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LEVETIRACETAM BEACON 100 MG/ML CONCENTRATE FOR SOLUTION FOR INFUSION

Active substance(s): LEVETIRACETAM

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Levetiracetam Beacon 100 mg/ml concentrate for solution for infusion

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml contains 100 mg of levetiracetam
Each 5 ml vial contains 500 mg of levetiracetam
Excipients with known effect:
Each vial contains 19.94 mg of sodium
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate)
Clear, colourless, liquid

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Levetiracetam Beacon 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 Beacon is indicated as adjunctive therapy


in the treatment of partial onset seizures with or without secondary
generalisation in adults, adolescents and children from 4 years 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.

Levetiracetam Beacon concentrate is an alternative for patients when oral
administration is temporarily not feasible.

4.2

Posology and method of administration

Posology
Levetiracetam Beacon therapy can be initiated with either intravenous or oral administration.
Conversion to or from oral to intravenous administration can be done directly without
titration. The total daily dose and frequency of administration should be maintained.
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.
Duration of treatment
There is no experience with administration of intravenous levetiracetam for longer period than
4 days.
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 children and adolescents weighting less than 50 kg: dose decrease should not
exceed 10 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:
[140-age (years)] x weight (kg)
----------------------------------------72 x serum creatinine (mg/dl)

CLcr (ml/min) =

(x 0.85 for women)

Then CLcr is adjusted for body surface area (BSA) as follows:
CLcr (ml/min)
CLcr (ml/min/1.73 m ) = ----------------------------x 1.73
BSA subject (m2)
2

Dosing adjustment for adult and adolescent patients weighing more than 50 kg with impaired
renal function:
Dose and frequency
Group
Creatinine clearance
(ml/min/1.73m2)
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
500 to 1,000 mg once daily (2)
End-stage renal disease patients
undergoing dialysis (1)
(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,
for young adolescents and children, using the following formula (Schwartz formula):
CLcr (ml/min/1.73 m2) =

Height (cm) x ks
------------------------------------------Serum Creatinine (mg/dl)

ks=0.55 in Children to less than 13 years and in adolescent female; ks= 0.7 in adolescent male
Dosing adjustment for children and adolescents patients weighing less than 50 kg with
impaired renal function:
Group

Normal
Mild
Moderate

Creatinine
clearance
(ml/min/1.73
m2)
> 80
50-79
30-49

Dose and frequency
Children from 4 years and adolescents weighting less
than 50kg
10 to 30 mg/kg (0.10 to 0.30 ml/kg) twice daily
10 to 20 mg/kg (0.10 to 0.20 ml/kg) twice daily
5 to 15 mg/kg (0.05 to 0.15 ml/kg) twice daily

Severe

< 30

5 to 10 mg/kg (0.05 to 0.10 ml/kg) twice daily

End-stage renal
disease patients
undergoing
dialysis
(1)

--

10 to 20 mg/kg (0.10 to 0.20 ml/kg) once daily (1) (2)

A 15mg/kg (0.15 ml/kg) loading dose is recommended on the first day of treatment with
levetiracetam.
(2)
Following dialysis, a 5 to 10 mg (0.05 to 0.1 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/1.73m2.
Paediatric population
The physician should prescribe the most appropriate pharmaceutical form, presentation and
strength according to age, weight and dose.
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 children aged 4 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 children and adolescents:
Weight

Starting dose:
10 mg/kg twice daily

Maximum dose:
30 mg/kg twice daily

15 kg (1)

150 mg twice daily

450 mg twice daily

20 kg (1)

200 mg twice daily

600 mg twice daily

25 kg

250 mg twice daily

750 mg twice daily

From 50 kg (2)

500 mg twice daily

1500 mg twice daily

(1)

Children 25 kg or less should preferably start the treatment with levetiracetam 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 and children less than 4 years.
The safety and efficacy of levetiracetam concentrate for solution for infusion in infants and
children less than 4 years have not been established.
Currently available data are described in sections 4.8, 5.1, and 5.2 but no recommendation on
a posology can be made.
Method of administration
Levetiracetam Beacon concentrate is for intravenous use only and the recommended dose
must be diluted in at least 100 ml of a compatible diluent and administered intravenously as a
15-minute intravenous infusion (see section 6.6).

4.3

Contraindications
Hypersensitivity to the active substance or other pyrrolidone derivatives or 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).
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
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 Beacon 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.

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.
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.
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 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.

4.6

Fertility, pregnancy and lactation

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 (see section 5.3).
Levetiracetam Beacon is not recommended during pregnancy and in women of childbearing
potential not using contraception unless clinically necessary.
Physiological changes during pregnancy may affect levetiracetam concentration. Decrease in
levetiracetam plasma concentrations has been observed during pregnancy. This decrease is
more pronounced during the third trimester (up to 60% of baseline concentration before
pregnancy). Appropriate clinical management of pregnant women treated with levetiracetam
should be ensured. Discontinuation of antiepileptic treatments may result in exacerbation of
the disease which could be harmful to the mother and the foetus.
Breastfeeding
Levetiracetam is excreted in human breast milk. Therefore, breast-feeding is not
recommended. However, if levetiracetam treatment is needed during breastfeeding, the
benefit/risk of the treatment should be weighed considering the importance of breastfeeding.
Fertility

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

4.7

Effects on ability to drive and use machines

Levetiracetam has minor or moderate influence on the ability to drive and use machines. Due
to possible different individual sensitivity, some patients might experience somnolence or
other central nervous system related symptoms, especially at the beginning of treatment or
following a dose increase. Therefore, caution is recommended in those patients when
performing skilled tasks, e.g. driving vehicles or operating machinery. Patients are advised
not to drive or use machines until it is established that their ability to perform such activities
is not affected.

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. 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. 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

Frequency category
Very common

Infections and
infestations

Common

Uncommon

Nasopharyngitis

Rare
Infection

Thrombocytopenia, Pancytopenia,
leukopenia
neutropenia

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

Convulsion, balance
disorder, dizziness,
lethargy, tremor

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

Choreoathetosis,
dyskinesia,
hyperkinesia

Nervous
system
disorders

Eye disorders

Somnolence,
headache

Diplopia, vision

blurred
Ear and
labyrinth
disorders

Vertigo

Respiratory,
thoracic and
mediastinal
disorders

Cough

Gastrointestina
l disorders

Abdominal pain,
diarrhoea, dyspepsia,
vomiting, nausea

Hepatobiliary
disorders
Skin and
subcutaneous
tissue disorders

Rash

Musculoskelet
al and
connective
tissue disorders
General
disorders and
administration
site conditions

Pancreatitis

Liver function test
abnormal

Hepatic failure,
hepatitis

Alopecia eczema,
pruritus,

Toxic epidermal
necrolysis,
Stevens-Johnson
syndrome,
erythema
multiforme

Muscular
weakness, myalgia

Asthenia/fatigue

Injury,
poisoning and
procedural
complications

Injury

Description of selected adverse reactions
The risk of anorexia is higher when levetiracetam is coadministered withtopiramate .
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 postmarketing 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 of 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 (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
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 and children from 4 years 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.
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

The pharmacokinetic profile has been characterized following oral administration. A single
dose of 1500 mg levetiracetam diluted in 100 ml of a compatible diluent and infused
intravenously over 15 minutes is bioequivalent to 1500 mg levetiracetam oral intake, given as
three 500 mg tablets.
The intravenous administration of doses up to 4000 mg diluted in 100 ml of 0.9 % sodium
chloride infused over 15 minutes and doses up to 2500 mg diluted in 100 ml of 0.9 % sodium
chloride infused over 5 minutes was evaluated. The pharmacokinetic and safety profiles did
not identify any safety concerns.
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. The time independent pharmacokinetic profile of levetiracetam
was also confirmed following 1500 mg intravenous infusion for 4 days with twice daily
dosing.
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.
Adults and adolescents
Distribution
Peak plasma concentration (Cmax) observed in 17 subjects following a single intravenous
dose of 1500 mg infused over 15 minutes was 51 ± 19 µg/ml (arithmetic average ± standard
deviation).
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 Keppra 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 Keppra, 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)
The pharmacokinetics in paediatric patients has not been investigated after intravenous
administration. However, based on the pharmacokinetic characteristics of levetiracetam, the
pharmacokinetics in adults after intravenous administration and the pharmacokinetics in

children after oral administration, the exposure (AUC) of levetiracetam is expected to be
similar in paediatric patients aged 4 to 12 years after intravenous and oral administration.
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.

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 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).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Sodium acetate trihydrate
Sodium chloride
Glacial acetic acid
Water for injection

6.2

Incompatibilities
This medicinal product must not be mixed with other medicinal products except those
mentioned in section 6.6.

6.3

Shelf life
3 years
From a microbiological point of view, the product should be used immediately
after dilution. If not used immediately in-use storage time and conditions prior
to use are the responsibility of the user and would normally not be longer than
24 hours at 2 to 8oC, unless dilution has taken place in controlled and validated
aseptic conditions.

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.
For storage conditions of the diluted medicinal product, see section 6.3.

6.5

Nature and contents of container
5 ml glass vial (type I) with polytetrafluoroethylene coated bromobutyl rubber
stoppers and sealed with an aluminium/polypropylene flip off cap. Each carton
contains 1 vial. The 10 vials pack-size consists of 10 single-vial boxes.
1, 10 vials
Not all pack sizes may be marketed

6.6

Special precautions for disposal

See Table 1 for the recommended preparation and administration of Levetiracetam Beacon
concentrate for solution for infusion to achieve a total daily dose of 500 mg, 1000 mg, 2000
mg, or 3000 mg in two divided doses.
Table 1. Preparation and administration of Levetiracetam Beacon concentrate for solution for
infusion.
Dose

Withdrawal Volume

Volume of
Diluent

Infusion
Time

Frequency of
administration

Total Daily
Dose

250 mg

2.5 ml (half 5 ml vial)

100 ml

15 minutes

Twice daily

500 mg/day

500 mg

5 ml (one 5 ml vial)

100 ml

15 minutes

Twice daily

1000 mg/day

1000 mg

10 ml (two 5 ml vials)

100 ml

15 minutes

Twice daily

2000 mg/day

1500 mg

15 ml (three 5 ml vials)

100 ml

15 minutes

Twice daily

3000 mg/day

This medicinal product is for single use only, any unused solution should be discarded.
Levetiracetam Beacon concentrate for solution for infusion was found to be physically
compatible and chemically stable for at least 24 hours when mixed with the following diluents
and stored in PVC bags at controlled room temperature 15-25°C.
Diluents:
• Sodium chloride 9 mg/ml (0.9%) solution for injection
• Lactated Ringer’s solution for injection
• Dextrose 50 mg/ml (5%) solution for injection
Medicinal product with particulate matter or discoloration should not be used.
Any unused product or waste material should be disposed of the accordance with local
requirements.

7

MARKETING AUTHORISATION HOLDER
Beacon Pharmaceuticals Ltd
85 High Street
Tunbridge Wells
Kent TN1 1YG
United Kingdom

8

MARKETING AUTHORISATION NUMBER(S)
PL 18157/0264

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
12/04/2013

10

DATE OF REVISION OF THE TEXT
11/07/2016

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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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