ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Keppra 250 mg film-coated tablets
2.
Each film-coated tablet contains 250 mg levetiracetam.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Blue, oblong, scored and debossed with the code “ucb” and “250” on one side.
4.
Keppra is indicated as monotherapy in the treatment of partial onset seizures with or without
secondary generalisation in patients 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,
children and infants from 1 month of age with epilepsy.
•
in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with
Juvenile Myoclonic Epilepsy.
•
in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12
years of age with Idiopathic Generalised Epilepsy.
Posology
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.
Special populations
Elderly (65 years and older)
2
Adjustment of the dose is recommended in elderly patients with compromised renal function (see
“Patients with 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:
cr ( l/ in)
CLcr (ml/min/1.73 m
2
) = ---------------------------- x 1.73
SA subject (
2
)
Dosing adjustment for adult and adolescents patients weighing more than 50 kg with impaired renal
function
Group
Creatinine clearance
(ml/min/1.73m
2
)
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 m
2
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 m
2
) = ------------------------------------
Serum Creatinine (mg/dl)
ks= 0.45 in Term infants to 1 year old; ks= 0.55 in Children to less than 13 years and in adolescent
female; ks= 0.7 in adolescent male
Dosing adjustment for infants, children and adolescents patients weighing less than 50 kg with
impaired renal function
3
Group
Creatinine
clearance
(ml/min/1.73 m
2
)
Dose and frequency
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
(1) (3)
10 to 20 mg/kg (0.10 to
0.20 ml/kg) once daily (2) (4)
(1) A 10.5 mg/kg (0.105 ml/kg) loading dose is recommended on the first day of treatment with
levetiracetam.
(2) A 15 mg/kg (0.15 ml/kg) loading dose is recommended on the first day of treatment with
levetiracetam.
(3) Following dialysis, a 3.5 to 7 mg/kg (0.035 to 0.07 ml/kg) supplemental dose is recommended.
(4) 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 m
2
.
Paediatric population
The physician should prescribe the most appropriate pharmaceutical form, presentation and strength
according to weight and dose.
Monotherapy
The safety and efficacy of Keppra in children and adolescents below 16 years as monotherapy
treatment have not been established.
There are no data available.
Add-on therapy for infants aged from 6 to 23 months, children (2 to 11 years) and adolescents (12 to
17 years) weighing less than 50 kg
The initial therapeutic dose is 10 mg/kg twice daily.
Depending upon the clinical response and tolerability, the dose can be increased up to 30 mg/kg twice
daily. Dose changes should not exceed increases or decreases of 10 mg/kg twice daily every two
weeks. The lowest effective dose should be used.
Dose in children 50 kg or greater is the same as in adults.
Dose recommendations for infants from 6 months of age, children and adolescents:
4
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 20 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 from 1 month to less than 6 months
The tablet formulation is not adapted for use in infants under the age of 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. The daily dose is administered in two equally divided doses.
Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipients.
Discontinuation
In accordance with current clinical practice, if Keppra 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).
Renal insuffiency
The administration of Keppra to patients with renal impairment may require dose adjustment. In
patients with severely impaired hepatic function, assessment of renal function is recommended before
dose selection (see section 4.2).
Suicide
Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with
anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled
trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and
behaviour. The mechanism of this risk is not known.
Therefore, patients should be monitored for signs of depression and/or suicidal ideation and
behaviours and appropriate treatment should be considered. Patients (and caregivers of patients)
should be advised to seek medical advice should signs of depression and/or suicidal ideation or
behaviour emerge.
Paediatric population
The tablet formulation is not adapted for use in infants under the age of 6 months.
5
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.
The safety and efficacy of levetiracetam has not been thoroughly assessed in infants with epilepsy
aged less than 1 year. Only 35 infants aged less than 1 year with partial onset seizures have been
exposed in clinical studies of which only 13 were aged < 6 months.
Antiepileptic medicinal products
Pre-marketing data from clinical studies conducted in adults indicate that Keppra 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 Keppra.
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. It is expected that other medicinal products excreted by
active tubular secretion could also reduce the renal clearance of the metabolite. The effect of
levetiracetam on probenecid was not studied and the effect of levetiracetam on other actively secreted
medicinal products,
e.g.
NSAIDs, sulfonamides and methotrexate, is unknown.
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.
Antacids
No data on the influence of antacids on the absorption of levetiracetam are available.
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.
Pregnancy
There are no adequate data available from the use of levetiracetam in pregnant women. Studies in
animals have shown reproductive toxicity (see section 5.3). The potential risk for human is unknown.
Keppra is not recommended during pregnancy and in women of childbearing potential not using
contraception unless clearly necessary.
As with other antiepileptic medicinal products, physiological changes during pregnancy may affect
levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed
6
during pregnancy. This decrease is more pronounced during the third trimester (up to 60% of baseline
concentration before pregnancy). Appropriate clinical management of pregnant women treated with
levetiracetam should be ensured. Discontinuation of antiepileptic treatments may result in exacerbation
of the disease which could be harmful to the mother and the foetus.
Breastfeeding
Levetiracetam is excreted in human breast milk. Therefore, breast-feeding is not recommended.
However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk of the treatment
should be weighed considering the importance of breastfeeding.
Fertility
No impact on fertility was detected in animal studies (see section 5.3). No clinical data are available,
potential risk for human is unknown.
No studies on the effects on the ability to drive and use machines have been performed.
Due to possible different individual sensitivity, some patients might experience somnolence or other
central nervous system related symptoms, especially at the beginning of treatment or following a dose
increase. Therefore, caution is recommended in those patients when performing skilled tasks,
e.g
.
driving vehicles or operating machinery. Patients are advised not to drive or use machines until it is
established that their ability to perform such activities is not affected.
Summary of the safety profile
Pooled safety data from clinical studies conducted with Keppra oral formulations in adult patients with
partial onset seizures showed that 46.4 % of the patients in the Keppra group and 42.2 % of the
patients in the placebo group experienced adverse reactions. Serious adverse reactions were
experienced in 2.4 % of the patients in the Keppra and 2.0 % of the patients in the placebo groups. The
most commonly reported adverse reactions were somnolence, asthenia and dizziness. In the pooled
safety analysis, there was no clear dose-response relationship but incidence and severity of the central
nervous system related adverse reactions decreased over time.
In monotherapy 49.8 % of the subjects experienced at least one drug related adverse reaction. The
most frequently reported adverse reactions were fatigue and somnolence.
A study conducted in adults and adolescents with myoclonic seizures (12 to 65 years) showed that
33.3 % of the patients in the Keppra group and 30.0 % of the patients in the placebo group
experienced adverse reactions that were judged to be related to treatment. The most commonly
reported adverse reactions were headache and somnolence. The incidence of adverse reactions in
patients with myoclonic seizures was lower than that in adult patients with partial onset seizures
(33.3 % versus 46.4 %).
A study conducted in adults and children (4 to 65 years) with idiopathic generalised epilepsy with
primary generalised tonic-clonic seizures showed that 39.2 % of the patients in the Keppra group and
29.8 % of the patients in the placebo group experienced adverse reactions that were judged to be
related to treatment. The most commonly reported adverse reaction was fatigue.
An increase in seizure frequency of more than 25 % was reported in 14 % of levetiracetam treated
adult and paediatric patients (4 to 16 years of age) with partial onset seizures, whereas it was reported
in 26 % and 21 % of placebo treated adult and paediatric patients, respectively.
When Keppra was used to treat primary generalised tonic-clonic seizures in adults and adolescents
with idiopathic generalised epilepsy, there was no effect on the frequency of absences.
