ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Zebinix 400 mg tablets
2.
Each tablet contains 400 mg of eslicarbazepine acetate.
For a full list of excipients, see section 6.1.
3.
Tablet.
White circular biconvex tablets, engraved ‘ESL 400’on one side and scored on the other side. The scoreline
is only to facilitate breaking for ease of swallowing and not to divide into equal doses.
4.
Zebinix is indicated as adjunctive therapy in adults with partial-onset seizures with or without secondary
generalisation.
Zebinix must be added to existing anticonvulsant therapy. The recommended starting dose is 400 mg once
daily which should be increased to 800 mg once daily after one or two weeks. Based on individual response,
the dose may be increased to 1200 mg once daily (see section 5.1).
Zebinix may be taken with or without food.
Elderly (over 65 years of age
)
Caution should be exercised in the treatment of elderly patients as there is limited safety information on the
use of Zebinix in these patients.
Paediatric population
Zebinix is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.
Patients with renal impairment
Caution should be exercised in the treatment of patients with renal impairment and the dose should be
adjusted according to creatinine clearance (CL
CR
) as follows:
- CL
CR
>60 ml/min: no dose adjustment required
- CL
CR
30-60 ml/min: initial dose of 400 mg every other day for 2 weeks followed by a once daily dose of
400 mg. However, based on individual response, the dose may be increased.
- CL
CR
<30 ml/min: use is not recommended in patients with severe renal impairment due to insufficient
data
Patients with hepatic impairment
No dose adjustment is needed in patients with mild to moderate hepatic impairment.
The pharmacokinetics of eslicarbazepine has not been evaluated in patients with severe hepatic impairment
(see section 4.4 and 5.2) and use in these patients is therefore not recommended.
2
Hypersensitivity to the active substance, to other carboxamide derivatives (e.g. carbamazepine,
oxcarbazepine) or to any of the excipients.
Known second or third degree atrioventricular (AV) block.
Zebinix has been associated with some central nervous system adverse reactions, such as dizziness and
somnolence, which could increase the occurrence of accidental injury.
Zebinix may decrease the effectiveness of hormonal contraceptives. Additional non-hormonal forms of
contraception are recommended when using Zebinix (see section 4.5 and 4.6).
As with other anti-epileptic medicinal products, if Zebinix is to be discontinued it is recommended to
withdraw it gradually to minimise the potential of increased seizure frequency.
Concomitant use of Zebinix with oxcarbazepine is not recommended because this may cause overexposure to
the active metabolites.
There is no experience regarding the withdrawal of concomitant use of anti-epileptic medicinal products
during treatment with Zebinix (switch to monotherapy).
Rash developed as an adverse reaction in 1.1% of total population treated with Zebinix in placebo-controlled
add-on studies in epileptic patients. If signs or symptoms of hypersensitivity develop, Zebinix must be
discontinued.
No cases of serious cutaneous reactions have been reported with eslicarbazepine acetate. Presence of
HLA-B*1502 allele in individuals of Han Chinese and Thai origin has been shown to be strongly associated
with the risk of developing Stevens-Johnson syndrome (SJS) when treated with carbamazepine. Therefore,
whenever possible, subjects of Han Chinese and Thai origin should be screened for this allele before starting
treatment with carbamazepine or chemically-related compounds. The presence of HLA-B*1502 allele in
other ethnicities is negligible. The allele HLA-B*1502 is not associated to SJS in the Caucasian population.
Hyponatraemia has been reported as an adverse reaction in less than 1% of patients treated with Zebinix.
Hyponatraemia is asymptomatic in most cases, however, it may be accompanied by clinical symptoms like
worsening of seizures, confusion, decreased consciousness. Frequency of hyponatraemia increased with
increasing eslicarbazepine acetate dose. In patients with pre-existing renal disease leading to hyponatraemia,
or in patients concomitantly treated with medicinal products which may themselves lead to hyponatraemia
(e.g. diuretics, desmopressin), serum sodium levels should be examined before and during treatment with
eslicarbazepine acetate. Furthermore, serum sodium levels should be determined if clinical signs of
hyponatraemia occur. Apart from this, sodium levels should be determined during routine laboratory
examination. If clinically relevant hyponatraemia develops, Zebinix should be discontinued.
The influence of Zebinix on primary generalised seizures has not been studied. Use is therefore not
recommended in these patients.
Prolongations in PR interval have been observed in clinical studies with eslicarbazepine acetate.
Caution should be exercised in patients with medical conditions (e.g. low levels of thyroxine, cardiac
conduction abnormalities), or when taking concomitant medicinal products
known to be associated with PR
prolongation.
Caution should be exercised in the treatment of patients with renal impairment and the dose should be
adjusted according to creatinine clearance (see section 4.2). In patients with CL
CR
<30 ml/min use is not
recommended due to insufficient data.
3
As clinical data are limited in patients with mild to moderate hepatic impairment and pharmacokinetic and
clinical data are missing in patients with severe hepatic impairment, Zebinix should be used with caution in
patients with mild to moderate hepatic impairment and is not recommended in patients with severe hepatic
impairment.
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic active substances in
several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic medicinal
products has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this
risk is not known and the available data do not exclude the possibility of an increased risk for eslicarbazepine
acetate. Therefore patients should be monitored for signs of 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 suicidal ideation or behaviour emerge.
Interaction studies have only been performed in adults.
Eslicarbazepine acetate is extensively converted to eslicarbazepine, which is mainly eliminated by
glucuronidation.
In vitro
eslicarbazepine is a weak inducer of CYP3A4 and UDP-glucuronyl transferases.
Therefore,
in vivo
eslicarbazepine may have an inducing effect on the metabolism of medicinal products
which are mainly eliminated by metabolism through CYP3A4 or conjugation through the UDP-glucuronyl
transferases. When initiating or discontinuing treatment with Zebinix or changing the dose, it may take 2 to 3
weeks to reach the new level of enzyme activity. This time delay must be taken into account when Zebinix is
being used just prior to or in combination with other medicines that require dose adjustment when
co-administered with Zebinix. Eslicarbazepine has inhibiting properties with respect to CYP2C19. Thus,
interactions can arise when co-administering high doses of eslicarbazepine acetate with medicinal products
that are mainly metabolised by CYP2C19.
Interactions with other antiepileptic medicinal products
Phenytoin
In a study in healthy subjects, concomitant administration of eslicarbazepine acetate 1,200 mg once daily and
phenytoin resulted in an average decrease of 31-33% in exposure to the active metabolite, eslicarbazepine,
most likely caused by an induction of glucuronidation, and an average increase of 31-35% in exposure to
phenytoin, most likely caused by an inhibition of CYP2C19. Based on individual response, the dose of
Zebinix may need to be increased and the dose of phenytoin may need to be decreased.
Lamotrigine
Glucuronidation is the major metabolic pathway for both eslicarbazepine and lamotrigine and therefore an
interaction could be expected. A study in healthy subjects with eslicarbazepine acetate 1,200 mg once daily
showed a minor average pharmacokinetic interaction (exposure of lamotrigine decreased 15%) between
eslicarbazepine acetate and lamotrigine and consequently no dose adjustments are required. However, due to
interindividual variability, the effect may be clinically relevant in some individuals.
Topiramate
In a study in healthy subjects, concomitant administration of eslicarbazepine acetate 1,200 mg once daily and
topiramate showed no significant change in exposure to eslicarbazepine but an 18% decrease in exposure to
topiramate, most likely caused by a reduced bioavailability of topiramate. No dose adjustment is required
.
Carbamazepine, valproate and levetiracetam
Concomitant treatment with carbamazepine increased the risk of the following adverse reactions: diplopia
(11.4% of subjects with concomitant carbamazepine, 2.4% of subjects without concomitant carbamazepine),
abnormal coordination (6.7% with concomitant carbamazepine, 2.7% without concomitant carbamazepine),
and dizziness (30.0% with concomitant carbamazepine, 11.5% without concomitant carbamazepine). The
risk of increase of other specific adverse reactions caused by co-administration of carbamazepine and
eslicarbazepine acetate cannot be excluded.
4
A population pharmacokinetics analysis of phase III studies in epileptic adult patients indicated that
carbamazepine increases eslicarbazepine clearance. Concomitant administration with valproate or
levetiracetam appeared not to affect the exposure to eslicarbazepine but has not been verified by
conventional interaction studies. Eslicarbazepine acetate slightly increased the clearance of carbamazepine.
However, due to the general limitations of the data, these results should be taken with care.
Other medicinal products
Oral contraceptives
Administration of eslicarbazepine acetate 1,200 mg once daily to female subjects using a combined oral
contraceptive showed an average decrease of 37% and 42% in systemic exposure to levonorgestrel and
ethinyloestradiol, respectively, most likely caused by an induction of CYP3A4. Therefore, women of
childbearing potential must use adequate contraception during treatment with Zebinix, and up to the end of
the current menstruation cycle after the treatment has been discontinued (see section 4.4 and 4.6).
Warfarin
Co-administration of eslicarbazepine acetate 1,200 mg once daily with warfarin showed a small (23%) but
statistically significant decrease in exposure to S-warfarin. There was no effect on the R-warfarin
pharmacokinetics or on coagulation. However, due to inter-individual variability in the interaction, special
attention on monitoring of INR should be performed the first weeks after initiation or ending concomitant
treatment of warfarin and eslicarbazepine acetate.
Digoxin
A study in healthy subjects showed no effect of eslicarbazepine acetate 1,200 mg once daily on digoxin
pharmacokinetics, suggesting that eslicarbazepine acetate has no effect on the transporter P-glycoprotein.
Monoamino Oxidase Inhibitors (MAOIs)
Based on a structural relationship of eslicarbazepine acetate to tricyclic antidepressants, an interaction
between eslicarbazepine acetate and MAOIs is theoretically possible.
Risk related to epilepsy and antiepileptic medicinal products in general
It has been shown that in the offspring of women with epilepsy, the prevalence of malformations is two to
three times greater than the rate of approximately 3 % in the general population. Most frequently reported are
cleft lip, cardiovascular malformations and neural tube defects. Multiple antiepileptic medicinal product
therapy may be associated with a higher risk of congenital malformations than monotherapy, therefore it is
important that monotherapy is practised whenever possible. Specialist advice should be given to women who
are likely to become pregnant or who are of child-bearing potential. The need for antiepileptic therapy
should be reviewed when a woman is planning to become pregnant. No sudden discontinuation of
antiepileptic therapy should be undertaken as this may lead to breakthrough seizures which could have
serious consequences for both mother and child.
Risk related to eslicarbazepine acetate
There are no data from the use of eslicarbazepine acetate in pregnant women. Studies in animals have shown
reproductive toxicity (see section 5.3). If women receiving eslicarbazepine acetate become pregnant or plan
to become pregnant, the use of Zebinix should be carefully re-evaluated. Minimum effective doses should be
given, and monotherapy whenever possible should be preferred at least during the first three months of
pregnancy. Patients should be counselled regarding the possibility of an increased risk of malformations and
given the opportunity to antenatal screening.
Monitoring and prevention
Antiepileptic medicinal products may contribute to folic acid deficiency, a possible contributory cause of
foetal abnormality. Folic acid supplementation is recommended before and during pregnancy. As the
5
efficacy of this supplementation is not proven, a specific antenatal diagnosis can be offered even for women
with a supplementary treatment of folic acid.
In the newborn child
Bleeding disorders in the newborn caused by antiepileptic medicinal products have been reported. As a
precaution, vitamin K1 should be administered as a preventive measure in the last few weeks of pregnancy
and to the newborn.
Women of childbearing potential/contraception
Eslicarbazepine acetate adversely interacts with oral contraceptives. Therefore, an alternative, effective and
safe method of contraception should be used during treatment and up to the end of the current menstrual
cycle after treatment has been stopped.
It is unknown whether eslicarbazepine acetate is excreted in human breast milk. Animal studies have shown
excretion of eslicarbazepine in breast milk. As a risk to the breast-fed child cannot be excluded breast-
feeding should be discontinued during treatment with Zebinix.
No studies on the effects on the ability to drive and use machines have been performed. Some patients might
experience dizziness, somnolence or visual disorders, particularly on initiation of treatment. Therefore,
patients should be advised that their physical and/ or mental abilities needed for operating machinery or
driving may be impaired and they are recommended not to do so until it has been established that their ability
to perform such activities is not affected.
In placebo-controlled studies involving 1,192 adult patients with partial-onset seizures (856 patients treated
with eslicarbazepine acetate and 336 treated with placebo), 45.3% of patients treated with eslicarbazepine
acetate and 24.4% of patients treated with placebo experienced adverse reactions.
Adverse reactions were usually mild to moderate in intensity and occurred predominantly during the first
weeks of treatment with eslicarbazepine acetate.
In the table below all adverse reactions, which occurred at an incidence greater than placebo and numerically
present in more than 1 patient are listed by System Organ Class and frequency:
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.
Within each frequency category, adverse reactions are presented in order of decreasing seriousness.
System Organ
Class
Very
common
Common
Uncommon
Rare
Blood and
lymphatic system
disorders
Anaemia
Thrombocytopenia,
leukopenia
Immune system
disorders
Hypersensitivity
Endocrine
disorders
Hypothyroidism
Metabolism and
nutrition disorders
Increased appetite,
decreased appetite,
hyponatraemia, electrolyte
imbalance, cachexia,
dehydration, obesity
Psychiatric
disorders
Insomnia, apathy,
depression, nervousness,
6
agitation, attention deficit/
hyperactivity disorder,
confusional state, mood
swings, crying,
psychomotor retardation,
stress, psychotic disorder
Nervous system
disorders
Dizziness*,
somnolence
Headache,
abnormal
coordination
*,
disturbance
in attention,
tremor
Memory impairment,
balance disorder, amnesia,
hypersomnia, sedation,
aphasia, dysaesthesia,
dystonia, lethargy,
parosmia, autonomic
nervous system imbalance,
cerebellar ataxia, cerebellar
syndrome, grand mal
convulsion, neuropathy
peripheral, sleep phase
rhythm disturbance,
nystagmus, speech
disorder, dysarthria,
hypoaesthesia, ageusia,
burning sensation
Eye disorders
Diplopia*,
vision
blurred
Vision disturbance,
oscillopsia, binocular eye
movement disorder, ocular
hyperaemia, saccadic eye
movement, eye pain
Ear and labyrinth
disorders
Vertigo
Ear pain, hypoacusis,
tinnitus
Cardiac disorders
Palpitations, bradycardia,
sinus bradycardia
Vascular disorders
Hypertension, hypotension,
orthostatic hypotension
Respiratory,
thoracic and
mediastinal
disorders
Dysphonia, epistaxis
Gastrointestinal
disorders
Nausea,
vomiting,
diarrhoea
Dyspepsia, gastritis,
abdominal pain, dry mouth,
abdominal discomfort,
abdominal distension,
duodenitis, epigastric
discomfort, gingival
hyperplasia, gingivitis ,
irritable bowel syndrome,
melaena, odynophagia,
stomach discomfort,
stomatitis, toothache
Pancreatitis
Hepatobiliary
disorders
Liver disorder
Skin and
subcutaneous tissue
disorders
Rash
Alopecia, dry skin,
hyperhidrosis, erythema,
nail disorder, skin disorder
Musculoskeletal
and connective
Myalgia, back pain, neck
pain
7
tissue disorders
Renal and urinary
disorders
Nocturia
Reproductive
system and breast
disorders
Menstruation irregular
General disorders
and administration
site conditions
Fatigue, gait
disturbance
Asthenia, malaise, chills,
oedema peripheral, adverse
drug reaction, peripheral
coldness
Investigations
Blood pressure decreased,
weight decreased, blood
pressure diastolic
decreased, blood pressure
increased, blood pressure
systolic decreased, blood
sodium decreased,
haematocrit decreased,
haemoglobin decreased,
heart rate increased,
transaminases increased,
triglycerides increased, tri-
iodothyronine (T3) free
decreased, thyroxine (T4)
free decreased
Injury and
poisoning
Drug toxicity, fall, joint
injury, poisoning, skin
injury
* In patients concomitantly treated with carbamazepine and eslicarbazepine acetate in placebo-controlled
studies, diplopia, abnormal coordination and dizziness were reported more frequently.
