LEVETIRACETAM SUN 100mg / ml perfusive solution concentrate medication leaflet

Levetiracetam SUN 100 mg/ml concentrate for solution for infusion

Each ml contains 100 mg of levetiracetam.

Each 5 ml vial contains 500 mg of levetiracetam.

Each vial contains 19 mg of sodium

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate).

Clear, colourless liquid.

Levetiracetam SUN is indicated as monotherapy in the treatment of partial onset seizures with orwithout secondary generalisation in adults and adolescents from 16 years of age with newly diagnosedepilepsy.

Levetiracetam SUN is indicated as adjunctive therapy

- in the treatment of partial onset seizures with or without secondary generalisation in adults,adolescents and children from 4 years 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 12years of age with Idiopathic Generalised Epilepsy.

Levetiracetam SUN concentrate is an alternative for patients when oral administration is temporarilynot feasible.

Levetiracetam therapy can be initiated with either intravenous or oral administration.

Conversion to or from oral to intravenous administration can be done directly without titration. Thetotal daily dose and frequency of administration should be maintained.

Partial onset seizures

The recommended dosing for monotherapy (from 16 years of age) and adjunctive therapy is the same;as outlined below.

Adults (≥18 years) and adolescents (12 to 17 years) weighing 50 kg or more

The initial therapeutic dose is 500 mg twice daily. This dose can be started on the first day oftreatment. However, a lower initial dose of 250 mg twice daily may be given based on physicianassessment of seizure reduction versus potential side effects. This can be increased to 500 mg twicedaily after two weeks.

Depending upon the clinical response and tolerability, the daily dose can be increased up to 1,500 mgtwice daily. Dose changes can be made in 250 mg or 500 mg twice daily increases or decreases everytwo to four weeks.

Adolescents (12 to 17 years) weighing below 50 kg and children from 4 years of age

The physician should prescribe the most appropriate pharmaceutical form, presentation and strengthaccording to weight, age and dose. Refer to Paediatric population section for dosing adjustmentsbased on weight.

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

If levetiracetam has to be discontinued it is recommended to withdraw it gradually (e.g. in adults andadolescents weighing more than 50 kg: 500 mg decreases twice daily every two to four weeks; inchildren and adolescents weighing less than 50 kg: dose decrease should not exceed 10 mg/kg twicedaily every two weeks).

Elderly (65 years and older)

Adjustment of the dose is recommended in elderly patients with compromised renal function (see'Renal impairment' below).

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 dosingtable, an estimate of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr in ml/minmay be estimated from serum creatinine (mg/dl) determination, for adults and adolescents weighing 50kg or more, the following formula:

[140-age (years)] x weight (kg)

CLcr (ml/min) = -------------------------------------- (x 0.85 for women)72 x serum creatinine (mg/dl)

Then CLcr is adjusted for body surface area (BSA) as follows:

CLcr (ml/min)

CL (ml/min/1.73 m2cr ) = -------------------------------- x 1.73

BSA subject (m2)

Dosing adjustment for adult and adolescent patients weighing more than 50 kg with impaired renalfunction

Group Creatinine clearance Dose and frequency(ml/min/1.73 m2)

Normal ≥ 80 500 to 1500 mg twice daily

Mild 50-79 500 to 1000 mg twice daily

Moderate 30-49 250 to 750 mg twice daily

Severe < 30 250 to 500 mg twice daily

End-stage renal disease patients -- 500 to 1000 mg once daily (2)undergoing dialysis (1)(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 renalfunction as levetiracetam clearance is related to renal function. This recommendation is based on astudy in adult renally impaired patients.

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

Height (cm) x ks

CLcr (ml/min/1.73 m2) = -------------------------------------------

Serum Creatinine (mg/dl)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 adolescent patients weighing less than 50 kg with impaired renalfunction

Group Creatinine clearance Dose and frequency(ml/min/1.73 m2) Children from 4 years and adolescents weighing lessthan 50 kg

Normal ≥ 80 10 to 30 mg/kg (0.10 to 0.30 ml/kg) twice daily

Mild 50-79 10 to 20 mg/kg (0.10 to 0.20 ml/kg) twice daily

Moderate 30-49 5 to 15 mg/kg (0.05 to 0.15 ml/kg) twice daily

Severe < 30 5 to 10 mg/kg (0.05 to 0.10 ml/kg) twice daily

End-stage renal -- 10 to 20 mg/kg (0.10 to 0.20 ml/kg) once daily (1) (2)disease patientsundergoing dialysis(1) A 15 mg/kg (0.15 ml/kg) loading dose is recommended on the first day of treatment withlevetiracetam.(2) Following dialysis, a 5 to 10 mg/kg (0.05 to 0.10 ml/kg) supplemental dose is recommended.

