Vales is indicated as monotherapy in the treatment of partial onset seizures with or

without secondary generalisation in adults and adolescents from 16 years of age with

newly diagnosed epilepsy.

Vales 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 tonicclonic seizures in adults and adolescents

from 12 years of age with Idiopathic Generalised Epilepsy.

Vales concentrate is an alternative for patients (adults and children from 4 years of age)

when oral administration is temporarily not feasible.

Posology

Vales 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.

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 (≥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

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.

Discontinuation

If levetiracetam 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 infants older than 6 months, children and adolescents weighting less than

50 kg: dose decrease should not exceed 10 mg/kg twice daily every two 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 “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:

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

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 > 80 500 to 1,500 mg twice daily Mild 50-79 500 to 1,000 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 undergoing dialysis (1) - 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= 0.55 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 Children from 4 years and adolescents weighing less than 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 disease patients undergoing dialysis - 10 to 20 mg/kg (0.10 to 0.20 ml/kg) one daily(1)(2) (1) A 15 mg/kg (0.15 ml/kg) loading dose is recommended on the first day of treatment with levetiracetam. (2) 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 age, weight and dose. The safety and efficacy of Levetiracetam concentrate for solution for infusion in infants and children less than 4 years have not been established The oral solution is the preferred formulation for use in infants and children under the age of 6 years. Monotherapy The safety and efficacy of Levetiracetam in children and adolescents below 16 years as monotherapy treatment have not been established. No data are available. Add-on therapy for children aged 4 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 children and adolescents: Weight Starting dose: 10 mg/kg twice daily Maximum dose: 30 mg/kg twice daily 15 kg(1) 150 mg twice daily 450 mg twice daily 20 kg(1) 200 mg twice daily 600 mg twice daily 25 kg 250 mg twice daily 750 mg twice daily From 50 kg(2) 500 mg twice daily 1,500 twice daily (1) Children 25 kg or less should preferably start the treatment with Levetiracetam 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 and children less than 4 years The safety and efficacy of levetiracetam 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. Method of administration–solution for infusion Vales 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).

Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipients listed in section 6.1

Renal impairment

The administration of levetiracetam 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 antiepileptic agents (including levetiracetam). A metaanalysis of randomized

placebocontrolled trials of antiepileptic 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

This medicinal product contains 2.5 mmol (or 57 mg) sodium per maximum single dose

(0.8 mmol (or 19 mg) per vial). To be taken into consideration by patients on a controlled

sodium diet.

Antiepileptic medicinal products

Premarketing data from clinical studies conducted in adults indicate that levetiracetam 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 levetiracetam.

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 steadystate serum concentrations of concomitantly

administered carbamazepine and valproate. However, data suggested a 20 % higher

levetiracetam clearance in children taking enzymeinducing 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.

Methotrexate

Concomitant administration of levetiracetam and methotrexate has been reported to decrease

methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to

potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully

monitored in patients treated concomitantly with the two drugs.

Oral contraceptives and other pharmacokinetics interactions

Levetiracetam 1,000 mg daily did not influence the pharmacokinetics of oral contraceptives

(ethinylestradiol 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.

Coadministration with digoxin, oral contraceptives and warfarin did not influence the

pharmacokinetics of levetiracetam.

Alcohol

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

Pregnancy

Levetiracetam blood levels may decrease during pregnancy.

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. In animal studies,

levetiracetam produced evidence of developmental toxicity, including teratogenic effects, at

doses similar to or greater than human therapeutic doses. Levetiracetam should be used during

pregnancy only if the potential benefit justifies the potential risk to the fetus.

Oral administration of levetiracetam to female rats throughout pregnancy and lactation led to

increased incidences of minor fetal skeletal abnormalities and retarded offspring growth preand/

or postnatally at doses ≥350 mg/kg/day (equivalent to the maximum recommended human

dose of 3000 mg [MRHD] on a mg/m2 basis) and with increased pup mortality and offspring

behavioral alterations at a dose of 1800 mg/kg/day (6 times the MRHD on a mg/m2 basis). The

developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m2 basis).

There was no overt maternal toxicity at the doses used in this study.

Oral administration of levetiracetam to pregnant rabbits during the period of organogenesis

resulted in increased embryo fetal mortality and increased incidences of minor fetal skeletal

abnormalities at doses ≥600 mg/kg/day (4 times MRHD on a mg/m2 basis) and in decreased

fetal weights and increased incidences of fetal malformations at a dose of 1800 mg/kg/day (12

times the MRHD on a mg/m2 basis). The developmental no effect dose was 200 mg/kg/day

(equivalent to the MRHD on a mg/m2 basis). Maternal toxicity was also observed at 1800

mg/kg/day.

