The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 19 July 2006 Keppra 250 mg, film-coated tablets Box of 60 tablets (CIP code: 356 013-6) Keppra 500 mg, film-coated tablets Box of 60 tablets (CIP code: 356 016-5) Keppra 1000 mg, film-coated tablets Box of 60 tablets (CIP code: 356 022-5) Keppra 100 mg/ml oral solution Vial containing 300 ml (CIP code: 370 238-1) Keppra 100 mg/ml concentrate for infusion Vial containing 5 ml, box of 10 vials (CIP: 375 893-8) Applicant: UCB SA levetiracetam list I Dates of Marketing Authorisations: Keppra 250 mg, 500 mg, 1000 mg film-coated tablets: 29 September 2000 Keppra 100 mg/ml oral solution: 03 March 2003 Keppra 100 mg/ml concentrate for infusion: 29 March 2006 Date of amendment of Marketing Authorisation: Keppra 250 mg, 500 mg, 1000 mg film-coated tablets, and Keppra 100 mg/ml oral solution: 13 September 2005 (Extension of indication to children from the age of 4 years). Reason for request: Keppra 250 mg, 500 mg, 1000 mg film-coated tablets: inclusion on the list of drugs reimbursed by National Insurance and approved for hospital use in the extension of indication children from the age of 4 years". Keppra 100 mg/ml oral solution: inclusion on the list of drugs reimbursed by National Insurance and approved for hospital use Keppra 100 mg/ml concentrate for infusion: inclusion on the list of drugs approved for hospital use Health Technology Assessment Division 1
1 CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient levetiracetam 1.2. Background Not an original product 1.3. Indication Keppra is indicated as add-on therapy in the treatment of partial onset seizures with or without secondary generalisation in adults and children from 4 years of age with epilepsy. Keppra concentrate for infusion is an alternative for patients when they are temporarily unable to take the oral form. 1.4. Dosage The total daily dose should be divided into two equal doses. Conversion between oral and intravenous administration can be done directly without titration. The total daily dose and frequency of administration should be maintained. Keppra concentrate for infusion is for intravenous use only and the recommended dose must be diluted in at least 100 ml of a compatible diluent and administered intravenously as a 15-minute intravenous infusion. There is no experience with administration of intravenous levetiracetam for a longer period than 4 days. Adults ( 18 years) and adolescents (12 17 years) weighting 50 kg or more The initial therapeutic dose is 500 mg twice daily. This dose may be given right from the start of treatment. The daily dose may be increased up to 1500 mg twice daily, depending on clinical response. Any increase or decrease in the dose should be made in steps of 500 mg twice daily every 2 4 weeks. Elderly subjects (65 years and older) Adjustment of the dose is recommended in elderly patients with impaired renal function (see SPC). Children aged 4 11 years and adolescents (12 17 years) weighing less than 50 kg The initial therapeutic dose is 10 mg twice daily. The daily dose may be increased up to 30 mg twice daily, depending on clinical response and tolerability. The dose should not be increased or decreased in steps of more than 10 mg/kg twice daily every two weeks. The lowest effective dose should be used. Dosage in children 50 kg or greater is the same as in adults. Doctors should prescribe the most appropriate pharmaceutical form and strength according to weight and dose. 2
Dosage recommendations for children and adolescents Initial (10 mg/kg 2x/day) and maximum (30 mg/kg 2x/day) doses Weight (kg) Initial Dose (mg twice daily) Maximum 15 (1) 150 450 20 (1) 200 600 25 250 750 From 50 (2) 500 1500 (1) Children 20 kg or less should preferably start treatment with Keppra 100 mg/ml oral solution (2) Dosage in children and adolescents 50 kg or greater is the same as in adults. The graduated syringe for the oral form contains up to 1000 mg of levetiracetam (corresponding to 10 ml) with a graduation every 25 mg (corresponding to 0.25 ml). A Keppra concentrate vial contains 500 mg of levetiracetam in 5 ml (corresponding to 100 mg/ml). Children under 4 years: Keppra is not recommended due to insufficient data on efficacy and safety. Patients with renal impairment: the dose of levetiracetam should be adjusted according to renal function (see SCP). Patients with hepatic impairment: dose adjustment is recommended in patients with severe hepatic impairment (see SPC). 2 SIMILAR MEDICINAL PRODUCTS 2.1 ATC Classification (2005) N N03 N03A N03AX N03AX14 : NERVOUS SYSTEM : ANTIEPILEPTICS : ANTIEPILEPTICS : OTHER ANTIEPILEPTICS : Levetiracetam 2.2 Medicines in the same therapeutic category Not applicable 2.3 Medicines with a similar therapeutic aim Antiepileptics indicated in children in the treatment of partial-onset seizures with or without secondary generalisation: Only in combination with other antiepileptics - Gabapentin - Neurontin and generic versions 600 mg, 800 mg, film-coated tablets, and Neurontin 100 mg, capsules (in children from the age of 3 years) 3
