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LEVETIRACETAM CRESCENT 500 MG FILM-COATED TABLETS

Active substance(s): LEVETIRACETAM / LEVETIRACETAM / LEVETIRACETAM

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Levetiracetam Crescent 500 mg film-coated Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 500 mg levetiracetam
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Film-coated tablet
Levetiracetam Crescent 500 mg film-coated Tablets
Yellow, oblong, with a single score line on one side.
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal
doses.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
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, and children 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.

4.2

Posology and method of administration

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 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 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 weighing 50 kg or more, the following formula:

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

Creatinine clearance
(ml/min/1.73m2)

Dose and frequency

Normal

> 80

500 to 1,500 mg twice daily

Mild

50-79

500 to 1,000 mg twice daily

Moderate

30-49

250 to 750 mg twice daily

Severe

< 30

250 to 500 mg twice daily

End-stage renal disease patients
undergoing dialysis (1)

-

500 to 1,000 mg once daily (2)

(1) A 750 mg loading dose is recommended on the first day of treatment with levetiracetam.
(2) Following dialysis, a 250 to 500 mg supplemental dose is recommended.
For children with renal impairment, levetiracetam dose needs to be adjusted based on the
renal function as levetiracetam clearance is related to renal function. This recommendation is
based on a study in adult renally impaired patients.
The CLcr in ml/min/1.73 m2 may be estimated from serum creatinine (mg/dl) determination
using, for young adolescents and children using the following formula (Schwartz formula):

ks= 0.45 in Term infants to 1 year old; ks= 0.55 in Children to less than 13 years and in
adolescent female; ks= 0.7 in adolescent male
Dosing adjustment for infants, children and adolescent patients weighing less than 50 kg with
impaired renal function:

Group

Creatinine clearance Dose and frequency (1)
(ml/min/1.73 m2)
Infants 1 to less than Infants 6 to 23
6 months
months, children
and adolescents
weighing less than
50 kg

Normal

> 80

7 to 21 mg/kg (0.07
to 0.21 ml/kg) twice
daily

10 to 30 mg/kg (0.10
to 0.30 ml/kg) twice
daily

Mild

50-79

7 to 14 mg/kg (0.07
to 0.14 ml/kg) twice
daily

10 to 20 mg/kg (0.10
to 0.20 ml/kg) twice
daily

Moderate

30-49

3.5 to 10.5 mg/kg
(0.035 to 0.105
ml/kg) twice daily

5 to 15 mg/kg (0.05
to 0.15 ml/kg) twice
daily

Severe

< 30

3.5 to 7 mg/kg (0.035 5 to 10 mg/kg (0.05
to 0.07 ml/kg) twice to 0.10 ml/kg) twice
daily
daily

End-stage renal
disease patients
undergoing dialysis

--

7 to 14 mg/kg (0.07
to 0.14 ml/kg) once
daily (2) (4)

10 to 20 mg/kg (0.10
to 0.20 ml/kg) once
daily (3) (5)

(1) A 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.
(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.
A Levetiracetam 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 a Levetiracetam oral solution
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 are available.
Add-on therapy for infants aged 6 months to 23 months, children (2 to 11 years) and
adolescents (12 to 17 years) weighing less than 50 kg
A Levetiracetam oral solution is the preferred formulation for use in infants and children
under the age of 6 years.
For children 6 years and above, a 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 25 kg
should be 250 mg twice daily with a maximum dose of 750 mg 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 month.
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.

4.3

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

4.4

Special warnings and precautions for use

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 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 anti-epileptic agents (including levetiracetam). A meta-analysis
of randomized placebo-controlled trials of anti-epileptic medicinal products has
shown a small increased risk of suicidal thoughts and 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
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.
Levetiracetam Crescent 750 mg film-coated Tablets
Excipients
Levetiracetam 750 mg film-coated tablets contain E110 colouring agent which may
cause allergic reactions.
4.5

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
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. Coadministration 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.

4.6

Fertility, pregnancy and lactation

Pregnancy
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.
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.

4.7

Effects on ability to drive and use machines

Levetiracetamn 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.

