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DRUG RECORD

 

LEVETIRACETAM

OVERVIEW
Levetiracetam

 

Introduction
Levetiracetam is a relatively unique anticonvulsant that is typically used in combination with other antiepileptic medications for partial onset seizures.  Levetiracetam has been linked to rare instances of serum aminotransferase and alkaline phosphatase elevations during treatment and to rare cases of clinically apparent drug induced liver disease.

Background
Levetiracetam (lee" ve tre ra' se tam) is a pyrrolidine derivative unrelated in structure to other anticonvulsant medications.  Its mechanism of action is not known, but it is believed to act by preventing secondary spread of focal seizure activity and to decrease simultaneous neuronal firing.  Levetiracetam was approved for use in epilepsy in 1999 and current indications are as adjunctive therapy for partial onset seizures, generalized tonic-clonic seizures and myoclonic seizures in both children and adults.  Levetiracetam is available as tablets of 250, 500, 750 and 1000 mg generically and under the brand name Keppra.  Liquid oral and injectable forms are also available.  The recommended initial dose in adults is 500 mg twice daily with dose escalation based upon tolerance and effect to a maximum of 1500 mg twice daily.  Dosing in children is based upon body weight.  Common side effects include dizziness, somnolence and fatigue.

Hepatotoxicity
Prospective studies reported that chronic levetiracetam therapy was not accompanied by significant elevations in serum aminotransferase levels and clinically apparent liver injury was not observed.  Since its approval for use and wide spread availability, however, levetiracetam has been linked to rare instances of serum enzyme elevations and occasional cases of clinically apparent liver injury.  The time to onset of liver injury after starting levetiracetam has ranged from 1 week to 5 months and the usual pattern of injury has been hepatocellular.  Immunoallergic features and autoantibodies were rare.  At least one case of acute liver failure attributed to levetiracetam has been published, but the number of reported cases clinically apparent cases of liver injury has been few.  In addition, levetiracetam is usually considered a reasonable alternative therapy in patients who develop anticonvulsant hypersensitivity (DRESS) syndrome after aromatic anticonvulsant use.

Mechanism of Injury
The mechanism of levetiracetam hepatotoxicity is unknown, but is likely to be hypersensitivity.  Levetiracetam has minimal hepatic metabolism and does not affect CYP 450 isoenzyme activity.

Outcome and Management
A single case of acute liver failure attributed to levetiracetam has been published.  The liver injury recurred rapidly with reexposure.  Chronic injury from levetiracetam therapy has not been reported.  There is no evidence for cross sensitivity to hepatic injury between levetiracetam and other anticonvulsants.

Drug Class:  Anticonvulsants

 

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PRODUCT INFORMATION
Levetiracetam

 

REPRESENTATIVE TRADE NAMES
Levetiracetam – Generic, Keppra®

 

DRUG CLASS
Anticonvulsants

 

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH


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DRUG CAS REGISTRY NUMBER MOLECULAR FORMULA STRUCTURE
Levetiracetam 102767-28-2 C8-H14-N2-O2  Levetiraceta chemical structure

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REFERENCES
Levetiracetam

 

References updated: 24 February 2014

  1. Zimmerman HJ. Anticonvulsants. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999: pp. 498-516.  (Expert review of anticonvulsants and liver injury published in 1999; levetiracetam is not discussed).

  2. Pirmohamed M, Leeder SJ. Anticonvulsant agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013: pp 423-41.  (Review of anticonvulsant induced liver injury published; levetiracetam is not mentioned).

  3. McNamara JO. Pharmacology of the epilepsies. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 583-608.  (Textbook of pharmacology and therapeutics).

  4. Knowles SR, Shapiro LE, Shear NH. Anticonvulsant hypersensitivity syndrome: incidence, prevention and management. Drug Saf 1999; 21: 489-501. PubMed Citation  (Review of anticonvulsant hypersensitivity syndrome: triad of fever, rash and internal organ injury occurring 1-8 weeks after exposure to anticonvulsant; liver being most common internal organ involved. Occurs in 1:1000-1:10,000 initial exposures to phenytoin, carbamazepine, phenobarbital or lamotrigine, unrelated to dose, perhaps predisposed by valproate; liver injury arises 1-4 weeks after onset of rash and ranges in severity from asymptomatic ALT elevations to icteric hepatitis to acute liver failure. High mortality rate with jaundice; other organs involved include muscle, kidney, brain, heart and lung. Pseudolymphoma syndrome and serum sickness like syndrome are separate complications of anticonvulsants. Role of corticosteroids is uncertain; cross reactivity among the agents should be assumed).

  5. Hamer HM, Morris HH. Hypersensitivity syndrome to antiepileptic drugs: a review including new anticonvulsants. Clevel Clin J Med 1999; 66: 239-45. PubMed Citation  (Clinical review of anticonvulsant hypersensitivity syndrome: occurs in 1-5/10,000 users, higher risk in African Americans and affected siblings; liver involvement common, but most cases anicteric; other manifestations include facial edema, lymphadenopathy, bone marrow aplasia, pseudolymphoma, thyroiditis, interstitial nephritis, switching to valproate and benzodiazepines is safe, levetiracetam is also an option).