- Tiagabine - Gabitril 5 mg, 10 mg, and 15 mg, scored film-coated tablets (in adolescents over the age of 12 years) - Lamotrigine - Lamictal and generic versions, 5 mg, 25 mg, 50 mg, 100 mg and 200 mg, dispersible or chewable tablets and Lamictal 2 mg, dispersible tablets (in children 2 years or older) Existing medicinal product in the form of oral solution: - Vigabatrin - Sabril 500 mg, film-coated tablets and Sabril 500 mg, granulate for oral solution (in infants and children, only as a last resort) As a first- or second-line monotherapy and as add-on therapy - Phenobarbital - Gardenal 10 mg, 50 mg and 100 mg, tablets (in infants and children) - Phenytoin - Di-Hydan 100 mg, scored tablets (in infants and children) - Primidone - Mysoline 250 mg, scored tablets (in infants and children) - Topiramate - Epitomax 50 mg, 100 mg, and 200 mg, film-coated tablets (only as secondline therapy in children 2 years old and over) - Medicinal products in an oral solution form: Carbamazepine - Tegretol 100 mg/5 ml, oral suspension, Tegretol 200 mg, scored tablets and Tegretol SR 200 mg and 400 mg, filmcoated tablets (in infants and children) - Valproic acid - Depakine 200 mg and 500 mg, gastro-resistant tablets, Depakine 57.64 mg/ml, syrup, Depakine 200 mg/ml, oral solution and Depakine Chrono 500 mg, SR tablets (in infants and children) - Oxcarbazepine - Trileptal 150 mg, 300 mg, 600 mg, film-coated tablets and Trileptal 60 mg/ml, oral suspension (in children aged 6 years and over) Injected forms: - Valproic acid - Depakine 400 mg/4 ml, preparation for intravenous injection (in infants and children) - Phosphenytoin - Prodilantin 75 mg/ml, solution for injection (in children aged 5 years and over) - Phenobarbital - Gardenal 40 mg/2 ml and 200 mg/4 ml, injected forms (in infants and children 3 ANALYSIS OF AVAILABLE DATA Keppra, oral forms The data submitted by the company consist of studies carried out in children: - 2 pharmacokinetic studies, not discussed in the rest of this Opinion, - 1 phase III trial comparing levetiracetam with placebo (N159), - 1 study of long-term safety. Keppra, injected form No data on efficacy and safety in children have been submitted. 4
3.2 Efficacy Trial N159 1,2,3 This randomised, placebo-controlled, double-blind, phase III trial evaluated the efficacy and tolerability of levetiracetam as add-on therapy with one or two antiepileptics in the treatment of treatment-resistant partial-onset seizures in children aged 4 16 years. Trial design The trial lasted 28 weeks. The dose of levetiracetam used was 20 mg/kg/day for 2 weeks, followed by 40 mg/kg/day for 2 weeks (titration period). If this was well tolerated, 60 mg/kg/day were given for 10 weeks (evaluation period). Inclusion criteria Children aged 4 16 years: - having partial-onset seizures, with or without secondary generalisation, not controlled by antiepileptic therapy, - having at least 4 seizures a week before randomisation, - treated with a maximum of 2 antiepileptics at inclusion (intermittent prescription of benzodiazepine was permitted as a third antiepileptic. If benzodiazepine was prescribed regularly, it was classed as one of the two antiepileptics). Endpoints - The primary endpoint was frequency of seizures per week during the treatment period (14 weeks). - Secondary endpoints included the proportion of responders (percentage of patients with a decrease of more than 50% in number of seizures per week compared with baseline) and the percentage of seizure-free patients from the start of the evaluation period. The intent-to-treat (ITT) population was analysed. Results - 216 patients included - ITT population: n = 198 (placebo: n = 97, levetiracetam: n = 101) - At inclusion, all patients were treated with at least one antiepileptic: 30.7% of children in the levetiracetam group were treated with a single antiepileptic, compared with 37.1% in the placebo group, 60.4% in the levetiracetam group were treated with two antiepileptics, compared with 55.7% in the placebo group, 8.9% of children in the levetiracetam group were also treated with a benzodiazepine, compared with 7.2% in the placebo group. 1 Evaluation of the efficacy and tolerability of levetiracetam add-on treatment in refractory pediatric patients with partial onset seizures: a 28-week double-blind, placebo-controlled multi-center trial. RRCE04E2401 Trial N159 2 Glauser, Gauer, Chen, and LEV N159 pediatric study group. Multicenter, double-blind, placebo-controlled trial of add-on levetiracetam (Keppra ) therapy (up to 60 mg/kg/day) in pediatric patients with refractory partial epilepsy. Epilepsia 2004; 45 Suppl 7: 186. 3 Glauser TA et al. Double-blind placebo-controlled trial of add-on levetiracetam in pediatric partial seizures. Neurology, (1 of 2) 2006: 1654-60. 5
