LEVETIRACETAM ACTAVIS GROUP 100mg / ml oral solution medication leaflet

Levetiracetam Actavis Group 100 mg/ml oral solution

Each ml contains 100 mg levetiracetam.

Each ml contains 1.50 mg of methyl parahydroxybenzoate (E218), 0.15 mg of propylparahydroxybenzoate (E216), 290 mg of maltitol liquid (E965), 3,26 mg propylene glycol (E 1520)and 0.25 mg of sodium.

For the full list of excipients, see section 6.1.

Oral solution.

Clear, faint yellowish-brown solution.

Levetiracetam Actavis Group is indicated as monotherapy in the treatment of partial onset seizureswith or without secondary generalisation in adults and adolescents from 16 years of age with newlydiagnosed epilepsy.

Levetiracetam Actavis Group is indicated as 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 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 from12 years of age with Idiopathic Generalised Epilepsy.

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 1500 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 1 month 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.

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; ininfants older than 6 months, children and adolescents weighing less than 50 kg: dose decrease shouldnot exceed 10 mg/kg twice daily every two weeks; in infants (less than 6 months): dose decreaseshould not exceed 7 mg/ kg twice daily 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 adolescentsweighing 50 kg 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)

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

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 patientsundergoing dialysis (1) - 500 to 1000 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 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, for youngadolescents, children and infants, using the following formula (Schwartz formula):

Height (cm) x ks

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

Serum Creatinine (mg/dl)ks= 0.45 in term infants to 1 year old; ks= 0.55 in children to less than 13 years and in adolescentfemale; ks= 0.7 in adolescent male

Dosing adjustment for infants, children and adolescent patients weighing less than 50 kg withimpaired renal function:

Dose and frequency (1)

Creatinine

Group clearance Infants 1 to less than Infants 6 to 23 months, children(ml/min/1.73m2) 6 months and adolescents weighing lessthan 50 kg

Normal ≥ 80 7 to 21 mg/kg (0.07 to 10 to 30 mg/kg (0.10 to0.21 ml/kg) twice daily 0.30 ml/kg) twice daily

Mild 50-79 7 to 14 mg/kg (0.07 to 10 to 20 mg/kg (0.10 to0.14 ml/kg) twice daily 0.20 ml/kg) twice daily

Moderate 30-49 3.5 to 10.5 mg/kg (0.035 5 to 15 mg/kg (0.05 toto 0.105 ml/kg) twice 0.15 ml/kg) twice dailydaily

Severe < 30 3.5 to 7 mg/kg (0.035 to 5 to 10 mg/kg (0.05 to0.07 ml/kg) twice daily 0.10 ml/kg) twice daily

End-stage renal 7 to 14 mg/kg (0.07 to 10 to 20 mg/kg (0.10 todisease patients -- 0.14 ml/kg) once daily (2) 0.20 ml/kg) once daily (3) (5)undergoing dialysis (4)(1) Levetiracetam Actavis Group oral solution should be used for doses under 250 mg, for doses notmultiple of 250 mg when dosing recommendation is not achievable by taking multiple tablets and forpatients unable to swallow tablets.(2) A 10.5 mg/kg (0.105 ml/kg) loading dose is recommended on the first day of treatment withlevetiracetam.(3) A 15 mg/kg (0.15 ml/kg) loading dose is recommended on the first day of treatment withlevetiracetam.(4) Following dialysis, a 3.5 to 7 mg/kg (0.035 to 0.07 ml/kg) supplemental dose is recommended.(5) 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 oral solution is the preferred formulation for use in infants and children under the age of 6 years.

In addition, the available dose strengths of the tablets are not appropriate for initial treatment inchildren weighing less than 25 kg, for patients unable to swallow tablets or for the administration ofdoses below 250 mg. In all of the above cases Levetiracetam oral solution should be used.

The safety and efficacy of levetiracetam in children and adolescents below 16 years as monotherapytreatment 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 infants aged 6 to 23 months, children (2 to 11 years) and adolescents (12 to17 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 by 10 mg/kg twicedaily every 2 weeks up to 30 mg/kg twice daily. Dose changes should not exceed increases ordecreases of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used for allindications.

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 infants from 6 months of age, children and adolescents:

Weight Starting dose: Maximum dose:10 mg/kg twice daily 30 mg/kg twice daily6 kg (1) 60 mg (0.6 ml) twice daily 180 mg (1.8 ml) twice daily10 kg (1) 100 mg (1 ml) twice daily 300 mg (3 ml) twice daily15 kg (1) 150 mg (1.5 ml) twice daily 450 mg (4.5 ml) twice daily20 kg (1) 200 mg (2 ml) twice daily 600 mg (6 ml) 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 Levetiracetam Actavis Group100 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 aged from 1 month to less than 6 months

The initial therapeutic dose is 7 mg/kg twice daily.

Depending upon the clinical response and tolerability, the dose can be increased by 7 mg/kg twicedaily every 2 weeks up to recommended dose of 21 mg/kg twice daily. Dose changes should notexceed 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 Levetiracetam Actavis Group 100 mg/ml oral solution.

