Keppra

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 250 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 250 mg levetiracetam. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
Blue, 13mm oblong, scored and debossed with the code “ucb” and “250” 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 
 
Keppra 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.  
 
Keppra 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 



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infants older than 6 months, children and adolescents weighting less than 50 kg: dose decrease should 
not exceed 10 mg/kg twice daily every two weeks; in infants (less than 6 months): dose decrease 
should not exceed 7 mg/kg twice daily every two weeks).  
 
Special populations 
 
Elderly (65 years and older) 
 
Adjustment of the dose is recommended in elderly patients with compromised renal function (see 
“Renal impairment” below). 
 
Renal impairment 
 
The daily dose must be individualised according to renal function.  
 
For adult patients, refer to the following table and adjust the dose as indicated. To use this dosing 
table, an estimate of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr in ml/min 
may be estimated from serum creatinine (mg/dl) determination, for adults and adolescents weighting 
50 kg or more, the following formula: 
 
 [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) 
CLcr (ml/min/1.73 m2) = ---------------------------- 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 

(ml/min/1.73m2) 
Dose and frequency 

Normal 
Mild 
Moderate 
Severe 
End-stage renal disease patients 
undergoing dialysis (1) 

≥ 80 
50-79 
30-49 
< 30 
- 

500 to 1,500 mg twice daily 
500 to 1,000 mg twice daily 
250 to 750 mg twice daily 
250 to 500 mg twice daily 
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, for young 
adolescents, children and infants, using the following formula (Schwartz formula):  
 
 Height (cm) x ks 
CLcr (ml/min/1.73 m2) = ------------------------------------ 
 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 
 



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Dosing adjustment for infants, children and adolescents 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 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 to 
0.07 ml/kg) twice daily  

5 to 10 mg/kg (0.05 to 
0.10 ml/kg) twice 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) Keppra 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. Keppra 
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 Keppra oral solution should be used. 
 
Monotherapy 
 
The safety and efficacy of Keppra in children and adolescents below 16 years as monotherapy 
treatment have not been established. 
No data are available. 
 



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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 
 
Keppra oral solution is the preferred formulation for use in infants and children under the age of 6 
years.  
 
For children 6 years and above, Keppra oral solution should be used for doses under 250 mg, for doses 
not multiple of 250 mg when dosing recommendation is not achievable by taking multiple tablets and 
for patients unable to swallow tablets 
The lowest effective dose should be used. The starting dose for a child or adolescent of 25kg should be 
250mg twice daily with a maximum dose of 750mg twice daily. 
Dose in children 50 kg or greater is the same as in adults. 
 
Add-on therapy for infants aged from 1 month to less than 6 months 
 
The 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. After oral administration the bitter taste of levetiracetam may be 
experienced. 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 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 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. 
 



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Abnormal and aggressive behaviours  
Levetiracetam may cause psychotic symptoms and behavioural abnormalities including irritability and 
aggressiveness. Patients treated with levetiracetam should be monitored for developing psychiatric 
signs suggesting important mood and/or personality changes. If such behaviours are noticed, treatment 
adaptation or gradual discontinuation should be considered. If discontinuation is considered, please 
refer to section 4.2. 
 
Worsening of seizures 
As with other types of antiepileptic drugs, levetiracetam may rarely exacerbate seizure frequency or 
severity. This paradoxical effect was mostly reported within the first month after levetiracetam 
initiation or increase of the dose, and was reversible upon drug discontinuation or dose decrease. 
Patients should be advised to consult their physician immediately in case of aggravation of epilepsy. 
 
Electrocardiogram QT interval prolongation 
Rare cases of ECG QT interval prolongation have been observed during the post-marketing 
surveillance. Levetiracetam should be used with caution in patients with QTc-interval prolongation, in 
patients concomitantly treated with drugs affecting the QTc-interval, or in patients with relevant pre-
existing cardiac disease or electrolyte disturbances. 
 
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. 
 
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 



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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 
 
Women of child bearing potential  
Specialist advice should be given to women who are of childbearing potential. Treatment with 
levetiracetam should be reviewed when a woman is planning to become pregnant. As with all 
antiepileptic medicines, sudden discontinuation of levetiracetam should be avoided as this may lead to 
breakthrough seizures that could have serious consequences for the woman and the unborn child. 
Monotherapy should be preferred whenever possible because therapy with multiple antiepileptic 
medicines AEDs could be associated with a higher risk of congenital malformations than 
monotherapy, depending on the associated antiepileptics. 
 
Pregnancy 
A large amount of postmarketing data on pregnant women exposed to levetiracetam monotherapy 
(more than 1800, among which in more than 1500 exposure occurred during the 1st trimester) do not 
suggest an increase in the risk for major congenital malformations. Only limited evidence is available 
on the neurodevelopment of children exposed to Keppra monotherapy in utero. However, current 
epidemiological studies (on about 100 children) do not suggest an increased risk of 
neurodevelopmental disorders or delays.  
Levetiracetam can be used during pregnancy, if after careful assessment it is considered clinically 
needed. In such case, the lowest effective dose is recommended.  
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.  
 
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. 
 



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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 Frequency category Very common Common Uncommon  Rare 
Infections and 
infestations 

Nasopharyngit
is  

  Infection 

Blood and lymphatic 
system disorders 

  Thrombocytopeni
a, leukopenia 

Pancytopenia, 
neutropenia, 
agranulocytosis 

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/irrit
ability 

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, 
delirium 

Nervous system 
disorders 

Somnolence, 
headache 

Convulsion, 
balance 
disorder, 
dizziness, 
lethargy, tremor 

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

Choreoathetosis, 
dyskinesia, 
hyperkinesia, gait 
disturbance, 
encephalopathy, 
seizures 
aggravated 



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MedDRA SOC Frequency category Very common Common Uncommon  Rare 
Eye disorders   Diplopia, vision 

blurred 
 

Ear and labyrinth 
disorders 

 Vertigo   

Cardiac disorders    Electrocardiogram 
QT prolonged 

Respiratory, thoracic 
and mediastinal 
disorders 

 Cough   

Gastrointestinal 
disorders 

 Abdominal pain, 
diarrhoea, 
dyspepsia, 
vomiting, 
nausea 

 Pancreatitis 

Hepatobiliary 
disorders 

  Liver function test 
abnormal 

Hepatic failure, 
hepatitis 

Renal and Urinary 
Disorders 

   Acute Kidney 
injury 

Skin and 
subcutaneous tissue 
disorders 

 Rash Alopecia, eczema, 
pruritus,  

Toxic epidermal 
necrolysis, 
Stevens-Johnson 
syndrome, 
erythema 
multiforme 

Musculoskeletal and 
connective tissue 
disorders 

  Muscular 
weakness, myalgia 

Rhabdomyolysis 
and blood creatine 
phosphokinase 
increased* 

General disorders 
and administration 
site conditions 

 Asthenia/ 
fatigue 

  

Injury, poisoning 
and procedural 
complications 

  Injury  

 
* Prevalence is significantly higher in Japanese patients when compared to non-Japanese patients.  
 
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. 
 
Cases of encephalopathy generally occurred at the beginning of the treatment (few days to a few 
months) and were reversible after treatment discontinuation. 
 
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. 



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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 Keppra 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 national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms 
 
Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma 
were observed with Keppra 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 -ethyl-2-oxo-1-
pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances. 
 

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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 -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 



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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, 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 



13 

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 Keppra with other substances, or vice versa, 
is unlikely. 
 



14 

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) 
 
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 



15 

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-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 fetuses.  
 
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 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 
 
Tablet core 
Croscarmellose sodium 
Macrogol 6000 
Silica colloidal anhydrous 
Magnesium stearate 
 



16 

Film-coating 
Polyvinyl alcohol-part.hydrolyzed 
Titanium dioxide (E171) 
Macrogol 3350 
Talc 
Indigo carmine aluminium lake (E132) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Aluminium/PVC blisters placed into cardboard boxes containing 20, 30, 50, 60, 100 film-coated 
tablets and multipacks containing 200 (2 packs of 100) film-coated tablets. 
 
Aluminium/PVC perforated unit dose blisters placed into cardboard boxes containing 100 x 1 film-
coated tablet.  
 
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 
 
UCB Pharma SA  
Allée de la Recherche 60 
B-1070 Brussels 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/146/001 
EU/1/00/146/002 
EU/1/00/146/003 
EU/1/00/146/004 
EU/1/00/146/005 
EU/1/00/146/029 
EU/1/00/146/034 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 29 September 2000 



17 

Date of latest renewal: 20 August 2015 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu  
 



18 

1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 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. 
Yellow, 16 mm oblong, scored and debossed with the code “ucb” and “500” 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 
 
Keppra 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.  
 
Keppra 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 



19 

infants older than 6 months, children and adolescents weighting less than 50 kg: dose decrease should 
not exceed 10 mg/kg twice daily every two weeks; in infants (less than 6 months): dose decrease 
should not exceed 7 mg/kg twice daily every two weeks).  
 
Special populations 
 
Elderly (65 years and older) 
 
Adjustment of the dose is recommended in elderly patients with compromised renal function (see 
“Renal impairment” below). 
 
Renal impairment 
 
The daily dose must be individualised according to renal function. 
 
For adult patients, refer to the following table and adjust the dose as indicated. To use this dosing 
table, an estimate of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr in ml/min 
may be estimated from serum creatinine (mg/dl) determination, for adults and adolescents weighting 
50 kg or more, the following formula: 
 
 [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) 
CLcr (ml/min/1.73 m2) = ---------------------------- 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 

(ml/min/1.73m2) 
Dose and frequency 

Normal 
Mild 
Moderate 
Severe 
End-stage renal disease patients 
undergoing dialysis (1) 

≥ 80 
50-79 
30-49 
< 30 
- 

500 to 1,500 mg twice daily 
500 to 1,000 mg twice daily 
250 to 750 mg twice daily 
250 to 500 mg twice daily 
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, for young 
adolescents, children and infants, using the following formula (Schwartz formula):  
 
 Height (cm) x ks 
CLcr (ml/min/1.73 m2) = ------------------------------------- 
 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 
 



20 

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

Group Creatinine 
clearance 
(ml/min/1.73m2) 

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 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 to 
0.07 ml/kg) twice daily  

5 to 10 mg/kg (0.05 to 
0.10 ml/kg) twice 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) Keppra 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. Keppra 
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 Keppra oral solution should be used. 
 
Monotherapy 
 
The safety and efficacy of Keppra in children and adolescents below 16 years as monotherapy 
treatment have not been established. 
No data are available. 



21 

Add-on therapy for infants aged 6 to 23 months, children (2 to 11 years) and adolescents (12 to 17 
years) weighing less than 50 kg 
 
Keppra oral solution is the preferred formulation for use in infants and children under the age of 6 
years.  
 
For children 6 years and above, Keppra oral solution should be used for doses under 250 mg, for doses 
not multiple of 250 mg when dosing recommendation is not achievable by taking multiple tablets and 
for patients unable to swallow tablets. 
 
The lowest effective dose should be used. The starting dose for a child or adolescent of 25kg should be 
250mg twice daily with a maximum dose of 750mg twice daily. Dose in children 50 kg or greater is 
the same as in adults. 
 
Add-on therapy for infants aged from 1 month to less than 6 months 
 
The 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. After oral administration the bitter taste of levetiracetam may be 
experienced. 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 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 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. 
 



22 

Abnormal and aggressive behaviours  
Levetiracetam may cause psychotic symptoms and behavioural abnormalities including irritability and 
aggressiveness. Patients treated with levetiracetam should be monitored for developing psychiatric 
signs suggesting important mood and/or personality changes. If such behaviours are noticed, treatment 
adaptation or gradual discontinuation should be considered. If discontinuation is considered, please 
refer to section 4.2. 
 
Worsening of seizures 
As with other types of antiepileptic drugs, levetiracetam may rarely exacerbate seizure frequency or 
severity. This paradoxical effect was mostly reported within the first month after levetiracetam 
initiation or increase of the dose, and was reversible upon drug discontinuation or dose decrease. 
Patients should be advised to consult their physician immediately in case of aggravation of epilepsy. 
 
Electrocardiogram QT interval prolongation 
Rare cases of ECG QT interval prolongation have been observed during the post-marketing 
surveillance. Levetiracetam should be used with caution in patients with QTc-interval prolongation, in 
patients concomitantly treated with drugs affecting the QTc-interval, or in patients with relevant pre-
existing cardiac disease or electrolyte disturbances. 
 
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. 
 
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 



23 

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 
 
Women of child bearing potential  
Specialist advice should be given to women who are of childbearing potential. Treatment with 
levetiracetam should be reviewed when a woman is planning to become pregnant. As with all 
antiepileptic medicines, sudden discontinuation of levetiracetam should be avoided as this may lead to 
breakthrough seizures that could have serious consequences for the woman and the unborn child. 
Monotherapy should be preferred whenever possible because therapy with multiple antiepileptic 
medicines AEDs could be associated with a higher risk of congenital malformations than 
monotherapy, depending on the associated antiepileptics. 
 
Pregnancy 
A large amount of postmarketing data on pregnant women exposed to levetiracetam monotherapy 
(more than 1800, among which in more than 1500 exposure occurred during the 1st trimester) do not 
suggest an increase in the risk for major congenital malformations. Only limited evidence is available 
on the neurodevelopment of children exposed to Keppra monotherapy in utero. However, current 
epidemiological studies (on about 100 children) do not suggest an increased risk of 
neurodevelopmental disorders or delays.  
Levetiracetam can be used during pregnancy, if after careful assessment it is considered clinically 
needed. In such case, the lowest effective dose is recommended. 
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.  
 
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. 
 



24 

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 Frequency category Very common Common Uncommon  Rare 
Infections and 
infestations 

Nasopharyngitis    Infection 

Blood and 
lymphatic system 
disorders 

  Thrombocytopeni
a, leukopenia 

Pancytopenia, 
neutropenia, 
agranulocytosis 

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/irrit
ability 

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, 
delirium 

Nervous system 
disorders 

Somnolence, 
headache 

Convulsion, 
balance 
disorder, 
dizziness, 
lethargy, tremor 

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

Choreoathetosis, 
dyskinesia, 
hyperkinesia, gait 
disturbance, 
encephalopathy, 
seizures 
aggravated 



25 

MedDRA SOC Frequency category Very common Common Uncommon  Rare 
Eye disorders   Diplopia, vision 

blurred 
 

Ear and labyrinth 
disorders 

 Vertigo   

Cardiac disorders    Electrocardiogram 
QT prolonged 

Respiratory, 
thoracic and 
mediastinal 
disorders 

 Cough   

Gastrointestinal 
disorders 

 Abdominal 
pain, diarrhoea, 
dyspepsia, 
vomiting, 
nausea 

 Pancreatitis 

Hepatobiliary 
disorders 

  Liver function test 
abnormal 

Hepatic failure, 
hepatitis 

Renal and 
Urinary Disorders 

   Acute Kidney 
injury 

Skin and 
subcutaneous 
tissue disorders 

 Rash Alopecia, eczema, 
pruritus,  

Toxic epidermal 
necrolysis, 
Stevens-Johnson 
syndrome, 
erythema 
multiforme 

Musculoskeletal 
and connective 
tissue disorders 

  Muscular 
weakness, 
myalgia 

Rhabdomyolysis 
and blood creatine 
phosphokinase 
increased* 

General disorders 
and 
administration 
site conditions 

 Asthenia/fatigue   

Injury, poisoning 
and procedural 
complications 

  Injury  

 
* Prevalence is significantly higher in Japanese patients when compared to non-Japanese patients.  
 