Patient characteristics Levetiracetam (n = 101) Placebo (n = 97) Median age (years) 10.4. 9.7. Most common concomitant antiepileptics (%) Carbamazepine Topiramate Valproate Lamotrigine Oxcarbazepine 34.7 28.7 25.7 22.8 12.9 Median number of seizures/week 4.7 5.3 38.1 32.0 28.9 20.6 10.3 Statistical analysis (Kruskal-Wallis test) showed that the reduction in frequency of weekly seizures with levetiracetam (-1.6 seizures) was greater than that observed with placebo (-0.7 seizure). There was a higher percentage of responders in the levetiracetam group than in the placebo group: - 44.6% (45 patients) in the levetiracetam group, - 19.6% (19 patients) in the placebo group, Seven patients in the levetiracetam group were seizure-free compared with 1 patient in the placebo group. 3.3 Undesirable effects In the studies submitted in the dossier, the safety profile of levetiracetam (tablet form) in children was the same as that for adults. Trial N159 Frequency of main undesirable events during treatment (%) Levetiracetam Placebo Infection 28.7 28.9 Drowsiness 22.8 11.3 Accidental injuries 16.8 10.3 Vomiting 14.9 13.4 Headache 13.9 14.4 Five patients treated with levetiracetam discontinued treatment because of adverse events compared with nine patients in the placebo group. 55.4% patients in the levetiracetam group reported adverse events possibly related to treatment compared with 40.2% in the placebo group. 6
Open-label study of long-term safety This study was carried out in 223 children, 139 of whom had already received levetiracetam for between 6 and 14 weeks. Mean follow-up was 18 months. Overall, 97% of the children (216/223) experienced at least one adverse event during the treatment period. The most common adverse events were: - infection 52.0% - fever 24.7% - accidental injury 21.1% - headache 21.1% - otitis media 21.1% - drowsiness 20.6% - pharyngitis 20.6% 11 children discontinued treatment with levetiracetam because of an adverse event. The dosage was reduced in 50 children. According to PSUR [Periodic Safety Update Report] data from 30 November 1999 to 31 August 2004, the main adverse events reported in children (aged 1 month to 16 years) treated with levetiracetam were psychiatric disorders (29%) and neurological disorders (17%). One case of suicide was reported. 3.4 Conclusion The results of trial N159 showed that weekly frequency of partial-onset seizures decreased by -1.6 seizures in patients treated with levetiracetam compared with -0.7 seizures in patients treated with placebo. The profile of adverse events reported during the treatment period was the same for both groups. The main adverse events reported with levetiracetam were neurological and mental disorders. 4 TRANSPARENCY COMMITTEE CONCLUSIONS 4.1 Actual benefit Epileptic seizures are symptoms of a very wide range of heterogeneous disorders. Epilepsy is defined as the spontaneous medium and long-term seizure repetition. It can cause marked deterioration in the patient's quality of life. In children, epilepsy and its treatment can have major repercussions on the different stages of cognitive, behaviour and social acquisition. These drugs are given as preventive therapy. They are second-line drugs. The efficacy/undesirable effects ratio is high. Alternative drugs are available. 7
Public health benefit Burden of the disease Public health need Anticipated impact of Keppra in this indication Conclusion Partial epilepsy is a common disorder. Repeated seizures in some patients are likely to cause marked deterioration in quality of life. Overall, partial epilepsy is a moderate burden on public health. The burden corresponding to the population of children suffering from partial epilepsy after failure of monotherapy is small because of the small number of patients concerned. There is a need because pharmacoresistant partial epilepsy is still common and causes major incapacity. The need is particularly marked in children as there are few treatment options. It cannot be quantified. One may assume that Keppra will have an impact on morbidity (including quality of life) but this has not yet been verified in real-life practice. At population scale, this impact can only be small and it is not guaranteed. Making Keppra available should therefore provide a partial response to the identified need. In the current state of knowledge and taking account of the other drugs currently available, a public health benefit is expected for Keppra. This benefit is minor. The level of actual benefit for these medicinal products is substantial. 