When levetiracetam was administered orally to pregnant rats during the period of

organogenesis, fetal weights were decreased and the incidence of fetal skeletal variations was

increased at a dose of 3600 mg/kg/day (12 times the MRHD). 1200 mg/kg/day (4 times the

MRHD) was a developmental no effect dose. There was no evidence of maternal toxicity in

this study.

Treatment of rats during the last third of gestation and throughout lactation produced no

adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the

MRHD on a mg/m2 basis).

Lactation

Levetiracetam is excreted in human milk. Because of the potential for serious adverse

reactions in nursing infants from levetiracetam, a decision should be made whether to

discontinue nursing or discontinue the drug, taking into account the importance of the drug to

the mother.

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.

 

Levetiracetam has minor or moderate influence on the ability to drive and use machines.

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.

Summary of the safety profile

The most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness.

The adverse reaction profile presented below is based on the analysis of pooled placebocontrolled clinical trials with all indications studied, with a total of 3,416 patients treated with levetiracetam. These data are supplemented with the use of levetiracetam in corresponding openlabel extension studies, as well as postmarketing experience. The safety profile of levetiracetam is generally similar across age groups (adult and paediatric patients) and across the approved epilepsy indications.

Tabulated list of adverse reactions

Adverse reactions reported in clinical studies (adults, adolescents, children and infants > 1 month) and from postmarketing experience are listed in the following table per System Organ Class and per frequency. Adverse reactions are presented in the order of decreasing seriousness and their frequency is defined as follows: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000).

MedDRA SOC	Frequency category
	Very common	Common	Uncommon	Rare
Infections and infestations	Nasopharyngitis			Infection
Blood and lymphatic system disorders			Thrombocytopenia, leukopenia	Pancytopenia (, neutropenia, agranulocytosis
Immune system disorders				Drug reaction with eosinophilia and systemic symptoms (DRESS). Hypersensitivity (including angioedema and anaphylaxis
Metabolism and nutrition disorders		Anorexia	Weight decreased, weight increase	Hyponatraemia
Psychiatric disorders		Depression, hostility / aggression, anxiety, insomnia, nervousness / irritability	Suicide attempt), suicidal ideation psychotic disorder), abnormal behaviour), hallucination, anger, confusional state, panic attack, affect lability/mood swings, agitation	Completed suicide), personality disorder, thinking abnormal
Nervous system disorders	Somnolence, headache	Convulsion, balance disorder, dizziness, lethargy, tremor	Amnesia, memory impairment, coordination abnormal/ataxia, paraesthesia, disturbance in attention	Choreoathetosis, dyskinesia), hyperkinesia
Eye disorders			Diplopia, vision blurred
Ear and labyrinth disorders		Vertigo
Respiratory, thoracic and mediastinal disorders		Cough
Gastrointestinal disorders		Abdominal pain, diarrhea, dyspepsia, vomiting, nausea		Pancreatitis
Hepatobiliary disorders			Liver function test abnormal	Hepatic failure, hepatitis
Skin and subcutaneous tissue disorders		Rash	Alopecia, eczema, pruritus,	Toxic epidermal necrolysis, Stevens Johnson syndrome), erythema multiforme
Musculoskeletal and connective tissue disorders			Muscular weakness, myalgia
General disorders and administration site conditions		Asthenia/fatigue
Injury, poisoning and procedural complications			Injury

Description of selected adverse reactions

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.

Paediatric population

In patients aged 1 month to less than 4 years, a total of 190 patients have been treated with levetiracetam in placebo controlled and open label extension studies. Sixty of these patients were treated with levetiracetam in placebo controlled studies. In patients aged 416 years, a total of 645 patients have been treated with levetiracetam in placebo controlled and open label extension studies. 233 of these patients were treated with levetiracetam in placebo controlled studies. In both these paediatric age ranges, these data are supplemented with the postmarketing experience of the use of levetiracetam.

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

The adverse reaction profile of levetiracetam is generally similar across age groups and across the approved epilepsy indications. Safety results in paediatric patients in placebo-controlled clinical studies were consistent with the safety profile of levetiracetam in adults except for behavioural and psychiatric adverse reactions which were more common in children than in adults. In children and adolescents aged 4 to 16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), mood swings (common, 2.1%), affect lability (common, 1.7%), aggression (common, 8.2%), abnormal behaviour (common, 5.6%), and lethargy (common, 3.9%) were reported more frequently than in other age ranges or in the overall safety profile. In infants and children aged 1 month to less than 4 years, irritability (very common, 11.7%) and coordination abnormal (common, 3.3%) were reported more frequently than in other age groups or in the overall safety profile.

