International Journal of Medicine and Biomedical Research Volume 2 Issue 3 September – December 2013 www.ijmbr.com Michael Joanna Publications Levetiracetam: A Review of its use in the treatment of epilepsy
Swaroop HS1, Ananya C1*, Nithin K2, Jayashankar CA3, Satish Babu HV 4, Srinivas BN1 1Department of Pharmacology, 2Department of Neurology, 3Department of General Medicine, 4Department of Neurosurgery, Vydehi Institute of Medical Sciences and Research Centre, 82 EPIP Area, Whitefield, Bangalore-560066, Karnataka, India *Corresponding author Received: 08.05.13; Accepted: 25.10.13 ABSTRACT
Background: Levetiracetam is a novel antiepileptic drug. It is marketed
worldwide since 2000. Aim: The paper reviewed the mechanism of action,
pharmacokinetics, adverse drug reactions, contraindications and uses of levetiracetam in the treatment of various types of epileptic seizures. Methods:
Literature searches were done to identify relevant studies. Results: Levetiracetam
acts by binding to the synaptic vesicle protein SV2A, thereby modulation of one or more of its actions and ultimately affecting neural excitability. It has less protein binding and lacks hepatic metabolism. In contrast to traditional therapy, it has a wide safety margin and does not require serum drug monitoring. It does not interact with other anti-epileptics. Conclusion: The above-mentioned
favourable pharmacological benefits of LEV make it an important first-line or adjunctive therapy for epileptic seizures. Key words: Levetiracetam, epilepsy, synaptic vesicle protein, seizures, efficacy,
of the epilepsy depends on appropriate classification of seizure type and the epileptic syndrome.[2] The Epilepsy is a group of disorder characterized by two older or first generation antiepileptic drugs like or more unprovoked seizures. The estimated average phenytoin, carbamazepine and sodium valproate are prevalence of epilepsy in US is 6.8 per 1000, Europe widely used but they have increased risk of adverse is 5.5 per 1000, and Asia is 1.5 to 14 per 1000 people reactions and drug interactions.[3] They also require respectively.[1] Epilepsy is classified based on the therapeutic monitoring. Therefore, new or second source of seizure into partial and generalized generation drugs are preferred due to favourable side seizures.[1] About 2/3rd of newly diagnosed epilepsies effect profile and less chance of drug interactions.[4] are partial or secondarily generalized. The treatment Levetiracetam (LEV) is a second generation Int J Med Biomed Res 2013;2(3):166-172 Swaroop et al.: Levetiracetam in the treatment of epilepsy antiepileptic drug. It is chemically unrelated to other involved in the molecular basis of epilepsy.[17] antiepileptic drugs and is the α-ethyl analogue of the nootropic agent piracetam.[5] It was discovered in 1992 through screening in audiogenic seizure susceptible mice.[6] It is marketed worldwide since 2000.[7] It has been found to be well tolerated with a administration. The oral bioavailability of LEV is favourable pharmacokinetic profile that includes more than 95%. It attains peak plasma concentration minimal protein binding, lack of hepatic metabolism approximately one hour after oral administration. [18] and twice a day dosing.[5-7] It was initially approved It reaches steady state concentration within 48 hours in the US only as adjunctive therapy for partial-onset of initiation of therapy. Food reduces the peak plasma seizures.[8] However, it is recently approved as an concentration of LEV by 20% and delays it by 1.5 adjunctive therapy for primary generalized tonic- hours.[18,19] There is a linear relationship between clonic seizures, myoclonic seizures of juvenile LEV dose and LEV serum level over a dose range of myoclonic epilepsy and partial onset seizures with or 500–5000 mg.[18,19] LEV is less than 10% bound to without secondary generalization.[8] It has also been plasma proteins and this protein binding is not found to be effective in patients with Lennox-Gastaut clinically relevant.[19,20] Only 27% of LEV is syndrome.[8,9] Recently, it is also widely used in the metabolized and metabolism is not dependent on the liver cytochrome P450 enzyme system.[19] The main neurosurgery.[ 9] metabolic pathway is hydrolysis of the acetamide group in the blood to yield an inactive carboxylic In contrast to traditional therapy, LEV has a wide derivative. LEV is predominantly excreted unchanged safety margin without any requirement for serum through the kidneys and its plasma half-life is 7 ± 1 drug monitoring, and no interactions with other hour in adults.[19,20] The half life can be prolonged by antiepileptics.[10] This favourable pharmacological an average of 2.5 hours in the elderly, most likely due profile makes LEV an attractive first-line or to decreased creatinine clearance with age.[20] Also, in adjunctive therapy for epileptic seizures.[10] patients with impaired renal function, a dose adjustment is needed, dependent on the creatinine MECHANISM OF ACTION
