- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Tablets:Each film-coated tablet contains 250 mg levetiracetam, 500 mg levetiracetam, 750 mg levetiracetam or 1000 mg levetiracetam.Excipient with known effect:Keppra 750 mg film-coated Tablets: Each film-coated tablet contains 0.19 mg of sunset yellow FCF (E110).
Oral solution:Each ml contains 100 mg levetiracetam.Excipients: methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216) and 300 mg maltitol liquid.
Solution for infusion:Each ml contains 100 mg of levetiracetam.Each 5 ml vial contains 500 mg of levetiracetam.Excipients:Each vial contains 19 mg of sodium.For thefull list of excipients, see section 6.1.
Film-coated tablet:Blue, oblong, scored and debossed with the code ucb and 250 on one side.Yellow, oblong, scored and debossed with the code ucb 500 on one side. Orange, oblong, scored and debossed with the code ucb 750 on one side. White, oblong, scored and debossed with the code ucb 1000 on one side.
Oral solution:Clear liquid.
Concentrate for solution for infusion (sterile concentrate).Clear, colourless, concentrate.
Monotherapy for adults and adolescents from 16 years of ageThe recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily.
Add-on therapy for adults (≥18 years) and adolescents (12 to 17 years) weighing 50 kg or moreThe initial therapeutic dose is 500 mg twice daily. This dose can be started on the first day of treatment. Depending upon the clinical response and tolerability, the daily dose can be increased up to 1,500 mg twice daily. Dose changes can be made in 500 mg twice daily increases or decreases every two to four weeks.
Duration of treatmentThere is no experience with administration of intravenous levetiracetam for longer period than 4 days.
Elderly (65 years and older)Adjustment of the dose is recommended in elderly patients with compromised renal function (see Renal impairment below).
Renal impairmentThe daily dose must be individualised according to renal function. For adult patients, refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr in ml/min may be estimated from serum creatinine (mg/dl) determination, for adults and adolescents weighting 50 kg or more, the following formula:Dosing adjustment for adult and adolescents patients weighing more than 50 kg with impaired renal function:
|Group||Creatinine clearance (ml/min/1.73m2)||Dose and frequency|
|Normal Mild Moderate Severe End-stage renal disease patients undergoing dialysis (1)||> 80 50-79 30-49 < 30 -||500 to 1,500 mg twice daily 500 to 1,000 mg twice daily 250 to 750 mg twice daily 250 to 500 mg twice daily 500 to 1,000 mg once daily (2)|
|Group||Creatinine clearance (ml/min/1.73 m2)||Dose and frequency (1)|
|Infants 1 to less than 6 months||Infants 6 to 23 months, children and adolescents weighing less than 50 kg|
|Normal||> 80||7 to 21 mg/kg (0.07 to 0.21 ml/kg) twice daily||10 to 30 mg/kg (0.10 to 0.30 ml/kg) twice daily|
|Mild||50-79||7 to 14 mg/kg (0.07 to 0.14 ml/kg) twice daily||10 to 20 mg/kg (0.10 to 0.20 ml/kg) twice daily|
|Moderate||30-49||3.5 to 10.5 mg/kg (0.035 to 0.105 ml/kg) twice daily||5 to 15 mg/kg (0.05 to 0.15 ml/kg) twice daily|
|Severe||< 30||3.5 to 7 mg/kg (0.035 to 0.07 ml/kg) twice daily||5 to 10 mg/kg (0.05 to 0.10 ml/kg) twice daily|
|End-stage renal disease patients undergoing dialysis||--||7 to 14 mg/kg (0.07 to 0.14 ml/kg) once daily (2) (4)||10 to 20 mg/kg (0.10 to 0.20 ml/kg) once daily (3) (5)|
Hepatic impairmentNo dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate the renal insufficiency. Therefore a 50 % reduction of the daily maintenance dose is recommended when the creatinine clearance is < 60 ml/min/1.73 m2.