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. 
 
Cases of encephalopathy generally occurred at the beginning of the treatment (few days to a few 
months) and were reversible after treatment discontinuation. 
 
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 



26 

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 Keppra 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 levetiracetamtreated 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 national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms 
 
Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma 
were observed with Keppra 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 -ethyl-2-oxo-1-
pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


27 

 
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 -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 



28 

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, 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 



29 

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 Keppra with other substances, or vice versa, 
is unlikely. 
 



30 

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) 
 
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 



31 

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-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 fetuses.  
 
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 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 
 
Tablet core: 
Croscarmellose sodium 
Macrogol 6000 
Silica colloidal anhydrous  
Magnesium stearate 
 



32 

Film-coating: 
Polyvinyl alcohol-part. hydrolyzed 
Titanium dioxide (E171) 
Macrogol 3350 
Talc 
Iron oxide yellow (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Aluminium/PVC blisters placed into cardboard boxes containing 10, 20, 30, 50, 60, 100, 120 film-
coated tablets and multipacks containing 200 (2 packs of 100) film-coated tablets. 
 
Aluminium/PVC perforated unit dose blisters placed into cardboard boxes containing 100 x 1 film-
coated tablet.  
 
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 
 
UCB Pharma SA  
Allée de la Recherche 60 
B-1070 Brussels 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/146/006 
EU/1/00/146/007 
EU/1/00/146/008 
EU/1/00/146/009 
EU/1/00/146/010 
EU/1/00/146/011 
EU/1/00/146/012 
EU/1/00/146/013 
EU/1/00/146/035 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 



33 

 
Date of first authorisation: 29 September 2000 
Date of latest renewal: 20 August 2015 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu  



34 

1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 750 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 750 mg levetiracetam. 
 
Excipient with known effect:  
Each film-coated tablet contains 0.19 mg of sunset yellow FCF (E110). 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
Orange, 18 mm oblong, scored and debossed with the code “ucb” and “750” 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 
 
Keppra 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.  
 
Keppra 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. 
 



35 

Discontinuation 
If levetiracetam has to be discontinued it is recommended to withdraw it gradually (e.g. in adults and 
adolescents weighing more than 50 kg: 500 mg decreases twice daily every two to four weeks; in 
infants older than 6 months, children and adolescents weighting less than 50 kg: dose decrease should 
not exceed 10 mg/kg twice daily every two weeks; in infants (less than 6 months): dose decrease 
should not exceed 7 mg/kg twice daily every two weeks).  
 
Special populations 
 
Elderly (65 years and older) 
 
Adjustment of the dose is recommended in elderly patients with compromised renal function (see 
“Renal impairment” below). 
 
Renal impairment 
 
The daily dose must be individualised according to renal function.  
 
For adult patients, refer to the following table and adjust the dose as indicated. To use this dosing 
table, an estimate of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr in ml/min 
may be estimated from serum creatinine (mg/dl) determination, for adults and adolescents weighting 
50 kg or more, the following formula: 
 
 [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) 
CLcr (ml/min/1.73 m2) = ---------------------------- 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 

(ml/min/1.73m2) 
Dose and frequency 

Normal 
Mild 
Moderate 
Severe 
End-stage renal disease patients 
undergoing dialysis (1) 

≥ 80 
50-79 
30-49 
< 30 
- 

500 to 1,500 mg twice daily 
500 to 1,000 mg twice daily 
250 to 750 mg twice daily 
250 to 500 mg twice daily 
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, for young 
adolescents, children and infants, using the following formula (Schwartz formula):  
 
 Height (cm) x ks 
CLcr (ml/min/1.73 m2) = ------------------------------------ 
 Serum Creatinine (mg/dl) 
 



36 

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 adolescents patients weighing less than 50 kg with 
impaired renal function: 

Group Creatinine 
clearance 
(ml/min/1.73m2) 

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 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 to 
0.07 ml/kg) twice daily  

5 to 10 mg/kg (0.05 to 
0.10 ml/kg) twice 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) Keppra 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. Keppra 
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 Keppra oral solution should be used. 
 



37 

Monotherapy 
 
The safety and efficacy of Keppra in children and adolescents below 16 years as monotherapy 
treatment have not been established. 
No data are available. 
 
Add-on therapy for infants aged 6 to 23 months, children (2 to 11 years) and adolescents (12 to 17 
years) weighing less than 50 kg 
 
Keppra oral solution is the preferred formulation for use in infants and children under the age of 6 
years.  
 
For children 6 years and above, Keppra oral solution should be used for doses under 250 mg, for doses 
not multiple of 250 mg when dosing recommendation is not achievable by taking multiple tablets and 
for patients unable to swallow tablets 
The lowest effective dose should be used. The starting dose for a child or adolescent of 25kg should be 
250mg twice daily with a maximum dose of 750mg twice daily. Dose in children 50 kg or greater is 
the same as in adults. 
 
Add-on therapy for infants aged from 1 month to less than 6 months 
 
The 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. After oral administration the bitter taste of levetiracetam may be 
experienced. 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 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 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.  
 



38 

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. 
 
Abnormal and aggressive behaviours  
Levetiracetam may cause psychotic symptoms and behavioural abnormalities including irritability and 
aggressiveness. Patients treated with levetiracetam should be monitored for developing psychiatric 
signs suggesting important mood and/or personality changes. If such behaviours are noticed, treatment 
adaptation or gradual discontinuation should be considered. If discontinuation is considered, please 
refer to section 4.2. 
 
Worsening of seizures 
As with other types of antiepileptic drugs, levetiracetam may rarely exacerbate seizure frequency or 
severity. This paradoxical effect was mostly reported within the first month after levetiracetam 
initiation or increase of the dose, and was reversible upon drug discontinuation or dose decrease. 
Patients should be advised to consult their physician immediately in case of aggravation of epilepsy. 
 
Electrocardiogram QT interval prolongation 
Rare cases of ECG QT interval prolongation have been observed during the post-marketing 
surveillance. Levetiracetam should be used with caution in patients with QTc-interval prolongation, in 
patients concomitantly treated with drugs affecting the QTc-interval, or in patients with relevant pre-
existing cardiac disease or electrolyte disturbances. 
 
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. 
 
Excipients 
Keppra 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.  
 



39 

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 
 
Women of child bearing potential  
Specialist advice should be given to women who are of childbearing potential. Treatment with 
levetiracetam should be reviewed when a woman is planning to become pregnant. As with all 
antiepileptic medicines, sudden discontinuation of levetiracetam should be avoided as this may lead to 
breakthrough seizures that could have serious consequences for the woman and the unborn child. 
Monotherapy should be preferred whenever possible because therapy with multiple antiepileptic 
medicines AEDs could be associated with a higher risk of congenital malformations than 
monotherapy, depending on the associated antiepileptics. 
 
Pregnancy 
A large amount of postmarketing data on pregnant women exposed to levetiracetam monotherapy 
(more than 1800, among which in more than 1500 exposure occurred during the 1st trimester) do not 
suggest an increase in the risk for major congenital malformations. Only limited evidence is available 
on the neurodevelopment of children exposed to Keppra monotherapy in utero. However, current 
epidemiological studies (on about 100 children) do not suggest an increased risk of 
neurodevelopmental disorders or delays.  
Levetiracetam can be used during pregnancy, if after careful assessment it is considered clinically 
needed. In such case, the lowest effective dose is recommended. 
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.  
 
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. 
 



40 

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 Frequency category Very common Common Uncommon  Rare 
Infections and 
infestations 

Nasopharyngitis    Infection 

Blood and 
lymphatic system 
disorders 

  Thrombocytopeni
a, leukopenia 

Pancytopenia, 
neutropenia, 
agranulocytosis 

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 



41 

MedDRA SOC Frequency category Very common Common Uncommon  Rare 
Psychiatric 
disorders 

 Depression, 
hostility/ 
aggression, 
anxiety,  
insomnia, 
nervousness/ir
ritability 

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, 
delirium 

Nervous system 
disorders 

Somnolence, 
headache 

Convulsion, 
balance 
disorder, 
dizziness, 
lethargy, 
tremor 

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

Choreoathetosis, 
dyskinesia, 
hyperkinesia, gait 
disturbance, 
encephalopathy, 
seizures aggravated 

Eye disorders   Diplopia, vision 
blurred 

 

Ear and labyrinth 
disorders 

 Vertigo   

Cardiac disorders    Electrocardiogram 
QT prolonged 

Respiratory, 
thoracic and 
mediastinal 
disorders 

 Cough   

Gastrointestinal 
disorders 

 Abdominal 
pain, 
diarrhoea, 
dyspepsia, 
vomiting, 
nausea 

 Pancreatitis 

Hepatobiliary 
disorders 

  Liver function 
test abnormal 

Hepatic failure, 
hepatitis 

Renal and 
Urinary Disorders 

   Acute Kidney injury 

Skin and 
subcutaneous 
tissue disorders 

 Rash Alopecia, eczema, 
pruritus,  

Toxic epidermal 
necrolysis, Stevens-
Johnson syndrome, 
erythema 
multiforme 

Musculoskeletal 
and connective 
tissue disorders 

  Muscular 
weakness, 
myalgia 

Rhabdomyolysis 
and blood creatine 
phosphokinase 
increased* 

General disorders 
and 
administration 
site conditions 

 Asthenia/fatig
ue 

  



42 

MedDRA SOC Frequency category Very common Common Uncommon  Rare 
Injury, poisoning 
and procedural 
complications 

  Injury  

 
* Prevalence is significantly higher in Japanese patients when compared to non-Japanese patients. 
 
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. 
 
Cases of encephalopathy generally occurred at the beginning of the treatment (few days to a few 
months) and were reversible after treatment discontinuation. 
 
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 Keppra 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 



43 

professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms 
 
Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma 
were observed with Keppra 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 -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 -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 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


44 

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 



45 

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. 
 



46 

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. 
 



47 

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-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 fetuses.  
 



48 

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 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 
 
Tablet core: 
Croscarmellose sodium 
Macrogol 6000 
Silica colloidal anhydrous. 
Magnesium stearate 
 
Film-coating: 
Polyvinyl alcohol-part. hydrolyzed 
Titanium dioxide (E171) 
Macrogol 3350 
Talc  
Sunset yellow FCF aluminium lake (E110) 
Iron oxide red (E172) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Aluminium/PVC blisters placed into cardboard boxes containing 20, 30, 50, 60, 80, 100 film-coated 
tablets and multipacks containing 200 (2 packs of 100) film-coated tablets. 
 
Aluminium/PVC perforated unit dose blisters placed into cardboard boxes containing 100 x 1 film-
coated tablet.  
 
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. 



49 

 
 
7. MARKETING AUTHORISATION HOLDER 
 
UCB Pharma SA  
Allée de la Recherche 60 
B-1070 Brussels 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/146/014 
EU/1/00/146/015 
EU/1/00/146/016 
EU/1/00/146/017 
EU/1/00/146/018 
EU/1/00/146/019 
EU/1/00/146/028 
EU/1/00/146/036 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 29 September 2000 
Date of latest renewal: 20 August 2015 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 



50 

1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 1000 mg film-coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each film-coated tablet contains 1,000 mg levetiracetam. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Film-coated tablet. 
White, 19 mm oblong, scored and debossed with the code “ucb” and “1000” 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 
 
Keppra 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.  
 
Keppra 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 



51 

infants older than 6 months, children and adolescents weighting less than 50 kg: dose decrease should 
not exceed 10 mg/kg twice daily every two weeks; in infants (less than 6 months): dose decrease 
should not exceed 7 mg/kg twice daily every two weeks).  
 
Special populations 
 
Elderly (65 years and older) 
 
Adjustment of the dose is recommended in elderly patients with compromised renal function (see 
“Renal impairment” below). 
 
Renal impairment 
 
The daily dose must be individualised according to renal function.  
 
For adult patients, refer to the following table and adjust the dose as indicated. To use this dosing 
table, an estimate of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr in ml/min 
may be estimated from serum creatinine (mg/dl) determination, for adults and adolescents weighting 
50 kg or more, the following formula: 
 
 [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) 
CLcr (ml/min/1.73 m2) = ---------------------------- 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 

(ml/min/1.73m2) 
Dose and frequency 

Normal 
Mild 
Moderate 
Severe 
End-stage renal disease patients 
undergoing dialysis (1) 

≥ 80 
50-79 
30-49 
< 30 
- 

500 to 1,500 mg twice daily 
500 to 1,000 mg twice daily 
250 to 750 mg twice daily 
250 to 500 mg twice daily 
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, for young 
adolescents, children and infants, using the following formula (Schwartz formula):  
 
 Height (cm) x ks 
CLcr (ml/min/1.73 m2) = ------------------------------------- 
 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 
 



52 

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

Group Creatinine 
clearance 
(ml/min/1.73m2) 

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 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 to 
0.07 ml/kg) twice daily  

5 to 10 mg/kg (0.05 to 
0.10 ml/kg) twice 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) Keppra 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. Keppra 
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 Keppra oral solution should be used. 
 
Monotherapy 
 
The safety and efficacy of Keppra in children and adolescents below 16 years as monotherapy 
treatment have not been established. 
No data are available. 
 



53 

Add-on therapy for infants aged 6 to 23 months, children (2 to 11 years) and adolescents (12 to 17 
years) weighing less than 50 kg 
 
Keppra oral solution is the preferred formulation for use in infants and children under the age of 6 
years.  
 
For children 6 years and above, Keppra oral solution should be used for doses under 250 mg, for doses 
not multiple of 250 mg when dosing recommendation is not achievable by taking multiple tablets and 
for patients unable to swallow tablets 
 
The lowest effective dose should be used. The starting dose for a child or adolescent of 25kg should be 
250mg twice daily with a maximum dose of 750mg twice daily. Dose in children 50 kg or greater is 
the same as in adults. 
Add-on therapy for infants aged from 1 month to less than 6 months 
 
The 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. After oral administration the bitter taste of levetiracetam may be 
experienced. 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 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 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. 
 
Abnormal and aggressive behaviours  



54 

Levetiracetam may cause psychotic symptoms and behavioural abnormalities including irritability and 
aggressiveness. Patients treated with levetiracetam should be monitored for developing psychiatric 
signs suggesting important mood and/or personality changes. If such behaviours are noticed, treatment 
adaptation or gradual discontinuation should be considered. If discontinuation is considered, please 
refer to section 4.2. 
 
