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Ana José Fierro
Epilepsy is the world’s most frequent severe neurological chronic disorder, affecting some 40 million people.(1) Epilepsy is a chronic pathology of cerebral function characterised by recurrence of epileptic crisis or clinical manifestations resulting from an excessive neuronal discharge. It consists of paroxysmal episodes of motor, sensory or psychological disorders, with or without altered consciousness. In Spain, the incidence of epilepsy is 50 new cases per 100,000 inhabitants per year, with prevalence at five to ten cases per 1,000 inhabitants. Epilepsy is a disorder with important social and economic consequences, so there is a demand for more efficacious treatments with fewer adverse effects.(2)
A huge amount of experience has been gained in the use of classical antiepileptic drugs (AEDs), especially the four of greatest importance – phenobarbital, phenytoin, carbamazepine and valproate. The main problems with the majority of classical drugs – apart from the existence of a group of drug-resistant patients – are due to the pharmacokinetic characteristics of these drugs: firstly, they exert strong induction/inhibition of the cytochrome P450, making the use of AEDs concomitantly with other drugs difficult, and secondly, they bind to plasma proteins, necessitating monitoring of plasma levels. Furthermore, it is necessary to be aware of potential adverse reactions – haematological, hepatic or cutaneous – and those affecting the central nervous system.(2) The introduction of a new generation of drugs – oxcarbazepine, gabapentin, lamotrigine, levetiracetam, tiagabine, topiramate, zonisamide, vigabatrin and phelbamate – has, in some cases, led to improved tolerance, ease of use and reduction in potential adverse interactions, even though efficacy in patients with recently diagnosed epilepsy has not been shown to be greater than with classical AEDs.(3)
Levetiracetam is a pyrrolidine derivative whose molecular weight is 170.21 g/mol. Its chemical formula is C8H14N2O2.
Mechanism of action
Levetiracetam is chemically related to piracetam
(a nootropic drug). The exact mechanism of action by which levetiracetam induces protection preceding seizures is unknown. However, it does not seem to be related to the mechanisms identified for currently used drugs.(4) In vitro and in vivo experiences suggest that levetiracetam does not alter basic cellular characteristics and normal neurotransmission. Some in vitro studies have shown that levetiracetam affects intraneuronal levels of Ca(2+) through partial inhibition of currents of Ca2+ type N and by reducing the release of Ca(2+) from the intraneuronal reserve. Moreover, the drug partially inverts the reduction of GABA-dependent and glycine currents induced by zinc and beta-carbolines.
The complete and linear absorption of levetiracetam means its plasma levels can be predicted after oral administration, so plasma level monitoring is not required. Levetiracetam has an oral bioavailability of almost 100%. The steady state is reached after two days of treatment with twice-daily dosage. Levetiracetam does not strongly bind to plasma proteins and, because it is metabolised in the kidneys, the dose must be reduced in cases of impaired renal function.(2)
Serum concentrations of some AEDs were determined before and after adding treatment with levetiracetam in four phase III clinical trials in patients with refractory partial epilepsy who received stable treatment with AEDs. Levetiracetam neither increases nor diminishes steady-state concentrations of carbamazepine, phenytoin, valproic acid, lamotrigine, gabapentin, phenobarbital or primidone.(5) It was therefore not necessary to adjust doses of these AEDs after adding levetiracetam to or retiring it from the therapeutic regimen of the patient.
Levetiracetam is rapidly absorbed after oral doses of 250–5,000 mg. T(max) is reached 1.3 ± 0.7 hours after administration. C(max) is 31 μg/ml after single administration of 1,000 mg, and 43 μg/ml after 1,000 mg twice a day. The absorption rate was dose- and food-independent, although both factors reduced speed of absorption.
Neither levetiracetam nor its primary metabolite bind to plasma proteins to a significant degree (< 10%). Distribution volume is approximately 0.5–0.7 l/kg.
Levetiracetam metabolises by hydroxylation, hydrolysis of acetamide and opening of the pyrrolidine ring. Acetamide hydrolysis is the main metabolic path in humans (24% of dose) and it converts into the primary metabolite ucb L057. Data available indicate that hydrolysis of levetiracetam occurs through serinesterases but not through cholinesterases or carboxylesterases. No inhibition of cytochrome P450 isoforms has been detected.