The mechanism of action of levetiracetam is different The absence of hepatic metabolism and of protein from first-generation and other second-generation anti-epileptic drugs (AEDs).[11] It does not work by interactions.[20] the three classic routes of other AEDs: sodium pharmacokinetic interactions with drugs like oral channel modulation, low-voltage-activated (T-type) calcium channel modulation, or direct gamma- However, some studies have suggested lower LEV aminobutyric acid (GABA) facilitation.[11] It is levels or higher clearance in patients taking enzyme- postulated to act by binding to synaptic vesicle inducing AEDs.[21] Autoinduction probably does not protein 2A (SV2A) and thereby modulation of one or occur with LEV, but one study involving short more of its actions, ultimately affecting neural intensive monitoring suggested a drop in serum levels excitability.[12] It is devoid of anticonvulsant activity after the fifth day of administration of the drug.[ 22] in the two classic acute seizure models used for AED screening, including the maximal electric shock PUBLISHED
seizure test and the pentylenetetrazol seizure test.[13] REACTIONS
However, it demonstrates anticonvulsive effects in the acute corneal electroshock model and selective According to the study by Ben Machen et al., overall incidence of adverse events was comparable between pilocarpine and kainic acid induced models.[13,14] LEV the placebo (53%) and LEV (55%) groups.[23] The exerts significant antiepileptic effect, even after commonest adverse reactions seen with LEV therapy discontinuation of therapy, in kindled models and in were asthenia (13.8%), infection (7.2%), somnolence the double mutant (tm/tm, zi/zi) spontaneously (6.1%) and headache (3.3%). Around 7.1% patients epileptic rat (SER) model.[14] LEV also has been discontinued the therapy due to the adverse reactions. found to selectively inhibit N-type Ca2+ channels,[15] During the monotherapy phase of LEV, 4 patients activate GABA current[16] and possess novel developed the serious adverse events, 2 experienced desynchronizing effect on neurons that might be Int J Med Biomed Res 2013;2(3):166-172 Swaroop et al.: Levetiracetam in the treatment of epilepsy convulsions, 3rd patient had oesophagitis related to increase in stress and the fourth patient had an The initial adult dose when used as an adjunct is 1 g unintended pregnancy. [23] Bootsma et al.[24] reviewed on the first day of treatment.[32] The daily dose is then the clinical experience of LEV and mentioned that increased in steps of 1 g every 2 to 4 weeks until overall 5% of patients were affected by adverse drug effective antiepileptic control is achieved.[32] It can be reactions. The most prevalent adverse events at increased to a maximum dose of 3 g daily.[32] The almost each assessment point were mood disorder, initial dose in children weighing less than 50 kg is 20 tiredness and sleepiness.[24] A remarkable side effect mg/kg daily.[32] It is increased in steps of 20 mg/kg of LEV was positive behavior, reported by about 7% every 2 weeks to a maximum of 60 mg/kg daily.[32] of patients at 3, 6, 9, and 15 months.[24] Children and adolescents weighing 50 kg or more are given the usual adult dose.[32] When used as According to a review by Lyseng-Williamson, monotherapy, the initial dose of LEV is 500 mg psychiatric and behavioral adverse events were daily.[32] It is increased after 2 weeks to 1 g daily.[32] common with LEV.[25] They occurred in >1% and Further increases may be made in steps of 500 mg <10% of patients. Suicidal ideation or behavior was every 2 weeks up to a maximum of 3 g daily.[32] An reported in 0.5-0.7% of the patients. Certain injection formulation is also available for LEV.[32] subgroups of patients especially children with a past history of psychiatric illness and mental retardation PRECAUTIONS
had a greater risk of developing psychiatric adverse events or suicidal behavior and ideation. [25] In Kossoff et al. and Mula et al. studies, up to 13% of
LEV therapy or transition should be attained
neuropsychiatric gradually to avoid precipitating an increase in the symptoms.[26,27] Symptoms were mild, including frequency of seizures.[33] LEV should be used with agitation, hostility, apathy, anxiety, emotional caution in patients with renal impairment, and/or liability and depression.[26,27] In the same studies, severe hepatic impairment.[33] about 1% of pediatric or adult patients had experienced serious neuropsychiatric symptoms including hallucinations, suicidal ideations or REVIEW OF EARLIER STUDIES FOR
psychosis.[26] In these cases, there was a significant EFFICACY AND TOLERABILITY