Worsening of seizures 
As with other types of antiepileptic drugs, levetiracetam may rarely exacerbate seizure frequency or 
severity. This paradoxical effect was mostly reported within the first month after levetiracetam 
initiation or increase of the dose, and was reversible upon drug discontinuation or dose decrease. 
Patients should be advised to consult their physician immediately in case of aggravation of epilepsy. 
 
Electrocardiogram QT interval prolongation 
Rare cases of ECG QT interval prolongation have been observed during the post-marketing 
surveillance. Levetiracetam should be used with caution in patients with QTc-interval prolongation, in 
patients concomitantly treated with drugs affecting the QTc-interval, or in patients with relevant pre-
existing cardiac disease or electrolyte disturbances. 
 
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. 
 
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 



55 

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 
 
Women of child bearing potential  
Specialist advice should be given to women who are of childbearing potential. Treatment with 
levetiracetam should be reviewed when a woman is planning to become pregnant. As with all 
antiepileptic medicines, sudden discontinuation of levetiracetam should be avoided as this may lead to 
breakthrough seizures that could have serious consequences for the woman and the unborn child. 
Monotherapy should be preferred whenever possible because therapy with multiple antiepileptic 
medicines AEDs could be associated with a higher risk of congenital malformations than 
monotherapy, depending on the associated antiepileptics. 
 
Pregnancy 
A large amount of postmarketing data on pregnant women exposed to levetiracetam monotherapy 
(more than 1800, among which in more than 1500 exposure occurred during the 1st trimester) do not 
suggest an increase in the risk for major congenital malformations. Only limited evidence is available 
on the neurodevelopment of children exposed to Keppra monotherapy in utero. However, current 
epidemiological studies (on about 100 children) do not suggest an increased risk of 
neurodevelopmental disorders or delays.  
Levetiracetam can be used during pregnancy, if after careful assessment it is considered clinically 
needed. In such case, the lowest effective dose is recommended. 
 
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.  
 
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. 
 



56 

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 Frequency category Very common Common Uncommon  Rare 
Infections and 
infestations 

Nasopharyngitis    Infection 

Blood and 
lymphatic system 
disorders 

  Thrombocytopenia
, leukopenia 

Pancytopenia, 
neutropenia, 
agranulocytosis 

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/irr
itability 

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, delirium 

Nervous system 
disorders 

Somnolence, 
headache 

Convulsion, 
balance 
disorder, 
dizziness, 
lethargy, 
tremor 

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

Choreoathetosis, 
dyskinesia, 
hyperkinesia, gait 
disturbance, 
encephalopathy, 
seizures aggravated 

Eye disorders   Diplopia, vision 
blurred 

 



57 

MedDRA SOC Frequency category Very common Common Uncommon  Rare 
Ear and labyrinth 
disorders 

 Vertigo   

Cardiac disorders    Electrocardiogram 
QT prolonged 

Respiratory, 
thoracic and 
mediastinal 
disorders 

 Cough   

Gastrointestinal 
disorders 

 Abdominal 
pain, diarrhoea, 
dyspepsia, 
vomiting, 
nausea 

 Pancreatitis 

Hepatobiliary 
disorders 

  Liver function test 
abnormal 

Hepatic failure, 
hepatitis 

Renal and Urinary 
Disorders 

   Acute Kidney 
injury 

Skin and 
subcutaneous 
tissue disorders 

 Rash Alopecia, eczema, 
pruritus,  

Toxic epidermal 
necrolysis, Stevens-
Johnson syndrome, 
erythema 
multiforme 

Musculoskeletal 
and connective 
tissue disorders 

  Muscular 
weakness, myalgia 

Rhabdomyolysis 
and blood creatine 
phosphokinase 
increased* 

General disorders 
and administration 
site conditions 

 Asthenia/ 
fatigue 

  

Injury, poisoning 
and procedural 
complications 

  Injury  

 
* Prevalence is significantly higher in Japanese patients when compared to non-Japanese patients.  
 
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. 
 
Cases of encephalopathy generally occurred at the beginning of the treatment (few days to a few 
months) and were reversible after treatment discontinuation. 
 
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. 
 



58 

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 Keppra 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 national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms 
 
Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma 
were observed with Keppra 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 -ethyl-2-oxo-1-
pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances. 
 



59 

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 -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 



60 

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, 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 



61 

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 Keppra with other substances, or vice versa, 
is unlikely. 
 



62 

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) 
 
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 concentration 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 



63 

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-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 fetuses.  
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 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 
 
Tablet core: 
Croscarmellose sodium 
Macrogol 6000 
Silica colloidal anhydrous  
Magnesium stearate 
 
Film-coating: 
Polyvinyl alcohol-part. hydrolyzed 



64 

Titanium dioxide (E171) 
Macrogol 3350 
Talc 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Aluminium/PVC blisters placed into cardboard boxes containing 10, 20, 30, 50, 60, 100 film-coated 
tablets and multipacks containing 200 (2 packs of 100) film-coated tablets. 
 
Aluminium/PVC perforated unit dose blisters placed into cardboard boxes containing 100 x 1 film-
coated tablet.  
 
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 
 
UCB Pharma SA  
Allée de la Recherche 60 
B-1070 Brussels 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/146/020 
EU/1/00/146/021 
EU/1/00/146/022 
EU/1/00/146/023 
EU/1/00/146/024 
EU/1/00/146/025 
EU/1/00/146/026 
EU/1/00/146/037 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 29 September 2000 
Date of latest renewal: 20 August 2015 
 



65 

 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu  
 



66 

1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 100 mg/ml oral solution 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each ml contains 100 mg levetiracetam 
 
Excipients with known effect:  
Each ml contains 2.7 mg of methyl parahydroxybenzoate (E218), 0.3 mg of propyl 
parahydroxybenzoate (E216) and 300 mg of maltitol liquid. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Oral solution. 
Clear liquid. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Keppra 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.  
 
Keppra 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. 
 



67 

Discontinuation 
If levetiracetam has to be discontinued it is recommended to withdraw it gradually (e.g. in adults and 
adolescents weighing more than 50 kg: 500 mg decreases twice daily every two to four weeks; in 
infants older than 6 months, children and adolescents weighting less than 50 kg: dose decrease should 
not exceed 10 mg/kg twice daily every two weeks; in infants (less than 6 months): dose decrease 
should not exceed 7 mg/ kg twice daily every two weeks).  
 
Special populations 
 
Elderly (65 years and older) 
 
Adjustment of the dose is recommended in elderly patients with compromised renal function (see 
“Renal impairment” below). 
 
Renal impairment 
 
The daily dose must be individualised according to renal function.  
 
For adult patients, refer to the following table and adjust the dose as indicated. To use this dosing 
table, an estimate of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr in ml/min 
may be estimated from serum creatinine (mg/dl) determination, for adults and adolescents weighting 
50 kg or more, the following formula: 
 
 [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) 
CLcr (ml/min/1.73 m2) = ---------------------------- 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 

(ml/min/1.73m2) 
Dose and frequency 

Normal 
Mild 
Moderate 
Severe 
End-stage renal disease patients 
undergoing dialysis (1) 

≥ 80 
50-79 
30-49 
< 30 
- 

500 to 1,500 mg twice daily 
500 to 1,000 mg twice daily 
250 to 750 mg twice daily 
250 to 500 mg twice daily 
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, for young 
adolescents, children and infants, using the following formula (Schwartz formula):  
 
 Height (cm) x ks 
CLcr (ml/min/1.73 m2) = ------------------------------------ 
 Serum Creatinine (mg/dl) 
 



68 

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 adolescents patients weighing less than 50 kg with 
impaired renal function: 

Group Creatinine 
clearance 
(ml/min/1.73m2) 

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 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 to 
0.07 ml/kg) twice daily  

5 to 10 mg/kg (0.05 to 
0.10 ml/kg) twice 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) Keppra 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. 
 
Keppra 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 Keppra oral solution should be used. 
 
Monotherapy 
 
The safety and efficacy of Keppra in children and adolescents below 16 years as monotherapy 
treatment have not been established. 
No data are available. 
 



69 

Add-on therapy for infants aged 6 to 23 months, children (2 to 11 years) and adolescents (12 to 17 
years) weighing less than 50 kg 
 
The initial therapeutic dose is 10 mg/kg twice daily.  
Depending upon the clinical response and tolerability, the dose can be increased up to 30 mg/kg twice 
daily. Dose changes should not exceed increases or decreases of 10 mg/kg twice daily every two 
weeks. The lowest effective dose should be used. 
Dose in children 50 kg or greater is the same as in adults. 
 
Dose recommendations for infants from 6 months of age, children and adolescents: 

Weight Starting dose:  
10 mg/kg twice daily 
 

Maximum dose:  
30 mg/kg twice daily 

6 kg (1) 60 mg (0.6 ml) twice daily 180 mg (1.8 ml) twice daily 
10 kg (1) 100 mg (1 ml) twice daily 300 mg (3 ml) twice daily 
15 kg (1) 150 mg (1.5 ml) twice daily 450 mg (4.5 ml) twice daily 
20 kg (1) 200 mg (2 ml) twice daily 600 mg (6 ml) twice 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 Keppra 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 Keppra 100 mg/ml oral solution. 
 
Dose recommendations for infants aged from 1 month to less than 6 months: 
 

Weight Starting dose:  
7 mg/kg twice daily 
 

Maximum dose:  
21 mg/kg twice daily 

4 kg 28 mg (0.3 ml) twice daily 84 mg (0.85 ml) twice daily 
5 kg 35 mg (0.35 ml) twice daily 105 mg (1.05 ml) twice daily 
7 kg 49 mg (0.5 ml)twice 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. After oral administration the bitter taste of levetiracetam may be experienced. 
 



70 

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 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. 
 
Abnormal and aggressive behaviours  
Levetiracetam may cause psychotic symptoms and behavioural abnormalities including irritability and 
aggressiveness. Patients treated with levetiracetam should be monitored for developing psychiatric 
signs suggesting important mood and/or personality changes. If such behaviours are noticed, treatment 
adaptation or gradual discontinuation should be considered. If discontinuation is considered, please 
refer to section 4.2. 
 
Worsening of seizures 
As with other types of antiepileptic drugs, levetiracetam may rarely exacerbate seizure frequency or 
severity. This paradoxical effect was mostly reported within the first month after levetiracetam 
initiation or increase of the dose, and was reversible upon drug discontinuation or dose decrease. 
Patients should be advised to consult their physician immediately in case of aggravation of epilepsy. 
 
Electrocardiogram QT interval prolongation 
Rare cases of ECG QT interval prolongation have been observed during the post-marketing 
surveillance. Levetiracetam should be used with caution in patients with QTc-interval prolongation, in 
patients concomitantly treated with drugs affecting the QTc-interval, or in patients with relevant pre-
existing cardiac disease or electrolyte disturbances. 
 
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. 



71 

 
Excipients 
Keppra 100 mg/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 
 
Women of child bearing potential  
Specialist advice should be given to women who are of childbearing potential. Treatment with 
levetiracetam should be reviewed when a woman is planning to become pregnant. As with all 
antiepileptic medicines, sudden discontinuation of levetiracetam should be avoided as this may lead to 



72 

breakthrough seizures that could have serious consequences for the woman and the unborn child. 
Monotherapy should be preferred whenever possible because therapy with multiple antiepileptic 
medicines AEDs could be associated with a higher risk of congenital malformations than 
monotherapy, depending on the associated antiepileptics. 
 
Pregnancy 
A large amount of postmarketing data on pregnant women exposed to levetiracetam monotherapy 
(more than 1800, among which in more than 1500 exposure occurred during the 1st trimester) do not 
suggest an increase in the risk for major congenital malformations. Only limited evidence is available 
on the neurodevelopment of children exposed to Keppra monotherapy in utero. However, current 
epidemiological studies (on about 100 children) do not suggest an increased risk of 
neurodevelopmental disorders or delays.  
Levetiracetam can be used during pregnancy, if after careful assessment it is considered clinically 
needed. In such case, the lowest effective dose is recommended. 
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.  
 
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.  
 
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). 
 



73 

MedDRA SOC Frequency category Very common Common Uncommon  Rare 
Infections and 
infestations 

Nasopharyngitis    Infection 

Blood and 
lymphatic 
system disorders 

  Thrombocytopeni
a, leukopenia 

Pancytopenia, 
neutropenia, 
agranulocytosis 

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, delirium 

Nervous system 
disorders 

Somnolence, 
headache 

Convulsion, 
balance 
disorder, 
dizziness, 
lethargy, 
tremor 

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

Choreoathetosis, 
dyskinesia, 
hyperkinesia, gait 
disturbance, 
encephalopathy, 
seizures aggravated 

Eye disorders   Diplopia, vision 
blurred 

 

Ear and labyrinth 
disorders 

 Vertigo   

Cardiac 
disorders 

   Electrocardiogram 
QT prolonged 

Respiratory, 
thoracic and 
mediastinal 
disorders 

 Cough   

Gastrointestinal 
disorders 

 Abdominal 
pain, 
diarrhoea, 
dyspepsia, 
vomiting, 
nausea 

 Pancreatitis 

Hepatobiliary 
disorders 

  Liver function test 
abnormal 

Hepatic failure, 
hepatitis 



74 

MedDRA SOC Frequency category Very common Common Uncommon  Rare 
Renal and 
Urinary 
Disorders 

   Acute Kidney 
injury 

Skin and 
subcutaneous 
tissue disorders 

 Rash Alopecia, eczema, 
pruritus,  

Toxic epidermal 
necrolysis, 
Stevens-Johnson 
syndrome, 
erythema 
multiforme 

Musculoskeletal 
and connective 
tissue disorders 

  Muscular 
weakness, 
myalgia 

Rhabdomyolysis 
and blood creatine 
phosphokinase 
increased* 

General 
disorders and 
administration 
site conditions 

 Asthenia/ 
fatigue 

  

Injury, poisoning 
and procedural 
complications 

  Injury  

 
* Prevalence is significantly higher in Japanese patients when compared to non-Japanese patients.  
 
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. 
 
Cases of encephalopathy generally occurred at the beginning of the treatment (few days to a few 
months) and were reversible after treatment discontinuation. 
 
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, 



75 

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 Keppra 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 national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms 
 
Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma 
were observed with Keppra 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 -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 -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 

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76 

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 



77 

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). 
 



78 

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 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 



79 

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) 
 
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. 
 



80 

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 fetuses.  
 
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 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 
Glycerol (E422) 
Maltitol liquid (E965) 
Acesulfame potassium (E950) 
Grape flavour 
Purified water 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 



81 

After first opening: 7 months 
 
6.4 Special precautions for storage 
 
Store in the original bottle in order to protect from light. 
 
6.5 Nature and contents of container 
 
300 ml amber glass bottle (type III) with a white child resistant closure (polypropylene) in a cardboard 
box also containing a 10 ml graduated oral syringe (polypropylene, polyethylene) and an adaptor for 
the syringe (polyethylene). 
 
150 ml amber glass bottle (type III) with a white child resistant closure (polypropylene) in a cardboard 
box also containing a 3 ml graduated oral syringe (polypropylene, polyethylene) and an adaptor for the 
syringe (polyethylene). 
 