7
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. For clinical trials, the 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); very rare
(<1/10,000), not known (cannot be estimated from the available data). Data from post-marketing
experience are insufficient to support an estimate of their incidence in the population to be treated.
-
Infections and infestations
Common: infection, nasopharyngitis
-
Blood and lymphatic system disorders
Common: thrombocytopenia
Not known: leukopenia, neutropenia, pancytopenia (with bone marrow suppression identified in some
of the cases)
-
Metabolism and nutrition disorders
Common: anorexia, weight increase.
Not known: weight loss
-
Psychiatric disorders
Common: agitation, depression, emotional lability/mood swings, hostility/aggression, insomnia,
nervousness/irritability, personality disorders, thinking abnormal
Not known: abnormal behaviour, anger, anxiety, confusion, hallucination, psychotic disorder, suicide,
suicide attempt and suicidal ideation
-
Nervous system disorders
Very common: somnolence
Common: amnesia, ataxia, convulsion, dizziness, headache, hyperkinesia, tremor, balance disorder,
disturbance in attention, memory impairment.
Not known: paraesthesia
-
Eye disorders
Common: diplopia, vision blurred
-
Ear and labyrinth disorders
Common: vertigo
-
Respiratory, thoracic and mediastinal disorders
Common: cough increased
-
Gastrointestinal disorders
Common: abdominal pain, diarrhoea, dyspepsia, nausea, vomiting
Not known: pancreatitis
-
Hepatobiliary disorders
Not known: hepatic failure, hepatitis, liver function test abnormal
-
Skin and subcutaneous tissue disorders
Common: rash, eczema, pruritus
Not known: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme and alopecia
- Musculoskeletal and connective tissue disorders
Common: myalgia
-
General disorders and administration site conditions
8
Very common: asthenia/fatigue
-
Injury, poisoning and procedural complications
Common: accidental injury
Description of selected adverse reactions
The risk of anorexia is higher when topiramate is coadministered with levetiracetam.
In several cases of alopecia, recovery was observed when levetiracetam was discontinued.
Paediatric population
A study conducted in paediatric patients (4 to 16 years) with partial onset seizures showed that 55.4 %
of the patients in the Keppra group and 40.2 % of the patients in the placebo group experienced
adverse reactions. Serious adverse reactions were experienced in none of the patients in the Keppra
group and 1.0 % of the patients in the placebo group. The most commonly reported adverse reactions
were somnolence, hostility, nervousness, emotional lability, agitation, anorexia, asthenia and headache
in the paediatric population. Safety results in paediatric patients were consistent with the safety profile
of levetiracetam in adults except for behavioural and psychiatric adverse reaction which were more
common in children than in adults (38.6 % versus 18.6 %). However, the relative risk was similar in
children as compared to adults.
A study conducted in paediatric patients (1 month to less than 4 years) with partial onset seizures
showed that 21.7 % of the patients in the Keppra group and 7.1 % of the patients in the placebo group
experienced adverse reactions. No serious adverse reactions were experienced in patients in the
Keppra or placebo group.
During the long-term follow-up study N01148, the most frequent drug-
related treatment-emergent adverse reactions in the 1
month – <4
years group were irritability (7.9
%),
convulsion (7.2
%), somnolence (6.6
%), psychomotor hyperactivity (3.3
%), sleep disorder (3.3
%),
and aggression (3.3
%). Safety results in paediatric patients were consistent with the safety profile of
levetiracetam in older children aged 4 to 16
years.
A double-blind, placebo-controlled paediatric safety study with a non-inferiority design has assessed
the cognitive and neuropsychological effects of Keppra 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 behavioral and emotional functioning indicated a
worsening in Keppra treated patients on aggressive behavior as measured in a standardised and
systematic way using a validated instrument (CBCL – Achenbach Child Behavior Checklist).
However subjects, who took Keppra 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 behavior were not worse than baseline.
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.
9
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group
: antiepileptics, other antiepileptics, ATC code: N03AX14.
The active substance, levetiracetam, is a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-
pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances.
Mechanism of action
The mechanism of action of levetiracetam still remains to be fully elucidated but appears to be
different from the mechanisms of current antiepileptic medicinal products.
In vitro
and
in vivo
experiments suggest that levetiracetam does not alter basic cell characteristics and normal
neurotransmission.
In vitro
studies show that levetiracetam affects intraneuronal Ca2+ levels by partial inhibition of N-
type Ca2+ currents and by reducing the release of Ca2+ from intraneuronal stores. In addition it
partially reverses the reductions in GABA- and glycine-gated currents induced by zinc and β-
carbolines. Furthermore, levetiracetam has been shown in
in vitro
studies to bind to a specific site in
rodent brain tissue. This binding site is the synaptic vesicle protein 2A, believed to be involved in
vesicle fusion and neurotransmitter exocytosis. Levetiracetam and related analogs show a rank order of
affinity for binding to the synaptic vesicle protein 2A which correlates with the potency of their anti-
seizure protection in the mouse audiogenic model of epilepsy. This finding suggests that the
interaction between levetiracetam and the synaptic vesicle protein 2A seems to contribute to the
antiepileptic mechanism of action of the medicinal product.
Pharmacodynamic effects
Levetiracetam induces seizure protection in a broad range of animal models of partial and primary
generalised seizures without having a pro-convulsant effect. The primary metabolite is inactive.
In man, an activity in both partial and generalised epilepsy conditions (epileptiform
discharge/photoparoxysmal response) has confirmed the broad spectrum pharmacological profile of
levetiracetam.
Clinical efficacy and safety
Adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation
in adults, adolescents, children and infants from 1 month of age with epilepsy:
In adults, levetiracetam efficacy has been demonstrated in 3 double-blind, placebo-controlled studies
at 1000 mg, 2000 mg, or 3000 mg/day, given in 2 divided doses, with a treatment duration of up to 18
weeks. In a pooled analysis, the percentage of patients who achieved 50 % or greater reduction from
baseline in the partial onset seizure frequency per week at stable dose (12/14 weeks) was of 27.7 %,
31.6 % and 41.3 % for patients on 1000, 2000 or 3000 mg levetiracetam respectively and of 12.6 %
for patients on placebo.
Paediatric population
In paediatric patients (4 to 16 years of age), levetiracetam efficacy was established in a double-blind,
placebo-controlled study, which included 198 patients and had a treatment duration of 14 weeks. In
this study, the patients received levetiracetam as a fixed dose of 60 mg/kg/day (with twice a day
dosing).
44.6 % of the levetiracetam treated patients and 19.6 % of the patients on placebo had a 50 % or
greater reduction from baseline in the partial onset seizure frequency per week. With continued long-
10
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 month and a dose of 25 mg/kg/day titrating to 50 mg/kg/day for
infants and children 6 month to less than 4 years old, was use in this study. The total daily dose was
administered b.i.d.
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.
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
11
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 (C
max
) are achieved at 1.3 hours after dosing. Steady-state is achieved after
two days of a twice daily administration schedule.
Peak concentrations (C
max
) are typically 31 and 43 µg/ml following a single 1,000 mg dose and
repeated 1,000 mg twice daily dose, respectively.
The extent of absorption is dose-independent and is not altered by food.
Distribution
No tissue distribution data are available in humans.
Neither levetiracetam nor its primary metabolite are significantly bound to plasma proteins (< 10 %).
The volume of distribution of levetiracetam is approximately 0.5 to 0.7 l/kg, a value close to the total
body water volume.
Biotransformation
Levetiracetam is not extensively metabolised in humans. The major metabolic pathway (24 % of the
dose) is an enzymatic hydrolysis of the acetamide group. Production of the primary metabolite,
ucb L057, is not supported by liver cytochrome P
450
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.