A double blind, placebo controlled paediatric safety study with a non inferiority design has assessed the cognitive and neuropsychological effects of levetiracetam in children 4 to 16 years of age with partial onset seizures. It was concluded that Vales was not different (non inferior) from placebo with regard to the change from baseline of the LeiterR Attention and Memory, Memory Screen Composite score in the perprotocol population. Results related to behavioural and emotional functioning indicated a worsening in levetiracetam treated patients on aggressive behaviour as measured in a standardised and systematic way using a validated instrument (CBCL – Achenbach Child Behavior Checklist). However subjects, who took levetiracetam 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.

 

To report any side effects

  Saudi Arabia

National Pharmacovigilance & Drug Safety Center (NPC)

Fax: +966-11-205-7662

Call NPC at: +966-11-2038222, Exts: 2317-2356-2353-2354-2334-2340.

Toll free phone: 8002490000

E-mail: npc.drug@sfda.gov.sa

Website: www.sfda.gov.sa/npc

  Other GCC States

Please contact the relevant competent authority.

Symptoms

Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression

and coma were observed with levetiracetam 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.

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

The active substance, levetiracetam, is a pyrrolidone derivative (Senantiomer of αethyl-2-

oxo-1pyrrolidine acetamide), chemically unrelated to existing antiepileptic active

substances.

Mechanism of action

The mechanism of action of levetiracetam still remains to be fully elucidated. 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 Ntype Ca2+ currents and by reducing the release of Ca2+ from intraneuronal

stores. In addition, it partially reverses the reductions in GABA and glycinegated currents

induced by zinc and βcarbolines.

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 antiseizure 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 proconvulsant 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

doubleblind, Placebo controlled study, which included 198 patients and had a treatment

duration of 14 weeks. In this study, the patients received levetiracetam as a fixed dose of

60 mg/kg/day (with twice a day dosing).

44.6 % of the levetiracetam treated patients and 19.6 % of the patients on placebo had

a 50 % or greater reduction from baseline in the partial onset seizure frequency per week.

With continued long-term treatment, 11.4 % of the patients were seizure free for at least 6

months and 7.2 % were seizure free for at least 1 year.

In paediatric patients (1 month to less than 4 years of age), levetiracetam efficacy was

established in a double-blind, placebo controlled study, which included 116 patients and

had a treatment duration of 5 days. In this study, patients were prescribed 20 mg/kg, 25

mg/kg, 40 mg/kg or 50 mg/kg daily dose of oral solution based on their age titration

schedule. A dose of 20 mg/kg/day titrating to 40 mg/kg/day for infants one month to less

than six months and a dose of 25 mg/kg/day titrating to 50 mg/kg/day for infants and

children 6 months to less than 4 years old, was use in this study. The total daily dose was

administered twice daily.

The primary measure of effectiveness was the responder rate (percent of patients with ≥

50 % reduction from baseline in average daily partial onset seizure frequency) assessed by

a blinded central reader using a 48 hour video EEG. The efficacy analysis consisted of

109 patients who had at least 24 hours of video EEG in both baseline and evaluation

periods. 43.6 % of the levetiracetam treated patients and 19.6 % of the patients on placebo

were considered as responders. The results are consistent across age group. With

continued long term treatment, 8.6 % of the patients were seizure free for at least 6

months and 7.8 % were seizure free for at least 1 year.

35 infants aged less than 1 year with partial onset seizures have been exposed in placebo

control clinical studies of which only 13 were aged < 6 months.

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 24week 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.

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.

The pharmacokinetic profile has been characterized following oral administration. A 

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

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 Vales 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 dose

(approximately 93 % of the dose was excreted within 48 hours). Excretion via faeces

accounted for only 0.3 % of the dose.

The cumulative urinary excretion of levetiracetam and its primary metabolite accounted

for 66 % and 24 % of the dose, respectively during the first 48 hours.

The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml/min/kg respectively

indicating that levetiracetam is excreted by glomerular filtration with subsequent tubular

reabsorption and that the primary metabolite is also excreted by active tubular secretion in

addition to glomerular filtration. Levetiracetam elimination is correlated to creatinine

clearance.

Elderly

In the elderly, the half-life is increased by about 40 % (10 to 11 hours). This is related to

the decrease in renal function in this population (see section 4.2).

Renal impairment

The apparent body clearance of both levetiracetam and of its primary metabolite is

correlated to the creatinine clearance. It is therefore recommended to adjust the

maintenance daily dose of Vales, based on creatinine clearance in patients with moderate

and severe renal impairment (see section 4.2).