No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients withsevere hepatic impairment, the creatinine clearance may underestimate the renal insufficiency.

Therefore a 50 % reduction of the daily maintenance dose is recommended when the creatinineclearance is < 60 ml/min/1.73 m2.

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

The safety and efficacy of Levetiracetam SUN in children and adolescents below 16 years asmonotherapy treatment have not been established.

No data are available.

Adolescents (16 and 17 years of age) weighing 50 kg or more with partial onset seizures with orwithout secondary generalisation with newly diagnosed epilepsy

Please refer to the above section on Adults (≥18 years) and adolescents (12 to 17 years) weighing 50kg or more.

Add-on therapy for children aged 4 to 11 years and adolescents (12 to 17 years) weighing less than50 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 twicedaily. Dose changes should not exceed increases or decreases of 10 mg/kg twice daily every twoweeks. The lowest effective dose should be used for all indications.

Dose in children 50 kg or greater is the same as in adults for all indications.

Please refer to the above section on Adults (≥18 years) and adolescents (12 to 17 years) weighing 50kg or more for all indications.

Dose recommendations for children and adolescents:

Weight Starting dose: Maximum dose:10 mg/kg twice daily 30 mg/kg twice daily15 kg (1) 150 mg twice daily 450 mg twice daily20 kg (1) 200 mg twice daily 600 mg twice daily25 kg 250 mg twice daily 750 mg twice daily

From 50 kg(2) 500 mg twice daily 1500 mg twice daily(1) Children 25 kg or less should preferably start the treatment with an oral solution.(2) Dose in children and adolescents 50 kg or more is the same as in adults.

Add-on therapy for infants and children less than 4 years

The safety and efficacy of Levetiracetam SUN concentrate for solution for infusion in infants andchildren 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 aposology can be made.

Levetiracetam SUN concentrate is for intravenous use only and the recommended dose must bediluted in at least 100 ml of a compatible diluent and administered intravenously as a 15-minuteintravenous infusion (see section 6.6).

Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipientslisted in section 6.1.

The administration of levetiracetam to patients with renal impairment may require dose adjustment. Inpatients with severely impaired hepatic function, assessment of renal function is recommended beforedose selection (see section 4.2).

Acute kidney injury

The use of levetiracetam has been very rarely associated with acute kidney injury, with a time to onsetranging from a few days to several months.

Blood cell counts

Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leucopenia,thrombocytopenia and pancytopenia) have been described in association with levetiracetamadministration, generally at the beginning of the treatment. Complete blood cell counts are advised inpatients experiencing important weakness, pyrexia, recurrent infections or coagulation disorders(section 4.8).

Suicide

Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated withanti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlledtrials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts andbehaviour. The mechanism of this risk is not known.

Therefore patients should be monitored for signs of depression and/or suicidal ideation and behavioursand appropriate treatment should be considered. Patients (and caregivers of patients) should be advisedto seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge.

Abnormal and aggressive behaviours

Levetiracetam may cause psychotic symptoms and behavioural abnormalities including irritability andaggressiveness. Patients treated with levetiracetam should be monitored for developing psychiatricsigns suggesting important mood and/or personality changes. If such behaviours are noticed, treatmentadaptation or gradual discontinuation should be considered. If discontinuation is considered, pleaserefer to section 4.2.

Worsening of seizures

As with other types of antiepileptic drugs, levetiracetam may rarely exacerbate seizure frequency orseverity. This paradoxical effect was mostly reported within the first month after levetiracetaminitiation or increase of the dose, and was reversible upon drug discontinuation or dose decrease.

Patients should be advised to consult their physician immediately in case of aggravation of epilepsy.

Lack of efficacy or seizure worsening has for example been reported in patients with epilepsyassociated with sodium voltage-gated channel alpha subunit 8 (SCN8A) mutations.

Electrocardiogram QT interval prolongation

Rare cases of ECG QT interval prolongation have been observed during the post-marketingsurveillance. Levetiracetam should be used with caution in patients with QTc-interval prolongation, inpatients concomitantly treated with drugs affecting the QTc-interval, or in patients with relevant pre-existing cardiac disease or electrolyte disturbances.