12
In vitro
, levetiracetam and its primary metabolite have been shown not to inhibit the major human
liver cytochrome P
450
isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl
transferase (UGT1A1 AND UGT1A6]) and epoxide hydroxylase activities. In addition, levetiracetam
does not affect the
in vitro
glucuronidation of valproic acid.
In human hepatocytes in culture, levetiracetam had little or no effect on CYP1A2, SULT1E1 or
UGT1A1. Levetiracetam caused mild induction of CYP2B6 and CYP3A4. The in vitro data and in
vivo interaction data on oral contraceptives, digoxin and warfarin indicate that no significant enzyme
induction is expected in vivo. Therefore, the interaction of Keppra with other substances, or
vice versa,
is unlikely.
Elimination
The plasma half-life in adults was 7±1 hours and did not vary either with dose, route of administration
or repeated administration. The mean total body clearance was 0.96 ml/min/kg.
The major route of excretion was via urine, accounting for a mean 95 % of the dose (approximately
93 % of the dose was excreted within 48 hours). Excretion
via
faeces accounted for only 0.3 % of the
dose.
The cumulative urinary excretion of levetiracetam and its primary metabolite accounted for 66 % and
24 % of the dose, respectively during the first 48 hours.
The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml/min/kg respectively indicating
that levetiracetam is excreted by glomerular filtration with subsequent tubular reabsorption and that
the primary metabolite is also excreted by active tubular secretion in addition to glomerular filtration.
Levetiracetam elimination is correlated to creatinine clearance.
Elderly
In the elderly, the half-life is increased by about 40 % (10 to 11 hours). This is related to the decrease
in renal function in this population (see section 4.2).
Renal impairment
The apparent body clearance of both levetiracetam and of its primary metabolite is correlated to the
creatinine clearance. It is therefore recommended to adjust the maintenance daily dose of Keppra,
based on creatinine clearance in patients with moderate and severe renal impairment (see section 4.2).
In anuric end-stage renal disease adult subjects the half-life was approximately 25 and 3.1 hours
during interdialytic and intradialytic periods, respectively.
The fractional removal of levetiracetam was 51 % during a typical 4-hour dialysis session.
Hepatic impairment
In subjects with mild and moderate hepatic impairment, there was no relevant modification of the
clearance of levetiracetam. In most subjects with severe hepatic impairment, the clearance of
levetiracetam was reduced by more than 50 % due to a concomitant renal impairment (see section 4.2).
Peadiatric 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.
13
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 AED.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, genotoxicity and carcinogenicity.
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 effects on male or female fertility or reproduction performance were observed in rats at
doses up to 1800 mg/kg/day (x 6 the MRHD on a mg/m2 or exposure basis) in parents and F1
generation.
Two embryo-fetal development (EFD) studies were performed in rats at 400, 1200 and
3600 mg/kg/day. At 3600 mg/kg/day, in only one of the 2 EFD studies, there was a slight decrease in
fetal weight associated with a marginal increase in skeletal variations/minor anomalies. There was no
effect on 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-fetal development studies were performed in rabbits covering doses of 200, 600, 800,
1200 and 1800 mg/kg/day. The dose level of 1800 mg/kg/day induced a marked maternal toxicity and
a decrease in fetal weight associated with increased incidence of fetuses with cardiovascular/skeletal
anomalies. The NOAEL was <200 mg/kg/day for the dams and 200 mg/kg/day for the fetuses (equal
to the MRHD on a mg/m2 basis).
A peri- and post-natal development study was performed in rats with levetiracetam doses of 70, 350
and 1800 mg/kg/day. The NOAEL was ≥ 1800 mg/kg/day for the F0 females, and for the survival,
growth and development of the F1 offspring up to weaning (x 6 the MRHD on a mg/m2 basis).
Neonatal and juvenile animal studies in rats and dogs demonstrated that there were no adverse effects
seen in any of the standard developmental or maturation endpoints at doses up to 1800 mg/kg/day (x 6
– 17 the MRHD on a mg/m2 basis).
14
6.
6.1 List of excipients
Core:
Croscarmellose sodium
Macrogol 6000
Silica colloidal anhydrous
Magnesium stearate
Film-coating
Opadry 85F20694:
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 and 200 (2 x 100)
film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
UCB Pharma SA
Allée de la Recherche 60
B-1070 Brussels
Belgium
8.
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
15
EU/1/00/146/029
9.
Date of first authorisation: 29 September 2000
Date of lastest renewal: 08 July 2005
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu
16
1.
Keppra 500 mg film-coated tablets
2.
Each film-coated tablet contains 500 mg levetiracetam.
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Yellow, oblong, scored and debossed with the code “ucb” and “500” on one side.
4.
Keppra is indicated as monotherapy in the treatment of partial onset seizures with or without
secondary generalisation in patients 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,
children and infants from 1 month of age with epilepsy.
•
in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with
Juvenile Myoclonic Epilepsy.
•
in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12
years of age with Idiopathic Generalised Epilepsy.
Posology
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.
Special populations
Elderly (65 years and older)
17
Adjustment of the dose is recommended in elderly patients with compromised renal function (see
“Patients with 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:
cr ( l/ in)
CLcr (ml/min/1.73 m
2
) = ---------------------------- x 1.73
SA subject (
2
)
Dosing adjustment for adult and adolescents patients weighing more than 50 kg with impaired renal
function
Group
Creatinine clearance
(ml/min/1.73m
2
)
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 m
2
may be estimated from serum creatinine (mg/dl) determination using, for
young adolescents, children and infants, using the following formula (Schwartz formula):
Height (cm) x ks
CLcr (ml/min/1.73 m
2
) = -------------------------------------
Serum Creatinine (mg/dl)
ks= 0.45 in Term infants to 1 year old; ks= 0.55 in Children to less than 13 years and in adolescent
female; ks= 0.7 in adolescent male
Dosing adjustment for infants, children and adolescents patients weighing less than 50 kg with
impaired renal function
18
Group
Creatinine
clearance
(ml/min/1.73m
2
)
Dose and frequency
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 (1)
(3)
10 to 20 mg/kg (0.10 to
0.20 ml/kg) once daily (2) (4)
(1) A 10.5 mg/kg (0.105 ml/kg) loading dose is recommended on the first day of treatment with
levetiracetam.
(2) A 15 mg/kg (0.15 ml/kg) loading dose is recommended on the first day of treatment with
levetiracetam.
(3) Following dialysis, a 3.5 to 7 mg/kg (0.035 to 0.07 ml/kg) supplemental dose is recommended.
(4) 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 m
2
.
Paediatric population
The physician should prescribe the most appropriate pharmaceutical form, presentation and strength
according to weight and dose.
Monotherapy
The safety and efficacy of Keppra in children and adolescents below 16 years as monotherapy
treatment have not been established.
There are no data 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
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:
19
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 20 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 from 1 month to less than 6 months
The tablet formulation is not adapted for use in infants under the age of 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. The daily dose is administered in two equally divided doses.
Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipients.
Discontinuation
In accordance with current clinical practice, if Keppra 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).
Renal insufficiency
The administration of Keppra to patients with renal impairment may require dose adjustment. In
patients with severely impaired hepatic function, assessment of renal function is recommended before
dose selection (see section 4.2).
Suicide
Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with
anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled
trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and
behaviour. The mechanism of this risk is not known.
Therefore, patients should be monitored for signs of depression and/or suicidal ideation and
behaviours and appropriate treatment should be considered. Patients (and caregivers of patients)
should be advised to seek medical advice should signs of depression and/or suicidal ideation or
behaviour emerge.
Paediatric population
The tablet formulation is not adapted for use in infants under the age of 6 months.
20
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.