association between psychiatric adverse events and previous history of febrile convulsions and status According to SKATE trial by Lambrechts et al.,[34] epilepticus.[27] which was conducted to assess the efficacy safety of LEV as an add on therapy in partial epilepsy in adults There have been many case reports about the adverse ≥16 years of age group, 86.9% patients completed the reactions of LEV. In Mahta et al case study,[28] a 45 16 weeks of treatment.[34] The reduction in frequency year old man developed interstitial nephritis after the of partial onset seizures was 62.5%. 19.3% of the escalating dose of LEV. The patient was normal after patients became seizure free and 56.6% had a the withdrawal of the drug.[28] In Newsome et al. reduction in seizures frequency of ≥ 50%.[34] This study,[29] a 9 year old girl developed interstitial lung study concluded that LEV is effective and safe as add disease after increasing the dose of LEV. The patient on therapy in partial epilepsy.[34] was normal after the withdrawal of the drug. In this case, the girl had a previous history of pneumonia, The efficacy of LEV in pediatric population was mental retardation and cerebral palsy.[29] In another studied by Lee et al.[35] It was observed that 48% of case report by Calabro et al,[30] it was reported that the patients showed a seizure reduction of ≥50%, and two young men experienced loss of libido and 22% of the patients became seizure free.[35] Also, anhedonia. In some case studies it has been there was a reduction of in seizure by ≥50% in 52% mentioned that LEV also leads to bleeding disorders of children with partial seizures, and 44% of children and pancytopenia.[30] with generalized seizures.[35] LEV has not been found to interfere with cognitive According to Berkovic et al.,[36] LEV produced a function. It, however, improves the quality of life of greater mean reduction of about 56.5% in GTC patients with epilepsy.[31] seizures frequency per week over the treatment period then placebo where it was 28.2%.[36] The percentage DOSAGE RECOMMENDATIONS
of patients who had ≥50% reduction of GTC seizure Int J Med Biomed Res 2013;2(3):166-172 Swaroop et al.: Levetiracetam in the treatment of epilepsy frequency per week during the treatment period was monotherapy group, the median percent reduction in 72.2% for LEV and 45.2% for placebo (p < 0.001).[36] partial seizure frequency compared with baseline was During the evaluation period the percent of patients 73.8% with a responder rate of 59.2%.[42] In an open free of GTC seizures with of 24.1% for LEV vs 8.3% study by Alsaadi et al., 82% of patients remained on for placebo with a p-value of 0.009.[36] LEV for atleast 1 year with more than 50% of patients remaining seizure free.[43] In a comparative study of LEV vs carbamazepine (CBZ) in newly diagnosed epilepsy by Brodie et A few studies proved the efficacy of LEV in al.,[37] 73.0% of patients randomized to LEV and prophylactic therapy of postoperative seizures and 72.8% receiving controlled release carbamazepine traumatic brain injuries. Milligan TA et al., conducted were seizure free at the last evaluated dose for ≥6 a study to assess the efficacy and tolerability of months.[37] The remission rates at the end of 6 month levetiracetam versus phenytoin after supratentorial to 1 year were 80.1% of LEV and 85.4% of CBZ.[37] neurosurgery.[44] It was concluded that both LEV and In a multicenter, placebo, controlled study of LEV for phenytoin (PHT) were associated with a low risk of myoclonic seizures by Nochtar et al.,[38] a reduction early postoperative seizures and a moderate risk of in ≥50% in the number of days per week with myoclonic seizures was seen in 58.3% of patients in significantly fewer early adverse reactions than the LEV group and 23.3% of patients in the placebo phenytoin.[44] In another comparative study of LEV group (p < 0.001).[38] LEV treated patients had higher versus PHT on seizure prophylaxis in severe freedom from myoclonic seizures 25.5% vs 5.0% for traumatic brain injury by Jones et al.,[45] the final placebo (p = 0.004). [38] conclusion was that LEV is as effective as phenytoin in preventing early posttraumatic seizures but is In a double blind, placebo controlled, randomized associated with an increased seizure tendency on clinical trial of LEV in partial seizures by Cereghino EEG analysis.[45] et al.,[39] a ≥50% reduction in seizure frequency were seen 33.0% patients with 1000mg/day and 39.8% of Zachenhofer et al. conducted a study on perioperative patients with 3000mg/day.[39] The placebo group had LEV for prevention of seizures in supratentorial brain 10.8% reduction in seizure frequency (p < 0.00 1).[39] tumor surgery.[46] It was observed that perioperative Also, in the LEV group, 5.52% of patients became LEV in supratentorial brain tumor patients was well completely free of seizures.[39] According to Gurses et tolerated.[46] Compared with the literature, it resulted al.,[40] which was conducted to study the efficacy of in low (2.6%) seizure frequency in the early LEV as on add on therapy in patients with startle postoperative period.[46] Additionally, its advantage of epilepsy, it was found that 60% of patients responded lacking cytochrome P450 enzyme induction allowed chemotherapy in malignant glioma patients.