The use of eslicarbazepine acetate is associated with increase in the PR interval. Adverse reactions associated
with PR interval prolongation (e.g. AV block, syncope, bradycardia) may occur. No second or higher degree
AV block was seen in eslicarbazepine acetate treated patients.
Rare adverse reactions such as bone marrow depression, anaphylactic reactions, severe cutaneous reactions
(e.g. Stevens-Johnson Syndrome), systemic lupus erythematosus or serious cardiac arrhythmias did not occur
during the placebo-controlled studies of the epilepsy program with eslicarbazepine acetate. However, they
have been reported with oxcarbazepine. Therefore, their occurrence after treatment with Zebinix cannot be
excluded.
Central nervous symptoms such as vertigo, walking instability and hemi-paresis have been observed with
accidental Zebinix overdose. There is no known specific antidote. Symptomatic and supportive treatment
should be administered as appropriate. Eslicarbazepine acetate metabolites can effectively be cleared by
haemodialysis, if necessary (see section 5.2).
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiepileptics, Carboxamide derivatives, ATC code:
N03AF04
Mechanism of action
8
The precise mechanisms of action of eslicarbazepine acetate are unknown. However, in vitro
electrophysiological studies indicate that both eslicarbazepine acetate and its metabolites stabilise the
inactivated state of voltage-gated sodium channels, preventing their return to the activated state and thereby
sustaining repetitive neuronal firing.
Pharmacodynamic effect
Eslicarbazepine acetate and its active metabolites prevented the development of seizures in nonclinical
models predictive of anticonvulsant efficacy in man. In humans, the pharmacological activity of
eslicarbazepine acetate is primarily exerted through the active metabolite eslicarbazepine.
Clinical experience
The efficacy and safety of eslicarbazepine acetate has been demonstrated in three phase III double-blind
placebo-controlled studies in 1,049 adult patients with partial epilepsy refractory to treatment with one to
three concomitant anti-epileptic medicinal products. Oxcarbazepine and felbamate were not allowed as
concomitant medicinal products in these studies. Eslicarbazepine acetate was tested at doses of 400 mg,
800 mg and 1200 mg, once daily. Eslicarbazepine acetate 800 mg once daily and 1200 mg once daily were
significantly more effective than placebo in reducing seizure frequency over a 12-week maintenance period.
The percentage of subjects with a 50% reduction in seizure frequency over all phase III studies was 19% for
placebo, 21% for eslicarbazepine acetate 400 mg, 34% for eslicarbazepine acetate 800 mg and 36% for
eslicarbazepine acetate 1200 mg daily.
5.2 Pharmacokinetic properties
Absorption
Eslicarbazepine acetate is extensively converted to
eslicarbazepine. Plasma levels of eslicarbazepine acetate
usually remain below the limit of quantification, following oral administration. Eslicarbazepine t
max
is
attained at 2 to 3 h post-dose. Bioavailability may be assumed as high because the amount of metabolites
recovered in urine corresponded to more than 90% of an eslicarbazepine acetate dose.
Distribution
The binding of eslicarbazepine to plasma proteins is relatively low (<40%) and independent from
concentration.
In vitro
studies have shown that plasma protein binding was not relevantly affected by the
presence of warfarin, diazepam, digoxin, phenytoin and tolbutamide. The binding of warfarin, diazepam,
digoxin, phenytoin and tolbutamide was not significantly affected by the presence of eslicarbazepine.
Biotransformation
Eslicarbazepine acetate is rapidly and extensively biotransformed to its major active metabolite
eslicarbazepine by hydrolytic first-pass metabolism. Peak plasma
concentrations (C
max
) of eslicarbazepine
are attained at 2-3 hours post-dose and steady state plasma concentrations are attained after 4 to 5 days of
once daily dosing, consistent with an effective half-life in the order of 20-24 h. In studies in healthy subjects
and epileptic adult patients, the apparent half-life of eslicarbazepine was 10-20 h and 13-20 h, respectively.
Minor metabolites in plasma are R-licarbazepine and oxcarbazepine, which were shown to be active, and the
glucuronic acid conjugates of eslicarbazepine acetate, eslicarbazepine, R-licarbazepine and oxcarbazepine.
Eslicarbazepine acetate does not affect its own metabolism or clearance.
In studies with eslicarbazepine in fresh human hepatocytes a mild activation of UGT1A1 mediated
glucuronidation was observed.
Excretion
Eslicarbazepine acetate metabolites are eliminated from the systemic circulation primarily by renal excretion,
in the unchanged and glucuronide conjugate forms. In total, eslicarbazepine and its glucuronide correspond
to more than 90% of total metabolites excreted in urine, approximately two thirds in the unchanged form and
one third as glucuronide conjugate.
Linearity / non-linearity
9
The pharmacokinetics of eslicarbazepine is linear and dose-proportional in the range 400-1200 mg both in
healthy subjects and patients.
Elderly (over 65 years of age
)
The pharmacokinetic profile of eslicarbazepine acetate is unaffected in the elderly patients with creatinine
clearance >60 ml/min (see section 4.2).
Renal impairment
Eslicarbazepine acetate metabolites are eliminated from the systemic circulation primarily by renal excretion.
A study in patients with mild to severe renal impairment showed that clearance is dependent on renal
function. During treatment with Zebinix dose adjustment is recommended in patients with creatinine
clearance <60 ml/min (see section 4.2).
Haemodialysis removes eslicarbazepine acetate metabolites from plasma.
Hepatic impairment
The pharmacokinetics and metabolism of eslicarbazepine acetate were evaluated in healthy subjects and
moderately liver-impaired patients after multiple oral doses. Moderate hepatic impairment did not affect the
pharmacokinetics of eslicarbazepine acetate. No dose adjustment is recommended in patients with mild to
moderate liver impairment (see section 4.2).
The pharmacokinetics of eslicarbazepine has not been evaluated in patients with severe hepatic impairment.
Gender
Studies in healthy subjects and patients showed that pharmacokinetics of eslicarbazepine acetate were not
affected by gender.
5.3 Preclinical safety data
Adverse affects observed in animal studies occurred at exposure levels appreciably lower than the clinical
exposure levels to eslicarbazepine (the principal and pharmacologically active metabolite of eslicarbazepine
acetate). Safety margins based on comparative exposure have thus not been established.
Evidence of nephrotoxicity was observed in repeated dose toxicity studies in the rat, but was not seen in
studies in mice or dogs, and is consistent with an exacerbation of spontaneous chronic progressive
nephropathy in this species.
Liver centrilobular hypertrophy was seen in repeated dose toxicity studies in mice and rats and an increased
incidence of liver tumours was observed in the carcinogenicity study in mice; these findings are consistent
with an induction of hepatic microsomal enzymes, an effect which has not been observed in patients
receiving eslicarbazepine acetate.
Genotoxicity studies with eslicarbazepine acetate indicate no special hazards for humans.
Impairment of fertility was observed in female rats; decreases in implantations and live embryos seen in the
mouse fertility study may also indicate effects on female fertility, however, corpora lutea counts were not
evaluated. Eslicarbazepine acetate was not teratogenic in the rat or rabbit, but did induce skeletal
abnormalities in the mouse. Ossification delays, reduced foetal weights, an increase in minor skeletal and
visceral abnormalities were observed at maternal toxic doses in embryotoxicity studies in mice, rats and
rabbits. A delay in sexual development of the F1 generation was observed in peri/post natal studies in mice
and rats.
6.
6.1 List of excipients
10
Povidone K 29/32
Croscarmellose sodium
Magnesium stearate
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
Zebinix 400 mg tablets are packaged in ALU/ALU or ALU/PVC blisters placed into cardboard boxes
containing 7, 14 or 28 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
BIAL - Portela & Cª
, SA
À Av. da Siderurgia Nacional 4745-457 S. Mamede do Coronado - Portugal
tel: +351 22 986 61 00
fax: +351 22 986 61 99
e-mail: info@bial.com
9.
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu/
.
11
1.
Zebinix 600 mg tablets
2.
Each tablet contains 600 mg of eslicarbazepine acetate.
For a full list of excipients, see section 6.1.
3.
Tablet.
White oblong tablets, engraved ‘ESL 600’on one side and scored on the other side. The tablet can be divided
into equal halves.
4.
Zebinix is indicated as adjunctive therapy in adults with partial-onset seizures with or without secondary
generalisation.
Zebinix must be added to existing anticonvulsant therapy. The recommended starting dose is 400 mg once
daily which should be increased to 800 mg once daily after one or two weeks. Based on individual response,
the dose may be increased to 1200 mg once daily (see section 5.1).
Zebinix may be taken with or without food.
Elderly (over 65 years of age
)
Caution should be exercised in the treatment of elderly patients as there is limited safety information on the
use of Zebinix in these patients.
Paediatric population
Zebinix is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.
Patients with renal impairment
Caution should be exercised in the treatment of patients with renal impairment and the dose should be
adjusted according to creatinine clearance (CL
CR
) as follows:
- CL
CR
>60 ml/min: no dose adjustment required
- CL
CR
30-60 ml/min: initial dose of 400 mg every other day for 2 weeks followed by a once daily dose of
400 mg. However, based on individual response, the dose may be increased.
- CL
CR
<30 ml/min: use is not recommended in patients with severe renal impairment due to insufficient
data
Patients with hepatic impairment
No dose adjustment is needed in patients with mild to moderate hepatic impairment.
The pharmacokinetics of eslicarbazepine has not been evaluated in patients with severe hepatic impairment
(see section 4.4 and 5.2) and use in these patients is therefore not recommended.
12
Hypersensitivity to the active substance, to other carboxamide derivatives (e.g. carbamazepine,
oxcarbazepine) or to any of the excipients.
Known second or third degree atrioventricular (AV) block.
Zebinix has been associated with some central nervous system adverse reactions, such as dizziness and
somnolence, which could increase the occurrence of accidental injury.
Zebinix may decrease the effectiveness of hormonal contraceptives. Additional non-hormonal forms of
contraception are recommended when using Zebinix (see section 4.5 and 4.6).
As with other anti-epileptic medicinal products, if Zebinix is to be discontinued it is recommended to
withdraw it gradually to minimise the potential of increased seizure frequency.
Concomitant use of Zebinix with oxcarbazepine is not recommended because this may cause overexposure to
the active metabolites.
There is no experience regarding the withdrawal of concomitant use of anti-epileptic medicinal products
during treatment with Zebinix (switch to monotherapy).
Rash developed as an adverse reaction in 1.1% of total population treated with Zebinix in placebo-controlled
add-on studies in epileptic patients. If signs or symptoms of hypersensitivity develop, Zebinix must be
discontinued.
No cases of serious cutaneous reactions have been reported with eslicarbazepine acetate. Presence of
HLA-B*1502 allele in individuals of Han Chinese and Thai origin has been shown to be strongly associated
with the risk of developing Stevens-Johnson syndrome (SJS) when treated with carbamazepine. Therefore,
whenever possible, subjects of Han Chinese and Thai origin should be screened for this allele before starting
treatment with carbamazepine or chemically-related compounds. The presence of HLA-B*1502 allele in
other ethnicities is negligible. The allele HLA-B*1502 is not associated to SJS in the Caucasian population.
Hyponatraemia has been reported as an adverse reaction in less than 1% of patients treated with Zebinix.
Hyponatraemia is asymptomatic in most cases, however, it may be accompanied by clinical symptoms like
worsening of seizures, confusion, decreased consciousness. Frequency of hyponatraemia increased with
increasing eslicarbazepine acetate dose. In patients with pre-existing renal disease leading to hyponatraemia,
or in patients concomitantly treated with medicinal products which may themselves lead to hyponatraemia
(e.g. diuretics, desmopressin), serum sodium levels should be examined before and during treatment with
eslicarbazepine acetate. Furthermore, serum sodium levels should be determined if clinical signs of
hyponatraemia occur. Apart from this, sodium levels should be determined during routine laboratory
examination. If clinically relevant hyponatraemia develops, Zebinix should be discontinued.
The influence of Zebinix on primary generalised seizures has not been studied. Use is therefore not
recommended in these patients.
Prolongations in PR interval have been observed in clinical studies with eslicarbazepine acetate.
Caution should be exercised in patients with medical conditions (e.g. low levels of thyroxine, cardiac
conduction abnormalities), or when taking concomitant medicinal products
known to be associated with PR
prolongation.
13
Caution should be exercised in the treatment of patients with renal impairment and the dose should be
adjusted according to creatinine clearance (see section 4.2). In patients with CL
CR
<30 ml/min use is not
recommended due to insufficient data.
As clinical data are limited in patients with mild to moderate hepatic impairment and pharmacokinetic and
clinical data are missing in patients with severe hepatic impairment, Zebinix should be used with caution in
patients with mild to moderate hepatic impairment and is not recommended in patients with severe hepatic
impairment.
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic active substances in
several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic medicinal
products has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this
risk is not known and the available data do not exclude the possibility of an increased risk for eslicarbazepine
acetate. Therefore patients should be monitored for signs of 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 suicidal ideation or behaviour emerge.
Interaction studies have only been performed in adults.
Eslicarbazepine acetate is extensively converted to eslicarbazepine, which is mainly eliminated by
glucuronidation.
In vitro
eslicarbazepine is a weak inducer of CYP3A4 and UDP-glucuronyl transferases.
Therefore,
in vivo
eslicarbazepine may have an inducing effect on the metabolism of medicinal products
which are mainly eliminated by metabolism through CYP3A4 or conjugation through the UDP-glucuronyl
transferases. When initiating or discontinuing treatment with Zebinix or changing the dose, it may take 2 to 3
weeks to reach the new level of enzyme activity. This time delay must be taken into account when Zebinix is
being used just prior to or in combination with other medicines that require dose adjustment when
co-administered with Zebinix. Eslicarbazepine has inhibiting properties with respect to CYP2C19. Thus,
interactions can arise when co-administering high doses of eslicarbazepine acetate with medicinal products
that are mainly metabolised by CYP2C19.
Interactions with other antiepileptic medicinal products
Phenytoin
In a study in healthy subjects, concomitant administration of eslicarbazepine acetate 1,200 mg once daily and
phenytoin resulted in an average decrease of 31-33% in exposure to the active metabolite, eslicarbazepine,
most likely caused by an induction of glucuronidation, and an average increase of 31-35% in exposure to
phenytoin, most likely caused by an inhibition of CYP2C19. Based on individual response, the dose of
Zebinix may need to be increased and the dose of phenytoin may need to be decreased.
Lamotrigine
Glucuronidation is the major metabolic pathway for both eslicarbazepine and lamotrigine and therefore an
interaction could be expected. A study in healthy subjects with eslicarbazepine acetate 1,200 mg once daily
showed a minor average pharmacokinetic interaction (exposure of lamotrigine decreased 15%) between
eslicarbazepine acetate and lamotrigine and consequently no dose adjustments are required. However, due to
interindividual variability, the effect may be clinically relevant in some individuals.
Topiramate
In a study in healthy subjects, concomitant administration of eslicarbazepine acetate 1,200 mg once daily and
topiramate showed no significant change in exposure to eslicarbazepine but an 18% decrease in exposure to
topiramate, most likely caused by a reduced bioavailability of topiramate. No dose adjustment is required
.
Carbamazepine, valproate and levetiracetam
Concomitant treatment with carbamazepine increased the risk of the following adverse reactions: diplopia
(11.4% of subjects with concomitant carbamazepine, 2.4% of subjects without concomitant carbamazepine),
14
abnormal coordination (6.7% with concomitant carbamazepine, 2.7% without concomitant carbamazepine),
and dizziness (30.0% with concomitant carbamazepine, 11.5% without concomitant carbamazepine). The
risk of increase of other specific adverse reactions caused by co-administration of carbamazepine and
eslicarbazepine acetate cannot be excluded.
A population pharmacokinetics analysis of phase III studies in epileptic adult patients indicated that
carbamazepine increases eslicarbazepine clearance. Concomitant administration with valproate or
levetiracetam appeared not to affect the exposure to eslicarbazepine but has not been verified by
conventional interaction studies. Eslicarbazepine acetate slightly increased the clearance of carbamazepine.
However, due to the general limitations of the data, these results should be taken with care.
Other medicinal products
Oral contraceptives
Administration of eslicarbazepine acetate 1,200 mg once daily to female subjects using a combined oral
contraceptive showed an average decrease of 37% and 42% in systemic exposure to levonorgestrel and
ethinyloestradiol, respectively, most likely caused by an induction of CYP3A4. Therefore, women of
childbearing potential must use adequate contraception during treatment with Zebinix, and up to the end of
the current menstruation cycle after the treatment has been discontinued (see section 4.4 and 4.6).
Warfarin
Co-administration of eslicarbazepine acetate 1,200 mg once daily with warfarin showed a small (23%) but
statistically significant decrease in exposure to S-warfarin. There was no effect on the R-warfarin
pharmacokinetics or on coagulation. However, due to inter-individual variability in the interaction, special
attention on monitoring of INR should be performed the first weeks after initiation or ending concomitant
treatment of warfarin and eslicarbazepine acetate.
Digoxin
A study in healthy subjects showed no effect of eslicarbazepine acetate 1,200 mg once daily on digoxin
pharmacokinetics, suggesting that eslicarbazepine acetate has no effect on the transporter P-glycoprotein.
Monoamino Oxidase Inhibitors (MAOIs)
Based on a structural relationship of eslicarbazepine acetate to tricyclic antidepressants, an interaction
between eslicarbazepine acetate and MAOIs is theoretically possible.
Risk related to epilepsy and antiepileptic medicinal products in general
It has been shown that in the offspring of women with epilepsy, the prevalence of malformations is two to
three times greater than the rate of approximately 3 % in the general population. Most frequently reported are
cleft lip, cardiovascular malformations and neural tube defects. Multiple antiepileptic medicinal product
therapy may be associated with a higher risk of congenital malformations than monotherapy, therefore it is
important that monotherapy is practised whenever possible. Specialist advice should be given to women who
are likely to become pregnant or who are of child-bearing potential. The need for antiepileptic therapy
should be reviewed when a woman is planning to become pregnant. No sudden discontinuation of
antiepileptic therapy should be undertaken as this may lead to breakthrough seizures which could have
serious consequences for both mother and child.
Risk related to eslicarbazepine acetate
There are no data from the use of eslicarbazepine acetate in pregnant women. Studies in animals have shown
reproductive toxicity (see section 5.3). If women receiving eslicarbazepine acetate become pregnant or plan
to become pregnant, the use of Zebinix should be carefully re-evaluated. Minimum effective doses should be
given, and monotherapy whenever possible should be preferred at least during the first three months of
pregnancy. Patients should be counselled regarding the possibility of an increased risk of malformations and
given the opportunity to antenatal screening.
15
Monitoring and prevention
Antiepileptic medicinal products may contribute to folic acid deficiency, a possible contributory cause of
foetal abnormality. Folic acid supplementation is recommended before and during pregnancy. As the
efficacy of this supplementation is not proven, a specific antenatal diagnosis can be offered even for women
with a supplementary treatment of folic acid.
In the newborn child
Bleeding disorders in the newborn caused by antiepileptic medicinal products have been reported. As a
precaution, vitamin K1 should be administered as a preventive measure in the last few weeks of pregnancy
and to the newborn.
Women of childbearing potential/contraception
Eslicarbazepine acetate adversely interacts with oral contraceptives. Therefore, an alternative, effective and
safe method of contraception should be used during treatment and up to the end of the current menstrual
cycle after treatment has been stopped.
It is unknown whether eslicarbazepine acetate is excreted in human breast milk. Animal studies have shown
excretion of eslicarbazepine in breast milk. As a risk to the breast-fed child cannot be excluded breast-
feeding should be discontinued during treatment with Zebinix.
No studies on the effects on the ability to drive and use machines have been performed. Some patients might
experience dizziness, somnolence or visual disorders, particularly on initiation of treatment. Therefore,
patients should be advised that their physical and/ or mental abilities needed for operating machinery or
driving may be impaired and they are recommended not to do so until it has been established that their ability
to perform such activities is not affected.
In placebo-controlled studies involving 1,192 adult patients with partial-onset seizures (856 patients treated
with eslicarbazepine acetate and 336 treated with placebo), 45.3% of patients treated with eslicarbazepine
acetate and 24.4% of patients treated with placebo experienced adverse reactions.
Adverse reactions were usually mild to moderate in intensity and occurred predominantly during the first
weeks of treatment with eslicarbazepine acetate.
In the table below all adverse reactions, which occurred at an incidence greater than placebo and numerically
present in more than 1 patient are listed by System Organ Class and frequency:
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.
Within each frequency category, adverse reactions are presented in order of decreasing seriousness.
System Organ
Class
Very
common
Common
Uncommon
Rare
Blood and
lymphatic system
disorders
Anaemia
Thrombocytopenia,
leukopenia
Immune system
disorders
Hypersensitivity
Endocrine
disorders
Hypothyroidism
Metabolism and
nutrition disorders
Increased appetite,
decreased appetite,
hyponatraemia, electrolyte
imbalance, cachexia,
16
dehydration, obesity
Psychiatric
disorders
Insomnia, apathy,
depression, nervousness,
agitation, attention deficit/
hyperactivity disorder,
confusional state, mood
swings, crying,
psychomotor retardation,
stress, psychotic disorder
Nervous system
disorders
Dizziness*,
somnolence
Headache,
abnormal
coordination
*,
disturbance
in attention,
tremor
Memory impairment,
balance disorder, amnesia,
hypersomnia, sedation,
aphasia, dysaesthesia,
dystonia, lethargy,
parosmia, autonomic
nervous system imbalance,
cerebellar ataxia, cerebellar
syndrome, grand mal
convulsion, neuropathy
peripheral, sleep phase
rhythm disturbance,
nystagmus, speech
disorder, dysarthria,
hypoaesthesia, ageusia,
burning sensation
Eye disorders
Diplopia*,
vision
blurred
Vision disturbance,
oscillopsia, binocular eye
movement disorder, ocular
hyperaemia, saccadic eye
movement, eye pain
Ear and labyrinth
disorders
Vertigo
Ear pain, hypoacusis,
tinnitus
Cardiac disorders
Palpitations, bradycardia,
sinus bradycardia
Vascular disorders
Hypertension, hypotension,
orthostatic hypotension
Respiratory,
thoracic and
mediastinal
disorders
Dysphonia, epistaxis
Gastrointestinal
disorders
Nausea,
vomiting,
diarrhoea
Dyspepsia, gastritis,
abdominal pain, dry mouth,
abdominal discomfort,
abdominal distension,
duodenitis, epigastric
discomfort, gingival
hyperplasia, gingivitis ,
irritable bowel syndrome,
melaena, odynophagia,
stomach discomfort,
stomatitis, toothache
Pancreatitis
Hepatobiliary
disorders
Liver disorder
Skin and
subcutaneous tissue
Rash
Alopecia, dry skin,
hyperhidrosis, erythema,
17
disorders
nail disorder, skin disorder
Musculoskeletal
and connective
tissue disorders
Myalgia, back pain, neck
pain
Renal and urinary
disorders
Nocturia
Reproductive
system and breast
disorders
Menstruation irregular
General disorders
and administration
site conditions
Fatigue, gait
disturbance
Asthenia, malaise, chills,
oedema peripheral, adverse
drug reaction, peripheral
coldness
Investigations
Blood pressure decreased,
weight decreased, blood
pressure diastolic
decreased, blood pressure
increased, blood pressure
systolic decreased, blood
sodium decreased,
haematocrit decreased,
haemoglobin decreased,
heart rate increased,
transaminases increased,
triglycerides increased, tri-
iodothyronine (T3) free
decreased, thyroxine (T4)
free decreased
Injury and
poisoning
Drug toxicity, fall, joint
injury, poisoning, skin
injury
* In patients concomitantly treated with carbamazepine and eslicarbazepine acetate in placebo-controlled
studies, diplopia, abnormal coordination and dizziness were reported more frequently.
The use of eslicarbazepine acetate is associated with increase in the PR interval. Adverse reactions associated
with PR interval prolongation (e.g. AV block, syncope, bradycardia) may occur. No second or higher degree
AV block was seen in eslicarbazepine acetate treated patients.
Rare adverse reactions such as bone marrow depression, anaphylactic reactions, severe cutaneous reactions
(e.g. Stevens-Johnson Syndrome), systemic lupus erythematosus or serious cardiac arrhythmias did not occur
during the placebo-controlled studies of the epilepsy program with eslicarbazepine acetate. However, they
have been reported with oxcarbazepine. Therefore, their occurrence after treatment with Zebinix cannot be
excluded.
Central nervous symptoms such as vertigo, walking instability and hemi-paresis have been observed with
accidental Zebinix overdose. There is no known specific antidote. Symptomatic and supportive treatment
should be administered as appropriate. Eslicarbazepine acetate metabolites can effectively be cleared by
haemodialysis, if necessary (see section 5.2).
5.
5.1 Pharmacodynamic properties
18
Pharmacotherapeutic group: Antiepileptics, Carboxamide derivatives, ATC code:
N03AF04
Mechanism of action
The precise mechanisms of action of eslicarbazepine acetate are unknown. However, in vitro
electrophysiological studies indicate that both eslicarbazepine acetate and its metabolites stabilise the
inactivated state of voltage-gated sodium channels, preventing their return to the activated state and thereby
sustaining repetitive neuronal firing.
Pharmacodynamic effect
Eslicarbazepine acetate and its active metabolites prevented the development of seizures in nonclinical
models predictive of anticonvulsant efficacy in man. In humans, the pharmacological activity of
eslicarbazepine acetate is primarily exerted through the active metabolite eslicarbazepine.
Clinical experience
The efficacy and safety of eslicarbazepine acetate has been demonstrated in three phase III double-blind
placebo-controlled studies in 1,049 adult patients with partial epilepsy refractory to treatment with one to
three concomitant anti-epileptic medicinal products. Oxcarbazepine and felbamate were not allowed as
concomitant medicinal products in these studies. Eslicarbazepine acetate was tested at doses of 400 mg,
800 mg and 1200 mg, once daily. Eslicarbazepine acetate 800 mg once daily and 1200 mg once daily were
significantly more effective than placebo in reducing seizure frequency over a 12-week maintenance period.
The percentage of subjects with a 50% reduction in seizure frequency over all phase III studies was 19% for
placebo, 21% for eslicarbazepine acetate 400 mg, 34% for eslicarbazepine acetate 800 mg and 36% for
eslicarbazepine acetate 1200 mg daily.
5.2 Pharmacokinetic properties
Absorption
Eslicarbazepine acetate is extensively converted to
eslicarbazepine. Plasma levels of eslicarbazepine acetate
usually remain below the limit of quantification, following oral administration. Eslicarbazepine t
max
is
attained at 2 to 3 h post-dose. Bioavailability may be assumed as high because the amount of metabolites
recovered in urine corresponded to more than 90% of an eslicarbazepine acetate dose.
Distribution
The binding of eslicarbazepine to plasma proteins is relatively low (<40%) and independent from
concentration.
In vitro
studies have shown that plasma protein binding was not relevantly affected by the
presence of warfarin, diazepam, digoxin, phenytoin and tolbutamide. The binding of warfarin, diazepam,
digoxin, phenytoin and tolbutamide was not significantly affected by the presence of eslicarbazepine.
Biotransformation
Eslicarbazepine acetate is rapidly and extensively biotransformed to its major active metabolite
eslicarbazepine by hydrolytic first-pass metabolism. Peak plasma
concentrations (C
max
) of eslicarbazepine
are attained at 2-3 hours post-dose and steady state plasma concentrations are attained after 4 to 5 days of
once daily dosing, consistent with an effective half-life in the order of 20-24 h. In studies in healthy subjects
and epileptic adult patients, the apparent half-life of eslicarbazepine was 10-20 h and 13-20 h, respectively.
Minor metabolites in plasma are R-licarbazepine and oxcarbazepine, which were shown to be active, and the
glucuronic acid conjugates of eslicarbazepine acetate, eslicarbazepine, R-licarbazepine and oxcarbazepine.
Eslicarbazepine acetate does not affect its own metabolism or clearance.
In studies with eslicarbazepine in fresh human hepatocytes a mild activation of UGT1A1 mediated
glucuronidation was observed.
Excretion
Eslicarbazepine acetate metabolites are eliminated from the systemic circulation primarily by renal excretion,
in the unchanged and glucuronide conjugate forms. In total, eslicarbazepine and its glucuronide correspond
19
to more than 90% of total metabolites excreted in urine, approximately two thirds in the unchanged form and
one third as glucuronide conjugate.
Linearity / non-linearity
The pharmacokinetics of eslicarbazepine is linear and dose-proportional in the range 400-1200 mg both in
healthy subjects and patients.
Elderly (over 65 years of age
)
The pharmacokinetic profile of eslicarbazepine acetate is unaffected in the elderly patients with creatinine
clearance >60 ml/min (see section 4.2).
Renal impairment
Eslicarbazepine acetate metabolites are eliminated from the systemic circulation primarily by renal excretion.
A study in patients with mild to severe renal impairment showed that clearance is dependent on renal
function. During treatment with Zebinix dose adjustment is recommended in patients with creatinine
clearance <60 ml/min (see section 4.2).
Haemodialysis removes eslicarbazepine acetate metabolites from plasma.
Hepatic impairment
The pharmacokinetics and metabolism of eslicarbazepine acetate were evaluated in healthy subjects and
moderately liver-impaired patients after multiple oral doses. Moderate hepatic impairment did not affect the
pharmacokinetics of eslicarbazepine acetate. No dose adjustment is recommended in patients with mild to
moderate liver impairment (see section 4.2).
The pharmacokinetics of eslicarbazepine has not been evaluated in patients with severe hepatic impairment.
Gender
Studies in healthy subjects and patients showed that pharmacokinetics of eslicarbazepine acetate were not
affected by gender.
5.3 Preclinical safety data
Adverse affects observed in animal studies occurred at exposure levels appreciably lower than the clinical
exposure levels to eslicarbazepine (the principal and pharmacologically active metabolite of eslicarbazepine
acetate). Safety margins based on comparative exposure have thus not been established.
Evidence of nephrotoxicity was observed in repeated dose toxicity studies in the rat, but was not seen in
studies in mice or dogs, and is consistent with an exacerbation of spontaneous chronic progressive
nephropathy in this species.
Liver centrilobular hypertrophy was seen in repeated dose toxicity studies in mice and rats and an increased
incidence of liver tumours was observed in the carcinogenicity study in mice; these findings are consistent
with an induction of hepatic microsomal enzymes, an effect which has not been observed in patients
receiving eslicarbazepine acetate.
Genotoxicity studies with eslicarbazepine acetate indicate no special hazards for humans.
Impairment of fertility was observed in female rats; decreases in implantations and live embryos seen in the
mouse fertility study may also indicate effects on female fertility, however, corpora lutea counts were not
evaluated. Eslicarbazepine acetate was not teratogenic in the rat or rabbit, but did induce skeletal
abnormalities in the mouse. Ossification delays, reduced foetal weights, an increase in minor skeletal and
visceral abnormalities were observed at maternal toxic doses in embryotoxicity studies in mice, rats and
rabbits. A delay in sexual development of the F1 generation was observed in peri/post natal studies in mice
and rats.
20
6.
6.1 List of excipients
Povidone K 29/32
Croscarmellose sodium
Magnesium stearate
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
Zebinix 600 mg tablets are packed in ALU/ALU or ALU/PVC blisters placed into cardboard boxes
containing 30 or 60 tablets.
Zebinix 600 mg tablets are packed in HDPE bottles with polypropylene child resistant closure, placed into
cardboard boxes, containing 90 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
BIAL - Portela & Cª
, SA
À Av. da Siderurgia Nacional 4745-457 S. Mamede do Coronado - Portugal
tel: +351 22 986 61 00
fax: +351 22 986 61 99
e-mail: info@bial.com
8.
EU/1/09/514/007-011
9.
Date of first authorisation: 21.04.2009
21
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu/
.
22
1.
Zebinix 800 mg tablets
2.
Each tablet contains 800 mg of eslicarbazepine acetate.
For a full list of excipients, see section 6.1.
3.
Tablet.
White oblong tablets, engraved ‘ESL 800’on one side and scored on the other side. The tablet can be divided
into equal halves.
4.
Zebinix is indicated as adjunctive therapy in adults with partial-onset seizures with or without secondary
generalisation.
Zebinix must be added to existing anticonvulsant therapy. The recommended starting dose is 400 mg once
daily which should be increased to 800 mg once daily after one or two weeks. Based on individual response,
the dose may be increased to 1200 mg once daily (see section 5.1).
Zebinix may be taken with or without food.
Elderly (over 65 years of age
)
Caution should be exercised in the treatment of elderly patients as there is limited safety information on the
use of Zebinix in these patients.
Paediatric population
Zebinix is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.
Patients with renal impairment
Caution should be exercised in the treatment of patients with renal impairment and the dose should be
adjusted according to creatinine clearance (CL
CR
) as follows:
- CL
CR
>60 ml/min: no dose adjustment required
- CL
CR
30-60 ml/min: initial dose of 400 mg every other day for 2 weeks followed by a once daily dose of
400 mg. However, based on individual response, the dose may be increased.
- CL
CR
<30 ml/min: use is not recommended in patients with severe renal impairment due to insufficient
data
Patients with hepatic impairment
No dose adjustment is needed in patients with mild to moderate hepatic impairment.
The pharmacokinetics of eslicarbazepine has not been evaluated in patients with severe hepatic impairment
(see section 4.4 and 5.2) and use in these patients is therefore not recommended.
23
Hypersensitivity to the active substance, to other carboxamide derivatives (e.g. carbamazepine,
oxcarbazepine) or to any of the excipients.
Known second or third degree atrioventricular (AV) block.
Zebinix has been associated with some central nervous system adverse reactions, such as dizziness and
somnolence, which could increase the occurrence of accidental injury.
Zebinix may decrease the effectiveness of hormonal contraceptives. Additional non-hormonal forms of
contraception are recommended when using Zebinix (see section 4.5 and 4.6).
As with other anti-epileptic medicinal products, if Zebinix is to be discontinued it is recommended to
withdraw it gradually to minimise the potential of increased seizure frequency.
Concomitant use of Zebinix with oxcarbazepine is not recommended because this may cause overexposure to
the active metabolites.
There is no experience regarding the withdrawal of concomitant use of anti-epileptic medicinal products
during treatment with Zebinix (switch to monotherapy).
Rash developed as an adverse reaction in 1.1% of total population treated with Zebinix in placebo-controlled
add-on studies in epileptic patients. If signs or symptoms of hypersensitivity develop, Zebinix must be
discontinued.
No cases of serious cutaneous reactions have been reported with eslicarbazepine acetate. Presence of
HLA-B*1502 allele in individuals of Han Chinese and Thai origin has been shown to be strongly associated
with the risk of developing Stevens-Johnson syndrome (SJS) when treated with carbamazepine. Therefore,
whenever possible, subjects of Han Chinese and Thai origin should be screened for this allele before starting
treatment with carbamazepine or chemically-related compounds. The presence of HLA-B*1502 allele in
other ethnicities is negligible. The allele HLA-B*1502 is not associated to SJS in the Caucasian population.
Hyponatraemia has been reported as an adverse reaction in less than 1% of patients treated with Zebinix.
Hyponatraemia is asymptomatic in most cases, however, it may be accompanied by clinical symptoms like
worsening of seizures, confusion, decreased consciousness. Frequency of hyponatraemia increased with
increasing eslicarbazepine acetate dose. In patients with pre-existing renal disease leading to hyponatraemia,
or in patients concomitantly treated with medicinal products which may themselves lead to hyponatraemia
(e.g. diuretics, desmopressin), serum sodium levels should be examined before and during treatment with
eslicarbazepine acetate. Furthermore, serum sodium levels should be determined if clinical signs of
hyponatraemia occur. Apart from this, sodium levels should be determined during routine laboratory
examination. If clinically relevant hyponatraemia develops, Zebinix should be discontinued.
The influence of Zebinix on primary generalised seizures has not been studied. Use is therefore not
recommended in these patients.
Prolongations in PR interval have been observed in clinical studies with eslicarbazepine acetate.
Caution should be exercised in patients with medical conditions (e.g. low levels of thyroxine, cardiac
conduction abnormalities), or when taking concomitant medicinal products
known to be associated with PR
prolongation.
Caution should be exercised in the treatment of patients with renal impairment and the dose should be
adjusted according to creatinine clearance (see section 4.2). In patients with CL
CR
<30 ml/min use is not
recommended due to insufficient data.
24
As clinical data are limited in patients with mild to moderate hepatic impairment and pharmacokinetic and
clinical data are missing in patients with severe hepatic impairment, Zebinix should be used with caution in
patients with mild to moderate hepatic impairment and is not recommended in patients with severe hepatic
impairment.
Suicidal ideation and behaviour have been reported in patients treated with anti-epileptic active substances in
several indications. A meta-analysis of randomised placebo controlled trials of anti-epileptic medicinal
products has also shown a small increased risk of suicidal ideation and behaviour. The mechanism of this
risk is not known and the available data do not exclude the possibility of an increased risk for eslicarbazepine
acetate. Therefore patients should be monitored for signs of 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 suicidal ideation or behaviour emerge.
Interaction studies have only been performed in adults.
Eslicarbazepine acetate is extensively converted to eslicarbazepine, which is mainly eliminated by
glucuronidation.
In vitro
eslicarbazepine is a weak inducer of CYP3A4 and UDP-glucuronyl transferases.
Therefore,
in vivo
eslicarbazepine may have an inducing effect on the metabolism of medicinal products
which are mainly eliminated by metabolism through CYP3A4 or conjugation through the UDP-glucuronyl
transferases. When initiating or discontinuing treatment with Zebinix or changing the dose, it may take 2 to 3
weeks to reach the new level of enzyme activity. This time delay must be taken into account when Zebinix is
being used just prior to or in combination with other medicines that require dose adjustment when
co-administered with Zebinix. Eslicarbazepine has inhibiting properties with respect to CYP2C19. Thus,
interactions can arise when co-administering high doses of eslicarbazepine acetate with medicinal products
that are mainly metabolised by CYP2C19.
Interactions with other antiepileptic medicinal products
Phenytoin
In a study in healthy subjects, concomitant administration of eslicarbazepine acetate 1,200 mg once daily and
phenytoin resulted in an average decrease of 31-33% in exposure to the active metabolite, eslicarbazepine,
most likely caused by an induction of glucuronidation, and an average increase of 31-35% in exposure to
phenytoin, most likely caused by an inhibition of CYP2C19. Based on individual response, the dose of
Zebinix may need to be increased and the dose of phenytoin may need to be decreased.
Lamotrigine
Glucuronidation is the major metabolic pathway for both eslicarbazepine and lamotrigine and therefore an
interaction could be expected. A study in healthy subjects with eslicarbazepine acetate 1,200 mg once daily
showed a minor average pharmacokinetic interaction (exposure of lamotrigine decreased 15%) between
eslicarbazepine acetate and lamotrigine and consequently no dose adjustments are required. However, due to
interindividual variability, the effect may be clinically relevant in some individuals.
Topiramate
In a study in healthy subjects, concomitant administration of eslicarbazepine acetate 1,200 mg once daily and
topiramate showed no significant change in exposure to eslicarbazepine but an 18% decrease in exposure to
topiramate, most likely caused by a reduced bioavailability of topiramate. No dose adjustment is required
.
Carbamazepine, valproate and levetiracetam
Concomitant treatment with carbamazepine increased the risk of the following adverse reactions: diplopia
(11.4% of subjects with concomitant carbamazepine, 2.4% of subjects without concomitant carbamazepine),
abnormal coordination (6.7% with concomitant carbamazepine, 2.7% without concomitant carbamazepine),
and dizziness (30.0% with concomitant carbamazepine, 11.5% without concomitant carbamazepine). The
25
risk of increase of other specific adverse reactions caused by co-administration of carbamazepine and
eslicarbazepine acetate cannot be excluded.
A population pharmacokinetics analysis of phase III studies in epileptic adult patients indicated that
carbamazepine increases eslicarbazepine clearance. Concomitant administration with valproate or
levetiracetam appeared not to affect the exposure to eslicarbazepine but has not been verified by
conventional interaction studies. Eslicarbazepine acetate slightly increased the clearance of carbamazepine.
However, due to the general limitations of the data, these results should be taken with care.
Other medicinal products
Oral contraceptives
Administration of eslicarbazepine acetate 1,200 mg once daily to female subjects using a combined oral
contraceptive showed an average decrease of 37% and 42% in systemic exposure to levonorgestrel and
ethinyloestradiol, respectively, most likely caused by an induction of CYP3A4. Therefore, women of
childbearing potential must use adequate contraception during treatment with Zebinix, and up to the end of
the current menstruation cycle after the treatment has been discontinued (see section 4.4 and 4.6).
Warfarin
Co-administration of eslicarbazepine acetate 1,200 mg once daily with warfarin showed a small (23%) but
statistically significant decrease in exposure to S-warfarin. There was no effect on the R-warfarin
pharmacokinetics or on coagulation. However, due to inter-individual variability in the interaction, special
attention on monitoring of INR should be performed the first weeks after initiation or ending concomitant
treatment of warfarin and eslicarbazepine acetate.
Digoxin
A study in healthy subjects showed no effect of eslicarbazepine acetate 1,200 mg once daily on digoxin
pharmacokinetics, suggesting that eslicarbazepine acetate has no effect on the transporter P-glycoprotein.
Monoamino Oxidase Inhibitors (MAOIs)
Based on a structural relationship of eslicarbazepine acetate to tricyclic antidepressants, an interaction
between eslicarbazepine acetate and MAOIs is theoretically possible.
Risk related to epilepsy and antiepileptic medicinal products in general
It has been shown that in the offspring of women with epilepsy, the prevalence of malformations is two to
three times greater than the rate of approximately 3 % in the general population. Most frequently reported are
cleft lip, cardiovascular malformations and neural tube defects. Multiple antiepileptic medicinal product
therapy may be associated with a higher risk of congenital malformations than monotherapy, therefore it is
important that monotherapy is practised whenever possible. Specialist advice should be given to women who
are likely to become pregnant or who are of child-bearing potential. The need for antiepileptic therapy
should be reviewed when a woman is planning to become pregnant. No sudden discontinuation of
antiepileptic therapy should be undertaken as this may lead to breakthrough seizures which could have
serious consequences for both mother and child.
Risk related to eslicarbazepine acetate
There are no data from the use of eslicarbazepine acetate in pregnant women. Studies in animals have shown
reproductive toxicity (see section 5.3). If women receiving eslicarbazepine acetate become pregnant or plan
to become pregnant, the use of Zebinix should be carefully re-evaluated. Minimum effective doses should be
given, and monotherapy whenever possible should be preferred at least during the first three months of
pregnancy. Patients should be counselled regarding the possibility of an increased risk of malformations and
given the opportunity to antenatal screening.
Monitoring and prevention
26
Antiepileptic medicinal products may contribute to folic acid deficiency, a possible contributory cause of
foetal abnormality. Folic acid supplementation is recommended before and during pregnancy. As the
efficacy of this supplementation is not proven, a specific antenatal diagnosis can be offered even for women
with a supplementary treatment of folic acid.
In the newborn child
Bleeding disorders in the newborn caused by antiepileptic medicinal products have been reported. As a
precaution, vitamin K1 should be administered as a preventive measure in the last few weeks of pregnancy
and to the newborn.
Women of childbearing potential/contraception
Eslicarbazepine acetate adversely interacts with oral contraceptives. Therefore, an alternative, effective and
safe method of contraception should be used during treatment and up to the end of the current menstrual
cycle after treatment has been stopped.
It is unknown whether eslicarbazepine acetate is excreted in human breast milk. Animal studies have shown
excretion of eslicarbazepine in breast milk. As a risk to the breast-fed child cannot be excluded breast-
feeding should be discontinued during treatment with Zebinix.
No studies on the effects on the ability to drive and use machines have been performed. Some patients might
experience dizziness, somnolence or visual disorders, particularly on initiation of treatment. Therefore,
patients should be advised that their physical and/ or mental abilities needed for operating machinery or
driving may be impaired and they are recommended not to do so until it has been established that their ability
to perform such activities is not affected.
In placebo-controlled studies involving 1,192 adult patients with partial-onset seizures (856 patients treated
with eslicarbazepine acetate and 336 treated with placebo), 45.3% of patients treated with eslicarbazepine
acetate and 24.4% of patients treated with placebo experienced adverse reactions.
Adverse reactions were usually mild to moderate in intensity and occurred predominantly during the first
weeks of treatment with eslicarbazepine acetate.
In the table below all adverse reactions, which occurred at an incidence greater than placebo and numerically
present in more than 1 patient are listed by System Organ Class and frequency:
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.
Within each frequency category, adverse reactions are presented in order of decreasing seriousness.
System Organ
Class
Very
common
Common
Uncommon
Rare
Blood and
lymphatic system
disorders
Anaemia
Thrombocytopenia,
leukopenia
Immune system
disorders
Hypersensitivity
Endocrine
disorders
Hypothyroidism
Metabolism and
nutrition disorders
Increased appetite,
decreased appetite,
hyponatraemia, electrolyte
imbalance, cachexia,
dehydration, obesity
27
Psychiatric
disorders
Insomnia, apathy,
depression, nervousness,
agitation, attention deficit/
hyperactivity disorder,
confusional state, mood
swings, crying,
psychomotor retardation,
stress, psychotic disorder
Nervous system
disorders
Dizziness*,
somnolence
Headache,
abnormal
coordination
*,
disturbance
in attention,
tremor
Memory impairment,
balance disorder, amnesia,
hypersomnia, sedation,
aphasia, dysaesthesia,
dystonia, lethargy,
parosmia, autonomic
nervous system imbalance,
cerebellar ataxia, cerebellar
syndrome, grand mal
convulsion, neuropathy
peripheral, sleep phase
rhythm disturbance,
nystagmus, speech
disorder, dysarthria,
hypoaesthesia, ageusia,
burning sensation
Eye disorders
Diplopia*,
vision
blurred
Vision disturbance,
oscillopsia, binocular eye
movement disorder, ocular
hyperaemia, saccadic eye
movement, eye pain
Ear and labyrinth
disorders
Vertigo
Ear pain, hypoacusis,
tinnitus
Cardiac disorders
Palpitations, bradycardia,
sinus bradycardia
Vascular disorders
Hypertension, hypotension,
orthostatic hypotension
Respiratory,
thoracic and
mediastinal
disorders
Dysphonia, epistaxis
Gastrointestinal
disorders
Nausea,
vomiting,
diarrhoea
Dyspepsia, gastritis,
abdominal pain, dry mouth,
abdominal discomfort,
abdominal distension,
duodenitis, epigastric
discomfort, gingival
hyperplasia, gingivitis ,
irritable bowel syndrome,
melaena, odynophagia,
stomach discomfort,
stomatitis, toothache
Pancreatitis
Hepatobiliary
disorders
Liver disorder
Skin and
subcutaneous tissue
disorders
Rash
Alopecia, dry skin,
hyperhidrosis, erythema,
nail disorder, skin disorder
28
Musculoskeletal
and connective
tissue disorders
Myalgia, back pain, neck
pain
Renal and urinary
disorders
Nocturia
Reproductive
system and breast
disorders
Menstruation irregular
General disorders
and administration
site conditions
Fatigue, gait
disturbance
Asthenia, malaise, chills,
oedema peripheral, adverse
drug reaction, peripheral
coldness
Investigations
Blood pressure decreased,
weight decreased, blood
pressure diastolic
decreased, blood pressure
increased, blood pressure
systolic decreased, blood
sodium decreased,
haematocrit decreased,
haemoglobin decreased,
heart rate increased,
transaminases increased,
triglycerides increased, tri-
iodothyronine (T3) free
decreased, thyroxine (T4)
free decreased
Injury and
poisoning
Drug toxicity, fall, joint
injury, poisoning, skin
injury
* In patients concomitantly treated with carbamazepine and eslicarbazepine acetate in placebo-controlled
studies, diplopia, abnormal coordination and dizziness were reported more frequently.
The use of eslicarbazepine acetate is associated with increase in the PR interval. Adverse reactions associated
with PR interval prolongation (e.g. AV block, syncope, bradycardia) may occur. No second or higher degree
AV block was seen in eslicarbazepine acetate treated patients.
Rare adverse reactions such as bone marrow depression, anaphylactic reactions, severe cutaneous reactions
(e.g. Stevens-Johnson Syndrome), systemic lupus erythematosus or serious cardiac arrhythmias did not occur
during the placebo-controlled studies of the epilepsy program with eslicarbazepine acetate. However, they
have been reported with oxcarbazepine. Therefore, their occurrence after treatment with Zebinix cannot be
excluded.
Central nervous symptoms such as vertigo, walking instability and hemi-paresis have been observed with
accidental Zebinix overdose. There is no known specific antidote. Symptomatic and supportive treatment
should be administered as appropriate. Eslicarbazepine acetate metabolites can effectively be cleared by
haemodialysis, if necessary (see section 5.2).
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Antiepileptics, Carboxamide derivatives, ATC code:
N03AF04
29
Mechanism of action
The precise mechanisms of action of eslicarbazepine acetate are unknown. However, in vitro
electrophysiological studies indicate that both eslicarbazepine acetate and its metabolites stabilise the
inactivated state of voltage-gated sodium channels, preventing their return to the activated state and thereby
sustaining repetitive neuronal firing.
Pharmacodynamic effect
Eslicarbazepine acetate and its active metabolites prevented the development of seizures in nonclinical
models predictive of anticonvulsant efficacy in man. In humans, the pharmacological activity of
eslicarbazepine acetate is primarily exerted through the active metabolite eslicarbazepine.
Clinical experience
The efficacy and safety of eslicarbazepine acetate has been demonstrated in three phase III double-blind
placebo-controlled studies in 1,049 adult patients with partial epilepsy refractory to treatment with one to
three concomitant anti-epileptic medicinal products. Oxcarbazepine and felbamate were not allowed as
concomitant medicinal products in these studies. Eslicarbazepine acetate was tested at doses of 400 mg,
800 mg and 1200 mg, once daily. Eslicarbazepine acetate 800 mg once daily and 1200 mg once daily were
significantly more effective than placebo in reducing seizure frequency over a 12-week maintenance period.
The percentage of subjects with a 50% reduction in seizure frequency over all phase III studies was 19% for
placebo, 21% for eslicarbazepine acetate 400 mg, 34% for eslicarbazepine acetate 800 mg and 36% for
eslicarbazepine acetate 1200 mg daily.
5.2 Pharmacokinetic properties
Absorption
Eslicarbazepine acetate is extensively converted to
eslicarbazepine. Plasma levels of eslicarbazepine acetate
usually remain below the limit of quantification, following oral administration. Eslicarbazepine t
max
is
attained at 2 to 3 h post-dose. Bioavailability may be assumed as high because the amount of metabolites
recovered in urine corresponded to more than 90% of an eslicarbazepine acetate dose.
Distribution
The binding of eslicarbazepine to plasma proteins is relatively low (<40%) and independent from
concentration.
In vitro
studies have shown that plasma protein binding was not relevantly affected by the
presence of warfarin, diazepam, digoxin, phenytoin and tolbutamide. The binding of warfarin, diazepam,
digoxin, phenytoin and tolbutamide was not significantly affected by the presence of eslicarbazepine.
Biotransformation
Eslicarbazepine acetate is rapidly and extensively biotransformed to its major active metabolite
eslicarbazepine by hydrolytic first-pass metabolism. Peak plasma
concentrations (C
max
) of eslicarbazepine
are attained at 2-3 hours post-dose and steady state plasma concentrations are attained after 4 to 5 days of
once daily dosing, consistent with an effective half-life in the order of 20-24 h. In studies in healthy subjects
and epileptic adult patients, the apparent half-life of eslicarbazepine was 10-20 h and 13-20 h, respectively.
Minor metabolites in plasma are R-licarbazepine and oxcarbazepine, which were shown to be active, and the
glucuronic acid conjugates of eslicarbazepine acetate, eslicarbazepine, R-licarbazepine and oxcarbazepine.
Eslicarbazepine acetate does not affect its own metabolism or clearance.
In studies with eslicarbazepine in fresh human hepatocytes a mild activation of UGT1A1 mediated
glucuronidation was observed.
Excretion
Eslicarbazepine acetate metabolites are eliminated from the systemic circulation primarily by renal excretion,
in the unchanged and glucuronide conjugate forms. In total, eslicarbazepine and its glucuronide correspond
to more than 90% of total metabolites excreted in urine, approximately two thirds in the unchanged form and
one third as glucuronide conjugate.
30
Linearity / non-linearity
The pharmacokinetics of eslicarbazepine is linear and dose-proportional in the range 400-1200 mg both in
healthy subjects and patients.
Elderly (over 65 years of age
)
The pharmacokinetic profile of eslicarbazepine acetate is unaffected in the elderly patients with creatinine
clearance >60 ml/min (see section 4.2).
Renal impairment
Eslicarbazepine acetate metabolites are eliminated from the systemic circulation primarily by renal excretion.
A study in patients with mild to severe renal impairment showed that clearance is dependent on renal
function. During treatment with Zebinix dose adjustment is recommended in patients with creatinine
clearance <60 ml/min (see section 4.2).
Haemodialysis removes eslicarbazepine acetate metabolites from plasma.
Hepatic impairment
The pharmacokinetics and metabolism of eslicarbazepine acetate were evaluated in healthy subjects and
moderately liver-impaired patients after multiple oral doses. Moderate hepatic impairment did not affect the
pharmacokinetics of eslicarbazepine acetate. No dose adjustment is recommended in patients with mild to
moderate liver impairment (see section 4.2).
The pharmacokinetics of eslicarbazepine has not been evaluated in patients with severe hepatic impairment.
Gender
Studies in healthy subjects and patients showed that pharmacokinetics of eslicarbazepine acetate were not
affected by gender.
5.3 Preclinical safety data
Adverse affects observed in animal studies occurred at exposure levels appreciably lower than the clinical
exposure levels to eslicarbazepine (the principal and pharmacologically active metabolite of eslicarbazepine
acetate). Safety margins based on comparative exposure have thus not been established.
Evidence of nephrotoxicity was observed in repeated dose toxicity studies in the rat, but was not seen in
studies in mice or dogs, and is consistent with an exacerbation of spontaneous chronic progressive
nephropathy in this species.
Liver centrilobular hypertrophy was seen in repeated dose toxicity studies in mice and rats and an increased
incidence of liver tumours was observed in the carcinogenicity study in mice; these findings are consistent
with an induction of hepatic microsomal enzymes, an effect which has not been observed in patients
receiving eslicarbazepine acetate.
Genotoxicity studies with eslicarbazepine acetate indicate no special hazards for humans.
Impairment of fertility was observed in female rats; decreases in implantations and live embryos seen in the
mouse fertility study may also indicate effects on female fertility, however, corpora lutea counts were not
evaluated. Eslicarbazepine acetate was not teratogenic in the rat or rabbit, but did induce skeletal
abnormalities in the mouse. Ossification delays, reduced foetal weights, an increase in minor skeletal and
visceral abnormalities were observed at maternal toxic doses in embryotoxicity studies in mice, rats and
rabbits. A delay in sexual development of the F1 generation was observed in peri/post natal studies in mice
and rats.
6.
31
6.1 List of excipients
Povidone K 29/32
Croscarmellose sodium
Magnesium stearate
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
Zebinix 800 mg tablets are packed in ALU/ALU or ALU/PVC blisters placed into cardboard boxes
containing 20, 30, 60 or 90 tablets.
Zebinix 800 mg tablets are packed in HDPE bottles with polypropylene child resistant closure, placed into
cardboard boxes, containing 90 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7.
BIAL - Portela & Cª
, SA
À Av. da Siderurgia Nacional 4745-457 S. Mamede do Coronado - Portugal
tel: +351 22 986 61 00
fax: +351 22 986 61 99
e-mail: info@bial.com
8.
EU/1/09/514/012-020
9.
Date of first authorisation: 21.04.2009
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA)
http://www.emea.europa.eu/
.
32
ANNEX II
A.
MANUFACTURING AUTHORISATION HOLDER
RESPONSIBLE FOR BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
33
A. MANUFACTURING AUTHORISATION HOLDER RESPONSIBLE FOR BATCH RELEASE
Name and address of the manufacturer responsible for batch release
BIAL -Portela & Cª, S.A.
À Av. da Siderurgia Nacional
4745-457 S. Mamede do Coronado
Portugal
B. CONDITIONS OF THE MARKETING AUTHORISATION
Medicinal product subject to medical prescription.
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE
OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
Pharmacovigilance system
The MAH must ensure that the system of pharmacovigilance, as described in version 3.0 presented in
Module 1.8.1. of the Marketing Authorisation Application, is in place and functioning before and whilst the
product is on the market.
Risk Management plan
The MAH commits to performing the studies and additional pharmacovigilance activities detailed in the
Pharmacovigilance Plan, as agreed in version 4.0 of the Risk Management Plan (RMP) presented in Module
1.8.2. of the Marketing Authorisation Application and any subsequent updates of the RMP agreed by the
CHMP.
As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, the
updated RMP should be submitted at the same time as the next Periodic Safety Update Report (PSUR).
In addition, an updated RMP should be submitted
•
When new information is received that may impact on the current Safety Specification,
Pharmacovigilance Plan or risk minimisation activities
•
Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached
•
At the request of the EMEA
34
ANNEX III
LABELLING AND PACKAGE LEAFLET
35
A. LABELLING
36
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Box of 7, 14 or 28 tablets
1.