150 ml amber glass bottle (type III) with a white child resistant closure (polypropylene) in a cardboard 
box also containing a 1 ml graduated oral syringe (polypropylene, polyethylene) and an adaptor for the 
syringe (polyethylene). 
 
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 
 
UCB Pharma SA  
Allée de la Recherche 60 
B-1070 Brussels 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/00/146/027 
EU/1/00/146/031 
EU/1/00/146/032 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 29 September 2000 
Date of latest renewal: 20 August 2015 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu  
 



82 

1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 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. 
 
Excipient with known effect: 
Each vial contains 19 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 
 
Keppra 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.  
 
Keppra 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. 

 
Keppra concentrate is an alternative for patients when oral administration is temporarily not feasible. 
 
4.2 Posology and method of administration 
 
Posology 
 
Keppra 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. 
 



83 

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) 
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) 
CLcr (ml/min/1.73 m2) = ---------------------------- 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 

(ml/min/1.73m2) 
Dose and frequency 

Normal 
Mild 
Moderate 
Severe 
End-stage renal disease patients 
undergoing dialysis (1) 

≥ 80 
50-79 
30-49 
< 30 
- 

500 to 1,500 mg twice daily 
500 to 1,000 mg twice daily 
250 to 750 mg twice daily 
250 to 500 mg twice daily 
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. 
 



84 

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):  
 
 Height (cm) x ks 
CLcr (ml/min/1.73 m2) = ------------------------------------ 
 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 Creatinine 
clearance 
(ml/min/1.73m2) 

Dose and frequency 
Children from 4 years and adolescents weighing less than 
50 kg 

Normal ≥ 80 10 to 30 mg/kg (0.10 to 0.30 ml/kg) twice daily 
Mild 50-79 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 5 to 10 mg/kg (0.05 to 0.10 ml/kg) twice daily  
End-stage renal 
disease patients 
undergoing dialysis  

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

(1) A 15 mg/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/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. 
 
Monotherapy 
 
The safety and efficacy of Keppra in children below and adolescents 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. 
 



85 

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 Keppra 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 Keppra 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 
Keppra 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 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 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. 
 



86 

Abnormal and aggressive behaviours  
Levetiracetam may cause psychotic symptoms and behavioural abnormalities including irritability and 
aggressiveness. Patients treated with levetiracetam should be monitored for developing psychiatric 
signs suggesting important mood and/or personality changes. If such behaviours are noticed, treatment 
adaptation or gradual discontinuation should be considered. If discontinuation is considered, please 
refer to section 4.2. 
 
Worsening of seizures 
As with other types of antiepileptic drugs, levetiracetam may rarely exacerbate seizure frequency or 
severity. This paradoxical effect was mostly reported within the first month after levetiracetam 
initiation or increase of the dose, and was reversible upon drug discontinuation or dose decrease. 
Patients should be advised to consult their physician immediately in case of aggravation of epilepsy. 
 
Electrocardiogram QT interval prolongation 
Rare cases of ECG QT interval prolongation have been observed during the post-marketing 
surveillance. Levetiracetam should be used with caution in patients with QTc-interval prolongation, in 
patients concomitantly treated with drugs affecting the QTc-interval, or in patients with relevant pre-
existing cardiac disease or electrolyte disturbances. 
 
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 
This medicinal product contains 2.5 mmol (or 57 mg) sodium per maximum single dose (0.8 mmol (or 
19 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. 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 
 



87 

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. 
 
Alcohol 
No data on the interaction of levetiracetam with alcohol are available. 
 
4.6 Fertility, pregnancy and lactation 
 
Women of child bearing potential  
Specialist advice should be given to women who are of childbearing potential. Treatment with 
levetiracetam should be reviewed when a woman is planning to become pregnant. As with all 
antiepileptic medicines, sudden discontinuation of levetiracetam should be avoided as this may lead to 
breakthrough seizures that could have serious consequences for the woman and the unborn child. 
Monotherapy should be preferred whenever possible because therapy with multiple antiepileptic 
medicines AEDs could be associated with a higher risk of congenital malformations than 
monotherapy, depending on the associated antiepileptics. 
 
Pregnancy 
A large amount of postmarketing data on pregnant women exposed to levetiracetam monotherapy 
(more than 1800, among which in more than 1500 exposure occurred during the 1st trimester) do not 
suggest an increase in the risk for major congenital malformations. Only limited evidence is available 
on the neurodevelopment of children exposed to Keppra monotherapy in utero. However, current 
epidemiological studies (on about 100 children) do not suggest an increased risk of 
neurodevelopmental disorders or delays.  
Levetiracetam can be used during pregnancy, if after careful assessment it is considered clinically 
needed. In such case, the lowest effective dose is recommended. 
 
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.  
 
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. 
 



88 

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 Keppra intravenous use and since oral and 
intravenous formulations are bioequivalent, the safety information of Keppra intravenous will rely on 
Keppra 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 Common Uncommon  Rare 
Infections and 
infestations 

Nasopharyngitis    Infection 

Blood and 
lymphatic system 
disorders 

  Thrombocytopeni
a, leukopenia 

Pancytopenia, 
neutropenia, 
agranulocytosis 

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/ir
ritability 

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, delirium 



89 

MedDRA SOC Frequency category Very common Common Uncommon  Rare 
Nervous system 
disorders 

Somnolence, 
headache 

Convulsion, 
balance 
disorder, 
dizziness, 
lethargy, 
tremor 

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

Choreoathetosis, 
dyskinesia, 
hyperkinesia, gait 
disturbance, 
encephalopathy, 
seizures aggravated 

Eye disorders   Diplopia, vision 
blurred 

 

Ear and labyrinth 
disorders 

 Vertigo   

Cardiac disorders    Electrocardiogram 
QT prolonged 

Respiratory, 
thoracic and 
mediastinal 
disorders 

 Cough   

Gastrointestinal 
disorders 

 Abdominal 
pain, 
diarrhoea, 
dyspepsia, 
vomiting, 
nausea 

 Pancreatitis 

Hepatobiliary 
disorders 

  Liver function test 
abnormal 

Hepatic failure, 
hepatitis 

Renal and Urinary 
Disorders 

   Acute Kidney 
injury 

Skin and 
subcutaneous 
tissue disorders 

 Rash Alopecia, eczema, 
pruritus,  

Toxic epidermal 
necrolysis, 
Stevens-Johnson 
syndrome, 
erythema 
multiforme 

Musculoskeletal 
and connective 
tissue disorders 

  Muscular 
weakness, 
myalgia 

Rhabdomyolysis 
and blood creatine 
phosphokinase 
increased* 

General disorders 
and 
administration 
site conditions 

 Asthenia/ 
fatigue 

  

Injury, poisoning 
and procedural 
complications 

  Injury  

 
* Prevalence is significantly higher in Japanese patients when compared to non-Japanese patients.  
 
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. 
 
Cases of encephalopathy generally occurred at the beginning of the treatment (few days to a few 
months) and were reversible after treatment discontinuation. 



90 

 
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 Keppra 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 levetiracetamtreated 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 national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms 
 
Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma 
were observed with Keppra 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. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


91 

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 -ethyl-2-oxo-1-
pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances. 
 
Mechanism of action 
 
The mechanism of action of levetiracetam still remains to be fully elucidated. In vitro and in vivo 
experiments suggest that levetiracetam does not alter basic cell characteristics and normal 
neurotransmission. 
 
In vitro studies show that levetiracetam affects intraneuronal Ca2+ levels by partial inhibition of N-type 
Ca2+ currents and by reducing the release of Ca2+ from intraneuronal stores. In addition, it partially 
reverses the reductions in GABA- and glycine-gated currents induced by zinc and β-carbolines. 
Furthermore, levetiracetam has been shown in in vitro studies to bind to a specific site in rodent brain 
tissue. This binding site is the synaptic vesicle protein 2A, believed to be involved in vesicle fusion 
and neurotransmitter exocytosis. Levetiracetam and related analogues show a rank order of affinity for 
binding to the synaptic vesicle protein 2A which correlates with the potency of their anti-seizure 
protection in the mouse audiogenic model of epilepsy. This finding suggests that the interaction 
between levetiracetam and the synaptic vesicle protein 2A seems to contribute to the antiepileptic 
mechanism of action of the medicinal product. 
 
Pharmacodynamic effects 
 
Levetiracetam induces seizure protection in a broad range of animal models of partial and primary 
generalised seizures without having a pro-convulsant effect. The primary metabolite is inactive. 
In man, an activity in both partial and generalised epilepsy conditions (epileptiform 
discharge/photoparoxysmal response) has confirmed the broad spectrum pharmacological profile of 
levetiracetam. 
 
Clinical efficacy and safety 
 
Adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation 
in adults, adolescents 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. 



92 

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, 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 



93 

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. 



94 

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. 
 



95 

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 fetuses.  
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 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 acetate 
Glacial acetic acid 
Sodium chloride 
Water for injections 
 
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 8°C, 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) closed by a polytetrafluoroethylene grey chlorobutyl rubber stopper or an 
uncoated grey bromobutyl rubber stopper and sealed with an aluminium/polypropylene flip cap.  
Each carton contains 10 vials. 
 



96 

6.6 Special precautions for disposal and other handling 
 
See Table 1 for the recommended preparation and administration of Keppra concentrate for solution 
for infusion to achieve a total daily dose of 500 mg, 1,000 mg, 2,000 mg, or 3,000 mg in two divided 
doses. 
 
Table 1. Preparation and administration of Keppra 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. 
 
Keppra 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 medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
UCB Pharma SA  
Allée de la Recherche 60 
B-1070 Brussels 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/146/030 
EU/1/00/146/033 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 29 September 2000 
Date of latest renewal: 20 August 2015 
 
 



97 

10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu  
 
  



98 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A.  MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 
 



99 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release 
 
Film-coated tablets 
 
UCB Pharma SA or Aesica Pharmaceuticals S.r.l. 
Chemin du Foriest Via Praglia, 15 
B-1420 Braine-l’Alleud I-10044 Pianezza 
Belgium  Italy 
 
Concentrate for solution for infusion 
 
UCB Pharma SA or Aesica Pharmaceuticals S.r.l. 
Chemin du Foriest Via Praglia, 15 
B-1420 Braine-l’Alleud I-10044 Pianezza 
Belgium Italy 
 
Oral solution 
 
NextPharma SAS or UCB Pharma SA  
17, Route de Meulan       Chemin du Foriest  
F-78520 Limay        B-1420 Braine-l’Alleud  
France         Belgium 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
 Periodic Safety Update Reports 
 
The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) provided for 
under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT  
 
 Risk Management Plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP.  
 
An updated RMP should be submitted:  

 At the request of the European Medicines Agency;  
 Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 



100 

as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached. 

 
If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the 
same time. 
 
 
  



101 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

  



102 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
  



103 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Box of 20, 30, 50, 60, 100, 100 (100 x 1) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 250 mg film-coated tablets 
Levetiracetam 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 250 mg levetiracetam. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
20 film-coated tablets 
30 film-coated tablets 
50 film-coated tablets 
60 film-coated tablets 
100 film-coated tablets 
100 x 1 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



104 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
UCB Pharma SA 
Allée de la Recherche 60 
B-1070 Brussels 
BELGIUM 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/146/001 20 tablets 
EU/1/00/146/002 30 tablets 
EU/1/00/146/003 50 tablets 
EU/1/00/146/004 60 tablets 
EU/1/00/146/005 100 tablets 
EU/1/00/146/029 200 tablets (2 packs of 100) 
EU/1/00/146/034 100 x 1 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Keppra 250 mg 
Justification for not including Braille accepted 100 x 1 tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
  



105 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Box of 200 (2 x 100) containing blue box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 250 mg film-coated tablets 
Levetiracetam 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 250 mg levetiracetam. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Multipack: 200 (2 packs of 100) film-coated tablets  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



106 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
UCB Pharma SA 
Allée de la Recherche 60 
B-1070 Brussels 
BELGIUM 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/146/001 20 tablets 
EU/1/00/146/002 30 tablets 
EU/1/00/146/003 50 tablets 
EU/1/00/146/004 60 tablets 
EU/1/00/146/005 100 tablets 
EU/1/00/146/029 200 tablets (2 packs of 100) 
EU/1/00/146/034 100 x 1 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Keppra 250 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
  
  



107 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Intermediate packaging containing 100 tablets for box of 200 (2 x 100) tablets without blue box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 250 mg film-coated tablets 
Levetiracetam 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 250 mg levetiracetam. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
100 film-coated tablets 
Component of a multipack, can’t be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



108 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
UCB Pharma SA 
Allée de la Recherche 60 
B-1070 Brussels 
BELGIUM 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Keppra 250 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Not applicable 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
Not applicable 
  



109 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Aluminium/PVC blister 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 250 mg film-coated tablets 
Levetiracetam  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
UCB logo. 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot  
 
 
5. OTHER 
 
  



110 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Box of 10, 20, 30, 50, 60, 100, 100 (100 x 1), 120 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 500 mg film-coated tablets 
Levetiracetam 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 500 mg levetiracetam. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 film-coated tablets 
20 film-coated tablets 
30 film-coated tablets 
50 film-coated tablets 
60 film-coated tablets 
100 film-coated tablets 
100 x 1 film-coated tablets 
120 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



111 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
UCB Pharma SA 
Allée de la Recherche 60 
B-1070 Brussels 
BELGIUM 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/146/006 10 tablets 
EU/1/00/146/007 20 tablets 
EU/1/00/146/008 30 tablets 
EU/1/00/146/009 50 tablets 
EU/1/00/146/010 60 tablets 
EU/1/00/146/011 100 tablets 
EU/1/00/146/012 120 tablets 
EU/1/00/146/013 200 tablets (2 packs of 100) 
EU/1/00/146/035 100 x 1 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Keppra 500 mg 
Justification for not including Braille accepted 100 x 1 tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  



112 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Box of 200 (2 x 100) with blue box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 500 mg film-coated tablets 
Levetiracetam 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 500 mg levetiracetam. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Multipack: 200 (2 packs of 100) film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



113 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
UCB Pharma SA 
Allée de la Recherche 60 
B-1070 Brussels 
BELGIUM 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/146/006 10 tablets 
EU/1/00/146/007 20 tablets 
EU/1/00/146/008 30 tablets 
EU/1/00/146/009 50 tablets 
EU/1/00/146/010 60 tablets 
EU/1/00/146/011 100 tablets 
EU/1/00/146/012 120 tablets 
EU/1/00/146/013 200 tablets (2 packs of 100) 
EU/1/00/146/035 100 x 1 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Keppra 500 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
  



114 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Intermediate packaging containing 100 tablets for box of 200 (2 x 100) tablets without blue box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 500 mg film-coated tablets 
Levetiracetam 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 500 mg levetiracetam. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
100 film-coated tablets 
Component of a multipack, can’t be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