Available data in children did not suggest impact on growth and puberty. However, long term effectson learning, intelligence, growth, endocrine function, puberty and childbearing potential in childrenremain unknown.

This medicinal product contains 2.5 mmol (or 57 mg) sodium per maximum single dose (0.8 mmol (or19 mg) per vial). To be taken into consideration by patients on a controlled sodium diet.

Antiepileptic medicinal products

Pre-marketing data from clinical studies conducted in adults indicate that levetiracetam did notinfluence the serum concentrations of existing antiepileptic medicinal products (phenytoin,carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that theseantiepileptic medicinal products did not influence the pharmacokinetics of levetiracetam.

As in adults, there is no evidence of clinically significant medicinal product interactions in paediatricpatients receiving up to 60 mg/kg/day levetiracetam. A retrospective assessment of pharmacokineticinteractions in children and adolescents with epilepsy (4 to 17 years) confirmed that adjunctive therapywith orally administered levetiracetam did not influence the steady-state serum concentrations ofconcomitantly administered carbamazepine and valproate. However, data suggested a 20% higherlevetiracetam clearance in children taking enzyme-inducing antiepileptic medicinal products. Doseadjustment is not required.

Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown toinhibit the renal clearance of the primary metabolite but not of levetiracetam. Nevertheless, theconcentration of this metabolite remains low.

Concomitant administration of levetiracetam and methotrexate has been reported to decreasemethotrexate clearance, resulting in increased/prolonged blood methotrexate concentration topotentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored inpatients treated concomitantly with the two drugs

Oral contraceptives and other pharmacokinetics interactions

Levetiracetam 1000 mg daily did not influence the pharmacokinetics of oral contraceptives (ethinyl-estradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone) were notmodified. Levetiracetam 2000 mg daily did not influence the pharmacokinetics of digoxin andwarfarin; prothrombin times were not modified. Co-administration with digoxin, oral contraceptivesand warfarin did not influence the pharmacokinetics of levetiracetam.

Alcohol

No data on the interaction of levetiracetam with alcohol are available.

Women of child bearing potential

Specialist advice should be given to women who are of childbearing potential. Treatment withlevetiracetam should be reviewed when a woman is planning to become pregnant. As with allantiepileptic medicines, sudden discontinuation of levetiracetam should be avoided as this may lead tobreakthrough seizures that could have serious consequences for the woman and the unborn child.

Monotherapy should be preferred whenever possible because therapy with multiple antiepilepticmedicines AEDs could be associated with a higher risk of congenital malformations thanmonotherapy, depending on the associated antiepileptics.

A large amount of postmarketing data on pregnant women exposed to levetiracetam monotherapy(more than 1800, among which in more than 1500 exposure occurred during the 1st trimester) do notsuggest an increase in the risk for major congenital malformations. Only limited evidence is availableon the neurodevelopment of children exposed to levetiracetam monotherapy in utero. However,current epidemiological studies (on about 100 children) do not suggest an increased risk ofneurodevelopmental disorders or delays.

Levetiracetam can be used during pregnancy, if after careful assessment it is considered clinicallyneeded. In such case, the lowest effective dose is recommended.

Physiological changes during pregnancy may affect levetiracetam concentration. Decrease inlevetiracetam plasma concentrations has been observed during pregnancy. This decrease is morepronounced during the third trimester (up to 60% of baseline concentration before pregnancy).

Appropriate clinical management of pregnant women treated with levetiracetam should be ensured.

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 treatmentshould be weighed considering the importance of breastfeeding.

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

Levetiracetam has minor or moderate influence on the ability to drive and use machines. Due topossible different individual sensitivity, some patients might experience somnolence or other centralnervous system related symptoms, especially at the beginning of treatment or following a doseincrease. 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 isestablished that their ability to perform such activities is not affected.

The most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigueand dizziness. The adverse reaction profile presented below is based on the analysis of pooledplacebo-controlled clinical trials with all indications studied, with a total of 3416 patients treated withlevetiracetam. These data are supplemented with the use of levetiracetam in corresponding open-labelextension studies, as well as post-marketing experience. The safety profile of levetiracetam isgenerally similar across age groups (adult and paediatric patients) and across the approved epilepsyindications. Since there was limited exposure for levetiracetam intravenous use and since oral andintravenous formulations are bioequivalent, the safety information of levetiracetam intravenous willrely on levetiracetam oral use.

