Levetiracetam tablets are 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.
Levetiracetam tablets are 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-colonic seizures in adults and adolescents from 12 years of
age with Idiopathic Generalized Epilepsy.
 

Posology
Partial onset seizures
The recommended dosing for monotherapy (from 16 years of age) and adjunctive therapy is the same as
outlined below.
All indications
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.
However, a lower initial dose of 250 mg twice daily may be given based on physician assessment of seizure
reduction versus potential side effects. This can be increased to 500 mg twice daily after two weeks.
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 250 mg or 500 mg twice daily increases or decreases every two 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 strength
according to weight, age and dose. Refer to Paediatric population section for dosing adjustments based on
weight.
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 weighing less than 50 kg: dose decrease should not exceed 10
mg/kg twice daily every two weeks; in infants (less than 6 months): dose decrease should not exceed 7
mg/kg twice daily every two weeks).
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 individualized 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 weighing 50 kg or more,
the following formula:

CLcr​(ml/min)=72×serum creatinine (mg/dl)[140−age (years)]×weight (kg)​×(0.85 for women)

Then CLcrCL_{cr}CLcr​ is adjusted for body surface area (BSA) as follows:

CLcr(ml/min/1.73m2)=CLcr(ml/min)×1.73BSA (m2)CL_{cr} (ml/min/1.73 m^2) = \frac{CL_{cr} (ml/min) \times 1.73}{BSA \, \text{(m}^2\text{)}}CLcr​(ml/min/1.73m2)=BSA(m2)CLcr​(ml/min)×1.73​

Dosing adjustment for adult and adolescent patients weighing more than 50 kg with impaired renal function:

Notes:

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

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

• In adult patients with impaired renal function, levetiracetam dose needs to be adjusted based on renal function as creatinine clearance is related to renal function. This recommendation is based on a study in adult renally impaired patients.

For children, adolescents, and infants:

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

CLcr(ml/min/1.73m2)=Height (cm)×kSerum creatinine (mg/dl)CL_{cr} (ml/min/1.73 m^2) = \frac{\text{Height (cm)} \times k}{\text{Serum creatinine (mg/dl)}}CLcr​(ml/min/1.73m2)=Serum creatinine (mg/dl)Height (cm)×k​

• k = 0.45 in Term infants to 1 year old;

• k = 0.55 in Children to less than 13 years and in adolescent female;

• k = 0.7 in adolescent male.

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

(1)An oral solution of levetiracetam should be used for doses under 250 mg, for doses not multiple of 250 mg
when dosing recommendation is not achievable by taking multiple tablets and for patients unable to swallow
tablets.
(2) A 10.5 mg/kg (0.105 ml/kg) loading dose is recommended on the first day of treatment with levetiracetam.
(3) A 15 mg/kg (0.15 ml/kg) loading dose is recommended on the first day of treatment with levetiracetam.
(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.
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 tablet formulation is not adapted for use in infants and children under the age of 6 years. An oral
solution of levetiracetam is the preferred formulation for use in this population. In addition, the available
dose strengths of the tablets are not appropriate for initial treatment in children weighing less than 25 kg, for
patients unable to swallow tablets or for the administration of doses below 250 mg. In all of the above cases
an oral solution of levetiracetam should be used.

Monotherapy
The safety and efficacy of levetiracetam in children and adolescents below 16 years as monotherapy
treatment have not been established.
No data is available.
Adolescents (16 and 17 years of age) weighing 50 kg or more with partial onset seizures with or without
secondary generalisation with newly diagnosed epilepsy.
Please refer to the above section on adults (≥ 18 years) and adolescents (12 to 17 years) weighing 50 kg or more.

Add-on therapy for infants aged from 6 to 23 months, children (2 to 11 years) and adolescents (12 to 17
years) weighing less than 50 kg.
An oral solution of levetiracetam is the preferred formulation for use in infants and children under the age of 6 years.
For children 6 years and above, an oral solution of levetiracetam should be used for doses under 250 mg, for
doses not multiple of 250 mg when dosing recommendation is not achievable by taking multiple tablets and
for patients unable to swallow tablets.
The lowest effective dose should be used for all indications. The starting dose for a child or adolescent of
25kg should be 250mg twice daily with a maximum dose of 750mg twice daily.
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 50 kg or
more for all indications.
Add-on therapy for infants aged from 1 month to less than 6 months.
The oral solution is the formulation to use in infants.
Method of administration
The film-coated tablets must be taken orally, swallowed with a sufficient quantity of liquid and may be taken
with or without food. After oral administration the bitter taste of levetiracetam may be experienced. The
daily dose is administered in two equally divided doses.

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 behaviour have been reported in patients treated with antiepileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of antiepileptic 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.

Abnormal and aggressive behaviors.
Levetiracetam may cause psychotic symptoms and behavioral abnormalities including irritability and
aggressiveness. Patients treated with levetiracetam should be monitored for developing psychiatric signs
suggesting important mood and/or personality changes. If such behaviors are noticed, treatment adaptation or
gradual discontinuation should be considered. If discontinuation is considered, please refer to section 4.2.

Worsening of seizures
As with other types of antiepileptic drugs, levetiracetam may rarely exacerbate seizure frequency or severity.
This paradoxical effect was mostly reported within the first month after levetiracetam initiation 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 epilepsy associated 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-marketing surveillance.
Levetiracetam should be used with caution in patients with QTc-interval prolongation, in patients
concomitantly treated with drugs affecting the QTc-interval, or in patients with relevant pre-existing cardiac
disease or electrolyte disturbances.

Paediatric population
The tablet formulation is not adapted for use in infants and children under the age of 6 years.
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.
 

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 paediatric patients
receiving up to 60 mg/kg/day levetiracetam.
A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4 to
17 years) confirmed that adjunctive therapy with orally administered levetiracetam did not influence the
steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However,
data suggested a 20% higher levetiracetam clearance in children taking enzyme-inducing antiepileptic
medicinal products. Dose adjustment is not required.

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

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.
 

Specialist advice should be given to women who are of childbearing potential. Treatment with levetiracetam
should be reviewed when a woman is planning to become pregnant. As with all antiepileptic medicines,
sudden discontinuation of levetiracetam should be avoided as this may lead to breakthrough seizures that
could have serious consequences for the woman and the unborn child.
Monotherapy should be preferred whenever possible because therapy with multiple antiepileptic medicines
AEDs could be associated with a higher risk of congenital malformations than monotherapy, depending on
the associated antiepileptics.
 

Pregnancy
A large amount of post marketing data on pregnant women exposed to levetiracetam monotherapy (more
than 1800, among which in more than 1500 exposure occurred during the 1st trimester do not suggest an
increase in the risk for major congenital malformations. Only limited evidence is available on the
neurodevelopment of children exposed to levetiracetam monotherapy in utero. However, current
epidemiological studies (on about 100 children) do not suggest an increased risk of neurodevelopmental
disorders or delays.
Levetiracetam can be used during pregnancy, if after careful assessment it is considered clinically needed. In
such case, the lowest effective dose is recommended.
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.
 

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 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
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.
**Very rare cases of development of obsessive-compulsive disorders (OCD) in patients with underlying
history of OCD or psychiatric disorders have been observed in post-marketing surveillance.
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.

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 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 paediatric
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 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 levetiracetam 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 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 effect(s):
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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 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 α -ethyl-2-oxo-1-
pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances.
Mechanism of action
The mechanism of action of levetiracetam still remains to be fully elucidated. 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 glycine-gated currents induced by zinc and β - carbolines.
Furthermore, levetiracetam has been shown in in vitro studies to bind to a specific site in rodent brain
tissue. This binding site is the synaptic vesicle protein 2A, believed to be involved in vesicle fusion and
neurotransmitter exocytosis. Levetiracetam and related 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
generalised seizures without having a pro-convulsant effect. The primary metabolite is inactive.
In man, an activity in both partial and generalised epilepsy conditions (epileptiform
discharge/photoparoxysmal response) has confirmed the broad spectrum pharmacological profile of
levetiracetam.
 

Clinical efficacy and safety
Adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation in
adults, adolescents, children and infants from 1 month of age with epilepsy.
In adults, levetiracetam efficacy has been demonstrated in 3 double-blind, placebo-controlled studies at
1000 mg, 2000 mg, or 3000 mg/day, given in 2 divided doses, with a treatment duration of up to 18 weeks.
In a pooled analysis, the percentage of patients who achieved 50% or greater reduction from baseline in the
partial onset seizure frequency per week at stable dose (12/14 weeks) was of 27.7%, 31.6% and 41.3% for
patients on 1000, 2000 or 3000 mg levetiracetam respectively and of 12.6% for patients on placebo.
 

Paediatric population
In paediatric patients (4 to 16 years of age), levetiracetam efficacy was established in a double-blind,
placebo-controlled study, which included 198 patients and had a treatment duration of 14 weeks. In this
study, the patients received levetiracetam as a fixed dose of 60 mg/kg/day (with twice a day dosing).
44.6% of the levetiracetam treated patients and 19.6% of the patients on placebo had a 50% or greater
reduction from baseline in the partial onset seizure frequency per week. With continued long-term
treatment, 11.4% of the patients were seizure-free for at least 6 months and 7.2% were seizure-free for at least 1 year.

In paediatric patients (1 month to less than 4 years of age), levetiracetam efficacy was established in a
double-blind, placebo-controlled study, which included 116 patients and had a treatment duration of 5 days.
In this study, patients were prescribed 20 mg/kg, 25 mg/kg, 40 mg/kg or 50 mg/kg daily dose of oral
solution based on their age titration schedule. A dose of 20 mg/kg/day titrating to 40 mg/kg/day for infants
one month to less than six 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 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 μ g/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 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 Levetiracetam tablets 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 Levetiracetam
tablets, 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).
 

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 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 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 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).
 

Croscarmellose Sodium
Povidone K-30
Colloidal silicon dioxide (Aerosil 200)
Magnesium Stearate
Purified water
Hypromellose 15 cp
Opadry 85F32004 Yellow
Purified water
 

Not applicable.
 

No special precautions for storage.
 

Leracet 500 mg film-coated tablet is packed into a blister package consisting of clear PVC/PE /PVDC /Alu foil; each blister
contains 15 tablets. Two clear PVC/PE /PVDC /Alu blisters, each blister containing 15 units of Leracet 500 mg film coated
tablet, are packed into a carton box with an insert leaflet. Each pack contains 30 tablets.
 

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