115 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
UCB Pharma SA 
Allée de la Recherche 60 
B-1070 Brussels 
BELGIUM 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Keppra 500 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Not applicable 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
Not applicable 
 
 



116 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Aluminium/PVC blister 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 500 mg film-coated tablets 
Levetiracetam  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
UCB logo. 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot  
 
 
5. OTHER 
 
  



117 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Box of 20, 30, 50, 60, 80, 100, 100 (100 x 1) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 750 mg film-coated tablets 
Levetiracetam  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 750 mg levetiracetam. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains sunset yellow (E 110). See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
20 film-coated tablets 
30 film-coated tablets 
50 film-coated tablets 
60 film-coated tablets 
80 film-coated tablets 
100 film-coated tablets 
100 x 1 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 



118 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
UCB Pharma SA 
Allée de la Recherche 60 
B-1070 Brussels 
BELGIUM 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/146/014 20 tablets 
EU/1/00/146/015 30 tablets 
EU/1/00/146/016 50 tablets 
EU/1/00/146/017 60 tablets 
EU/1/00/146/018 80 tablets 
EU/1/00/146/019 100 tablets 
EU/1/00/146/028 200 tablets (2 packs of 100) 
EU/1/00/146/036 100 x 1 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Keppra 750 mg 
Justification for not including Braille accepted 100 x 1 tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
  



119 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Box of 200 (2 x 100) with blue box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 750 mg film-coated tablets 
Levetiracetam  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 750 mg levetiracetam. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains sunset yellow (E 110). See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Multipack: 200 (2 packs of 100) film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 



120 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
UCB Pharma SA 
Allée de la Recherche 60 
B-1070 Brussels 
BELGIUM 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/146/014 20 tablets 
EU/1/00/146/015 30 tablets 
EU/1/00/146/016 50 tablets 
EU/1/00/146/017 60 tablets 
EU/1/00/146/018 80 tablets 
EU/1/00/146/019 100 tablets 
EU/1/00/146/028 200 tablets (2 packs of 100) 
EU/1/00/146/036 100 x 1 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Keppra 750 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
 
 
  



121 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Intermediate packaging containing 100 tablets for box of 200 (2 x 100) tablets without blue box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 750 mg film-coated tablets 
Levetiracetam  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 750 mg levetiracetam. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains sunset yellow (E 110). See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
100 film-coated tablets 
Component of a multipack, can’t be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



122 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
UCB Pharma SA 
Allée de la Recherche 60 
B-1070 Brussels 
BELGIUM 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Keppra 750 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Not applicable 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
Not applicable 
  



123 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Aluminium/PVC blister 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 750 mg film-coated tablets 
Levetiracetam  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
UCB logo. 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot  
 
 
5. OTHER 
 
  



124 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Box of 10, 20, 30, 50, 60, 100, 100 (100 x 1) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 1000 mg film-coated tablets 
Levetiracetam  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 1,000 mg levetiracetam. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
10 film-coated tablets 
20 film-coated tablets 
30 film-coated tablets 
50 film-coated tablets 
60 film-coated tablets 
100 film-coated tablets 
100 x 1 film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



125 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
UCB Pharma SA 
Allée de la Recherche 60 
B-1070 Brussels 
BELGIUM 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/146/020 10 tablets 
EU/1/00/146/021 20 tablets 
EU/1/00/146/022 30 tablets 
EU/1/00/146/023 50 tablets 
EU/1/00/146/024 60 tablets 
EU/1/00/146/025 100 tablets 
EU/1/00/146/026 200 tablets (2 packs of 100) 
EU/1/00/146/037 100 x 1 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Keppra 1000 mg 
Justification for not including Braille accepted 100 x 1 tablets 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN:  



126 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Box of 200 (2 x 100) with blue box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 1000 mg film-coated tablets 
Levetiracetam  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 1,000 mg levetiracetam. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Multipack: 200 (2 packs of 100) film-coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



127 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
UCB Pharma SA 
Allée de la Recherche 60 
B-1070 Brussels 
BELGIUM 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/146/020 10 tablets 
EU/1/00/146/021 20 tablets 
EU/1/00/146/022 30 tablets 
EU/1/00/146/023 50 tablets 
EU/1/00/146/024 60 tablets 
EU/1/00/146/025 100 tablets 
EU/1/00/146/026 200 tablets (2 packs of 100) 
EU/1/00/146/037 100 x 1 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Keppra 1000 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
 
 



128 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Intermediate packaging containing 100 tablets for box of 200 (2 x 100) tablets without blue box 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 1000 mg film-coated tablets 
Levetiracetam 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each film-coated tablet contains 1,000 mg levetiracetam. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
100 film-coated tablets 
Component of a multipack, can’t be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Oral use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 
 OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 



129 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
UCB Pharma SA 
Allée de la Recherche 60 
B-1070 Brussels 
BELGIUM 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Keppra 1000 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
Not applicable 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
Not applicable 
 



130 

 MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
Aluminium/PVC blister 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 1000 mg film-coated tablets 
Levetiracetam  
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
UCB logo. 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot  
 
 
5. OTHER 
 
 
  



131 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
Bottle of 300 ml 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 100 mg/ml oral solution 
Levetiracetam  
For adults and children aged 4 years and older. 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml contains 100 mg levetiracetam. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains E216, E218 and maltitol liquid.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
300 ml oral solution  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
Only use the 10 ml syringe included in the package. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
Do not use after 7 months of first opening the bottle. 
Date of opening only for the outer carton 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original bottle in order to protect from light. 
 



132 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
UCB Pharma SA 
Allée de la Recherche 60 
B-1070 Brussels 
BELGIUM 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/146/027  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Keppra 100 mg/ml only for the outer carton 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
 



133 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
Bottle of 150 ml 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 100 mg/ml oral solution 
Levetiracetam  
For children aged 6 months to less than 4 years. 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml contains 100 mg levetiracetam. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains E216, E218 and maltitol liquid.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
150 ml oral solution 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
Only use the 3 ml syringe included in the package. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
Do not use after 7 months of first opening the bottle. 
Date of opening only for the outer carton 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original bottle in order to protect from light. 
 



134 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
UCB Pharma SA 
Allée de la Recherche 60 
B-1070 Brussels 
BELGIUM 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/146/031  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Keppra 100 mg/ml only for the outer carton 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
   



135 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
Bottle of 150 ml 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 100 mg/ml oral solution 
Levetiracetam  
For children aged 1 month to less than 6 months. 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml contains 100 mg levetiracetam. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains E216, E218 and maltitol liquid.  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
150 ml oral solution  
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
Only use the 1 ml syringe included in the package. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
Do not use after 7 months of first opening the bottle. 
Date of opening only for the outer carton 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original bottle in order to protect from light. 
 



136 

 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
UCB Pharma SA 
Allée de la Recherche 60 
B-1070 Brussels 
BELGIUM 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/146/032  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Keppra 100 mg/ml only for the outer carton 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
   



137 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Box of 10 vials 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Keppra 100 mg/ml concentrate for solution for infusion 
Levetiracetam 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One vial contains 500 mg/5 ml levetiracetam. 
Each ml contains 100 mg levetiracetam. 
 
 
3. LIST OF EXCIPIENTS 
 
Other ingredients include sodium acetate, glacial acetic acid, sodium chloride, water for injections. 
See the package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
500 mg/5 ml 
 
10 vials of concentrate for solution for infusion 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use 
 
Read the package leaflet before use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
Use immediately after dilution. 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
 



138 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
UCB Pharma SA 
Allée de la Recherche 60 
B-1070 Brussels 
BELGIUM 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/00/146/030 (polytetrafluoroethylene -faced stopper) 
EU/1/00/146/033 (Uncoated stopper)  
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted  
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
   



139 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
Vial of 5 ml 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Keppra 100 mg/ml sterile concentrate 
Levetiracetam 
IV 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
 
3. EXPIRY DATE 
 
EXP  
Use immediately after dilution. 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
500 mg/5 ml  
 
 
6. OTHER 
 
  



140 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



141 

Package Leaflet: Information for the patient 
 

Keppra 250 mg film-coated tablets 
Keppra 500 mg film-coated tablets 
Keppra 750 mg film-coated tablets 
Keppra 1000 mg film-coated tablets 

Levetiracetam 
 

Read all of this leaflet carefully before you or your child start taking this medicine because it 
contains important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
 If you get any side effects talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Keppra is and what it is used for 
2. What you need to know before you take Keppra 
3. How to take Keppra 
4. Possible side effects 
5. How to store Keppra 
6. Contents of the pack and other information 
 
 
1. What Keppra is and what it is used for 
 
Levetiracetam is an antiepileptic medicine (a medicine used to treat seizures in epilepsy). 
 
Keppra is used:  

 on its own in adults and adolescents from 16 years of age with newly diagnosed epilepsy, to 
treat a certain form of epilepsy. Epilepsy is a condition where the patients have repeated fits 
(seizures). Levetiracetam is used for the epilepsy form in which the fits initially affect only 
one side of the brain, but could thereafter extend to larger areas on both sides of the brain 
(partial onset seizure with or without secondary generalisation). Levetiracetam has been given 
to you by your doctor to reduce the number of fits. 

 as an add-on to other antiepileptic medicines to treat: 
 partial onset seizures with or without generalisation in adults, adolescents, children and 

infants from one month of age; 
 myoclonic seizures (short, shock-like jerks of a muscle or group of muscles) in adults and 

adolescents from 12 years of age with juvenile myoclonic epilepsy; 
 primary generalised tonic-clonic seizures (major fits, including loss of consciousness) in 

adults and adolescents from 12 years of age with idiopathic generalised epilepsy (the type of 
epilepsy that is thought to have a genetic cause). 

 
 
2. What you need to know before you take Keppra 
 
Do not take Keppra 
 If you are allergic to levetiracetam, pyrrolidone derivatives or any of the other ingredients of 

this medicine (listed in Section 6).  
 



142 

Warnings and precautions 
Talk to your doctor before taking Keppra 
 If you suffer from kidney problems, follow your doctor’s instructions. He/she may decide if 

your dose should be adjusted. 
 If you notice any slow down in the growth or unexpected puberty development of your child, 

please contact your doctor. 
 A small number of people being treated with anti-epileptics such as Keppra have had thoughts 

of harming or killing themselves. If you have any symptoms of depression and/or suicidal 
ideation, please contact your doctor. 

 If you have a family or medical history of irregular heart rhythm (visible on an 
electrocardiogram), or if you have a disease and/or take a treatment that make(s) you prone to 
heartbeat irregularities or salt imbalances. 

 
Tell your doctor or pharmacist if any of the following side effects gets serious or last longer than a few 
days: 
 Abnormal thoughts, feeling irritable or reacting more aggressively than usually, or if you or 

your family and friends notice important changes in mood or behaviour. 
 Aggravation of epilepsy 

Your seizures may rarely become worse or happen more often, mainly during the first month 
after the start of the treatment or increase of the dose. If you experience any of these new 
symptoms while taking Keppra, see a doctor as soon as possible. 

 
Children and adolescents 
 
 Keppra is not indicated in children and adolescents below 16 years on its own (monotherapy).  
 
Other medicines and Keppra 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Do not take macrogol (a drug used as laxative) for one hour before and one hour after taking 
levetiracetam as this may results in a loss of its effect.  
 
Pregnancy and breast-feeding 
If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine. Levetiracetam can be used during pregnancy, only 
if after careful assessment it is considered necessary by your doctor. 
You should not stop your treatment without discussing this with your doctor. 
A risk of birth defects for your unborn child cannot be completely excluded.  
Breast-feeding is not recommended during treatment. 
 
Driving and using machines 
Keppra may impair your ability to drive or operate any tools or machinery, as it may make you feel 
sleepy. This is more likely at the beginning of treatment or after an increase in the dose. You should 
not drive or use machines until it is established that your ability to perform such activities is not 
affected. 
 
Keppra 750 mg tablets contain Sunset Yellow FCF (E110).  
Sunset Yellow FCF (E110) colouring agent may cause allergic reactions. 
 
 
3. How to take Keppra 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
 
Take the number of tablets following your doctor’s instructions. 



143 

Keppra must be taken twice a day, once in the morning and once in the evening, at about the same 
time each day. 
 
Monotherapy 

 
 Dose in adults and adolescents (from 16 years of age): 

General dose: between 1000 mg and 3,000 mg each day. 
When you will first start taking Keppra, your doctor will prescribe you a lower dose during 2 
weeks before giving you the lowest general dose. 
Example: if your daily dose is 1000 mg, your reduced starting dose is 2 tablets of 250 mg in the 
morning and 2 tablets of 250 mg in the evening. 

 
Add-on therapy 

 
 Dose in adults and adolescents (12 to 17 years) weighing 50 kg or more: 

General dose: between 1,000 mg and 3,000 mg each day. 
Example: if your daily dose is 1,000 mg, you might take 2 tablets of 250 mg in the morning and 
2 tablets of 250 mg in the evening. 

 
 Dose in infants (1 month to 23 months), children (2 to 11 years) and adolescents (12 to 17 

years) weighing less than 50 kg: 
Your doctor will prescribe the most appropriate pharmaceutical form of Keppra according to the 
age, weight and dose. 
 
Keppra 100 mg/ml oral solution is a formulation more appropriate to infants and children under 
the age of 6 years and to children and adolescent (from 6 to 17 years) weighing less than 50kg 
and when tablets don’t allow accurate dosage. 

 
Method of administration 
Swallow Keppra tablets with a sufficient quantity of liquid (e.g. a glass of water). You may take 
Keppra with or without food. After oral administration the bitter taste of levetiracetam may be 
experienced. 
 
Duration of treatment 
 Keppra is used as a chronic treatment. You should continue Keppra treatment for as long as 

your doctor has told you. 
 Do not stop your treatment without your doctor’s advice as this could increase your seizures.  
 
If you take more Keppra than you should 
The possible side effects of an overdose of Keppra are sleepiness, agitation, aggression, decrease of 
alertness, inhibition of breathing and coma. 
Contact your doctor if you took more tablets than you should. Your doctor will establish the best 
possible treatment of overdose. 
 
If you forget to take Keppra: 
Contact your doctor if you have missed one or more doses.  
Do not take a double dose to make up for a forgotten tablet.  
 
If you stop taking Keppra: 
If stopping treatment, Keppra should be discontinued gradually to avoid an increase of seizures. 
Should your doctor decide to stop your Keppra treatment, he/she will instruct you about the gradual 
withdrawal of Keppra. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 



144 

4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor immediately, or go to your nearest emergency department, if you experience: 
 
 weakness, feel light-headed or dizzy or have difficulty breathing, as these may be signs of a 

serious allergic (anaphylactic) reaction 
 swelling of the face, lips, tongue and throat (Quincke’s oedema) 
 flu-like symptoms and a rash on the face followed by an extended rash with a high temperature, 

increased levels of liver enzymes seen in blood tests and an increase in a type of white blood cell 
(eosinophilia) and enlarged lymph nodes (Drug Reaction with Eosinophilia and Systemic 
Symptoms [DRESS]) 

 symptoms such as low urine volume, tiredness, nausea, vomiting, confusion and swelling in the 
legs, ankles or feet, as this may be a sign of sudden decrease of kidney function 

 a skin rash which may form blisters and look like small targets (central dark spots surrounded by a 
paler area, with a dark ring around the edge) (erythema multiforme) 

 a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and 
genitals (Stevens-Johnson syndrome) 

 a more severe form of rash causing skin peeling in more than 30% of the body surface (toxic 
epidermal necrolysis) 

 signs of serious mental changes or if someone around you notices signs of confusion, somnolence 
(sleepiness), amnesia (loss of memory), memory impairment (forgetfulness), abnormal behaviour 
or other neurological signs including involuntary or uncontrolled movements. These could be 
symptoms of an encephalopathy. 