The safety and efficacy of levetiracetam has not been thoroughly assessed in infants with epilepsy
aged less than 1 year. Only 35 infants aged less than 1 year with partial onset seizures have been
exposed in clinical studies of which only 13 were aged < 6 months.
Antiepileptic medicinal products
Pre-marketing data from clinical studies conducted in adults indicate that Keppra 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 Keppra.
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. It is expected that other medicinal products excreted by
active tubular secretion could also reduce the renal clearance of the metabolite. The effect of
levetiracetam on probenecid was not studied and the effect of levetiracetam on other actively secreted
medicinal products,
e.g.
NSAIDs, sulfonamides and methotrexate, is unknown.
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.
Antacids
No data on the influence of antacids on the absorption of levetiracetam are available.
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.
Pregnancy
There are no adequate data available from the use of levetiracetam in pregnant women. Studies in
animals have shown reproductive toxicity (see section 5.3). The potential risk for human is unknown.
Keppra is not recommended during pregnancy and in women of childbearing potential not using
contraception unless clearly necessary.
21
As with other antiepileptic medicinal products, physiological changes during pregnancy may affect
levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed
during pregnancy. This decrease is more pronounced during the third trimester (up to 60% of baseline
concentration before pregnancy). Appropriate clinical management of pregnant women treated with
levetiracetam should be ensured. Discontinuation of antiepileptic treatments may result in exacerbation
of the disease which could be harmful to the mother and the foetus.
Breastfeeding
Levetiracetam is excreted in human breast milk. Therefore, breast-feeding is not recommended.
However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk of the treatment
should be weighed considering the importance of breastfeeding.
Fertility
No impact on fertility was detected in animal studies (see section 5.3). No clinical data are available,
potential risk for human is unknown.
No studies on the effects on the ability to drive and use machines have been performed.
Due to possible different individual sensitivity, some patients might experience somnolence or other
central nervous system related symptoms, especially at the beginning of treatment or following a dose
increase. Therefore, caution is recommended in those patients when performing skilled tasks,
e.g
.
driving vehicles or operating machinery. Patients are advised not to drive or use machines until it is
established that their ability to perform such activities is not affected.
Summary of the safety profile
Pooled safety data from clinical studies conducted with Keppra oral formulations in adult patients with
partial onset seizures showed that 46.4 % of the patients in the Keppra group and 42.2 % of the
patients in the placebo group experienced adverse reactions. Serious adverse reactions were
experienced in 2.4 % of the patients in the Keppra and 2.0 % of the patients in the placebo groups. The
most commonly reported adverse reactions were somnolence, asthenia and dizziness. In the pooled
safety analysis, there was no clear dose-response relationship but incidence and severity of the central
nervous system related adverse reactions decreased over time.
In monotherapy 49.8 % of the subjects experienced at least one drug related adverse reaction. The
most frequently reported adverse reactions were fatigue and somnolence.
A study conducted in adults and adolescents with myoclonic seizures (12 to 65 years) showed that
33.3 % of the patients in the Keppra group and 30.0 % of the patients in the placebo group
experienced adverse reactions that were judged to be related to treatment. The most commonly
reported adverse reactions were headache and somnolence. The incidence of adverse reactions in
patients with myoclonic seizures was lower than that in adult patients with partial onset seizures
(33.3 % versus 46.4 %).
A study conducted in adults and children (4 to 65 years) with idiopathic generalised epilepsy with
primary generalised tonic-clonic seizures showed that 39.2 % of the patients in the Keppra group and
29.8 % of the patients in the placebo group experienced adverse reactions that were judged to be
related to treatment. The most commonly reported adverse reaction was fatigue.
An increase in seizure frequency of more than 25 % was reported in 14 % of levetiracetam treated
adult and paediatric patients (4 to 16 years of age) with partial onset seizures, whereas it was reported
in 26 % and 21 % of placebo treated adult and paediatric patients, respectively.
22
When Keppra was used to treat primary generalised tonic-clonic seizures in adults and adolescents
with idiopathic generalised epilepsy, there was no effect on the frequency of absences.
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. For clinical trials, the 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); very rare
(<1/10,000), not known (cannot be estimated from the available data). Data from post-marketing
experience are insufficient to support an estimate of their incidence in the population to be treated.
-
Infections and infestations
Common: infection, nasopharyngitis
-
Blood and lymphatic system disorders
Common: thrombocytopenia
Not known: leukopenia, neutropenia, pancytopenia (with bone marrow suppression identified in some
of the cases)
-
Metabolism and nutrition disorders
Common: anorexia, weight increase.
Not known: weight loss
-
Psychiatric disorders
Common: agitation, depression, emotional lability /mood swings, hostility/aggression, insomnia,
nervousness/irritability, personality disorders, thinking abnormal
Not known: abnormal behaviour, anger, anxiety, confusion, hallucination, psychotic disorder, suicide,
suicide attempt and suicidal ideation
-
Nervous system disorders
Very common: somnolence
Common: amnesia, ataxia, convulsion, dizziness, headache, hyperkinesia, tremor, balance disorder,
disturbance in attention, memory impairment.
Not known: paraesthesia
-
Eye disorders
Common: diplopia, vision blurred
-
Ear and labyrinth disorders
Common: vertigo
-
Respiratory, thoracic and mediastinal disorders
Common: cough increased
-
Gastrointestinal disorders
Common: abdominal pain, diarrhoea, dyspepsia, nausea, vomiting
Not known: pancreatitis
- Hepatobiliary disorders
Not known: hepatic failure, hepatitis, liver function test abnormal
-
Skin and subcutaneous tissue disorders
Common: rash, eczema, pruritus
Not known: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme and alopecia
-
Musculoskeletal and connective tissue disorders
23
Common: myalgia
-
General disorders and administration site conditions
Very common: asthenia/fatigue.
-
Injury, poisoning and procedural complications
Common: accidental injury
Description of selected adverse reactions
The risk of anorexia is higher when topiramate is coadministered with levetiracetam.
In several cases of alopecia, recovery was observed when levetiracetam was discontinued.
Paediatric population
A study conducted in paediatric patients (4 to 16 years) with partial onset seizures showed that 55.4 %
of the patients in the Keppra group and 40.2 % of the patients in the placebo group experienced
adverse reactions. Serious adverse reactions were experienced in none of the patients in the Keppra
group and 1.0 % of the patients in the placebo group. The most commonly reported adverse reactions
were somnolence, hostility, nervousness, emotional lability, agitation, anorexia, asthenia and headache
in the paediatric population. Safety results in paediatric patients 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 (38.6 % versus 18.6 %). However, the relative risk was similar in
children as compared to adults.
A study conducted in paediatric patients (1 month to less than 4 years) with partial onset seizures
showed that 21.7 % of the patients in the Keppra group and 7.1 % of the patients in the placebo group
experienced adverse reactionsundesirable effects. No serious adverse reactions were experienced in
patients in the Keppra or placebo group. During the long-term follow-up study N01148, the most
frequent drug-related treatment-emergent adverse reactions in the 1 month – <4 years group were
irritability (7.9 %), convulsion (7.2 %), somnolence (6.6 %), psychomotor hyperactivity (3.3 %), sleep
disorder (3.3 %), and aggression (3.3 %). Safety results in paediatric patients were consistent with the
safety profile of levetiracetam in older children aged 4 to 16 years.
A double-blind, placebo-controlled paediatric safety study with a non-inferiority design has assessed
the cognitive and neuropsychological effects of Keppra 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 behavioral and emotional functioning indicated a
worsening in Keppra treated patients on aggressive behavior as measured in a standardised and
systematic way using a validated instrument (CBCL – Achenbach Child Behavior Checklist).