4.2 Improvement in actual benefit Keppra in oral form contributes a level III improvement in actual benefit in the extended indication in view of the low risk of pharmacokinetic interactions with levetiracetam and the lack of pharmaceutically appropriate third-generation antiepileptics for use in children, Keppra 100 mg/ml oral solution, an addition to the current Keppra range of 250 mg, 500 mg and 100 mg film-coated tablets, does not contribute any improvement in actual benefit (level V) in adults. Keppra 100 mg/ml concentrate for infusion contributes a level IV improvement in actual benefit in this indication in view of the absence of injected formulations of thirdgeneration antiepileptics. 4.3 Therapeutic use 4 The 2004 French consensus conference established that the management strategy for pharmacoresistant partial epilepsy in adults also applied to children, with features.. First-line drugs recommended as monotherapy are carbamazepine or valproic acid because their benefit-risk ratio is better than that of phenytoin and phenobarbital (Grade C recommendation). 4 Fédération Française de Neurologie (FFN) and the Ligue Française contre l Epilepsie (LFCE). Proceedings of a consensus conference, Prise en charge des épilepsies partielles pharmaco-résistantes [Management of drugresistant partial epilepsy]. ANAES, March 2004. 8
Monotherapy should use optimum-dose carbamazepine at least once (expert panel opinion). Carbamazepine should be prescribed with caution in children because of the risks of exacerbation of some types of epilepsy. Unlike in adults, vigabatrin could be used to treat drug-resistant partial epilepsy in infants, but its prescription remains restricted because of the risk of onset of irreversible visual field constriction (AFSSAPS press release, September 2002). Among the new antiepileptics, lamotrigine was the subject of a pharmacovigilance information letter to prescribers (December 2005) because of serious dermatologic adverse events, mainly toxic epidermal necrolysis. Combination therapy should only be used at least after monotherapy has failed at least twice. There are insufficient data to support any particular combination of drugs. Prescription of the combination valproate-lamotrigine is governed by specific rules because of the risk of dermatologic toxicity from lamotrigine. The combination of two antiepileptics chosen should ideally include antiepileptics which are not enzyme inducers, which are rapidly titrated, and which avoid the need for a lunchtime midday dose. Combinations of more than two antiepileptic drugs are not recommended. If one or more forms of combination therapy fail, epilepsy and its treatment should be reassessed at a specialist centre. An injected form is recommended in acute symptomatic epileptic seizures if an injected benzodiazepine is inappropriate. In addition, it is an alternative pharmaceutical form when the oral route cannot be used. 4.4 Target population Keppra is indicated as add-on therapy in children aged 4 years or over with epilepsy, in the treatment of partial-onset seizures with or without secondary generalisation. The target population for Keppra has been estimated from the following data [INSEE, 2005 demographic data; ANAES 2004]: - Number of children aged 4 16 (January 1, 2006): 9 730 000 - Prevalence of epilepsy: 5-7 - Frequency of cases of partial-onset seizures: 60% - Effectiveness of monotherapy about 70-80% of cases Add-on therapy with Keppra will be indicated in about 20-30% of these cases. The number of children likely to be given Keppra as add-on therapy after failure of monotherapy would therefore be between 5840 and 12 300. 4.5 Transparency Committee recommendations The Committee recommended inclusion on the list of medicines reimbursed by National Insurance and on the list of medicines approved for use by hospitals and various public services of Keppra 250 mg, 500 mg and 1000 mg, film-coated tablets in the extended indication of children aged 4 years and over. The Committee recommended inclusion on the list of medicines reimbursed by National Insurance of Keppra 100 mg/ml oral solution and on the list of medicines approved for use by hospitals and various public services of Keppra 100 mg/ml oral solution and of Keppra 100 mg/ml concentrate for infusion in the indication. 9
The Transparency Committee asked for the long-term study currently in progress to monitor adults treated with Keppra to be extended to children. This study should make it possible to: - establish the profile of patients treated (sociodemographic data, history, diagnosis by a specialist in epilepsy, concomitant disorders, etc), - establish prescribing rules (indication, dosage, concomitant prescription, etc) and a treatment strategy, - confirm that Keppra is effective in real-life practice using criteria yet to be defined by the Scientific Committee. The study duration should be established by an independent scientific committee, based on evidence, and should be sufficient to satisfy the Committee's request. 4.5.1 Packaging: Suitable for the prescription conditions. 4.5.2 Reimbursement rate: 65% 10