 
The most frequently reported side effects are nasopharyngitis, somnolence (sleepiness), headache, 
fatigue and dizziness. At the beginning of the treatment or at dose increase side effects like sleepiness, 
tiredness and dizziness may be more common. These effects should however decrease over time. 
 
Very common: may affect more than 1 in 10 people 
 nasopharyngitis; 
 somnolence (sleepiness), headache. 
 
Common: may affect up to 1 in 10 people 
 anorexia (loss of appetite); 
 depression, hostility or aggression, anxiety, insomnia, nervousness or irritability; 
 convulsion, balance disorder (equilibrium disorder), dizziness (sensation of 

unsteadiness),lethargy (lack of energy and enthusiasm), tremor (involuntary trembling); 
 vertigo (sensation of rotation); 
 cough; 
 abdominal pain, diarrhoea, dyspepsia (indigestion), vomiting, nausea; 
 rash; 
 asthenia/fatigue (tiredness). 
 
Uncommon: may affect up to 1 in 100 people 
 decreased number of blood platelets, decreased number of white blood cells;  
 weight decrease, weight increase; 
 suicide attempt and suicidal ideation, mental disorder, abnormal behaviour, hallucination, anger, 

confusion, panic attack, emotional instability/mood swings, agitation; 
 amnesia (loss of memory), memory impairment (forgetfulness), abnormal coordination/ataxia 

(impaired coordinated movements), paraesthesia (tingling), disturbance in attention (loss of 
concentration); 

 diplopia (double vision), vision blurred; 
 elevated/abnormal values in a liver function test;  
 hair loss, eczema, pruritus;  



145 

 muscle weakness, myalgia (muscle pain); 
 injury. 
 
Rare: may affect up to 1 in 1,000 people 
 infection; 
 decreased number of all blood cell types;  
 severe allergic reactions (DRESS, anaphylactic reaction [severe and important allergic reaction], 

Quincke’s oedema [swelling of the face, lips, tongue and throat]); 
 decreased blood sodium concentration; 
 suicide, personality disorders (behavioural problems), thinking abnormal (slow thinking, unable 

to concentrate); 
 delirium; 
 encephalopathy (see sub-section “Tell your doctor immediately” for a detailed description of 

symptoms); 
 seizures may become worse or happen more often; 
 uncontrollable muscle spasms affecting the head, torso and limbs, difficulty in controlling 

movements, hyperkinesia (hyperactivity); 
 change of the heart rhythm (Electrocardiogram);  
 pancreatitis; 
 liver failure, hepatitis; 
 sudden decrease in kidney function; 
 skin rash, which may form blisters and looks like small targets (central dark spots surrounded 

by a paler area, with a dark ring around the edge) (erythema multiforme), a widespread rash with 
blisters and peeling skin, particularly around the mouth, nose, eyes and  genitals (Stevens–
Johnson syndrome), and a more severe form causing skin peeling in more than 30% of the body 
surface (toxic epidermal necrolysis); 

 rhabdomyolysis (breakdown of muscle tissue) and associated blood creatine phosphokinase 
increase. Prevalence is significantly higher in Japanese patients when compared to non-Japanese 
patients. 

 limp or difficulty walking. 
 

Reporting of side effects 
If you get any side effects talk to your doctor or pharmacist. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store Keppra 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date stated on the carton box and blister after EXP. 
The expiry date refers to the last day of the month. 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Keppra contains 
The active substance is called levetiracetam.  
One tablet of Keppra 250 mg contains 250 mg of levetiracetam. 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


146 

One tablet of Keppra 500 mg contains 500 mg of levetiracetam. 
One tablet of Keppra 750 mg contains 750 mg of levetiracetam. 
One tablet of Keppra 1,000 mg contains 1,000 mg of levetiracetam. 
 
The other ingredients are:  
Tablet core: croscarmellose sodium, macrogol 6000, silica colloidal anhydrous, magnesium stearate. 
Film-coating: Polyvinyl alcohol-part. hydrolyzed, titanium dioxide (E171), macrogol 3350, talc, 
colourants*. 
 
* The colourants are: 
250 mg tablet: indigo carmine aluminium lake (E132) 
500 mg tablet: iron oxide yellow (E172) 
750 mg tablet: sunset yellow FCF (E110), iron oxide red (E172) 
 
What Keppra looks like and contents of the pack 
Keppra 250 mg film-coated tablets are blue, 13 mm oblong, scored and debossed with the code “ucb” 
and “250” on one side. 
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.  
 
Keppra 500 mg film-coated tablets are yellow, 16 mm oblong, scored and debossed with the code 
“ucb” and “500” on one side. 
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.  
 
Keppra 750 mg film-coated tablets are orange, 18 mm oblong, scored and debossed with the code 
“ucb” and “750” on one side. 
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.  
 
Keppra 1000 mg film-coated tablets are white, 19 mm oblong, scored and debossed with the code 
“ucb” and“1000” on one side.  
The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.  
 
Keppra tablets are packaged in blister packs supplied in cardboard boxes containing: 
 250 mg: 20, 30, 50, 60, 100 x 1, 100 film-coated tablets and multipacks containing 200 (2 packs 

of 100) film-coated tablets 
 

 500 mg: 10, 20, 30, 50, 60, 100 x 1, 100, 120 film-coated tablets and multipacks containing 200 
(2 packs of 100) film-coated tablets 

 
 750 mg: 20, 30, 50, 60, 80, 100 x 1, 100 film-coated tablets and multipacks containing 200 (2 

packs of 100) film-coated tablets 
 

 1000 mg: 10, 20, 30, 50, 60, 100 x 1, 100 film-coated tablets and multipacks containing 200 (2 
packs of 100) film-coated tablets 

 
The 100 x 1 tablet packs are available in aluminium/PVC perforated unit dose blisters. All other packs 
are available in standard aluminium/PVC blisters.  
 
Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder 
UCB Pharma SA, Allée de la Recherche 60, B-1070 Brussels, Belgium. 
 
Manufacturer 
UCB Pharma SA, Chemin du Foriest, B-1420 Braine-l’Alleud, Belgium. 
or   Aesica Pharmaceuticals S.r.l., Via Praglia 15, I-10044 Pianezza, Italy 
 



147 

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien 
UCB Pharma SA/NV 
Tel/Tél: + 32 / (0)2 559 92 00 
 

Lietuva 
UCB Pharma Oy Finland 
Tel: +358 9 2514 4221 (Suomija) 
 

България 
Ю СИ БИ България ЕООД 
Teл.: + 359 (0) 2 962 30 49 

Luxembourg/Luxemburg 
UCB Pharma SA/NV 
Tél/Tel: + 32 / (0)2 559 92 00 
 

Česká republika 
UCB s.r.o. 
Tel: + 420 221 773 411 
 

Magyarország 
UCB Magyarország Kft. 
Tel.: + 36-(1) 391 0060 
 

Danmark 
UCB Nordic A/S 
Tlf: + 45 / 32 46 24 00 
 

Malta 
Pharmasud Ltd. 
Tel: + 356 / 21 37 64 36 
 

Deutschland 
UCB Pharma GmbH 
Tel: + 49 /(0) 2173 48 4848 
 

Nederland 
UCB Pharma B.V. 
Tel.: + 31 / (0)76-573 11 40 
 

Eesti 
UCB Pharma Oy Finland  
Tel: +358 9 2514 4221 (Soome) 
 

Norge 
UCB Nordic A/S 
Tlf: + 45 / 32 46 24 00 
 

Ελλάδα 
UCB Α.Ε.  
Τηλ: + 30 / 2109974000 
 

Österreich 
UCB Pharma GmbH 
Tel: + 43 (0)1 291 80 00  
 

España 
UCB Pharma, S.A. 
Tel: + 34 / 91 570 34 44 
 

Polska 
UCB Pharma Sp. z o.o. 
Tel: + 48 22 696 99 20 
 

France 
UCB Pharma S.A. 
Tél: + 33 / (0)1 47 29 44 35 

Portugal 
UCB Pharma (Produtos Farmacêuticos), Lda 
Tel: + 351 / 21 302 5300 
 

Hrvatska 
Medis Adria d.o.o. 
Tel: +385 (0) 1 230 34 46 
 

România 
UCB Pharma Romania S.R.L. 
Tel: + 40 21 300 29 04 
 

Ireland 
UCB (Pharma) Ireland Ltd. 
Tel: + 353 / (0)1-46 37 395  
 

Slovenija 
Medis, d.o.o. 
Tel: + 386 1 589 69 00 
 

Ísland 
Vistor hf. 
Tel: + 354 535 7000 
 

Slovenská republika 
UCB s.r.o., organizačná zložka 
Tel: + 421 (0) 2 5920 2020 
 

Italia 
UCB Pharma S.p.A. 
Tel: + 39 / 02 300 791 

Suomi/Finland 
UCB Pharma Oy Finland 
Puh/Tel: +358 9 2514 4221 
 



148 

Κύπρος 
Lifepharma (Z.A.M.) Ltd 
Τηλ: + 357 22 34 74 40  
 

Sverige 
UCB Nordic A/S 
Tel: + 46 / (0) 40 29 49 00 

Latvija 
UCB Pharma Oy Finland 
Tel: +358 9 2514 4221 (Somija) 
 

United Kingdom 
UCB Pharma Ltd. 
Tel : + 44 / (0)1753 534 655 

 
This leaflet was last revised in {month/YYYY} 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 



149 

 Package Leaflet: Information for the patient 
 

Keppra 100 mg/ml oral solution 
Levetiracetam 

 
Read all of this leaflet carefully before you or your child start taking this medicine because it 
contains important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
 If you get any side effects talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet:  
1. What Keppra is and what it is used for 
2. What you need to know before you take Keppra 
3. How to take Keppra 
4. Possible side effects 
5. How to store Keppra 
6. Contents of the pack and other information 
 
 
1. What Keppra is and what it is used for 
 
Levetiracetam is an antiepileptic medicine (a medicine used to treat seizures in epilepsy). 
 
Keppra is used:  

 on its own in adults and adolescents from 16 years of age with newly diagnosed epilepsy, to 
treat a certain form of epilepsy. Epilepsy is a condition where the patients have repeated fits 
(seizures). Levetiracetam is used for the epilepsy form in which the fits initially affect only 
one side of the brain, but could thereafter extend to larger areas on both sides of the brain 
(partial onset seizure with or without secondary generalisation). Levetiracetam has been given 
to you by your doctor to reduce the number of fits. 

 as an add-on to other antiepileptic medicines to treat: 
 partial onset seizures with or without generalisation in adults, adolescents, children and 

infants from one month of age 
 myoclonic seizures (short, shock-like jerks of a muscle or group of muscles) in adults and 

adolescents from 12 years of age with juvenile myoclonic epilepsy 
 primary generalised tonic-clonic seizures(major fits, including loss of consciousness) in 

adults and adolescents from 12 years of age with idiopathic generalised epilepsy (the type of 
epilepsy that is thought to have a genetic cause). 

 
 
2. What you need to know before you take Keppra 
 
Do not take Keppra 
 If you are allergic to levetiracetam, pyrrolidone derivatives or any of the other ingredients of 

this medicine (listed in Section 6).  
 
Warnings and precautions 
Talk to your doctor before taking Keppra 
 If you suffer from kidney problems, follow your doctor’s instructions. He/she may decide if 

your dose should be adjusted. 
 If you notice any slow down in the growth or unexpected puberty development of your child, 

please contact your doctor. 



150 

 A small number of people being treated with anti-epileptics such as Keppra have had thoughts 
of harming or killing themselves. If you have any symptoms of depression and/or suicidal 
ideation, please contact your doctor. 

 If you have a family or medical history of irregular heart rhythm (visible on an 
electrocardiogram), or if you have a disease and/or take a treatment that make(s) you prone to 
heartbeat irregularities or salt imbalances. 
 

Tell your doctor or pharmacist if any of the following side effects gets serious or last longer than a few 
days: 
 Abnormal thoughts, feeling irritable or reacting more aggressively than usually, or if you or 

your family and friends notice important changes in mood or behaviour.  
 Aggravation of epilepsy 

Your seizures may rarely become worse or happen more often, mainly during the first month 
after the start of the treatment or increase of the dose. If you experience any of these new 
symptoms while taking Keppra, see a doctor as soon as possible. 

 
Children and adolescents 
 Keppra is not indicated in children and adolescents below 16 years on it’s own (monotherapy) 
 
Other medicines and Keppra 
Tell your doctor or pharmacist if you are taking or have recently taken or might take any other 
medicines. 
 
Do not take macrogol (a drug used as laxative) for one hour before and one hour after taking 
levetiracetam as this may results in a reduction of its effect.  
 
Pregnancy and breast-feeding 
If you are pregnant or breastfeeding, think you may be pregnant, or are planning to have a baby, ask 
your doctor for advice before taking this medicine. Levetiracetam can be used during pregnancy, only 
if after careful assessment it is considered necessary by your doctor. 
You should not stop your treatment without discussing this with your doctor. 
A risk of birth defects for your unborn child cannot be completely excluded.  
Breast-feeding is not recommended during treatment. 
 
Driving and using machines 
Keppra may impair your ability to drive or operate any tools or machinery, as it may make you feel 
sleepy. This is more likely at the beginning of treatment or after an increase in the dose. You should 
not drive or use machines until it is established that your ability to perform such activities is not 
affected. 
 
Keppra contains methyl parahydroxybenzoate, propyl parahydroxybenzoate and maltitol 
Keppra oral solution includes methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate 
(E216) which may cause allergic reactions (possibly delayed).  
Keppra oral solution also contains maltitol. If you have been told by your doctor that you have an 
intolerance to some sugars, contact your doctor before taking this medicinal product. 
 
 
3. How to take Keppra 
 
Always take this medicine exactly as your doctor or pharmacist has told you. Check with your doctor 
or pharmacist if you are not sure. 
Keppra must be taken twice a day, once in the morning and once in the evening, at about the same 
time each day. 
Take the oral solution following your doctor’s instructions. 
 



151 

Monotherapy 

 
Dose in adults and adolescents (from 16 years of age): 
Measure the appropriate dosage using the 10 ml syringe included in the package for patients 4 years 
and above. 
General dose: Keppra is taken twice daily, in two equally divided doses, each individual dose being 
measured between 5 ml (500mg) and 15 ml (1500mg).  
When you will first start taking Keppra, your doctor will prescribe you a lower dose during 2 weeks 
before giving you the lowest general dose. 
 