  6. Betts T, Waegemans T, Crawford P. A multicentre, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy. Seizure 2000; 9: 80-7. PubMed Citation  (Comparison of levetiracetam–2000 or 4000 mg daily–compared to placebo as add-on treatment for 24 weeks in 119 patients with refractory seizures; “there were no significant changes in clinical laboratory parameters…” and no specific mention of ALT levels).

  7. Nash EM, Sangha KS. Levetiracetam. Am J Health Syst Pharm 2000; 58: 1195-9. PubMed Citation  (Review of pharmacology and efficacy of levetiracetam, a new anticonvulsant that received rapid approval and is used as adjunctive therapy only; no hepatic metabolism; no mention of hepatic side effects or ALT elevations during therapy).

  8. Jain KK. An assessment of levetiracetam as an anti-epileptic drug. Exp Opin Invest Drugs 2000; 9: 1611-24. PubMed Citation  (Review of levetiracetam use in both partial epilepsy and generalized seizures; no mention of hepatic side effects).

  9. Partap S, Fisher PG. Levetiracetam for seizures in children with brain tumors and other cancers. Pediatr Blood Cancer 2009; 52: 288-9. PubMed Citation  (Extensive review of chemistry, pharmacology, metabolism and pharmacokinetics of levetiracetam; it does not undergo hepatic metabolism, no interaction with CYP 450 isoenzymes and no significant drug-drug interactions).

  10. Abou-Khalil B. Levetiracetam in the treatment of epilepsy. Neuropsychiatr Dis Treat 2008; 4: 507-23. PubMed Citation  (Review on use of levetiracetam in epilepsy; serious adverse events are rare; allergic rash in <1%; no mention of hepatic toxicity or ALT elevations).

  11. Tan TC, de Boer BW, Mitchell A, Delriviere L, Adams LA, Jeffrey GP, Macquillan G. Levetiracetam as a possible cause of fulminant liver failure. Neurology 2008; 71: 685-6. PubMed Citation  (Patient developed acute liver failure 1 month after being switched from oxcarbazepine to levetiracetam [bilirubin 34.6 mg/dL, ALT 1610 U/L, Alk P 246 U/L], which recurred on restarting levetiracetam post liver transplant [bilirubin rising to 4.5 mg/dL, ALT 350 U/L, Alk P 650 U/L], resolving within 2 weeks of stopping).

  12. Skopp G, Schmitt HP, Pedal I. [Fulminant liver failure in a patient on carbamazepine and levetiracetam treatment associated with status epilepticus]. Arch Kriminol 2006; 217: 161-75. German. PubMed Citation  (Patient on long term carbamazepine and levetiracetam developed acute liver failure after a period of status epilepticus and mild but prolonged hypotension; autopsy was more compatible with ischemic hepatitis than drug induced liver injury and no routine liver tests [bilirubin, ALT, Alk P, LDH, CPK, protime] provided).

  13. Briggs DE, French JA. Levetiracetam safety profiles and tolerability in epilepsy patients. Expert Opin Drug Saf 2004; 3: 415-24. PubMed Citation  (Analysis of safety in phase II and III prelicensure trials of levetiracetam; adverse events in 15%, most commonly somnolence, asthenia, headache and infection, little change in weight and no reports of hepatotoxicity or ALT elevations).

  14. Patsalos PN. Clinical pharmacokinetics of levetiracetam. Clin Pharmacokinet 2004; 43: 707-24. PubMed Citation  (Review of chemical properties, pharmacokinetics, and pharmacology of levetiracetam which is a pyrrolidone derivative, structurally unrelated to other anticonvulsants, rapid absorption and little hepatic metabolism or effects of CYP isoenzymes).

  15. LaRoche SM. A new look at the second-generation antiepileptic drugs: a decade of experience. Neurologist 2007; 13: 133-9. PubMed Citation  (Review of second generation anticonvulsants approved since 1994 including felbamate, gabapentin, lamotrigine, topiramate, tiagabine, levetiracetam, oxcarbazepine, zonisamide and pregabalin; no mention of liver toxicity from levetiracetam). 

  16. Björnsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scan 2008; 118: 281-90. PubMed Citation  (Review of all anticonvulsants; suggests that clinically significant hepatotoxicity has not been reported with levetiracetam). 

  17. Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. PubMed Citation  (Among 300 cases of drug induced liver disease in the US collected between 2004 and 2008, no case was attributed to levetiracetam).

  18. Gallerani M, Mari E, Boari B, Carletti R, Marra A, Cavallo M. Pancytopenia associated with levetiracetam treatment. Clin Drug Investig 2009; 29: 747-51. PubMed Citation  (65 year old woman developed pancytopenia 9 days after starting levetiracetam followed by pneumonia, gallstone obstruction and multiple liver abscesses [bilirubin 5.4 mg/dL, ALT 127 U/L, Alk P 1169 U/L], ultimately resolving after antibiotic therapy and stopping levetiracetam).

