, Volume 60, Issue 4, pp 871-893
Date: 17 Sep 2012

Levetiracetam

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Summary

Abstract

Levetiracetam, the S-enantiomer of α-ethyl-2-oxo-1-pyrollidine acetamide, is approved for use as adjunctive therapy in adult patients with partial onset seizures.

Oral levetiracetam 1000, 2000 and 3000 mg/day administered as adjunctive therapy for up to 18 weeks significantly increased responder rates and reduced seizure frequency compared with placebo in 3 well designed pivotal trials in adults with treatment-refractory partial seizures with or without secondary generalisation. Levetiracetam 3000 mg/day also significantly increased the number of seizure-free patients, but the effects of levetiracetam 1000 and 2000 mg/day on this end-point were unclear. Effects on seizure severity were not assessed in these trials.

Although not yet approved as monotherapy or for use in paediatric patients, efficacy was observed with levetiracetam 3000 mg/day as monotherapy in adult patients with refractory partial seizures with or without secondary generalisation and with the 10 to 40 mg/kg/day dosage as adjunctive therapy in children with refractory partial seizures. However, these data are limited.

Oral levetiracetam 1000, 2000 and 3000 mg/day as adjunctive therapy is generally well tolerated with an overall incidence of adverse events similar to that observed with placebo. The most commonly reported events in individual clinical trials were CNS-related and included somnolence, asthenia, headache and dizziness.

Levetiracetam administered as adjunctive therapy does not appear to interact with other anticonvulsant drugs, and no clinically relevant interactions were observed between levetiracetam and digoxin, warfarin or probenecid; oral contraceptive protective efficacy was also not affected by levetiracetam.

Conclusions: Levetiracetam is a new anticonvulsant agent with a favourable tolerability profile and a low potential for drug interactions. It has shown efficacy as adjunctive therapy in patients with treatment-refractory partial onset seizures with or without secondary generalisation in clinical trials. Direct comparative trials with other anticonvulsant agents are not yet available, but placebo-controlled clinical evidence to date suggests that levetiracetam (1000, 2000 and 3000 mg/day) is a useful option as adjunctive therapy in patients with this subtype of epilepsy.

Pharmacodynamic Properties

Although the exact mechanism of action of levetiracetam is yet to be defined, various theories have been proposed including changes in γ-aminobutyric acid (GABA) metabolism and turnover, inhibition of depolarising ion currents, calcium channel-dependent effects and dopaminergic activation. Levetiracetam appears to act via a specific binding site in the brain which is present predominantly in the membranes of the CNS, as observed in a single in vitro study. In this study, compounds structurally related to levetiracetam, but not conventional anti-convulsant drugs, showed some affinity for the same binding site.

Levetiracetam was effective in animal models of partial seizures with or without secondary generalisation (especially in amygdala-kindled rats and pilocarpine- and kainic acid-induced seizures in rats). Levetiracetam appeared to be more effective in phenytoin nonresponders than phenytoin responders in 1 study.

Oral or intraperitoneal levetiracetam inhibited tonic seizures induced audiogenically, electrically and chemically in most rodent models, but effects on clonic seizures appeared to be less marked.

Levetiracetam is active in models of chronic epilepsy but not those of acute seizures.

Levetiracetam appears to possess antiepileptogenic properties according to rodent studies. Intraperitoneal levetiracetam prevented the induced increases in seizure severity and duration of after discharges and inhibited induced clonic convulsions.

No detrimental cognitive effects were observed with levetiracetam (500, 1000 or 1500 mg/day for 1 week) administered as adjunctive therapy to 10 patients with partial (with or without secondary generalisation) or generalised seizures.

Tolerance did not develop after 14 or 28 days’ treatment with levetiracetam in 2 studies in rodent models with chemically induced seizures, but tolerance was observed after 10 to 21 days’ treatment in another study in amygdala-kindled rats.

Pharmacokinetic Properties

Levetiracetam (250 to 5000mg) is rapidly and almost completely absorbed after oral administration, and the absolute oral bioavailability is almost 100%. Maximum plasma concentrations (Cmax) and area under the plasma concentration-time curve (AUC) increase dose-dependently over the 500 to 5000mg range, and steady state is achieved after 2 days.

Levetiracetam is only minimally bound to plasma proteins (<10%) and appears to cross the blood-brain barrier.

Levetiracetam mainly undergoes renal elimination with about two-thirds of an administered dose recovered in the urine as unchanged drug and about one-quarter as inactive metabolites. Metabolism is not hepatic but primarily occurs via enzymatic hydrolysis in a number of tissues including blood cells. Levetiracetam is rapidly cleared after oral administration. Its terminal elimination half-life (t1/2β) is independent of dose and ranges from 6 to 8 hours; this value increases to about 10 to 11 hours in elderly patients.

Some pharmacokinetic changes occur in mild to severe renal impairment; Cmax and the AUC of levetiracetam were higher and t1/2β was longer at steady state. In patients with anuric end-stage renal impairment undergoing haemodialysis, the clearance of levetiracetam was reduced (by ≈70%) versus values in healthy volunteers and t1/2β during the period between dialysis treatments was increased to ≈25 hours. Mild to moderate hepatic impairment does not significantly affect the pharmacokinetics of levetiracetam. Changes in various parameters (e.g. AUC, t1/2β and total body clearance) were noted in patients with severe hepatic impairment but may have been associated with concomitant renal disease.

In children with partial seizures, Cmax and AUC of a single oral dose of adjunctive levetiracetam (adjusted for a 1 mg/kg dose) were lower and apparent total body clearance (of a ≈20 mg/kg dosage) was higher but t1/2β was similar to values observed in adults with epilepsy.

Levetiracetam (500 to 4000 mg/day for up to 48 weeks) administered as adjunctive therapy does not appear to interact with other anticonvulsant drugs, as observed in studies in patients predominantly with refractory partial seizures with or without secondary generalisation. Similarly, no interaction was observed between single dose levetiracetam 250 to 1000mg and stable regimens of valproic acid 200 to 2500mg, ethosuximide 500mg or phenobarbital 100mg in patients with photosensitive epilepsy. No clinically relevant interactions were observed between levetiracetam 2000 mg/day and digoxin or warfarin. Probenecid increased the plasma concentrations of the major (inactive) metabolite of levetiracetam although the clinical relevance of this is unclear. In addition, levetiracetam (500mg twice daily for 21 days) does not appear to affect the protective efficacy of oral contraceptives.

Therapeutic Efficacy

The anticonvulsant efficacy of orally administered adjunctive levetiracetam in patients with refractory partial seizures (simple and complex) with or without secondary generalisation has been demonstrated in 3 well designed, placebocontrolled, pivotal trials.

In these trials in 273 to 302 evaluable patients (286 to 324 patients initially randomised), levetiracetam 1000, 2000 and 3000 mg/day for up to 18 weeks was significantly more effective than placebo at reducing seizure frequency and increasing responder rates (defined as the percentage of patients with a ≥50% reduction in seizure frequency versus baseline) during or after the double-blind treatment. The percentage reduction in partial seizure frequency over placebo ranged from 16.4 to 27.7% with levetiracetam (1000 to 3000 mg/day). The number of seizure-free patients was significantly greater with levetiracetam 3000 mg/day than with placebo, but effects of the 1000 and 2000 mg/day dosages on this end-point were not clear.

The efficacy of levetiracetam was not influenced by seizure subtype in 1 trial, but in another trial the frequency of complex partial and secondary generalised seizures, but not that of simple partial seizures, was significantly reduced versus placebo.

In a supportive trial (n = 86), levetiracetam 2000 mg/day significantly increased responder rates and appeared to reduce seizure frequency and increase the number of seizure-free patients compared with placebo. Increasing the dosage from 2000 to 4000 mg/day does not appear to provide any additional benefit in terms of responder rates based on data from the nonblind phase of this trial.

Seizure severity was not assessed in most trials. However, the severity of seizures was generally unchanged after 16 weeks’ treatment with levetiracetam 500 to 2000 mg/day in a small (n = 9 to 17 at the different dosage levels) early pilot trial in patients predominantly with refractory partial seizures with or without secondary generalisation. Similarly, quality of life was only assessed in 1 trial in which significant improvements from baseline were observed with levetiracetam 1000 and/or 3000 mg/day in seizure worry and overall quality of life on the 7-item QOLIE-31 questionnaire. A significantly greater improvement was observed for most parameters in levetiracetam responders compared with nonresponders.