Dose recommendations for infants aged from 1 month to less than 6 months:

Weight Starting dose: Maximum dose:7 mg/kg twice daily 21 mg/kg twice daily4 kg 28 mg (0.3 ml) twice daily 84 mg (0.85 ml) twice daily5 kg 35 mg (0.35 ml) twice daily 105 mg (1.05 ml) twice daily7 kg 49 mg (0.5 ml) twice daily 147 mg (1.5 ml) twice daily

Three presentations are available:

- A 300 ml bottle with a 10 ml oral syringe (delivering up to 1000 mg levetiracetam) graduatedevery 0.25 ml (corresponding to 25 mg). This presentation should be prescribed for childrenaged 4 years and older, adolescents and adults.

- A 300 ml bottle with a 3 ml oral syringe (delivering up to 300 mg levetiracetam) graduatedevery 0.1 ml (corresponding to 10 mg). In order to ensure the accuracy of the dosing, thispresentation should be prescribed for infants and young children aged from 6 months to lessthan 4 years.

- A 300 ml bottle with a 1 ml oral syringe (delivering up to 100 mg levetiracetam) graduatedevery 0.05 ml (corresponding to 5 mg). In order to ensure the accuracy of the dosing, thispresentation should be prescribed for infants aged 1 month to less than 6 months.

The oral solution may be diluted in a glass of water or baby’s bottle and may be taken with or withoutfood. After oral administration the bitter taste of levetiracetam may be experienced.

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 andbehaviours 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 orbehaviour 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.

Methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216)

Levetiracetam Actavis Group 100 mg/ml oral solution contains methyl parahydroxybenzoate (E218)and propyl parahydroxybenzoate (E216) which may cause allergic reactions (possibly delayed).

Maltitol liquid

Levetiracetam Actavis Group 100 mg/ml oral solution contains maltitol liquid. Patients with rarehereditary problems of fructose intolerance should not take this medicinal product.

Propylene glycol (E1520)

Levetiracetam Actavis Group 100 mg/ml oral solution contains 3,26 mg propylene glycol (E1520) ineach ml.

Co-administration with any substrate for alcohol dehydrogenase such as ethanol may induce seriousadverse effects in neonates.

This medicinal product contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially‘sodium-free’.

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 pharmacokinetic interactions in children and adolescents with epilepsy(4 to 17 years) confirmed that adjunctive therapy with orally administered levetiracetam did notinfluence the steady-state serum concentrations of concomitantly administered carbamazepine andvalproate. However, data suggested a 20 % higher levetiracetam clearance in children taking enzyme-inducing antiepileptic medicinal products. Dose adjustment 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.

Laxatives

There have been isolated reports of decreased levetiracetam efficacy when the osmotic laxativemacrogol has been concomitantly administered with oral levetiracetam. Therefore, macrogol shouldnot be taken orally for one hour before and for one hour after taking levetiracetam.

Food and alcohol

The extent of absorption of levetiracetam was not altered by food, but the rate of absorption wasslightly reduced.

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.

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 Frequency category

SOC Very Common Uncommon Rare Very rarecommon

Infections and Nasopharyng Infectioninfestations itis

Blood and Thrombocytop Pancytopenia,lymphatic enia, neutropenia,system leukopenia agranulocytosisdisorders

Immune Drug reactionsystem withdisorders eosinophilia andsystemicsymptoms(DRESS),

Hypersensitivity(includingangioedema andanaphylaxis)

Metabolism Anorexia Weight Hyponatraemiaand nutrition decreased,disorders weight increase

Psychiatric Depression, Suicide Completed Obsessivedisorders hostility/ attempt, suicide, compulsiveaggression, suicidal personality disorder**anxiety, ideation, disorder,insomnia, psychotic thinkingnervousness disorder, abnormal,/ irritability abnormal deliriumbehaviour,hallucination,anger,confusionalstate, panicattack, affectlability/moodswings,agitation

MedDRA Frequency category

SOC Very Common Uncommon Rare Very rarecommon

Nervous Somnolence, Convulsion, Amnesia, Choreoathetosis,system headache balance memory dyskinesia,disorders disorder, impairment, hyperkinesia,dizziness, coordination gait disturbance,lethargy, abnormal/ataxi encephalopathy,tremor a, paraesthesia, seizuresdisturbance in aggravated,attention Neurolepticmalignantsyndrome*

Eye disorders Diplopia,vision blurred

Ear and Vertigolabyrinthdisorders

Cardiac Electrocardiogradisorders m QT prolonged

Respiratory, Coughthoracic andmediastinaldisorders

Gastrointestin Abdominal Pancreatitisal disorders pain,diarrhoea,dyspepsia,vomiting,nausea

Hepatobiliary Liver function Hepatic failure,disorders test abnormal hepatitis

Renal and Acute Kidney

Urinary injury

Disorders

Skin and Rash Alopecia, Toxic epidermalsubcutaneous eczema, necrolysis,tissue pruritus, Stevens-Johnsondisorders syndrome,erythemamultiforme

Musculoskelet Muscular Rhabdomyolysisal and weakness, and bloodconnective myalgia creatinetissue phosphokinasedisorders increased*

General Asthenia/disorders and fatigueadministrationsite conditions

Injury, Injurypoisoning andproceduralcomplications

* Prevalence is significantly higher in Japanese patients when compared to non-Japanese patients.

