VITRAM is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalization in adults and adolescents from 16 years of age with newly diagnosed epilepsy.

VITRAM is indicated as adjunctive therapy

·         in the treatment of partial onset seizures with or without secondary generalization 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 generalized tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalized Epilepsy.

Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

VITRAM must be taken twice a day, once in the morning and once in the evening, at about the same time each day.

Take the oral solution following your doctor’s instructions. Posology

Monotherapy for adults and adolescents from 16 years of age

Measure the appropriate dosage using the 10 ml syringe included in the package for patients 4 years and above.

General dose: VITRAM is taken twice daily, in two equally divided doses, each individual dose being measured between 5 ml (500mg) and 15 ml (1500mg).

When you will first start taking VITRAM, your doctor will prescribe you a lower dose

during 2 weeks before giving you the lowest general dose.

Add-on therapy for adults and adolescents from 12 to 17 years

Measure the appropriate dosage using the 10 ml syringe included in the package for patients of 4 years and above.

General dose: VITRAM is taken twice daily, in two equally divided doses, each individual dose being measured between 5 ml (500mg) and 15 ml (1500mg).

Add-on therapy for children 6 months and older

Your doctor will prescribe the most appropriate pharmaceutical form of VITRAM according to the age, weight and dose.

For children 6 months to 4 years, measure the appropriate dosage using the syringe included in the package.

For children above 4 years, measure the appropriate dosage using the syringe included in the package.

General dose: VITRAM is taken twice daily, in two equally divided doses, each individual dose being measured between 0.1 ml (10mg) and 0.3 ml (30mg), per kg bodyweight of the child. (see table below for dose examples).

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

For infants 1 month to less than 6 months, measure the appropriate dosage using the syringe included in the package.

General dose: VITRAM is taken twice daily, in two equally divided doses, each individual dose being measured between 0.07 ml (7mg) and 0.21 ml (21mg), per kg bodyweight of the infant. (see table below for dose examples).

Method of administration

After measuring the correct dosage with an appropriate syringe, VITRAM oral solution may be diluted in a glass of water or baby’s bottle. You may take VITRAM with or without food.

Instructions for use:

•         Open the bottle: press the cap and turn it anticlockwise (figure 1)

•         Separate the adaptor from the syringe (figure 2). Insert the adaptor into the bottle neck (figure 3). Ensure it is well fixed.

•         Take the syringe and put it in the adaptor opening (figure 4). Turn the bottle upside down (figure 5).

Fill the syringe with a small amount of solution by pulling the piston down (figure 5A), then push the piston upward in order to remove any possible bubble (figure 5B). Pull the piston down to the graduation mark corresponding to the quantity in milliliters (ml) prescribed by your doctor (figure 5C).

Turn the bottle the right way up (figure 6A). Remove the syringe from the adaptor (figure 6B).

•         Empty the contents of the syringe in a glass of water or baby’s bottle by pushing the piston to the bottom of the syringe (figure 7).

•         Drink the whole contents of the glass/baby’s bottle.

•         Close the bottle with the plastic screw cap.

•         Wash the syringe with water only (figure 8).

Duration of treatment

VITRAM is used as a chronic treatment. You should continue VITRAM treatment for as long as your doctor has told you.

Do not stop your treatment without your doctor’s advice as this could increase your seizures.

If you take more VITRAM than you should

The possible side effects of an overdose of VITRAM are sleepiness, agitation, aggression, decrease of alertness, inhibition of breathing and coma.

Contact your doctor if you took more VITRAM than you should. Your doctor will establish the best possible treatment of overdose.

If you forget to take VITRAM:

Contact your doctor if you have missed one or more doses. Do not take a double dose to make up for a forgotten dose.

If you stop taking VITRAM:

If stopping treatment, VITRAM should be discontinued gradually to avoid an increase of seizures. Should your doctor decide to stop your VITRAM treatment, he/she will instruct you about the gradual withdrawal of VITRAM.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

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).

Acute Kidney injury

The use of levetiracetam has been very rarely associated with acute kidney injury, with a time to onset ranging 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 levetiracetam administration, generally at the beginning of the treatment. Complete blood cell counts are advised in patients experiencing important weakness, pyrexia, recurrent infections or coagulation disorders (section 4.8).

Suicide

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

Therefore, patients should be monitored for signs of depression and/or suicidal ideation and behaviors 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 behavior emerge.

Pediatric 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

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

It also contains maltitol liquid; patients with rare hereditary problems of fructose intolerance should not take this medicinal product.

Antiepileptic medicinal products

Pre-marketing 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 pediatric patients receiving up to 60 mg/kg/day levetiracetam.

A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4 to 17 years) confirmed that adjunctive therapy with orally administered levetiracetam did not influence the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data suggested a 20 % higher levetiracetam clearance in children taking enzyme- inducing antiepileptic medicinal products. Dose adjustment is not required.

