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LEVETIRACETAM BRISTOL LABS 100MG/ML ORAL SOLUTION

Active substance(s): LEVETIRACETAM / LEVETIRACETAM

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SUMMARY OF PRODUCT CHARACTERISTICS
1

NAME OF THE MEDICINAL PRODUCT
Levetiracetam Bristol Labs 100mg/ml Oral Solution

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each ml of solution contains 100 mg Levetiracetam.
Excipients with known effect:
Each ml of solution contains 1.5 mg of methyl parahydroxybenzoate (E218),
0.18 mg of propyl parahydroxybenzoate (E216) and 300 mg of liquid maltitol.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Oral solution
A clear, colorless grape flavoured liquid

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, 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.

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:
[140-age (years)] x weight (kg)
CLcr (ml/min) =

(x 0.85 for women)
72 x serum creatinine (mg/dl)

Then CLcr is adjusted for body surface area (BSA) as follows:
CLcr (ml/min)
2

CLcr (ml/min/ 1.73m ) =

x 1.73
BSA subject m2

Dosing adjustment for adult and adolescents patients weighing more than 50 kg
with impaired renal function:
Group
Creatinine clearance Dose and frequency
(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

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/1.73m2 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/1.73m2) =
Serum Creatinine (mg/dl)
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
(ml/min/1.73
m2)

Dose and frequency (1)
Infants 1 to less than 6
months

Infants 6 to 23 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

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

Severe

< 30

3.5 to 10.5 mg/kg (0.035
to 0.105 ml/kg) twice
daily
3.5 to 7 mg/kg (0.035 to
0.07 ml/kg) twice daily
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 (3) (5)

End-stage
renal
disease
patients
undergoin
g dialysis

-

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

(2) (4)

(1)

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/1.73m2.

Paediatric population
The physician should prescribe the most appropriate pharmaceutical form,
presentation and strength according to age, weight and dose.
Levetiracetam oral solution is the preferred formulation for use in infants and
children under the age of 6 years. 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 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 from 6 to 23 months, children (2 to 11 years)
and adolescents (12 to 17 years) weighing less than 50 kg
The initial therapeutic dose is 10 mg/kg twice daily.
Depending upon the clinical response and tolerability, the dose can be increased
up to 30 mg/kg twice daily. Dose changes should not exceed increases or
decreases of 10 mg/kg twice daily every two weeks. The lowest effective dose
should be used.
Dose in children 50 kg or greater is the same as in adults.
Dose recommendations for infants from 6 months of age, children and
adolescents:
Weight

Starting dose:
Maximum dose:
10 mg/kg twice daily
30 mg/kg twice daily
6 kg (1)
60 mg (0.6 ml) twice
180 mg (1.8 ml) twice
daily
daily
10 kg (1)
100 mg (1 ml) twice
300 mg (3 ml) twice
daily
daily
15 kg (1)
150 mg (1.5 ml) twice
450 mg (4.5 ml) twice
daily
daily
20 kg (1)
200 mg (2 ml) twice
600 mg (6 ml) twice
daily
daily
25 kg
250 mg twice daily
750 mg twice daily
From 50 kg (2)
500 mg twice daily
1,500 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 aged from 1 month to less than 6 months
The initial therapeutic dose is 7 mg/kg twice daily.
Depending upon the clinical response and tolerability, the dose can be increased
up to 21 mg/kg twice daily. Dose changes should not exceed increases or
decreases of 7 mg/kg twice daily every two weeks. The lowest effective dose
should be used.
Infants should start the treatment with Levetiracetam 100 mg/ml oral solution.
Dose recommendations for infants aged from 1 month to less than 6 months:
Weight
Starting dose:
Maximum dose:
7 mg/kg twice daily
21 mg/kg twice daily
4 kg
28 mg (0.3 ml) twice
84 mg (0.85 ml) twice
daily
daily
5 kg
35 mg (0.35 ml) twice
105 mg (1.05 ml) twice