However subjects, who took Keppra 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 behavior were not worse than baseline.
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
24
include haemodialysis. The dialyser extraction efficiency is 60 % for levetiracetam and 74 % for the
primary metabolite.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group
: antiepileptics, other antiepileptics, ATC code: N03AX14.
The active substance, levetiracetam, is a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-
pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances.
Mechanism of action
The mechanism of action of levetiracetam still remains to be fully elucidated but appears to be
different from the mechanisms of current antiepileptic medicinal products.
In vitro
and
in vivo
experiments suggest that levetiracetam does not alter basic cell characteristics and normal
neurotransmission.
In vitro
studies show that levetiracetam affects intraneuronal Ca2+ levels by partial inhibition of N-
type Ca2+ currents and by reducing the release of Ca2+ from intraneuronal stores. In addition it
partially reverses the reductions in GABA- and glycine-gated currents induced by zinc and β-
carbolines. Furthermore, levetiracetam has been shown in
in vitro
studies to bind to a specific site in
rodent brain tissue. This binding site is the synaptic vesicle protein 2A, believed to be involved in
vesicle fusion and neurotransmitter exocytosis. Levetiracetam and related analogs show a rank order of
affinity for binding to the synaptic vesicle protein 2A which correlates with the potency of their anti-
seizure protection in the mouse audiogenic model of epilepsy. This finding suggests that the
interaction between levetiracetam and the synaptic vesicle protein 2A seems to contribute to the
antiepileptic mechanism of action of the medicinal product.
Pharmacodynamic effects
Levetiracetam induces seizure protection in a broad range of animal models of partial and primary
generalised seizures without having a pro-convulsant effect. The primary metabolite is inactive.
In man, an activity in both partial and generalised epilepsy conditions (epileptiform
discharge/photoparoxysmal response) has confirmed the broad spectrum pharmacological profile of
levetiracetam.
Clinical efficacy and safety
Adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation
in adults, adolescents, children and infants from 1 month of age with epilepsy:
In adults, levetiracetam efficacy has been demonstrated in 3 double-blind, placebo-controlled studies
at 1000 mg, 2000 mg, or 3000 mg/day, given in 2 divided doses, with a treatment duration of up to
18 weeks. In a pooled analysis, the percentage of patients who achieved 50 % or greater reduction
from baseline in the partial onset seizure frequency per week at stable dose (12/14 weeks) was of
27.7 %, 31.6 % and 41.3 % for patients on 1000, 2000 or 3000 mg levetiracetam respectively and of
12.6 % for patients on placebo.
Paediatric population
In paediatric patients (4 to 16 years of age), levetiracetam efficacy was established in a double-blind,
placebo-controlled study, which included 198 patients and had a treatment duration of 14 weeks. In
this study, the patients received levetiracetam as a fixed dose of 60 mg/kg/day (with twice a day
dosing).
25
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 month and a dose of 25 mg/kg/day titrating to 50 mg/kg/day for
infants and children 6 month to less than 4 years old, was use in this study. The total daily dose was
administered b.i.d.
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.
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.
26
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 (C
max
) are achieved at 1.3 hours after dosing. Steady-state is achieved after
two days of a twice daily administration schedule.
Peak concentrations (C
max
) are typically 31 and 43 µg/ml following a single 1,000 mg dose and
repeated 1,000 mg twice daily dose, respectively.
The extent of absorption is dose-independent and is not altered by food.
Distribution
No tissue distribution data are available in humans.
Neither levetiracetam nor its primary metabolite are significantly bound to plasma proteins (< 10 %).
The volume of distribution of levetiracetam is approximately 0.5 to 0.7 l/kg, a value close to the total
body water volume.
Biotransformation
Levetiracetam is not extensively metabolised in humans. The major metabolic pathway (24 % of the
dose) is an enzymatic hydrolysis of the acetamide group. Production of the primary metabolite,
ucb L057, is not supported by liver cytochrome P
450
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.
27
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 P
450
isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl
transferase (UGT1A1 and UGT1A6) and epoxide hydroxylase activities. In addition, levetiracetam
does not affect the
in vitro
glucuronidation of valproic acid.
In human hepatocytes in culture, levetiracetam had little or no effect on CYP1A2, SULT1E1 or
UGT1A1. Levetiracetam caused mild induction of CYP2B6 and CYP3A4. The in vitro data and in
vivo interaction data on oral contraceptives, digoxin and warfarin indicate that no significant enzyme
induction is expected in vivo. Therefore, the interaction of Keppra with other substances, or
vice versa,
is unlikely.
Elimination
The plasma half-life in adults was 7±1 hours and did not vary either with dose, route of administration
or repeated administration. The mean total body clearance was 0.96 ml/min/kg.
The major route of excretion was via urine, accounting for a mean 95 % of the dose (approximately
93 % of the dose was excreted within 48 hours). Excretion
via
faeces accounted for only 0.3 % of the
dose.
The cumulative urinary excretion of levetiracetam and its primary metabolite accounted for 66 % and
24 % of the dose, respectively during the first 48 hours.
The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml/min/kg respectively indicating
that levetiracetam is excreted by glomerular filtration with subsequent tubular reabsorption and that
the primary metabolite is also excreted by active tubular secretion in addition to glomerular filtration.
Levetiracetam elimination is correlated to creatinine clearance.
Elderly
In the elderly, the half-life is increased by about 40 % (10 to 11 hours). This is related to the decrease
in renal function in this population (see section 4.2).
Renal impairment
The apparent body clearance of both levetiracetam and of its primary metabolite is correlated to the
creatinine clearance. It is therefore recommended to adjust the maintenance daily dose of Keppra,
based on creatinine clearance in patients with moderate and severe renal impairment (see section 4.2).
In anuric end-stage renal disease adult subjects the half-life was approximately 25 and 3.1 hours
during interdialytic and intradialytic periods, respectively.
The fractional removal of levetiracetam was 51 % during a typical 4-hour dialysis session.
Hepatic impairment
In subjects with mild and moderate hepatic impairment, there was no relevant modification of the
clearance of levetiracetam. In most subjects with severe hepatic impairment, the clearance of
levetiracetam was reduced by more than 50 % due to a concomitant renal impairment (see section 4.2).
Peadiatric population
Children (4 to 12 years)
28
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 AED.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, genotoxicity and carcinogenicity.
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 effects on male or female fertility or reproduction performance were observed in rats at
doses up to 1800 mg/kg/day (x 6 the MRHD on a mg/m2 or exposure basis) in parents and F1
generation.
Two embryo-fetal development (EFD) studies were performed in rats at 400, 1200 and
3600 mg/kg/day. At 3600 mg/kg/day, in only one of the 2 EFD studies, there was a slight decrease in
fetal weight associated with a marginal increase in skeletal variations/minor anomalies. There was no
effect on 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-fetal development studies were performed in rabbits covering doses of 200, 600, 800,
1200 and 1800 mg/kg/day. The dose level of 1800 mg/kg/day induced a marked maternal toxicity and
a decrease in fetal weight associated with increased incidence of fetuses with cardiovascular/skeletal
anomalies. The NOAEL was <200 mg/kg/day for the dams and 200 mg/kg/day for the fetuses (equal
to the MRHD on a mg/m2 basis).
A peri- and post-natal development study was performed in rats with levetiracetam doses of 70, 350
and 1800 mg/kg/day. The NOAEL was ≥ 1800 mg/kg/day for the F0 females, and for the survival,
growth and development of the F1 offspring up to weaning (x 6 the MRHD on a mg/m2 basis).
29
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.