Add-on therapy 
 
Dose in adults and adolescents (12 to 17 years): 
Measure the appropriate dosage using the 10 ml syringe included in the package for patients of 4 years 
and above. 
General dose: Keppra is taken twice daily, in two equally divided doses, each individual dose being 
measured between 5 ml (500mg) and 15 ml (1500mg).  
 
Dose in children 6 months and older : 
Your doctor will prescribe the most appropriate pharmaceutical form of Keppra according to the age, 
weight and dose. 
For children 6 months to 4 years, measure the appropriate dosage using the 3 ml syringe included in 
the package.  
For children above 4 years, measure the appropriate dosage using the 10 ml syringe included in the 
package. 
General dose: Keppra is taken twice daily, in two equally divided doses, each individual dose being 
measured between 0.1 ml (10mg) and 0.3 ml (30mg), per kg bodyweight of the child. (see table below 
for dose examples).  
 
Dose in children 6 months and older: 

Weight Starting dose: 0.1 ml/kg twice daily Maximum dose: 0.3 ml/kg twice daily 
6 kg  0.6 ml twice daily 1.8 ml twice daily 
8 kg 0.8 ml twice daily 2.4 ml twice daily 
10 kg  1 ml twice daily 3 ml twice daily 
15 kg  1.5 ml twice daily 4.5 ml twice daily 
20 kg  2 ml twice daily 6 ml twice daily 
25 kg 2.5 ml twice daily 7.5 ml twice daily 
From 50 kg  5 ml twice daily 15 ml twice daily 

 
Dose in infants (1 month to less than 6 months): 
For infants 1 month to less than 6 months, measure the appropriate dosage using the 1 ml syringe 
included in the package.  
General dose: Keppra is taken twice daily, in two equally divided doses, each individual dose being 
measured between 0.07 ml (7mg) and 0.21 ml (21mg), per kg bodyweight of the infant. (see table 
below for dose examples).  
 
Dose in infants (1 month to less than 6 months): 
 

Weight Starting dose: 0.07 ml/kg twice 
daily 

Maximum dose: 0.21 ml/kg twice 
daily 

4 kg 0.3 ml twice daily 0.85 ml twice daily 
5 kg 0.35 ml twice daily 1.05 ml twice daily 
6 kg 0.45 ml twice daily 1.25 ml twice daily 
7 kg 0.5 ml twice daily 1.5 ml twice daily 

 



152 

Method of administration: 
 
After measuring the correct dosage with an appropriate syringe, Keppra oral solution may be diluted in 
a glass of water or baby’s bottle. You may take Keppra with or without food. After oral administration 
the bitter taste of levetiracetam may be experienced. 
 
Instructions for use: 
 Open the bottle: press the cap and turn it anticlockwise (figure 1) 
 
 
 
 
 
 
 
 
 Separate the adaptor from the syringe (figure 2). Insert the adaptor into the bottle neck (figure 

3). Ensure it is well fixed. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Take the syringe and put it in the adaptor opening (figure 4). Turn the bottle upside down 

(figure 5).  
 
 
 
 
 
 
 
 
 
 
 
 Fill the syringe with a small amount of solution by pulling the piston down (figure 5A), then 

push the piston upward in order to remove any possible bubble (figure 5B). Pull the piston down 
to the graduation mark corresponding to the quantity in milliliters (ml) prescribed by your 
doctor (figure 5C).  

 
 
 
 
 
 
 
 
 



153 

 Turn the bottle the right way up (figure 6A). Remove the syringe from the adaptor (figure 6B). 

 
 
 Empty the contents of the syringe in a glass of water or baby’s bottle by pushing the piston to 

the bottom of the syringe (figure 7).  
 
 
 
 
 
 
 
 Drink the whole contents of the glass/baby’s bottle. 
 
 Close the bottle with the plastic screw cap. 
 
 Wash the syringe with water only (figure 8). 
 
Duration of treatment: 
 Keppra is used as a chronic treatment. You should continue Keppra treatment for as long as 

your doctor has told you. 
 Do not stop your treatment without your doctor’s advice as this could increase your seizures.  
 
If you take more Keppra than you should 
The possible side effects of an overdose of Keppra are sleepiness, agitation, aggression, decrease of 
alertness, inhibition of breathing and coma. 
Contact your doctor if you took more Keppra than you should. Your doctor will establish the best 
possible treatment of overdose. 
 
If you forget to take Keppra: 
Contact your doctor if you have missed one or more doses.  
Do not take a double dose to make up for a forgotten dose.  
 
If you stop taking Keppra: 
If stopping treatment, Keppra should be discontinued gradually to avoid an increase of seizures. 
Should your doctor decide to stop your Keppra treatment, he/she will instruct you about the gradual 
withdrawal of Keppra. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Tell your doctor immediately, or go to your nearest emergency department, if you experience: 
 
 weakness, feel light-headed or dizzy or have difficulty breathing, as these may be signs of a 

serious allergic (anaphylactic) reaction 
 swelling of the face, lips, tongue and throat (Quincke’s oedema) 



154 

 flu-like symptoms and a rash on the face followed by an extended rash with a high temperature, 
increased levels of liver enzymes seen in blood tests and an increase in a type of white blood cell 
(eosinophilia) and enlarged lymph nodes (Drug Reaction with Eosinophilia and Systemic 
Symptoms [DRESS]),. 

 symptoms such as low urine volume, tiredness, nausea, vomiting, confusion and swelling in the 
legs, ankles or feet, as this may be a sign of sudden decrease of kidney function 

 a skin rash which may form blisters and look like small targets (central dark spots surrounded by a 
paler area, with a dark ring around the edge) (erythema multiforme) 

 a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and 
genitals (Stevens-Johnson syndrome) 

 a more severe form of rash causing skin peeling in more than 30% of the body surface (toxic 
epidermal necrolysis) 

 signs of serious mental changes or if someone around you notices signs of confusion, somnolence 
(sleepiness), amnesia (loss of memory), memory impairment (forgetfulness), abnormal behaviour 
or other neurological signs including involuntary or uncontrolled movements. These could be 
symptoms of an encephalopathy. 

 
The most frequently reported adverse reactions were nasopharyngitis, somnolence (sleepiness), 
headache, fatigue and dizziness. At the beginning of the treatment or at dose increase side effects like 
sleepiness, tiredness and dizziness may be more common. These effects should however decrease over 
time. 
 
Very common: may affect more than 1 in 10 people 
 nasopharyngitis; 
 somnolence (sleepiness), headache. 

 
Common: may affect up to 1 in 10 people 
 anorexia (loss of appetite); 
 depression, hostility or aggression, anxiety, insomnia, nervousness or irritability; 
 convulsion, balance disorder (equilibrium disorder), dizziness (sensation of unsteadiness), 

lethargy (lack of energy and enthusiasm), tremor (involuntary trembling); 
 vertigo (sensation of rotation); 
 cough; 
 abdominal pain, diarrhoea, dyspepsia (indigestion), vomiting, nausea; 
 rash; 
 asthenia/fatigue (tiredness). 
 
Uncommon: may affect up to 1 in 100 people 
 decreased number of blood platelets, decreased number of white blood cells;  
 weight decrease, weight increase; 
 suicide attempt and suicidal ideation, mental disorder, abnormal behaviour, hallucination, anger, 

confusion, panic attack, emotional instability/mood swings, agitation; 
 amnesia (loss of memory), memory impairment (forgetfulness), abnormal coordination/ataxia 

(impaired coordinated movements), paraesthesia (tingling), disturbance in attention (loss of 
concentration); 

 diplopia (double vision), vision blurred; 
 elevated/abnormal values in a liver function test; 
 hair loss, eczema, pruritus;  
 muscle weakness, myalgia (muscle pain); 
 injury. 
 
Rare: may affect up to 1 in 1,000 people 
 infection; 
 decreased number of all blood cell types;  



155 

 severe allergic reactions (DRESS, anaphylactic reaction [severe and important allergic reaction], 
Quincke’s oedema [swelling of the face, lips, tongue and throat]); 

 decreased blood sodium concentration; 
 suicide, personality disorders (behavioural problems), thinking abnormal (slow thinking, unable 

to concentrate); 
 delirium; 
 encephalopathy (see sub-section “Tell your doctor immediately” for a detailed description of 

symptoms); 
 seizures may become worse or happen more often; 
 uncontrollable muscle spasms affecting the head, torso and limbs, difficulty in controlling 

movements, hyperkinesia (hyperactivity); 
 change of the heart rhythm (Electrocardiogram); 
 pancreatitis; 
 liver failure, hepatitis; 
 sudden decrease in kidney function; 
 skin rash, which may form blisters and looks like small targets (central dark spots surrounded 

by a paler area, with a dark ring around the edge) (erythema multiforme), a widespread rash with 
blisters and peeling skin, particularly around the mouth, nose, eyes and genitals (Stevens-
Johnson syndrome), and a more severe form causing skin peeling in more than 30% of the body 
surface (toxic epidermal necrolysis); 

 rhabdomyolysis (breakdown of muscle tissue) and associated blood creatine phosphokinase 
increase. Prevalence is significantly higher in Japanese patients when compared to non-Japanese 
patients. 

 limp or difficulty walking. 
 

 
Reporting of side effects 
If you get any side effects talk to your doctor or pharmacist. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store Keppra 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date stated on the cardboard box and bottle after EXP: 
The expiry date refers to the last day of the month. 
Do not use after 7 months of first opening the bottle. 
 
Store in the original bottle, in order to protect from light. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Keppra contains 
The active substance is called levetiracetam. Each ml contains 100 mg of levetiracetam. 
 
The other ingredients are: sodium citrate, citric acid monohydrate, methyl parahydroxybenzoate 
(E218), propyl parahydroxybenzoate (E216), ammonium glycyrrhizate, glycerol (E422), maltitol 
liquid (E965), acesulfame potassium (E950), grape flavour, purified water. 
 

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156 

What Keppra looks like and contents of the pack 
Keppra 100 mg/ml oral solution is a clear liquid. 
The 300 ml glass bottle of Keppra (for children aged 4 years and above, adolescents and adults) is 
packed in a cardboard box containing a 10 ml oral syringe (graduated every 0.25 ml) and an adaptor 
for the syringe. 
The 150 ml glass bottle of Keppra (for infants and young children aged from 6 months to less than 4 
years) is packed in a cardboard box containing a 3 ml oral syringe (graduated every 0.1 ml) and an 
adaptor for the syringe. 
The 150 ml glass bottle of Keppra (for infants aged 1 month to less than 6 months) is packed in a 
cardboard box containing a 1 ml oral syringe (graduated every 0.05 ml) and an adaptor for the syringe. 
 
Marketing Authorisation Holder  
UCB Pharma S.A. Allée de la Recherche 60, B-1070 Brussels, Belgium. 
Manufacturer 
NextPharma SAS, 17 Route de Meulan, F-78520 Limay, France. 
or   UCB Pharma SA, Chemin du Foriest, B-1420 Braine-l’Alleud, Belgium  
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 
België/Belgique/Belgien 
UCB Pharma SA/NV 
Tel/Tél: + 32 / (0)2 559 92 00 
 

Lietuva 
UCB Pharma Oy Finland 
Tel: +358 9 2514 4221 (Suomija) 
 

България 
Ю СИ БИ България ЕООД 
Teл.: + 359 (0) 2 962 30 49 

Luxembourg/Luxemburg 
UCB Pharma SA/NV 
Tél/Tel: + 32 / (0)2 559 92 00 
 

Česká republika 
UCB s.r.o. 
Tel: + 420 221 773 411 
 

Magyarország 
UCB Magyarország Kft. 
Tel.: + 36-(1) 391 0060 
 

Danmark 
UCB Nordic A/S 
Tlf: + 45 / 32 46 24 00 
 

Malta 
Pharmasud Ltd. 
Tel: + 356 / 21 37 64 36 
 

Deutschland 
UCB Pharma GmbH 
Tel: + 49 /(0) 2173 48 4848 
 

Nederland 
UCB Pharma B.V. 
Tel.: + 31 / (0)76-573 11 40 
 

Eesti 
UCB Pharma Oy Finland  
Tel: +358 9 2514 4221 (Soome) 
 

Norge 
UCB Nordic A/S 
Tlf: + 45 / 32 46 24 00 
 

Ελλάδα 
UCB Α.Ε.  
Τηλ: + 30 / 2109974000 
 

Österreich 
UCB Pharma GmbH 
Tel: + 43 (0)1 291 80 00  
 

España 
UCB Pharma, S.A. 
Tel: + 34 / 91 570 34 44 
 

Polska 
UCB Pharma Sp. z o.o. 
Tel: + 48 22 696 99 20 
 

France 
UCB Pharma S.A. 
Tél: + 33 / (0)1 47 29 44 35 

Portugal 
UCB Pharma (Produtos Farmacêuticos), Lda 
Tel: + 351 / 21 302 5300 
 



157 

Hrvatska 
Medis Adria d.o.o. 
Tel: +385 (0) 1 230 34 46 
 

România 
UCB Pharma Romania S.R.L. 
Tel: + 40 21 300 29 04 
 

Ireland 
UCB (Pharma) Ireland Ltd. 
Tel: + 353 / (0)1-46 37 395  
 

Slovenija 
Medis, d.o.o. 
Tel: + 386 1 589 69 00 
 

Ísland 
Vistor hf. 
Tel: + 354 535 7000 
 

Slovenská republika 
UCB s.r.o., organizačná zložka 
Tel: + 421 (0) 2 5920 2020 
 

Italia 
UCB Pharma S.p.A. 
Tel: + 39 / 02 300 791 

Suomi/Finland 
UCB Pharma Oy Finland 
Puh/Tel: +358 9 2514 4221 
 

Κύπρος 
Lifepharma (Z.A.M.) Ltd 
Τηλ: + 357 22 34 74 40  
 

Sverige 
UCB Nordic A/S 
Tel: + 46 / (0) 40 29 49 00 

Latvija 
UCB Pharma Oy Finland 
Tel: +358 9 2514 4221 (Somija) 
 

United Kingdom 
UCB Pharma Ltd. 
Tel : + 44 / (0)1753 534 655 

 
This leaflet was last revised in {month/YYYY} 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 



158 

Package Leaflet: Information for the patient 
 

Keppra 100 mg/ml concentrate for solution for infusion 
Levetiracetam 

 
Read all of this leaflet carefully before you or your child start using this medicine because it 
contains important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
 If you get any side effects talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet  
1. What Keppra is and what it is used for 
2. What you need to know before you are given Keppra 
3. How Keppra is given 
4. Possible side effects 
5. How to store Keppra 
6. Contents of the pack and other information 
 
 
1. What Keppra is and what it is used for 
 
Levetiracetam is an antiepileptic medicine (a medicine used to treat seizures in epilepsy).  
 
