Zebinix

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Zebinix 200 mg tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 200 mg of eslicarbazepine acetate. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Tablet. 
White oblong tablets, engraved ’ESL 200’ on one side and scored on the other side, with a length of 
11 mm. The tablet can be divided into equal doses. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Zebinix is indicated as: 
 
• monotherapy in the treatment of partial-onset seizures, with or without secondary generalisation, in 

adults with newly diagnosed epilepsy; 

• adjunctive therapy in adults, adolescents and children aged above 6 years, with partial-onset 
seizures with or without secondary generalisation.  

 
4.2 Posology and method of administration 
 
Posology 
 
Adults 
Zebinix may be taken as monotherapy or 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 1,200 mg once daily. Some 
patients on monotherapy regimen may benefit from a dose of 1,600 mg once daily (see section 5.1). 
 
Special populations 
 
Elderly (over 65 years of age) 
No dose adjustment is needed in the elderly population provided that the renal function is not 
disturbed. Due to very limited data on the 1,600 mg monotherapy regimen in the elderly, this dose is 
not recommended for this population. 
 
Renal impairment 
Caution should be exercised in the treatment of patients, adult and children above 6 years of age, with 
renal impairment and the dose should be adjusted according to creatinine clearance (CLCR) as follows: 
- CLCR >60 ml/min: no dose adjustment required. 
- CLCR 30-60 ml/min: initial dose of 200 mg (or 5 mg/kg in children above 6 years) once daily or 

400 mg (or 10 mg/kg in children above 6 years) every other day for 2 weeks followed by a once 
daily dose of 400 mg (or 10 mg/kg in children above 6 years). However, based on individual 
response, the dose may be increased. 



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- CLCR <30 ml/min: use is not recommended in patients with severe renal impairment due to 
insufficient data. 

 
Hepatic impairment 
No dose adjustment is needed in patients with mild to moderate hepatic impairment.  
The pharmacokinetics of eslicarbazepine acetate has not been evaluated in patients with severe hepatic 
impairment (see sections 4.4 and 5.2) and use in these patients is, therefore, not recommended. 
 
Paediatric population 
Children above 6 years of age 
The recommended starting dose is 10 mg/kg/day once daily. Dosage should be increased in weekly or 
bi-weekly increments of 10 mg/kg/day up to 30 mg/kg/day, based on individual response. The 
maximum dose is 1,200 mg once daily (see section 5.1). 
 
Children with a body weight of ≥60 kg 
Children with a body weight of 60 kg or more should be given the same dose as for adults. 
The safety and efficacy of eslicarbazepine acetate in children aged 6 years and below has not yet been 
established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation 
on a posology can be made. 
 
Method of administration 
 
Oral use. 
Zebinix may be taken with or without food. 
 
Switching preparations 
Based on comparative bioavailability data for the tablet and the suspension formulations, switching  
patients from one formulation to the other can be done. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance, to other carboxamide derivatives (e.g. carbamazepine, 
oxcarbazepine) or to any of the excipients listed in section 6.1.  
 
Second or third degree atrioventricular (AV) block. 
 
4.4 Special warnings and precautions for use 
 
Suicidal ideation 
 
Suicidal ideation and behaviour have been reported in patients treated with antiepileptic active 
substances in several indications. A meta-analysis of randomised placebo-controlled trials of 
antiepileptic 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. 
 
Nervous system disorders 
 
Eslicarbazepine acetate has been associated with some central nervous system adverse reactions, such 
as dizziness and somnolence, which could increase the occurrence of accidental injury.  
 
Other warnings and precautions 
 



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If Zebinix is to be discontinued it is recommended to withdraw it gradually to minimise the potential 
of increased seizure frequency.  
 
 
Cutaneous reactions 
 
Rash developed as an adverse reaction in 1.2% of total population treated with Zebinix in clinical 
studies in epileptic patients. Urticaria and angioedema cases have been reported in patients taking 
Zebinix. Angioedema in the context of hypersensitivity/anaphylactic reaction associated with 
laryngeal oedema can be fatal. If signs or symptoms of hypersensitivity develop, eslicarbazepine 
acetate must be discontinued immediately and alternative treatment should be initiated.  
Severe cutaneous adverse reactions (SCARS) including Stevens-Johnson syndrome (SJS)/toxic 
epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), 
which can be life-threatening or fatal, have been reported in post-marketing experience with Zebinix 
treatment. At the time of prescription patients should be advised of the signs and symptoms and 
monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, 
Zebinix should be withdrawn immediately and an alternative treatment considered (as appropriate). If 
the patients have developed such reactions, treatment with Zebinix must not be restarted in these 
patients at any time.  
 
HLA-B* 1502 allele - in Han Chinese, Thai and other Asian populations 
 
HLA-B* 1502 in individuals of Han Chinese and Thai origin has been shown to be strongly associated 
with the risk of developing the severe cutaneous reactions known as Stevens Johnson syndrome (SJS) 
when treated with carbamazepine. The chemical structure of eslicarbazepine acetate is similar to that 
of carbamazepine, and it is possible that patients who are positive for HLA-B*1502 may also be at risk 
for SJS after treatment with eslicarbazepine acetate. The prevalence of HLA-B*1502 carrier is about 
10% in Han Chinese and Thai populations. Whenever possible, these individuals should be screened 
for this allele before starting treatment with carbamazepine or chemically-related active substances. If 
patients of these ethnic origins are tested positive for HLA- B*1502 allele, the use of eslicarbazepine 
acetate may be considered if the benefits are thought to exceed risks. 
Because of the prevalence of this allele in other Asian populations (e.g, above 15% in the Philippines 
and Malaysia), testing genetically at risk populations for the presence of HLA- B*1502 may be 
considered. 
 
HLA-A*3101 allele- European descent and Japanese populations 
 
There are some data that suggest HLA-A*3101 is associated with an increased risk of carbamazepine 
induced cutaneous adverse drug reactions including SJS, TEN, Drug rash with eosinophilia (DRESS), 
or less severe acute generalized exanthematous pustulosis (AGEP) and maculopapular rash in people 
of European descent and the Japanese. 
The frequency of the HLA-A*3101 allele varies widely between ethnic populations. HLA-A*3101 
allele has a prevalence of 2 to 5% in European populations and about 10% in Japanese population. 
The presence of HLA-A*3101 allele may increase the risk for carbamazepine induced cutaneous 
reactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of European 
ancestry, whereas its absence may reduce the risk from 5.0% to 3.8%. 
There are insufficient data supporting a recommendation for HLA-A*3101 screening before starting 
carbamazepine or chemically-related compounds treatment. 
If patients of European descent or Japanese origin are known to be positive for HLA-A*3101 allele, 
the use of carbamazepine or chemically-related compounds may be considered if the benefits are 
thought to exceed risks. 
 
Hyponatraemia 
 
Hyponatraemia has been reported as an adverse reaction in 1.5% of patients treated with Zebinix. 
Hyponatraemia is asymptomatic in most cases, however, it may be accompanied by clinical symptoms 



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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, carbamazepine), 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, eslicarbazepine acetate should be discontinued. 
 
PR interval 
 
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. 
 
Renal impairment 
 
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 CLCR <30 ml/min use is 
not recommended due to insufficient data. 
 
Hepatic impairment 
 
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, eslicarbazepine acetate should 
be used with caution in patients with mild to moderate hepatic impairment and is not recommended in 
patients with severe hepatic impairment. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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. In vivo eslicarbazepine showed an inducing effect on the metabolism of medicinal 
products that are mainly eliminated by metabolism through CYP3A4 (e.g. Simvastatin). Thus, an 
increase in the dose of the medicinal products that are mainly metabolised through CYP3A4 may be 
required, when used concomitantly with eslicarbazepine acetate. Eslicarbazepine in vivo may have an 
inducing effect on the metabolism of medicinal products that are mainly eliminated by 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 
medicinal products 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 (e.g. Phenytoin). 
 
Interactions with other antiepileptic medicinal products 
 
Carbamazepine 
In a study in healthy subjects, concomitant administration of eslicarbazepine acetate 800 mg once 
daily and carbamazepine 400 mg twice daily resulted in an average decrease of 32% in exposure to the 
active metabolite eslicarbazepine, most likely caused by an induction of glucuronidation. No change in 
exposure to carbamazepine or its metabolite carbamazepine-epoxide was noted. Based on individual 
response, the dose of eslicarbazepine acetate may need to be increased if used concomitantly with 



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carbamazepine. Results from patient studies showed that concomitant treatment increased the risk of 
the following adverse reactions: diplopia, abnormal coordination and dizziness. The risk of increase of 
other specific adverse reactions caused by co-administration of carbamazepine and eslicarbazepine 
acetate cannot be excluded. 
 
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 eslicarbazepine acetate 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 inter-individual 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.  
 
Valproate and levetiracetam 
A population pharmacokinetics analysis of phase III studies in epileptic adult patients indicated that 
concomitant administration with valproate or levetiracetam did not affect the exposure to 
eslicarbazepine but this has not been verified by conventional interaction studies.  
 
Oxcarbazepine 
Concomitant use of eslicarbazepine acetate with oxcarbazepine is not recommended because this may 
cause overexposure to the active metabolites. 
 
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 ethinylestradiol, 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 section4.6). 
 
Simvastatin 
A study in healthy subjects showed an average decrease of 50% in systemic exposure to simvastatin 
when co-administered with eslicarbazepine acetate 800 mg once daily, most likely caused by an 
induction of CYP3A4. An increase of the simvastatin dose may be required when used concomitantly 
with eslicarbazepine acetate. 
 
Rosuvastatin 
There was an average decrease of 36-39% in systemic exposure in healthy subjects when 
co-administered with eslicarbazepine acetate 1,200 mg once daily. The mechanism for this reduction 
is unknown, but could be due to interference of transporter activity for rosuvastatin alone or in 



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combination with induction of its metabolism. Since the relationship between exposure and drug 
activity is unclear, the monitoring of response to therapy (e.g., cholesterol levels) is recommended. 
 
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.  
 
4.6 Fertility, pregnancy and lactation 
 
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. 
 
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. 
 
Pregnancy 
 
There are no data from the use of eslicarbazepine acetate in pregnant women. Studies in animals have 
shown reproductive toxicity (see Fertility). 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 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 



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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. 
 
Breast-feeding 
 
It is unknown whether eslicarbazepine acetate is excreted in human 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 eslicarbazepine acetate.  
 
Fertility 
 
There are no data on the effects of eslicarbazepine acetate on human fertility. Studies in animals have 
shown impairment of fertility after treatment with eslicarbazepine acetate (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Zebinix has minor to moderate influence on the ability to drive and use machines. 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. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
In clinical studies (adjunctive therapy treatment and monotherapy), 2,434 patients with partial-onset 
seizures were treated with eslicarbazepine acetate (1,983 adult patients and 451 paediatric patients) 
and 51% of those patients experienced adverse reactions. 
 
Adverse reactions were usually mild to moderate in intensity and occurred predominantly during the 
first weeks of treatment with eslicarbazepine acetate.  
 
The risks that have been identified for Zebinix are mainly class-based, dose-dependent undesirable 
effects. The most common adverse reactions reported, in placebo controlled adjunctive therapy studies 
with adult epileptic patients and in an active controlled monotherapy study comparing eslicarbazepine 
acetate with carbamazepine controlled release, were dizziness, somnolence, headache, and nausea. The 
majority of adverse reactions were reported in <3% of subjects in any treatment group. 
 
Severe cutaneous adverse reactions (SCARS), including Stevens-Johnson syndrome (SJS)/toxic 
epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) 
have been reported in post-marketing experience with Zebinix treatment (see section 4.4). 
 
Tabulated list of adverse reactions 
Adverse reactions associated with eslicarbazepine acetate obtained from clinical studies and post-
marketing surveillance are tabulated below. 
 
The following convention has been used for the classification of adverse reactions very common 
(≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and not known (frequency 
cannot be estimated from available data). Within each frequency category, adverse reactions are 
presented in order of decreasing seriousness. 
 
Table 1: Treatment emergent adverse reactions associated with Zebinix obtained from  clinical studies 
and post-marketing surveillance 
System Organ 
Class 

Very  
common 

Common Uncommon Not known 



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Blood and 
lymphatic 
system disorders 

  Anaemia Thrombocytopenia,
leukopenia 

Immune system 
disorders 

  Hypersensitivity  

Endocrine 
disorders 

  Hypothyroidism  

Metabolism and 
nutrition 
disorders 

 Hyponatraemia, 
decreased 
appetite 

Electrolyte 
imbalance, 
dehydration, 
hypochloraemia 

 

Psychiatric 
disorders 

 Insomnia Psychotic 
disorder,  
apathy, 
depression, 
nervousness, 
agitation, 
irritability, 
attention deficit/ 
hyperactivity 
disorder, 
confusional 
state, mood 
swings, crying, 
psychomotor 
retardation, 
anxiety   

 

Nervous system 
disorders 

Dizziness, 
somnolence 
 

Headache, 
disturbance in 
attention, 
tremor, ataxia, 
balance disorder 

Coordination 
abnormal, 
memory 
impairment, 
amnesia, 
hypersomnia, 
sedation, 
aphasia, 
dysaesthesia, 
dystonia, 
lethargy, 
parosmia, 
cerebellar 
syndrome, 
convulsion, 
peripheral 
neuropathy, 
nystagmus, 
speech disorder, 
dysarthria, 
burning 
sensation, 
paraesthesia, 
migraine 

 



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Eye disorders  Diplopia, vision 
blurred 

Visual 
impairment, 
oscillopsia, 
binocular eye 
movement 
disorder, ocular 
hyperaemia 

 

Ear and 
labyrinth 
disorders 

 Vertigo 
 

Hypoacusis, 
tinnitus 

 

Cardiac 
disorders 

  Palpitations, 
bradycardia 

 

Vascular 
disorders 

  Hypertension 
(including 
hypertensive 
crisis), 
hypotension, 
orthostatic 
hypotension, 
flushing, 
peripheral 
coldness 

 

Respiratory, 
thoracic and 
mediastinal 
disorders 

  Epistaxis, chest 
pain 

 

Gastrointestinal 
disorders 

 Nausea, 
vomiting, 
diarrhoea 

Constipation, 
dyspepsia, 
gastritis, 
abdominal pain, 
dry mouth, 
abdominal 
discomfort, 
abdominal 
distension, 
gingivitis, 
melaena, 
toothache 

Pancreatitis 

Hepatobiliary 
disorders 

  Liver disorder  

Skin and 
subcutaneous 
tissue disorders 

 Rash 
 

Alopecia, dry 
skin, 
hyperhidrosis, 
erythema, skin 
disorder, 
pruritus, 
dermatitis 
allergic 

Toxic epidermal 
necrolysis, Stevens-
Johnson syndrome, 
drug reaction with 
eosinophilia and 
systemic symptoms 
(DRESS), 
angioedema, 
urticaria 

Musculoskeletal 
and connective 
tissue disorders 

  Myalgia, bone 
metabolism 
disorder, 
muscular 
weakness, pain 
in extremity 

 



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Renal and 
urinary 
disorders 

  Urinary tract 
infection 

 

General 
disorders and 
administration 
site conditions 

 Fatigue, gait 
disturbance, 
asthenia 

Malaise, chills, 
oedema 
peripheral  

 

Investigations  Weight 
increased 

Blood pressure 
decreased, 
weight 
decreased, blood 
pressure 
increased, blood 
sodium 
decreased, blood 
chloride 
decreased, 
osteocalcin 
increased, 
haematocrit 
decreased, 
haemoglobin 
decreased, 
transaminases 
increased 

 

Injury, 
poisoning and 
procedural 
complications  

  Drug toxicity, 
fall, thermal 
burn  

 

 
Description of selected adverse reactions 
 
Eye and nervous system disorders 
In patients concomitantly treated with carbamazepine and eslicarbazepine acetate in placebo-
controlled studies, the following adverse reactions were observed: 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), see 
section 4.5. 
 
PR interval 
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.  
 
Class related adverse reactions 
Rare adverse reactions such as bone marrow depression, anaphylactic reactions, 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 eslicarbazepine acetate cannot be 
excluded. 
 
There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in 
patients on long-term therapy with the structurally related antiepileptic drugs carbamazepine and 
oxcarbazepine. The mechanism by which bone metabolism is affected has not been identified. 
 
Paediatric population 



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In placebo-controlled studies involving patients aged from 2 to 18 years with partial-onset seizures 
(238 patients treated with eslicarbazepine acetate and 189 with placebo), 35.7% of patients treated 
with eslicarbazepine acetate and 19% of patients treated with placebo experienced adverse reactions. 
The most common adverse reaction in the group treated with eslicarbazepine acetate were diplopia 
(5.0%), somnolence (8.0%) and vomiting (4.6%). 
 
The adverse reaction profile of eslicarbazepine acetate is generally similar across age goups. In the age 
group from 6 to 11 years of age, the most common adverse reactions observed in more than two 
patients treated with eslicarbazepine acetate were diplopia (9.5%), somnolence (7.4%), diziness 
(6.3%), convulsion (6.3%) and nausea (3.2%); in the age group from 12 to 18 years were somnolence 
(7.4%), vomiting (4.2%), diplopia (3.2%) and fatigue (3.2%). The safety of Zebinix in children aged 6 
years and below has not yet been established. 
 
The safety profile of eslicarbazepine acetate was generally similar between adult and paediatric 
patients, except for agitation (common, 1.3%) and abdominal pain (common, 2.1%) which were more 
common in children than in adults. Dizziness; somnolence; vertigo; asthenia; gait disturbance; tremor; 
ataxia; balance disorder; vision blurred; diarrhoea; rash and hyponatraemia were less common in 
children than in adults. Dermatitis allergic (uncommon, 0.8%) was reported only in the paediatric 
population. 
 
Long-term safety data in the paediatric population obtained from open label extensions of the phase III 
study was consistent with the known safety profile of the product with no new findings of concern. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms observed after an overdose of eslicarbazepine acetate are primarily associated with central 
nervous symptoms (e.g. seizures of all types, status epilepticus) and cardiac disorders (e.g. cardiac 
arrhythmia). 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. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
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, precluding their return to the activated state and 
thereby preventing repetitive neuronal firing.  
 
Pharmacodynamic effect 
 

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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 efficacy 
 
Adult population 
The efficacy of eslicarbazepine acetate as adjunctive therapy has been demonstrated in four phase III 
double-blind placebo-controlled studies in 1,703 randomized adult patients with partial epilepsy 
refractory to treatment with one to three concomitant antiepileptic medicinal products. Oxcarbazepine 
and felbamate were not allowed as concomitant medicinal products in these studies. Eslicarbazepine 
acetate was tested at doses of 400 mg (in -301 and -302 studies only), 800 mg and 1,200 mg, once 
daily. Eslicarbazepine acetate 800 mg once daily and 1,200 mg once daily were significantly more 
effective than placebo in reducing seizure frequency over a 12-week maintenance period. The 
percentage of subjects with ≥50% reduction (1581 analyzed) in seizure frequency in the phase III 
studies was 19.3% for placebo, 20.8% for eslicarbazepine acetate 400 mg, 30.5% for eslicarbazepine 
acetate 800 mg and 35.3% for eslicarbazepine acetate 1,200 mg daily.  
 