6.1 List of excipients
Core:
Croscarmellose sodium
Macrogol 6000
Silica colloidal anhydrous
Magnesium stearate
Film-coating
Opadry 85F32004:
Polyvinyl alcohol-part. hydrolyzed
Titanium dioxide (E171)
Macrogol 3350
Talc
Iron oxide yellow (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
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 and 200
(2 x 100) film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
UCB Pharma SA
Allée de la Recherche 60
B-1070 Brussels
Belgium
8.
30
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
9.
Date of first authorisation: 29 September 2000
Date of last renewal: 08 July 2005
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu
31
1.
Keppra 750 mg film-coated tablets
2.
Each film-coated tablet contains 750 mg levetiracetam.
Excipient:
Each film-coated tablet contains 0.19 mg of sunset yellow FCF (E110).
For a full list of excipients, see section 6.1.
3.
Film-coated tablet.
Orange, oblong, scored and debossed with the code “ucb” and “750” on one side.
4.
Keppra is indicated as monotherapy in the treatment of partial onset seizures with or without
secondary generalisation in patients 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,
children and infants from 1 month of age with epilepsy.
•
in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with
Juvenile Myoclonic Epilepsy.
•
in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12
years of age with Idiopathic Generalised Epilepsy.
Posology
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.
32
Special populations
Elderly (65 years and older)
Adjustment of the dose is recommended in elderly patients with compromised renal function (see
“Patients with 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:
cr ( l/ in)
CLcr (ml/min/1.73 m
2
) = ---------------------------- x 1.73
SA subject (
2
)
Dosing adjustment for adult and adolescents patients weighing more than 50 kg with impaired renal
function
Group
Creatinine clearance
(ml/min/1.73m
2
)
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 m
2
may be estimated from serum creatinine (mg/dl) determination using, for
young adolescents, children and infants, using the following formula (Schwartz formula):
Height (cm) x ks
CLcr (ml/min/1.73 m
2
) = ------------------------------------
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
33
Dosing adjustment for infants, children and adolescents patients weighing less than 50 kg with
impaired renal function
Group
Creatinine
clearance
(ml/min/1.73m
2
)
Dose and frequency
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 (1)
(3)
10 to 20 mg/kg (0.10 to
0.20 ml/kg) once daily (2) (4)
(1) A 10.5 mg/kg (0.105 ml/kg) loading dose is recommended on the first day of treatment with
levetiracetam.
(2) A 15 mg/kg (0.15 ml/kg) loading dose is recommended on the first day of treatment with
levetiracetam.
(3) Following dialysis, a 3.5 to 7 mg/kg (0.035 to 0.07 ml/kg) supplemental dose is recommended.
(4) 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 m
2
.
Paediatric population
The physician should prescribe the most appropriate pharmaceutical form, presentation and strength
according to weight and dose.
Monotherapy
The safety and efficacy of Keppra in children and adolescents below 16 years as monotherapy
treatment have not been established.
There are no data 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
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:
34
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 20 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 from 1 month to less than 6 months
The tablet formulation is not adapted for use in infants under the age of 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. The daily dose is administered in two equally divided doses.
Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipients.
Discontinuation
In accordance with current clinical practice, if Keppra 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).
Renal insufficiency
The administration of Keppra to patients with renal impairment may require dose adjustment. In
patients with severely impaired hepatic function, assessment of renal function is recommended before
dose selection (see section 4.2).
Suicide
Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with
anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled
trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and
behaviour. The mechanism of this risk is not known.
Therefore, patients should be monitored for signs of depression and/or suicidal ideation and
behaviours and appropriate treatment should be considered. Patients (and caregivers of patients)
should be advised to seek medical advice should signs of depression and/or suicidal ideation or
behaviour emerge.
Paediatric population
The tablet formulation is not adapted for use in infants under the age of 6 months.
35
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.
The safety and efficacy of levetiracetam has not been thoroughly assessed in infants with epilepsy
aged less than 1 year. Only 35 infants aged less than 1 year with partial onset seizures have been
exposed in clinical studies of which only 13 were aged < 6 months.
Excipients
Keppra 750 mg film-coated tablets contain E110 colouring agent which may cause allergic reactions.
Antiepileptic medicinal products
Pre-marketing data from clinical studies conducted in adults indicate that Keppra 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 Keppra.
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. It is expected that other medicinal products excreted by
active tubular secretion could also reduce the renal clearance of the metabolite. The effect of
levetiracetam on probenecid was not studied and the effect of levetiracetam on other actively secreted
medicinal products,
e.g.
NSAIDs, sulfonamides and methotrexate, is unknown.
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.
Antacids
No data on the influence of antacids on the absorption of levetiracetam are available.
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.
Pregnancy
There are no adequate data available from the use of levetiracetam in pregnant women. Studies in
animals have shown reproductive toxicity (see section 5.3). The potential risk for human is unknown.
36
Keppra is not recommended during pregnancy and in women of childbearing potential not using
contraception unless clearly necessary.
As with other antiepileptic medicinal products, physiological changes during pregnancy may affect
levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed
during pregnancy. This decrease is more pronounced during the third trimester (up to 60% of baseline
concentration before pregnancy). Appropriate clinical management of pregnant women treated with
levetiracetam should be ensured. Discontinuation of antiepileptic treatments may result in exacerbation
of the disease which could be harmful to the mother and the foetus.
Breastfeeding
Levetiracetam is excreted in human breast milk. Therefore, breast-feeding is not recommended.
However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk of the treatment
should be weighed considering the importance of breastfeeding.
Fertility
No impact on fertility was detected in animal studies (see section 5.3). No clinical data are available,
potential risk for human is unknown.
No studies on the effects on the ability to drive and use machines have been performed.
Due to possible different individual sensitivity, some patients might experience somnolence or other
central nervous system related symptoms, especially at the beginning of treatment or following a dose
increase. Therefore, caution is recommended in those patients when performing skilled tasks,
e.g
.
driving vehicles or operating machinery. Patients are advised not to drive or use machines until it is
established that their ability to perform such activities is not affected.
Summary of the safety profile
Pooled safety data from clinical studies conducted with Keppra oral formulations in adult patients with
partial onset seizures showed that 46.4 % of the patients in the Keppra group and 42.2 % of the
patients in the placebo group experienced adverse reactions. Serious adverse reactions were
experienced in 2.4 % of the patients in the Keppra and 2.0 % of the patients in the placebo groups. The
most commonly reported adverse reactions were somnolence, asthenia and dizziness. In the pooled
safety analysis, there was no clear dose-response relationship but incidence and severity of the central
nervous system related adverse reactions decreased over time.
In monotherapy 49.8 % of the subjects experienced at least one drug related adverse reaction. The
most frequently reported adverse reactions were fatigue and somnolence.
A study conducted in adults and adolescents with myoclonic seizures (12 to 65 years) showed that
33.3 % of the patients in the Keppra group and 30.0 % of the patients in the placebo group
experienced adverse reactions that were judged to be related to treatment. The most commonly
reported adverse reactions were headache and somnolence. The incidence of adverse reactions in
patients with myoclonic seizures was lower than that in adult patients with partial onset seizures
(33.3 % versus 46.4 %).
A study conducted in adults and children (4 to 65 years) with idiopathic generalised epilepsy with
primary generalised tonic-clonic seizures showed that 39.2 % of the patients in the Keppra group and
29.8 % of the patients in the placebo group experienced adverse reactions that were judged to be
related to treatment. The most commonly reported adverse reaction was fatigue.
37
An increase in seizure frequency of more than 25 % was reported in 14 % of levetiracetam treated
adult and paediatric patients (4 to 16 years of age) with partial onset seizures, whereas it was reported
in 26 % and 21 % of placebo treated adult and paediatric patients, respectively.
When Keppra was used to treat primary generalised tonic-clonic seizures in adults and adolescents
with idiopathic generalised epilepsy, there was no effect on the frequency of absences.
Tabulated lis 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. For clinical trials, the 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); very rare
(<1/10,000), not known (cannot be estimated from the available data). Data from post-marketing
experience are insufficient to support an estimate of their incidence in the population to be treated.
-
Infections and infestations
Common: infection, nasopharyngitis
-
Blood and lymphatic system disorders
Common: thrombocytopenia
Not known: leukopenia, neutropenia, pancytopenia (with bone marrow suppression identified in some
of the cases)
-
Metabolism and nutrition disorders
Common: anorexia, weight increase.
Not known: weight loss
-
Psychiatric disorders
Common: agitation, depression, emotional lability/mood swings, hostility/aggression, insomnia,
nervousness/irritability, personality disorders, thinking abnormal
Not known: abnormal behaviour, anger, anxiety, confusion, hallucination, psychotic disorder, suicide,
suicide attempt and suicidal ideation
-
Nervous system disorders
Very common: somnolence
Common: amnesia, ataxia, convulsion, dizziness, headache, hyperkinesia, tremor, balance disorder,
disturbance in attention, memory impairment.
Not known: paraesthesia
-
Eye disorders
Common: diplopia, vision blurred
-
Ear and labyrinth disorders
Common: vertigo
-
Respiratory, thoracic and mediastinal disorders
Common: cough increased
-
Gastrointestinal disorders
Common: abdominal pain, diarrhoea, dyspepsia, nausea, vomiting
Not known: pancreatitis
- Hepatobiliary disorders
Not known: hepatic failure, hepatitis, liver function test abnormal
-
Skin and subcutaneous tissue disorders
38
Common: rash, eczema, pruritus
Not known: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme and alopecia
-
Musculoskeletal and connective tissue disorders
Common: myalgia
-
General disorders and administration site conditions
Very common: asthenia/fatigue.
-
Injury, poisoning and procedural complications
Common: accidental injury
Description of selected adverse reactions
The risk of anorexia is higher when topiramate is coadministered with levetiracetam.
In several cases of alopecia, recovery was observed when levetiracetm was discontinued.
Paediatric population
A study conducted in paediatric patients (4 to 16 years) with partial onset seizures showed that 55.4 %
of the patients in the Keppra group and 40.2 % of the patients in the placebo group experienced
adverse reactions. Serious adverse reactions were experienced in none of the patients in the Keppra
group and 1.0 % of the patients in the placebo group. The most commonly reported adverser reactions
were somnolence, hostility, nervousness, emotional lability, agitation, anorexia, asthenia and headache
in the paediatric population. Safety results in paediatric patients 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 (38.6 % versus 18.6 %). However, the relative risk was similar in
children as compared to adults.
A study conducted in paediatric patients (1 month to less than 4 years) with partial onset seizures
showed that 21.7 % of the patients in the Keppra group and 7.1 % of the patients in the placebo group
experienced adverse reactions. No serious undesirable effects were experienced in patients in the
Keppra or placebo group. During the long-term follow-up study N01148, the most frequent drug-
related treatment-emergent adverse reactions in the 1 month – <4 years group were irritability (7.9 %),
convulsion (7.2 %), somnolence (6.6 %), psychomotor hyperactivity (3.3 %), sleep disorder (3.3 %),
and aggression (3.3 %). Safety results in paediatric patients were consistent with the safety profile of
levetiracetam in older children aged 4 to 16 years.
A double-blind, placebo-controlled paediatric safety study with a non-inferiority design has assessed
the cognitive and neuropsychological effects of Keppra 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 behavioral and emotional functioning indicated a
worsening in Keppra treated patients on aggressive behavior as measured in a standardised and
systematic way using a validated instrument (CBCL – Achenbach Child Behavior Checklist).
However subjects, who took Keppra 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 behavior were not worse than baseline.
Symptoms
Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma
were observed with Keppra overdoses.
39
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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group
: antiepileptics, other antiepileptics, ATC code: N03AX14.
The active substance, levetiracetam, is a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-
pyrrolidine acetamide), chemically unrelated to existing antiepileptic active substances.
Mechanism of action
The mechanism of action of levetiracetam still remains to be fully elucidated but appears to be
different from the mechanisms of current antiepileptic medicinal products.
In vitro
and
in vivo
experiments suggest that levetiracetam does not alter basic cell characteristics and normal
neurotransmission.
In vitro
studies show that levetiracetam affects intraneuronal Ca2+ levels by partial inhibition of N-
type Ca2+ currents and by reducing the release of Ca2+ from intraneuronal stores. In addition it
partially reverses the reductions in GABA- and glycine-gated currents induced by zinc and β-
carbolines. Furthermore, levetiracetam has been shown in
in vitro
studies to bind to a specific site in
rodent brain tissue. This binding site is the synaptic vesicle protein 2A, believed to be involved in
vesicle fusion and neurotransmitter exocytosis. Levetiracetam and related analogs show a rank order of
affinity for binding to the synaptic vesicle protein 2A which correlates with the potency of their anti-
seizure protection in the mouse audiogenic model of epilepsy. This finding suggests that the
interaction between levetiracetam and the synaptic vesicle protein 2A seems to contribute to the
antiepileptic mechanism of action of the medicinal product.
Pharmacodynamic effects
Levetiracetam induces seizure protection in a broad range of animal models of partial and primary
generalised seizures without having a pro-convulsant effect. The primary metabolite is inactive.
In man, an activity in both partial and generalised epilepsy conditions (epileptiform
discharge/photoparoxysmal response) has confirmed the broad spectrum pharmacological profile of
levetiracetam.
Clinical efficacy and safety
Adjunctive therapy in the treatment of partial onset seizures with or without secondary generalisation
in adults, adolescents, children and infants from 1 month of age with epilepsy:
In adults, levetiracetam efficacy has been demonstrated in 3 double-blind, placebo-controlled studies
at 1000 mg, 2000 mg, or 3000 mg/day, given in 2 divided doses, with a treatment duration of up to
18 weeks. In a pooled analysis, the percentage of patients who achieved 50 % or greater reduction
from baseline in the partial onset seizure frequency per week at stable dose (12/14 weeks) was of
27.7 %, 31.6 % and 41.3 % for patients on 1000, 2000 or 3000 mg levetiracetam respectively and of
12.6 % for patients on placebo.
Paediatric population
40
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 month and a dose of 25 mg/kg/day titrating to 50 mg/kg/day for
infants and children 6 month to less than 4 years old, was use in this study. The total daily dose was
administered b.i.d.
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.
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.
41
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 (C
max
) are achieved at 1.3 hours after dosing. Steady-state is achieved after
two days of a twice daily administration schedule.
Peak concentrations (C
max
) are typically 31 and 43 µg/ml following a single 1,000 mg dose and
repeated 1,000 mg twice daily dose, respectively.
The extent of absorption is dose-independent and is not altered by food.
Distribution
No tissue distribution data are available in humans.
Neither levetiracetam nor its primary metabolite are significantly bound to plasma proteins (< 10 %).
The volume of distribution of levetiracetam is approximately 0.5 to 0.7 l/kg, a value close to the total
body water volume.
Biotransformation
Levetiracetam is not extensively metabolised in humans. The major metabolic pathway (24 % of the
dose) is an enzymatic hydrolysis of the acetamide group. Production of the primary metabolite,
ucb L057, is not supported by liver cytochrome P
450
isoforms. Hydrolysis of the acetamide group was
measurable in a large number of tissues including blood cells. The metabolite ucb L057 is
pharmacologically inactive.
42
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 P
450
isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl
transferase (UGT1A1 and UGT1A6) and epoxide hydroxylase activities. In addition, levetiracetam
does not affect the
in vitro
glucuronidation of valproic acid.
In human hepatocytes in culture, levetiracetam had little or no effect on CYP1A2, SULT1E1 or
UGT1A1. Levetiracetam caused mild induction of CYP2B6 and CYP3A4. The in vitro data and in
vivo interaction data on oral contraceptives, digoxin and warfarin indicate that no significant enzyme
induction is expected in vivo. Therefore, the interaction of Keppra with other substances, or
vice versa,
is unlikely.
Elimination
The plasma half-life in adults was 7±1 hours and did not vary either with dose, route of administration
or repeated administration. The mean total body clearance was 0.96 ml/min/kg.
The major route of excretion was via urine, accounting for a mean 95 % of the dose (approximately
93 % of the dose was excreted within 48 hours). Excretion
via
faeces accounted for only 0.3 % of the
dose.
The cumulative urinary excretion of levetiracetam and its primary metabolite accounted for 66 % and
24 % of the dose, respectively during the first 48 hours.
The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml/min/kg respectively indicating
that levetiracetam is excreted by glomerular filtration with subsequent tubular reabsorption and that
the primary metabolite is also excreted by active tubular secretion in addition to glomerular filtration.
Levetiracetam elimination is correlated to creatinine clearance.
Elderly
In the elderly, the half-life is increased by about 40 % (10 to 11 hours). This is related to the decrease
in renal function in this population (see section 4.2).
Renal impairment
The apparent body clearance of both levetiracetam and of its primary metabolite is correlated to the
creatinine clearance. It is therefore recommended to adjust the maintenance daily dose of Keppra,
based on creatinine clearance in patients with moderate and severe renal impairment (see section 4.2).
In anuric end-stage renal disease adult subjects the half-life was approximately 25 and 3.1 hours
during interdialytic and intradialytic periods, respectively.
The fractional removal of levetiracetam was 51 % during a typical 4-hour dialysis session.
Hepatic impairment
In subjects with mild and moderate hepatic impairment, there was no relevant modification of the
clearance of levetiracetam. In most subjects with severe hepatic impairment, the clearance of
levetiracetam was reduced by more than 50 % due to a concomitant renal impairment (see section 4.2).
Peadiatric population
43
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 AED.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, genotoxicity and carcinogenicity.
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 effects on male or female fertility or reproduction performance were observed in rats at
doses up to 1800 mg/kg/day (x 6 the MRHD on a mg/m2 or exposure basis) in parents and F1
generation.
Two embryo-fetal development (EFD) studies were performed in rats at 400, 1200 and
3600 mg/kg/day. At 3600 mg/kg/day, in only one of the 2 EFD studies, there was a slight decrease in
fetal weight associated with a marginal increase in skeletal variations/minor anomalies. There was no
effect on 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-fetal development studies were performed in rabbits covering doses of 200, 600, 800,
1200 and 1800 mg/kg/day. The dose level of 1800 mg/kg/day induced a marked maternal toxicity and
a decrease in fetal weight associated with increased incidence of fetuses with cardiovascular/skeletal
anomalies. The NOAEL was <200 mg/kg/day for the dams and 200 mg/kg/day for the fetuses (equal
to the MRHD on a mg/m2 basis).
44
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.
6.1 List of excipients
Core:
Croscarmellose sodium
Macrogol 6000
Silica colloidal anhydrous.
Magnesium stearate
Film-coating
Opadry 85F23452:
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 and 200 (2 x
100) film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
UCB Pharma SA
Allée de la Recherche 60
B-1070 Brussels
Belgium
45
8.
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
9.
Date of first authorisation: 29 September 2000
Date of last renewal: 08 July 2005
Detailed information on this medicinal product is available on the website of the European Medicines
Agency
http://www.ema.europa.eu
46
1.
FURTHER INFORMATION
What Keppra contains
The active substance is called levetiracetam. Each ml of solution for infusion 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 (Keppra concentrate) is a clear, colourless, sterile liquid.
Keppra concentrate 5 ml vial is packed in a cardboard box of 10 vials.
Marketing Authorisation Holder and Manufacturer
Marketing Authorisation Holder: UCB Pharma SA, Allée de la Recherche 60, B-1070 Brussels,
Belgium.
Manufacturers: UCB Pharma SA, Chemin du Foriest, B-1420 Braine-l’Alleud, Belgium
or
UCB Pharma S.p.A., Via Praglia, 15, I-10044 Pianezza, Italy.
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
Luxembourg/Luxemburg
UCB Pharma SA/NV
Tél/Tel: + 32 / (0)2 559 92 00
България
Ю СИ БИ България ЕООД
Teл.: + 359 (0) 2 962 30 49
Magyarország
UCB Magyarország Kft.
Tel.: + 36-(1) 391 0060
Česká republika
UCB s.r.o.
Tel: + 420 221 773 411
Malta
Pharmasud Ltd.
Tel: +356 / 21 37 64 36
Danmark
Nederland
162
UCB Nordic A/S
Tlf: + 45 / 32 46 24 00
UCB Pharma B.V.
Tel.: + 31 / (0)76-573 11 40
Deutschland
UCB Pharma GmbH
Tel: + 49 /(0) 2173 48 4847
Norge
UCB Nordic A/S
Tlf: +45 / 32 46 24 00
Eesti
UCB Pharma Oy Finland
Tel: +358 10 234 6800 (Soome)
Österreich
UCB Pharma GmbH
Tel: + 43 (1) 291 80 00
Ελλάδα
UCB Α.Ε.
Τηλ: + 30 / 2109974000
Polska
UCB Pharma Sp. z o.o.
Tel.: + 48 22 696 99 20
España
UCB Pharma, S.A.
Tel: + 34 / 91 570 34 44
Portugal
UCB Pharma (Produtos Farmacêuticos), Lda
Tel: + 351 / 21 302 5300
France
UCB Pharma S.A.
Tél: + 33 / (0)1 47 29 44 35
România
UCB Pharma România 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 10 234 6800
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 10 234 6800 (Somija)
United Kingdom
UCB Pharma Ltd.
Tel : + 44 / (0)1753 534 655
Lietuva
UCB Pharma Oy Finland
Tel: + 358 10 234 6800 (Suomija)
This leaflet was last approved in
Detailed information on this medicine is available on the European Medicines Agency web site:
http://www.ema.europa.eu
----------------------------------------------------------------------------------------------------------------------------
163
The following information is intended for doctor and nurses only
:
Direction 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 (0.9%) injection
• Lactated Ringer’s injection
• Dextrose 5% injection
164
ANNEX IV
GROUNDS FOR ONE ADDITIONAL RENEWAL
165
Grounds for one additional renewal
Based upon the data that have become available since the last renewal of the Marketing Authorisation,
the CHMP considers that the benefit-risk balance of Keppra remains positive, but considers that its
safety profile is to be closely monitored for the following reasons:
Keppra has been authorised for children from 4 years old (approved September 2005) and more
recently for children from 1 month to 4 years old (approved September 2009). Due to the recent
addition of these sensitive populations to the therapeutic indication, limited safety information is
available in these age groups. The CHMP considers that more safety experience needs to be gained in
children, and decided that the MAH should continue to submit yearly PSURs and 6-monthly specific
safety reports for children < 4 years old in between yearly PSURs.
Therefore, based upon the safety profile of Keppra, which requires the submission of yearly PSURs
and 6-monthly specific safety reports for children < 4 years old in between yearly PSURs, the CHMP
concluded that the MAH should submit one additional renewal application in 5 years time.
166
Source: European Medicines Agency
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