Keppra is used: 

 on its own in adults and adolescents from 16 years of age with newly diagnosed epilepsy, to 
treat a certain form of epilepsy. Epilepsy is a condition where the patients have repeated fits 
(seizures). Levetiracetam is used for the epilepsy form in which the fits initially affect only 
one side of the brain, but could thereafter extend to larger areas on both sides of the brain 
(partial onset seizure with or without secondary generalisation). Levetiracetam has been given 
to you by your doctor to reduce the number of fits. 

 as an add-on to other antiepileptic medicines to treat: 
 partial onset seizures with or without generalisation in in adults, adolescents and children 

from 4 years of age 
 myoclonic seizures (short, shock-like jerks of a muscle or group of muscles) in adults and 

adolescents from 12 years of age with juvenile myoclonic epilepsy. 
 primary generalised tonic-clonic seizures (major fits, including loss of consciousness) in 

adults and adolescents from 12 years of age with idiopathic generalised epilepsy (the type of 
epilepsy that is thought to have a genetic cause). 
 

 
Keppra concentrate for solution for infusion is an alternative for patients when administration of the 
antiepileptic oral Keppra medicine is temporarily not feasible. 
 
 
2. What you need to know before you are given Keppra 
 
Do not use Keppra 
 If you are allergic to levetiracetam, pyrrolidone derivatives or any of the other ingredients of 

this medicine (listed in Section 6).  
 



159 

Warnings and precautions 
Talk to your doctor before you are given Keppra 
 If you suffer from kidney problems, follow your doctor’s instructions. He/she may decide if 

your dose should be adjusted. 
 If you notice any slow down in the growth or unexpected puberty development of your child, 

please contact your doctor. 
 A small number of people being treated with anti-epileptics such as Keppra have had thoughts 

of harming or killing themselves. If you have any symptoms of depression and/or suicidal 
ideation, please contact your doctor. 

 If you have a family or medical history of irregular heart rhythm (visible on an 
electrocardiogram), or if you have a disease and/or take a treatment that make(s) you prone to 
heartbeat irregularities or salt imbalances. 

 
Tell your doctor or pharmacist if any of the following side effects gets serious or last longer than a few 
days: 
 Abnormal thoughts, feeling irritable or reacting more aggressively than usually, or if you or 

your family and friends notice important changes in mood or behaviour. 
 Aggravation of epilepsy 

Your seizures may rarely become worse or happen more often, mainly during the first month 
after the start of the treatment or increase of the dose. If you experience any of these new 
symptoms while taking Keppra, see a doctor as soon as possible. 

 
Children and adolescents 
 
 Keppra is not indicated in children and adolescents below 16 years on it’s own (monotherapy) 
 
Other medicines and Keppra 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription. 
 
Do not take macrogol (a drug used as laxative) for one hour before and one hour after taking 
levetiracetam as this may results in a reduction of its effect.  
 
Pregnancy and breast-feeding 
If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a baby, ask 
your doctor for advice before taking this medicine. Levetiracetam can be used during pregnancy, only 
if after careful assessment it is considered necessary by your doctor. 
You should not stop your treatment without discussing this with your doctor. 
A risk of birth defects for your unborn child cannot be completely excluded.  
Breast-feeding is not recommended during treatment. 
 
Driving and using machines 
Keppra may impair your ability to drive or operate any tools or machinery, as it may make you feel 
sleepy. This is more likely at the beginning of treatment or after an increase in the dose. You should 
not drive or use machines until it is established that your ability to perform such activities is not 
affected. 
 
Keppra contains sodium 
One maximum single dose of Keppra concentrate contains 2.5 mmol (or 57 mg) of sodium (0.8 mmol 
(or 19 mg) of sodium per vial). This should be taken into consideration if you are on a controlled 
sodium diet. 
 
 
3. How Keppra is given 
 
A doctor or a nurse will administer you Keppra as an intravenous infusion. 



160 

Keppra must be administered twice a day, once in the morning and once in the evening, at about the 
same time each day. 
 
The intravenous formulation is an alternative to your oral administration. You can switch from the 
film-coated tablets or from the oral solution to the intravenous formulation or reverse directly without 
dose adaptation. Your total daily dose and frequency of administration remain identical. 
 
Monotherapy 

 
Dose in adults and adolescents (from 16 years of age): 
General dose: between 1000 mg and 3,000 mg each day. 
When you will first start taking Keppra, your doctor will prescribe you a lower dose during 2 weeks 
before giving you the lowest general dose. 
 
Add-on therapy 
 
Dose in adults and adolescents (12 to 17 years) weighing 50 kg or more: 
General dose: between 1,000 mg and 3,000 mg each day. 
 
Dose in children (4 to 11 years) and adolescents (12 to 17 years) weighing less than 50 kg: 
General dose: between 20 mg per kg bodyweight and 60 mg per kg bodyweight each day. 
 
Method and route of administration: 
Keppra is for intravenous use. 
The recommended dose must be diluted in at least 100 ml of a compatible diluent and infused over 15-
minutes. 
For doctors and nurses, more detailed direction for the proper use of Keppra is provided in section 6. 
 
Duration of treatment: 
 There is no experience with administration of intravenous levetiracetam for a longer period than 

4 days. 
 
If you stop using Keppra: 
If stopping treatment, as with other antiepileptic medicines, Keppra should be discontinued gradually 
to avoid an increase of seizures. Should your doctor decide to stop your Keppra treatment, he/she will 
instruct you about the gradual withdrawal of Keppra. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Tell your doctor immediately, or go to your nearest emergency department, if you experience: 
 
 weakness, feel light-headed or dizzy or have difficulty breathing, as these may be signs of a 

serious allergic (anaphylactic) reaction 
 swelling of the face, lips, tongue and throat (Quincke’s oedema) 
 flu-like symptoms and a rash on the face followed by an extended rash with a high temperature, 

increased levels of liver enzymes seen in blood tests and an increase in a type of white blood cell 
(eosinophilia) and enlarged lymph nodes (Drug Reaction with Eosinophilia and Systemic 
Symptoms [DRESS]),. 

 symptoms such as low urine volume, tiredness, nausea, vomiting, confusion and swelling in the 
legs, ankles or feet, as this may be a sign of sudden decrease of kidney function 

 a skin rash which may form blisters and look like small targets (central dark spots surrounded by a 
paler area, with a dark ring around the edge) (erythema multiforme) 



161 

 a widespread rash with blisters and peeling skin, particularly around the mouth, nose, eyes and 
genitals (Stevens-Johnson syndrome) 

 a more severe form of rash causing skin peeling in more than 30% of the body surface (toxic 
epidermal necrolysis) 

 signs of serious mental changes or if someone around you notices signs of confusion, somnolence 
(sleepiness), amnesia (loss of memory), memory impairment (forgetfulness), abnormal behaviour 
or other neurological signs including involuntary or uncontrolled movements. These could be 
symptoms of an encephalopathy. 

 
The most frequently reported adverse reactions were nasopharyngitis, somnolence (sleepiness), 
headache, fatigue and dizziness. At the beginning of the treatment or at dose increase side effects like 
sleepiness, tiredness and dizziness may be more common. These effects should however decrease over 
time. 
 
Very common: may affect more than 1 in 10 people 
 nasopharyngitis; 
 somnolence (sleepiness), headache. 

 
Common: may affect up to 1 in 10 people 
 anorexia (loss of appetite); 
 depression, hostility or aggression, anxiety, insomnia, nervousness or irritability; 
 convulsion, balance disorder (equilibrium disorder), dizziness (sensation of unsteadiness), 

lethargy (lack of energy and enthusiasm), tremor (involuntary trembling); 
 vertigo (sensation of rotation); 
 cough; 
 abdominal pain, diarrhoea, dyspepsia (indigestion), vomiting, nausea; 
 rash; 
 asthenia/fatigue (tiredness). 
 
Uncommon: may affect up to 1 in 100 people 
 decreased number of blood platelets, decreased number of white blood cells;  
 weight decrease, weight increase; 
 suicide attempt and suicidal ideation, mental disorder, abnormal behaviour, hallucination, anger, 

confusion, panic attack, emotional instability/mood swings, agitation; 
 amnesia (loss of memory), memory impairment (forgetfulness), abnormal coordination/ataxia 

(impaired coordinated movements), paraesthesia (tingling), disturbance in attention (loss of 
concentration); 

 diplopia (double vision), vision blurred; 
 elevated/abnormal values in a liver function test; 
 hair loss, eczema, pruritus;  
 muscle weakness, myalgia (muscle pain); 
 injury. 
 
Rare: may affect up to 1 in 1,000 people 
 infection; 
 decreased number of all blood cell types;  
 severe allergic reactions (DRESS, anaphylactic reaction [severe and important allergic reaction], 

Quincke’s oedema [swelling of the face, lips, tongue and throat]); 
 decreased blood sodium concentration; 
 suicide, personality disorders (behavioural problems), thinking abnormal (slow thinking, unable 

to concentrate); 
 delirium; 
 encephalopathy (see sub-section “Tell your doctor immediately” for a detailed description of 

symptoms); 
 seizures may become worse or happen more often; 



162 

 uncontrollable muscle spasms affecting the head, torso and limbs, difficulty in controlling 
movements, hyperkinesia (hyperactivity); 

 change of the heart rhythm (Electrocardiogram); 
 pancreatitis; 
 liver failure, hepatitis; 
 sudden decrease in kidney function; 
 skin rash, which may form blisters and looks like small targets (central dark spots surrounded 

by a paler area, with a dark ring around the edge) (erythema multiforme), a widespread rash with 
blisters and peeling skin, particularly around the mouth, nose, eyes and genitals (Stevens-
Johnson syndrome), and a more severe form causing skin peeling in more than 30% of the body 
surface (toxic epidermal necrolysis); 

 rhabdomyolysis (breakdown of muscle tissue) and associated blood creatine phosphokinase 
increase. Prevalence is significantly higher in Japanese patients when compared to non-Japanese 
patients. 

 limp or difficulty walking. 
 
Reporting of side effects 
If you get any side effects talk to your doctor or pharmacist. This includes any possible side effects not 
listed in this leaflet. You can also report side effects directly via the national reporting system listed in 
Appendix V. By reporting side effects you can help provide more information on the safety of this 
medicine. 
 
 
5. How to store Keppra 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date stated on the vial and carton box after EXP: 
The expiry date refers to the last day of the month. 
 
This medicine does not require any special storage conditions. 
 
 
6. Contents of the pack and other information 
 
What Keppra contains 
The active substance is called levetiracetam. Each ml contains 100 mg of levetiracetam. 
The other ingredients are: sodium acetate, glacial acetic acid, sodium chloride, water for injections. 
 
What Keppra looks like and contents of the pack 
Keppra concentrate for solution for infusion (sterile concentrate) is a clear, colourless liquid. 
Keppra concentrate for solution for infusion is packed in a cardboard box containing 10 vials of 5 ml.  
 
Marketing Authorisation Holder 
UCB Pharma SA, Allée de la Recherche 60, B-1070 Brussels, Belgium. 
 
Manufacturer 
UCB Pharma SA, Chemin du Foriest, B-1420 Braine-l’Alleud, Belgium  
or    Aesica Pharmaceuticals S.r.l., Via Praglia, 15, I-10044 Pianezza, Italy. 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


163 

België/Belgique/Belgien 
UCB Pharma SA/NV 
Tel/Tél: + 32 / (0)2 559 92 00 
 

Lietuva 
UCB Pharma Oy Finland 
Tel: +358 9 2514 4221 (Suomija) 
 

България 
Ю СИ БИ България ЕООД 
Teл.: + 359 (0) 2 962 30 49 

Luxembourg/Luxemburg 
UCB Pharma SA/NV 
Tél/Tel: + 32 / (0)2 559 92 00 
 

Česká republika 
UCB s.r.o. 
Tel: + 420 221 773 411 
 

Magyarország 
UCB Magyarország Kft. 
Tel.: + 36-(1) 391 0060 
 

Danmark 
UCB Nordic A/S 
Tlf: + 45 / 32 46 24 00 
 

Malta 
Pharmasud Ltd. 
Tel: + 356 / 21 37 64 36 
 

Deutschland 
UCB Pharma GmbH 
Tel: + 49 /(0) 2173 48 4848 
 

Nederland 
UCB Pharma B.V. 
Tel.: + 31 / (0)76-573 11 40 
 

Eesti 
UCB Pharma Oy Finland  
Tel: +358 9 2514 4221 (Soome) 
 

Norge 
UCB Nordic A/S 
Tlf: + 45 / 32 46 24 00 
 

Ελλάδα 
UCB Α.Ε.  
Τηλ: + 30 / 2109974000 
 

Österreich 
UCB Pharma GmbH 
Tel: + 43 (0)1 291 80 00  
 

España 
UCB Pharma, S.A. 
Tel: + 34 / 91 570 34 44 
 

Polska 
UCB Pharma Sp. z o.o. 
Tel: + 48 22 696 99 20 
 

France 
UCB Pharma S.A. 
Tél: + 33 / (0)1 47 29 44 35 

Portugal 
UCB Pharma (Produtos Farmacêuticos), Lda 
Tel: + 351 / 21 302 5300 
 

Hrvatska 
Medis Adria d.o.o. 
Tel: +385 (0) 1 230 34 46 
 

România 
UCB Pharma Romania S.R.L. 
Tel: + 40 21 300 29 04 
 

Ireland 
UCB (Pharma) Ireland Ltd. 
Tel: + 353 / (0)1-46 37 395  
 

Slovenija 
Medis, d.o.o. 
Tel: + 386 1 589 69 00 
 

Ísland 
Vistor hf. 
Tel: + 354 535 7000 
 

Slovenská republika 
UCB s.r.o., organizačná zložka 
Tel: + 421 (0) 2 5920 2020 
 

Italia 
UCB Pharma S.p.A. 
Tel: + 39 / 02 300 791 

Suomi/Finland 
UCB Pharma Oy Finland 
Puh/Tel: +358 9 2514 4221 
 

Κύπρος 
Lifepharma (Z.A.M.) Ltd 
Τηλ: + 357 22 34 74 40  
 

Sverige 
UCB Nordic A/S 
Tel: + 46 / (0) 40 29 49 00 



164 

Latvija 
UCB Pharma Oy Finland 
Tel: +358 9 2514 4221 (Somija) 
 

United Kingdom 
UCB Pharma Ltd. 
Tel : + 44 / (0)1753 534 655 

 
This leaflet was last revised in {month/YYYY} 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 
--------------------------------------------------------------------------------------------------------------------------- 
 
The following information is intended for healthcare professionals only: 
Directions for the proper use of Keppra is provided in section 3. 
 
One vial of Keppra concentrate contains 500 mg levetiracetam (5 ml concentrate of 100 mg/ml). See 
Table 1 for the recommended preparation and administration of Keppra concentrate 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 Keppra concentrate 
 

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. 
 
In use shelf life: 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 8°C, unless dilution has taken place 
in controlled and validated aseptic conditions. 
 
Keppra concentrate was found to be physically compatible and chemically stable when mixed with the 
following diluents for at least 24 hours 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 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET