LEVETIRACETAM 1000 MG FILM-COATED TABLETS
Active substance(s): LEVETIRACETAM
1 NAME OF THE MEDICINAL PRODUCT
Levetiracetam 1000 mg film-coated tablets
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 1000 mg levetiracetam.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
White, capsule shaped, biconvex, length: 20.9 mm to 21.3 mm, width: 8.9 mm to 9.3
mm and thickness: 7.3 mm to 7.9 mm, film-coated tablets plain on both sides.
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 partial onset seizures with or without secondary generalisation
in adults adolescents, children and infants from 1 month of age with epilepsy
in the treatment of myoclonic seizures in adults and adolescents from 12 years of
age with Juvenile Myoclonic Epilepsy
in the treatment of primary generalised tonic-clonic seizures in adults and adolescents
from 12 years of age with Idiopathic Generalised Epilepsy
Posology and method of administration
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.
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).
Elderly (65 years and older)
Adjustment of the dose is recommended in elderly patients with compromised renal
function (see “Renal impairment” below).
The daily dose must be individualised according to renal function.
For adult patients, refer to the following table and adjust the dose as indicated. To use
this 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
(x 0.85 for
72 x serum creatinine
Then CLcr is adjusted for body surface area (BSA) as follows:
Dosing adjustment for adult and adolescents patients weighing more than 50 kg with
impaired renal function:
Dose and frequency
500 to 1,500 mg
500 to 1,000 mg
End-stage renal disease
250 to 750 mg twice
250 to 500 mg twice
500 to 1,000 mg once
A 750 mg loading dose is recommended on the first day of treatment with
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, for young adolescents, children and infants, using the following
formula (Schwartz formula):
Height (cm) x ks
CLcr (ml/min/1. 73
ks= 0.55 in Children to less than 13 years and in adolescent female; ks= 0.7 in
Dosing adjustment for children and adolescents patients weighing less than 50 kg
with impaired renal function:
Dose and frequency (1)
Infants 1 to
less than 6
Infants 6 to
than 50 kg
7 to 21 mg/kg
(o.07 to 0.21
10 to 30
7 to 14 mg/kg
(0.07 to 0.14
10 to 20
3.5 to 10.5
5 to 15
3.5 to 7 mg/kg
(0.035 to 0.07
5 to 10
7 to 14 mg/kg
(0.07 to 0.14
daily (2) (4)
10 to 20
daily (3) (5)
An oral solution 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.
A 10.5 mg/kg (0.105 ml/kg) loading dose is recommended on the first day of
treatment with levetiracetam.
A 15 mg/kg (0.15 ml/kg) loading dose is recommended on the first day of treatment
Following dialysis, a 3.5 to 7 mg/kg (0.035 to 0.07 ml/kg) supplemental dose is
Following dialysis, a 5 to 10 mg/kg (0.05 to 0.10 ml/kg) supplemental dose is
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
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 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 should be used.
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 from 6 to 23 months, children (2 to 11 years) and
adolescents (12 to 17 years) weighing less than 50 kg
An oral solution is the preferred formulation for use in infants and children under the
age of 6 years.
For children 6 years and above, levetiracetam oral solution 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. 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.
Add-on therapy for infants aged from 1 month to less than 6 months
An 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. The daily dose is administered in two
equally divided doses.
Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of
the excipients listed in section 6.1.
Special warnings and precautions for use
The administration of Levetiracetam tablets 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 attempt, suicidal ideation and behaviour have been reported in
patients treated with anti-epileptic agents (including levetiracetam). A metaanalysis of randomized placebo-controlled 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.
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.
Interaction with other medicinal products and other forms of interaction
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 (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.
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.
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.
Fertility, Pregnancy and lactation
Postmarketing data from several prospective pregnancy registries have documented
outcomes in over 1000 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).
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.
Levetiracetam is excreted in human breast milk. Therefore, breast-feeding is not
However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk
of the treatment should be weighed considering the importance of breastfeeding.
No impact on fertility was detected in animal studies (see section 5.3). No clinical
data are available, potential risk for human is unknown.
Effects on ability to drive and use machines
Levetiracetam has minor or moderate influence on the ability to drive and use
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).
Description of selected adverse reactions
The risk of anorexia is higher when levetiracetam is coadministered with topiramate.
In several cases of alopecia, recovery was observed when levetiracetam was
Bone marrow suppression was identified in some of the cases of pancytopenia.
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
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 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.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal
product. Healthcare professionals are asked to report any suspected adverse reactions
Yellow Card Scheme at
Somnolence, agitation, aggression, depressed level of consciousness, respiratory
depression and coma were observed with levetiracetam overdoses.
Management of overdose
After an acute overdose, the stomach may be emptied by gastric lavage or by
induction of emesis. There is no specific antidote for levetiracetam. Treatment of an
overdose will be symptomatic and may include haemodialysis. The dialyser
extraction efficiency is 60 % for levetiracetam and 74 % for the primary metabolite.
Pharmacotherapeutic group: antiepileptics, other antiepileptics, ATC code:
The active substance, levetiracetam, is a pyrrolidone derivative (S-enantiomer of αethyl-2-oxo-1-pyrrolidine acetamide), chemically unrelated to existing antiepileptic
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.
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, placebocontrolled 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.
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 seizurefree 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 tonicclonic 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 longterm 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
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
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.
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.
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
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
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
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,
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
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.
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).
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 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
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).
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 enzymeinducing AED.
Preclinical safety data
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
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)
List of excipients
Povidone K- 30
Silica colloidal anhydrous
Hypromellose 6cp (E464) (for 250mg, 500mg and 750mg film-coated tablets)
Hypromellose 15cp (E464) (for 1000mg film-coated tablets)
Titanium dioxide (E171)
Macrogol 400 (for 250mg, 500mg and 750mg film-coated tablets)
Macrogol 6000 (for 1000mg film-coated tablets)
Indigo carmine aluminium lake (E132) (for 250mg and 750mg film-coated tablets)
Iron oxide yellow (E172) (for 500mg film-coated tablets)
Iron oxide red (E172) (for 750mg film-coated tablets)
Special precautions for storage
This medicinal product does not require any special storage conditions.
Nature and contents of container
Levetiracetam 1000 mg film-coated tablets
Aluminium/PVC/PE/PVDC blisters placed into cardboard boxes containing
10, 20, 30, 50, 60, 100, 120 and 200 film-coated tablets.
Not all pack sizes may be marketed
Special precautions for disposal
Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.
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