Tuesday, October 25, 2016

Keppra film-coated Tablets 250mg, 500mg, 750mg, 1000mg, Keppra 100mg / ml oral solution, Keppra 100mg / ml concentrate for solution for infusion





1. Name Of The Medicinal Product



Keppra 250 mg film-coated tablets.



Keppra 500 mg film-coated tablets.



Keppra 750 mg film-coated tablets.



Keppra 1000 mg film-coated tablets.



Keppra 100 mg/ml, oral solution.



Keppra 100 mg/ml concentrate for solution for infusion


2. Qualitative And Quantitative Composition



Tablets:



Each film-coated tablet contains 250 mg levetiracetam, 500 mg levetiracetam, 750 mg levetiracetam & excipient colouring agent E110 or 1000 mg levetiracetam.



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 dose contains 57 mg of sodium.



For a full list of excipients, see section 6.1.



3. Pharmaceutical Form



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.



4. Clinical Particulars



4.1 Therapeutic Indications



Keppra is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in patients from 16 years of age with newly diagnosed epilepsy.



Keppra is indicated as adjunctive therapy



• in the treatment of partial onset seizures with or without secondary generalisation in adults and children from 1 month of age with epilepsy.



• in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.



• in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy.



Keppra concentrate is an alternative for patients (adults and children from 4 years of age) when oral administration is temporarily not feasible.



4.2 Posology And Method Of Administration



Posology



Monotherapy for adults and adolescents from 16 years of age



The 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 (



The 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 treatment



There is no experience with administration of intravenous levetiracetam for longer period than 4 days.



Special populations



Elderly (65 years and older)



Adjustment of the dose is recommended in elderly patients with compromised renal function (see “Patients with renal impairment” below).



Renal impairment



The 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)



(1) A 750 mg loading dose is recommended on the first day of treatment with levetiracetam.



(2) Following dialysis, a 250 to 500 mg supplemental dose is recommended.



For children with renal impairment, levetiracetam dose needs to be adjusted based on the renal function as levetiracetam clearance is related to renal function. This recommendation is based on a study in adult renally impaired patients.



The CLcr in ml/min/1.73 m2 may be estimated from serum creatinine (mg/dl) determination using, for young adolescents and children using the following formula (Schwartz formula):





ks= 0.45 in Term infants to 1 year old; ks= 0.55 in Children to less than 13 years and in adolescent female; ks= 0.7 in adolescent male



Dosing adjustment for children and adolescents patients weighing less than 50 kg with impaired renal function
































Group




Creatinine clearance (ml/min/1.73 m2)




Dose and frequency


 


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 (1) (3)




10 to 20 mg/kg (0.10 to 0.20 ml/kg) once daily (2) (4)



(1) A 10.5 mg/kg (0.105 ml/kg) loading dose is recommended on the first day of treatment with levetiracetam.



(2) A 15 mg/kg (0.15 ml/kg) loading dose is recommended on the first day of treatment with levetiracetam.



(3) Following dialysis, a 3.5 to 7 mg/kg (0.035 to 0.07 ml/kg) supplemental dose is recommended.



(4) Following dialysis, a 5 to 10 mg/kg (0.05 to 0.10 ml/kg) supplemental dose is recommended.



Hepatic impairment



No 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 population



The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to weight and dose.



The safety and efficacy of Keppra concentrate for solution for infusion in infants and children less than 4 years have not been established.



Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on a posology can be made.



Monotherapy



The 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 infants aged from 6 to 23 months, children (2 to 11 years) and adolescents (12 to 17 years) weighing less than 50 kg



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



(1) Children 20 kg or less should preferably start the treatment with Keppra 100 mg/ml oral solution.



(2) Dose in children and adolescents 50 kg or more is the same as in adults.



Add-on therapy for infants from 1 month to less than 6 months



The tablet formulation is not adapted for use in infants under the age of 6 months. 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 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



Three presentations are available:



- A 300 ml bottle with graduated oral syringe containing up to 1000 mg levetiracetam (corresponding to 10 ml) with a graduation every 0.25 ml (corresponding to 25 mg).



This presentation should be prescribed for children older than 4 years, adolescents and adults.



- A 150 ml bottle with graduated oral syringe containing up to 300 mg levetiracetam (corresponding to 3 ml) with a graduation every 0.1 ml (corresponding to10 mg)



In order to ensure the accuracy of the dosing, the smaller bottle (150 ml) and syringe graduated from 0.1 to 3 ml per graduation of 0.1 ml should be prescribed for infants older than 6 months and young children.



- A 150 ml bottle with graduated oral syringe containing up to 100 mg levetiracetam (corresponding to 1 ml) with a graduation every 0.05 ml (corresponding to 5 mg)



In order to ensure the accuracy of the dosing, the smaller bottle (150 ml) and syringe graduated from 0.05 to 1 ml per graduation of 0.05 ml should be prescribed for infants less than 6 months.



Method of administration - tablets



The 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 administration – oral solution



The oral solution may be diluted in a glass of water 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 infusion



Keppra 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).



4.3 Contraindications



Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipients.



4.4 Special Warnings And Precautions For Use



Discontinuation



In 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 insufficiency



The 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).



Suicide



Suicide, 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 population



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.



Excipients - tablets



Keppra 750 mg film-coated tablets contain E110 colouring agent which may cause allergic reactions.



Excipients – oral solution



Keppra 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 infusion



This medicinal product contains 2.5 mmol (or 57 mg) sodium per maximum single dose. To be taken into consideration by patients on a controlled sodium diet.



4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction



Antiepileptic medicinal products



Pre-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.



Probenecid



Probenecid (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 interactions



Levetiracetam 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.



Antacids



No data on the influence of antacids on the absorption of levetiracetam are available.



Food and alcohol



The 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.



4.6 Pregnancy And Lactation



Pregnancy



There 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.



Breastfeeding



Levetiracetam 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.



Fertility



No impact on fertility was detected in animal studies (see section 5.3). No clinical data are available, potential risk for human is unknown.



4.7 Effects On Ability To Drive And Use Machines



No studies on the effects on the ability to drive and use machines have been performed.



Due to possible different individual sensitivity, some patients might experience somnolence or other central nervous system related symptoms, especially at the beginning of treatment or following a dose increase. Therefore, caution is recommended in those patients when performing skilled tasks, e.g. driving vehicles or operating machinery. Patients are advised not to drive or use machines until it is established that their ability to perform such activities is not affected.



4.8 Undesirable Effects



Summary of the safety profile



Pooled safety data from clinical studies conducted with Keppra oral formulations in adult patients with partial onset seizures showed that 46.4 % of the patients in the Keppra group and 42.2 % of the patients in the placebo group experienced adverse reactions. Serious adverse reactions were experienced in 2.4 % of the patients in the Keppra and 2.0 % of the patients in the placebo groups.



The most commonly reported adverse reactions were somnolence, asthenia and dizziness. In the pooled safety analysis, there was no clear dose-response relationship but incidence and severity of the central nervous system related adverse reactions decreased over time.



In monotherapy 49.8 % of the subjects experienced at least one drug related adverse reaction. The most frequently reported adverse reactions were fatigue and somnolence.



A study conducted in adults and adolescents with myoclonic seizures (12 to 65 years) showed that 33.3 % of the patients in the Keppra group and 30.0 % of the patients in the placebo group experienced adverse reactions that were judged to be related to treatment. The most commonly reported adverse reactions were headache and somnolence. The incidence of adverse reactions in patients with myoclonic seizures was lower than that in adult patients with partial onset seizures (33.3 % versus 46.4 %).



A study conducted in adults and children (4 to 65 years) with idiopathic generalised epilepsy with primary generalised tonic-clonic seizures showed that 39.2 % of the patients in the Keppra group and 29.8 % of the patients in the placebo group experienced undesirable effects that were judged to be related to treatment. The most commonly reported adverse reaction was fatigue.



An increase in seizure frequency of more than 25 % was reported in 14 % of levetiracetam treated adult and paediatric patients (4 to 16 years of age) with partial onset seizures, whereas it was reported in 26 % and 21 % of placebo treated adult and paediatric patients, respectively.



When Keppra was used to treat primary generalised tonic-clonic seizures in adults and adolescents with idiopathic generalised epilepsy, there was no effect on the frequency of absences.



Adverse reactions that resulted from Keppra intravenous use are similar to those associated with Keppra oral use. The most frequently reported adverse reactions were dizziness, somnolence, headache and postural dizziness. Since there was limited exposure for Keppra intravenous use and since oral and intravenous formulations are bioequivalent, the safety information of Keppra intravenous will rely on Keppra oral use.



Tabulated list of adverse reactions



Adverse reactions reported in clinical studies (adults, adolescents and children) and from post-marketing experience are listed in the following table per System Organ Class and per frequency. For clinical trials, the frequency is defined as follows: very common (



- Infections and infestations



Common: infection, nasopharyngitis



- Blood and lymphatic system disorders



Common: thrombocytopenia



Not known: leukopenia, neutropenia, pancytopenia (with bone marrow suppression identified in some of the cases).



- Metabolism and nutrition disorders



Common: anorexia, weight increase.



Not known: weight loss



- Psychiatric disorders



Common: agitation, depression, emotional lability /mood swings, hostility/aggression, insomnia, nervousness/irritability, personality disorders, thinking abnormal.



Not known: abnormal behaviour, anger, anxiety, confusion, hallucination, psychotic disorder, suicide, suicide attempt and suicidal ideation.



- Nervous system disorders



Very common: somnolence.



Common: amnesia, ataxia, convulsion, dizziness, headache, hyperkinesia, tremor, balance disorder, disturbance in attention, memory impairment



Not known: paraesthesia



- Eye disorders



Common: diplopia, vision blurred



- Ear and labyrinth disorders



Common: vertigo



- Respiratory, thoracic and mediastinal disorders



Common: cough increased



- Gastrointestinal disorders



Common: abdominal pain, diarrhoea, dyspepsia, nausea, vomiting.



Not known: pancreatitis



- Hepatobiliary disorders



Not known: hepatic failure, hepatitis, liver function test abnormal



- Skin and subcutaneous tissue disorders



Common: rash, eczema, pruritus



Not known: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme and alopecia



- Musculoskeletal and connective tissue disorders



Common: myalgia



- General disorders and administration site conditions



Very common: asthenia/fatigue.



- Injury, poisoning and procedural complications



Common: accidental injury



Description of selected adverse reactions



The risk of anorexia is higher when topiramate is coadministered with levetiracetam.



In several cases of alopecia, recovery was observed when levetiracetam was discontinued.



Paediatric population



A study conducted in paediatric patients (4 to 16 years) with partial onset seizures showed that 55.4 % of the patients in the Keppra group and 40.2 % of the patients in the placebo group experienced adverse reactions. Serious adverse reactions were experienced in none of the patients in the Keppra group and 1.0 % of the patients in the placebo group. The most commonly reported adverse reactions were somnolence, hostility, nervousness, emotional lability, agitation, anorexia, asthenia and headache in the paediatric population. Safety results in paediatric patients 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 (38.6 % versus 18.6 %). However, the relative risk was similar in children as compared to adults.



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 behavioral and emotional functioning indicated a worsening in Keppra treated patients on aggressive behavior as measured in a standardized 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.



4.9 Overdose



Symptoms



Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with Keppra overdoses.



Management of overdose



After 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.



5. Pharmacological Properties



5.1 Pharmacodynamic Properties



Pharmacotherapeutic group: antiepileptics, other antiepileptics, ATC code: N03AX14.



The active substance, levetiracetam, is a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances.



Mechanism of action



The 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 effects



Levetiracetam 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 safety



Adjunctive 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 population



In 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 month and a dose of 25 mg/kg/day titrating to 50 mg/kg/day for infants and children 6 month 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



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.



5.2 Pharmacokinetic Properties



Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear with low intra- and inter-subject variability. There is no modification of the clearance after repeated administration. The time independent pharmacokinetic profile of levetiracetam was also confirmed following 1500 mg intravenous infusion for 4 days with b.i.d dosing.



There is no evidence for any relevant gender, race or circadian variability. The pharmacokinetic profile is comparable in healthy volunteers and in patients with epilepsy.



Due to its complete and linear absorption, plasma levels can be predicted from the oral dose of levetiracetam expressed as mg/kg bodyweight. Therefore there is no need for plasma level monitoring of levetiracetam.



A significant correlation between saliva and plasma concentrations has been shown in adults and children (ratio of saliva/plasma concentrations ranged from 1 to 1.7 for oral tablet formulation and after 4 hours post-dose for oral solution formulation).



The pharmacokinetic profile has been characterized following oral administration. A single dose of 1500 mg levetiracetam diluted in 100 ml of a compatible diluent and infused intravenously over 15 minutes is bioequivalent to 1500 mg levetiracetam oral intake, given as three 500 mg tablets.



The intravenous administration of doses up to 4000 mg diluted in 100 ml of 0.9 % sodium chloride infused over 15 minutes and doses up to 2500 mg diluted in 100 ml of 0.9 % sodium chloride infused over 5 minutes was evaluated. The pharmacokinetic and safety profiles did not identify any safety concerns.



Adults and adolescents



Absorption



Levetiracetam 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.



Distribution



No 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).



Biotransformation



Levetiracetam 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.



Elimination



The 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 dos

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