The clinical benefits of levetiracetam 1000 and 3000 mg/day appear to be maintained for up to 2 years in terms of seizure frequency according to 1 large trial.

Limited data suggest that levetiracetam may be effective when used as monotherapy in adults, and as adjunctive therapy in children with refractory partial seizures.

Tolerability

The overall incidence of adverse events with adjunctive levetiracetam 1000, 2000 and 3000 mg/day was similar to that with placebo (55 to 89.1% vs 53 to 88.4%) when administered for up to 24 weeks in patients predominantly with refractory partial seizures with or without secondary generalisation. In these trials, CNS-related adverse events were generally the most commonly reported and included somnolence, asthenia, headache and dizziness. The incidence of accidental injury was more common with placebo than with levetiracetam 1000, 2000 and 3000 mg/day in 3 trials but appeared to be similar between levetiracetam 1000 or 2000 mg/day and placebo in another trial.

The incidence of serious adverse events with levetiracetam (1000 to 3000 mg/day) was 2 to 7.7% which was broadly similar to that observed with placebo (1 to 10.5%).

No clinically significant changes were observed in laboratory parameters, physical or neurological examinations, ECG assessments or vital signs with any dosage of levetiracetam.

No serious treatment-related adverse events were reported after 12 weeks’ of levetiracetam 3000 mg/day monotherapy in 1 trial. When administered as adjunctive therapy to children with refractory partial seizures in 1 trial, adverse events reported with levetiracetam (40 mg/kg/day for 8 weeks) were generally similar to those observed in studies in adult patients.

Dosage and Administration

Levetiracetam is indicated for use as adjunctive therapy in adult patients with partial seizures. Treatment is initiated with a 1000 mg/day dosage and can be increased by l000mg every 2 to 4 weeks to a maximum of 3000 mg/day. The daily dosage should be administered in 2 divided doses. As with other anti-convulsant drugs, levetiracetam withdrawal (if necessary) should be performed gradually to reduce the risk of increased seizure frequency.

Dosage reduction is not necessary in patients with hepatic impairment, but dosage should be reduced in patients with impaired renal function based on individual creatinine clearance levels. A 750mg loading dose is recommended on the first day of treatment in patients undergoing dialysis according to European data, and a supplemental 250 or 500mg dose is recommended after dialysis. Similarly, a dosage reduction may be necessary in elderly patients if renal clearance is reduced.

The use of levetiracetam in children (<16 years) has not yet been established. Administration during pregnancy and to nursing mothers needs to be considered carefully because use in these populations has also not been well established.

Various sections of the manuscript reviewed by: E. Ben-Menachem, Department of Clinical Neuroscience, Sahlgrenska University Hospital, Gothenburg, Sweden; R. Beran, Neurologist, Chatswood, New South Wales, Australia; J. Cereghino, Epilepsy Center, Oregon Health Sciences University, Portland, Oregon, USA; L. Cohen, University of Cincinnati College of Medicine and Pharmacy, Cincinnati, Ohio, USA; W. Löscher, Department of Pharmacology, Toxicology and Pharmacy, School of Veterinary Medicine, Hanover, Germany; P. Patsalos, Pharmacology and Therapeutics Unit, Institute of Neurology and Neurosciences, London, England; R. Riva, Institute of Clinical Neurology, University of Bologna, Bologna, Italy.

Data Selection

Sources: Medical literature published in any language since 1983 on levetiracetam, identified using AdisBase (a proprietary database of Adis International, Auckland, New Zealand), Medline and EMBASE. Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: AdisBase search terms were ‘levetiracetam’ or ‘UCB-L059’ or UCBL-059’. Medline search terms were ‘levetiracetam’ or ‘UCB L059’. EMBASE search terms were ‘levetiracetam’ or ‘L 059’ or ‘UCB 059’ or ‘UCB L059’. Searches were last updated 18 Sep 2000.
Selection: Studies in patients with refractory partial seizures who received adjunctive levetiracetam. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Levetiracetam, epilepsy, partial seizures, pharmacodynamics, pharmacokinetics, therapeutic use, treatment, tolerability, dosage and administration.