Zebinix 400 mg tablets
Eslicarbazepine acetate
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 400 mg of eslicarbazepine acetate.
3.
LIST OF EXCIPIENTS
4.
7 tablets
14 tablets
28 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF
THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
37
BIAL-Portela & Cª, S.A.
À Av. da Siderurgia Nacional
4745-457 S. Mamede do Coronado
Portugal
EU/1/09/514/001 7 tablets - ALU/ALU blister
EU/1/09/514/002 14 tablets - ALU/ALU blister
EU/1/09/514/003 28 tablets - ALU/ALU blister
EU/1/09/514/004 7 tablets - PVC/ALU blister
EU/1/09/514/005 14 tablets - PVC/ALU blister
EU/1/09/514/006 28 tablets - PVC/ALU blister
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Zebinix 400 mg
38
MINIMUM PARTICULARS TO APPEAR ON BLISTERS
ALU/ALU blister
PVC/ALU blister
1.
Zebinix 400 mg tablets
Eslicarbazepine acetate
2.
BIAL
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
39
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Box of 30 or 60 tablets
1.
Zebinix 600 mg tablets
Eslicarbazepine acetate
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 600 mg of eslicarbazepine acetate.
3.
LIST OF EXCIPIENTS
4.
30 tablets
60 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF
THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
BIAL-Portela & Cª, S.A.
40
À Av. da Siderurgia Nacional
4745-457 S. Mamede do Coronado
Portugal
EU/1/09/514/007 30 tablets - ALU/ALU blister
EU/1/09/514/008 60 tablets - ALU/ALU blister
EU/1/09/514/009 30 tablets - PVC/ALU blister
EU/1/09/514/010 60 tablets - PVC/ALU blister
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Zebinix 600 mg
41
MINIMUM PARTICULARS TO APPEAR ON BLISTERS
ALU/ALU blister
PVC/ALU blister
1.
Zebinix 600 mg tablets
Eslicarbazepine acetate
2.
BIAL
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
42
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND ON THE IMMEDIATE
PACKAGING
HPDE bottles carton and HPDE bottles of 90 tablets
1.
Zebinix 600 mg tablets
Eslicarbazepine acetate
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 600 mg of eslicarbazepine acetate.
3.
LIST OF EXCIPIENTS
4.
90 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF
THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
43
BIAL-Portela & Cª, S.A.
À Av. da Siderurgia Nacional
4745-457 S. Mamede do Coronado
Portugal
EU/1/09/514/011
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Zebinix 600 mg
(outer pack only)
44
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
Box of 20, 30, 60 or 90 tablets
1.
Zebinix 800 mg tablets
Eslicarbazepine acetate
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet contains 800 mg of eslicarbazepine acetate.
3.
LIST OF EXCIPIENTS
4.
20 tablets
30 tablets
60 tablets
90 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF
THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
45
BIAL-Portela & Cª, S.A.
À Av. da Siderurgia Nacional
4745-457 S. Mamede do Coronado
Portugal
EU/1/09/514/012 20 tablets - ALU/ALU blister
EU/1/09/514/013 30 tablets - ALU/ALU blister
EU/1/09/514/014 60 tablets - ALU/ALU blister
EU/1/09/514/015 90 tablets - ALU/ALU blister
EU/1/09/514/016 20 tablets - PVC/ALU blister
EU/1/09/514/017 30 tablets - PVC/ALU blister
EU/1/09/514/018 60 tablets - PVC/ALU blister
EU/1/09/514/019 90 tablets - PVC/ALU blister
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Zebinix 800 mg
46
MINIMUM PARTICULARS TO APPEAR ON BLISTERS
ALU/ALU blister
PVC/ALU blister
1.
Zebinix 800 mg tablets
Eslicarbazepine acetate
2.
BIAL
3.
EXPIRY DATE
EXP
4.
BATCH NUMBER
Lot
5.
OTHER
47
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND ON THE IMMEDIATE
PACKAGING
HPDE bottles carton and HPDE bottles of 90 tablets
1.
Zebinix 800 mg tablets
Eslicarbazepine acetate
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
Each tablet constains 800 mg of eslicarbazepine acetate.
3.
LIST OF EXCIPIENTS
4.
90 tablets
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
Oral use.
Read the package leaflet before use.
6.
SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT OF
THE REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children.
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP
9.
SPECIAL STORAGE CONDITIONS
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE
48
BIAL-Portela & Cª, S.A.
À Av. da Siderurgia Nacional
4745-457 S. Mamede do Coronado
Portugal
EU/1/09/514/020
13. BATCH NUMBER
Lot
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
Zebinix 800 mg
(outer pack only)
49
B. PACKAGE LEAFLET
50
PACKAGE LEAFLET: INFORMATION FOR THE USER
Zebinix 400 mg tablets
Eslicarbazepine acetate
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their
symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell
your doctor or pharmacist.
In this leaflet
:
1. What Zebinix is and what it is used for
2. Before you take Zebinix
3. How to take Zebinix
4. Possible side effects
5.
How to store Zebinix
6.
1.
WHAT ZEBINIX IS AND WHAT IT IS USED FOR
Zebinix belongs to a group of medicines called anti-epileptics used to treat epilepsy, a condition where
someone has repeated seizures or fits.
Zebinix is used in adult patients who are already taking other anti-epileptic medicines and are still
experiencing seizures that affect one part of the brain (partial seizure). These seizures may or may not be
followed by a seizure affecting all of the brain (secondary generalisation).
Zebinix has been given to you by your doctor to reduce your number of seizures.
2.
BEFORE YOU TAKE ZEBINIX
Do not take Zebinix if
:
•
you are allergic (hypersensitive) to the active substance (eslicarbazepine acetate), to other
carboxamide derivatives (e.g. carbamazepine or oxcarbazepine, medicines used to treat epilepsy) or to
any of the other ingredients
•
you suffer from a certain type of heart rhythm disorder (second or third degree atrioventricular (AV)
block)
Take special care with Zebinix
Contact your doctor immediately if:
•
you have rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue. These
could be signs of an allergic reaction.
•
you suffer from confusion, worsening of seizures or decreased consciousness which can be signs of
low blood salt levels
Please tell your doctor if:
•
you have kidney problems. Your doctor may need to adjust the dose. Zebinix is not recommended in
patients with severe renal disease.
•
you have liver problems. Zebinix is not recommended in patients with severe liver problems.
51
Further information
•
you are taking any medicine which can cause an abnormality on the ECG (electrocardiogram) called
increased PR interval. If you are not sure if the medicines you are taking could have this effect, discuss
with your doctor.
•
you suffer from a heart disease such as heart failure or heart attack.
•
you suffer from seizures that begin with a widespread electric discharge that involves both sides of the
brain
Zebinix may make you feel dizzy and/or drowsy, particularly at the beginning of treatment. Take special care
when taking Zebinix to avoid accidental injury (fall).
A small number of people being treated with anti-epileptics have had thoughts of harming or killing
themselves. If at any time you have these thoughts, when taking Zebinix, contact your doctor immediately.
Children
Zebinix is not to be given to children and adolescents.
Taking other medicines
•
Tell your doctor if you are taking phenytoin (a medicine used to treat epilepsy) since your dose may
need to be adjusted.
•
Tell your doctor if you are taking carbamazepine (a medicine used to treat epilepsy) since the following
side effects of Zebinix may occur in higher frequency: seeing double, abnormal coordination and
dizziness.
•
Tell your doctor if you are taking the blood thinner - warfarin.
•
Tell your doctor if you are taking tricyclic antidepressants e.g. amitriptyline.
•
Tell your doctor if you are taking hormonal/oral contraceptives. Zebinix may make hormonal
contraceptives such as the contraceptive pill less effective. Therefore it is recommended that you use
other forms of safe and effective contraception, when taking Zebinix up to the end of the current
menstrual cycle after stopping treatment.
•
Do not take oxcarbazepine (a medicine used to treat epilepsy) with Zebinix, as it is not known whether it
is safe to take these medicines together.
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription. This is just in case any of them interfere with how Zebinix works
or how Zebinix interferes with their effect.
Taking Zebinix with food and drink
Zebinix tablets may be taken with or without food.
Pregnancy and breast-feeding
Tell your doctor immediately if you are pregnant or planning to become pregnant. You must only take
Zebinix during pregnancy if your doctor tells you.
Research has shown an increased risk of birth defects in children of women taking anti-epileptic medicines.
On the other hand effective anti-epileptic therapy must not be interrupted since the worsening of the disease
is harmful to both the mother and the unborn child.
Do not breast-feed while you are taking Zebinix. It is not known whether it passes into breast milk.
See
‘
Taking other medicines’ section for advice about contraception.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Zebinix may make you feel dizzy, drowsy and affect your vision, particularly at the beginning of treatment.
If this happens to you, do not drive or use any tools or machines.
52
3.
HOW TO TAKE ZEBINIX
Always take Zebinix exactly as your doctor has told you. You should check with your doctor or pharmacist
if you are not sure.
Adults
There are two dosing regimes for adults:
Dose when you start treatment
400 mg dose once daily for one or two weeks, before increasing to the maintenance dose. Your doctor will
decide whether you will be given this dose for one or two weeks.
Maintenance dose
The
usual maintenance dose is 800 mg once daily.
Depending on how you respond to Zebinix, your dose may be increased to 1200 mg once daily.
Elderly (over 65 years of age)
If you are elderly your doctor will decide the suitable dose for you.
Patients with kidney problems
If you have kidney problems you will usually be given a lower dose of Zebinix. Your doctor will work out
the correct dose for you. Zebinix is not recommended if you have severe kidney problems.
Patients with liver problems
The dose is the same as for adults. However, Zebinix is not recommended if you have severe liver problems.
Please talk to your doctor if you are unsure about the dose you should be taking.
Method and route of administration
Swallow the tablet with a glass of water.
If you take more Zebinix than you should
If you accidently take more Zebinix than you should, tell a doctor or go to a hospital accident and emergency
department immediately. Take the medicine pack with you. This is so the doctor knows what you have taken.
If you forget to take Zebinix
If you forget to take a tablet, take it as soon as you remember and carry on as usual. Do not take a double
dose to make up for the one you have missed.
If you stop taking Zebinix
Do not stop taking your tablets suddenly. If you do, you are at risk of having more seizures. Your doctor will
decide how long you should take Zebinix for. Should your doctor decide to stop your treatment with Zebinix
your dose will usually be reduced gradually. It is important that your treatment is completed as advised by
your doctor or your symptoms may get worse.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Zebinix can cause side effects, although not everybody gets them.
The following side effects can be very serious. If they happen to you stop taking Zebinix and tell a doctor or
go to a hospital immediately, as you may need urgent medical treatment
:
•
Rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue. These could be
signs of an allergic reaction
53
The frequency of possible side effects listed below is defined as using the following convention:
very common (affects more than 1 user in 10)
common (affects 1 to 10 users in 100)
uncommon (affects 1 to 10 users in 1,000)
rare (affects 1 to 10 users in 10,000)
very rare (affects less than 1 user in 10,000)
Very common
side effects are:
•
Feeling dizzy or sleepy
Common
side effects are:
•
Feeling unsteady or having a sensation of spinning or floating
•
Feeling sick or vomiting
•
Headache
•
Diarrhoea
•
Seeing double or blurred vision
•
Difficulty in concentration
•
Feeling low in energy or tired
•
Shaking
•
Clumsiness
•
Skin rash
•
Numbness and tingling in hands and feet
Uncommon
side effects are:
•
Hypersensitivity
•
Worsening of seizures
•
Underactive thyroid gland.
Symptoms include cold intolerance, large tongue, thin and brittle fingernails
or hair and low body temperature.
•
Increased levels of circulating fats in your blood
•
Difficulty in sleeping
•
Liver problems
•
High or low blood pressure or a fall in blood pressure on standing up
•
Blood tests showing that you have low levels of salts or sodium in your blood or a reduction in red blood
cells
•
Dehydration
•
Eye movement changes, fuzzy vision, red eye or eye pain
•
Having falls
•
Poor memory or forgetfulness
•
Crying, feeling depressed, nervous or confused, lack of interest or emotion
•
Inability to speak or write or understand spoken or written language
•
Agitated
•
Mood changes or hallucinations
•
Difficulty in speaking
•
Nosebleed
•
Weight loss and general ill health (Cachexia)
•
Feeling numb in any part of your body
•
Burning sensation
•
Disturbances in the sense of smell and/or tasting
•
Ear pain or ringing in the ears
•
Swelling in your legs and arms
•
Heart burn, stomach upset, abdominal pain, abdominal bloating and discomfort or dry mouth
•
Blood in faeces
•
Inflamed gums, mouth inflammation or toothache
54
•
Painful swallowing
•
Sweating or having dry skin
•
Nail or skin changes (e.g. red skin)
•
Hair loss
•
Having irregular periods
•
Increased urine production during night time
•
Feeling generally unwell or having chills
•
Increased or decreased appetite
•
Weight loss or extreme weight gain
•
Muscle pain
•
Back pain or neck pain
•
Cold limbs
•
Faster, slower or irregular heart beat
•
Feeling sleepy
•
Neurological movement disorder where your muscles contract causing twisting and repetitive
movements or abnormal postures. Symptoms include tremors, pain, cramping.
•
Irritable Bowel Syndrome (IBS). Symptoms include chronic abdominal cramps and diarrhoea or
constipation.
Rare
side effects are:
•
Reduction in blood platelets which increases risk of bleeding or bruising
•
Severe pain in the back and stomach
•
Reduction in white blood cells which makes infections more likely
The use of Zebinix is associated with an abnormality in ECG (electrocardiogram) called increase in
PR interval. Side effects associated with this ECG abnormality (e.g. fainting and slowing of heart beat) may
occur.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your
doctor or pharmacist.
5.
HOW TO STORE ZEBINIX
Keep out of the reach and sight of children.
Do not use Zebinix after the expiry date, which is stated on the blister package and the carton after EXP. The
expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Zebinix contains
•
The active substance is eslicarbazepine acetate. Each tablet contains 400 mg of eslicarbazepine acetate.
•
The other ingredients are povidone K29/32, croscarmellose sodium and magnesium stearate.
What Zebinix looks like and contents of the pack
Zebinix 400 mg tablets are white, circular and biconvex. The tablets have ‘ESL 400’engraved on one side
and are scored on the other side. The scoreline is only to facilitate breaking the tablet into two for ease of
swallowing, and it does not divide the tablet into two equal doses.
55
The tablets are packaged in blisters in cardboard boxes containing 7, 14 or 28 tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
BIAL - Portela & Cª
, S.A., À Av. da Siderurgia Nacional
4745-457 S. Mamede do Coronado
Portugal
tel: +351 22 986 61 00
fax: +351 22 986 61 99
e-mail: info@bial.com
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Eisai Europe Ltd
Tél/Tel: + 32 (0) 2 735 45 34
Luxembourg/Luxemburg
Eisai Europe Ltd.
Tél/Tel: + 32 (0) 2 735 45 34
(Belgique/Belgien)
България
BIAL-Portela & Cª., S.A.
Teл.: + 351 22 986 61 00
(Португалия)
Magyarország
Eisai GesmbH
Tel.: + 36 1 230 43 20
Česká republika
Eisai GesmbH organizační složka
Tel: +420 242 485 839
Malta
BIAL-Portela & Cª., S.A.
Tel: + 351 22 986 61 00
(Il-Portugall)
Danmark
Eisai AB
Tlf: + 46 (0) 8 501 01 600'
(Sverige)
Nederland
Eisai Europe Ltd.
Tél/Tel: + 32 (0) 2 735 45 34
(België/Belgique)
Deutschland
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
Norge
Eisai AB
Tlf: + 46 (0) 8 501 01 600
(Sverige)
Eesti
BIAL-Portela & Cª, S.A.
Tel: +351 22 986 61 00
(Portugal)
Österreich
Eisai GesmbH
Tel: + 43 (0) 1 535 1980-0
Ελλάδα
Arriani Pharmaceuticals S.A.
Τηλ: + 30 210 668 3000
Polska
BIAL-Portela & Cª, S.A.
Tel.: + 351 22 986 61 00
(Portugália)
España
BIAL Industrial Farmacéutica, S.A.
Tel: + 34 94 443 80 00
Portugal
BIAL-Portela & Cª., S.A.
Tel.: + 351 22 986 61 00
56
France
Eisai SAS
Tél: + (33) 1 47 67 00 05
România
BIAL-Portela & Cª, S.A.
Tel: + 351 22 986 61 00
(Portugalia)
Ireland
Eisai Ltd.
Tel: + 44(0) 208 600 1400
(United Kingdom)
Slovenija
BIAL-Portela & Cª, S.A.
Tel: + 351 22 986 61 00
(Portugalska)
Ísland
Eisai AB
Sími: + 46 (0) 8 501 01 600
(Svíþjóð)
Slovenská republika
Eisai GesmbH organizační složka
Tel: + 420 242 485 839
(Česká republika)
Italia
Eisai S.r.l.
Tel: + 39 02 518 1401
Suomi/Finland
Eisai AB
Puh/Tel: + 46 (0) 8 501 01 600
(Ruotsi)
Κύπρος
BIAL-Portela & Cª, S.A.
Τηλ: + 351 22 986 61 00
(Πορτογαλία)
Sverige
Eisai AB
Tel: + 46 (0) 8 501 01 600
Latvija
BIAL-Portela & Cª, S.A.
Tel: + 351 22 986 61 00
(Portugāle)
United Kingdom
Eisai Ltd.
Tel: + 44 (0) 208 600 1400
Lietuva
BIAL-Portela & Cª, S.A.
Tel: + 351 22 986 61 00
(Portugalija)
This leaflet was last approved in
MMM/YYYY
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site:
57
PACKAGE LEAFLET: INFORMATION FOR THE USER
Zebinix 600 mg tablets
Eslicarbazepine acetate
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their
symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell
your doctor or pharmacist.
In this leaflet
:
1. What Zebinix is and what it is used for
2. Before you take Zebinix
3. How to take Zebinix
4. Possible side effects
5.
How to store Zebinix
6.
Further information
1.
WHAT ZEBINIX IS AND WHAT IT IS USED FOR
Zebinix belongs to a group of medicines called anti-epileptics used to treat epilepsy, a condition where
someone has repeated seizures or fits.
Zebinix is used in adult patients who are already taking other anti-epileptic medicines and are still
experiencing seizures that affect one part of the brain (partial seizure). These seizures may or may not be
followed by a seizure affecting all of the brain (secondary generalisation).
Zebinix has been given to you by your doctor to reduce your number of seizures.
2.
BEFORE YOU TAKE ZEBINIX
Do not take Zebinix if
:
•
you are allergic (hypersensitive) to the active substance (eslicarbazepine acetate), to other
carboxamide derivatives (e.g. carbamazepine or oxcarbazepine, medicines used to treat epilepsy) or to
any of the other ingredients
•
you suffer from a certain type of heart rhythm disorder (second or third degree atrioventricular (AV)
block)
Take special care with Zebinix
Contact your doctor immediately if:
•
you have rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue. These
could be signs of an allergic reaction.
•
you suffer from confusion, worsening of seizures or decreased consciousness which can be signs of
low blood salt levels
Please tell your doctor if:
•
you have kidney problems. Your doctor may need to adjust the dose. Zebinix is not recommended in
patients with severe renal disease.
•
you have liver problems. Zebinix is not recommended in patients with severe liver problems.
58
•
you are taking any medicine which can cause an abnormality on the ECG (electrocardiogram) called
increased PR interval. If you are not sure if the medicines you are taking could have this effect, discuss
with your doctor.
•
you suffer from a heart disease such as heart failure or heart attack.
•
you suffer from seizures that begin with a widespread electric discharge that involves both sides of the
brain
Zebinix may make you feel dizzy and/or drowsy, particularly at the beginning of treatment. Take special care
when taking Zebinix to avoid accidental injury (fall).
A small number of people being treated with anti-epileptics have had thoughts of harming or killing
themselves. If at any time you have these thoughts, when taking Zebinix, contact your doctor immediately.
Children
Zebinix is not to be given to children and adolescents.
Taking other medicines
•
Tell your doctor if you are taking phenytoin (a medicine used to treat epilepsy) since your dose may
need to be adjusted.
•
Tell your doctor if you are taking carbamazepine (a medicine used to treat epilepsy) since the following
side effects of Zebinix may occur in higher frequency: seeing double, abnormal coordination and
dizziness.
•
Tell your doctor if you are taking the blood thinner - warfarin.
•
Tell your doctor if you are taking tricyclic antidepressants e.g. amitriptyline.
•
Tell your doctor if you are taking hormonal/oral contraceptives. Zebinix may make hormonal
contraceptives such as the contraceptive pill less effective. Therefore it is recommended that you use
other forms of safe and effective contraception, when taking Zebinix up to the end of the current
menstrual cycle after stopping treatment.
•
Do not take oxcarbazepine (a medicine used to treat epilepsy) with Zebinix, as it is not known whether it
is safe to take these medicines together.
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription. This is just in case any of them interfere with how Zebinix works
or how Zebinix interferes with their effect.
Taking Zebinix with food and drink
Zebinix tablets may be taken with or without food.
Pregnancy and breast-feeding
Tell your doctor immediately if you are pregnant or planning to become pregnant. You must only take
Zebinix during pregnancy if your doctor tells you.
Research has shown an increased risk of birth defects in children of women taking anti-epileptic medicines.
On the other hand effective anti-epileptic therapy must not be interrupted since the worsening of the disease
is harmful to both the mother and the unborn child.
Do not breast-feed while you are taking Zebinix. It is not known whether it passes into breast milk.
See
‘
Taking other medicines’ section for advice about contraception.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Zebinix may make you feel dizzy, drowsy and affect your vision, particularly at the beginning of treatment.
If this happens to you, do not drive or use any tools or machines.
59
3.
HOW TO TAKE ZEBINIX
Always take Zebinix exactly as your doctor has told you. You should check with your doctor or pharmacist
if you are not sure.
Adults
There are two dosing regimes for adults:
Dose when you start treatment
400 mg dose once daily for one or two weeks, before increasing to the maintenance dose. Your doctor will
decide whether you will be given this dose for one or two weeks.
Maintenance dose
The
usual maintenance dose is 800 mg once daily.
Depending on how you respond to Zebinix, your dose may be increased to 1200 mg once daily.
Elderly (over 65 years of age)
If you are elderly your doctor will decide the suitable dose for you.
Patients with kidney problems
If you have kidney problems you will usually be given a lower dose of Zebinix. Your doctor will work out
the correct dose for you. Zebinix is not recommended if you have severe kidney problems.
Patients with liver problems
The dose is the same as for adults. However, Zebinix is not recommended if you have severe liver problems.
Please talk to your doctor if you are unsure about the dose you should be taking.
Method and route of administration
Swallow the tablet with a glass of water.
If you take more Zebinix than you should
If you accidently take more Zebinix than you should, tell a doctor or go to a hospital accident and emergency
department immediately. Take the medicine pack with you. This is so the doctor knows what you have taken.
If you forget to take Zebinix
If you forget to take a tablet, take it as soon as you remember and carry on as usual. Do not take a double
dose to make up for the one you have missed.
If you stop taking Zebinix
Do not stop taking your tablets suddenly. If you do, you are at risk of having more seizures. Your doctor will
decide how long you should take Zebinix for. Should your doctor decide to stop your treatment with Zebinix
your dose will usually be reduced gradually. It is important that your treatment is completed as advised by
your doctor or your symptoms may get worse.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Zebinix can cause side effects, although not everybody gets them.
The following side effects can be very serious. If they happen to you stop taking Zebinix and tell a doctor or
go to a hospital immediately, as you may need urgent medical treatment
:
•
Rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue. These could be
signs of an allergic reaction
60
The frequency of possible side effects listed below is defined as using the following convention:
very common (affects more than 1 user in 10)
common (affects 1 to 10 users in 100)
uncommon (affects 1 to 10 users in 1,000)
rare (affects 1 to 10 users in 10,000)
very rare (affects less than 1 user in 10,000)
Very common
side effects are:
•
Feeling dizzy or sleepy
Common
side effects are:
•
Feeling unsteady or having a sensation of spinning or floating
•
Feeling sick or vomiting
•
Headache
•
Diarrhoea
•
Seeing double or blurred vision
•
Difficulty in concentration
•
Feeling low in energy or tired
•
Shaking
•
Clumsiness
•
Skin rash
•
Numbness and tingling in hands and feet
Uncommon
side effects are:
•
Hypersensitivity
•
Worsening of seizures
•
Underactive thyroid gland.
Symptoms include cold intolerance, large tongue, thin and brittle fingernails
or hair and low body temperature.
•
Increased levels of circulating fats in your blood
•
Difficulty in sleeping
•
Liver problems
•
High or low blood pressure or a fall in blood pressure on standing up
•
Blood tests showing that you have low levels of salts or sodium in your blood or a reduction in red blood
cells
•
Dehydration
•
Eye movement changes, fuzzy vision, red eye or eye pain
•
Having falls
•
Poor memory or forgetfulness
•
Crying, feeling depressed, nervous or confused, lack of interest or emotion
•
Inability to speak or write or understand spoken or written language
•
Agitated
•
Mood changes or hallucinations
•
Difficulty in speaking
•
Nosebleed
•
Weight loss and general ill health (Cachexia)
•
Feeling numb in any part of your body
•
Burning sensation
•
Disturbances in the sense of smell and/or tasting
•
Ear pain or ringing in the ears
•
Swelling in your legs and arms
•
Heart burn, stomach upset, abdominal pain, abdominal bloating and discomfort or dry mouth
•
Blood in faeces
•
Inflamed gums, mouth inflammation or toothache
61
•
Painful swallowing
•
Sweating or having dry skin
•
Nail or skin changes (e.g. red skin)
•
Hair loss
•
Having irregular periods
•
Increased urine production during night time
•
Feeling generally unwell or having chills
•
Increased or decreased appetite
•
Weight loss or extreme weight gain
•
Muscle pain
•
Back pain or neck pain
•
Cold limbs
•
Faster, slower or irregular heart beat
•
Feeling sleepy
•
Neurological movement disorder where your muscles contract causing twisting and repetitive
movements or abnormal postures. Symptoms include tremors, pain, cramping.
•
Irritable Bowel Syndrome (IBS). Symptoms include chronic abdominal cramps and diarrhoea or
constipation.
Rare
side effects are:
•
Reduction in blood platelets which increases risk of bleeding or bruising
•
Severe pain in the back and stomach
•
Reduction in white blood cells which makes infections more likely
The use of Zebinix is associated with an abnormality in ECG (electrocardiogram) called increase in
PR interval. Side effects associated with this ECG abnormality (e.g. fainting and slowing of heart beat) may
occur.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your
doctor or pharmacist.
5.
HOW TO STORE ZEBINIX
Keep out of the reach and sight of children.
Do not use Zebinix after the expiry date, which is stated on the blister package, bottle and the carton after
EXP. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Zebinix contains
•
The active substance is eslicarbazepine acetate. Each tablet contains 600 mg of eslicarbazepine acetate.
•
The other ingredients are povidone K29/32, croscarmellose sodium and magnesium stearate.
What Zebinix looks like and contents of the pack
Zebinix 600 mg tablets are white and oblong. The tablets have ‘ESL 600’engraved on one side and are
scored on the other side, enabling the tablets to be divided into equal halves.
62
The tablets are packaged in blisters in cardboard boxes containing 30 or 60 tablets, and in HDPE bottles with
child resistant closure in cardboard boxes containing 90 tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
BIAL - Portela & Cª
, S.A., À Av. da Siderurgia Nacional
4745-457 S. Mamede do Coronado
Portugal
tel: +351 22 986 61 00
fax: +351 22 986 61 99
e-mail: info@bial.com
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Eisai Europe Ltd
Tél/Tel: + 32 (0) 2 735 45 34
Luxembourg/Luxemburg
Eisai Europe Ltd.
Tél/Tel: + 32 (0) 2 735 45 34
(Belgique/Belgien)
България
BIAL-Portela & Cª., S.A.
Teл.: + 351 22 986 61 00
(Португалия)
Magyarország
Eisai GesmbH
Tel.: + 36 1 230 43 20
Česká republika
Eisai GesmbH organizační složka
Tel: +420 242 485 839
Malta
BIAL-Portela & Cª., S.A.
Tel: + 351 22 986 61 00
Il-Portugall)
Danmark
Eisai AB
Tlf: + 46 (0) 8 501 01 600
(Sverige)
Nederland
Eisai Europe Ltd.
Tél/Tel: + 32 (0) 2 735 45 34
(België/Belgique)
Deutschland
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
Norge
Eisai AB
Tlf: + 46 (0) 8 501 01 600
(Sverige)
Eesti
BIAL-Portela & Cª, S.A.
Tel: +351 22 986 61 00
(Portugal)
Österreich
Eisai GesmbH
Tel: + 43 (0) 1 535 1980-0
Ελλάδα
Arriani Pharmaceuticals S.A.
Τηλ: + 30 210 668 3000
Polska
BIAL-Portela & Cª, S.A.
Tel.: + 351 22 986 61 00
(Portugália)
España
BIAL Industrial Farmacéutica, S.A.
Tel: + 34 94 443 80 00
Portugal
BIAL-Portela & Cª., S.A.
Tel.: + 351 22 986 61 00
63
France
Eisai SAS
Tél: + (33) 1 47 67 00 05
România
BIAL-Portela & Cª, S.A.
Tel: + 351 22 986 61 00
(Portugalia)
Ireland
Eisai Ltd.
Tel: + 44(0) 208 600 1400
(United Kingdom)
Slovenija
BIAL-Portela & Cª, S.A.
Tel: + 351 22 986 61 00
(Portugalska)
Ísland
Eisai AB
Sími: + 46 (0) 8 501 01 600
(Svíþjóð)
Slovenská republika
Eisai GesmbH organizační složka
Tel: + 420 242 485 839
(Česká republika)
Italia
Eisai S.r.l.
Tel: + 39 02 518 1401
Suomi/Finland
Eisai AB
Puh/Tel: + 46 (0) 8 501 01 600
(Ruotsi)
Κύπρος
BIAL-Portela & Cª, S.A.
Τηλ: + 351 22 986 61 00
(Πορτογαλία)
Sverige
Eisai AB
Tel: + 46 (0) 8 501 01 600
Latvija
BIAL-Portela & Cª, S.A.
Tel: + 351 22 986 61 00
(Portugāle)
United Kingdom
Eisai Ltd.
Tel: + 44 (0) 208 600 1400
Lietuva
BIAL-Portela & Cª, S.A.
Tel: + 351 22 986 61 00
(Portugalija)
This leaflet was last approved in
MMM/YYYY
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site:
64
PACKAGE LEAFLET: INFORMATION FOR THE USER
Zebinix 800 mg tablets
Eslicarbazepine acetate
Read all of this leaflet carefully before you start taking this medicine.
-
Keep this leaflet. You may need to read it again.
-
If you have any further questions, ask your doctor or pharmacist.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even if their
symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell
your doctor or pharmacist.
In this leaflet
:
1.
What Zebinix is and what it is used for
3.
How to take Zebinix
4.
Possible side effects
5.
How to store Zebinix
6.
Further information
1.
WHAT ZEBINIX IS AND WHAT IT IS USED FOR
Zebinix belongs to a group of medicines called anti-epileptics used to treat epilepsy, a condition where
someone has repeated seizures or fits.
Zebinix is used in adult patients who are already taking other anti-epileptic medicines and are still
experiencing seizures that affect one part of the brain (partial seizure). These seizures may or may not be
followed by a seizure affecting all of the brain (secondary generalisation).
Zebinix has been given to you by your doctor to reduce your number of seizures.
2.
BEFORE YOU TAKE ZEBINIX
Do not take Zebinix if
:
•
you are allergic (hypersensitive) to the active substance (eslicarbazepine acetate), to other
carboxamide derivatives (e.g. carbamazepine or oxcarbazepine, medicines used to treat epilepsy) or to
any of the other ingredients
•
you suffer from a certain type of heart rhythm disorder (second or third degree atrioventricular (AV)
block)
Take special care with Zebinix
Contact your doctor immediately if:
•
you have rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue. These
could be signs of an allergic reaction.
•
you suffer from confusion, worsening of seizures or decreased consciousness which can be signs of
low blood salt levels
Please tell your doctor if:
•
you have kidney problems. Your doctor may need to adjust the dose. Zebinix is not recommended in
patients with severe renal disease.
•
you have liver problems. Zebinix is not recommended in patients with severe liver problems.
65
2.
Before you take Zebinix
•
you are taking any medicine which can cause an abnormality on the ECG (electrocardiogram) called
increased PR interval. If you are not sure if the medicines you are taking could have this effect, discuss
with your doctor.
•
you suffer from a heart disease such as heart failure or heart attack.
•
you suffer from seizures that begin with a widespread electric discharge that involves both sides of the
brain
Zebinix may make you feel dizzy and/or drowsy, particularly at the beginning of treatment. Take special care
when taking Zebinix to avoid accidental injury (fall).
A small number of people being treated with anti-epileptics have had thoughts of harming or killing
themselves. If at any time you have these thoughts, when taking Zebinix, contact your doctor immediately.
Children
Zebinix is not to be given to children and adolescents.
Taking other medicines
•
Tell your doctor if you are taking phenytoin (a medicine used to treat epilepsy) since your dose may
need to be adjusted.
•
Tell your doctor if you are taking carbamazepine (a medicine used to treat epilepsy) since the following
side effects of Zebinix may occur in higher frequency: seeing double, abnormal coordination and
dizziness.
•
Tell your doctor if you are taking the blood thinner - warfarin.
•
Tell your doctor if you are taking tricyclic antidepressants e.g. amitriptyline.
•
Tell your doctor if you are taking hormonal/oral contraceptives. Zebinix may make hormonal
contraceptives such as the contraceptive pill less effective. Therefore it is recommended that you use
other forms of safe and effective contraception, when taking Zebinix up to the end of the current
menstrual cycle after stopping treatment.
•
Do not take oxcarbazepine (a medicine used to treat epilepsy) with Zebinix, as it is not known whether it
is safe to take these medicines together.
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including
medicines obtained without a prescription. This is just in case any of them interfere with how Zebinix works
or how Zebinix interferes with their effect.
Taking Zebinix with food and drink
Zebinix tablets may be taken with or without food.
Pregnancy and breast-feeding
Tell your doctor immediately if you are pregnant or planning to become pregnant. You must only take
Zebinix during pregnancy if your doctor tells you.
Research has shown an increased risk of birth defects in children of women taking anti-epileptic medicines.
On the other hand effective anti-epileptic therapy must not be interrupted since the worsening of the disease
is harmful to both the mother and the unborn child.
Do not breast-feed while you are taking Zebinix. It is not known whether it passes into breast milk.
See
‘
Taking other medicines’ section for advice about contraception.
Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
Zebinix may make you feel dizzy, drowsy and affect your vision, particularly at the beginning of treatment.
If this happens to you, do not drive or use any tools or machines.
66
3.
HOW TO TAKE ZEBINIX
Always take Zebinix exactly as your doctor has told you. You should check with your doctor or pharmacist
if you are not sure.
Adults
There are two dosing regimes for adults:
Dose when you start treatment
400 mg dose once daily for one or two weeks, before increasing to the maintenance dose. Your doctor will
decide whether you will be given this dose for one or two weeks.
Maintenance dose
The
usual maintenance dose is 800 mg once daily.
Depending on how you respond to Zebinix, your dose may be increased to 1200 mg once daily.
Elderly (over 65 years of age)
If you are elderly your doctor will decide the suitable dose for you.
Patients with kidney problems
If you have kidney problems you will usually be given a lower dose of Zebinix. Your doctor will work out
the correct dose for you. Zebinix is not recommended if you have severe kidney problems.
Patients with liver problems
The dose is the same as for adults. However, Zebinix is not recommended if you have severe liver problems.
Please talk to your doctor if you are unsure about the dose you should be taking.
Method and route of administration
Swallow the tablet with a glass of water.
If you take more Zebinix than you should
If you accidently take more Zebinix than you should, tell a doctor or go to a hospital accident and emergency
department immediately. Take the medicine pack with you. This is so the doctor knows what you have taken.
If you forget to take Zebinix
If you forget to take a tablet, take it as soon as you remember and carry on as usual. Do not take a double
dose to make up for the one you have missed.
If you stop taking Zebinix
Do not stop taking your tablets suddenly. If you do, you are at risk of having more seizures. Your doctor will
decide how long you should take Zebinix for. Should your doctor decide to stop your treatment with Zebinix
your dose will usually be reduced gradually. It is important that your treatment is completed as advised by
your doctor or your symptoms may get worse.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Zebinix can cause side effects, although not everybody gets them.
The following side effects can be very serious. If they happen to you stop taking Zebinix and tell a doctor or
go to a hospital immediately, as you may need urgent medical treatment
:
•
Rash, swallowing or breathing problems, swelling of your lips, face, throat or tongue. These could be
signs of an allergic reaction
67
The frequency of possible side effects listed below is defined as using the following convention:
very common (affects more than 1 user in 10)
common (affects 1 to 10 users in 100)
uncommon (affects 1 to 10 users in 1,000)
rare (affects 1 to 10 users in 10,000)
very rare (affects less than 1 user in 10,000)
Very common
side effects are:
•
Feeling dizzy or sleepy
Common
side effects are:
•
Feeling unsteady or having a sensation of spinning or floating
•
Feeling sick or vomiting
•
Headache
•
Diarrhoea
•
Seeing double or blurred vision
•
Difficulty in concentration
•
Feeling low in energy or tired
•
Shaking
•
Clumsiness
•
Skin rash
•
Numbness and tingling in hands and feet
Uncommon
side effects are:
•
Hypersensitivity
•
Worsening of seizures
•
Underactive thyroid gland.
Symptoms include cold intolerance, large tongue, thin and brittle fingernails
or hair and low body temperature.
•
Increased levels of circulating fats in your blood
•
Difficulty in sleeping
•
Liver problems
•
High or low blood pressure or a fall in blood pressure on standing up
•
Blood tests showing that you have low levels of salts or sodium in your blood or a reduction in red blood
cells
•
Dehydration
•
Eye movement changes, fuzzy vision, red eye or eye pain
•
Having falls
•
Poor memory or forgetfulness
•
Crying, feeling depressed, nervous or confused, lack of interest or emotion
•
Inability to speak or write or understand spoken or written language
•
Agitated
•
Mood changes or hallucinations
•
Difficulty in speaking
•
Nosebleed
•
Weight loss and general ill health (Cachexia)
•
Feeling numb in any part of your body
•
Burning sensation
•
Disturbances in the sense of smell and/or tasting
•
Ear pain or ringing in the ears
•
Swelling in your legs and arms
•
Heart burn, stomach upset, abdominal pain, abdominal bloating and discomfort or dry mouth
•
Blood in faeces
•
Inflamed gums, mouth inflammation or toothache
68
•
Painful swallowing
•
Sweating or having dry skin
•
Nail or skin changes (e.g. red skin)
•
Hair loss
•
Having irregular periods
•
Increased urine production during night time
•
Feeling generally unwell or having chills
•
Increased or decreased appetite
•
Weight loss or extreme weight gain
•
Muscle pain
•
Back pain or neck pain
•
Cold limbs
•
Faster, slower or irregular heart beat
•
Feeling sleepy
•
Neurological movement disorder where your muscles contract causing twisting and repetitive
movements or abnormal postures. Symptoms include tremors, pain, cramping.
•
Irritable Bowel Syndrome (IBS). Symptoms include chronic abdominal cramps and diarrhoea or
constipation.
Rare
side effects are:
•
Reduction in blood platelets which increases risk of bleeding or bruising
•
Severe pain in the back and stomach
•
Reduction in white blood cells which makes infections more likely
The use of Zebinix is associated with an abnormality in ECG (electrocardiogram) called increase in
PR interval. Side effects associated with this ECG abnormality (e.g. fainting and slowing of heart beat) may
occur.
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please tell your
doctor or pharmacist.
5.
HOW TO STORE ZEBINIX
Keep out of the reach and sight of children.
Do not use Zebinix after the expiry date, which is stated on the blister package, bottle and the carton after
EXP. The expiry date refers to the last day of that month.
This medicine does not require any special storage conditions.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Zebinix contains
•
The active substance is eslicarbazepine acetate. Each tablet contains 800 mg of eslicarbazepine acetate.
•
The other ingredients are povidone K29/32, croscarmellose sodium and magnesium stearate.
What Zebinix looks like and contents of the pack
Zebinix 800 mg tablets are white and oblong. The tablets have ‘ESL 800’engraved on one side and are
scored on the other side, enabling the tablets to be divided into equal halves.
69
The tablets are packaged in blisters in cardboard boxes containing 20, 30, 60 or 90 tablets, and in HDPE
bottles with child resistant closure in cardboard boxes containing 90 tablets.
Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
BIAL - Portela & Cª
, S.A., À Av. da Siderurgia Nacional
4745-457 S. Mamede do Coronado
Portugal
tel: +351 22 986 61 00
fax: +351 22 986 61 99
e-mail: info@bial.com
For any information about this medicine, please contact the local representative of the Marketing
Authorisation Holder:
België/Belgique/Belgien
Eisai Europe Ltd
Tél/Tel: + 32 (0) 2 735 45 34
Luxembourg/Luxemburg
Eisai Europe Ltd.
Tél/Tel: + 32 (0) 2 735 45 34
(Belgique/Belgien)
България
BIAL-Portela & Cª., S.A.
Teл.: + 351 22 986 61 00
(Португалия)
Magyarország
Eisai GesmbH
Tel.: + 36 1 230 43 20
Česká republika
Eisai GesmbH organizační složka
Tel: +420 242 485 839
Malta
BIAL-Portela & Cª., S.A.
Tel: + 351 22 986 61 00
(Il-Portugall)
Danmark
Eisai AB
Tlf: + 46 (0) 8 501 01 600
(Sverige)
Nederland
Eisai Europe Ltd.
Tél/Tel: + 32 (0) 2 735 45 34
(België/Belgique)
Deutschland
Eisai GmbH
Tel: + 49 (0) 69 66 58 50
Norge
Eisai AB
Tlf: + 46 (0) 8 501 01 600
(Sverige)
Eesti
BIAL-Portela & Cª, S.A.
Tel: +351 22 986 61 00
(Portugal)
Österreich
Eisai GesmbH
Tel: + 43 (0) 1 535 1980-0
Ελλάδα
Arriani Pharmaceuticals S.A.
Τηλ: + 30 210 668 3000
Polska
BIAL-Portela & Cª, S.A.
Tel.: + 351 22 986 61 00
(Portugália)
España
BIAL Industrial Farmacéutica, S.A.
Tel: + 34 94 443 80 00
Portugal
BIAL-Portela & Cª., S.A.
Tel.: + 351 22 986 61 00
70
France
Eisai SAS
Tél: + (33) 1 47 67 00 05
România
BIAL-Portela & Cª, S.A.
Tel: + 351 22 986 61 00
(Portugalia)
Ireland
Eisai Ltd.
Tel: + 44(0) 208 600 1400
(United Kingdom)
Slovenija
BIAL-Portela & Cª, S.A.
Tel: + 351 22 986 61 00
(Portugalska)
Ísland
Eisai AB
Sími: + 46 (0) 8 501 01 600
(Svíþjóð)
Slovenská republika
Eisai GesmbH organizační složka
Tel: + 420 242 485 839
(Česká republika)
Italia
Eisai S.r.l.
Tel: + 39 02 518 1401
Suomi/Finland
Eisai AB
Puh/Tel: + 46 (0) 8 501 01 600
(Ruotsi)
Κύπρος
BIAL-Portela & Cª, S.A.
Τηλ: + 351 22 986 61 00
(Πορτογαλία)
Sverige
Eisai AB
Tel: + 46 (0) 8 501 01 600
Latvija
BIAL-Portela & Cª, S.A.
Tel: + 351 22 986 61 00
(Portugāle)
United Kingdom
Eisai Ltd.
Tel: + 44 (0) 208 600 1400
Lietuva
BIAL-Portela & Cª, S.A.
Tel: + 351 22 986 61 00
(Portugalija)
This leaflet was last approved in
MMM/YYYY
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web site:
71
Source: European Medicines Agency
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