In anuric end-stage renal disease adult subjects the half life was approximately 25 and 3.1

hours during interdialytic and intradialytic periods, respectively.

The fractional removal of levetiracetam was 51 % during a typical 4hour dialysis session.

Hepatic impairment

In subjects with mild and moderate hepatic impairment, there was no relevant

modification of the clearance of levetiracetam. In most subjects with severe hepatic

impairment, the clearance of levetiracetam was reduced by more than 50 % due to a

concomitant renal impairment (see section 4.2).

Paediatric population

Children (4 to 12 years)

Following single oral dose administration (20 mg/kg) to epileptic children (6 to 12 years),

the half-life of levetiracetam was 6.0 hours. The apparent body weight adjusted clearance

was approximately 30 % higher than in epileptic adults.

Following repeated oral dose administration (20 to 60 mg/kg/day) to epileptic children (4

to 12 years), levetiracetam was rapidly absorbed. Peak plasma concentration was

observed 0.5 to 1.0 hour after dosing. Linear and dose proportional increases were

observed for peak plasma concentrations and area under the curve. The elimination halflife

was approximately 5 hours. The apparent body clearance was 1.1 ml/min/kg.

Nonclinical data reveal no special hazard for humans based on conventional studies of

safety pharmacology, genotoxicity and carcinogenic potential.

Adverse effects not observed in clinical studies but seen in the rat and to a lesser extent in

the mouse at exposure levels similar to human exposure levels and with possible 

relevance for clinical use were liver 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 at doses up to 1800 mg/kg/day (x 6 the MRHD on a mg/m2 or exposure

basis) in parents and F1 generation.

Two embryo fetal development (EFD) studies were performed in rats at 400, 1200 and

3600 mg/kg/day. At 3600 mg/kg/day, in only one of the 2 EFD studies, there was a slight

decrease in fetal weight associated with a marginal increase in skeletal variations/minor

anomalies. There was no effect on embryo mortality 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/m2 basis) and 1200 mg/kg/day for

fetuses.

Four embryo fetal 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 and a decrease in fetal weight associated with increased incidence of

fetuses with cardiovascular/skeletal anomalies. The NOAEL was <200 mg/kg/day for the

dams and 200 mg/kg/day for the fetuses (equal to the MRHD on a mg/m2 basis).

A periand postnatal development study was performed in rats with levetiracetam doses of

70, 350 and 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 effects seen in any of the standard developmental or maturation endpoints at

doses up to 1800 mg/kg/day (x 617 the MRHD on a mg/m2 basis)

- Sodium acetate anhydrous

- Sodium chloride

- Glacial acetic acid for pH adjustment

- Water for injection.

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

The shelf life is 2 years Vales vials are for single use only, any unused solution must be discarded. After Dilution: Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C. From a microbiological point of view, the product should be used immediately after dilution. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 – 8°C.

Store below 30°C.

For storage conditions after dilution of the medicinal product see section 6.3

Do not use beyond the expiry date or if the product shows any sign of deterioration.

Vales 500 mg: 5 ml EP type I clear glass vial, with grey 20 mm bromobutyl rubber stopper and sealed with 20 mm Aluminum seal with center tear off plastic top flip-off seal, each 10 vials packaged in carton with folded leaflet.

Before administration, the product should be visually inspected for any particulate matter

and discoloration.

For single use only. Any unused solution should be discarded.

Vales concentrate was found to be physically compatible and chemically stable when

mixed with the following diluents for at least 24 hours and stored in PVC bags at

controlled room Temperature at 25°C.

Diluents:

• Sodium Chloride 0.9% injection

• Lactated Ringer’s injection

• Dextrose 5% injection

The diluted solution should be visually inspected and should not be used in presence of

visible particulate matters or discoloration.

See the table for the recommended preparation and administration of Vales concentrate

for solution for infusion to achieve a total daily dose of 500 mg, 1000 mg, 2000 mg, or

3000 mg in two divided doses.

Dose Withdrawal Volume Volume of Diluent Infusion Time Frequency of administration Total Daily Dose 250 mg 250 mg 2.5 ml (half 5 ml vial) 100 ml 15 minutes Twice daily 500 mg 500 mg 5 ml (one 5 ml vial) 100 ml 15 minutes Twice daily 1000 mg 1000 mg 10 ml (two 5 ml vials) 100 ml 15 minutes Twice daily 1500 mg 1500 mg 15 ml (three 5 ml vials) 100 ml 15 minutes Twice daily