Levetiracetam

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Levetiracetam
Levetiracetam.svg
Levetiracetam3d.png
Systematic (IUPAC) name
(S)-2-(2-oxopyrrolidin-1-yl)butanamide
Clinical data
Trade names Keppra
AHFS/Drugs.com monograph
MedlinePlus a699059
Pregnancy cat. B3 (AU) C (US)
Legal status Prescription Only (S4) (AU) Prescription only
Routes Oral, intravenous
Pharmacokinetic data
Bioavailability ~100%
Protein binding <10%
Metabolism Enzymatic hydrolysis of acetamide group
Half-life 6 - 8 hr
Excretion Urinary
Identifiers
CAS number 102767-28-2 YesY
ATC code N03AX14
PubChem CID 5284583
DrugBank DB01202
ChemSpider 4447633 YesY
UNII 44YRR34555 YesY
KEGG D00709 YesY
ChEMBL CHEMBL1286 YesY
Chemical data
Formula C8H14N2O2 
Mol. mass 170.209 g/mol
 N (what is this?)  (verify)

Levetiracetam (INN) /lɛvɨtɪˈræsɨtæm/ 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 has been available as a generic brand in the United States.

Medical uses[edit]

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, bipolar disorder 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[edit]

Levetiracetam is generally well tolerated.[6] According to the package insert listed for Levetiracetam,[7] Adverse reactions include
-Psychiatric reactions
-Suicidal Behavior And Ideation
-Somnolence And Fatigue
-Dermatologic Reactions
-Coordination Difficulties
-Hematologic Abnormalities

Suicidal Ideation: Antiepileptic drugs (AEDs), including KEPPRA XR, increases the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Studies have shown almost a doubling of risk of suicidal ideation from 0.2% to 0.4% for those taking the medication compared to placebo. Symptoms have been reported within 1 week of starting the medication with improvement following discontinuation. A study published in 2005 suggests that the addition of pyridoxine (vitamin B6) may curtail some of the psychiatric symptoms.[8]

Somnolence: A study found somnolence as a reported symptom in 7.8% of patients taking Keppra XR compared to 2.5% in the placebo group. Patients should be monitored for exhibiting effects of somnolence before driving and operating machinery.

Serious Dermatological Reactions: Although rare, Stevens-Johnson syndrome (SJS) and Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with levetiracetam. Recommendations are to discontinue Keppra 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[9]

Measured Hematologic Abnormalities: One study of patients receiving Keppra IR showed decreased RBC, decreased mean hematocrit and mean hemoglobin compared to placebo. None of the patients however, experienced any symptoms related to the decreased blood counts and the medications were continued.

A meta-analysis done in 2008 Journal of Neuropyschiatry Disease and Treatment[6] compared three studies conducted in 2000 analyzing the safety of therapeutic doses of levetiracetam for patients suffering partial seizures in an attempt to better quantify the most common side effects. They found the following incidence for 769 patients:[10][11][12]

Symptoms:
Weakness (15%)

Somnolence (15%)

Headache (14%)

Infection (13%)

Dizziness (9%)

Depression (4%)

Drug Interactions[edit]

No significant pharmacokinetic interactions were observed between levetiracetam or its major metabolite and concomitant medications.[13] The pharmacokinetic profile of Keppra is not influenced by phenytoin, phenobarbital, primidone, carbamazepine, valproic acid, lamotrigine, gabapentin, digoxin, oral contraceptives ethinylestradiol, and warfarin.[14]

Drug Toxicity[edit]

The highest human dose observed in the clinical development was 6000 mg / day or Keppra IR, double the highest recommended dose. No major adverse events were reported except for drowsiness in development trials. Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with immediate-release KEPPRA overdoses in postmarketing use.

Contraindications[edit]

There are no absolute Contraindications to starting a Keppra regimen unless previous hypersensitivity reaction to levetiracetam or metabolites[7]
Keppra is a Pregnancy Category C drug, meaning that animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite the risks.

Special Populations[edit]


Pregnancy: Keppra 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.[7]

A study in the Journal Neurology retrospectively looked at 671 human pregnancies with known maternal exposure to Keppra and found that the rate of Major Congenital Malformations (MCM) was not significantly higher when Keppra 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 Keppra monotherapy to be a suitable regimen if anti-epileptic medication is needed during pregnancy.[15]

Elderly[edit]

Keppra 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.[16]

Measurement in bodily fluids[edit]

Assay of levetiracetam[17][edit]

There are only a few papers published reporting therapeutic drug monitoring methods of levetiracetam. Three of them employed HPLC with UV-detection,[18][19][20] and two methods were using GC with NPD-detection.[19][21] Microemulsion electrokinetic chromatography with UV-detection was utilized in one method.[22] Two methods facilitating chiral separation of the S- and R- enantiomer of levetiracetam, one utilizing GC–MS and the other HPLC–UV, were published.[23][24] 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,[20] sample preparation with SPE or liquid–liquid extraction is necessary. Pucci et al.[20] 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.[25] studied the concentration of levetiracetam in both serum and saliva of patients with epilepsy.

Various HPLC,[26][27][28][29][30][31][32] and LC-MS,[33][34][35] methods have been reported for the determination of levetiracetam in pure and pharmaceutical dosage forms.

Mechanism of action[edit]

The exact mechanism by which levetiracetam acts to treat epilepsy is unknown. However, the drug binds to a synaptic vesicle glycoprotein, SV2A,[36] and inhibits presynaptic calcium channels [37] reducing neurotransmitter release and acting as a neuromodulator. This is believed to impede impulse conduction across synapses.[38]

Available forms[edit]

  • Ready-to-administer bags of sodium chloride injection, at concentrations of 500 mg/100 mL, 1000 mg/100 mL and 1500 mg/100 mL[39]
  • 250 mg tablets
  • 500 mg tablets
  • 750 mg tablets
  • 1000 mg tablets

See also[edit]

References[edit]

  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. ^ 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. doi:10.2146/ajhp070607. PMID 19265183. 
  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. doi:10.1073/pnas.1121081109. PMC 3479491. PMID 22869752. 
  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. doi:10.1212/WNL.0b013e318236f0fd. PMC 3208950. PMID 22013182. 
  6. ^ a b 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. 
  7. ^ a b c "HIGHLIGHTS OF PRESCRIBING INFORMATION". UCB, Inc. Retrieved 29 May 2014. 
  8. ^ "Clinical Epilepsy: Pediatrics". Epilepsia 46 (s8): 142–67. 2005. doi:10.1111/j.1528-1167.2005.460801_16.x. 
  9. ^ Griebel ML. Acute management of hypersensitivity reactions and seizures. Epilepsia. 1998;39(7):S17–S21
  10. ^ Ben-Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3000 mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. Epilepsia. 2000;41:1276–83.
  11. ^ Cereghino JJ, Biton V, Abou-Khalil B, et al. Levetiracetam for partial seizures: results of a double-blind, randomized clinical trial. Neurology. 2000;55:236–42.
  12. ^ Shorvon SD, Lowenthal A, Janz D, et al. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. Epilepsia. 2000;41:1179–86.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ Prafulla Kumar Sahu, M. Mathrusri Annapurna; Analytical Method development by Liquid Chromatography, LAP LAMBERT Academic Publishing GmbH & Co. KG, Germany, ISBN 978-3-8443-2869-1.
  18. ^ N. Ratnaraj, H.C. Doheny, P.N. Patsalos, Ther. Drug Monit. 18 (1996) 154.
  19. ^ a b T.A. Vermeij, P.M. Edelbroek, J. Chromatogr. B Biomed. Appl. 662 (1994) 134.
  20. ^ a b c V. Pucci, F. Bugamelli, R. Mandrioli, A. Ferranti, E. Kenndler, M.A. Raggi, Biomed. Chromatogr. 18 (2004) 37.
  21. ^ R. Coupez, R. Straetemans, G. Sehgal, A. Stockis, Z.S. Lu, J. Clin. Pharmacol. 43 (2003) 1370.
  22. ^ M. Ivanova, A. Piunti, E. Marziali, N. Komarova, M.A. Raggi, E. Kenndler, Electrophoresis 24 (2003) 992.
  23. ^ N. Isoherranen, M. Roeder, S. Soback, B. Yagen, V. Schurig, M. Bialer, J. Chromatogr. B Biomed. Sci. Appl. 745 (2000) 325.
  24. ^ N. Isoherranen, B. Yagen, S. Soback, M. Roeder, V. Schurig, M. Bialer, Epilepsia 42 (2001) 825.
  25. ^ 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.
  26. ^ 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).
  27. ^ C. Manuela, M. Susan, A. Fiorenzo, R. Roberto and B. Agostino, J chromatogr B., 2008, 873(1), 129.
  28. ^ N. Appala Raja, J. Venkateswara Rao, K. Vanitha Prakash, K. Mukkanti and K. Srinivasu, E Journal of Chemistry, 2008, 5(S2), 1098.
  29. ^ J. Valarmathy, L. Samueljoshua, G. Rathinavel, C. Selvin Thanija and T. Sivakumar,Research J Pharm and Tech., 2008, 1(3), 395.
  30. ^ J. Marten Lobenhoffer and S.M. Bode Boger, J Chromatogr B., 2005, 815, 197.
  31. ^ N. Ratnaraj, C. Doheny Helen and N. Patsalos Philip, Ther Drug Monit, 1996, 18(2), 154.
  32. ^ A.C. Vermeij and P.M. Edelbroek, J Chromatogr B., 1994, 662,134.
  33. ^ M. Kamal Matar, J Pharm Biomed Anal., 2008, 48(3), 822.
  34. ^ G. Saravanan, G. Jhothy, Y. Suresh, A. Annerao, M. Ramakrishna, M. Yogeshwar Reddy and B. Ravibabu, Chromatographia, 2008, 67, 173.
  35. ^ Tiedong Guo, M. Lisa Oswald, M. Damodara Rao and J. Steven Soldin, Clinica Chimica Acta, 2007, 375, 115.
  36. ^ 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. 
  37. ^ 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. 
  38. ^ 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. 
  39. ^ "Mylan Inc. (MYL) Launches Innovative Version of Antiepileptic Drug Levetiracetam". ClinicaSpace (press release) (Mylan). 20 Jan 2012. Retrieved 22 Jan 2012. 

External links[edit]