Probenecid

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

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 (ethinyl- estradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone) were not modified. Levetiracetam 2,000 mg daily did not influence the pharmacokinetics of digoxin and warfarin; prothrombin times were not modified. Co-administration with digoxin, oral contraceptives and warfarin did not influence the pharmacokinetics of levetiracetam.

Laxatives

There have been isolated reports of decreased levetiracetam efficacy when the osmotic laxative

macrogol has been concomitantly administered with oral levetiracetam. Therefore, macrogol should not 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 was slightly reduced.

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

Pregnancy

Post-marketing data from several prospective pregnancy registries have documented outcomes in over 1,000 women exposed to levetiracetam monotherapy during the first trimester of pregnancy. Overall, these data do not suggest a substantial increase in the risk for major congenital malformations, although a teratogenic risk cannot be completely excluded. Therapy with multiple antiepileptic medicinal products is associated with a higher risk of congenital malformations than monotherapy and, therefore, monotherapy should be considered. Studies in animals have shown reproductive toxicity (see section 5.3).

VITRAM is not recommended during pregnancy and in women of childbearing potential not using contraception unless clinically necessary.

Physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester (up to 60% of baseline concentration before pregnancy). Appropriate clinical management of pregnant women treated with levetiracetam should be ensured.

Discontinuation of antiepileptic treatments may result in exacerbation of the disease which could be harmful to the mother and the foetus.

Breastfeeding

Levetiracetam is excreted in human breast milk. Therefore, breast-feeding is not recommended. However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk of the treatment should be weighed considering the importance of breastfeeding.

Fertility

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

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 placebo- controlled clinical trials with all indications studied, with a total of 3,416 patients treated with levetiracetam. These data are supplemented with the use of levetiracetam in corresponding open-label extension studies, as well as post-marketing experience. The safety profile of levetiracetam is generally similar across age groups (adult and pediatric 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 post-marketing 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).

* Prevalence is significantly higher in Japanese patients when compared to non-Japanese patients. Cases of encephalopathy have been rarely observed after levetiracetam administration. These undesirable effects generally occurred at the beginning of the treatment (few days to a few months) and were reversible after treatment discontinuation.

Description of selected adverse reactions

The risk of anorexia is higher when levetiracetam is co-administered 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.

Pediatric 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 4-16 years, a total of 645 patients have been treated with levetiracetam in placebo-controlled and open label extension studies. 233 of these patients were treated with levetiracetam in placebo-controlled studies. In both these pediatric age ranges, these data are supplemented with the post-marketing 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 pediatric patients in placebo-controlled clinical studies were consistent with the safety profile of levetiracetam in adults except for behavioral 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 behavior (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 pediatric 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 VITRAM was not different (non inferior) from placebo with regard to the change from baseline of the Leiter-R Attention and Memory, Memory Screen Composite score in the per-protocol population. Results related to behavioral and emotional functioning indicated a worsening in levetiracetam treated patients on aggressive behavior as measured in a standardized and systematic way using a validated instrument (CBCL – Achenbach Child Behavior Checklist). However, subjects, who took levetiracetam in the long-term open label follow-up study, did not experience a worsening, on average, in their behavioral and emotional functioning; in particular measures of aggressive behavior were not worse than baseline.

To report any side effect(s):

•  Saudi Arabia:

•  Other GCC states:

Please contact the relevant competent authority.

Symptoms

Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with VITRAM 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 hemodialysis. The dialyzer 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 (S-enantiomer of a-ethyl-2-oxo-1- pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances.

Mechanism of action

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

In vitro studies show that levetiracetam affects intraneuronal Ca2+ levels by partial inhibition of N- type Ca2+ currents and by reducing the release of Ca2+ from intraneuronal stores. In addition, it partially reverses the reductions in GABA- and glycine-gated currents induced by zinc and carbolines. Furthermore, levetiracetam has been shown in in vitro studies to bind to a specific site in rodent brain tissue. This binding site is the synaptic vesicle protein 2A, believed to be involved in vesicle fusion and neurotransmitter exocytosis. Levetiracetam and related analogs show a rank order of affinity for binding to the synaptic vesicle protein 2A which correlates with the potency of their anti-seizure protection in the mouse audiogenic model of epilepsy. This finding suggests that the interaction between levetiracetam and the synaptic vesicle protein 2A seems to contribute to the antiepileptic mechanism of action of the medicinal product.

Pharmacodynamic effects

Levetiracetam induces seizure protection in a broad range of animal models of partial and primary generalized seizures without having a pro-convulsant effect. The primary metabolite is inactive.

In man, an activity in both partial and generalized 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 generalization 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.