The efficacy of eslicarbazepine acetate as monotherapy has been demonstrated in a double-blind, 
active controlled (carbamazepine controlled release) study, involving 815 randomized adult patients 
with newly diagnosed partial-onset seizures. Eslicarbazepine acetate was tested at once-daily doses of 
800 mg, 1,200 mg and 1,600 mg. The doses of the active comparator, carbamazepine controlled 
release, were 200 mg, 400 mg and 600 mg, twice-daily. All subjects were randomized to the lowest 
dose level and only if a seizure occurred subjects were to be escalated to the next dose level. From the 
815 randomized patients, 401 patients were treated with eslicarbazepine acetate once-daily [271 
patients (67.6%) remained at dose of 800 mg, 70 patients (17.5%) remained at dose of 1,200 mg and 
60 patients (15.0%) were treated with 1,600 mg]. In the primary efficacy analysis, in which drop-outs 
were considered as non-responders, 71.1% subjects were classified as seizure free in the 
eslicarbazepine acetate group and 75.6% in the carbamazepine controlled release group during the 
26 week evaluation period (average risk difference -4.28%, 95% confidence interval: [-10,30; 1,74]. 
The treatment effect observed during the 26-week evaluation period was maintained over 1 year of 
treatment with 64.7 % eslicarbazepine acetate subjects and 70.3 % carbamazepine controlled release 
subjects classified as seizure free (average risk difference -5.46%, 95% confidence interval: [-11.88; 
0.97]. In the analysis of treatment failure (seizure risk) based on time to event analysis (Kaplan-Meier 
analysis and Cox regression), the Kaplan-Meier estimates of seizure risk at the end of the evaluation 
period was 0.06 with carbamazepine and 0.12 with eslicarbazepine acetate and by the end of 1 year 
with an additional increased risk to 0.11 with carbamazepine and 0.19 with eslicarbazepine acetate 
(p=0.0002). 
 
At 1 year, the probability for subjects to withdraw due to either adverse reactions or lack of efficacy 
was 0.26 for eslicarbazepine acetate and 0.21 for carbamazepine controlled release.  
The efficacy of eslicarbazepine acetate as conversion to monotherapy was evaluated in 2 double-blind, 
randomized controlled studies in 365 adult patients with partial-onset seizures. Eslicarbazepine acetate 
was tested at doses of 1,200 mg and 1,600 mg once-daily. Seizure-free rates during the entire 10-week 
monotherapy period were 7.6% (1,600 mg) and 8.3 % (1,200 mg) in one study and 10.0% (1,600 mg) 
and 7.4 % (1,200 mg) in the other study, respectively. 
 
Elderly population 
The safety and efficacy of eslicarbazepine acetate as adjunctive therapy for partial seizures in elderly 
patients were evaluated in one non-controlled study, with a duration of 26 weeks, in 72 elderly (aged 
≥ 65 years). The data shows that the incidence of adverse reactions in this population (65.3 %) is 
similar to the general population enrolled in the double-blind epilepsy studies (66.8%). The most 
frequent individual adverse reactions were dizziness (12.5% of subjects), somnolence (9.7%), fatigue, 
convulsion and hyponatraemia (8.3%, each), nasopharyngitis (6.9%) and upper respiratory tract 
infection (5.6%). A total of 50 of the 72 subjects starting the study completed the 26-week treatment 
period that corresponds to a retention rate of 69.4% (see section 4.2 for information on elderly use). 



14 

There is limited data on monotherapy regimen available in the erldely population. Only a few subjects 
(N=27) aged above 65 years were treated with eslicarbazepine acetate in monotherapy study. 
 
Paediatric population 
The efficacy and safety of eslicarbazepine acetate as adjunctive therapy for partial-onset seizures in 
children was evaluated in one phase II study in children aged from 6 to 16 years (N=123) and one 
phase III study in children aged from 2 to 18 years (N=304). Both studies were double-blind and 
placebo controlled with a duration of maintenance of 8 weeks (study 208) and 12 weeks (study 305), 
respectively. Study 208 included 2 additional subsequent long-term, open-label extensions (1 year in 
part II and 2 years in part III) and Study 305 included 4 subsequent long-term, open-label extension 
periods (1 year in Parts II, III and IV and 2 years in Part V). Eslicarbazepine acetate was tested at 
doses of 20 and 30 mg/kg/day, up to a maximum of 1,200 mg/day. The target dose was 30 mg/kg/day 
in study 208 and 20 mg/kg/day in study 305. Doses could be adjusted based on tolerability and 
treatment response. 
 
In the double-blind period of the phase II study, evaluation of efficacy was a secondary objective. The 
least square mean reduction in standardised seizure frequency from baseline to maintenance period 
was significantly (p<0.001) higher with eslicarbazepine acetate (-34.8%) compared to placebo (-
13.8%). Forty-two patients (50.6%) in the eslicarbazepine acetate group compared to 10 patients 
(25.0%) in the placebo group were responders (≥50% reduction of standardised seizure frequency), 
resulting in a significant difference (p=0.009).  
 
In the double-blind period of the phase III study, the least square mean reduction in standardised 
seizure frequency with eslicarbazepine acetate (-18.1% versus baseline) was different to placebo (-
8.6% versus baseline) but not statistically significant (p=0.2490). Forty-one patients (30.6%) in the 
eslicarbazepine acetate group compared to 40 patients (31.0%) in the placebo group were responders 
(≥50% reduction of standardised seizure frequency), resulting in a non-significant difference 
(p=0.9017). Post-hoc subgroup analyses for the phase III study were conducted by age strata and 
above 6 years, as well as by dose. In children above 6 years, 36 patients (35.0%) in the eslicarbazepine 
acetate group compared to 29 patients (30.2%) in the placebo group were responders (p=0.4759) and 
the least square mean reduction in standardised seizure frequency was higher in the eslicarbazepine 
acetate group compared to placebo (-24.4% versus -10.5%); however, the difference of 13.9% was not 
statistically significant (p=0.1040). A total of 39% patients in study 305 were up titrated to the 
maximum possible dose (30 mg/kg/day). Amongst these, when excluding patients aged 6 years and 
younger, 14 (48.3%) and 11 (30.6%) of patients in the eslicarbazepine acetate and placebo group, 
respectively, were responders (p=0.1514). Although the robustness of these post-hoc subgroup 
analyses is limited, the data suggest an age and dose dependent increase in effect size. 
 
In the subsequent 1-year open-label extension (Part II) of the phase III study (ITT set N=225) the total 
responder rate was 46.7% (steadily increasing from 44.9% (weeks 1-4) to 57.5% (weeks > 40)). The 
total median standardised seizure frequency was 6.1 (decreasing from 7.0 (weeks 1-4) to 4.0 (weeks > 
40), resulting in a median relative change compared to the baseline period of -46.7%). The median 
relative change was larger in the previous placebo group (-51.4%) than in the previous ESL group (-
40.4%). The proportion of patients with exacerbation (increase of ≥25%) compared to the baseline 
period was 14.2%.  
 
In the subsequent 3 open-label extensions (ITT set N=148), the overall responder rate was 26.6% 
when compared to baseline Parts III–V (i.e. the last 4 weeks in part II). The total median standardised 
seizure frequency was 2.4 (resulting in a median relative change from Baseline Part III–V of -22.9%). 
The overall median relative decrease in Part I was greater in patients treated with ESL (-25.8%) than 
in patients treated with placebo (-16.4%). The overall proportion of patients with exacerbation 
(increase of ≥25%) compared to Baseline Parts III–V was 25.7%.  
 
Of the 183 patients who completed parts I and II of the study, 152 patients were enrolled into part III. 
Of these, 65 patients had received ESL and 87 patients had received placebo during the double-blind 
part of the study. 14 patients (9.2%) completed open-label treatment with ESL through Part V. The 
most common reason for withdrawal during any part of the study was sponsor request (30 patients in 



15 

part III [19.7% of the patients who entered part III], 9 in part IV [9.6% of the patients who entered part 
IV], and 43 in part V [64.2% of the patients who entered Part V]). 
 
Taking into consideration the limitations of open label uncontrolled data, the long-term response to 
eslicarbazepine acetate in the open-label parts of the study was overall maintained. 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Zebinix in one or more subsets of the paediatric population in the treatment of epilepsy with partial 
onset seizures (see section 4.2 for information on paediatric use). 
 
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 
Cmax is attained at 2 to 3 hours post-dose (tmax). 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. The 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 hours. In studies in healthy subjects and epileptic adult patients, the apparent half-life of 
eslicarbazepine was 10-20 hours and 13-20 hours, 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. 
 
Eslicarbazepine is a weak inducer of CYP3A4 and has inhibiting properties with respect to CYP2C19 
(as stated in section 4.5). 
 
In studies with eslicarbazepine in fresh human hepatocytes a mild induction of UGT1A1 mediated 
glucuronidation was observed. 
 
Elimination 
 
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 
 



16 

The pharmacokinetics of eslicarbazepine acetate is linear and dose-proportional in the range 
400-1,200 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 adult 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, adult and children above 6 years of age with creatinine clearance <60 ml/min (see section 
4.2).  
In children from 2 to 6 years of age, the use of eslicarbazepine acetate is not recommended. At this age 
the intrinsic activity of the elimination process has not yet reached maturation. 
 
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 acetate 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.  
 
Paediatric population 
 
Similar to adults, eslicarbazepine acetate is extensively converted to eslicarbazepine. Plasma levels of 
eslicarbazepine acetate usually remain below the limit of quantification, following oral administration. 
Eslicarbazepine Cmax is attained at 2 to 3 hours post-dose (tmax). Body weight was shown to have an 
effect on volume of distribution and clearance. Furthermore, a role of age independently of weight 
with regards to clearance of eslicarbazepine acetate could not be excluded, in particular for the 
youngest age group (2-6 years). 
 
Children aged 6 years and below 
 
Population pharmacokinetics indicate that in the subgroup of children aged from 2 to 6 years, doses of 
27.5 mg/kg/day and 40 mg/kg/day are required in order to achieve exposures that are equivalent to the 
therapeutic doses of 20 and 30 mg/kg/day in children above 6 years of age. 
 
Children above 6 years of age 
 
Population pharmacokinetics indicate that comparable eslicarbazepine exposure is observed between 
20 and 30 mg/kg/day in children above 6 years old and adults with 800 and 1200 mg of 
eslicarbazepine acetate once-daily, respectively (see section 4.2). 
 
5.3 Preclinical safety data 



17 

 
Adverse reactions 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. 
 
Juvenile animals studies 
 
In repeat-dose studies in juvenile dogs, the toxicity profile was comparable to that observed in adult 
animals. In the 10-month study decreases in bone mineral content, bone area and/or bone mineral 
density in lumbar vertebrae and/or femur were observed in high-dose female animals at exposure 
levels lower than the clinical exposure levels to eslicarbazepine in children. 
 
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 anomalies were observed at maternal toxic doses in embryotoxicity studies in 
mice, rats and rabbits. A delay in the sexual development of the F1 generation was observed in 
peri/postnatal studies in mice and rats. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Povidone K 29/32 
Croscarmellose sodium  
Magnesium stearate 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
4 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
PVC/Aluminium blisters placed into cardboard boxes containing 20 or 60 tablets.  



18 

 
HDPE bottles with polypropylene child resistant closure, inside a cardboard box, containing 60 tablets. 
 
Not all pack sizes may be marketed.  
 
6.6 Special precautions for disposal  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
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. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/514/021-023 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 21.04.2009 
 
Date of latest renewal: 22.01.2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 

http://www.ema.europa.eu/


19 

1. NAME OF THE MEDICINAL PRODUCT 
 
Zebinix 400 mg tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 400 mg of eslicarbazepine acetate. 
 
For the full list of excipients, see section 6.1.  
 
 
3. PHARMACEUTICAL FORM 
 
Tablet. 
 
White circular biconvex tablets, engraved ‘ESL 400’on one side and scored on the other side, with a 
diameter of 11 mm.. The scoreline is only to facilitate breaking for ease of swallowing and not to 
divide into equal doses.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Zebinix is indicated as: 
 
• monotherapy in the treatment of partial-onset seizures, with or without secondary generalisation, in 

adults with newly diagnosed epilepsy; 

• adjunctive therapy in adults, adolescents and children aged above 6 years, with partial-onset 
seizures with or without secondary generalisation. 

 
4.2 Posology and method of administration 
 
Posology 
 
Adults 
Zebinix may be taken as monotherapy or 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 1,200 mg once daily Some patients 
on monotherapy regimen may benefit from a dose of 1,600 mg once daily (see section 5.1). 
 
Special populations 
 
Elderly (over 65 years of age) 
No dose adjustment is needed in the elderly population provided that the renal function is not 
disturbed. Due to very limited data on the 1,600 mg monotherapy regimen in the elderly, this dose is 
not recommended for this population. 
 
Renal impairment 
Caution should be exercised in the treatment of patients, adult and children above 6 years of age, with 
renal impairment and the dose should be adjusted according to creatinine clearance (CLCR) as follows: 
- CLCR >60 ml/min: no dose adjustment required. 
- CLCR 30-60 ml/min: initial dose of 200 mg (or 5 mg/kg in children above 6 years) once daily or 

400 mg (or 10 mg/kg in children above 6 years) every other day for 2 weeks followed by a once 



20 

daily dose of 400 mg (or 10 mg/kg in children above 6 years). However, based on individual 
response, the dose may be increased. 

- CLCR <30 ml/min: use is not recommended in patients with severe renal impairment due to 
insufficient data. 

 
Hepatic impairment 
No dose adjustment is needed in patients with mild to moderate hepatic impairment.  
The pharmacokinetics of eslicarbazepine acetate has not been evaluated in patients with severe hepatic 
impairment (see sections 4.4 and 5.2) and use in these patients is, therefore, not recommended. 
 
Paediatric population 
Children above 6 years of age 
The recommended starting dose is 10 mg/kg/day once daily. Dosage should be increased in weekly or 
bi-weekly increments of 10 mg/kg/day up to 30 mg/kg/day, based on individual response. The 
maximum dose is 1,200 mg once daily (see section 5.1). 
 
Children with a body weight of ≥60 kg 
Children with a body weight of 60 kg or more should be given the same dose as for adults. 
The safety and efficacy of eslicarbazepine acetate in children aged 6 years and below has not yet been 
established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation 
on a posology can be made. 
 
Method of administration 
 
Oral use. 
Zebinix may be taken with or without food. 
 
Switching preparations 
Based on comparative bioavailability data for the tablet and the suspension formulations, switching  
patients from one formulation to the other can be done. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance, to other carboxamide derivatives (e.g. carbamazepine, 
oxcarbazepine) or to any of the excipients listed in section 6.1.  
 
Second or third degree atrioventricular (AV) block. 
 
4.4 Special warnings and precautions for use 
 
Suicidal ideation 
 
Suicidal ideation and behaviour have been reported in patients treated with antiepileptic active 
substances in several indications. A meta-analysis of randomised placebo-controlled trials of 
antiepileptic 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. 
 
Nervous system disorders 
 
Eslicarbazepine acetate has been associated with some central nervous system adverse reactions, such 
as dizziness and somnolence, which could increase the occurrence of accidental injury.  
 



21 

Other warnings and precautions 
 
If Zebinix is to be discontinued it is recommended to withdraw it gradually to minimise the potential 
of increased seizure frequency.  
 
Cutaneous reactions 
 
Rash developed as an adverse reaction in 1.2% of total population treated with Zebinix in  clinical 
studies in epileptic patients. Urticaria and angioedema cases have been reported in patients taking 
Zebinix. Angioedema in the context of hypersensitivity/anaphylactic reaction associated with 
laryngeal oedema can be fatal. If signs or symptoms of hypersensitivity develop, eslicarbazepine 
acetate must be discontinued immediately and alternative treatment should be initiated.  
Severe cutaneous adverse reactions (SCARS) including Stevens-Johnson syndrome (SJS)/toxic 
epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), 
which can be life-threatening or fatal, have been reported in post-marketing experience with Zebinix 
treatment. At the time of prescription patients should be advised of the signs and symptoms and 
monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, 
Zebinix should be withdrawn immediately and an alternative treatment considered (as appropriate). If 
the patients have developed such reactions, treatment with Zebinix must not be restarted in these 
patients at any time. 
 
HLA-B* 1502 allele - in Han Chinese, Thai and other Asian populations 
 
HLA-B* 1502 in individuals of Han Chinese and Thai origin has been shown to be strongly associated 
with the risk of developing the severe cutaneous reactions known as Stevens Johnson syndrome (SJS) 
when treated with carbamazepine. The chemical structure of eslicarbazepine acetate is similar to that 
of carbamazepine, and it is possible that patients who are positive for HLA-B*1502 may also be at risk 
for SJS after treatment with eslicarbazepine acetate. The prevalence of HLA-B*1502 carrier is about 
10% in Han Chinese and Thai populations. Whenever possible, these individuals should be screened 
for this allele before starting treatment with carbamazepine or chemically-related active substances. If 
patients of these ethnic origins are tested positive for HLA- B*1502 allele, the use of eslicarbazepine 
acetate may be considered if the benefits are thought to exceed risks. 
Because of the prevalence of this allele in other Asian populations (e.g, above 15% in the Philippines 
and Malaysia), testing genetically at risk populations for the presence of HLA- B*1502 may be 
considered. 
 
HLA-A*3101 allele- European descent and Japanese populations 
 
There are some data that suggest HLA-A*3101 is associated with an increased risk of carbamazepine 
induced cutaneous adverse drug reactions including SJS, TEN, Drug rash with eosinophilia (DRESS), 
or less severe acute generalized exanthematous pustulosis (AGEP) and maculopapular rash in people 
of European descent and the Japanese. 
The frequency of the HLA-A*3101 allele varies widely between ethnic populations. HLA-A*3101 
allele has a prevalence of 2 to 5% in European populations and about 10% in Japanese population. 
The presence of HLA-A*3101 allele may increase the risk for carbamazepine induced cutaneous 
reactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of European 
ancestry, whereas its absence may reduce the risk from 5.0% to 3.8%. 
There are insufficient data supporting a recommendation for HLA-A*3101 screening before starting 
carbamazepine or chemically-related compounds treatment. 
If patients of European descent or Japanese origin are known to be positive for HLA-A*3101 allele, 
the use of carbamazepine or chemically-related compounds may be considered if the benefits are 
thought to exceed risks. 
 
Hyponatraemia 
 



22 

Hyponatraemia has been reported as an adverse reaction in 1.5% 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, carbamazepine), 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, eslicarbazepine acetate should be discontinued. 
 
PR interval 
 
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. 
 
Renal impairment 
 
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 CLCR <30 ml/min use is 
not recommended due to insufficient data. 
 
Hepatic impairment 
 
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, eslicarbazepine acetate should 
be used with caution in patients with mild to moderate hepatic impairment and is not recommended in 
patients with severe hepatic impairment. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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. In vivo eslicarbazepine showed an inducing effect on the metabolism of medicinal 
products that are mainly eliminated by metabolism through CYP3A4 (e.g. Simvastatin). Thus, an 
increase in the dose of the medicinal products that are mainly metabolised through CYP3A4 may be 
required, when used concomitantly with eslicarbazepine acetate. Eslicarbazepine in vivo may have an 
inducing effect on the metabolism of medicinal products that are mainly eliminated by 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 
medicinal products 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 (e.g. Phenytoin). 
 
Interactions with other antiepileptic medicinal products 
 
Carbamazepine 
In a study in healthy subjects, concomitant administration of eslicarbazepine acetate 800 mg once 
daily and carbamazepine 400 mg twice daily resulted in an average decrease of 32% in exposure to the 
active metabolite eslicarbazepine, most likely caused by an induction of glucuronidation. No change in 



23 

exposure to carbamazepine or its metabolite carbamazepine-epoxide was noted. Based on individual 
response, the dose of eslicarbazepine acetate may need to be increased if used concomitantly with 
carbamazepine. Results from patient studies showed that concomitant treatment increased the risk of 
the following adverse reactions: diplopia, abnormal coordination and dizziness. The risk of increase of 
other specific adverse reactions caused by co-administration of carbamazepine and eslicarbazepine 
acetate cannot be excluded.  
 
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 eslicarbazepine acetate 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 inter-individual 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.  
 
Valproate and levetiracetam 
A population pharmacokinetics analysis of phase III studies in epileptic adult patients indicated that 
concomitant administration with valproate or levetiracetam did not affect the exposure to 
eslicarbazepine but this has not been verified by conventional interaction studies.  
 
Oxcarbazepine 
Concomitant use of eslicarbazepine acetate with oxcarbazepine is not recommended because this may 
cause overexposure to the active metabolites. 
 
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 ethinylestradiol, 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 4.6). 
 