Paediatric populationThe physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to age, weight and dose.The tablet formulation is not adapted for use in infants and children under the age of 6 years. Keppra oral solution is the preferred formulation for use in this population. In addition, the available dose strengths of the tablets are not appropriate for initial treatment in children weighing less than 25 kg, for patients unable to swallow tablets or for the administration of doses below 250 mg. In all of the above cases Keppra oral solution should be used.The safety and efficacy of Keppra concentrate for solution for infusion in infants and children less than 4 years have not been established.
MonotherapyThe safety and efficacy of Keppra in children and adolescents below 16 years as monotherapy treatment have not been established.There are no data available.
Add-on therapy for children aged 4 to 11 years and adolescents (12 to 17 years) weighing less than 50 kgKeppra oral solution is the preferred formulation for use in infants and children under the age of 6 years. The initial therapeutic dose is 10 mg/kg twice daily. Depending upon the clinical response and tolerability, the dose can be increased up to 30 mg/kg twice daily. Dose changes should not exceed increases or decreases of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used.Dose in children 50 kg or greater is the same as in adults.Dose recommendations for infants from 6 months of age, children and adolescents:
|Weight||Starting dose: 10 mg/kg twice daily||Maximum dose: 30 mg/kg twice daily|
|6 kg (1)||60 mg (0.6 ml) twice daily||180 mg (1.8 ml) twice daily|
|10 kg (1)||100 mg (1 ml) twice daily||300 mg (3 ml) twice daily|
|15 kg (1)||150 mg (1.5 ml) twice daily||450 mg (4.5 ml) twice daily|
|20 kg (1)||200 mg (2 ml) twice daily||600 mg (6 ml) twice daily|
|25 kg||250 mg twice daily||750 mg twice daily|
|From 50 kg (2)||500 mg twice daily||1,500 mg twice daily|
Add-on therapy for infants aged from 1 month to less than 6 month.The oral solution is the formulation to use in infants.The initial therapeutic dose is 7 mg/kg twice daily. Depending upon the clinical response and tolerability, the dose can be increased up to 21 mg/kg twice daily. Dose changes should not exceed increases or decreases of 7 mg/kg twice daily every two weeks. The lowest effective dose should be used.Infants should start the treatment with Keppra 100 mg/ml oral solution.Dose recommendations for infants aged from 1 month to less than 6 months:
|Weight||Starting dose: 7 mg/kg twice daily||Maximum dose: 21 mg/kg twice daily|
|4 kg||28 mg (0.3 ml) twice daily||84 mg (0.85 ml) twice daily|
|5 kg||35 mg (0.35 ml) twice daily||105 mg (1.05 ml) twice daily|
|7 kg||49 mg (0.5 ml)twice daily||147 mg (1.5 ml) twice daily|
Method of administration - tabletsThe film-coated tablets must be taken orally, swallowed with a sufficient quantity of liquid and may be taken with or without food. The daily dose is administered in two equally divided doses.
Method of administrationThe oral solution may be diluted in a glass of water or baby's bottle and may be taken with or without food. A graduated oral syringe, an adaptor for the syringe and instructions for use in the package leaflet are provided with Keppra.The daily dose is administered in two equally divided doses.
Method of administration solution for infusionKeppra therapy can be initiated with either intravenous or oral administration.Conversion to or from oral to intravenous administration can be done directly without titration. The total daily dose and frequency of administration should be maintained.Keppra concentrate 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 (see section 6.6).
DiscontinuationIn accordance with current clinical practice, if Keppra has to be discontinued it is recommended to withdraw it gradually (e.g. in adults and adolescents weighing more than 50 kg: 500 mg decreases twice daily every two to four weeks; in children and adolescents weighting less than 50 kg: dose decrease should not exceed 10 mg/kg twice daily every two weeks).
Renal insufficiencyThe administration of Keppra to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection (see section 4.2).
SuicideSuicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known. Therefore patients should be monitored for signs of depression and/or suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge.
Paediatric populationThe tablet formulation is not adapted for use in infants and children under the age of 6 years. Available data in children did not suggest impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.The safety and efficacy of levetiracetam has not been thoroughly assessed in infants with epilepsy aged less than 1 year. Only 35 infants aged less than 1 year with partial onset seizures have been exposed in clinical studies of which only 13 were aged < 6 months.
Excipients - tabletsKeppra 750 mg film-coated tablets contain E110 colouring agent which may cause allergic reactions.
Excipients oral solutionKeppra 100 mg/ml oral solution includes methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216) which may cause allergic reactions (possibly delayed).It also includes maltitol liquid; patients with rare hereditary problems of fructose intolerance should not take this medicinal product.
Excipients solution for infusionThis medicinal product contains 2.5 mmol (or 57 mg) sodium per maximum single dose(0.8 mmol(or 19 mg )per vial). To be taken into consideration by patients on a controlled sodium diet.
Antiepileptic medicinal productsPre-marketing data from clinical studies conducted in adults indicate that Keppra did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of Keppra.As in adults, there is no evidence of clinically significant medicinal product interactions in paediatric patients receiving up to 60 mg/kg/day levetiracetam.A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4 to 17 years) confirmed that adjunctive therapy with orally administered levetiracetam did not influence the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data suggested a 20 % higher levetiracetam clearance in children taking enzyme-inducing antiepileptic medicinal products. Dose adjustment is not required.
ProbenecidProbenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite, but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low. It is expected that other medicinal products excreted by active tubular secretion could also reduce the renal clearance of the metabolite. The effect of levetiracetam on probenecid was not studied and the effect of levetiracetam on other actively secreted medicinal products, e.g. NSAIDs, sulfonamides and methotrexate, is unknown.
Oral contraceptives and other pharmacokinetics interactionsLevetiracetam 1,000 mg daily did not influence the pharmacokinetics of oral contraceptives (ethinyl-estradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone) were not modified. Levetiracetam 2,000 mg daily did not influence the pharmacokinetics of digoxin and warfarin; prothrombin times were not modified. Co-administration with digoxin, oral contraceptives and warfarin did not influence the pharmacokinetics of levetiracetam.
AntacidsNo data on the influence of antacids on the absorption of levetiracetam are available.
Food and alcoholThe extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced.No data on the interaction of levetiracetam with alcohol are available.
PregnancyThere are no adequate data available from the use of levetiracetam in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for human is unknown.Keppra is not recommended during pregnancy and in women of childbearing potential not using contraception unless clearly necessary. As with other antiepileptic medicinal products, physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester (up to 60% of baseline concentration before pregnancy). Appropriate clinical management of pregnant women treated with levetiracetam should be ensured. Discontinuation of antiepileptic treatments may result in exacerbation of the disease which could be harmful to the mother and the foetus.
BreastfeedingLevetiracetam is excreted in human breast milk. Therefore, breast-feeding is not recommended. However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk of the treatment should be weighed considering the importance of breastfeeding.
FertilityNo impact on fertility was detected in animal studies (see section 5.3). No clinical data are available, potential risk for human is unknown.
Summary of the safety profileThe adverse event profile presented below is based on the analysis of pooled placebo-controlled clinical trials with all indications studied, with a total of 3,416 patients treated with levetiracetam. These data are supplemented with the use of levetiracetam in corresponding open-label extension studies, as well as post-marketing experience. The most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness. The safety profile of levetiracetam is generally similar across age groups (adult and paediatric patients) and across the approved epilepsy indications.
Tabulated list of adverse reactionsAdverse reactions reported in clinical studies (adults, adolescents, children and infants > 1 month) and from post-marketing experience are listed in the following table per System Organ Class and per frequency. The frequency is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000).