The half-life of the drug was 7 ± 1 hours and did not change with dose, administration route or repeated administration. Total mean clearance was 0.96 ml/kg/min.The most important excretion pathway was the urinary one, reaching 95% of the dose. Renal clearances of levetiracetam and its metabolite ucb L057 were, respectively, 0.6 ml/kg/minand 4.2 ml/kg/min, indicating that levetiracetam is excreted through glomerular filtration and partial tubular reabsorption, while its metabolite is excreted through active tubular secretion and glomerular filtration.
A total of 904 patients were randomised to three pivotal trials. Before randomisation, all patients received stable doses of a maximum of two AEDs (N051 and N132) or one classical AED (N138). All efficacy analyses were performed on the “intention-
to-treat” population, defined as all patients randomised for treatment who at least had a seizure during the evaluation period. The primary parameter of efficacy was weekly frequency of partial seizure onset, calculated over the entire evaluation period. Secondary parameters of efficacy included a responder index (referring to patients who experienced a 50% reduction in frequency of onset of partial seizures).
A double-blind, multicentre, two-period, crossover study of three treatments with doses of 1 g/day and 2 g/day of levetiracetam against placebo was carried out on 324 patients.(6) Levetiracetam was added to a stable antiepileptic treatment. Regarding the primary efficacy variable, a statistically significant reduction was observed: reduction over placebo was 16.9% for levetiracetam 1 g and 18.5% for levetiracetam 2 g (p < 0.001). No significant differences were seen between the two levetiracetam groups. Responder rates were 22.8% for the 1 g/day group (p = 0.019), 31.6% for the 2 g/day group (p < 0.001) and 10.4% for the placebo group.
A multicentre, randomised, double-blind, placebo-controlled, parallel-group study was carried out on 294 adult patients with partial seizures who were refractory to standard AED therapy and taking a maximum of two classical AEDs.(7) Patients were randomised to 1 g/day or 3 g/day of levetiracetam or placebo. Regarding the primary efficacy variable, significantly lower seizure frequencies were observed in the two levetiracetam groups compared with the placebo group (p < 0.001 for both active groups). There was a trend towards a lower seizure frequency in the 3 g/day group compared to the 1 g/day group, but no statistically significant difference between the two doses was observed. The percentage of responders was 33% in the levetiracetam 1 g/day group and 39.8% in the 3 g/day group, compared with 10.8% for the placebo group. Both differences were statistically significant for the intention-to-treat population (p < 0.001). Health-related quality of life was not improved in the active groups.
A multicentre, double-blind, placebo-controlled, parallel-group study was carried out.(8) A total of 286 patients were randomised to either placebo or
3 g/day levetiracetam. The frequency of onset of partial seizures was lower in the levetiracetam group than in the placebo group (p < 0.001). The mean percentage of reduction in the frequency of onset of seizures in the addition period was 7.2% for the placebo group over 39.9% in the levetiracetam group (p < 0.001). The responder rate was 42.1% in the levetiracetam group over 16.7% in the placebo group (p < 0.001). The response to treatment (using six measures of improvement) was higher in the 3 g/day levetiracetam group over placebo (p < 0.001). During the monotherapy period the mean percentage of reduction of seizure frequency over the baseline period was 73.8% in the 3 g levetiracetam group and was statistically significant (p = 0.037). The responder rate in this period was 59.2% in the 3 g/day levetiracetam group.
A multicentre, randomised, double-blind, placebo-controlled study was carried out in Taiwan to assess the efficacy and safety of levetiracetam. In this study 94 patients with refractory partial-onset epilepsy took part. It was concluded that add-on therapy with levetiracetam with doses over 2,000 mg/day had significantly more effect than placebo and was usually well tolerated.(9)
A meta-analysis evaluating the three phase III clinical trials concluded that levetiracetam as adjunct therapy shows benefits in relation to the number of seizure-free days gained in patients with refractory epilepsy.(10)
Preliminary data show that levetiracetam can be useful in treating a wide variety of neuropathic pain syndromes and seems to be easier to use than oxcarbazepine, topiramate and zonisamide because it requires neither dose adjustment in cases of organic dysfunction nor laboratory monitoring, and it seems to be better tolerated than, and not to be associated with, unique toxicities observed with oxcarbazepine, topiramate and zonisamide.(11)
Because no clinical trial has been undertaken to compare new AEDs, indirect adjusted comparisons have been undertaken between levetiracetam and other AEDs using the results of a meta-analysis.(12) In the doses used, levetiracetam was more effective in relation to responder rate than gabapentin (odds ratio 2.64; CI 95% 1.51 – 4.63) and lamotrigine (odds ratio 1.86; CI 95% 1.04 – 3.34) and also well tolerated. The abandonment rate was lower for levetiracetam than for topiramate (odds ratio 0.52; CI 95% 0.29 – 0.93) and oxcarbazepine (odds ratio 0.55; CI 95% 0.33 – 0.92), with comparable efficacy. The study concludes that in order to confirm these findings, more comparative clinical trials and long-term studies are needed with these AEDs.