Adverse reactions reported in clinical studies (adults, adolescents, children and infants > 1 month) andfrom post-marketing experience are listed in the following table per System Organ Class and perfrequency. Adverse reactions are presented in the order of decreasing seriousness and their frequencyis defined as follows: very common (≥1/10); common (≥ 1/100 to <1/10); uncommon: (≥ 1/1000 to<1/100); rare (≥ 1/10000 to <1/1000) and very rare (<1/10000).

MedDRA SOC Frequency category

Very common Common Uncommon Rare Very rare

Infections and Nasopharyngitis Infectioninfestations

Blood and Thrombocytopenia, Pancytopenialymphatic leukopenia neutropenia,system agranulocytosisdisorders

Immune system Drug reactiondisorders with eosinophiliaand systemicsymptoms(DRESS)(1),hypersensitivity(includingangioedema andanaphylaxis)

Metabolism and Anorexia Weight decreased, Hyponatraemianutrition weight increasedisorders

Psychiatric Depression, Suicide attempt, Completed Obsessive

MedDRA SOC Frequency category

Very common Common Uncommon Rare Very raredisorders hostility/ suicidal ideation, suicide, compulsiveaggression, psychotic disorder, personality disorder(2)anxiety, abnormal disorder, thinkinginsomnia, behaviour, abnormal,nervousness/ hallucination, deliriumirritability anger, confusionalstate, panic attack,affectlability/moodswings, agitation

Nervous system Somnolence, Convulsion, Amnesia, memory Choreoathetosis,disorders headache balance impairment, dyskinesia,disorder, coordination hyperkinesia, gaitdizziness, abnormal/ataxia, disturbance,lethargy, paraesthesia, encophalopathy,tremor disturbance in seizuresattention aggravated,neurolepticmalignantsyndrome(3)

Eye disorders Diplopia, visionblurred

Ear and Vertigolabyrinthdisorders

Cardiac Electrocardiogradisorders m QT prolonged

Respiratory, Coughthoracic andmediastinaldisorders

Gastrointestinal Abdominal Pancreatitisdisorders pain,diarrhoea,dyspepsia,vomiting,nausea

Hepatobiliary Liver function test Hepatic failure,disorders abnormal hepatitis

Renal and Acute kidneyurinary injurydisorders

Skin and Rash Alopecia, eczema, Toxic epidermalsubcutaneous pruritus, necrolysis,tissue disorders Stevens-Johnsonsyndrome,erythemamultiforme

Musculoskeletal Muscular Rhabdomyolysisand connective weakness, myalgia and blood creatinetissue disorders phosphokinaseincreased(3)

General Asthenia/fatigdisorders and ueadministration

MedDRA SOC Frequency category

Very common Common Uncommon Rare Very raresite conditions

Injury, Injurypoisoning andproceduralcomplications(1) See Description of selected adverse reactions.(2) Very rare cases of development of obsessive-compulsive disorders (OCD) in patients withunderlying history of OCD or psychiatric disorders have been observed in post-marketingsurveillance.(3) Prevalence is significantly higher in Japanese patients when compared to non-Japanese patients.

Multiorgan hypersensitivity reactions

Multiorgan hypersensitivity reactions (also known as Drug Reaction with Eosinophilia and Systemic

Symptoms, DRESS) have been reported rarely in patients treated with levetiracetam. Clinicalmanifestations may develop 2 to 8 weeks after starting treatment. These reactions are variable inexpression, but typically present with fever, rash, facial oedema, lymphadenopathies, haematologicabnormalities and can be associated with involvement of different organ systems, mostly the liver. Ifmultiorgan hypersensitivity reaction is suspected, levetiracetam should be discontinued.

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

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

Bone marrow suppression was identified in some of the cases of pancytopenia.

Cases of encephalopathy generally occurred at the beginning of the treatment (few days to a fewmonths) and were reversible after treatment discontinuation.

In patients aged 1 month to less than 4 years, a total of 190 patients have been treated withlevetiracetam in placebo-controlled and open label extension studies. Sixty of these patients weretreated with levetiracetam in placebo-controlled studies. In patients aged 4-16 years, a total of 645patients 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 thesepaediatric age ranges, these data are supplemented with the post-marketing experience of the use oflevetiracetam.