7 kg

daily
49 mg (0.5 ml) twice
daily

daily
147 mg (1.5 ml) twice
daily

Three presentations are available:
- A 300 ml bottle with a 10 ml oral syringe (delivering up to 1000 mg
levetiracetam) graduated every 0.25 ml (corresponding to 25 mg).
This presentation should be prescribed for children aged 4 years and older,
adolescents and adults.
- A 150 ml bottle with a 3 ml oral syringe (delivering up to 300 mg
levetiracetam) graduated every 0.1 ml (corresponding to 10 mg).
In order to ensure the accuracy of the dosing, this presentation should be
prescribed for infants and young children aged from 6 months to less than 4
years.
- A 150 ml bottle with a 1 ml oral syringe (delivering up to 100 mg
levetiracetam) graduated every 0.05 ml (corresponding to 5 mg).
In order to ensure the accuracy of the dosing, this presentation should be
prescribed for infants aged 1 month to less than 6 months.
Method of administration
The oral solution may be diluted in a glass of water or baby's bottle and may be
taken with or without food.

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 very rarely associated with acute kidney
injury, with a time to onset ranging from a few days to several months.

Blood cell counts
Rare cases of decreased blood cell counts (neutropenia, agranulocytosis,
leucopenia, thrombocytopenia and pancytopenia) have been described in
association with levetiracetam administration, generally at the beginning of the
treatment. Complete blood cell counts are advised in patients experiencing
important weakness, pyrexia, recurrent infections or coagulation disorders
(section 4.8).

Suicide
Suicide, suicide attempt, suicidal ideation and behaviour have been reported in
patients treated with 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.
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 100mg/ml oral solution contains methyl parahydroxybenzoate
(E218) and propyl parahydroxybenzoate (E216) which may cause allergic
reactions (possibly delayed).
It also contains maltitol liquid; patients with rare hereditary problems of
fructose intolerance should not take this medicinal product.

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. Co-administration with
digoxin, oral contraceptives and warfarin did not influence the
pharmacokinetics of levetiracetam.
Laxatives
There have been isolated reports of decreased levetiracetam efficacy when the
osmotic laxative macrogol has been concomitantly administered with oral
levetiracetam. Therefore, macrogol should not be taken orally for one hour
before and for one hour after taking levetiracetam.
Food and alcohol
The extent of absorption of levetiracetam was not altered by food, but the rate
of absorption was slightly reduced.
No data on the interaction of levetiracetam with alcohol are available.

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 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, the potential risk for humans 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.
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
Blood and
lymphatic
system
disorders
Immune
system
disorders

Frequency category
Very
Common
common
Nasopharyngiti
s

Eye
disorders
Ear and
labyrinth

Somnolence,
headache

Anorexia

Weight decreased ,
weight increase

Depression,
hostility/
aggression, anxiety,
insomnia,
nervousness/irritabil
ity

Suicide attempt,
suicidal ideation,
psychotic disorder,
abnormal
behaviour,
hallucination,
anger, confusional
state , panic attack,
affect lability/mood
swings, agitation
Amnesia, memory
impairment,
coordination
abnormal/ataxia,
paraesthesia,
disturbance in
attention

Convulsion,
balance disorder,
dizziness, lethargy,
tremor

Diplopia, vision
blurred
Vertigo

Rare
Infection

Thrombocytopenia,
leukopenia

Metabolis
m and
nutrition
disorders
Psychiatric
disorders

Nervous
system
disorders

Uncommon

Pancytopenia,
neutropenia,
agranulocytosis
Drug reaction with
eosinophilia and
systemic symptoms
(DRESS),
Hypersensitivity
(including
angioedema and
anaphylaxis)
Hyponatraemia

Completed suicide,
personality disorder,
thinking abnormal

Choreoathetosis,
dyskinesia,
hyperkinesia

MedDRA
SOC
disorders
Respiratory
, thoracic
and
mediastinal
disorders
Gastrointes
tinal
disorders
Hepatobilia
ry
disorders
Renal and
Urinary
Disorders
Skin and
subcutaneo
us tissue
disorders