|MedDRA SOC||Frequency category|
|Infections and infestations||Nasopharyngitis||Infection|
|Blood and lymphatic system disorders||Thrombocytopenia, leukopenia||Pancytopenia (, neutropenia, agranulocytosis|
|Immune system disorders||Drug reaction with eosinophilia and systemic symptoms (DRESS)|
|Metabolism and nutrition disorders||Anorexia||Weight decreased , weight increase||Hyponatraemia|
|Psychiatric disorders||Depression, hostility/ aggression, anxiety, insomnia, nervousness/irritability||Suicide attempt), suicidal ideation psychotic disorder), abnormal behaviour), hallucination(), anger(), confusional state ,panic attack affect lability/mood swings, agitation||Completed suicide), personality disorder, thinking abnormal|
|Nervous system disorders||Somnolence, headache||Convulsion, balance disorder, dizziness, lethargy, tremor||Amnesia, memory impairment, coordination abnormal/ataxia, paraesthesia, disturbance in attention||Choreoathetosis, dyskinesia), hyperkinesia|
|Eye disorders||Diplopia, vision blurred|
|Ear and labyrinth disorders||Vertigo|
|Respiratory, thoracic and mediastinal disorders||Cough|
|Gastrointestinal disorders||Abdominal pain, diarrhoea, dyspepsia, vomiting, nausea||Pancreatitis|
|Hepatobiliary disorders||Liver function test abnormal||Hepatic failure, hepatitis|
|Skin and subcutaneous tissue disorders||Rash||Alopecia, eczema, pruritus,||Toxic epidermal necrolysis, Stevens-Johnson syndrome), erythema multiforme|
|Musculoskeletal and connective tissue disorders||Muscular weakness, myalgia|
|General disorders and administration site conditions||Asthenia/fatigue|
|Injury, poisoning and procedural complications||Injury|
Description of selected adverse reactionsThe risk of anorexia is higher when topiramate is coadministered with levetiracetam.In several cases of alopecia, recovery was observed when levetiracetam was discontinued.Bone marrow suppression was identified in some of the cases of pancytopenia.
Paediatric populationIn patients aged 1 month to less than 4 years, a total of 190 patients have been treated with levetiracetam in placebo-controlled and open label extension studies. Sixty (60) of these patients were treated with levetiracetam in placebo-controlled studies. In patients aged 4-16 years, a total of 645 patients have been treated with levetiracetam in placebo-controlled and open label extension studies. 233 of these patients were treated with levetiracetam in placebo-controlled studies. In both these paediatric age ranges, these data are supplemented with the post-marketing experience of the use of levetiracetam.The adverse event profile of levetiracetam is generally similar across age groups and across the approved epilepsy indications. Safety results in paediatric patients in placebo-controlled clinical studies were consistent with the safety profile of levetiracetam in adults except for behavioural and psychiatric adverse reactions which were more common in children than in adults. In children and adolescents aged 4 to 16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), mood swings (common, 2.1%), affect lability (common, 1.7%), aggression (common, 8.2%), abnormal behaviour (common, 5.6%), and lethargy (common, 3.9%) were reported more frequently than in other age ranges or in the overall safety profile. In infants and children aged 1 month to less than 4 years, irritability (very common, 11.7%) and coordination abnormal (common, 3.3%) were reported more frequently than in other age groups or in the overall safety profile. A double-blind, placebo-controlled paediatric safety study with a non-inferiority design has assessed the cognitive and neuropsychological effects of Keppra in children 4 to 16 years of age with partial onset seizures. It was concluded that Keppra was not different (non inferior) from placebo with regard to the change from baseline of the Leiter-R Attention and Memory, Memory Screen Composite score in the per-protocol population. Results related to behavioural and emotional functioning indicated a worsening in Keppra treated patients on aggressive behaviour as measured in a standardised and systematic way using a validated instrument (CBCL Achenbach Child Behavior Checklist). However subjects, who took Keppra in the long-term open label follow-up study, did not experience a worsening, on average, in their behavioural and emotional functioning; in particular measures of aggressive behaviour were not worse than baseline. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system:UKThe Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard Ireland Pharmacovigilance Section Irish Medicines Board Kevin O'Malley House Earlsfort Centre Earlsfort Terrace IRL - Dublin 2 Tel: +353 1 6764971 Fax: +353 1 6762517 Website: www.imb.ie e-mail: firstname.lastname@example.org
SymptomsSomnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with Keppra overdoses.
Management of overdoseAfter an acute overdose, the stomach may be emptied by gastric lavage or by induction of emesis. There is no specific antidote for levetiracetam. Treatment of an overdose will be symptomatic and may include haemodialysis. The dialyser extraction efficiency is 60 % for levetiracetam and 74 % for the primary metabolite.