In addition, 101 infants aged less than 12 months have been exposed in a post authorization safetystudy. No new safety concerns for levetiracetam were identified for infants less than 12 months of agewith epilepsy.

The adverse reaction profile of levetiracetam is generally similar across age groups and across theapproved epilepsy indications. Safety results in paediatric patients in placebo-controlled clinicalstudies were consistent with the safety profile of levetiracetam in adults except for behavioural andpsychiatric adverse reactions which were more common in children than in adults. In children andadolescents aged 4 to 16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), moodswings (common, 2.1%), affect lability (common, 1.7%), aggression (common, 8.2%), abnormalbehaviour (common, 5.6%), and lethargy (common, 3.9%) were reported more frequently than in otherage 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 morefrequently 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 assessedthe cognitive and neuropsychological effects of levetiracetam in children 4 to 16 years of age withpartial onset seizures. It was concluded that levetiracetam was not different (non inferior) fromplacebo 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 emotionalfunctioning indicated a worsening in levetiracetam treated patients on aggressive behaviour asmeasured in a standardized and systematic way using a validated instrument (CBCL - Achenbach

Child Behavior Checklist). However, subjects, who took levetiracetam in the long-term open labelfollow-up study, did not experience a worsening, on average, in their behavioural and emotionalfunctioning; in particular measures of aggressive behavior were not worse than baseline.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and comawere observed with levetiracetam overdoses.

There is no specific antidote for levetiracetam. Treatment of an overdose will be symptomatic and mayinclude haemodialysis. The dialyser extraction efficiency is 60 % for levetiracetam and 74 % for theprimary metabolite.

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

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

The mechanism of action of levetiracetam still remains to be fully elucidated. In vitro and in vivoexperiments suggest that levetiracetam does not alter basic cell characteristics and normalneurotransmission.

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 partiallyreverses 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 braintissue. This binding site is the synaptic vesicle protein 2A, believed to be involved in vesicle fusionand neurotransmitter exocytosis. Levetiracetam and related analogues show a rank order of affinity forbinding to the synaptic vesicle protein 2A which correlates with the potency of their anti-seizureprotection in the mouse audiogenic model of epilepsy. This finding suggests that the interactionbetween levetiracetam and the synaptic vesicle protein 2A seems to contribute to the antiepilepticmechanism of action of the medicinal product.

Levetiracetam induces seizure protection in a broad range of animal models of partial and primarygeneralised seizures without having a pro-convulsant effect. The primary metabolite is inactive. Inman, an activity in both partial and generalised epilepsy conditions (epileptiform discharge/photoparoxysmal response) has confirmed the broad spectrum pharmacological profile oflevetiracetam.

Adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisationin adults, adolescents and children from 4 years of age with epilepsy:

In adults, levetiracetam efficacy has been demonstrated in 3 double-blind, placebo-controlled studiesat 1000 mg, 2000 mg, or 3000 mg/day, given in 2 divided doses, with a treatment duration of up to 18weeks. In a pooled analysis, the percentage of patients who achieved 50% or greater reduction frombaseline 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% forpatients on placebo.

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. Inthis study, the patients received levetiracetam as a fixed dose of 60 mg/kg/day (with twice a daydosing).44.6% of the levetiracetam treated patients and 19.6% of the patients on placebo had a 50% or greaterreduction from baseline in the partial onset seizure frequency per week. With continued long-termtreatment, 11.4% of the patients were seizure-free for at least 6 months and 7.2% were seizure-free forat least 1 year.35 infants aged less than 1 year with partial onset seizures have been exposed in placebo-control clinicalstudies of which only 13 were aged < 6 months.

Monotherapy in the treatment of partial onset seizures with or without secondary generalisation inpatients 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 orolder with newly or recently diagnosed epilepsy. The patients had to present with unprovoked partialseizures or with generalized tonic-clonic seizures only. The patients were randomized tocarbamazepine CR 400 - 1200 mg/day or levetiracetam 1000 - 3000 mg/day, the duration of thetreatment 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% ofcarbamazepine-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% and58.5% of subjects on levetiracetam and on carbamazepine CR respectively).

In a study reflecting clinical practice, the concomitant antiepileptic medication could be withdrawn ina limited number of patients who responded to levetiracetam adjunctive therapy (36 adult patients outof 69).

Adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents from 12 years ofage with Juvenile Myoclonic Epilepsy.

