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LEVETIRACETAM DESITIN 750MG COATED GRANULES IN SACHET

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Levetiracetam Desitin 750 mg coated granules

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each sachet contains 750 mg levetiracetam.
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM
Coated granules in sachet
Sachets with white or almost white, round, coated granules (diameter approx. 2 mm).

4

CLINICAL PARTICULARS

4.1

Therapeutic indications
Levetiracetam Desitin is indicated as monotherapy in the treatment of partial onset
seizures with or without secondary generalisation in adults and adolescents from 16
years of age with newly diagnosed epilepsy.
Levetiracetam Desitin is indicated as adjunctive therapy
• in the treatment of partial onset seizures with or without secondary generalisation
in adults, adolescents, children and infants from 1 month of age with epilepsy.
• in the treatment of myoclonic seizures in adults and adolescents from 12 years of
age with Juvenile Myoclonic Epilepsy.


4.2

in the treatment of primary generalised tonic-clonic seizures in adults and
adolescents from 12 years of age with Idiopathic Generalised Epilepsy.

Posology and method of administration
Posology
• Monotherapy for adults and adolescents from 16 years of age

The recommended starting dose is 250 mg twice daily which should be increased to
an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be
further increased by 250 mg twice daily every two weeks depending upon the clinical
response. The maximum dose is 1,500 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)
Adjustment of the dose is recommended in elderly patients with compromised renal
function (see “Renal impairment” below).

Renal impairment
The daily dose must be individualised according to renal function.
For adult patients, refer to the following table and adjust the dose as indicated. To use
this dosing table, an estimate of the patient's creatinine clearance (CLcr) in ml/min is
needed. The CLcr in ml/min may be estimated from serum creatinine (mg/dl)
determination, for adults and adolescents weighting 50 kg or more, using the
following formula:

Then CLcr is adjusted for body surface area (BSA) as follows:

Table 1: Dosing adjustment for adult and adolescent patients weighing more
than 50 kg with impaired renal function

Group
Normal
Mild
Moderate
Severe
End-stage renal disease
patients undergoing dialysis

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

Dose and frequency
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)
(1)

A 750 mg loading dose is recommended on the first day of treatment with
levetiracetam.
(2)

Following dialysis, a 250 to 500 mg supplemental dose is recommended.

For children with renal impairment, levetiracetam dose needs to be adjusted based on
the renal function as levetiracetam clearance is related to renal function. This
recommendation is based on a study in adult renally impaired patients.
The CLcr in ml/min/1.73 m² may be estimated from serum creatinine (mg/dl)
determination, for young adolescents, children and infants, using the following
formula (Schwartz formula):

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

Table 2: Dosing adjustment for infants, children and adolescent patients
weighing less than 50 kg with impaired renal function

Group

Creatinine
clearance
(ml/min/1.73m²)

Normal

> 80

Mild

50-79

Moderate

30-49

Severe

< 30

End-stage renal
disease patients
undergoing dialysis

--

(1)

Dose and frequency (1)
Infants 1 to less than 6
Infants 6 to 23 months,
months
children and adolescents
weighing less than 50 kg
7 to 21 mg/kg (0.07 to
10 to 30 mg/kg (0.10 to
0.21 ml/kg) twice daily
0.30 ml/kg)twice daily
7 to 14 mg/kg (0.07 to
10 to 20 mg/kg (0.10 to
0.14 ml/kg) twice daily
0.20 ml/kg) twice daily
3.5 to 10.5 mg/kg (0.035 5 to 15 mg/kg (0.05 to 0.15
to 0.105 ml/kg) twice
ml/kg) twice daily
daily
3.5 to 7 mg/kg (0.035 to 5 to 10 mg/kg (0.05 to 0.10
0.07 ml/kg) twice daily
ml/kg) twice daily
10 to 20 mg/kg (0.10 to
7 to 14 mg/kg (0.07 to
0.14 ml/kg) once daily (2) 0.20 ml/kg)once daily (3) (5)
(4)

Levetiracetam oral solution should be used for doses under 250 mg.
A 10.5 mg/kg (0.105 ml/kg) loading dose is recommended on the first day
of treatment with levetiracetam.
(2)

(3)

A 15 mg/kg (0.15 ml/kg) loading dose is recommended on the first day of
treatment with levetiracetam.
(4)

Following dialysis, a 3.5 to 7 mg/kg (0.035 to 0.07 ml/kg) supplemental
dose is recommended.
(5)

Following dialysis, a 5 to 10 mg/kg (0.05 to 0.10 ml/kg) supplemental dose is
recommended.
Hepatic impairment
No dose adjustment is needed in patients with mild to moderate hepatic impairment.
In patients with severe hepatic impairment, the creatinine clearance may
underestimate the renal insufficiency. Therefore a 50 % reduction of the daily
maintenance dose is recommended when the creatinine clearance is < 60 ml/min/1.73
m².

Paediatric population

The physician should prescribe the most appropriate pharmaceutical form and
strength according to age, weight and dose.

The coated granules formulation is not adapted for use in infants and children
under the age of 6 years. Levetiracetam oral solution is the preferred
formulation for use in this population. In addition, the available dose strengths
of the coated granules in sachet are not appropriate for initial treatment in
children weighing less than 25 kg or for the administration of doses below 250
mg. In all of the above cases levetiracetam oral solution should be used.
Monotherapy
The safety and efficacy of levetiracetam in children and adolescents below 16 years
as monotherapy treatment have not been established.
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

Levetiracetam oral solution is the preferred formulation for use in infants and
children under the age of 6 years.
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.

Table 3: Dose recommendations for infants from 6 months of age, children and
adolescents
Weight
6 kg (1)
10 kg (1)
15 kg (1)
20 kg (1)
25 kg
From 50 kg (2)

Starting dose:
10 mg/kg twice daily
60 mg (0.6 ml) twice daily
100 mg (1 ml) twice daily
150 mg (1.5 ml) twice daily
200 mg (2 ml) twice daily
250 mg twice daily
500 mg twice daily

Maximum dose:
30 mg/kg twice daily
180 mg (1.8 ml) twice daily
300 mg (3 ml) twice daily
450 mg (4.5 ml) twice daily
600 mg (6 ml) twice daily
750 mg twice daily
1,500 mg twice daily

(1) )

Children 25 kg or less should preferably start the treatment with
levetiracetam oral solution.
(2)

Dose in children and adolescents 50 kg or more is the same as in adults.

Add-on therapy for infants aged from 1 month to less than 6 months
The oral solution is the formulation to use in infants.
Method of administration
The coated granules 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.
The coated granules may also be suspended by shaking for a minimum of 2 minutes
in at least 10 ml of water and administered via a feeding tube that should be rinsed
twice with 10 ml of water each immediately after administration. If this method of
administration is used, the suspension should be prepared immediately before
administration.
Each sachet is for single use only.

4.3

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

4.4

Special warnings and precautions for use
Discontinuation
In accordance with current clinical practice, if Levetiracetam Desitin 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 Levetiracetam Desitin 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 coated granules formulation is not adapted for use in infants and children
under the age of 6 years.

Available data in children did not suggest impact on growth and puberty. However,
long term effects on learning, intelligence, growth, endocrine function, puberty and
childbearing potential in children remain unknown.
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.

4.5

Interaction with other medicinal products and other forms of interaction
Antiepileptic medicinal products
Pre-marketing data from clinical studies conducted in adults indicate that
levetiracetam did not influence the serum concentrations of existing antiepileptic
medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital,
lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal
products did not influence the pharmacokinetics of levetiracetam.

As in adults, there is no evidence of clinically significant medicinal product
interactions in paediatric patients receiving up to 60 mg/kg/day levetiracetam.
A retrospective assessment of pharmacokinetic interactions in children and
adolescents with epilepsy (4 to 17 years) confirmed that adjunctive therapy with
orally administered levetiracetam did not influence the steady-state serum
concentrations of concomitantly administered carbamazepine and valproate.
However, data suggested a 20 % higher levetiracetam clearance in children taking
enzyme-inducing antiepileptic medicinal products. Dose adjustment is not required.
Probenecid
Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has
been shown to inhibit the renal clearance of the primary metabolite, but not of
levetiracetam. Nevertheless, the concentration of this metabolite remains low. 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 pharmacokinetic interactions
Levetiracetam 1,000 mg daily did not influence the pharmacokinetics of oral
contraceptives (ethinylestradiol and levonorgestrel); endocrine parameters
(luteinizing hormone and progesterone) were not modified. Levetiracetam 2,000 mg
daily did not influence the pharmacokinetics of digoxin and warfarin; prothrombin
times were not modified. 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.

4.6

Fertility, pregnancy and lactation
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.
Levetiracetam Desitin 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 breast-feeding,
the benefit/risk of the treatment should be weighed considering the importance of
breast-feeding.
Fertility
No impact on fertility was detected in animal studies (see section 5.3). No clinical
data are available, potential risk for human is unknown.

4.7

Effects on ability to drive and use machines
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.

4.8

Undesirable effects
Summary of the safety profile

The adverse event profile presented below is based on the analysis of pooled
placebo-controlled clinical trials with all indications studied, with a total of
3,416 patients treated with levetiracetam. These data are supplemented with
the use of levetiracetam in corresponding open-label extension studies, as well
as post-marketing experience. The most frequently reported adverse reactions
were nasopharyngitis, somnolence, headache, fatigue and dizziness. The safety
profile of levetiracetam is generally similar across age groups (adult and
paediatric patients) and across the approved epilepsy indications.

Tabulated list of adverse reactions

Adverse reactions reported in clinical studies (adults, adolescents, children and
infants > 1 month) and from post-marketing experience are listed in the following
table per System Organ Class and per frequency. 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) and very rare (<1/10,000).





Nervous system
disorders



Infections and
infestations
Blood and
lymphatic system
disorders
Metabolism and
nutrition
disorders
Psychiatric
disorders

Very common
Nasopharyngitis

Common



MedDRA SOC

Frequency category
Uncommon

Thrombocytopenia,
leukopenia
Anorexia

Somnolence,
headache

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

Convulsion, balance
disorder, dizziness,
lethargy, tremor

Eye disorders
Ear and labyrinth
disorders
Respiratory,
thoracic and
mediastinal
disorders
Gastrointestinal
disorders
Hepatobiliary
disorders
Skin and
subcutaneous
tissue disorders

Musculoskeletal
and connective
tissue disorders
General disorders
and
administration
site conditions

Pancytopenia,
neutropenia

Weight decreased,
weight increase

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

Rare
Infection

Completed
suicide,
personality
disorder, thinking
abnormal

Choreoathetosis,
dyskinesia,
hyperkinesia

Vertigo
Cough

Pancreatitis

Abdominal pain,
diarrhoea, dyspepsia,
vomiting, nausea

Rash

Liver function test
abnormal
Alopecia, eczema,
pruritus,

Muscular weakness,
myalgia
Asthenia/fatigue

Hepatic failure,
hepatitis
Toxic epidermal
necrolysis,
Stevens-Johnson
syndrome,
erythema
multiforme

Injury, poisoning
and procedural
complications

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.

Bone marrow suppression was identified in some of the cases of pancytopenia.

Paediatric population
.

In patients aged 1 month to less than 4 years, a total of 190 patients have been
treated with levetiracetam in placebo-controlled and open label extension
studies. Sixty (60) of these patients were treated with levetiracetam in placebocontrolled studies. In patients aged 4-16 years, a total of 645 patients have
been treated with levetiracetam in placebo-controlled and open label extension
studies. 233 of these patients were treated with levetiracetam in placebocontrolled studies. In both these paediatric age ranges, these data are
supplemented with the post-marketing experience of the use of levetiracetam.
The adverse event profile of levetiracetam is generally similar across age
groups and across the approved epilepsy indications. Safety results in
paediatric patients in placebo-controlled clinical studies were consistent with
the safety profile of levetiracetam in adults except for behavioural and
psychiatric adverse reactions which were more common in children than in
adults. In children and adolescents aged 4 to 16 years, vomiting (very
common, 11.2%), agitation (common, 3.4%), mood swings (common, 2.1%),
affect lability (common, 1.7%), aggression (common, 8.2%), abnormal
behaviour (common, 5.6%), and lethargy (common, 3.9%) were reported more
frequently than in other age ranges or in the overall safety profile. In infants
and children aged 1 month to less than 4 years, irritability (very common,
11.7%) and coordination abnormal (common, 3.3%) were reported more
frequently than in other age groups or in the overall safety profile.
A double-blind, placebo-controlled paediatric safety study with a non-inferiority
design has assessed the cognitive and neuropsychological effects of levetiracetam in
children 4 to 16 years of age with partial onset seizures. It was concluded that
levetiracetam was not different (non inferior) from placebo with regard to the change
from baseline of the Leiter-R Attention and Memory, Memory Screen Composite
score in the per-protocol population. Results related to behavioural and emotional
functioning indicated a worsening in levetiracetam treated patients on aggressive
behaviour as measured in a standardized and systematic way using a validated
instrument (CBCL – Achenbach Child Behavior Checklist).

However subjects, who took levetiracetam in the long-term open label follow-up
study, did not experience a worsening, on average, in their behavioural and emotional
functioning; in particular measures of aggressive behaviour were not worse than
baseline.

4.9

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

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties
Pharmacotherapeutic group: antiepileptics, other antiepileptics
ATC code: N03AX14.
The active substance, levetiracetam, is a pyrrolidone derivative (S-enantiomer of ethyl-2-oxo-1-pyrrolidine acetamide), chemically unrelated to existing antiepileptic
active substances.

α

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 -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

β

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, placebocontrolled studies at 1000 mg, 2000 mg, or 3000 mg/day, given in 2 divided doses,
with a treatment duration of up to 18 weeks. In a pooled analysis, the percentage of
patients who achieved 50 % or greater reduction from baseline in the partial onset
seizure frequency per week at stable dose (12/14 weeks) was of 27.7 %, 31.6 % and
41.3 % for patients on 1000, 2000 or 3000 mg levetiracetam respectively and of
12.6 % for patients on placebo.
Paediatric population:
In paediatric patients (4 to 16 years of age), levetiracetam efficacy was established in
a double-blind, placebo-controlled study, which included 198 patients and had a
treatment duration of 14 weeks. In this study, the patients received levetiracetam as a
fixed dose of 60 mg/kg/day (with twice a day dosing).
44.6 % of the levetiracetam treated patients and 19.6 % of the patients on placebo had
a 50 % or greater reduction from baseline in the partial onset seizure frequency per
week. With continued long-term treatment, 11.4 % of the patients were seizure-free
for at least 6 months and 7.2 % were seizure-free for at least 1 year.
In paediatric patients (1 month to less than 4 years of age), levetiracetam efficacy was
established in a double-blind, placebo-controlled study, which included 116 patients
and had a treatment duration of 5 days. In this study, patients were prescribed 20
mg/kg, 25 mg/kg, 40 mg/kg or 50 mg/kg daily dose of oral solution based on their age
titration schedule. A dose of 20 mg/kg/day titrating to 40 mg/kg/day for infants one
month to less than six months and a dose of 25 mg/kg/day titrating to 50 mg/kg/day
for infants and children 6 months to less than 4 years old, was use in this study. The
total daily dose was administered 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 seizurefree 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, noninferiority 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 tonicclonic 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 longterm treatment, 28.6 % of the patients were free of myoclonic seizures for at least 6
months and 21.0 % were free of myoclonic seizures for at least 1 year.
Adjunctive therapy in the treatment of primary generalised tonic-clonic seizures in
adults and adolescents from 12 years of age with idiopathic generalised epilepsy.
Levetiracetam efficacy was established in a 24-week double-blind, placebo-controlled
study which included adults, adolescents and a limited number of children suffering

from idiopathic generalized epilepsy with primary generalized tonic-clonic (PGTC)
seizures in different syndromes (juvenile myoclonic epilepsy, juvenile absence
epilepsy, childhood absence epilepsy, or epilepsy with Grand Mal seizures on
awakening). In this study, levetiracetam dose was 3000 mg/day for adults and
adolescents or 60 mg/kg/day for children, given in 2 divided doses.
72.2 % of the levetiracetam treated patients and 45.2 % of the patients on placebo had
a 50 % or greater decrease in the frequency of PGTC seizures per week. With
continued long-term treatment, 47.4 % of the patients were free of tonic-clonic
seizures for at least 6 months and 31.5 % were free of tonic-clonic seizures for at least
1 year.

5.2

Pharmacokinetic properties
Levetiracetam is a highly soluble and permeable compound. Levetiracetam is rapidly
absorbed after oral administration with a close to complete absolute bioavailability.
The pharmacokinetics and bioequivalence of Levetiracetam Desitin 1000 mg coated
granules in sachet and Levetiracetam Desitin 1500 mg coated granules in sachet were
investigated in two studies in healthy volunteer subjects. In a first study,
Levetiracetam Desitin 1000 mg coated granules in sachet was compared with filmcoated reference tablets containing 1000 mg Levetiracetam. In a second study,
Levetiracetam Desitin 1500 mg coated granules in sachet was compared with two
film-coated reference tablets containing 750 mg Levetiracetam. Both studies were
carried out in 16 healthy volunteers (each time eight females and eight males)
according to an open-label, controlled crossover design with randomly assigned
sequences. Each subject was studied on two occasions at least one week apart for
washout purposes. Based on the plasma pharmacokinetics of Levetiracetam after the
oral administration of Levetiracetam Desitin 1000 mg coated granules in sachet and
Levetiracetam Desitin 1500 mg coated granules in sachet, Levetiracetam Desitin
coated granules in sachet were evidenced to be bioequivalent with the reference filmcoated tablets (Table 4).
The time courses of the plasma concentrations were almost superimposable (Figure
1). Levetiracetam Desitin 1000 mg coated granules in sachet were bioequivalent with
the film-coated reference tablets with regard to the maximum exposure (Cmax) and
total exposure (AUC) to Levetiracetam: the 90% confidence intervals of the ratios for
test to reference were 90 to 113% and 97 to 106%, respectively. Levetiracetam
Desitin 1500 mg coated granules in sachet were bioequivalent with the film-coated
reference tablets with regard to the maximum exposure (Cmax) and total exposure
(AUC) to Levetiracetam: the 90% confidence intervals of the ratios for test to
reference were 89 to103 % and 97 to 104%, respectively. There were no relevant
differences with regard to the time to reach Cmax (tmax) and the half-life (t½).
Table 4: Mean values of the pharmacokinetics of Levetiracetam after single oral
doses of 1000 mg and 1500 mg Levetiracetam Desitin coated granules in sachet
and the reference film-coated tablets

Single doses of 1000 mg
Levetiracteam

Single doses of 1500 mg
Levetiracteam

Levetiracetam
Desitin coated
granules in
sachet
Cmax
tmax
AUC(0tz)
AUC(0∞)


µg/ml
min
µg.h/ml

Film-coated
reference
tablets

42.0

Levetiracetam
Desitin coated
granules in
sachet

Film-coated
reference
tablets

64.6

448.4

461.4

264.7

35

450.6

35

67.3

35

41.7
40

458.8

262.2

µg.h/ml

271.7
268.4
6.58

6.90

h

6.65

6.61

Legend: geometric mean of Cmax, AUC(0-tz), and AUC(0-∞), arithmetic mean of t½
and median of tmax for single oral doses of 1000 (first study) and 1500 mg
Levetiracetam (second study) by means of Levetiracetam Desitin coated granules in
sachet and the reference film-coated tablets

Figure 1: Time courses of the geometric mean plasma concentrations of
Levetiracetam after single oral doses of 1000 mg and 1500 mg Levetiracetam
Desitin coated granules in sachet and the reference film-coated tablets
Time course of the geometric mean concentra

Time course of the geometric mean concentra
60000

40000

Treatment
Treatment

Treatment
Treatment

50000

concentrations [ng/mL]

concentrations [ng/mL]

30000

20000

40000

30000

20000

10000
10000

0

0
0

6

12

18

24

Time after dosing [hours]

30

0

6

12

18

24

30

Time after dosing [hours]

Legend: time courses of the geometric mean plasma concentrations of Levetiracetam
after single oral doses of 1000 (first study: left panel) and 1500 mg Levetiracetam
(second study: right panel) by means of Levetiracetam Desitin coated granules in
sachet ( ) and film-coated reference tablets ( ).
The pharmacokinetic profile is linear with low intra- and inter-subject variability.
There is no modification of the clearance after repeated administration. There is no
evidence for any relevant gender, race or circadian variability. The pharmacokinetic
profile is comparable in healthy volunteers and in patients with epilepsy.
Due to its complete and linear absorption, plasma levels can be predicted from the
oral dose of levetiracetam expressed as mg/kg bodyweight. Therefore there is no need
for plasma level monitoring of levetiracetam.

A significant correlation between saliva and plasma concentrations has been shown in
adults and children (ratio of saliva/plasma concentrations ranged from 1 to 1.7 for
oral tablet formulation and after 4 hours post-dose for oral solution formulation).
Adults and adolescents
Absorption
Levetiracetam is rapidly absorbed after oral administration. Oral absolute
bioavailability is close to 100 %. Peak plasma concentrations (Cmax) are achieved at
1.3 hours after dosing. Steady-state is achieved after two days of a twice daily
administration schedule. Peak concentrations (Cmax) are typically 31 and 43 g/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.

μ

Distribution
No tissue distribution data are available in humans.
Neither levetiracetam nor its primary metabolite are significantly bound to plasma
proteins (< 10 %).
The volume of distribution of levetiracetam is approximately 0.5 to 0.7 l/kg, a value
close to the total body water volume.
Biotransformation
Levetiracetam is not extensively metabolised in humans. The major metabolic
pathway (24 % of the dose) is an enzymatic hydrolysis of the acetamide group.
Production of the primary metabolite, ucb L057, is not supported by liver cytochrome
P450 isoforms. Hydrolysis of the acetamide group was measurable in a large number
of tissues including blood cells. The metabolite ucb L057 is pharmacologically
inactive.
Two minor metabolites were also identified. One was obtained by hydroxylation of
the pyrrolidone ring (1.6 % of the dose) and the other one by opening of the
pyrrolidone ring (0.9 % of the dose). Other unidentified components accounted only
for 0.6 % of the dose.
No enantiomeric interconversion was evidenced in vivo for either levetiracetam or its
primary metabolite.
In vitro, levetiracetam and its primary metabolite have been shown not to inhibit the
major human liver cytochrome P450 isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1
and 1A2), glucuronyl transferase (UGT1A1 AND UGT1A6) and epoxide

hydroxylase activities. In addition, levetiracetam does not affect the in vitro
glucuronidation of valproic acid.
In human hepatocytes in culture, levetiracetam had little or no effect on CYP1A2,
SULT1E1 or UGT1A1. Levetiracetam caused mild induction of CYP2B6 and
CYP3A4. The in vitro data and in vivo interaction data on oral contraceptives,
digoxin and warfarin indicate that no significant enzyme induction is expected in
vivo. Therefore, the interaction of levetiracetam with other substances, or vice versa,
is unlikely.
Elimination
The plasma half-life in adults was 7±1 hours and did not vary either with dose, route
of administration or repeated administration. The mean total body clearance was 0.96
ml/min/kg.
The major route of excretion was via urine, accounting for a mean 95 % of the dose
(approximately 93 % of the dose was excreted within 48 hours). Excretion via faeces
accounted for only 0.3 % of the dose.
The cumulative urinary excretion of levetiracetam and its primary metabolite
accounted for 66 % and 24 % of the dose, respectively during the first 48 hours.
The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml/min/kg
respectively indicating that levetiracetam is excreted by glomerular filtration with
subsequent tubular reabsorption and that the primary metabolite is also excreted by
active tubular secretion in addition to glomerular filtration. Levetiracetam elimination
is correlated to creatinine clearance.
Elderly
In the elderly, the half-life is increased by about 40 % (10 to 11 hours). This is related
to the decrease in renal function in this population (see section 4.2).
Renal impairment
The apparent body clearance of both levetiracetam and of its primary metabolite is
correlated to the creatinine clearance. It is therefore recommended to adjust the
maintenance daily dose of Levetiracetam Desitin, based on creatinine clearance in
patients with moderate and severe renal impairment (see section 4.2).
In anuric end-stage renal disease adult subjects the half-life was approximately 25 and
3.1 hours during interdialytic and intradialytic periods, respectively.
The fractional removal of levetiracetam was 51 % during a typical 4-hour dialysis
session.
Hepatic impairment

In subjects with mild and moderate hepatic impairment, there was no relevant
modification of the clearance of levetiracetam. In most subjects with severe hepatic
impairment, the clearance of levetiracetam was reduced by more than 50 % due to a
concomitant renal impairment (see section 4.2).
Paediatric population
Children (4 to 12 years)
Following single oral dose administration (20 mg/kg) to epileptic children (6 to 12
years), the half-life of levetiracetam was 6.0 hours. The apparent body weight
adjusted clearance was approximately 30 % higher than in epileptic adults.
Following repeated oral dose administration (20 to 60 mg/kg/day) to epileptic
children (4 to 12 years), levetiracetam was rapidly absorbed. Peak plasma
concentration was observed 0.5 to 1.0 hour after dosing. Linear and dose proportional
increases were observed for peak plasma concentrations and area under the curve.
The elimination half-life was approximately 5 hours. The apparent body clearance
was 1.1 ml/min/kg.
Infants and children (1 month to 4 years)
Following single dose administration (20 mg/kg) of a 100 mg/ml oral solution to
epileptic children (1 month to 4 years), levetiracetam was rapidly absorbed and peak
plasma concentrations were observed approximately 1 hour after dosing. The
pharmacokinetic results indicated that half-life was shorter (5.3 h) than for adults (7.2
h) and apparent clearance was faster (1.5 ml/min/kg) than for adults (0.96 ml/min/kg).
In the population pharmacokinetic analysis conducted in patients from 1 month to 16
years of age, body weight was significantly correlated to apparent clearance
(clearance increased with an increase in body weight) and apparent volume of
distribution. Age also had an influence on both parameters. This effect was
pronounced for the younger infants, and subsided as age increased, to become
negligible around 4 years of age.
In both population pharmacokinetic analyses, there was about a 20 % increase of
apparent clearance of levetiracetam when it was co-administered with an enzymeinducing 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/m²basis) 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).

Environmental Risk Assessment (ERA)
The use of Levetiracetam Desitin in accordance with the product information
is not likely to result in an unacceptable
environmental impact (see section 6.6).

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients
Povidone K30
Cellulose, microcrystalline
Silica, colloidal anhydrous
Magnesium stearate

Poly(vinyl alcohol)
Titanium dioxide (E 171)
Macrogol 3350
Talc

6.2

Incompatibilities
Not applicable.

6.3

Shelf life
3 years.

6.4

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

6.5

Nature and contents of container
Paper/Alu/PE sachets
Pack size of 20, 50, 60, 100, 200 sachets
Not all pack sizes may be marketed.

6.6

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

7

MARKETING AUTHORISATION HOLDER
Desitin Arzneimittel GmbH
Weg beim Jäger 214
22335 Hamburg
Germany

8

MARKETING AUTHORISATION NUMBER(S)
PL 14040/0022

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
08/07/2011

10

DATE OF REVISION OF THE TEXT
05/04/2013

Expand Transcript

Source: Medicines and Healthcare Products Regulatory Agency

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

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