Levetiracetam 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.
Levetiracetam is indicated as adjunctive therapy
• In the treatment of myoclonic seizures in adults and adolescents from 12 years of age with
Juvenile Myoclonic Epilepsy.
• In the treatment of primary generalised tonic-clonic seizures in adults and adolescents from
12 years of age with Idiopathic Generalised Epilepsy.

Posology:
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; 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 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:

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

(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):

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

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 oral solution is the preferred formulation for use in infants and children under the age of 6
years. In addition, the oral solution should be used 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.”
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 infants aged 6 to 23 months, children (2 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 infants from 6 months of age, children and adolescents:

(1) Children 25 kg or less should preferably start the treatment with Levetiracetam Actavis
Group 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 from 1 month to less than 6 months The initial therapeutic dose is 7
mg/kg twice daily.
Depending upon the clinical response and tolerability, the dose can be increased up to 21 mg/kg
twice daily. Dose changes should not exceed increases or decreases of 7 mg/kg twice daily every
two weeks.
The lowest effective dose should be used.
Infants should start the treatment with Levetiracetam Actavis Group 100 mg/ml oral solution.
Dose recommendations for infants aged from 1 month to less than 6 months:

Method of administration
The oral solution may be diluted in a glass of water or baby's bottle and may be taken with or
without food.

Renal insufficiency
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 anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebocontrolled
trials of anti-epileptic 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
Levetiracetam contains 2.6 mmol (or 59.82 mg) sodium per maximum single dose [or 0.867
mmol (or 19.94 mg) per vial]. To be taken into consideration by patients on a controlled
sodium diet

Antiepileptic medicinal products
Pre-marketing data from clinical studies conducted in adults indicate that levetiracetam did
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.
Dosage 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. It is expected that other
medicinal products excreted by active tubular secretion could also reduce the renal clearance
of the metabolite. The effect of levetiracetam on probenecid was not studied and the effect of
levetiracetam on other actively secreted medicinal products, e.g. NSAIDs, sulfonamides and
methotrexate, is unknown.

Oral contraceptives and other pharmacokinetic 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.
“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.”
“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
The extent of absorption of levetiracetam was not altered by food, but the rate of absorption
was slightly reduced.”

Pregnancy
Postmarketing 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.

Levetiracetam is not recommended during pregnancy and in women of childbearing potential
not using contraception unless clearly 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.

No studies on the effects on the ability to drive and use machines have been performed.
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 adverse event 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 open-label extension studies, as well as post-marketing experience. The most
frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue
and dizziness. The safety profile of levetiracetam is generally similar across age groups
(adult and paediatric patients) and across the approved epilepsy indications. Since there was
limited exposure for levetiracetam intravenous use and since oral and intravenous
formulations are bioequivalent, the safety information of levetiracetam intravenous will rely
on levetiracetam oral use.
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. The 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).

Description of selected adverse reactions
The risk of anorexia is higher when topiramate is coadministered with levetiracetam.
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 (60) 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.
The adverse event 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 per-protocol 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):
• Saudi Arabia:
The National Pharmacovigilance and Drug Safety Centre (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
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
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
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 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 analogues
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 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, noninferiority
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 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 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 P450isoforms (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 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 Actavis Group, 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 foetuses.
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 foetuses (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).

Liquid Maltitol (Lycasin 75/75)
Ammonium Glycrrhizinate
Acesulfame Potassium
White Grape Flavor
Glycerol
Methyl Paraben
Propyl Paraben
Sodium Citrate
Purified Water

Not applicable.

Store in original container to protect from light.
Do not store above 30°C.
Do not use after 7 months of first opening the bottle.

150 ml Amber colored glass bottles

Any unused product should be disposed of in accordance with local requirements.