Levetiracetam efficacy was established in a double-blind, placebo-controlled study of 16 weeksduration, in patients 12 years of age and older suffering from idiopathic generalized epilepsy withmyoclonic seizures in different syndromes. The majority of patients presented with juvenile myoclonicepilepsy.

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 thepatients were free of myoclonic seizures for at least 6 months and 21.0% were free of myoclonicseizures for at least 1 year.

Adjunctive therapy in the treatment of primary generalised tonic-clonic seizures in adults andadolescents from 12 years of age with idiopathic generalised epilepsy.

Levetiracetam efficacy was established in a 24-week double-blind, placebo-controlled study whichincluded adults, adolescents and a limited number of children suffering from idiopathic generalizedepilepsy with primary generalized tonic-clonic (PGTC) seizures in different syndromes (juvenilemyoclonic 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 andadolescents 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 greaterdecrease in the frequency of PGTC seizures per week. With continued long-term treatment, 47.4% ofthe patients were free of tonic-clonic seizures for at least 6 months and 31.5% were free of tonic-clonicseizures for at least 1 year.

The pharmacokinetic profile has been characterized following oral administration. A single dose of1500 mg levetiracetam diluted in 100 ml of a compatible diluent and infused intravenously over 15minutes 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 chlorideinfused over 15 minutes and doses up to 2500 mg diluted in 100 ml of 0.9% sodium chloride infusedover 5 minutes was evaluated. The pharmacokinetic and safety profiles did not identify any safetyconcerns.

Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear withlow intra- and inter-subject variability. There is no modification of the clearance after repeatedadministration. The time independent pharmacokinetic profile of levetiracetam was also confirmedfollowing 1500 mg intravenous infusion for 4 days with twice daily dosing.

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

Adults and adolescents

Peak plasma concentration (Cmax) observed in 17 subjects following a single intravenous dose of1500 mg infused over 15 minutes was 51 ± 19 μg/mL (arithmetic average ± standard deviation).

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 totalbody water volume.

Levetiracetam is not extensively metabolised in humans. The major metabolic pathway (24 % of thedose) 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 wasmeasurable in a large number of tissues including blood cells. The metabolite ucb L057 ispharmacologically inactive.

Two minor metabolites were also identified. One was obtained by hydroxylation of the pyrrolidonering (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 primarymetabolite.

In vitro, levetiracetam and its primary metabolite have been shown not to inhibit the major humanliver cytochrome P450 isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyltransferase (UGT1A1 and UGT1A6) and epoxide hydroxylase activities. In addition, levetiracetamdoes 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 invivo interaction data on oral contraceptives, digoxin and warfarin indicate that no significant enzymeinduction is expected in vivo. Therefore, the interaction of levetiracetam with other substances, or viceversa, is unlikely.

The plasma half-life in adults was 7±1 hours and did not vary either with dose, route of administrationor 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 (approximately93 % of the dose was excreted within 48 hours). Excretion via faeces accounted for only 0.3 % of thedose. 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 indicatingthat levetiracetam is excreted by glomerular filtration with subsequent tubular reabsorption and thatthe primary metabolite is also excreted by active tubular secretion in addition to glomerular filtration.

Levetiracetam elimination is correlated to creatinine clearance.

In the elderly, the half-life is increased by about 40 % (10 to 11 hours). This is related to the decreasein renal function in this population (see section 4.2).

The apparent body clearance of both levetiracetam and of its primary metabolite is correlated to thecreatinine clearance. It is therefore recommended to adjust the maintenance daily dose oflevetiracetam, 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 hoursduring interdialytic and intradialytic periods, respectively. The fractional removal of levetiracetam was51 % during a typical 4-hour dialysis session.

In subjects with mild and moderate hepatic impairment, there was no relevant modification of theclearance of levetiracetam. In most subjects with severe hepatic impairment, the clearance oflevetiracetam was reduced by more than 50 % due to a concomitant renal impairment (see section 4.2).

Children (4 to 12 years)

The pharmacokinetics in paediatric patients has not been investigated after intravenous administration.

However, based on the pharmacokinetic characteristics of levetiracetam, the pharmacokinetics in adultsafter intravenous administration and the pharmacokinetics in children after oral administration, theexposure (AUC) of levetiracetam is expected to be similar in paediatric patients aged 4 to 12 years afterintravenous and oral administration.