Frequency category
Very
Common
common

Rare

Cough

Abdominal pain,
diarrhoea,
dyspepsia,
vomiting, nausea

Pancreatitis

Liver function test
abnormal

Hepatic failure,
hepatitis
Acute kidney injury

Rash

Musculosk
eletal and
connective
tissue
disorders
General
disorders
and
administrat
ion site
conditions

Uncommon

Alopecia, eczema,
pruritus,

Toxic epidermal
necrolysis, StevensJohnson syndrome,
erythema multiforme

Muscular
weakness, myalgia

Rhabdomyolysis and
blood creatine
phosphokinase
increased*

Asthenia/fatigue

Injury,
poisoning
and
procedural
complicati
ons

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 co-administered with
topiramate.
In several cases of alopecia, recovery was observed when levetiracetam was

discontinued. Bone marrow suppression was identified in some of the cases of
pancytopenia.
Paediatric population
In patients aged 1 month to less than 4 years, a total of 190 patients have been
treated with levetiracetam in placebo-controlled and open label extension
studies. Sixty of these patients were treated with levetiracetam in placebocontrolled 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 placebocontrolled 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 noninferiority 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-2-oxo-1-pyrrolidine acetamide), chemically unrelated to existing
antiepileptic active substances.
Mechanism of action
The mechanism of action of levetiracetam still remains to be fully elucidated.
In vitro and in vivo experiments suggest that levetiracetam does not alter basic
cell characteristics and normal neurotransmission.
In vitro studies show that levetiracetam affects intraneuronal Ca2+ levels by
partial inhibition of N-type Ca2+ currents and by reducing the release of Ca2+
from intraneuronal stores. In addition it partially reverses the reductions in
GABA- and glycine-gated currents induced by zinc and β-carbolines.
Furthermore, levetiracetam has been shown in in vitro studies to bind to a
specific site in rodent brain tissue. This binding site is the synaptic vesicle
protein 2A, believed to be involved in vesicle fusion and neurotransmitter
exocytosis. Levetiracetam and related analogs show a rank order of affinity for
binding to the synaptic vesicle protein 2A which correlates with the potency of
their anti-seizure protection in the mouse audiogenic model of epilepsy. This

finding suggests that the interaction between levetiracetam and the synaptic
vesicle protein 2A seems to contribute to the antiepileptic mechanism of action
of the medicinal product.
Pharmacodynamic effects
Levetiracetam induces seizure protection in a broad range of animal models of
partial and primary generalised seizures without having a pro-convulsant
effect. The primary metabolite is inactive.
In man, an activity in both partial and generalised epilepsy conditions
(epileptiform discharge/photoparoxysmal response) has confirmed the broad
spectrum pharmacological profile of levetiracetam.
Clinical efficacy and safety
Adjunctive therapy in the treatment of partial onset seizures with or without
secondary generalisation in adults, adolescents, children and infants from 1
month of age with epilepsy.
In adults, levetiracetam efficacy has been demonstrated in 3 double-blind,
placebo-controlled studies at 1000 mg, 2000 mg, or 3000 mg/day, given in 2
divided doses, with a treatment duration of up to 18 weeks. In a pooled
analysis, the percentage of patients who achieved 50% or greater reduction
from baseline in the partial onset seizure frequency per week at stable dose
(12/14 weeks) was of 27.7%, 31.6% and 41.3% for patients on 1000, 2000 or
3000 mg levetiracetam respectively and of 12.6% for patients on placebo.
Paediatric population
In paediatric patients (4 to 16 years of age), levetiracetam efficacy was
established in a double-blind, placebo-controlled study, which included 198
patients and had a treatment duration of 14 weeks. In this study, the patients
received levetiracetam as a fixed dose of 60 mg/kg/day (with twice a day
dosing).
44.6% of the levetiracetam treated patients and 19.6% of the patients on
placebo had a 50% or greater reduction from baseline in the partial onset
seizure frequency per week. With continued long-term treatment, 11.4% of the
patients were seizure-free for at least 6 months and 7.2% were seizure-free for
at least 1 year.
In paediatric patients (1 month to less than 4 years of age), levetiracetam
efficacy was established in a double-blind, placebo-controlled study, which
included 116 patients and had a treatment duration of 5 days. In this study,
patients were prescribed 20 mg/kg, 25 mg/kg, 40 mg/kg or 50 mg/kg daily
dose of oral solution based on their age titration schedule. A dose of 20
mg/kg/day titrating to 40 mg/kg/day for infants one month to less than six
months and a dose of 25 mg/kg/day titrating to 50 mg/kg/day for infants and
children 6 months to less than 4 years old, was use in this study. The total daily
dose was administered twice daily.
The primary measure of effectiveness was the responder rate (percent of
patients with ≥ 50% reduction from baseline in average daily partial onset