Simvastatin 
A study in healthy subjects showed an average decrease of 50% in systemic exposure to simvastatin 
when co-administered with eslicarbazepine acetate 800 mg once daily, most likely caused by an 
induction of CYP3A4. An increase of the simvastatin dose may be required when used concomitantly 
with eslicarbazepine acetate. 
 
Rosuvastatin 



24 

There was an average decrease of 36-39% in systemic exposure in healthy subjects when 
co-administered with eslicarbazepine acetate 1,200 mg once daily. The mechanism for this reduction 
is unknown, but could be due to interference of transporter activity for rosuvastatin alone or in 
combination with induction of its metabolism. Since the relationship between exposure and drug 
activity is unclear, the monitoring of response to therapy (e.g., cholesterol levels) is recommended. 
 
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.  
 
4.6 Fertility, pregnancy and lactation 
 
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. 
 
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. 
 
Pregnancy 
There are no data from the use of eslicarbazepine acetate in pregnant women. Studies in animals have 
shown reproductive toxicity (see Fertility). 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 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 



25 

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. 
 
Breast-feeding 
It is unknown whether eslicarbazepine acetate is excreted in human 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 eslicarbazepine acetate.  
 
Fertility  
There are no data on the effects of eslicarbazepine acetate on human fertility. Studies in animals have 
shown impairment of fertility after treatment with eslicarbazepine acetate (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Zebinix has minor to moderate influence on the ability to drive and use machines. 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. 
 
4.8  Undesirable effects 
 
Summary of the safety profile 
In clinical studies (adjunctive therapy treatment and monotherapy), 2,434 patients with partial-onset 
seizures were treated with eslicarbazepine acetate (1,983 adult patients and 451 paediatric patients) 
and 51% of those patients experienced adverse reactions. 
 
Adverse reactions were usually mild to moderate in intensity and occurred predominantly during the 
first weeks of treatment with eslicarbazepine acetate.  
 
The risks that have been identified for Zebinix are mainly class-based, dose-dependent undesirable 
effects. The most common adverse reactions reported, in placebo controlled adjunctive therapy studies 
with adult epileptic patients and in an active controlled monotherapy study comparing eslicarbazepine 
acetate with carbamazepine controlled release, were dizziness, somnolence, headache, and nausea. The 
majority of adverse reactions were reported in <3% of subjects in any treatment group. 
 
Severe cutaneous adverse reactions (SCARS), including Stevens-Johnson syndrome (SJS)/toxic 
epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) 
have been reported in post-marketing experience with Zebinix treatment (see section 4.4). 
 
Tabulated list of adverse reactions 
Adverse reactions associated with eslicarbazepine acetate obtained from clinical studies and post-
marketing surveillance are tabulated below. 
 
The following convention has been used for the classification of adverse reactions very common 
(≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and not known (frequency 
cannot be estimated from available data). Within each frequency category, adverse reactions are 
presented in order of decreasing seriousness. 
 
Table 1: Treatment emergent adverse reactions associated with Zebinix obtained  clinical studies and 
post-marketing surveillance 
System Organ 
Class 

Very  
common 

Common Uncommon Not known 



26 

Blood and 
lymphatic 
system disorders 

  Anaemia Thrombocytopenia,
leukopenia 

Immune system 
disorders 

  Hypersensitivity  

Endocrine 
disorders 

  Hypothyroidism  

Metabolism and 
nutrition 
disorders 

 Hyponatraemia, 
decreased 
appetite 

Electrolyte 
imbalance, 
dehydration, 
hypochloraemia 

 

Psychiatric 
disorders 

 Insomnia Psychotic 
disorder, apathy, 
depression, 
nervousness, 
agitation, 
irritability, 
attention deficit/ 
hyperactivity 
disorder, 
confusional 
state, mood 
swings, crying, 
psychomotor 
retardation, 
anxiety  

 

Nervous system 
disorders 

Dizziness, 
somnolence 
 

Headache, 
disturbance in 
attention, 
tremor, ataxia, 
balance disorder 

Coordination 
abnormal, 
memory 
impairment, 
amnesia, 
hypersomnia, 
sedation, 
aphasia, 
dysaesthesia, 
dystonia, 
lethargy, 
parosmia, 
cerebellar 
syndrome, 
convulsion, 
peripheral 
neuropathy, 
nystagmus, 
speech disorder, 
dysarthria, 
burning 
sensation, 
paraesthesia, 
migraine 

 



27 

Eye disorders  Diplopia, vision 
blurred 

Visual 
impairment, 
oscillopsia, 
binocular eye 
movement 
disorder, ocular 
hyperaemia 

 

Ear and 
labyrinth 
disorders 

 Vertigo 
 

Hypoacusis, 
tinnitus 

 

Cardiac 
disorders 

  Palpitations, 
bradycardia 

 

Vascular 
disorders 

  Hypertension 
(including 
hypertensis 
crisis), 
hypotension, 
orthostatic 
hypotension, 
flushing, 
peripheral 
coldness 

 

Respiratory, 
thoracic and 
mediastinal 
disorders 

  Epistaxis, chest 
pain 

 

Gastrointestinal 
disorders 

 Nausea, 
vomiting, 
diarrhoea 

Constipation, 
dyspepsia, 
gastritis, 
abdominal pain, 
dry mouth, 
abdominal 
discomfort, 
abdominal 
distension, 
gingivitis, 
melaena, 
toothache 

Pancreatitis 

Hepatobiliary 
disorders 

  Liver disorder  

Skin and 
subcutaneous 
tissue disorders 

 Rash 
 

Alopecia, dry 
skin, 
hyperhidrosis, 
erythema, skin 
disorder, 
pruritus, 
dermatitis 
allergic 

Toxic epidermal 
necrolysis, Stevens-
Johnson syndrome, 
drug reaction with 
eosinophilia and 
systemic symptoms 
(DRESS), 
angioedema, 
urticaria 

Musculoskeletal 
and connective 
tissue disorders 

  Myalgia, bone 
metabolism 
disorder, 
muscular 
weakness, pain 
in extremity 

 



28 

Renal and 
urinary 
disorders 

  Urinary tract 
infection 

 

General 
disorders and 
administration 
site conditions 

 Fatigue, gait 
disturbance, 
asthenia 
 

Malaise, chills, 
oedema 
peripheral 

 

Investigations  Weight 
increased 

Blood pressure 
decreased, 
weight 
decreased, blood 
pressure 
increased, blood 
sodium 
decreased, blood 
chloride 
decreased, 
osteocalcin 
increased,   
haematocrit 
decreased, 
haemoglobin 
decreased, 
transaminases 
increased 

 

Injury, 
poisoning and 
procedural 
complications 

  Drug toxicity, 
fall, thermal 
burn 

 

 
Description of selected adverse reactions 
 
Eye and nervous system disorders 
In patients concomitantly treated with carbamazepine and eslicarbazepine acetate in placebo-
controlled studies, the following adverse reactions were observed: 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), see 
section 4.5. 
 
PR interval 
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.  
 
Class related adverse reactions 
Rare adverse reactions such as bone marrow depression, anaphylactic reactions, 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 eslicarbazepine acetate cannot be 
excluded. 
 
There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in 
patients on long-term therapy with the structurally related antiepileptic drugs carbamazepine and 
oxcarbazepine. The mechanism by which bone metabolism is affected has not been identified. 
 
Paediatric population 



29 

 
In placebo-controlled studies involving patients aged from 2 to 18 years with partial-onset seizures 
(238 patients treated with eslicarbazepine acetate and 189 with placebo), 35.7% of patients treated 
with eslicarbazepine acetate and 19% of patients treated with placebo experienced adverse reactions. 
The most common adverse reaction in the group treated with eslicarbazepine acetate were diplopia 
(5.0%), somnolence (8.0%) and vomiting (4.6%). 
 
The adverse reaction profile of eslicarbazepine acetate is generally similar across age goups. In the age 
group from 6 to 11 years of age, the most common adverse reactions observed in more than two 
patients treated with eslicarbazepine acetate were diplopia (9.5%), somnolence (7.4%), diziness 
(6.3%), convulsion (6.3%) and nausea (3.2%); in the age group from 12 to 18 years were somnolence 
(7.4%), vomiting (4.2%), diplopia (3.2%) and fatigue (3.2%). The safety of Zebinix in children aged 6 
years and below has not yet been established. 
 
The safety profile of eslicarbazepine acetate was generally similar between adult and paediatric 
patients, except for agitation (common, 1.3%) and abdominal pain (common, 2.1%) which were more 
common in children than in adults. Dizziness; somnolence; vertigo; asthenia; gait disturbance; tremor; 
ataxia; balance disorder; vision blurred; diarrhoea; rash and hyponatraemia were less common in 
children than in adults. Dermatitis allergic (uncommon, 0.8%) was reported only in the paediatric 
population. 
 
Long-term safety data in the paediatric population obtained from open label extensions of the Phase III 
study was consistent with the known safety profile of the product with no new findings of concern. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 

 
4.9 Overdose 
 
Symptoms observed after an overdose of eslicarbazepine acetate are primarily associated with central 
nervous symptoms (e.g. seizures of all types, status epilepticus) and cardiac disorders (e.g. cardiac 
arrhythmia). 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. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
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, precluding their return to the activated state and 
thereby preventing repetitive neuronal firing.  
 
Pharmacodynamic effect 
 

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


30 

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 efficacy 
 
Adult population 
The efficacy of eslicarbazepine acetate as adjunctive therapy has been demonstrated in four phase III 
double-blind placebo-controlled studies in 1,703 randomized adult patients with partial epilepsy 
refractory to treatment with one to three concomitant antiepileptic medicinal products. Oxcarbazepine 
and felbamate were not allowed as concomitant medicinal products in these studies. Eslicarbazepine 
acetate was tested at doses of 400 mg (in -301 and -302 studies only), 800 mg and 1,200 mg, once 
daily. Eslicarbazepine acetate 800 mg once daily and 1,200 mg once daily were significantly more 
effective than placebo in reducing seizure frequency over a 12-week maintenance period. The 
percentage of subjects with ≥50% reduction (1581 analyzed) in seizure frequency in the phase III 
studies was 19.3% for placebo, 20.8% for eslicarbazepine acetate 400 mg, 30.5% for eslicarbazepine 
acetate 800 mg and 35.3% for eslicarbazepine acetate 1,200 mg daily.  
 
The efficacy of eslicarbazepine acetate as monotherapy has been demonstrated in a double-blind, 
active controlled (carbamazepine controlled release) study, involving 815 randomized adult patients 
with newly diagnosed partial-onset seizures. Eslicarbazepine acetate was tested at once-daily doses of 
800 mg, 1,200 mg and 1,600 mg. The doses of the active comparator, carbamazepine controlled 
release, were 200 mg, 400 mg and 600 mg, twice-daily. All subjects were randomized to the lowest 
dose level and only if a seizure occurred subjects were to be escalated to the next dose level. From the 
815 randomized patients, 401 patients were treated with eslicarbazepine acetate once-daily [271 
patients (67.6%) remained at dose of 800 mg, 70 patients (17.5%) remained at dose of 1,200 mg and 
60 patients (15.0%) were treated with 1,600 mg]. In the primary efficacy analysis, in which drop-outs 
were considered as non-responders, 71.1% subjects were classified as seizure free in the 
eslicarbazepine acetate group and 75.6% in the carbamazepine controlled release group during the 
26 week evaluation period (average risk difference -4.28%, 95% confidence interval: [-10,30; 1,74]. 
The treatment effect observed during the 26-week evaluation period was maintained over 1 year of 
treatment with 64.7 % eslicarbazepine acetate subjects and 70.3 % carbamazepine controlled release 
subjects classified as seizure free (average risk difference -5.46%, 95% confidence interval: [-11.88; 
0.97]. In the analysis of treatment failure (seizure risk) based on time to event analysis (Kaplan-Meier 
analysis and Cox regression), the Kaplan-Meier estimates of seizure risk at the end of the evaluation 
period was 0.06 with carbamazepine and 0.12 with eslicarbazepine acetate and by the end of 1 year 
with an additional increased risk to 0.11 with carbamazepine and 0.19 with eslicarbazepine acetate 
(p=0.0002).  
 
At 1 year, the probability for subjects to withdraw due to either adverse reactions or lack of efficacy 
was 0.26 for eslicarbazepine acetate and 0.21 for carbamazepine controlled release.  
The efficacy of eslicarbazepine acetate as conversion to monotherapy was evaluated in 2 double-blind, 
randomized controlled studies in 365 adult patients with partial-onset seizures. Eslicarbazepine acetate 
was tested at doses of 1,200 mg and 1,600 mg once-daily. Seizure-free rates during the entire 10-week 
monotherapy period were 7.6% (1,600 mg) and 8.3 % (1,200 mg) in one study and 10.0% (1,600 mg) 
and 7.4 % (1,200 mg) in the other study, respectively. 
 
Elderly population 
The safety and efficacy of eslicarbazepine acetate as adjunctive therapy for partial seizures in elderly 
patients were evaluated in one non-controlled study, with a duration of 26 weeks, in 72 elderly (aged 
≥ 65 years). The data shows that the incidence of adverse reactions in this population (65.3 %) is 
similar to the general population enrolled in the double-blind epilepsy studies (66.8%). The most 
frequent individual adverse reactions were dizziness (12.5% of subjects), somnolence (9.7%), fatigue, 
convulsion and hyponatraemia (8.3%, each), nasopharyngitis (6.9%) and upper respiratory tract 
infection (5.6%). A total of 50 of the 72 subjects starting the study completed the 26-week treatment 
period that corresponds to a retention rate of 69.4% (see section 4.2 for information on elderly use). 



31 

There is limited data on monotherapy regimen available in the erldely population. Only a few subjects 
(N=27) aged above 65 years were treated with eslicarbazepine acetate in monotherapy study. 
 
Paediatric population 
The efficacy and safety of eslicarbazepine acetate as adjunctive therapy for partial-onset seizures in 
children was evaluated in one phase II study in children aged from 6 to 16 years (N=123) and one 
phase III study in children aged from 2 to 18 years (N=304). Both studies were double-blind and 
placebo controlled with a duration of maintenance of 8 weeks (study 208) and 12 weeks (study 305), 
respectively. Study 208 included 2 additional subsequent long-term, open-label extensions (1 year in 
part II and 2 years in part III) and Study 305 included 4 subsequent long-term, open-label extension 
periods (1 year in Parts II, III and IV and 2 years in Part V). Eslicarbazepine acetate was tested at 
doses of 20 and 30 mg/kg/day, up to a maximum of 1,200 mg/day. The target dose was 30 mg/kg/day 
in study 208 and 20 mg/kg/day in study 305. Doses could be adjusted based on tolerability and 
treatment response. 
 
In the double-blind period of the phase II study, evaluation of efficacy was a secondary objective. The 
least square mean reduction in standardised seizure frequency from baseline to maintenance period 
was significantly (p<0.001)  higher with eslicarbazepine acetate (-34.8%) compared to placebo (-
13.8%). Forty-two patients (50.6%) in the eslicarbazepine acetate group compared to 10 patients 
(25.0%) in the placebo group were responders (≥50% reduction of standardised seizure frequency), 
resulting in a significant difference (p=0.009).  
 
In the double-blind period of the phase III study, the least square mean reduction in standardised 
seizure frequency with eslicarbazepine acetate (-18.1% versus baseline) was different to placebo (-
8.6% versus baseline) but not statistically significant (p=0.2490). Forty-one patients (30.6%) in the 
eslicarbazepine acetate group compared to 40 patients (31.0%) in the placebo group were responders 
(≥50% reduction of standardised seizure frequency), resulting in a non-significant difference 
(p=0.9017). Post-hoc subgroup analyses for the phase III study were conducted by age strata and 
above 6 years, as well as by dose. In children above 6 years, 36 patients (35.0%) in the eslicarbazepine 
acetate group compared to 29 patients (30.2%) in the placebo group were responders (p=0.4759) and 
the least square mean reduction in standardised seizure frequency was higher in the eslicarbazepine 
acetate group compared to placebo (-24.4% versus -10.5%); however, the difference of 13.9% was not 
statistically significant (p=0.1040). A total of 39% patients in study 305 were up titrated to the 
maximum possible dose (30 mg/kg/day). Amongst these, when excluding patients aged 6 years and 
younger, 14 (48.3%) and 11 (30.6%) of patients in the eslicarbazepine acetate and placebo group, 
respectively, were responders (p=0.1514). Although the robustness of these post-hoc subgroup 
analyses is limited, the data suggest an age and dose dependent increase in effect size. 
 
In the subsequent 1-year open-label extension (Part II) of the phase III study (ITT set N=225) the total 
responder rate was 46.7% (steadily increasing from 44.9% (weeks 1-4) to 57.5% (weeks > 40)). The 
total median standardised seizure frequency was 6.1 (decreasing from 7.0 (weeks 1-4) to 4.0 (weeks > 
40), resulting in a median relative change compared to the baseline period of -46.7%). The median 
relative change was larger in the previous placebo group (-51.4%) than in the previous ESL group (-
40.4%). The proportion of patients with exacerbation (increase of ≥25%) compared to the baseline 
period was 14.2%. 
 
In the subsequent 3 open-label extensions (ITT set N=148), the overall responder rate was 26.6% 
when compared to baseline Parts III–V (i.e. the last 4 weeks in part II). The total median standardised 
seizure frequency was 2.4 (resulting in a median relative change from Baseline Part III–V of -22.9%). 
The overall median relative decrease in Part I was greater in patients treated with ESL (-25.8%) than 
in patients treated with placebo (-16.4%). The overall proportion of patients with exacerbation 
(increase of ≥25%) compared to Baseline Parts III–V was 25.7%.   
 
Of the 183 patients who completed parts I and II of the study, 152 patients were enrolled into part III. 
Of these, 65 patients had received ESL and 87 patients had received placebo during the double-blind 
part of the study. 14 patients (9.2%) completed open-label treatment with ESL through Part V. The 



32 

most common reason for withdrawal during any part of the study was sponsor request (30 patients in 
part III [19.7% of the patients who entered part III], 9 in part IV [9.6% of the patients who entered part 
IV], and 43 in part V [64.2% of the patients who entered Part V]). 
 
Taking into consideration the limitations of open label uncontrolled data, the long-term response to 
eslicarbazepine acetate in the open-label parts of the study was overall maintained. 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Zebinix in one or more subsets of the paediatric population in the treatment of epilepsy with partial 
onset seizures (see section 4.2 for information on paediatric use). 
 
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 
Cmax is attained at 2 to 3 hours post-dose (tmax). 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. The 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 hours. In studies in healthy subjects and epileptic adult patients, the apparent half-life of 
eslicarbazepine was 10-20 hours and 13-20 hours, 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. 
 
Eslicarbazepine is a weak inducer of CYP3A4 and has inhibiting properties with respect to CYP2C19 
(as stated in section 4.5). 
 
In studies with eslicarbazepine in fresh human hepatocytes a mild induction of UGT1A1 mediated 
glucuronidation was observed. 
 
Elimination 
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 
The pharmacokinetics of eslicarbazepine acetate is linear and dose-proportional in the range 
400-1,200 mg both in healthy subjects and patients. 
 
Elderly (over 65 years of age) 



33 

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 adult 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, adult and children above 6 years of age with creatinine clearance <60 ml/min (see section 
4.2).  
In children from 2 to 6 years of age, the use of eslicarbazepine acetate is not recommended. At this age 
the intrinsic activity of the elimination process has not yet reached maturation. 
 
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 acetate 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.  
 
Paediatric population 
 
Similar to adults, eslicarbazepine acetate is extensively converted to eslicarbazepine. Plasma levels of 
eslicarbazepine acetate usually remain below the limit of quantification, following oral administration. 
Eslicarbazepine Cmax is attained at 2 to 3 hours post-dose (tmax). Body weight was shown to have an 
effect on volume of distribution and clearance. Furthermore, a role of age independently of weight 
with regards to clearance of eslicarbazepine acetate could not be excluded, in particular for the 
youngest age group (2-6 years). 
 