Mechanism of actionThe mechanism of action of levetiracetam still remains to be fully elucidated but appears to be different from the mechanisms of current antiepileptic medicinal products. In vitro and in vivo experiments suggest that levetiracetam does not alter basic cell characteristics and normal neurotransmission.In vitro studies show that levetiracetam affects intraneuronal Ca2+ levels by partial inhibition of N-type Ca2+ currents and by reducing the release of Ca2+ from intraneuronal stores. In addition, it partially reverses the reductions in GABA- and glycine-gated currents induced by zinc and β-carbolines. Furthermore, levetiracetam has been shown in in vitro studies to bind to a specific site in rodent brain tissue. This binding site is the synaptic vesicle protein 2A, believed to be involved in vesicle fusion and neurotransmitter exocytosis. Levetiracetam and related analogues show a rank order of affinity for binding to the synaptic vesicle protein 2A which correlates with the potency of their anti-seizure protection in the mouse audiogenic model of epilepsy. This finding suggests that the interaction between levetiracetam and the synaptic vesicle protein 2A seems to contribute to the antiepileptic mechanism of action of the medicinal product.
Pharmacodynamic effectsLevetiracetam induces seizure protection in a broad range of animal models of partial and primary generalised seizures without having a pro-convulsant effect. The primary metabolite is inactive.In man, an activity in both partial and generalised epilepsy conditions (epileptiform discharge/photoparoxysmal response) has confirmed the broad spectrum pharmacological profile of levetiracetam.
Clinical efficacy and safetyAdjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents, children and infants from 1 month of age with epilepsy.In adults, levetiracetam efficacy has been demonstrated in 3 double-blind, placebo-controlled studies at 1000 mg, 2000 mg, or 3000 mg/day, given in 2 divided doses, with a treatment duration of up to 18 weeks. In a pooled analysis, the percentage of patients who achieved 50 % or greater reduction from baseline in the partial onset seizure frequency per week at stable dose (12/14 weeks) was of 27.7 %, 31.6 % and 41.3 % for patients on 1000, 2000 or 3000 mg levetiracetam respectively and of 12.6 % for patients on placebo.Paediatric populationIn paediatric patients (4 to 16 years of age), levetiracetam efficacy was established in a double-blind, placebo-controlled study, which included 198 patients and had a treatment duration of 14 weeks. In this study, the patients received levetiracetam as a fixed dose of 60 mg/kg/day (with twice a day dosing).44.6 % of the levetiracetam treated patients and 19.6 % of the patients on placebo had a 50 % or greater reduction from baseline in the partial onset seizure frequency per week. With continued long-term treatment, 11.4 % of the patients were seizure-free for at least 6 months and 7.2 % were seizure-free for at least 1 year.In paediatric patients (1 month to less than 4 years of age), levetiracetam efficacy was established in a double-blind, placebo-controlled study, which included 116 patients and had a treatment duration of 5 days. In this study, patients were prescribed 20 mg/kg, 25 mg/kg, 40 mg/kg or 50 mg/kg daily dose of oral solution based on their age titration schedule. A dose of 20 mg/kg/day titrating to 40 mg/kg/day for infants one month to less than six months and a dose of 25 mg/kg/day titrating to 50 mg/kg/day for infants and children 6 months to less than 4 years old, was use in this study. The total daily dose was administered b.i.d.The primary measure of effectiveness was the responder rate (percent of patients with ≥ 50 % reduction from baseline in average daily partial onset seizure frequency) assessed by a blinded central reader using a 48-hour video EEG. The efficacy analysis consisted of 109 patients who had at least 24 hours of video EEG in both baseline and evaluation periods. 43.6 % of the levetiracetam treated patients and 19.6 % of the patients on placebo were considered as responders. The results are consistent across age group. With continued long-term treatment, 8.6 % of the patients were seizure-free for at least 6 months and 7.8 % were seizure-free for at least 1 year.Monotherapy in the treatment of partial onset seizures with or without secondary generalisation in patients from 16 years of age with newly diagnosed epilepsy. Efficacy of levetiracetam as monotherapy was established in a double-blind, parallel group, non-inferiority comparison to carbamazepine controlled release (CR) in 576 patients 16 years of age or older with newly or recently diagnosed epilepsy. The patients had to present with unprovoked partial seizures or with generalized tonic-clonic seizures only. The patients were randomized to carbamazepine CR 400 1200 mg/day or levetiracetam 1000 3000 mg/day, the duration of the treatment was up to 121 weeks depending on the response. Six-month seizure freedom was achieved in 73.0 % of levetiracetam-treated patients and 72.8 % of carbamazepine-CR treated patients; the adjusted absolute difference between treatments was 0.2% (95 % CI: -7.8 8.2). More than half of the subjects remained seizure free for 12 months (56.6 % and 58.5 % of subjects on levetiracetam and on carbamazepine CR respectively).In a study reflecting clinical practice, the concomitant antiepileptic medication could be withdrawn in a limited number of patients who responded to levetiracetam adjunctive therapy (36 adult patients out of 69).
Adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.Levetiracetam efficacy was established in a double-blind, placebo-controlled study of 16 weeks duration, in patients 12 years of age and older suffering from idiopathic generalized epilepsy with myoclonic seizures in different syndromes. The majority of patients presented with juvenile myoclonic epilepsy.In this study, levetiracetam, dose was 3000 mg/day given in 2 divided doses. 58.3 % of the levetiracetam treated patients and 23.3 % of the patients on placebo had at least a 50 % reduction in myoclonic seizure days per week. With continued long-term treatment, 28.6 % of the patients were free of myoclonic seizures for at least 6 months and 21.0 % were free of myoclonic seizures for at least 1 year.Adjunctive therapy in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalised epilepsy.Levetiracetam efficacy was established in a 24-week double-blind, placebo-controlled study which included adults, adolescents and a limited number of children suffering from idiopathic generalized epilepsy with primary generalized tonic-clonic (PGTC) seizures in different syndromes (juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy, or epilepsy with Grand Mal seizures on awakening). In this study, levetiracetam dose was 3000 mg/day for adults and adolescents or 60 mg/kg/day for children, given in 2 divided doses.72.2 % of the levetiracetam treated patients and 45.2 % of the patients on placebo had a 50 % or greater decrease in the frequency of PGTC seizures per week. With continued long-term treatment, 47.4 % of the patients were free of tonic-clonic seizures for at least 6 months and 31.5 % were free of tonic-clonic seizures for at least 1 year.
Adults and adolescents
AbsorptionLevetiracetam is rapidly absorbed after oral administration. Oral absolute bioavailability is close to 100 %. Peak plasma concentrations (Cmax) are achieved at 1.3 hours after dosing. Steady-state is achieved after two days of a twice daily administration schedule.Peak concentrations (Cmax) are typically 31 and 43 µg/ml following a single 1,000 mg dose and repeated 1,000 mg twice daily dose, respectively.The extent of absorption is dose-independent and is not altered by food.
DistributionNo tissue distribution data are available in humans.Neither levetiracetam nor its primary metabolite are significantly bound to plasma proteins (< 10 %). The volume of distribution of levetiracetam is approximately 0.5 to 0.7 l/kg, a value close to the total body water volume.Peak plasma concentration (Cmax) observed in 17 subjects following a single intravenous dose of 1500 mg infused over 15 minutes was 51 ± 19 µg/mL (arithmetic average ± standard deviation).
BiotransformationLevetiracetam is not extensively metabolised in humans. The major metabolic pathway (24 % of the dose) is an enzymatic hydrolysis of the acetamide group. Production of the primary metabolite, ucb L057, is not supported by liver cytochrome P450 isoforms. Hydrolysis of the acetamide group was measurable in a large number of tissues including blood cells. The metabolite ucb L057 is pharmacologically inactive.Two minor metabolites were also identified. One was obtained by hydroxylation of the pyrrolidone ring (1.6 % of the dose) and the other one by opening of the pyrrolidone ring (0.9 % of the dose). Other unidentified components accounted only for 0.6 % of the dose.No enantiomeric interconversion was evidenced in vivo for either levetiracetam or its primary metabolite.In vitro, levetiracetam and its primary metabolite have been shown not to inhibit the major human liver cytochrome P450 isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase (UGT1A1 and UGT1A6) and epoxide hydroxylase activities. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid.In human hepatocytes in culture, levetiracetam had little or no effect on CYP1A2, SULT1E1 or UGT1A1. Levetiracetam caused mild induction of CYP2B6 and CYP3A4. The in vitro data and in vivo interaction data on oral contraceptives, digoxin and warfarin indicate that no significant enzyme induction is expected in vivo. Therefore, the interaction of Keppra with other substances, or vice versa, is unlikely.