[46] A pilot According to KEEPER trial by Morrell et al.,[41] study was conducted by Lim et al. studied the safety 57.9% patients under LEV experienced at least 50% and feasibility of switching from phenytoin to LEV reduction in frequency of partial onset seizures.[41] monotherapy for glioma-related seizure control Also, 40.1% patients experienced at least 75% following craniotomy.[47] It concluded that it is safe to reduction, and 20% demonstrated 100% seizure switch patients from PHT to LEV monotherapy reduction.[41] 74.3% of patients were considered following craniotomy for supratentorial glioma.[47] improved with 37% of patients showing marked improvement.[41] Recently, the HELLO trial was conducted by Bahr et al.[48] They assessed the efficacy and tolerability of LEV is established as efficacious in adjunctive intravenous and oral LEV in patients with a suspected therapy in partial and generalized seizures. A few primary brain tumor and symptomatic seizures studies demonstrated successful conversion to undergoing neurosurgery.[48] They concluded that monotherapy in refractory epilepsy.[42,43] Three after initiation of therapy with LEV, 100% of the studies with small number of patients demonstrated patients were seizure-free in the pre-surgery phase (3 its effectiveness as a single agent in partial days up to 4 weeks before surgery), 88% in the 48 h epilepsy.[42-44] Ben-Menachem et al. conducted a post-surgery phase and 84% in the early follow-up multicenter double blind trial to evaluate the efficacy phase (48 h to 4 weeks post surgery).[48] Treatment and tolerability of LEV monotherapy in refractory failure occurred in three patients even after dose partial epilepsy.[42] They concluded that in the LEV escalation to 3,000 mg/day.[48] Int J Med Biomed Res 2013;2(3):166-172 Swaroop et al.: Levetiracetam in the treatment of epilepsy according to the individual history, studies has According to a recent study by Weinstock et al., mild confirmed that prophylactic use of antiepileptic drug to moderate treatment emergent adverse events can reduce the incidence of post operative seizures.[56] occurred in 63% of enrolled subjects.[49] The most frequent of these were pyrexia and dry mouth. Most CONCLUSION
other treatment emergent adverse events were LEV is a novel, second generation antiepileptic drug. administration. They concluded that intravenous LEV It is approved for adjunctive therapy for adults with was well tolerated in children 1 month to 16 year.[49] partial, myoclonic, and generalized tonic clonic Another study by Ozkale et al., reported that in a seizures. It was proved efficacious as monotherapy in patient with multidrug refractory epilepsy and 3 mulitcenter studies and adjunctive therapy in 5 Ohtahara syndrome, accidental administration of LEV multicenter trials. These studies concluded that LEV in high dose of 300 mg/kg/d for 35 days showed no has similar efficacy as older AED's as in adverse effects.[50] Another review byet al., monotherapy. The advantages of LEV are its concluded that the current data leading to the minimal protein binding, lack of hepatic metabolism approval of LEV for use in infants and children with and twice daily dosing. The adverse reaction profile partial onset seizures is encouraging and more work of the drug is comparatively better than the older needs to be done about the efficacy across different AED's, except the psychiatric manifestations. These pediatric age groups.[51] manifestations are, however, found to be linked to past psychiatric history of the patients. These features ROLE IN THERAPY
of LEV make it an ideal drug for monothreapy. At LEV has been approved by European medicines monotherapy of LEV. Also, all the available agency (EMA) for use as a (i) monotherapy in the monotherapy studies have the drawback of having treatment of partial onset seizures with or without smaller sample size. secondary generalization in patients from 16 years of age with newly diagnosed epilepsy (ii) adjunctive REFERENCES
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J Neurooncol 2009; How to cite this article: Swaroop HS,
Ananya C, Nithin K, Jayashankar CA, Satish Franz K, Tatagiba M, Seifert V, Babu HV, Srinivas BN. Levetiracetam: A Weller M, Steinbach JP. Intravenous and oral levetiracetam in patients with a suspected primary brain Review of its use in the treatment of epilepsy. Int J Med neurosurgery: the HELLO trial. Acta Neurochir (Wien) 2013;2(3):166-172 2012;154:229-35. Conflict of Interest: None declared
Prospective open-label, This is an Open Access article distributed under the terms of the Creative Commons Attribution 3.0 License (http://creativecommons.org/licenses/by-nc-sa/3.0/) which permits unrestricted, non-commercial, share-alike use, distribution, and reproduction in any medium, provided the original work is properly cited. Int J Med Biomed Res 2013;2(3):166-172

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