Children aged 6 years and below 
Population pharmacokinetics indicate that in the subgroup of children aged from 2 to 6 years, doses of 
27.5 mg/kg/day and 40 mg/kg/day are required in order to achieve exposures that are equivalent to the 
therapeutic doses of 20 and 30 mg/kg/day in children above 6 years of age. 
 
Children above 6 years of age 
Population pharmacokinetics indicate that comparable eslicarbazepine exposure is observed between 
20 and 30 mg/kg/day in children above 6 years old and adults with 800 and 1200 mg of 
eslicarbazepine acetate once-daily, respectively (see section 4.2). 
 
5.3 Preclinical safety data 
 
Adverse reactions 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.  
 



34 

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. 
 
Juvenile animals studies 
In repeat-dose studies in juvenile dogs, the toxicity profile was comparable to that observed in adult 
animals. In the 10-month study decreases in bone mineral content, bone area and/or bone mineral 
density in lumbar vertebrae and/or femur were observed in high-dose female animals at exposure 
levels lower than the clinical exposure levels to eslicarbazepine in children. 
 
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 anomalies were observed at maternal toxic doses in embryotoxicity studies in 
mice, rats and rabbits. A delay in the sexual development of the F1 generation was observed in 
peri/postnatal studies in mice and rats. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Povidone K 29/32 
Croscarmellose sodium  
Magnesium stearate 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
5 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5  Nature and contents of container 
 
Aluminium/Aluminium or PVC/Aluminium blisters placed into cardboard boxes containing 7, 14 or 
28 tablets. 
 
Not all pack sizes may be marketed.  
 
6.6 Special precautions for disposal  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 



35 

 
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. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/514/001-006 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 21.04.2009 
 
Date of latest renewal: 22.01.2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


36 

1. NAME OF THE MEDICINAL PRODUCT 
 
Zebinix 600 mg tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 600 mg of eslicarbazepine acetate. 
 

For the full list of excipients, see section 6.1.  
 
 
3. PHARMACEUTICAL FORM 
 
Tablet. 
White oblong tablets, engraved ‘ESL 600’on one side and scored on the other side, with a length of 
17.3 mm. The tablet can be divided into equal doses.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Zebinix is indicated as: 
 
• monotherapy in the treatment of partial-onset seizures, with or without secondary generalisation, in 

adults with newly diagnosed epilepsy; 

• adjunctive therapy in adults, adolescents and children aged above 6 years, with partial-onset 
seizures with or without secondary generalisation. 

 
4.2 Posology and method of administration 
 
Posology 
 
Adults 
Zebinix may be taken as monotherapy or 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 1,200 mg once daily Some patients 
on monotherapy regimen may benefit from a dose of 1,600 mg once daily (see section 5.1). 
 
Special populations 
 
Elderly (over 65 years of age) 
No dose adjustment is needed in the elderly population provided that the renal function is not 
disturbed. Due to very limited data on the 1,600 mg monotherapy regimen in the elderly, this dose is 
not recommended for this population. 
 
Renal impairment 
Caution should be exercised in the treatment of patients, adult and children above 6 years of age, with 
renal impairment and the dose should be adjusted according to creatinine clearance (CLCR) as follows: 
- CLCR >60 ml/min: no dose adjustment required. 
- CLCR 30-60 ml/min: initial dose of 200 mg (or 5 mg/kg in children above 6 years) once daily or 

400 mg (or 10 mg/kg in children above 6 years) every other day for 2 weeks followed by a once 
daily dose of 400 mg (or 10 mg/kg in children above 6 years). However, based on individual 
response, the dose may be increased. 



37 

- CLCR <30 ml/min: use is not recommended in patients with severe renal impairment due to 
insufficient data. 

 
Hepatic impairment 
No dose adjustment is needed in patients with mild to moderate hepatic impairment.  
The pharmacokinetics of eslicarbazepine acetate has not been evaluated in patients with severe hepatic 
impairment (see sections 4.4 and 5.2) and use in these patients is, therefore, not recommended. 
 
Paediatric population 
Children above 6 years of age 
The recommended starting dose is 10 mg/kg/day once daily. Dosage should be increased in weekly or 
bi-weekly increments of 10 mg/kg/day up to 30 mg/kg/day, based on individual response. The 
maximum dose is 1,200 mg once daily (see section 5.1). 
 
Children with a body weight of ≥60 kg 
Children with a body weight of 60 kg or more should be given the same dose as for adults. 
The safety and efficacy of eslicarbazepine acetate in children aged 6 years and below has not yet been 
established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation 
on a posology can be made. 
 
Method of administration 
 
Oral use. 
Zebinix may be taken with or without food. 
 
Switching preparations 
Based on comparative bioavailability data for the tablet and the suspension formulations, switching  
patients from one formulation to the other can be done. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance, to other carboxamide derivatives (e.g. carbamazepine, 
oxcarbazepine) or to any of the excipients listed in section 6.1.  
 
Second or third degree atrioventricular (AV) block. 

 
4.4 Special warnings and precautions for use 
 
Suicidal ideation 
 
Suicidal ideation and behaviour have been reported in patients treated with antiepileptic active 
substances in several indications. A meta-analysis of randomised placebo-controlled trials of 
antiepileptic 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. 
 
Nervous system disorders 
 
Eslicarbazepine acetate has been associated with some central nervous system adverse reactions, such 
as dizziness and somnolence, which could increase the occurrence of accidental injury.  
 
Other warnings and precautions 
 



38 

If Zebinix is to be discontinued it is recommended to withdraw it gradually to minimise the potential 
of increased seizure frequency.  
 
Cutaneous reactions 
 
Rash developed as an adverse reaction in 1.2% of total population treated with Zebinix in clinical 
studies in epileptic patients. Urticaria and angioedema cases have been reported in patients taking 
Zebinix. Angioedema in the context of hypersensitivity/anaphylactic reaction associated with 
laryngeal oedema can be fatal. If signs or symptoms of hypersensitivity develop, eslicarbazepine 
acetate must be discontinued immediately and alternative treatment should be initiated.  
Severe cutaneous adverse reactions (SCARS) including Stevens-Johnson syndrome (SJS)/toxic 
epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), 
which can be life-threatening or fatal, have been reported in post-marketing experience with Zebinix 
treatment. At the time of prescription patients should be advised of the signs and symptoms and 
monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, 
Zebinix should be withdrawn immediately and an alternative treatment considered (as appropriate). If 
the patients have developed such reactions, treatment with Zebinix must not be restarted in these 
patients at any time. 
 
HLA-B* 1502 allele - in Han Chinese, Thai and other Asian populations 
 
HLA-B* 1502 in individuals of Han Chinese and Thai origin has been shown to be strongly associated 
with the risk of developing the severe cutaneous reactions known as Stevens Johnson syndrome (SJS) 
when treated with carbamazepine. The chemical structure of eslicarbazepine acetate is similar to that 
of carbamazepine, and it is possible that patients who are positive for HLA-B*1502 may also be at risk 
for SJS after treatment with eslicarbazepine acetate. The prevalence of HLA-B*1502 carrier is about 
10% in Han Chinese and Thai populations. Whenever possible, these individuals should be screened 
for this allele before starting treatment with carbamazepine or chemically-related active substances. If 
patients of these ethnic origins are tested positive for HLA- B*1502 allele, the use of eslicarbazepine 
acetate may be considered if the benefits are thought to exceed risks. 
Because of the prevalence of this allele in other Asian populations (e.g, above 15% in the Philippines 
and Malaysia), testing genetically at risk populations for the presence of HLA- B*1502 may be 
considered. 
 
HLA-A*3101 allele- European descent and Japanese populations 
 
There are some data that suggest HLA-A*3101 is associated with an increased risk of carbamazepine 
induced cutaneous adverse drug reactions including SJS, TEN, Drug rash with eosinophilia (DRESS), 
or less severe acute generalized exanthematous pustulosis (AGEP) and maculopapular rash in people 
of European descent and the Japanese. 
The frequency of the HLA-A*3101 allele varies widely between ethnic populations. HLA-A*3101 
allele has a prevalence of 2 to 5% in European populations and about 10% in Japanese population. 
The presence of HLA-A*3101 allele may increase the risk for carbamazepine induced cutaneous 
reactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of European 
ancestry, whereas its absence may reduce the risk from 5.0% to 3.8%. 
There are insufficient data supporting a recommendation for HLA-A*3101 screening before starting 
carbamazepine or chemically-related compounds treatment. 
If patients of European descent or Japanese origin are known to be positive for HLA-A*3101 allele, 
the use of carbamazepine or chemically-related compounds may be considered if the benefits are 
thought to exceed risks. 
 
Hyponatraemia 
 
Hyponatraemia has been reported as an adverse reaction in 1.5% 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 



39 

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, carbamazepine), 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, eslicarbazepine acetate should be discontinued. 
 
PR interval 
 
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. 
 
Renal impairment 
 
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 CLCR <30 ml/min use is 
not recommended due to insufficient data. 
 
Hepatic impairment 
 
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, eslicarbazepine acetate should 
be used with caution in patients with mild to moderate hepatic impairment and is not recommended in 
patients with severe hepatic impairment. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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. In vivo eslicarbazepine showed an inducing effect on the metabolism of medicinal 
products that are mainly eliminated by metabolism through CYP3A4 (e.g. Simvastatin). Thus, an 
increase in the dose of the medicinal products that are mainly metabolised through CYP3A4 may be 
required, when used concomitantly with eslicarbazepine acetate. Eslicarbazepine in vivo may have an 
inducing effect on the metabolism of medicinal products that are mainly eliminated by 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 
medicinal products 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 (e.g. Phenytoin). 
 
Interactions with other antiepileptic medicinal products 
 
Carbamazepine 
In a study in healthy subjects, concomitant administration of eslicarbazepine acetate 800 mg once 
daily and carbamazepine 400 mg twice daily resulted in an average decrease of 32% in exposure to the 
active metabolite eslicarbazepine, most likely caused by an induction of glucuronidation. No change in 
exposure to carbamazepine or its metabolite carbamazepine-epoxide was noted. Based on individual 
response, the dose of eslicarbazepine acetate may need to be increased if used concomitantly with 
carbamazepine. Results from patient studies showed that concomitant treatment increased the risk of 



40 

the following adverse reactions: diplopia, abnormal coordination and dizziness. The risk of increase of 
other specific adverse reactions caused by co-administration of carbamazepine and eslicarbazepine 
acetate cannot be excluded. 
  
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 eslicarbazepine acetate 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 inter-individual 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.  
 
Valproate and levetiracetam 
A population pharmacokinetics analysis of phase III studies in epileptic adult patients indicated that 
concomitant administration with valproate or levetiracetam did not affect the exposure to 
eslicarbazepine but this has not been verified by conventional interaction studies.  
 
Oxcarbazepine 
Concomitant use of eslicarbazepine acetate with oxcarbazepine is not recommended because this may 
cause overexposure to the active metabolites. 
 
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 ethinylestradiol, 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 4.6). 
 
Simvastatin 
A study in healthy subjects showed an average decrease of 50% in systemic exposure to simvastatin 
when co-administered with eslicarbazepine acetate 800 mg once daily, most likely caused by an 
induction of CYP3A4. An increase of the simvastatin dose may be required when used concomitantly 
with eslicarbazepine acetate. 
 
Rosuvastatin 
There was an average decrease of 36-39% in systemic exposure in healthy subjects when 
co-administered with eslicarbazepine acetate 1,200 mg once daily. The mechanism for this reduction 
is unknown, but could be due to interference of transporter activity for rosuvastatin alone or in 



41 

combination with induction of its metabolism. Since the relationship between exposure and drug 
activity is unclear, the monitoring of response to therapy (e.g., cholesterol levels) is recommended. 
 
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.  
 
4.6 Fertility, pregnancy and lactation 
 
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. 
 
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. 
 
Pregnancy 
There are no data from the use of eslicarbazepine acetate in pregnant women. Studies in animals have 
shown reproductive toxicity (see Fertility). 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 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. 



42 

 
Breast-feeding 
It is unknown whether eslicarbazepine acetate is excreted in human 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 eslicarbazepine acetate.  
 
Fertility 
There are no data on the effects of eslicarbazepine acetate on human fertility. Studies in animals have 
shown impairment of fertility after treatment with eslicarbazepine acetate (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Zebinix has minor to moderate influence on the ability to drive and use machines. 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. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
In clinical studies (adjunctive therapy treatment and monotherapy), 2,434 patients with partial-onset 
seizures were treated with eslicarbazepine acetate (1,983 adult patients and 451 paediatric patients) 
and 51% of those patients experienced adverse reactions. 
 
Adverse reactions were usually mild to moderate in intensity and occurred predominantly during the 
first weeks of treatment with eslicarbazepine acetate.  
 
The risks that have been identified for Zebinix are mainly class-based, dose-dependent undesirable 
effects. The most common adverse reactions reported, in placebo controlled adjunctive therapy  
studies with adult epileptic patients and in an active controlled monotherapy study comparing 
eslicarbazepine acetate with carbamazepine controlled release, were dizziness, somnolence, headache, 
and nausea. The majority of adverse reactions were reported in <3% of subjects in any treatment 
group. 
 
Severe cutaneous adverse reactions (SCARS), including Stevens-Johnson syndrome (SJS)/toxic 
epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) 
have been reported in post-marketing experience with Zebinix treatment (see section 4.4). 
 
Tabulated list of adverse reactions 
Adverse reactions associated with eslicarbazepine acetate obtained from clinical studies and post-
marketing surveillance are tabulated below. 
 
The following convention has been used for the classification of adverse reactions very common 
(≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and not known (frequency 
cannot be estimated from available data). Within each frequency category, adverse reactions are 
presented in order of decreasing seriousness. 
 
Table 1: Treatment emergent adverse reactions associated with Zebinix obtained from clinical studies 
and post-marketing surveillance 
System Organ 
Class 

Very  
common 

Common Uncommon Not known 

Blood and 
lymphatic 
system disorders 

  Anaemia Thrombocytopenia,
leukopenia 



43 

Immune system 
disorders 

  Hypersensitivity  

Endocrine 
disorders 

  Hypothyroidism  

Metabolism and 
nutrition 
disorders 

 Hyponatraemia, 
decreased 
appetite 

Electrolyte 
imbalance, 
dehydration, 
hypochloraemia 

 

Psychiatric 
disorders 

 Insomnia Psychotic 
disorder, apathy, 
depression, 
nervousness, 
agitation, 
irritability, 
attention deficit/ 
hyperactivity 
disorder, 
confusional 
state, mood 
swings, crying, 
psychomotor 
retardation, 
anxiety  

 

Nervous system 
disorders 

Dizziness, 
somnolence 
 

Headache, 
disturbance in 
attention, 
tremor, ataxia, 
balance disorder 

Coordination 
abnormal, 
memory 
impairment, 
amnesia, 
hypersomnia, 
sedation, 
aphasia, 
dysaesthesia, 
dystonia, 
lethargy, 
parosmia, 
cerebellar 
syndrome, 
convulsion, 
peripheral 
neuropathy, 
nystagmus, 
speech disorder, 
dysarthria, 
burning 
sensation, 
paraesthesia, 
migraine 

 

Eye disorders  Diplopia, vision 
blurred 

Visual 
impairment, 
oscillopsia, 
binocular eye 
movement 
disorder, ocular 
hyperaemia 

 



44 

Ear and 
labyrinth 
disorders 

 Vertigo 
 

Hypoacusis, 
tinnitus 

 

Cardiac 
disorders 

  Palpitations, 
bradycardia 

 

Vascular 
disorders 

  Hypertension 
(including 
hypertensive 
crisis), 
hypotension, 
orthostatic 
hypotension, 
flushing, 
peripheral 
coldness 

 

Respiratory, 
thoracic and 
mediastinal 
disorders 

  Epistaxis, chest 
pain 

 

Gastrointestinal 
disorders 

 Nausea, 
vomiting, 
diarrhoea 

Constipation, 
dyspepsia, 
gastritis, 
abdominal pain, 
dry mouth, 
abdominal 
discomfort, 
abdominal 
distension, 
gingivitis, 
melaena, 
toothache 

Pancreatitis 

Hepatobiliary 
disorders 

  Liver disorder  

Skin and 
subcutaneous 
tissue disorders 

 Rash 
 

Alopecia, dry 
skin, 
hyperhidrosis, 
erythema, skin 
disorder, 
pruritus, 
dermatitis 
allergic 

Toxic epidermal 
necrolysis, Stevens-
Johnson syndrome, 
drug reaction with 
eosinophilia and 
systemic symptoms 
(DRESS), 
angioedema, 
urticaria 

Musculoskeletal 
and connective 
tissue disorders 

  Myalgia, bone 
metabolism 
disorder, 
muscular 
weakness, pain 
in extremity 

 

Renal and 
urinary 
disorders 

  Urinary tract 
infection 

 

General 
disorders and 
administration 
site conditions 

 Fatigue, gait 
disturbance, 
asthenia 

Malaise, chills, 
oedema 
peripheral 

 



45 

Investigations  Weight 
increased 

Blood pressure 
decreased, 
weight 
decreased, blood 
pressure 
increased, blood 
sodium 
decreased, blood 
chloride 
decreased, 
osteocalcin 
increased, 
haematocrit 
decreased, 
haemoglobin 
decreased, 
transaminases 
increased 

 

Injury, 
poisoning and 
procedural 
complications 

  Drug toxicity, 
fall, thermal 
burn 

 

 
Description of selected adverse reactions 
 
Eye and nervous system disorders 
In patients concomitantly treated with carbamazepine and eslicarbazepine acetate in placebo-
controlled studies, the following adverse reactions were observed: 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), see 
section 4.5. 
 
PR interval 
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.  
 
Class related adverse reactions 
Rare adverse reactions such as bone marrow depression, anaphylactic reactions, 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 eslicarbazepine acetate cannot be 
excluded. 
 
There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in 
patients on long-term therapy with the structurally related antiepileptic drugs carbamazepine and 
oxcarbazepine. The mechanism by which bone metabolism is affected has not been identified. 
 
Paediatric population 
 
In placebo-controlled studies involving patients aged from 2 to 18 years with partial-onset seizures 
(238 patients treated with eslicarbazepine acetate and 189 with placebo), 35.7% of patients treated 
with eslicarbazepine acetate and 19% of patients treated with placebo experienced adverse reactions. 
The most common adverse reaction in the group treated with eslicarbazepine acetate were diplopia 
(5.0%), somnolence (8.0%) and vomiting (4.6%). 
 



46 

The adverse reaction profile of eslicarbazepine acetate is generally similar across age goups. In the age 
group from 6 to 11 years of age, the most common adverse reactions observed in more than two 
patients treated with eslicarbazepine acetate were diplopia (9.5%), somnolence (7.4%), diziness 
(6.3%), convulsion (6.3%) and nausea (3.2%); in the age group from 12 to 18 years were somnolence 
(7.4%), vomiting (4.2%), diplopia (3.2%) and fatigue (3.2%). The safety of Zebinix in children aged 6 
years and below has not yet been established. 
 
The safety profile of eslicarbazepine acetate was generally similar between adult and paediatric 
patients, except for agitation (common, 1.3%) and abdominal pain (common, 2.1%) which were more 
common in children than in adults. Dizziness; somnolence; vertigo; asthenia; gait disturbance; tremor; 
ataxia; balance disorder; vision blurred; diarrhoea; rash and hyponatraemia were less common in 
children than in adults. Dermatitis allergic (uncommon, 0.8%) was reported only in the paediatric 
population. 
 
Long-term safety data in the paediatric population obtained from open label extensions of the phase 
III study was consistent with the known safety profile of the product with no new findings of concern. 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms observed after an overdose of eslicarbazepine acetate are primarily associated with central 
nervous symptoms (e.g. seizures of all types, status epilepticus) and cardiac disorders (e.g. cardiac 
arrhythmia). 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. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
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, precluding their return to the activated state and 
thereby preventing 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 efficacy 
 
Adult population 
The efficacy of eslicarbazepine acetate as adjunctive therapy has been demonstrated in four phase III 
double-blind placebo-controlled studies in 1,703 randomized adult patients with partial epilepsy 
refractory to treatment with one to three concomitant antiepileptic medicinal products. Oxcarbazepine 

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


47 

and felbamate were not allowed as concomitant medicinal products in these studies. Eslicarbazepine 
acetate was tested at doses of 400 mg (in -301 and -302 studies only), 800 mg and 1,200 mg, once 
daily. Eslicarbazepine acetate 800 mg once daily and 1,200 mg once daily were significantly more 
effective than placebo in reducing seizure frequency over a 12-week maintenance period. The 
percentage of subjects with ≥50% reduction (1581 analyzed) in seizure frequency in the phase III 
studies was 19.3% for placebo, 20.8% for eslicarbazepine acetate 400 mg, 30.5% for eslicarbazepine 
acetate 800 mg and 35.3% for eslicarbazepine acetate 1,200 mg daily.  
 
The efficacy of eslicarbazepine acetate as monotherapy has been demonstrated in a double-blind, 
active controlled (carbamazepine controlled release) study, involving 815 randomized adult patients 
with newly diagnosed partial-onset seizures. Eslicarbazepine acetate was tested at once-daily doses of 
800 mg, 1,200 mg and 1,600 mg. The doses of the active comparator, carbamazepine controlled 
release, were 200 mg, 400 mg and 600 mg, twice-daily. All subjects were randomized to the lowest 
dose level and only if a seizure occurred subjects were to be escalated to the next dose level. From the 
815 randomized patients, 401 patients were treated with eslicarbazepine acetate once-daily [271 
patients (67.6%) remained at dose of 800 mg, 70 patients (17.5%) remained at dose of 1,200 mg and 
60 patients (15.0%) were treated with 1,600 mg]. In the primary efficacy analysis, in which drop-outs 
were considered as non-responders, 71.1% subjects were classified as seizure free in the 
eslicarbazepine acetate group and 75.6% in the carbamazepine controlled release group during the 
26 week evaluation period (average risk difference -4.28%, 95% confidence interval: [-10,30; 1,74]. 
The treatment effect observed during the 26-week evaluation period was maintained over 1 year of 
treatment with 64.7 % eslicarbazepine acetate subjects and 70.3 % carbamazepine controlled release 
subjects classified as seizure free (average risk difference -5.46%, 95% confidence interval: [-11.88; 
0.97]. In the analysis of treatment failure (seizure risk) based on time to event analysis (Kaplan-Meier 
analysis and Cox regression), the Kaplan-Meier estimates of seizure risk at the end of the evaluation 
period was 0.06 with carbamazepine and 0.12 with eslicarbazepine acetate and by the end of 1 year 
with an additional increased risk to 0.11 with carbamazepine and 0.19 with eslicarbazepine acetate 
(p=0.0002).  
 
At 1 year, the probability for subjects to withdraw due to either adverse reactions or lack of efficacy 
was 0.26 for eslicarbazepine acetate and 0.21 for carbamazepine controlled release.  
The efficacy of eslicarbazepine acetate as conversion to monotherapy was evaluated in 2 double-blind, 
randomized controlled studies in 365 adult patients with partial-onset seizures. Eslicarbazepine acetate 
was tested at doses of 1,200 mg and 1,600 mg once-daily. Seizure-free rates during the entire 10-week 
monotherapy period were 7.6% (1,600 mg) and 8.3 % (1,200 mg) in one study and 10.0% (1,600 mg) 
and 7.4 % (1,200 mg) in the other study, respectively. 
 
Elderly population 
The safety and efficacy of eslicarbazepine acetate as adjunctive therapy for partial seizures in elderly 
patients were evaluated in one non-controlled study, with a duration of 26 weeks, in 72 elderly (aged 
≥ 65 years). The data shows that the incidence of adverse reactions in this population (65.3 %) is 
similar to the general population enrolled in the double-blind epilepsy studies (66.8%). The most 
frequent individual adverse reactions were dizziness (12.5% of subjects), somnolence (9.7%), fatigue, 
convulsion and hyponatraemia (8.3%, each), nasopharyngitis (6.9%) and upper respiratory tract 
infection (5.6%). A total of 50 of the 72 subjects starting the study completed the 26-week treatment 
period that corresponds to a retention rate of 69.4% (see section 4.2 for information on elderly use). 
There is limited data on monotherapy regimen available in the erldely population. Only a few subjects 
(N=27) aged above 65 years were treated with eslicarbazepine acetate in monotherapy study. 
 
Paediatric population  
The efficacy and safety of eslicarbazepine acetate as adjunctive therapy for partial-onset seizures in 
children was evaluated in one phase II study in children aged from 6 to 16 years (N=123) and one 
phase III study in children aged from 2 to 18 years (N=304). Both studies were double-blind and 
placebo controlled with a duration of maintenance of 8 weeks (study 208) and 12 weeks (study 305), 
respectively. Study 208 included 2 additional subsequent long-term, open-label extensions (1 year in 
part II and 2 years in part III) and Study 305 included 4 subsequent long-term, open-label extension 



48 

periods (1 year in Parts II, III and IV and 2 years in Part V).  Eslicarbazepine acetate was tested at 
doses of 20 and 30 mg/kg/day, up to a maximum of 1,200 mg/day. The target dose was 30 mg/kg/day 
in study 208 and 20 mg/kg/day in study 305. Doses could be adjusted based on tolerability and 
treatment response. 
 
In the double-blind period of the phase II study, evaluation of efficacy was a secondary objective. The 
least square mean reduction in standardised seizure frequency from baseline to maintenance period 
was significantly (p<0.001) higher with eslicarbazepine acetate (-34.8%) compared to placebo (-
13.8%). Forty-two patients (50.6%) in the eslicarbazepine acetate group compared to 10 patients 
(25.0%) in the placebo group were responders (≥50% reduction of standardised seizure frequency), 
resulting in a significant difference (p=0.009).  
 
In the double-blind period of the phase III study, the least square mean reduction in standardised 
seizure frequency with eslicarbazepine acetate (-18.1% versus baseline) was different to placebo (-
8.6% versus baseline) but not statistically significant (p=0.2490). Forty-one patients (30.6%) in the 
eslicarbazepine acetate group compared to 40 patients (31.0%) in the placebo group were responders 
(≥50% reduction of standardised seizure frequency), resulting in a non-significant difference 
(p=0.9017). Post-hoc subgroup analyses for the phase III study were conducted by age strata and 
above 6 years, as well as by dose. In children above 6 years, 36 patients (35.0%) in the eslicarbazepine 
acetate group compared to 29 patients (30.2%) in the placebo group were responders (p=0.4759) and 
the least square mean reduction in standardised seizure frequency was higher in the eslicarbazepine 
acetate group compared to placebo (-24.4% versus -10.5%); however, the difference of 13.9% was not 
statistically significant (p=0.1040). A total of 39% patients in study 305 were up titrated to the 
maximum possible dose (30 mg/kg/day). Amongst these, when excluding patients aged 6 years and 
younger, 14 (48.3%) and 11 (30.6%) of patients in the eslicarbazepine acetate and placebo group, 
respectively, were responders (p=0.1514). Although the robustness of these post-hoc subgroup 
analyses is limited, the data suggest an age and dose dependent increase in effect size. 
 
In the subsequent 1-year open-label extension (Part II) of the phase III study (ITT set N=225) the total 
responder rate was 46.7% (steadily increasing from 44.9% (weeks 1-4) to 57.5% (weeks > 40)). The 
total median standardised seizure frequency was 6.1 (decreasing from 7.0 (weeks 1-4) to 4.0 (weeks > 
40), resulting in a median relative change compared to the baseline period of -46.7%). The median 
relative change was larger in the previous placebo group (-51.4%) than in the previous ESL group (-
40.4%). The proportion of patients with exacerbation (increase of ≥25%) compared to the baseline 
period was 14.2%. 
 
In the subsequent 3 open-label extensions (ITT set N=148), the overall responder rate was 26.6% 
when compared to baseline Parts III–V (i.e. the last 4 weeks in part II). The total median standardised 
seizure frequency was 2.4 (resulting in a median relative change from Baseline Part III–V of -22.9%). 
The overall median relative decrease in Part I was greater in patients treated with ESL (-25.8%) than 
in patients treated with placebo (-16.4%). The overall proportion of patients with exacerbation 
(increase of ≥25%) compared to Baseline Parts III–V was 25.7%. 
 
Of the 183 patients who completed parts I and II of the study, 152 patients were enrolled into part III. 
Of these, 65 patients had received ESL and 87 patients had received placebo during the double-blind 
part of the study. 14 patients (9.2%) completed open-label treatment with ESL through Part V. The 
most common reason for withdrawal during any part of the study was sponsor request (30 patients in 
part III [19.7% of the patients who entered part III], 9 in part IV [9.6% of the patients who entered part 
IV], and 43 in part V [64.2% of the patients who entered Part V]). 
 
Taking into consideration the limitations of open label uncontrolled data, the long-term response to 
eslicarbazepine acetate in the open-label parts of the study was overall maintained. 
 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Zebinix in one or more subsets of the paediatric population in the treatment of epilepsy with partial 
onset seizures (see section 4.2 for information on paediatric use). 



49 

 
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 
Cmax is attained at 2 to 3 hours post-dose (tmax). 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. The 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 hours. In studies in healthy subjects and epileptic adult patients, the apparent half-life of 
eslicarbazepine was 10-20 hours and 13-20 hours, 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. 
 
Eslicarbazepine is a weak inducer of CYP3A4 and has inhibiting properties with respect to CYP2C19 
(as stated in section 4.5). 
 
In studies with eslicarbazepine in fresh human hepatocytes a mild induction of UGT1A1 mediated 
glucuronidation was observed. 
 
Elimination 
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 
The pharmacokinetics of eslicarbazepine acetate is linear and dose-proportional in the range 
400-1,200 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 adult 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,adult and children above 6 years of age with creatinine clearance <60 ml/min (see section 
4.2).  
In children from 2 to 6 years of age, the use of eslicarbazepine acetate is not recommended. At this age 
the intrinsic activity of the elimination process has not yet reached maturation. 



50 

 
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 acetate 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.  
 
Paediatric population 
 
Similar to adults, eslicarbazepine acetate is extensively converted to eslicarbazepine. Plasma levels of 
eslicarbazepine acetate usually remain below the limit of quantification, following oral administration. 
Eslicarbazepine Cmax is attained at 2 to 3 hours post-dose (tmax). Body weight was shown to have an 
effect on volume of distribution and clearance. Furthermore, a role of age independently of weight 
with regards to clearance of eslicarbazepine acetate could not be excluded, in particular for the 
youngest age group (2-6 years). 
 
Children aged 6 years and below 
Population pharmacokinetics indicate that in the subgroup of children aged from 2 to 6 years, doses of 
27.5 mg/kg/day and 40 mg/kg/day are required in order to achieve exposures that are equivalent to the 
therapeutic doses of 20 and 30 mg/kg/day in children above 6 years of age. 
 
Children above 6 years of age 
Population pharmacokinetics indicate that comparable eslicarbazepine exposure is observed between 
20 and 30 mg/kg/day in children above 6 years old and adults with 800 and 1200 mg of 
eslicarbazepine acetate once-daily, respectively (see section 4.2). 
 
5.3 Preclinical safety data 
 
Adverse reactions 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. 
 
Juvenile animals studies 
In repeat-dose studies in juvenile dogs, the toxicity profile was comparable to that observed in adult 
animals. In the 10-month study decreases in bone mineral content, bone area and/or bone mineral 
density in lumbar vertebrae and/or femur were observed in high-dose female animals at exposure 
levels lower than the clinical exposure levels to eslicarbazepine in children. 
 



51 

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 anomalies were observed at maternal toxic doses in embryotoxicity studies in 
mice, rats and rabbits. A delay in the sexual development of the F1 generation was observed in 
peri/postnatal studies in mice and rats. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Povidone K 29/32 
Croscarmellose sodium  
Magnesium stearate 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
5 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5  Nature and contents of container 
 
Aluminium /Aluminium or PVC/Aluminium blisters placed into cardboard boxes containing 30 or 60 
tablets.  
 
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  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
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  
 



52 

 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/514/007-011 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 21.04.2009 
 
Date of latest renewal: 22.01.2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


53 

1. NAME OF THE MEDICINAL PRODUCT 
 
Zebinix 800 mg tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each tablet contains 800 mg of eslicarbazepine acetate. 
 
For the full list of excipients, see section 6.1.  
 
 
3. PHARMACEUTICAL FORM 
 
Tablet. 
White oblong tablets, engraved ‘ESL 800’on one side and scored on the other side, with a length of 19 
mm. The tablet can be divided into equal doses.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Zebinix is indicated as: 
 
• monotherapy in the treatment of partial-onset seizures, with or without secondary generalisation, in 

adults with newly diagnosed epilepsy; 

• adjunctive therapy in adults, adolescents and children aged above 6 years with partial-onset 
seizures with or without secondary generalisation. 

 
4.2 Posology and method of administration 
 
Posology 
 
Adults  
Zebinix may be taken as monotherapy or 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 1,200 mg once daily  Some 
patients on monotherapy regimen may benefit from a dose of 1,600 mg once daily (see section 5.1). 
 
Special populations 
 
Elderly (over 65 years of age) 
No dose adjustment is needed in the elderly population provided that the renal function is not 
disturbed. Due to very limited data on the 1,600 mg monotherapy regimen in the elderly, this dose is 
not recommended for this population. 
 
Renal impairment 
Caution should be exercised in the treatment of patients, adult and children above 6 years of age, with 
renal impairment and the dose should be adjusted according to creatinine clearance (CLCR) as follows: 
- CLCR >60 ml/min: no dose adjustment required. 
- CLCR 30-60 ml/min: initial dose of 200 mg (or 5 mg/kg in children above 6 years) once daily or 

400 mg (or 10 mg/kg in children above 6 years) every other day for 2 weeks followed by a once 
daily dose of 400 mg (or 10 mg/kg in children above 6 years). However, based on individual 
response, the dose may be increased. 



54 

- CLCR <30 ml/min: use is not recommended in patients with severe renal impairment due to 
insufficient data. 

 
Hepatic impairment 
No dose adjustment is needed in patients with mild to moderate hepatic impairment.  
The pharmacokinetics of eslicarbazepine acetate has not been evaluated in patients with severe hepatic 
impairment (see sections 4.4 and 5.2) and use in these patients is, therefore, not recommended. 
 
Paediatric population 
Children above 6 years of age 
The recommended starting dose is 10 mg/kg/day once daily. Dosage should be increased in weekly or 
bi-weekly increments of 10 mg/kg/day up to 30 mg/kg/daybased on individual response. the maximum 
dose is 1,200 mg once daily (see section 5.1). 
 
Children with a body weight of ≥60 kg 
Children with a body weight of 60 kg or more should be given the same dose as for adults. 
 
The safety and efficacy of eslicarbazepine acetate in children aged 6 years and below has not yet been 
established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation 
on a posology can be made. 
 
Method of administration 
 
Oral use. 
Zebinix may be taken with or without food. 
 
Switching preparations 
Based on comparative bioavailability data for the tablet and the suspension formulations, switching  
patients from one formulation to the other can be done. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance, to other carboxamide derivatives (e.g. carbamazepine, 
oxcarbazepine) or to any of the excipients listed in section 6.1.  
 
Second or third degree atrioventricular (AV) block. 
 
4.4 Special warnings and precautions for use 
 
Suicidal ideation 
 
Suicidal ideation and behaviour have been reported in patients treated with antiepileptic active 
substances in several indications. A meta-analysis of randomised placebo-controlled trials of 
antiepileptic 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. 
 
Nervous system disorders 
 
Eslicarbazepine acetate has been associated with some central nervous system adverse reactions, such 
as dizziness and somnolence, which could increase the occurrence of accidental injury.  
 
Other warnings and precautions 



55 

 
If Zebinix is to be discontinued it is recommended to withdraw it gradually to minimise the potential 
of increased seizure frequency.  
 
Cutaneous reactions 
 
Rash developed as an adverse reaction in 1.2% of total population treated with Zebinix in clinical 
studies in epileptic patients. Urticaria and angioedema cases have been reported in patients taking 
Zebinix. Angioedema in the context of hypersensitivity/anaphylactic reaction associated with 
laryngeal oedema can be fatal. If signs or symptoms of hypersensitivity develop, eslicarbazepine 
acetate must be discontinued immediately and alternative treatment should be initiated.  
Severe cutaneous adverse reactions (SCARS) including Stevens-Johnson syndrome (SJS)/toxic 
epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), 
which can be life-threatening or fatal, have been reported in post-marketing experience with Zebinix 
treatment. At the time of prescription patients should be advised of the signs and symptoms and 
monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, 
Zebinix should be withdrawn immediately and an alternative treatment considered (as appropriate). If 
the patients have developed such reactions, treatment with Zebinix must not be restarted in these 
patients at any time. 
 
HLA-B* 1502 allele - in Han Chinese, Thai and other Asian populations 
 
HLA-B* 1502 in individuals of Han Chinese and Thai origin has been shown to be strongly associated 
with the risk of developing the severe cutaneous reactions known as Stevens Johnson syndrome (SJS) 
when treated with carbamazepine. The chemical structure of eslicarbazepine acetate is similar to that 
of carbamazepine, and it is possible that patients who are positive for HLA-B*1502 may also be at risk 
for SJS after treatment with eslicarbazepine acetate. The prevalence of HLA-B*1502 carrier is about 
10% in Han Chinese and Thai populations. Whenever possible, these individuals should be screened 
for this allele before starting treatment with carbamazepine or chemically-related active substances. If 
patients of these ethnic origins are tested positive for HLA- B*1502 allele, the use of eslicarbazepine 
acetate may be considered if the benefits are thought to exceed risks. 
Because of the prevalence of this allele in other Asian populations (e.g, above 15% in the Philippines 
and Malaysia), testing genetically at risk populations for the presence of HLA- B*1502 may be 
considered. 
 
HLA-A*3101 allele- European descent and Japanese populations 
 
There are some data that suggest HLA-A*3101 is associated with an increased risk of carbamazepine 
induced cutaneous adverse drug reactions including SJS, TEN, Drug rash with eosinophilia (DRESS), 
or less severe acute generalized exanthematous pustulosis (AGEP) and maculopapular rash in people 
of European descent and the Japanese. 
The frequency of the HLA-A*3101 allele varies widely between ethnic populations. HLA-A*3101 
allele has a prevalence of 2 to 5% in European populations and about 10% in Japanese population. 
The presence of HLA-A*3101 allele may increase the risk for carbamazepine induced cutaneous 
reactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of European 
ancestry, whereas its absence may reduce the risk from 5.0% to 3.8%. 
There are insufficient data supporting a recommendation for HLA-A*3101 screening before starting 
carbamazepine or chemically-related compounds treatment. 
If patients of European descent or Japanese origin are known to be positive for HLA-A*3101 allele, 
the use of carbamazepine or chemically-related compounds may be considered if the benefits are 
thought to exceed risks. 
 
Hyponatraemia 
 
Hyponatraemia has been reported as an adverse reaction in 1.5% of patients treated with Zebinix. 
Hyponatraemia is asymptomatic in most cases, however, it may be accompanied by clinical symptoms 



56 

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, carbamazepine), 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, eslicarbazepine acetate should be discontinued. 
 
PR interval 
 
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. 
 
Renal impairment 
 
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 CLCR <30 ml/min use is 
not recommended due to insufficient data. 
 
Hepatic impairment 
 
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, eslicarbazepine acetate should 
be used with caution in patients with mild to moderate hepatic impairment and is not recommended in 
patients with severe hepatic impairment. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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. In vivo eslicarbazepine showed an inducing effect on the metabolism of medicinal 
products that are mainly eliminated by metabolism through CYP3A4 (e.g. Simvastatin). Thus, an 
increase in the dose of the medicinal products that are mainly metabolised through CYP3A4 may be 
required, when used concomitantly with eslicarbazepine acetate. Eslicarbazepine in vivo may have an 
inducing effect on the metabolism of medicinal products that are mainly eliminated by 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 
medicinal products 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 (e.g. Phenytoin). 
 
Interactions with other antiepileptic medicinal products 
 
Carbamazepine 
In a study in healthy subjects, concomitant administration of eslicarbazepine acetate 800 mg once 
daily and carbamazepine 400 mg twice daily resulted in an average decrease of 32% in exposure to the 
active metabolite eslicarbazepine, most likely caused by an induction of glucuronidation. No change in 
exposure to carbamazepine or its metabolite carbamazepine-epoxide was noted. Based on individual 
response, the dose of eslicarbazepine acetate may need to be increased if used concomitantly with 



57 

carbamazepine. Results from patient studies showed that concomitant treatment increased the risk of 
the following adverse reactions: diplopia, abnormal coordination and dizziness. The risk of increase of 
other specific adverse reactions caused by co-administration of carbamazepine and eslicarbazepine 
acetate cannot be excluded.  
 
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 eslicarbazepine acetate 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 inter-individual 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.  
 
Valproate and levetiracetam 
A population pharmacokinetics analysis of phase III studies in epileptic adult patients indicated that 
concomitant administration with valproate or levetiracetam did not affect the exposure to 
eslicarbazepine but this has not been verified by conventional interaction studies.  
 
Oxcarbazepine 
Concomitant use of eslicarbazepine acetate with oxcarbazepine is not recommended because this may 
cause overexposure to the active metabolites. 
 
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 ethinylestradiol, 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 and 4.6). 
 
Simvastatin 
A study in healthy subjects showed an average decrease of 50% in systemic exposure to simvastatin 
when co-administered with eslicarbazepine acetate 800 mg once daily, most likely caused by an 
induction of CYP3A4. An increase of the simvastatin dose may be required when used concomitantly 
with eslicarbazepine acetate. 
 
Rosuvastatin 
There was an average decrease of 36-39% in systemic exposure in healthy subjects when 
co-administered with eslicarbazepine acetate 1,200 mg once daily. The mechanism for this reduction 
is unknown, but could be due to interference of transporter activity for rosuvastatin alone or in 



58 

combination with induction of its metabolism. Since the relationship between exposure and drug 
activity is unclear, the monitoring of response to therapy (e.g., cholesterol levels) is recommended. 
 
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.  
 
4.6 Fertility, pregnancy and lactation 
 
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. 
 
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. 
 
Pregnancy 
There are no data from the use of eslicarbazepine acetate in pregnant women. Studies in animals have 
shown reproductive toxicity (see Fertility). 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 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. 



59 

 
Breast-feeding 
It is unknown whether eslicarbazepine acetate is excreted in human 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 eslicarbazepine acetate.  
 
Fertility 
There are no data on the effects of eslicarbazepine acetate on human fertility. Studies in animals have 
shown impairment of fertility after treatment with eslicarbazepine acetate (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Zebinix has minor to moderate influence on the ability to drive and use machines. 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. 
 
4.8 Undesirable effects 
 
Summary of the safety profile  
In clinical studies (adjunctive therapy treatment and monotherapy), 2,434 patients with partial-onset 
seizures were treated with eslicarbazepine acetate (1,983 adult patients and 451 paediatric patients) 
and 51% of those patients experienced adverse reactions. 
 
Adverse reactions were usually mild to moderate in intensity and occurred predominantly during the 
first weeks of treatment with eslicarbazepine acetate.  
 
The risks that have been identified for Zebinix are mainly class-based, dose-dependent  undesirable 
effects. The most common treatment-emergent adverse reactions reported, in placebo controlled 
adjunctive therapy studies with adult epileptic patients and in an active controlled monotherapy study 
comparing eslicarbazepine acetate with carbamazepine controlled release, were dizziness, somnolence, 
headache, and nausea. The majority of adverse reactions were reported in <3% of subjects in any 
treatment group. 
 
Severe cutaneous adverse reactions (SCARS), including Stevens-Johnson syndrome (SJS)/toxic 
epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) 
have been reported in post-marketing experience with Zebinix treatment (see section 4.4). 
 
Tabulated list of adverse reactions 
Adverse reactions associated with eslicarbazepine acetate obtained from clinical studies and post-
marketing surveillance are tabulated below. 
 
The following convention has been used for the classification of adverse reactions very common 
(≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and not known (frequency 
cannot be estimated from available data). Within each frequency category, adverse reactions are 
presented in order of decreasing seriousness. 
 
Table 1: Treatment emergent adverse reactions associated with Zebinix obtained from in clinical 
studies and post-marketing surveillance 
System Organ 
Class 

Very  
common 

Common Uncommon Not known 

Blood and 
lymphatic 
system disorders 

  Anaemia Thrombocytopenia,
leukopenia 



60 

Immune system 
disorders 

  Hypersensitivity  

Endocrine 
disorders 

  Hypothyroidism  

Metabolism and 
nutrition 
disorders 

 Hyponatraemia, 
decreased 
appetite 

Electrolyte 
imbalance, 
dehydration, 
hypochloraemia 

 

Psychiatric 
disorders 

 Insomnia Psychotic 
disorder, apathy, 
depression, 
nervousness, 
agitation, 
irritability, 
attention deficit/ 
hyperactivity 
disorder, 
confusional 
state, mood 
swings, crying, 
psychomotor 
retardation, 
anxiety  

 

Nervous system 
disorders 

Dizziness, 
somnolence 
 

Headache, 
disturbance in 
attention, 
tremor, ataxia, 
balance disorder 

Coordination 
abnormal, 
memory 
impairment, 
amnesia, 
hypersomnia, 
sedation, 
aphasia, 
dysaesthesia, 
dystonia, 
lethargy, 
parosmia, 
cerebellar 
syndrome, 
convulsion, 
peripheral 
neuropathy, 
nystagmus, 
speech disorder, 
dysarthria, 
burning 
sensation, 
paraesthesia, 
migraine 

 

Eye disorders  Diplopia, vision 
blurred 

Visual 
impairment, 
oscillopsia, 
binocular eye 
movement 
disorder, ocular 
hyperaemia 

 



61 

Ear and 
labyrinth 
disorders 

 Vertigo 
 

Hypoacusis, 
tinnitus 

 

Cardiac 
disorders 

  Palpitations, 
bradycardia 

 

Vascular 
disorders 

  Hypertension 
(including 
hypertensive 
crisis), 
hypotension, 
orthostatic 
hypotension, 
flushing, 
peripheral 
coldness 

 

Respiratory, 
thoracic and 
mediastinal 
disorders 

  Epistaxis, chest 
pain 

 

Gastrointestinal 
disorders 

 Nausea, 
vomiting, 
diarrhoea 

Constipation, 
dyspepsia, 
gastritis, 
abdominal pain, 
dry mouth, 
abdominal 
discomfort, 
abdominal 
distension, 
gingivitis , 
melaena, 
toothache 

Pancreatitis 

Hepatobiliary 
disorders 

  Liver disorder  

Skin and 
subcutaneous 
tissue disorders 

 Rash 
 

Alopecia, dry 
skin, 
hyperhidrosis, 
erythema, skin 
disorder, 
pruritus, 
dermatitis 
allergic 

Toxic epidermal 
necrolysis, Stevens-
Johnson syndrome, 
drug reaction with 
eosinophilia and 
systemic symptoms 
(DRESS), 
angioedema, 
urticaria 

Musculoskeletal 
and connective 
tissue disorders 

  Myalgia, bone 
metabolism 
disorder, 
muscular 
weakness, pain 
in extremity 

 

Renal and 
urinary 
disorders 

  Urinary tract 
infection 

 

General 
disorders and 
administration 
site conditions 

 Fatigue, gait 
disturbance, 
asthenia 

Malaise, chills, 
oedema 
peripheral 

 



62 

Investigations  Weight 
increased 

Blood pressure 
decreased, 
weight 
decreased, blood 
pressure 
increased, blood 
sodium 
decreased, blood 
chloride 
decreased, 
osteocalcin 
increased, 
haematocrit 
decreased, 
haemoglobin 
decreased, 
transaminases 
increased 

 

Injury, 
poisoning and 
procedural 
complications  

  Drug toxicity, 
fall, thermal 
burn 

 

 
Description of selected adverse reactions 
 
Eye and nervous system disorders 
In patients concomitantly treated with carbamazepine and eslicarbazepine acetate in placebo-
controlled studies, the following adverse reactions were observed: 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), see 
section 4.5. 
 
PR interval 
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.  
 
Class related adverse reactions 
Rare adverse reactions such as bone marrow depression, anaphylactic reactions, 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 eslicarbazepine acetate cannot be 
excluded. 
 
There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in 
patients on long-term therapy with the structurally related antiepileptic drugs carbamazepine and 
oxcarbazepine. The mechanism by which bone metabolism is affected has not been identified. 
 
Paediatric population 
 
In placebo-controlled studies involving patients aged from 2 to 18 years with partial-onset seizures 
(238 patients treated with eslicarbazepine acetate and 189 with placebo), 35.7% of patients treated 
with eslicarbazepine acetate and 19% of patients treated with placebo experienced adverse reactions.  
The most common adverse reaction in the group treated with eslicarbazepine acetate were diplopia 
(5.0%), somnolence (8.0%) and vomiting (4.6%). 
 



63 

The adverse reaction profile of eslicarbazepine acetate is generally similar across age goups. In the age 
group from 6 to 11 years of age, the most common adverse reaction observed in more than two 
patients treated with eslicarbazepine acetate were diplopia (9.5%), somnolence (7.4%), diziness 
(6.3%), convulsion (6.3%) and nausea (3.2%); in the age group from 12 to 18 years were somnolence 
(7.4%), vomiting (4.2%), diplopia (3.2%) and fatigue (3.2%). The safety of Zebinix in children aged 6 
years and below has not yet been established. 
 
The safety profile of eslicarbazepine acetate was generally similar between adult and paediatric 
patients, except for agitation (common, 1.3%) and abdominal pain (common, 2.1%) which were more 
common in children than in adults. Dizziness; somnolence; vertigo; asthenia; gait disturbance; tremor; 
ataxia; balance disorder; vision blurred; diarrhoea; rash and hyponatraemia were less common in 
children than in adults. Dermatitis allergic (uncommon, 0.8%) was reported only in the paediatric 
population. 
 
Long-term safety data in the paediatric population obtained from open label extensions of the phase III 
study was consistent with the known safety profile of the product with no new findings of concern. 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms observed after an overdose of eslicarbazepine acetate are primarily associated with central 
nervous symptoms (e.g. seizures of all types, status epilepticus) and cardiac disorders (e.g. cardiac 
arrhythmia). 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. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
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, precluding their return to the activated state and 
thereby preventing 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 efficacy 
 
Adult population 
The efficacy of eslicarbazepine acetate as adjunctive therapy has been demonstrated in four phase III 
double-blind placebo-controlled studies in 1,703 randomized adult patients with partial epilepsy 

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


64 

refractory to treatment with one to three concomitant antiepileptic medicinal products. Oxcarbazepine 
and felbamate were not allowed as concomitant medicinal products in these studies. Eslicarbazepine 
acetate was tested at doses of 400 mg (in -301 and -302 studies only), 800 mg and 1,200 mg, once 
daily. Eslicarbazepine acetate 800 mg once daily and 1,200 mg once daily were significantly more 
effective than placebo in reducing seizure frequency over a 12-week maintenance period. The 
percentage of subjects with ≥50% reduction (1581 analyzed) in seizure frequency in the phase III 
studies was 19.3% for placebo, 20.8% for eslicarbazepine acetate 400 mg, 30.5% for eslicarbazepine 
acetate 800 mg and 35.3% for eslicarbazepine acetate 1,200 mg daily.  
 
The efficacy of eslicarbazepine acetate as monotherapy has been demonstrated in a double-blind, 
active controlled (carbamazepine controlled release) study, involving 815 randomized adult patients 
with newly diagnosed partial-onset seizures. Eslicarbazepine acetate was tested at once-daily doses of 
800 mg, 1,200 mg and 1,600 mg. The doses of the active comparator, carbamazepine controlled 
release, were 200 mg, 400 mg and 600 mg, twice-daily. All subjects were randomized to the lowest 
dose level and only if a seizure occurred subjects were to be escalated to the next dose level. From the 
815 randomized patients, 401 patients were treated with eslicarbazepine acetate once-daily [271 
patients (67.6%) remained at dose of 800 mg, 70 patients (17.5%) remained at dose of 1,200 mg and 
60 patients (15.0%) were treated with 1,600 mg]. In the primary efficacy analysis, in which drop-outs 
were considered as non-responders, 71.1% subjects were classified as seizure free in the 
eslicarbazepine acetate group and 75.6% in the carbamazepine controlled release group during the 
26 week evaluation period (average risk difference -4.28%, 95% confidence interval: [-10,30; 1,74]. 
The treatment effect observed during the 26-week evaluation period was maintained over 1 year of 
treatment with 64.7 % eslicarbazepine acetate subjects and 70.3 % carbamazepine controlled release 
subjects classified as seizure free (average risk difference -5.46%, 95% confidence interval: [-11.88; 
0.97]. In the analysis of treatment failure (seizure risk) based on time to event analysis (Kaplan-Meier 
analysis and Cox regression), the Kaplan-Meier estimates of seizure risk at the end of the evaluation 
period was 0.06 with carbamazepine and 0.12 with eslicarbazepine acetate and by the end of 1 year 
with an additional increased risk to 0.11 with carbamazepine and 0.19 with eslicarbazepine acetate 
(p=0.0002). 
 
At 1 year, the probability for subjects to withdraw due to either adverse reactions or lack of efficacy 
was 0.26 for eslicarbazepine acetate and 0.21 for carbamazepine controlled release.  
The efficacy of eslicarbazepine acetate as conversion to monotherapy was evaluated in 2 double-blind, 
randomized controlled studies in 365 adult patients with partial-onset seizures. Eslicarbazepine acetate 
was tested at doses of 1,200 mg and 1,600 mg once-daily. Seizure-free rates during the entire 10-week 
monotherapy period were 7.6% (1,600 mg) and 8.3 % (1,200 mg) in one study and 10.0% (1,600 mg) 
and 7.4 % (1,200 mg) in the other study, respectively. 
 
Elderly population 
The safety and efficacy of eslicarbazepine acetate as adjunctive therapy for partial seizures in elderly 
patients were evaluated in one non-controlled study, with a duration of 26 weeks, in 72 elderly (aged 
≥ 65 years). The data shows that the incidence of adverse reactions in this population (65.3 %) is 
similar to the general population enrolled in the double-blind epilepsy studies (66.8%). The most 
frequent individual adverse reactions were dizziness (12.5% of subjects), somnolence (9.7%), fatigue, 
convulsion and hyponatraemia (8.3%, each), nasopharyngitis (6.9%) and upper respiratory tract 
infection (5.6%). A total of 50 of the 72 subjects starting the study completed the 26-week treatment 
period that corresponds to a retention rate of 69.4% (see section 4.2 for information on elderly use). 
There is limited data on monotherapy regimen available in the erldely population. Only a few subjects 
(N=27) aged above 65 years were treated with eslicarbazepine acetate in monotherapy study. 
 
Paediatric population 
The efficacy and safety of eslicarbazepine acetate as adjunctive therapy for partial-onset seizures in 
children was evaluated in one phase II study in children aged from 6 to 16 years (N=123) and one 
phase III study in children aged from 2 to 18 years (N=304). Both studies were double-blind and 
placebo controlled with a duration of maintenance of 8 weeks (study 208) and 12 weeks (study 305), 
respectively. Study 208 included 2 additional subsequent long-term, open-label extensions (1 year in 



65 

part II and 2 years in part III) and Study 305 included 4 subsequent long-term, open-label extension 
periods (1 year in Parts II, III and IV and 2 years in Part V). Eslicarbazepine acetate was tested at 
doses of 20 and 30 mg/kg/day, up to a maximum of 1,200 mg/day. The target dose was 30 mg/kg/day 
in study 208 and 20 mg/kg/day in study 305. Doses could be adjusted based on tolerability and 
treatment response. 
 
In the double-blind period of the phase II study, evaluation of efficacy was a secondary objective. The 
least square mean reduction in standardised seizure frequency from baseline to maintenance period 
was significantly (p<0.001) higher with eslicarbazepine acetate (-34.8%) compared to placebo (-
13.8%). Forty-two patients (50.6%) in the eslicarbazepine acetate group compared to 10 patients 
(25.0%) in the placebo group were responders (≥50% reduction of standardised seizure frequency), 
resulting in a significant difference (p=0.009).  
 
In the double-blind period of the phase III study, the least square mean reduction in standardised 
seizure frequency with eslicarbazepine acetate (-18.1% versus baseline) was different to placebo (-
8.6% versus baseline) but not statistically significant (p=0.2490). Forty-one patients (30.6%) in the 
eslicarbazepine acetate group compared to 40 patients (31.0%) in the placebo group were responders 
(≥50% reduction of standardised seizure frequency), resulting in a non-significant difference 
(p=0.9017). Post-hoc subgroup analyses for the phase III study were conducted by age strata and 
above 6 years, as well as by dose. In children above 6 years, 36 patients (35.0%) in the eslicarbazepine 
acetate group compared to 29 patients (30.2%) in the placebo group were responders (p=0.4759) and 
the least square mean reduction in standardised seizure frequency was higher in the eslicarbazepine 
acetate group compared to placebo (-24.4% versus -10.5%); however, the difference of 13.9% was not 
statistically significant (p=0.1040). A total of 39% patients in study 305 were up titrated to the 
maximum possible dose (30 mg/kg/day). Amongst these, when excluding patients aged 6 years and 
younger, 14 (48.3%) and 11 (30.6%) of patients in the eslicarbazepine acetate and placebo group, 
respectively, were responders (p=0.1514). Although the robustness of these post-hoc subgroup 
analyses is limited, the data suggest an age and dose dependent increase in effect size. 
 
In the subsequent 1-year open-label extension (Part II) of the phase III study (ITT set N=225) the total 
responder rate was 46.7% (steadily increasing from 44.9% (weeks 1-4) to 57.5% (weeks > 40)). The 
total median standardised seizure frequency was 6.1 (decreasing from 7.0 (weeks 1-4) to 4.0 (weeks > 
40), resulting in a median relative change compared to the baseline period of -46.7%). The median 
relative change was larger in the previous placebo group (-51.4%) than in the previous ESL group (-
40.4%). The proportion of patients with exacerbation (increase of ≥25%) compared to the baseline 
period was 14.2%. 
 
In the subsequent 3 open-label extensions (ITT set N=148), the overall responder rate was 26.6% 
when compared to baseline Parts III–V (i.e. the last 4 weeks in part II). The total median standardised 
seizure frequency was 2.4 (resulting in a median relative change from Baseline Part III–V of -22.9%). 
The overall median relative decrease in Part I was greater in patients treated with ESL (-25.8%) than 
in patients treated with placebo (-16.4%). The overall proportion of patients with exacerbation 
(increase of ≥25%) compared to Baseline Parts III–V was 25.7%. 
 
Of the 183 patients who completed parts I and II of the study, 152 patients were enrolled into part III. 
Of these, 65 patients had received ESL and 87 patients had received placebo during the double-blind 
part of the study. 14 patients (9.2%) completed open-label treatment with ESL through Part V. The 
most common reason for withdrawal during any part of the study was sponsor request (30 patients in 
part III [19.7% of the patients who entered part III], 9 in part IV [9.6% of the patients who entered part 
IV], and 43 in part V [64.2% of the patients who entered Part V]). 
 
Taking into consideration the limitations of open label uncontrolled data, the long-term response to 
eslicarbazepine acetate in the open-label parts of the study was overall maintained. 
 



66 

The European Medicines Agency has deferred the obligation to submit the results of studies with 
Zebinix in one or more subsets of the paediatric population in the treatment of epilepsy with partial 
onset seizures (see section 4.2 for information on paediatric use). 
 