EliminationThe plasma half-life in adults was 7±1 hours and did not vary either with dose, route of administration or repeated administration. The mean total body clearance was 0.96 ml/min/kg.The major route of excretion was via urine, accounting for a mean 95 % of the dose (approximately 93 % of the dose was excreted within 48 hours). Excretion via faeces accounted for only 0.3 % of the dose.The cumulative urinary excretion of levetiracetam and its primary metabolite accounted for 66 % and 24 % of the dose, respectively during the first 48 hours.The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml/min/kg respectively indicating that levetiracetam is excreted by glomerular filtration with subsequent tubular reabsorption and that the primary metabolite is also excreted by active tubular secretion in addition to glomerular filtration. Levetiracetam elimination is correlated to creatinine clearance.
ElderlyIn the elderly, the half-life is increased by about 40 % (10 to 11 hours). This is related to the decrease in renal function in this population (see section 4.2).
Renal impairmentThe apparent body clearance of both levetiracetam and of its primary metabolite is correlated to the creatinine clearance. It is therefore recommended to adjust the maintenance daily dose of Keppra, based on creatinine clearance in patients with moderate and severe renal impairment (see section 4.2).In anuric end-stage renal disease adult subjects the half-life was approximately 25 and 3.1 hours during interdialytic and intradialytic periods, respectively. The fractional removal of levetiracetam was 51 % during a typical 4-hour dialysis session.
Hepatic impairmentIn subjects with mild and moderate hepatic impairment, there was no relevant modification of the clearance of levetiracetam. In most subjects with severe hepatic impairment, the clearance of levetiracetam was reduced by more than 50 % due to a concomitant renal impairment (see section 4.2).
Children (4 to 12 years)Following single oral dose administration (20 mg/kg) to epileptic children (6 to 12 years), the half-life of levetiracetam was 6.0 hours. The apparent body weight adjusted clearance was approximately 30 % higher than in epileptic adults.Following repeated oral dose administration (20 to 60 mg/kg/day) to epileptic children (4 to 12 years), levetiracetam was rapidly absorbed. Peak plasma concentration was observed 0.5 to 1.0 hour after dosing. Linear and dose proportional increases were observed for peak plasma concentrations and area under the curve. The elimination half-life was approximately 5 hours. The apparent body clearance was 1.1 ml/min/kg.
Infants and children (1 month to 4 years)Following single dose administration (20 mg/kg) of a 100 mg/ml oral solution to epileptic children (1 month to 4 years), levetiracetam was rapidly absorbed and peak plasma concentrations were observed approximately 1 hour after dosing. The pharmacokinetic results indicated that half-life was shorter (5.3 h) than for adults (7.2 h) and apparent clearance was faster (1.5 ml/min/kg) than for adults (0.96 ml/min/kg).In the population pharmacokinetic analysis conducted in patients from 1 month to 16 years of age, body weight was significantly correlated to apparent clearance (clearance increased with an increase in body weight) and apparent volume of distribution. Age also had an influence on both parameters. This effect was pronounced for the younger infants, and subsided as age increased, to become negligible around 4 years of age.In both population pharmacokinetic analyses, there was about a 20 % increase of apparent clearance of levetiracetam when it was co-administered with an enzyme-inducing antiepileptic medicinal product.
Environmental Risk Assessment (ERA)The use of Keppra in accordance with the product information is not likely to result in an unacceptable environmental impact (see section 6.6).
TabletsKeppra 250 mg, Keppra 500 mg, Keppra 750 mg, Keppra 1000 mg film coated tabletsCore: Croscarmellose sodium, Macrogol 6000, silica colloidal anhydrous, magnesium stearate.
Keppra 250 mgFilm-coating: Opadry 85F20694: Polyvinyl alcohol-part.hydrolyzed, Titanium dioxide (E171), Macrogol 3350, Talc, Indigo carmine aluminium lake (E132).