Pediatric population

In pediatric patients (4 to 16 years of age), levetiracetam efficacy was established in a double- blind, placebo-controlled study, which included 198 patients and had a treatment duration of 14 weeks. In

this study, the patients received levetiracetam as a fixed dose of 60 mg/kg/day (with twice a day dosing).

44.6 % of the levetiracetam treated patients and 19.6 % of the patients on placebo had a 50 % or greater reduction from baseline in the partial onset seizure frequency per week. With continued long- term treatment, 11.4 % of the patients were seizure-free for at least 6 months and 7.2 % were seizure- free for at least 1 year.

In pediatric 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 generalization 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 generalized tonic-clonic seizures in adults and adolescents from 12 years of age with idiopathic generalized epilepsy.

Levetiracetam efficacy was established in a 24-week double-blind, placebo-controlled study which included adults, adolescents and a limited number of children suffering from idiopathic generalized epilepsy with primary generalized tonic-clonic (PGTC) seizures in different syndromes (juvenile myoclonic epilepsy, juvenile absence epilepsy, childhood absence epilepsy, or epilepsy with Grand Mal seizures on awakening). In this study, levetiracetam dose was 3000 mg/day for adults and adolescents or 60 mg/kg/day for children, given in 2 divided doses.

72.2 % of the levetiracetam treated patients and 45.2 % of the patients on placebo had a 50 % or greater decrease in the frequency of PGTC seizures per week. With continued long-term treatment,

47.4 % of the patients were free of tonic-clonic seizures for at least 6 months and 31.5% were free of tonic-clonic seizures for at least 1 year.

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

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

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

Adults and adolescents

Absorption

Levetiracetam is rapidly absorbed after oral administration. Oral absolute bioavailability is close to 100 %.

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

Peak concentrations (Cmax) are typically 31 and 43 μg/ml following a single 1,000 mg dose and

repeated 1,000 mg twice daily dose, respectively.

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

Distribution

No tissue distribution data are available in humans.

Neither levetiracetam nor its primary metabolite are significantly bound to plasma proteins (< 10 %).

The volume of distribution of levetiracetam is approximately 0.5 to 0.7 l/kg, a value close to the total body water volume.

Biotransformation

Levetiracetam is not extensively metabolized 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 VITRAM 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 VITRAM, based on creatinine clearance in patients with moderate and severe renal impairment (see section 4.2).

In anuric end-stage renal disease adult subjects the half-life was approximately 25 and 3.1 hours during interdialytic and intradialytic periods, respectively.

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

Hepatic 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).

Pediatric 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 single oral dose administration (20 mg/kg) to epileptic children (6 to 12 years), the half- life of levetiracetam was 6.0 hours. The apparent body weight adjusted clearance was approximately 30 % higher than in epileptic adults.

Following repeated oral dose administration (20 to 60 mg/kg/day) to epileptic children (4 to 12 years), levetiracetam was rapidly absorbed. Peak plasma concentration was observed 0.5 to 1.0 hour after dosing. Linear and dose proportional increases were observed for peak plasma concentrations and

area under the curve. The elimination half-life was approximately 5 hours. The apparent body clearance was 1.1 ml/min/kg.

Infants and children (1 month to 4 years)

Following single dose administration (20 mg/kg) of a 100 mg/ml oral solution to epileptic children (1 month to 4 years), levetiracetam was rapidly absorbed and peak plasma concentrations were observed approximately 1 hour after dosing. The pharmacokinetic results indicated that half-life was shorter (5.3 h) than for adults (7.2 h) and apparent clearance was faster (1.5 ml/min/kg) than for adults (0.96 ml/min/kg).

In the population pharmacokinetic analysis conducted in patients from 1 month to 16 years of age, body weight was significantly correlated to apparent clearance (clearance increased with an increase in body weight) and apparent volume of distribution. Age also had an influence on both parameters. This effect was pronounced for the younger infants, and subsided as age increased, to become negligible around 4 years of age.

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

Non-clinical 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-foetal 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 foetal weight associated with a marginal increase in skeletal variations /minor anomalies. There

was no effect 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/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 and a decrease in foetal weight associated with increased incidence of foetuses 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 peri- and post-natal 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 6 – 17 the MRHD on a mg/m2 basis).

Glycerol.

Propylparaben.

Methylparaben.

Ammonium Glycyrrhizinate.

Citric acid monohydrate.

Sodium citrate dehydrate.

Potassium Acesulfame.

Maltitol.

Grapefruit flavor.

Purified water.

Not applicable.

Store in the original bottle in order to protect from light.

Do not store above 30°C.

300 ml amber glass bottle (type III) with a white child resistant closure (polypropylene) in a cardboard box also containing a 10 ml graduated oral syringe (polypropylene, polyethylene) and an adaptor for the syringe (polyethylene).

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