4.8

Undesirable effects

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).
MedDRA
SOC
Infections and
infestations

Frequency category
Very common Common

Uncommon

Rare
Infection

Nasopharyngitis

Thrombocytopenia, Pancytopenia,
leukopenia
neutropenia,
agranulocytosis

Blood and
lymphatic
system
disorders
Immune system
disorders

Drug reaction
with
eosinophilia and
systemic
symptoms
(DRESS).
Hypersensitivity
(including
angioedema and
anaphylaxis)

Metabolism and
nutrition
disorders

Anorexia

Weight decreased,
weight increase

Hyponatraemia

Psychiatric
disorders

Depression,
hostility/
aggression,
anxiety,
insomnia,
nervousness/
irritability

Suicide attempt,
suicidal ideation
psychotic disorder,
abnormal
behaviour,
hallucination,
anger, confusional
state, panic attack
affect lability/mood
swings, agitation

Completed
suicide,
personality
disorder,
thinking
abnormal

MedDRA
SOC

Frequency category
Very common Common

Nervous system Somnolence,
disorders
headache

Convulsion,
balance disorder,
dizziness,
lethargy, tremor

Eye disorders

Uncommon

Rare

Amnesia, memory
impairment,
coordination
abnormal/ataxia,
paraesthesia,
disturbance in
attention

Choreoathetosis
dyskinesia,
hyperkinesia

Diplopia, vision
blurred

Ear and
labyrinth
disorders

Vertigo

Respiratory,
thoracic and
mediastinal
disorders

Cough

Gastrointestinal
disorders

Abdominal pain,
diarrhoea,
dyspepsia,
vomiting, nausea

Hepatobiliary
disorders

Pancreatitis

Liver function test
abnormal

Acute kidney
injury

Renal and
urinary
disorders
Skin and
subcutaneous
tissue disorders

Rash

Injury,
poisoning and
procedural
complications

Alopecia, eczema,
pruritus,

Toxic epidermal
necrolysis,
Stevens-Johnson
syndrome,
erythema
multiforme

Muscular weakness, Rhabdomyolysis
myalgia
and blood
creatine
phosphokinase
increased*

Musculoskeletal
and connective
tissue disorders

General
disorders and
administration
site conditions

Hepatic failure,
hepatitis

Asthenia/ fatigue

Injury

* Prevalence is significantly higher in Japanese patients when compared to nonJapanese patients.
Cases of encephalopathy have been rarely observed after levetiracetam
administration. These undesirable effects generally occurred at the beginning of the
treatment (few days to a few months) and were reversible after treatment
discontinuation.
Description of selected adverse reactions
The risk of anorexia is higher when levetiracetam is coadministered with topiramate.
In several cases of alopecia, recovery was observed when levetiracetam was
discontinued.
Bone marrow suppression was identified in some of the cases of pancytopenia.
Paediatric population
In patients aged 1 month to less than 4 years, a total of 190 patients have been treated
with levetiracetam in placebo-controlled and open label extension studies. Sixty of
these patients were treated with levetiracetam in placebo-controlled studies. In
patients aged 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 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
via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
4.9

Overdose
Symptoms
Somnolence, agitation, aggression, depressed level of consciousness, respiratory
depression and coma were observed with levetiracetam overdoses.
Management of overdose
After an acute overdose, the stomach may be emptied by gastric lavage or by
induction of emesis. There is no specific antidote for levetiracetam. Treatment of an
overdose will be symptomatic and may include haemodialysis. The dialyser
extraction efficiency is 60 % for levetiracetam and 74 % for the primary metabolite.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: antiepileptics, other antiepileptics, ATC code: N03AX14.
The active substance, levetiracetam, is a pyrrolidone derivative (S-enantiomer of α-ethyl-2oxo-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
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 placebocontrol 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.

5.2

Pharmacokinetic properties
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 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 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, 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 enzymeinducing antiepileptic medicinal product.

5.3

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 embryo mortality and no increased incidence of malformations. The
NOAEL (No Observed Adverse Effect Level) was 3600 mg/kg/day for pregnant female rats
(x 12 the MRHD on a mg/m2 basis) and 1200 mg/kg/day for 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)

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Core: Macrogol 4000, Croscarmellose sodium, Talc and Magnesium stearate
Film-coating: Opadry 85F32004: Polyvinyl alcohol-part.hydrolyzed, Titanium
dioxide (E171), Macrogol 3350, Talc, Iron oxide yellow (E172).

6.2

Incompatibilities
Not applicable

6.3

Shelf life
48 months

6.4

Special precautions for storage
Do not store above 30ºC.

6.5

Nature and contents of container
Aluminium/PVC blisters placed into cardboard boxes containing 60 film-coated
tablets.
Not all pack sizes may be marketed.

6.6

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

7

MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited,
Units 3 and 4,
Quidhampton Business Units,
Polhampton Lane,
Overton
RG25 3ED,
UK.

8

MARKETING AUTHORISATION NUMBER(S)

PL 20416/0247 – Levetiracetam Crescent 500 mg Film-Coated Tablets

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
22/09/2015

10

DATE OF REVISION OF THE TEXT
13/03/2017

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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