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 
Cmax is attained at 2 to 3 hours post-dose (tmax). 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. The 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 hours. In studies in healthy subjects and epileptic adult patients, the apparent half-life of 
eslicarbazepine was 10-20 hours and 13-20 hours, 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. 
 
Eslicarbazepine is a weak inducer of CYP3A4 and has inhibiting properties with respect to CYP2C19 
(as stated in section 4.5). 
 
In studies with eslicarbazepine in fresh human hepatocytes a mild induction of UGT1A1 mediated 
glucuronidation was observed. 
 
Elimination 
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 
The pharmacokinetics of eslicarbazepine acetate is linear and dose-proportional in the range 
400-1,200 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 adult patients with mild to severe renal impairment showed that clearance is 
dependent on renal function. During treatment with Zebinix dose adjustment is recommended in 



67 

patients, adult and children above 6 years of age with creatinine clearance <60 ml/min (see section 
4.2).  
In children from 2 to 6 years of age, the use of eslicarbazepine acetate is not recommended. At this age 
the intrinsic activity of the elimination process has not yet reached maturation. 
 
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 acetate 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.  
 
Paediatric population 
 
Similar to adults, eslicarbazepine acetate is extensively converted to eslicarbazepine. Plasma levels of 
eslicarbazepine acetate usually remain below the limit of quantification, following oral administration. 
Eslicarbazepine Cmax is attained at 2 to 3 hours post-dose (tmax). Body weight was shown to have an 
effect on volume of distribution and clearance. Furthermore, a role of age independently of weight 
with regards to clearance of eslicarbazepine acetate could not be excluded, in particular for the 
youngest age group (2-6 years). 
 
Children aged 6 years and below 
Population pharmacokinetics indicate that in the subgroup of children aged from 2 to 6 years, doses of 
27.5 mg/kg/day and 40 mg/kg/day are required in order to achieve exposures that are equivalent to the 
therapeutic doses of 20 and 30 mg/kg/day in children above 6 years of age. 
 
Children above 6 years of age 
Population pharmacokinetics indicate that comparable eslicarbazepine exposure is observed between 
20 and 30 mg/kg/day in children above 6 years old and adults with 800 and 1200 mg of 
eslicarbazepine acetate once-daily, respectively (see section 4.2). 
 
5.3 Preclinical safety data 
 
Adverse reactions 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. 
 
Juvenile animals studies 



68 

In repeat-dose studies in juvenile dogs, the toxicity profile was comparable to that observed in adult 
animals. In the 10-month study decreases in bone mineral content, bone area and/or bone mineral 
density in lumbar vertebrae and/or femur were observed in high-dose female animals at exposure 
levels lower than the clinical exposure levels to eslicarbazepine in children. 
 
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 anomalies were observed at maternal toxic doses in embryotoxicity studies in 
mice, rats and rabbits. A delay in the sexual development of the F1 generation was observed in 
peri/postnatal studies in mice and rats. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Povidone K 29/32 
Croscarmellose sodium  
Magnesium stearate 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
5 years. 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5  Nature and contents of container 
 
Aluminium / Aluminium or PVC/Aluminium blisters placed into cardboard boxes containing 20, 30, 
60 or 90 tablets and in multi-packs containing 180 (2 packs of 90) tablets. 
 
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  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
BIAL - Portela & Cª , SA 
À Av. da Siderurgia Nacional 4745-457 S. Mamede do Coronado - Portugal 



69 

tel: +351 22 986 61 00 
fax: +351 22 986 61 99 
e-mail: info@bial.com  
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/514/012-020 
 
EU/1/09/514/025-026 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 21.04.2009 
 
Date of latest renewal: 22.01.2014 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 

http://www.ema.europa.eu/


70 

1. NAME OF THE MEDICINAL PRODUCT 
 
Zebinix 50 mg/ml oral suspension 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each ml of oral suspension contains 50 mg of eslicarbazepine acetate. 
 
Excipients with known effect: 
 
Each ml of oral suspension contains 2.0 mg of methyl parahydroxybenzoate (E218) and approximately 
0.00001 mg of sulphites. 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Oral suspension. 
Off-white to white suspension.  
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Zebinix is indicated as: 
• monotherapy in the treatment of partial-onset seizures, with or without secondary generalisation, in 

adults with newly diagnosed epilepsy; 

• adjunctive therapy in adults, adolescents and children aged above 6 years, with partial-onset 
seizures with or without secondary generalisation. 

 
4.2 Posology and method of administration 
 
Posology 
 
Adults 
Zebinix may be taken as monotherapy or 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 1,200 mg once daily  Some 
patients on monotherapy regimen may benefit from a dose of 1,600 mg once daily (see section 5.1). 
Special populations 
 
Elderly (over 65 years of age) 
No dose adjustment is needed in the elderly population provided that the renal function is not 
disturbed. Due to very limited data on the 1,600 mg monotherapy regimen in the elderly, this dose is 
not recommended for this population. 
 
Renal impairment 
Caution should be exercised in the treatment of patients, adult and children above 6 years of age, with 
renal impairment and the dose should be adjusted according to creatinine clearance (CLCR) as follows: 
- CLCR >60 ml/min: no dose adjustment required. 
- CLCR 30-60 ml/min: initial dose of 200 mg (or 5 mg/kg in children above 6 years) once daily or 

400 mg (or 10 mg/kg in children above 6 years)every other day for 2 weeks followed by a once 
daily dose of 400 mg (or 10 mg/kg in children above 6 years). However, based on individual 
response, the dose may be increased. 



71 

- CLCR <30 ml/min: use is not recommended in patients with severe renal impairment due to 
insufficient data. 

 
Hepatic impairment 
No dose adjustment is needed in patients with mild to moderate hepatic impairment.  
The pharmacokinetics of eslicarbazepine acetate has not been evaluated in patients with severe hepatic 
impairment (see sections 4.4 and 5.2) and use in these patients is, therefore, not recommended. 
 
Paediatric population 
Children above 6 years of age 
The recommended starting dose is 10 mg/kg/day once daily. Dosage should be increased in weekly or 
bi-weekly increments of 10 mg/kg/day up to 30 mg/kg/day,based on individual response. The 
maximum dose is1,200 mg once daily (see section 5.1). 
 
Children with a body weight of ≥60 kg 
Children with a body weight of 60 kg or more should be given the same dose as for adults. 
The safety and efficacy of eslicarbazepine acetate in children aged 6 years and below has not yet been 
established. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation 
on a posology can be made. 
 
Method of administration 
 
Oral use. 
Zebinix may be taken with or without food. 
 
Switching preparations 
Based on comparative bioavailability data for the tablet and the suspension formulations, switching  
patients from one formulation to the other can be done. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance, to other carboxamide derivatives (e.g. carbamazepine, 
oxcarbazepine) or to any of the excipients listed in section 6.1.  
 
Second or third degree atrioventricular (AV) block. 
 
4.4 Special warnings and precautions for use 
 
Suicidal ideation 
 
Suicidal ideation and behaviour have been reported in patients treated with antiepileptic active 
substances in several indications. A meta-analysis of randomised placebo-controlled trials of 
antiepileptic 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. 
 
Nervous system disorders 
 
Eslicarbazepine acetate has been associated with some central nervous system adverse reactions, such 
as dizziness and somnolence, which could increase the occurrence of accidental injury.  
 
Other warnings and precautions 
 



72 

If Zebinix is to be discontinued it is recommended to withdraw it gradually to minimise the potential 
of increased seizure frequency.  
 
Cutaneous reactions 
 
Rash developed as an adverse reaction in 1.2% of total population treated with Zebinix in  clinical 
studies in epileptic patients. Urticaria and angioedema cases have been reported in patients taking 
Zebinix. Angioedema in the context of hypersensitivity/anaphylactic reaction associated with 
laryngeal oedema can be fatal. If signs or symptoms of hypersensitivity develop, eslicarbazepine 
acetate must be discontinued immediately and alternative treatment should be initiated.  
Severe cutaneous adverse reactions (SCARS) including Stevens-Johnson syndrome (SJS)/toxic 
epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), 
which can be life-threatening or fatal, have been reported in post-marketing experience with Zebinix 
treatment. At the time of prescription patients should be advised of the signs and symptoms and 
monitored closely for skin reactions. If signs and symptoms suggestive of these reactions appear, 
Zebinix should be withdrawn immediately and an alternative treatment considered (as appropriate). If 
the patients have developed such reactions, treatment with Zebinix must not be restarted in these 
patients at any time. 
 
HLA-B* 1502 allele - in Han Chinese, Thai and other Asian populations 
 
HLA-B* 1502 in individuals of Han Chinese and Thai origin has been shown to be strongly associated 
with the risk of developing the severe cutaneous reactions known as Stevens Johnson syndrome (SJS) 
when treated with carbamazepine. The chemical structure of eslicarbazepine acetate is similar to that 
of carbamazepine, and it is possible that patients who are positive for HLA-B*1502 may also be at risk 
for SJS after treatment with eslicarbazepine acetate. The prevalence of HLA-B*1502 carrier is about 
10% in Han Chinese and Thai populations. Whenever possible, these individuals should be screened 
for this allele before starting treatment with carbamazepine or chemically-related active substances. If 
patients of these ethnic origins are tested positive for HLA- B*1502 allele, the use of eslicarbazepine 
acetate may be considered if the benefits are thought to exceed risks. 
Because of the prevalence of this allele in other Asian populations (e.g, above 15% in the Philippines 
and Malaysia), testing genetically at risk populations for the presence of HLA- B*1502 may be 
considered. 
 
HLA-A*3101 allele- European descent and Japanese populations 
 
There are some data that suggest HLA-A*3101 is associated with an increased risk of carbamazepine 
induced cutaneous adverse drug reactions including SJS, TEN, Drug rash with eosinophilia (DRESS), 
or less severe acute generalized exanthematous pustulosis (AGEP) and maculopapular rash in people 
of European descent and the Japanese. 
The frequency of the HLA-A*3101 allele varies widely between ethnic populations. HLA-A*3101 
allele has a prevalence of 2 to 5% in European populations and about 10% in Japanese population. 
The presence of HLA-A*3101 allele may increase the risk for carbamazepine induced cutaneous 
reactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of European 
ancestry, whereas its absence may reduce the risk from 5.0% to 3.8%. 
There are insufficient data supporting a recommendation for HLA-A*3101 screening before starting 
carbamazepine or chemically-related compounds treatment. 
If patients of European descent or Japanese origin are known to be positive for HLA-A*3101 allele, 
the use of carbamazepine or chemically-related compounds may be considered if the benefits are 
thought to exceed risks. 
 
Hyponatraemia 
 
Hyponatraemia has been reported as an adverse reaction in 1.5% 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 



73 

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, carbamazepine), 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, eslicarbazepine acetate should be discontinued. 
 
PR interval 
 
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. 
 
Renal impairment 
 
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 CLCR <30 ml/min use is 
not recommended due to insufficient data. 
 
Hepatic impairment 
 
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, eslicarbazepine acetate should 
be used with caution in patients with mild to moderate hepatic impairment and is not recommended in 
patients with severe hepatic impairment. 
 
Zebinix oral suspension contains methyl parahydroxybenzoate (E218) which may cause allergic 
reactions (possibly delayed) and sulphites which may rarely cause severe hypersensitivity reactions 
and bronchospasm. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
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. In vivo eslicarbazepine showed an inducing effect on the metabolism of medicinal 
products that are mainly eliminated by metabolism through CYP3A4 (e.g. Simvastatin). Thus, an 
increase in the dose of the medicinal products that are mainly metabolised through CYP3A4 may be 
required, when used concomitantly with eslicarbazepine acetate. Eslicarbazepine in vivo may have an 
inducing effect on the metabolism of medicinal products that are mainly eliminated by 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 
medicinal products 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 (e.g. Phenytoin). 
 
Interactions with other antiepileptic medicinal products 
 
Carbamazepine 
In a study in healthy subjects, concomitant administration of eslicarbazepine acetate 800 mg once 
daily and carbamazepine 400 mg twice daily resulted in an average decrease of 32% in exposure to the 



74 

active metabolite eslicarbazepine, most likely caused by an induction of glucuronidation. No change in 
exposure to carbamazepine or its metabolite carbamazepine-epoxide was noted. Based on individual 
response, the dose of eslicarbazepine acetate may need to be increased if used concomitantly with 
carbamazepine. Results from patient studies showed that concomitant treatment increased the risk of 
the following adverse reactions: diplopia, abnormal coordination and dizziness. The risk of increase of 
other specific adverse reactions caused by co-administration of carbamazepine and eslicarbazepine 
acetate cannot be excluded. 
 
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 eslicarbazepine acetate 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 inter-individual 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.  
 
Valproate and levetiracetam 
A population pharmacokinetics analysis of phase III studies in epileptic adult patients indicated that 
concomitant administration with valproate or levetiracetam did not affect the exposure to 
eslicarbazepine but this has not been verified by conventional interaction studies.  
 
Oxcarbazepine 
Concomitant use of eslicarbazepine acetate with oxcarbazepine is not recommended because this may 
cause overexposure to the active metabolites. 
 
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 ethinylestradiol, 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 4.6). 
 
Simvastatin 
A study in healthy subjects showed an average decrease of 50% in systemic exposure to simvastatin 
when co-administered with eslicarbazepine acetate 800 mg once daily, most likely caused by an 
induction of CYP3A4. An increase of the simvastatin dose may be required when used concomitantly 
with eslicarbazepine acetate. 
 
Rosuvastatin 



75 

There was an average decrease of 36-39% in systemic exposure in healthy subjects when 
co-administered with eslicarbazepine acetate 1,200 mg once daily. The mechanism for this reduction 
is unknown, but could be due to interference of transporter activity for rosuvastatin alone or in 
combination with induction of its metabolism. Since the relationship between exposure and drug 
activity is unclear, the monitoring of response to therapy (e.g., cholesterol levels) is recommended. 
 
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.  
 
4.6 Fertility, pregnancy and lactation 
 
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. 
 
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. 
 
Pregnancy 
There are no data from the use of eslicarbazepine acetate in pregnant women. Studies in animals have 
shown reproductive toxicity (see Fertility). 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 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 



76 

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. 
 
Breast-feeding  
It is unknown whether eslicarbazepine acetate is excreted in human 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 eslicarbazepine acetate.  
 
Fertility 
There are no data on the effects of eslicarbazepine acetate on human fertility. Studies in animals have 
shown impairment of fertility after treatment with eslicarbazepine acetate (see section 5.3). 
 
4.7 Effects on ability to drive and use machines 
 
Zebinix has minor to moderate influence on the ability to drive and use machines. 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. 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
 In clinical studies (adjunctive therapy treatment and monotherapy), 2,434 patients with partial-onset 
seizures were treated with eslicarbazepine acetate (1,983 adult patients and 451 paediatric patients) 
and 51% of those patients experienced adverse reactions. 
Adverse reactions were usually mild to moderate in intensity and occurred predominantly during the 
first weeks of treatment with eslicarbazepine acetate.  
 
The risks that have been identified for Zebinix are mainly class-based, dose-dependent undesirable 
effects. The most common adverse reactions reported, in placebo controlled adjunctive therapy studies 
with adult epileptic patients and in an active controlled monotherapy study comparing eslicarbazepine 
acetate with carbamazepine controlled release, were dizziness, somnolence, headache, and nausea. The 
majority of adverse reactions were reported in <3% of subjects in any treatment group. 
 
Severe cutaneous adverse reactions (SCARS), including Stevens-Johnson syndrome (SJS)/toxic 
epidermal necrolysis (TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS) 
have been reported in post-marketing experience with Zebinix treatment (see section 4.4). 
 
Tabulated list of adverse reactions 
Adverse reactions associated with eslicarbazepine acetate obtained from clinical studies and post-
marketing surveillance are tabulated below. 
 
The following convention has been used for the classification of adverse reactions very common 
(≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100) and not known (frequency 
cannot be estimated from available data). Within each frequency category, adverse reactions are 
presented in order of decreasing seriousness. 
 
Table 1: Treatment emergent adverse reactions associated with Zebinix obtained from  clinical studies 
and post-marketing surveillance 
System Organ 
Class 

Very  
common 

Common Uncommon Not known 

Blood and 
lymphatic 
system disorders 

  Anaemia Thrombocytopenia,
leukopenia 



77 

Immune system 
disorders 

  Hypersensitivity  

Endocrine 
disorders 

  Hypothyroidism  

Metabolism and 
nutrition 
disorders 

 Hyponatraemia, 
decreased 
appetite 

Electrolyte 
imbalance, 
dehydration, 
hypochloraemia 

 

Psychiatric 
disorders 

 Insomnia Psychotic 
disorder, apathy, 
depression, 
nervousness, 
agitation, 
irritability, 
attention deficit/ 
hyperactivity 
disorder, 
confusional 
state, mood 
swings, crying, 
psychomotor 
retardation, 
anxiety   

 

Nervous system 
disorders 

Dizziness, 
somnolence 
 

Headache, 
disturbance in 
attention, 
tremor, ataxia, 
balance disorder 

Coordination 
abnormal, 
memory 
impairment, 
amnesia, 
hypersomnia, 
sedation, 
aphasia, 
dysaesthesia, 
dystonia, 
lethargy, 
parosmia, 
cerebellar 
syndrome, 
convulsion, 
peripheral 
neuropathy, 
nystagmus, 
speech disorder, 
dysarthria, 
burning 
sensation, 
paraesthesia, 
migraine 

 

Eye disorders  Diplopia, vision 
blurred 

Visual 
impairment, 
oscillopsia, 
binocular eye 
movement 
disorder, ocular 
hyperaemia 

 



78 

Ear and 
labyrinth 
disorders 

 Vertigo 
 

Hypoacusis, 
tinnitus 

 

Cardiac 
disorders 

  Palpitations, 
bradycardia 

 

Vascular 
disorders 

  Hypertension 
(including 
hypertensive 
crisis), 
hypotension, 
orthostatic 
hypotension, 
flushing, 
peripheral 
coldness 

 

Respiratory, 
thoracic and 
mediastinal 
disorders 

  Epistaxis, chest 
pain 

 

Gastrointestinal 
disorders 

 Nausea, 
vomiting, 
diarrhoea 

Constipation, 
dyspepsia, 
gastritis, 
abdominal pain, 
dry mouth, 
abdominal 
discomfort, 
abdominal 
distension, 
gingivitis, 
melaena, 
toothache 

Pancreatitis 

Hepatobiliary 
disorders 

  Liver disorder  

Skin and 
subcutaneous 
tissue disorders 

 Rash 
 

Alopecia, dry 
skin, 
hyperhidrosis, 
erythema, skin 
disorder, 
pruritus, 
dermatitis 
allergic 

Toxic epidermal 
necrolysis, Stevens-
Johnson syndrome, 
drug reaction with 
eosinophilia and 
systemic symptoms 
(DRESS), 
angioedema, 
urticaria 

Musculoskeletal 
and connective 
tissue disorders 

  Myalgia, bone 
metabolism 
disorder, 
muscular 
weakness, pain 
in extremity 

 

Renal and 
urinary 
disorders 

  Urinary tract 
infection 

 

General 
disorders and 
administration 
site conditions 

 Fatigue, gait 
disturbance, 
asthenia 

Malaise, chills, 
oedema 
peripheral  

 



79 

Investigations  Weight 
increased 

Blood pressure 
decreased, 
weight 
decreased, blood 
pressure 
increased, blood 
sodium 
decreased, blood 
chloride 
decreased, 
osteocalcin 
increased,   
haematocrit 
decreased, 
haemoglobin 
decreased, 
transaminases 
increased 

 

Injury, 
poisoning and 
procedural 
complications  

  Drug toxicity, 
fall, thermal 
burn  

 

 
Description of selected adverse reactions 
 
Eye and nervous system disorders 
In patients concomitantly treated with carbamazepine and eslicarbazepine acetate in placebo-
controlled studies, the following adverse reactions were observed: 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), see 
section 4.5. 
 
PR interval 
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.  
 
Class related adverse reactions 
Rare adverse reactions such as bone marrow depression, anaphylactic reactions, 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 eslicarbazepine acetate cannot be 
excluded. 
 