seizure frequency) assessed by a blinded central reader using a 48-hour video
EEG. The efficacy analysis consisted of 109 patients who had at least 24 hours
of video EEG in both baseline and evaluation periods. 43.6% of the
levetiracetam treated patients and 19.6% of the patients on placebo were
considered as responders. The results are consistent across age group. With
continued long-term treatment, 8.6% of the patients were seizure-free for at
least 6 months and 7.8% were seizure-free for at least 1 year.
35 infants aged less than 1 year with partial onset seizures have been exposed
in placebo-control clinical studies of which only 13 were aged < 6 months.
Monotherapy in the treatment of partial onset seizures with or without
secondary generalisation in patients from 16 years of age with newly
diagnosed epilepsy.
Efficacy of levetiracetam as monotherapy was established in a double-blind,
parallel group, non-inferiority comparison to carbamazepine controlled release
(CR) in 576 patients 16 years of age or older with newly or recently diagnosed
epilepsy. The patients had to present with unprovoked partial seizures or with
generalized tonic-clonic seizures only. The patients were randomized to
carbamazepine CR 400 – 1200 mg/day or levetiracetam 1000 - 3000 mg/day,
the duration of the treatment was up to 121 weeks depending on the response.
Six-month seizure freedom was achieved in 73.0% of levetiracetam-treated
patients and 72.8% of carbamazepine-CR treated patients; the adjusted
absolute difference between treatments was 0.2% (95% CI: -7.8 8.2). More
than half of the subjects remained seizure free for 12 months (56.6% and
58.5% of subjects on levetiracetam and on carbamazepine CR respectively).
In a study reflecting clinical practice, the concomitant antiepileptic medication
could be withdrawn in a limited number of patients who responded to
levetiracetam adjunctive therapy (36 adult patients out of 69).

Adjunctive therapy in the treatment of myoclonic seizures in adults and
adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.
Levetiracetam efficacy was established in a double-blind, placebo-controlled
study of 16 weeks duration, in patients 12 years of age and older suffering
from idiopathic generalized epilepsy with myoclonic seizures in different
syndromes. The majority of patients presented with juvenile myoclonic
epilepsy.
In this study, levetiracetam, dose was 3000 mg/day given in 2 divided doses.
58.3% of the levetiracetam treated patients and 23.3% of the patients on
placebo had at least a 50% reduction in myoclonic seizure days per week. With
continued long-term treatment, 28.6% of the patients were free of myoclonic
seizures for at least 6 months and 21.0% were free of myoclonic seizures for at
least 1 year.
Adjunctive therapy in the treatment of primary generalised tonic-clonic
seizures in adults and adolescents from 12 years of age with idiopathic

generalised epilepsy.
Levetiracetam efficacy was established in a 24-week double-blind, placebocontrolled 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 (C max ) 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 oral
solution, based on creatinine clearance in patients with moderate and severe
renal impairment (see section 4.2).
In anuric end-stage renal disease adult subjects the half-life was approximately
25 and 3.1 hours during interdialytic and intradialytic periods, respectively.
The fractional removal of levetiracetam was 51 % during a typical 4-hour
dialysis session.
Hepatic impairment
In subjects with mild and moderate hepatic impairment, there was no relevant
modification of the clearance of levetiracetam. In most subjects with severe
hepatic impairment, the clearance of levetiracetam was reduced by more than
50 % due to a concomitant renal impairment (see section 4.2).
Paediatric population
Children (4 to 12 years)
Following single oral dose administration (20 mg/kg) to epileptic children (6
to 12 years), the half-life of levetiracetam was 6.0 hours. The apparent body
weight adjusted clearance was approximately 30 % higher than in epileptic
adults.
Following repeated oral dose administration (20 to 60 mg/kg/day) to epileptic
children (4 to 12 years), levetiracetam was rapidly absorbed. Peak plasma
concentration was observed 0.5 to 1.0 hour after dosing. Linear and dose
proportional increases were observed for peak plasma concentrations and area
under the curve. The elimination half-life was approximately 5 hours. The
apparent body clearance was 1.1 ml/min/kg.
Infants and children (1 month to 4 years)
Following single dose administration (20 mg/kg) of a 100 mg/ml oral solution

to epileptic children (1 month to 4 years), levetiracetam was rapidly absorbed
and peak plasma concentrations were observed approximately 1 hour after
dosing. The pharmacokinetic results indicated that half-life was shorter (5.3 h)
than for adults (7.2 h) and apparent clearance was faster (1.5 ml/min/kg) than
for adults (0.96 ml/min/kg).
In the population pharmacokinetic analysis conducted in patients from 1
month to 16 years of age, body weight was significantly correlated to apparent
clearance (clearance increased with an increase in body weight) and apparent
volume of distribution. Age also had an influence on both parameters. This
effect was pronounced for the younger infants, and subsided as age increased,
to become negligible around 4 years of age.
In both population pharmacokinetic analyses, there was about a 20% increase
of apparent clearance of levetiracetam when it was co-administered with an
enzyme-inducing antiepileptic medicinal product.

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-fetal 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 fetal 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 fetuses.
Four embryo-fetal 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 fetal weight
associated with increased incidence of fetuses with cardiovascular/skeletal
anomalies. The NOAEL was <200 mg/kg/day for the dams and 200 mg/kg/day
for the fetuses (equal to the MRHD on a mg/m2 basis).

A peri- and post-natal development study was performed in rats with
levetiracetam doses of 70, 350 and 1800 mg/kg/day. The NOAEL was ≥ 1800
mg/kg/day for the F0 females, and for the survival, growth and development of
the F1 offspring up to weaning (x 6 the MRHD on a mg/ m2 basis).

Neonatal and juvenile animal studies in rats and dogs demonstrated that there
were no adverse effects seen in any of the standard developmental or
maturation endpoints at doses up to 1800 mg/kg/day (x 6 – 17 the MRHD on a
mg/m2 basis).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Sodium citrate
Citric acid, monohydrate
Methyl parahydroxybenzoate (E218)
Propyl parahydroxybenzoate (E216)
Ammonium glycyrrhizate
Acesulfame potassium
Glycerol
Liquid maltitol
ART Grape FL#10273 flavour (containing Propylene glycol)
Purified water

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
36 months
After first opening: 7 months

6.4

Special precautions for storage
This medicinal product does not require any special storage conditions.

6.5

Nature and contents of container
300 ml amber glass bottle (type III) with a polypropylene closure, in an outer
carton also containing a 10 ml graduated oral syringe and an adaptor for the
syringe.
200 ml amber glass bottle (type III) with a polypropylene closure, in an outer
carton also containing a 1ml and 3 ml graduated oral syringe and an adaptor
for the syringe.
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
Bristol Laboratories Ltd,
Unit 3, Canalside,
Northbridge Road
Berkhamsted
HP4 1EG, UK

8

MARKETING AUTHORISATION NUMBER(S)
PL 17907/0573

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
27/02/2017

10

DATE OF REVISION OF THE TEXT
27/02/2017

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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