  19. Broli M, Provini F, Naldi I, Bisulli F, Sama C, Baruzzi A, Tinuper P, Riva R.  Unexpected gamma glutamyltransferase rise increase during levetiracetam monotherapy. Epileptic Disord 2010; 12: 81-2. PubMed Citation  (58 year old woman developed persistent mild and asymptomatic elevations in GGT [initially 29 rising to 157 U/L, ALT normal] 4 months after being switched from valproate to levetiracetam, and resolving within 2 months of switching to lamotrigine).

  20. Müller CA, Schäfer M, Schneider S, Heimann HM, Hinzpeter A, Volkmar K, Förg A, et al. Efficacy and safety of levetiracetam for outpatient alcohol detoxification. Pharmacopsychiatry 2010; 43: 184-9. PubMed Citation  (Controlled trial of 7 days of levetiracetam versus placebo in 131 patients with alcohol dependence during withdrawal; “There were 3 cases of worsening of pre-existing liver parameter elevations”, but no details given).

  21. Richter C, Hinzpeter A, Schmidt F, Kienast T, Preuss UW, Plenge T, Heinz A, et al. Levetiracetam for the treatment of alcohol withdrawal syndrome: a multicenter, prospective, randomized, placebo-controlled trial. J Clin Psychopharmacol 2010; 30: 720-5. PubMed Citation  (Controlled trial of 7 days of levetiracetam versus placebo in 106 patients with alcohol dependence during withdrawal found no difference in withdrawal symptoms and no “negative influence on laboratory parameters including liver enzymes”). 

  22. Xiong N, Hou L, Lu N, Mohamed AA, Wang T, Huang Y. Probable levetiracetam-related serum alkaline phosphatase elevation. BMC Neurol 2012; 12: 97. PubMed Citation  (One year old Chinese girl with brain injury was found to have rising levels of Alk P 5 months after starting levetiracetam [Alk P 162 rising to 1613 and then 4557 U/L with normal bilirubin, ALT and GGT], resolving within 6 months of stopping).

  23. Gómez-Zorrilla S, Ferraz AV, Pedrós C, Lemus M, Peña C. Levetiracetam-induced drug reaction with eosinophilia and systemic symptoms syndrome. Ann Pharmacother
    2012; 46: e20. PubMed Citation  (31 year old man with brain tumor developed fever, rash and interstitial pneumonitis 49 days after starting levetiracetam, improving with dexamethasone therapy, but recurring [ALT 60 U/L] and resolving only after stopping levetiracetamin and switching to phenytoin).

  24. Sethi NK, Sethi PK, Torgovnick J, Arsura E, Cukierwar F. Asymptomatic elevation of liver enzymes due to levetiracetam: a case report. Drug Metabol Drug Interact 2013; 28: 123-4. PubMed Citation  (62 year old woman was found to have serum enzyme elevations without symptoms 10 days after starting levetiracetam therapy [bilirubin not given, ALT 289 U/L, Alk P 567 U/L], which fell to near normal levels within a week of stopping and did not rise with subsequent topiramate therapy).

  25. Drugs for epilepsy. Treat Guidel Med Lett 2013; 11: 9-18. PubMed Citation  (Concise review of the efficacy and safety of drugs used to treat epilepsy; levetiracetam can cause Stevens Johnson syndrome and toxic epidermal necrolysis, but liver adverse events were not mentioned).

  26. Gutiérrez-Grobe Y, Bahena-Gonzalez JA, Herrera-Gomar M, Mendoza-Diaz P, García-López S, González-Chon O. Acute liver failure associated with levetiracetam and lacosamide combination treatment for unspecified epileptic disorder. Case Rep Emerg Med 2013; 2013: 634174. PubMed Citation  (22 year old woman with status epilepticus 2 months after starting lacosamide and levetiracetam had markedly abnormal serum enzymes [bilirubin 2.1 mg/dL, ALT 4341 U/L, Alk P 74 U/L, CPK 2989 U/L, myoglobin in serum], falling to normal within 12 days of stopping both drugs).

  27. Azar NJ, Aune P. Acute pancreatitis and elevated liver transaminases after rapid titration of oral levetiracetam. J Clin Neurosci 2013 Oct 18. [Epub ahead of print] PubMed Citation  (25 year old woman developed fever, abdominal pain and fatigue within a week of starting levetiracetam [bilirubin 2.7 mg/dL, ALT 1083 U/L, Alk P 250 U/L, amylase 439 U/L], resolving within 7 days of stopping and not recurring with pregabalin).

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OTHER REFERENCE LINKS
Levetiracetam
  1. PubMed logoRecent References on Levetiracetam

  2. Clinical Trials logoTrials on Levetiracetam

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