PDF VERSION OF SUMMARY SHEET AVAILABLE

Levetiracetam is ‘indicated as adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in patients with epilepsy.’¹

There are insufficient data to recommend the use of levetiracetam in children and adolescents under 16 years of age.¹

Epilepsy is a serious neurological disorder characterised by recurrent, spontaneous seizures. Seizures are classified into two main groups, generalised and partial seizures, according to the area of the brain in which the abnormal discharge originates.

If discharge starts in a localised area of the brain, this is called a partial seizure. During a simple partial seizure (SPS) consciousness is unimpaired. If discharge spreads and affects larger areas of the brain, consciousness may be impaired or lost, known as a complex partial seizure (CPS). A secondary generalised seizure (SGS) may develop if the epileptic activity spreads to the entire brain.^2,3

The aim of treatment in epilepsy is to prevent the occurrence of seizures and to achieve complete seizure control with minimum side effects. Most patients will respond to the established antiepileptics, e.g. sodium valproate, phenytoin, carbamazepine, but around 30% often require treatment with more than one antiepileptic drug (AED) and may continue to have seizures despite drug treatment.⁴

Levetiracetam, a pyrrolidone derivative chemically unrelated to existing antiepileptics, was launched in the UK in November 2000. The mechanism of action of levetiracetam is not known but it does not appear to involve inhibitory or excitatory neurotransmission.

The recommended initial dose of levetiracetam is 500mg twice daily (bd), which can be increased depending on clinical response and tolerance to a maximum of 1500mg bd. Dose changes can be made in 500mg bd increments or decrements every two to four weeks.¹

Dosage adjustment is required in patients with impaired renal function or severe hepatic impairment. Refer to the Summary of Product Characteristics for full guidance.

Three pivotal, fully published phase III studies (n = 904) compared adjunctive therapy with levetiracetam 500mg- 1500mg bd with placebo in patients with refractory partial epilepsy.^5,6,7

The 3 trials were of similar design. To be eligible for inclusion into the studies, patients were required to have a 1 to 2 year history of refractory partial epilepsy, despite continued treatment with at least one AED. In two of the studies, 62%⁶ and 76%⁵ of patients were taking two AEDs. The proportion of patients taking >1 AED was not stated in the third study.⁷ The AEDs taken by patients in the studies included carbamazepine, phenytoin, valproate, vigabatrin, lamotrigine, and gabapentin.

Each study had a baseline period (8-12 weeks) for prospective determination of seizure frequency, followed by randomisation into a double-blind add-on treatment phase. To be eligible for entry into the add-on phase of each study, patients were required to have two^6,7 or four⁵ seizures per 4-week period during the baseline phase. Patients were then randomised to add-on treatment with placebo or levetiracetam. Dose titration occurred over the first 4-weeks, followed by a 12-14 week evaluation period of add-on therapy.

The primary endpoint in two of the three studies was the reduction in weekly partial seizure frequency.^5,6 In the phase III trial conducted by Ben-Menachem et al,⁷ after completion of the add-on phase, patients who responded to treatment had their concomitant AED discontinued, and entered a phase of monotherapy with levetiracetam (or continued with placebo). Although this study also provided data on the efficacy of levetiracetam as add-on therapy, the primary endpoint was the percentage of patients completing the 12-week monotherapy phase relative to the number of patients randomised to receive study medication. Levetiracetam is not currently licensed as monotherapy for the treatment of epilepsy.

Results from the three pivotal clinical trials demonstrated that levetiracetam 500mg–1500mg bd significantly reduced weekly partial seizure frequency compared with placebo and baseline (p < 0.006). These reductions in weekly partial seizure frequency were greater with the higher dosage of levetiracetam across the studies.

A greater reduction in the weekly frequency of all partial seizure subtypes (SPS, CPS, and SGS) was apparent with levetiracetam 500mg–1500mg bd compared with placebo in the two studies where this was reported.^5,6 Not all reductions were statistically significant.

The 50% responder rate (the proportion of patients achieving a > 50% reduction in seizure frequency) was significantly higher with levetiracetam at all doses than with placebo across the studies (p < 0.019). The 50% responder rates ranged from 10.4%- 16.7% with placebo, and from 22.8%- 42.1% with levetiracetam 500- 1500mg bd, being greatest with the higher dosage.

