant, valproic acid.[13]

Elderly

Levetiracetam is renally cleared and the incidence of impaired renal function is higher in this age group. 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 experience by young and elderly patients with CNS disorders.[14]

Measurement in bodily fluids

Assay of levetiracetam

There are only a few papers published reporting therapeutic drug monitoring methods of levetiracetam. Three of them employed HPLC with UV-detection,[15][16][17] and two methods were using GC with NPD-detection.[16][18] Microemulsion electrokinetic chromatography with UV-detection was utilized in one method.[19] Two methods facilitating chiral separation of the S- and R- enantiomer of levetiracetam, one utilizing GC–MS and the other HPLC–UV, were published.[20][21] These methods were designed to investigate in dogs the pharmacokinetic and pharmacodynamic properties of the two enantiomers separately. For routine therapeutic drug monitoring in men, these methods were not appropriate. In all but one of the methods,[17] sample preparation with SPE or liquid–liquid extraction is necessary. Pucci et al.[17] evaluated the feasibility of protein precipitation as the only sample preparation step in comparison to SPE. They concluded, that protein precipitation is a suitable and fast sample preparation for measuring routine patient samples. Mecarelli et al.[22] studied the concentration of levetiracetam in both serum and saliva of patients with epilepsy.

Various HPLC,[23][24][25][26][27][28][29] and LC-MS,[30][31][32] methods have been reported for the determination of levetiracetam in pure and pharmaceutical dosage forms.

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,[33] and inhibits presynaptic calcium channels [34] reducing neurotransmitter release and acting as a neuromodulator. This is believed to impede impulse conduction across synapses.[35]

Available forms

Avaliable as intravenous and oral formulations.

In 2015 Aprecia’s 3d-printed form of the drug was approved by the FDA.[36]

See also

References

  1. ^ Abou-Khalil B (June 2008). "Levetiracetam in the treatment of epilepsy". Neuropsychiatr Dis Treat 4 (3): 507–23.  
  2. ^ BNF 59. BMA & RPSGB. 2010. 
  3. ^ a b 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.  
  4. ^ 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.  
  5. ^ 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.  
  6. ^ 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.  
  7. ^ "Clinical Epilepsy: Pediatrics". Epilepsia 46 (s8): 142–67. 2005.  
  8. ^ Griebel ML. Acute management of hypersensitivity reactions and seizures. Epilepsia. 1998;39(7):S17–S21
  9. ^ 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.
  10. ^ 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.
  11. ^ "HIGHLIGHTS OF PRESCRIBING INFORMATION" (PDF). UCB, Inc. Retrieved 29 May 2014. 
  12. ^ Mawhinney E, Craig J, Morrow J,et al. Levetiracetam in pregnancy results from the UK and Ireland epilepsy and pregnancy registers. Neurology 2013;80:400–405.
  13. ^ "Study Weighs Safety of Epilepsy Drugs in Pregnancy". drugs.com. 
  14. ^ Cramer, J.A., Leppik, I.E., De Rue, K., Edrich, P., Krämer, G. Tolerability of levetiracetam in elderly patients with CNS disorders (2003) Epilepsy Research, 56 (2-3), pp. 135-145.
  15. ^ N. Ratnaraj, H.C. Doheny, P.N. Patsalos, Ther. Drug Monit. 18 (1996) 154.
  16. ^ a b T.A. Vermeij, P.M. Edelbroek, J. Chromatogr. B Biomed. Appl. 662 (1994) 134.
  17. ^ a b c V. Pucci, F. Bugamelli, R. Mandrioli, A. Ferranti, E. Kenndler, M.A. Raggi, Biomed. Chromatogr. 18 (2004) 37.
  18. ^ R. Coupez, R. Straetemans, G. Sehgal, A. Stockis, Z.S. Lu, J. Clin. Pharmacol. 43 (2003) 1370.
  19. ^ M. Ivanova, A. Piunti, E. Marziali, N. Komarova, M.A. Raggi, E. Kenndler, Electrophoresis 24 (2003) 992.
  20. ^ N. Isoherranen, M. Roeder, S. Soback, B. Yagen, V. Schurig, M. Bialer, J. Chromatogr. B Biomed. Sci. Appl. 745 (2000) 325.
  21. ^ N. Isoherranen, B. Yagen, S. Soback, M. Roeder, V. Schurig, M. Bialer, Epilepsia 42 (2001) 825.
  22. ^ O. Mecarelli, P. Li Voti, S. Pro, F.S. Romolo, M. Rotolo, P. Pulitano, N. Accornero, N. Vanacore, Saliva and serum levetiracetam concentrations in patients with epilepsy. Therapeutic Drug Monitoring (2007), 29(3), 313-318.
  23. ^ Prafulla Kumar Sahu*, Dillip Kumar Sahoo, M.M.Annapurna, M.E.Bhanoji Rao, Development and validation of an RP-HPLC method for determination of Levetiracetam in Bulk and Pharmaceutical Dosage Forms, Analytical Chemistry: An Indian Journal, 2009, 8(1).
  24. ^ C. Manuela, M. Susan, A. Fiorenzo, R. Roberto and B. Agostino, J chromatogr B., 2008, 873(1), 129.
  25. ^ N. Appala Raja, J. Venkateswara Rao, K. Vanitha Prakash, K. Mukkanti and K. Srinivasu, E Journal of Chemistry, 2008, 5(S2), 1098.
  26. ^ J. Valarmathy, L. Samueljoshua, G. Rathinavel, C. Selvin Thanija and T. Sivakumar,Research J Pharm and Tech., 2008, 1(3), 395.
  27. ^ J. Marten Lobenhoffer and S.M. Bode Boger, J Chromatogr B., 2005, 815, 197.
  28. ^ N. Ratnaraj, C. Doheny Helen and N. Patsalos Philip, Ther Drug Monit, 1996, 18(2), 154.
  29. ^ A.C. Vermeij and P.M. Edelbroek, J Chromatogr B., 1994, 662,134.
  30. ^ M. Kamal Matar, J Pharm Biomed Anal., 2008, 48(3), 822.
  31. ^ G. Saravanan, G. Jhothy, Y. Suresh, A. Annerao, M. Ramakrishna, M. Yogeshwar Reddy and B. Ravibabu, Chromatographia, 2008, 67, 173.
  32. ^ Tiedong Guo, M. Lisa Oswald, M. Damodara Rao and J. Steven Soldin, Clinica Chimica Acta, 2007, 375, 115.
  33. ^ 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.  
  34. ^ 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.  
  35. ^ Rogawski, MA (June 2006). "Diverse mechanisms of antiepileptic drugs in the development pipeline". Epilepsy Research 69 (3): 273–94.  
  36. ^ "FDA approves the first 3D-printed drug product | KurzweilAI". www.kurzweilai.net. October 13, 2015. Retrieved 2015-10-14. 

External links

  • PubMed Health A division of the National Library of Medicine at the National Institutes of Health.
  • Keppra (levetiracetam) Final Printed Label April 2009. Center for Drug Evaluation and Research, U.S. Food and Drug Administration. Accessed 29 July 2011.
  • Keppra UCB (manufacturer's website)
  • NIH MedLine drug information
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