Following single oral dose administration (20 mg/kg) to epileptic children (6 to 12 years), the half-lifeof 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 afterdosing. Linear and dose proportional increases were observed for peak plasma concentrations and areaunder the curve. The elimination half-life was approximately 5 hours. The apparent body clearancewas 1.1 ml/min/kg.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, genotoxicity and carcinogenic potential.

Adverse effects not observed in clinical studies but seen in the rat and to a lesser extent in the mouse atexposure levels similar to human exposure levels and with possible relevance for clinical use wereliver changes, indicating an adaptive response such as increased weight and centrilobular hypertrophy,fatty infiltration and increased liver enzymes in plasma.

No adverse reactions on male or female fertility or reproduction performance were observed in rats atdoses up to 1800 mg/kg/day (x 6 the MRHD on a mg/m2 or exposure basis) in parents and F1generation.

Two embryo-foetal development (EFD) studies were performed in rats at 400, 1200 and3600 mg/kg/day. At 3600 mg/kg/day, in only one of the 2 EFD studies, there was a slight decrease infoetal weight associated with a marginal increase in skeletal variations/minor anomalies. There was noeffect on embryomortality and no increased incidence of malformations. The NOAEL (No Observed

Adverse Effect Level) was 3600 mg/kg/day for pregnant female rats (x 12 the MRHD on a mg/m2basis) and 1200 mg/kg/day for fetuses.

Four embryo-foetal development studies were performed in rabbits covering doses of 200, 600, 800,1200 and 1800 mg/kg/day. The dose level of 1800 mg/kg/day induced a marked maternal toxicity anda decrease in foetal weight associated with increased incidence of fetuses with cardiovascular/skeletalanomalies. The NOAEL was <200 mg/kg/day for the dams and 200 mg/kg/day for the fetuses (equalto the MRHD on a mg/m2 basis).

A peri- and post-natal development study was performed in rats with levetiracetam doses of 70, 350and 1800 mg/kg/day. The NOAEL was ≥ 1800 mg/kg/day for the F0 females, and for the survival,growth and development of the F1 offspring up to weaning.(x 6 the MRHD on a mg/m2 basis).

Neonatal and juvenile animal studies in rats and dogs demonstrated that there were no adverse effectsseen in any of the standard developmental or maturation endpoints at doses up to 1800 mg/kg/day (x6-17 the MRHD on a mg/m2 basis).

Sodium acetate trihydrate

Glacial acetic acid

Sodium chloride

Water for injection

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

3 years.

From a microbiological point of view, the product should be used immediately after dilution. If notused immediately, in-use storage time and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlledand validated aseptic conditions.

This medicinal product does not require any special storage conditions.

For storage conditions of the diluted medicinal product, see section 6.3.

Levetiracetam SUN is packed in colorless tubular glass vial (type I) with 20 mm grey bromobutylrubber stopper sealed with white flip-top aluminum seal.

Each carton contains 10 vials.

See Table 1 for the recommended preparation and administration of Levetiracetam SUN concentratefor solution for infusion to achieve a total daily dose of 500 mg, 1000 mg, 2000 mg, or 3000 mg intwo divided doses.

Table 1. Preparation and administration of Levetiracetam SUN concentrate for solution for infusion

Dose Withdrawal Volume Volume of Infusion Frequency of Total Daily

Diluent Time administration Dose250 mg 2.5 ml (half 5 ml vial) 100 ml 15 minutes Twice daily 500 mg/day500 mg 5 ml (one 5 ml vial) 100 ml 15 minutes Twice daily 1000 mg/day1000 mg 10 ml (two 5 ml vials) 100 ml 15 minutes Twice daily 2000 mg/day1500 mg 15 ml (three 5 ml vials) 100 ml 15 minutes Twice daily 3000 mg/day

This medicinal product is for single use only, any unused solution should be discarded.

Levetiracetam SUN concentrate for solution for infusion was found to be physically compatible andchemically stable when mixed with the following diluents for at least 24 hours and stored in PVC bagsat controlled room temperature 15-25°C.

Diluents:

- Sodium chloride 9 mg/ml (0.9%) solution for injection

- Lactated Ringer's solution for injection

- Dextrose 50 mg-ml (5%) solution for injection

Medicinal product with particulate matter or discoloration should not be used.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Sun Pharmaceutical Industries Europe B.V.

Polarisavenue 872132 JH Hoofddorp

The Netherlands

EU/1/11/741/001

Date of first authorisation: 14 December 2011

Date of latest renewal: 14 November 2016

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.