Approved indications and therapeutic uses
Indications approved in Spain are epilepsy, complex partial seizures and simple partial convulsions. The drug is also indicated as concomitant therapy in the treatment of seizures of partial onset with or without secondary generalisation. It is also used as treatment in acquired epileptic aphasia, bipolar disorder, manic bipolar disorder type I, migraine prophylaxis, myoclonus, neuropathic pain, adjunct therapy in partial seizure, post-herpetic neuralgia, convulsions and spasticity.
The most frequent secondary effects include somnolence, headache, asthenia and catarrhal episodes (not caused by neutropenia). Alterations in behaviour can be produced (irritability, agitation, anxiety and depression) at the start of treatment in 13% of patients and, in rare cases, psychotic episodes can arise.(2)
Levetiracetam showed a favourable safety profile in certain population groups, such as children, the elderly and patients with hepatic dysfunction. Some adjustments were necessary in patients with reduced clearance of creatinine.(13)
After analysing the data derived from four prospective, randomised and placebo-controlled studies, it has been concluded that therapy with clinically important doses of levetiracetam was not associated with significant weight changes.(14)
It is not very likely that levetiracetam interacts with other substances, or vice versa, because levetiracetam does not affect the glucoronidation of valproic acid and does not cause enzymatic induction in cultures of human hepatocytes.(15)
The increased cost of treating patients with refractory epilepsy with levetiracetam can be partially offset by a reduction in other direct medical costs, due to an increase in the number of seizure-free days. Moreover, potential savings can be anticipated with the assumption that use of levetiracetam can reduce the number of candidates for surgical evaluation or surgery, due to reduction in seizure frequency.(16) Wilby et al examined the efficacy, tolerance and cost-efficacy of the new AEDs (gabapentine, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate and vigabatrin).(17) This integrated economic analysis suggested that the new AEDs used as adjunct therapy could be cost-effective compared with these treatments alone, with a quality-adjusted life-year cost of £20,000. More direct comparisons are needed for the different AEDs within clinical trials considering different treatment sequences – not only in monotherapy, but also in combined therapy.
1. Diario Médico 07/07/2006;14.
2. Información Terapéutica del Sistema Nacional de Salud 2004;28;2:33-40.
3. Ther Drug Monit 2002;24;1:74-80.
4. EPARs for authorised medicinal products for human use. Scientific discussion of Keppra. 2004;1. Available from: www.emea.eu.int
5. Epilepsy Res 2005;64;1-2:1-11.
6. Epilepsia 2000;41;9:1179-86.
7. Neurology 2000;25;55;2:236-42.
8. Epilepsia 2000;41;10:1276-83.
9. Epilepsia 2006;47;1:72-81.
10. Epilepsia 2003;44;10:1350-52.
11. Am J Geriatr Pharmacother 2003;1;1:18-37.
12. Clin Neuropharmacol 2005;28;2:72-8.
13. Expert Opin Drug Saf 2004;3;5:415-24.
14. Epilepsy Res 2003;56;2-3:121-6.
15. Consejo General del Colegios Oficiales de Farmacéuticos. Catálogo de Especialidades Farmacéuticas: Colección Consejo Plus (General Council of the Official Schools of Pharmacists. Catalogue of pharmaceutical specialties: Council Plus Collection). Las Rozas, CGCOF, 2005;1907.
16. Pharmacoeconomics 2005;29;9:493-503.
17. Health Technol Assess 2005;9;15:1-157;iii-iv.