A consistently higher number of patients became seizure-free with levetiracetam than placebo. This was only statistically significant with the 1500mg bd dose (p < 0.012). The proportion of seizure-free patients across the studies was 0- 0.9% with placebo, and 1.9%- 7.9% with levetiracetam (all doses).

A fourth study, which was only powered to assess safety and tolerability, provided additional data on the efficacy of levetiracetam 1000mg- 2000mg bd.⁸ Its findings were consistent with the results from the pivotal phase III trials.

The overall incidence of adverse events in the 4 published studies (the 3 pivotal studies and the safety and tolerability study) was similar across placebo and levetiracetam groups.

Adverse events observed consistently more frequently with levetiracetam 500mg–2000mg bd were somnolence, asthenia, headache, infection and dizziness. In the safety and tolerability study, the incidence of somnolence was greatest in the highest levetiracetam dosage group (2000mg bd). Conversely, asthenia was most commonly reported in patients in the lower dosage group (1000mg bd). Adverse events generally appeared within the first month of treatment.⁸ Somnolence was the most commonly reported reason for discontinuation in two of the four studies.^6,8 However, overall withdrawal rates across the studies were low; 6%- 14% with placebo and 8%- 18% with levetiracetam.

In clinical trials, levetiracetam did not influence the serum concentrations of concomitant AEDs (phenytoin, carbamazepine, valproate, phenobarbital, lamotrigine, gabapentin, and primidone). Additionally, these AEDs did not influence the pharmacokinetics of levetiracetam.¹

It is also known from clinical trials that levetiracetam at 1000mg/day did not influence the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel). The 2000mg daily dose did not influence the pharmacokinetics of digoxin or warfarin, or modify prothrombin times. Additionally, the pharmacokinetics of levetiracetam were unaffected by co-administration of digoxin, oral contraceptives, and warfarin.¹

At current prices, one years treatment costs:

• £602- £1807 with levetiracetam 500mg- 1500mg twice daily
• £193- £1343 with gabapentin 300mg- 2400mg daily, in divided doses
• £130- £1527 with lamotrigine 25mg- 400mg daily, in divided doses.

There are no data on which to base an assessment of the cost-effectiveness of levetiracetam as compared to the previously available add-on therapies.

Levetiracetam is an adjunctive therapy for the treatment of partial seizures.

In three pivotal placebo-controlled trials, treatment with levetiracetam 500mg-1500mg bd, in addition to concomitant antiepileptic therapy, significantly reduced the partial seizure frequency compared with placebo and baseline. The 50% responder rate was also significantly higher with levetiracetam at all doses than with placebo. A significant number of patients became seizure-free with the higher levetiracetam dose (1500mg bd) compared with placebo.

Adverse events observed more frequently with levetiracetam than placebo were somnolence, asthenia, headache, infection, and dizziness.

From the data available to date, levetiracetam does not appear to interact with other antiepileptic drugs.

Levetiracetam therefore offers an alternative add-on therapy for the treatment of partial epilepsy.

1. UCB Pharma Ltd. Keppra. Summary of Product Characteristics 2000.
2. Antiepileptic drugs and centrally acting muscle relaxants. In Rang H, Dale M, Ritter J, eds. Pharmacology, pp 566-78. London: Churchill Livingstone, 1999.
3. Michael T. Epilepsy (1) The Disease. Pharm J 1999;262:297-300.
4. Stephen L, Brodie M. New drug treatments for epilepsy. Prescribers' Journal 1998;38:98-106.
5. Shorvon SD, Lowenthal A, Janz D, Bielen E, Loiseau P. Multicenter double-blind, randomized, placebo-controlled trial of levetiracetam as add-on therapy in patients with refractory partial seizures. Epilepsia 2000;41(9):1179-86.
6. Cereghino JJ, Biton V, Abou-Khalil B, Dreifuss F, Gauer LJ et al. Levetiracetam for partial seizures. Neurology 2000;55:236-42.
7. Ben-Menachem E, Falter U. Efficacy and tolerability of levetiracetam 3000mg/d in patients with refractory partial seizures: a multicenter, double-blind, responder-selected study evaluating monotherapy. Epilepsia 2000;41(10):1276-83.
8. 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.

© MTRAC, Department of Medicines Management