** 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.

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 behavioral and emotionalfunctioning indicated a worsening in levetiracetam treated patients on aggressive behaviour asmeasured in a standardised and systematic way using a validated instrument (CBCL - Achenbach

Child Behaviour 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.

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 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 of α-ethyl-2-oxo-1-pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances.

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 analogs 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 (epileptiformdischarge/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, children and infants from 1 month 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 to18 weeks. 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.

In paediatric patients (1 month to less than 4 years of age), levetiracetam efficacy was established in adouble-blind, placebo-controlled study, which included 116 patients and had a treatment duration of5 days. In this study, patients were prescribed 20 mg/kg, 25 mg/kg, 40 mg/kg or 50 mg/kg daily doseof oral solution based on their age titration schedule. A dose of 20 mg/kg/day titrating to 40 mg/kg/dayfor infants one month to less than six months and a dose of 25 mg/kg/day titrating to 50 mg/kg/day forinfants and children 6 months to less than 4 years old, was use in this study. The total daily dose wasadministered twice daily.

The primary measure of effectiveness was the responder rate (percent of patients with ≥ 50% reductionfrom baseline in average daily partial onset seizure frequency) assessed by a blinded central readerusing a 48-hour video EEG. The efficacy analysis consisted of 109 patients who had at least 24 hoursof video EEG in both baseline and evaluation periods. 43.6% of the levetiracetam treated patients and19.6% of the patients on placebo were considered as responders. The results are consistent across agegroup. With continued long-term treatment, 8.6% of the patients were seizure-free for at least6 months and 7.8 % were seizure-free for at least 1 year.35 infants aged less than 1 year with partial onset seizures have been exposed in placebo-controlclinical studies 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.

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. There is no evidence for any relevant gender, race or circadian variability. Thepharmacokinetic 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 oflevetiracetam expressed as mg/kg bodyweight. Therefore there is no need for plasma level monitoringof levetiracetam.

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

Adults and adolescents

Levetiracetam is rapidly absorbed after oral administration. Oral absolute bioavailability is close to100 %.

Peak plasma concentrations (Cmax) are achieved at 1.3 hours after dosing. Steady-state is achieved aftertwo days of a twice daily administration schedule.

Peak concentrations (Cmax) are typically 31 and 43 µg/ml following a single 1000 mg dose andrepeated 1000 mg twice daily dose, respectively.

The extent of absorption is dose-independent and is not altered by food.

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% and24% 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 of

Levetiracetam Actavis Group, based on creatinine clearance in patients with moderate and severe renalimpairment (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 was 51% 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)

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.

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 wereobserved approximately 1 hour after dosing. The pharmacokinetic results indicated that half-life wasshorter (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 inbody weight) and apparent volume of distribution. Age also had an influence on both parameters. Thiseffect was pronounced for the younger infants, and subsided as age increased, to become negligiblearound 4 years of age.

In both population pharmacokinetic analyses, there was about a 20% increase of apparent clearance oflevetiracetam when it was co-administered with an enzyme-inducing antiepileptic medicinal product.

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 amg/m2 basis) 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(x 6- 17 the MRHD on a mg/m2 basis).

Sodium citrate

Citric acid monohydrate

Methyl parahydroxybenzoate (E218)

Propyl parahydroxybenzoate (E216)

Ammonium glycyrrhizate

Glycerin

Glycerol (E422)

Maltitol liquid (E965)

Acesulfame potassium (E950)

Grape flavour (contains propylene glycol)

Purified water

Not applicable.

3 years.

After first opening: 7 months

This medicinal product does not require any special storage conditions.

300 ml amber glass bottle (type III) with a white child resistant closure (polypropylene) in a cardboardbox also containing a 10 ml graduated oral syringe (polypropylene, polyethylene).

300 ml amber glass bottle (type III) with a white child resistant closure (polypropylene) in a cardboardbox also containing a 3 ml graduated oral syringe (polypropylene, polyethylene) and an adaptor for thesyringe (polyethylene).

300 ml amber glass bottle (type III) with a white child resistant closure (polypropylene) in a cardboardbox also containing a 1 ml graduated oral syringe (polypropylene, polyethylene) and an adaptor for thesyringe (polyethylene).

Not all pack sizes may be marketed.

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

Actavis Group PTC ehf.

Dalshraun 1220 Hafnarfjörður

Iceland

EU/1/11/738/001

EU/1/11/738/002

EU/1/11/738/003

Date of first authorisation: 5 December 2011

Date of latest renewal: 08 August 2016

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Detailed information on this product is available on the website of the European Medicines Agencyhttp://www.ema.europa.eu