Keppra 500 mgFilm-coating: Opadry 85F32004: Polyvinyl alcohol-part.hydrolyzed, Titanium dioxide (E171), Macrogol 3350, Talc, Iron oxide yellow (E172).
Keppra 750 mgFilm-coating: Opadry 85F23452: Polyvinyl alcohol-part.hydrolyzed, Titanium dioxide (E171), Macrogol 3350, Talc, sunset yellow FCF aluminium lake (E110), Iron oxide red (E172).
Keppra 1000 mgFilm-coating: Opadry 85F18422: Polyvinyl alcohol-part.hydrolyzed, Titanium dioxide (E171), Macrogol 3350, Talc.
Keppra 100 mg/ml, oral solutionSodium citrate, citric acid monohydrate, methyl parahydroxybenzoate (E 218), propyl parahydroxybenzoate (E 216), ammonium glycyrrhizate, glycerol (E 422), maltitol liquid (E 965), acesulfame potassium (E 950), grape flavour, purified water.
Keppra 100 mg/ml, concentrate for solution for infusionSodium acetate, glacial acetic acid, sodium chloride, water for injections
Tablets and oral solution:Not applicable
Solution for infusion:This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.
Oral Solution:3 years.After first opening: 7 months
Solution for Infusion:2 years.From a microbiological point of view, the product should be used immediately after dilution. If not used immediately, in-use storage time and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled and validated aseptic conditions.
Tablets:This medicinal product does not require any special storage conditions.
Oral solution:Store in the original container in order to protect from light.
Solution for Infusion:This medicinal product does not require any special storage conditions. For storage conditions of the diluted medicinal product, see section 6.3.
Tablets:Aluminium/PVC blisters placed into cardboard boxes containing 10, 20, 30, 50, 60, 100 film-coated tablets and multipacks containing 200 (2 packs of 100) film-coated tablets.Aluminium/PVC perforated unit dose blisters placed into cardboard boxes containing 100 x 1 film-coated tabletsNot all pack sizes may be marketed.
Oral Solution:300 ml amber glass bottle (type III) with a white child resistant closure (polypropylene) in a cardboard box also containing a 10 ml graduated oral syringe (polypropylene, polyethylene) and an adaptor for the syringe (polyethylene).150 ml amber glass bottle (type III) with a white child resistant closure (polypropylene) in a cardboard box also containing a 3 ml graduated oral syringe (polypropylene, polyethylene) and an adaptor for the syringe (polyethylene).150 ml amber glass bottle (type III) with a white child resistant closure (polypropylene) in a cardboard box also containing a 1 ml graduated oral syringe (polypropylene, polyethylene) and an adaptor for the syringe (polyethylene).
Solution for infusion:5 ml glass vial (type I) closed by a Teflon-faced grey chlorobutyl rubber stopper or an uncoated grey bromobutyl rubber stopper and sealed with an aluminium/polypropylene flip cap. Each carton contains 10 vials..
Tablets and oral solutionAny unused medicinal product or waste material should be disposed of in accordance with local requirements.
Solution for InfusionSee Table 1 for the recommended preparation and administration of Keppra concentrate to achieve a total daily dose of 500 mg, 1,000 mg, 2,000 mg, or 3,000 mg in two divided doses.
Table 1. Preparation and administration of Keppra concentrate
|Dose||Withdrawal Volume||Volume of Diluent||Infusion Time||Frequency of administration||Total Daily Dose|
|250 mg||2.5 ml (half 5 ml vial)||100 ml||15 minutes||Twice daily||500 mg/day|
|500 mg||5 ml (one 5 ml vial)||100 ml||15 minutes||Twice daily||1000 mg/day|
|1000 mg||10 ml (two 5 ml vials)||100 ml||15 minutes||Twice daily||2000 mg/day|
|1500 mg||15 ml (three 5 ml vials)||100 ml||15 minutes||Twice daily||3000 mg/day|
UCB Pharma Limited
208 Bath Road, Slough, Berkshire, SL1 3WE
+44 (0)1753 447 690
+44 (0) 1773 510123
+44 (0)1753 534 655