There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in 
patients on long-term therapy with the structurally related antiepileptic drugs carbamazepine and 
oxcarbazepine. The mechanism by which bone metabolism is affected has not been identified. 
 
Paediatric population 
 
In placebo-controlled studies involving patients aged from 2 to 18 years with partial-onset seizures 
(238 patients treated with eslicarbazepine acetate and 189 with placebo), 35.7% of patients treated 
with eslicarbazepine acetate and 19% of patients treated with placebo experienced adverse reactions. 
The most common adverse reaction in the group treated with eslicarbazepine acetate were diplopia 
(5.0%), somnolence (8.0%) and vomiting (4.6%). 
 



80 

The adverse reaction profile of eslicarbazepine acetate is generally similar across age goups. In the age 
group from 6 to 11 years of age, the most common adverse reaction observed in more than two 
patients treated with eslicarbazepine acetate were diplopia (9.5%), somnolence (7.4%), diziness 
(6.3%), convulsion (6.3%) and nausea (3.2%); in the age group from 12 to 18 years were somnolence 
(7.4%), vomiting (4.2%), diplopia (3.2%) and fatigue (3.2%). The safety of Zebinix in children aged 6 
years and below has not yet been established. 
 
The safety profile of eslicarbazepine acetate was generally similar between adult and paediatric 
patients, except for agitation (common, 1.3%) and abdominal pain (common, 2.1%) which were more 
common in children than in adults. Dizziness; somnolence; vertigo; asthenia; gait disturbance; tremor; 
ataxia; balance disorder; vision blurred; diarrhoea; rash and hyponatraemia were less common in 
children than in adults. Dermatitis allergic (uncommon, 0.8%) was reported only in the paediatric 
population. 
 
Long-term safety data in the paediatric population obtained from open label extensions of the phase III 
study was consistent with the known safety profile of the product with no new findings of concern. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Symptoms observed after an overdose of eslicarbazepine acetate are primarily associated with central 
nervous symptoms (e.g. seizures of all types, status epilepticus) and cardiac disorders (e.g. cardiac 
arrhythmia). 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. PHARMACOLOGICAL PROPERTIES 
 
5.1  Pharmacodynamic properties 
 
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, precludingtheir return to the activated state and 
thereby preventing 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 efficacy  
 
Adult population 

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


81 

The efficacy of eslicarbazepine acetate as adjunctive therapy has been demonstrated in four phase III 
double-blind placebo-controlled studies in 1,703 randomized adult patients with partial epilepsy 
refractory to treatment with one to three concomitant antiepileptic medicinal products. Oxcarbazepine 
and felbamate were not allowed as concomitant medicinal products in these studies. Eslicarbazepine 
acetate was tested at doses of 400 mg (in -301 and -302 studies only), 800 mg and 1,200 mg, once 
daily. Eslicarbazepine acetate 800 mg once daily and 1,200 mg once daily were significantly more 
effective than placebo in reducing seizure frequency over a 12-week maintenance period. The 
percentage of subjects with ≥50% reduction (1581 analyzed) in seizure frequency in the phase III 
studies was 19.3% for placebo, 20.8% for eslicarbazepine acetate 400 mg, 30.5% for eslicarbazepine 
acetate 800 mg and 35.3% for eslicarbazepine acetate 1,200 mg daily.  
 
The efficacy of eslicarbazepine acetate as monotherapy has been demonstrated in a double-blind, 
active controlled (carbamazepine controlled release) study, involving 815 randomized adult patients 
with newly diagnosed partial-onset seizures. Eslicarbazepine acetate was tested at once-daily doses of 
800 mg, 1,200 mg and 1,600 mg. The doses of the active comparator, carbamazepine controlled 
release, were 200 mg, 400 mg and 600 mg, twice-daily. All subjects were randomized to the lowest 
dose level and only if a seizure occurred subjects were to be escalated to the next dose level. From the 
815 randomized patients, 401 patients were treated with eslicarbazepine acetate once-daily [271 
patients (67.6%) remained at dose of 800 mg, 70 patients (17.5%) remained at dose of 1,200 mg and 
60 patients (15.0%) were treated with 1,600 mg]. In the primary efficacy analysis, in which drop-outs 
were considered as non-responders, 71.1% subjects were classified as seizure free in the 
eslicarbazepine acetate group and 75.6% in the carbamazepine controlled release group during the 
26 week evaluation period (average risk difference -4.28%, 95% confidence interval: [-10,30; 1,74]. 
The treatment effect observed during the 26-week evaluation period was maintained over 1 year of 
treatment with 64.7 % eslicarbazepine acetate subjects and 70.3 % carbamazepine controlled release 
subjects classified as seizure free (average risk difference -5.46%, 95% confidence interval: [-11.88; 
0.97]. In the analysis of treatment failure (seizure risk) based on time to event analysis (Kaplan-Meier 
analysis and Cox regression), the Kaplan-Meier estimates of seizure risk at the end of the evaluation 
period was 0.06 with carbamazepine and 0.12 with eslicarbazepine acetate and by the end of 1 year 
with an additional increased risk to 0.11 with carbamazepine and 0.19 with eslicarbazepine acetate 
(p=0.0002). 
 
At 1 year, the probability for subjects to withdraw due to either adverse reactions or lack of efficacy 
was 0.26 for eslicarbazepine acetate and 0.21 for carbamazepine controlled release.  
 
The efficacy of eslicarbazepine acetate as conversion to monotherapy was evaluated in 2 double-blind, 
randomized controlled studies in 365 adult patients with partial-onset seizures. Eslicarbazepine acetate 
was tested at doses of 1,200 mg and 1,600 mg once-daily. Seizure-free rates during the entire 10-week 
monotherapy period were 7.6% (1,600 mg) and 8.3 % (1,200 mg) in one study and 10.0% (1,600 mg) 
and 7.4 % (1,200 mg) in the other study, respectively. 
 
Elderly population 
The safety and efficacy of eslicarbazepine acetate as adjunctive therapy for partial seizures in elderly 
patients were evaluated in one non-controlled study, with a duration of 26 weeks, in 72 elderly (aged 
≥ 65 years). The data shows that the incidence of adverse reactions in this population (65.3 %) is 
similar to the general population enrolled in the double-blind epilepsy studies (66.8%).The most 
frequent individual adverse reactions were dizziness (12.5% of subjects), somnolence (9.7%), fatigue, 
convulsion and hyponatraemia (8.3%, each), nasopharyngitis (6.9%) and upper respiratory tract 
infection (5.6%). A total of 50 of the 72 subjects starting the study completed the 26-week treatment 
period that corresponds to a retention rate of 69.4% (see section 4.2 for information on elderly use). 
There is limited data on monotherapy regimen available in the erldely population. Only a few subjects 
(N=27) aged above 65 years were treated with eslicarbazepine acetate in monotherapy study. 
 
Paediatric population 
The efficacy and safety of eslicarbazepine acetate as adjunctive therapy for partial-onset seizures in 
children was evaluated in one phase II study in children aged from 6 to 16 years (N=123) and one 



82 

phase III study in children aged from 2 to 18 years (N=304). Both studies were double-blind and 
placebo controlled with a duration of maintenance of 8 weeks (study 208) and 12 weeks (study 305), 
respectively. Study 208 included 2 additional subsequent long-term, open-label extensions (1 year in 
part II and 2 years in part III) and Study 305 included 4 subsequent long-term, open-label extension 
periods (1 year in Parts II, III and IV and 2 years in Part V). Eslicarbazepine acetate was tested at 
doses of 20 and 30 mg/kg/day, up to a maximum of 1,200 mg/day. The target dose was 30 mg/kg/day 
in study 208 and 20 mg/kg/day in study 305. Doses could be adjusted based on tolerability and 
treatment response. 
 
In the double-blind period of the phase II study, evaluation of efficacy was a secondary objective, The 
least square mean reduction in standardised seizure frequency from baseline to maintenance period 
was significantly (p<0.001) higher with eslicarbazepine acetate (-34.8%) compared to placebo (-
13.8%). Forty-two patients (50.6%) in the eslicarbazepine acetate group compared to 10 patients 
(25.0%) in the placebo group were responders (≥50% reduction of standardised seizure frequency), 
resulting in a significant difference (p=0.009).  
 
In the the double-blind period of the phase III study, the least square mean reduction in standardised 
seizure frequency with eslicarbazepine acetate (-18.1% versus baseline) was different to placebo (-
8.6% versus baseline) but not statistically significant (p=0.2490). Forty-one patients (30.6%) in the 
eslicarbazepine acetate group compared to 40 patients (31.0%) in the placebo group were responders 
(≥50% reduction of standardised seizure frequency), resulting in a non-significant difference 
(p=0.9017). Post-hoc subgroup analyses for the phase III study were conducted by age strata and 
above 6 years, as well as by dose. In children above 6 years, 36 patients (35.0%) in the eslicarbazepine 
acetate group compared to 29 patients (30.2%) in the placebo group were responders (p=0.4759) and 
the least square mean reduction in standardised seizure frequency was higher in the eslicarbazepine 
acetate group compared to placebo (-24.4% versus -10.5%); however, the difference of 13.9% was not 
statistically significant (p=0.1040). A total of 39% patients in study 305 were up titrated to the 
maximum possible dose (30 mg/kg/day). Amongst these, when excluding patients aged 6 years and 
younger, 14 (48.3%) and 11 (30.6%) of patients in the eslicarbazepine acetate and placebo group, 
respectively, were responders (p=0.1514). Although the robustness of these post-hoc subgroup 
analyses is limited, the data suggest an age and dose dependent increase in effect size. 
 
In the subsequent 1-year open-label extension (Part II) of the phase III study (ITT set N=225) the total 
responder rate was 46.7% (steadily increasing from 44.9% (weeks 1-4) to 57.5% (weeks > 40)). The 
total median standardised seizure frequency was 6.1 (decreasing from 7.0 (weeks 1-4) to 4.0 (weeks > 
40), resulting in a median relative change compared to the baseline period of -46.7%). The median 
relative change was larger in the previous placebo group (-51.4%) than in the previous ESL group (-
40.4%). The proportion of patients with exacerbation (increase of ≥25%) compared to the baseline 
period was 14.2%.  
 
In the subsequent 3 open-label extensions (ITT set N=148), the overall responder rate was 26.6% 
when compared to baseline Parts III–V (i.e. the last 4 weeks in part II). The total median standardised 
seizure frequency was 2.4 (resulting in a median relative change from Baseline Part III–V of -22.9%). 
The overall median relative decrease in Part I was greater in patients treated with ESL (-25.8%) than 
in patients treated with placebo (-16.4%). The overall proportion of patients with exacerbation 
(increase of ≥25%) compared to Baseline Parts III–V was 25.7%.   
 
Of the 183 patients who completed parts I and II of the study, 152 patients were enrolled into part III. 
Of these, 65 patients had received ESL and 87 patients had received placebo during the double-blind 
part of the study. 14 patients (9.2%) completed open-label treatment with ESL through Part V. The 
most common reason for withdrawal during any part of the study was sponsor request (30 patients in 
part III [19.7% of the patients who entered part III], 9 in part IV [9.6% of the patients who entered part 
IV], and 43 in part V [64.2% of the patients who entered Part V]). 
 
Taking into consideration the limitations of open label uncontrolled data, the long-term response to 
eslicarbazepine acetate in the open-label parts of the study was overall maintained. 



83 

 
The European Medicines Agency has deferred the obligation to submit the results of studies with 
Zebinix in one or more subsets of the paediatric population in the treatment of epilepsy with partial 
onset seizures (see section 4.2 for information on paediatric use). 
 
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 
Cmax is attained at 2 to 3 hours post-dose (tmax). 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. The 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 hours. In studies in healthy subjects and epileptic adult patients, the apparent half-life of 
eslicarbazepine was 10-20 hours and 13-20 hours, 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. 
 
Eslicarbazepine is a weak inducer of CYP3A4 and has inhibiting properties with respect to CYP2C19 
(as stated in section 4.5). 
 
In studies with eslicarbazepine in fresh human hepatocytes a mild induction of UGT1A1 mediated 
glucuronidation was observed. 
 
Elimination 
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 
The pharmacokinetics of eslicarbazepine acetate is linear and dose-proportional in the range 
400-1,200 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 adult patients with mild to severe renal impairment showed that clearance is 
dependent on renal function. During treatment with Zebinix dose adjustment is recommended in 



84 

patients,adult and children above 6 years of age with creatinine clearance <60 ml/min (see section 
4.2).  
In children from 2 to 6 years of age, the use of eslicarbazepine acetate is not recommended. At this age 
the intrinsic activity of the elimination process has not yet reached maturation. 
 
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 acetate 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.  
 
Paediatric population 
 
Similar to adults, eslicarbazepine acetate is extensively converted to eslicarbazepine. Plasma levels of 
eslicarbazepine acetate usually remain below the limit of quantification, following oral administration. 
Eslicarbazepine Cmax is attained at 2 to 3 hours post-dose (tmax). Body weight was shown to have an 
effect on volume of distribution and clearance. Furthermore, a role of age independently of weight 
with regards to clearance of eslicarbazepine acetate could not be excluded, in particular for the 
youngest age group (2-6 years). 
 
Children aged 6 years and below 
Population pharmacokinetics indicate that in the subgroup of children aged from 2 to 6 years, doses of 
27.5 mg/kg/day and 40 mg/kg/day are required in order to achieve exposures that are equivalent to the 
therapeutic doses of 20 and 30 mg/kg/day in children above 6 years of age. 
 
Children above 6 years of age 
Population pharmacokinetics indicate that comparable eslicarbazepine exposure is observed between 
20 and 30 mg/kg/day in children above 6 years old and adults with 800 and 1200 mg of 
eslicarbazepine acetate once-daily, respectively (see section 4.2). 
 
5.3 Preclinical safety data 
 
Adverse reactions 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. 
 
Juvenile animals studies 



85 

In repeat-dose studies in juvenile dogs, the toxicity profile was comparable to that observed in adult 
animals. 
In the 10-month study decreases in bone mineral content, bone area and/or bone mineral density in 
lumbar vertebrae and/or femur were observed in high-dose female animals at exposure levels lower 
than the clinical exposure levels to eslicarbazepine in children. 
 
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 anomalies were observed at maternal toxic doses in embryotoxicity studies in 
mice, rats and rabbits. A delay in the sexual development of the F1 generation was observed in 
peri/postnatal studies in mice and rats. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Xanthan gum (E415) 
Macrogol-100 stearate 
Methyl parahydroxybenzoate (E218) 
Saccharin sodium (E954) 
Flavour Tutti-Frutti artificial (contains maltodextrin, propylene glycol, natural and artificial 
flavouring, and gum acacia (E414) 
Masking flavour (contains propylene glycol, water and natural and artificial flavouring) 
Purified water 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
3 years. 
After first opening: 2 months 
 
6.4 Special precautions for storage 
 
This medicinal product does not require any special storage conditions. 
 
6.5 Nature and contents of container 
 
Amber glass bottles with HDPE child resistant closures containing 200 ml oral suspension, inside a 
cardboard box. Each cardboard box contains a 10 ml polypropylene graduated syringe with 0.2 ml 
graduations, and a copolymer push-in bottle adapter. 
 
6.6 Special precautions for disposal  
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 



86 

 
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. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/514/024 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 21.04.2009 
 
Date of latest renewal: 22.01.2014 
 
 
10. DATE OF REVISION OF THE TEXT 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 
 

http://www.ema.europa.eu/


87 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH 
RELEASE 

 
B. CONDITIONS O R RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 



88 

A. MANUFACTURER(S) 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 OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION  
 
• Periodic Safety Update Reports 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

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

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

being received that may lead to a significant change to the benefit/risk profile or as the result 
of an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
 
 
 



89 

 
 
 
 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



90 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



91 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Box of 20 or 60 tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zebinix 200 mg tablets 
Eslicarbazepine acetate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 200 mg of eslicarbazepine acetate. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
20 tablets 
60 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



92 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
BIAL-Portela & Cª, S.A. 
À Av. da Siderurgia Nacional 
4745-457 S. Mamede do Coronado 
Portugal 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/514/021   20 tablets - PVC/ALU blister 
EU/1/09/514/022   60 tablets - PVC/ALU blister 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
zebinix 200 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
(only for outer packaging) 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
(only for outer packaging) 
 
 



93 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS  
 
PVC/ALU blister 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zebinix 200 mg tablets 
Eslicarbazepine acetate 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
BIAL 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



94 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND ON THE IMMEDIATE 
PACKAGING 
 
HPDE bottles carton and HPDE bottles of 60 tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zebinix 200 mg tablets 
Eslicarbazepine acetate  
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each tablet contains 200 mg of eslicarbazepine acetate. 
 
 
3. LIST OF EXCIPIENTS 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



95 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
BIAL-Portela & Cª, S.A. 
À Av. da Siderurgia Nacional 
4745-457 S. Mamede do Coronado 
Portugal 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/514/023 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
zebinix 200 mg 
 
(outer pack only) 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
(only for outer packaging) 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
(only for outer packaging) 
 
 
 



96 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
Box of 7, 14 or 28 tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
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. PHARMACEUTICAL FORM AND CONTENTS 
 
7 tablets 
14 tablets 
28 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



97 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
BIAL-Portela & Cª, S.A. 
À Av. da Siderurgia Nacional 
4745-457 S. Mamede do Coronado 
Portugal 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
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 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
zebinix 400 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
(only for outer packaging) 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
(only for outer packaging) 
 
 



98 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS  
 
ALU/ALU blister 
PVC/ALU blister 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zebinix 400 mg tablets 
Eslicarbazepine acetate 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
BIAL 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
 
 



99 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Box of 30 or 60 tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
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. PHARMACEUTICAL FORM AND CONTENTS 
 
30 tablets 
60 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



100 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
BIAL-Portela & Cª, S.A. 
À Av. da Siderurgia Nacional 
4745-457 S. Mamede do Coronado 
Portugal 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
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 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
zebinix 600 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
(only for outer packaging) 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
(only for outer packaging) 
 
 



101 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS  
 
ALU/ALU blister 
PVC/ALU blister 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zebinix 600 mg tablets 
Eslicarbazepine acetate 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
BIAL 
 
 
3. EXPIRY DATE 
 
EXP  
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
 



102 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND ON THE IMMEDIATE 
PACKAGING 
 
HPDE bottles carton and HPDE bottles of 90 tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
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. PHARMACEUTICAL FORM AND CONTENTS 
 
90 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



103 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
BIAL-Portela & Cª, S.A. 
À Av. da Siderurgia Nacional 
4745-457 S. Mamede do Coronado 
Portugal 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/514/011 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
zebinix 600 mg 
 
(outer pack only) 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
(only for outer packaging) 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
(only for outer packaging) 
 
 



104 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Box of 20, 30, 60 or 90 tablets 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
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. PHARMACEUTICAL FORM AND CONTENTS 
 
20 tablets 
30 tablets 
60 tablets 
90 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



105 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
BIAL-Portela & Cª, S.A. 
À Av. da Siderurgia Nacional 
4745-457 S. Mamede do Coronado 
Portugal 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
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 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
zebinix 800 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
(only for outer packaging) 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
(only for outer packaging) 
 
 



106 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS  
 
ALU/ALU blister 
PVC/ALU blister 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zebinix 800 mg tablets 
Eslicarbazepine acetate 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
BIAL 
 
 
3. EXPIRY DATE 
 
EXP 
  
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 



107 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND ON THE IMMEDIATE 
PACKAGING 
 
HPDE bottles carton and HPDE bottles of 90 tablets  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
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. PHARMACEUTICAL FORM AND CONTENTS 
 
90 tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



108 

 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
BIAL-Portela & Cª, S.A. 
À Av. da Siderurgia Nacional 
4745-457 S. Mamede do Coronado 
Portugal 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/514/020 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
zebinix 800 mg 
 
(outer pack only) 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
(only for outer packaging) 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
(only for outer packaging) 
 
 



109 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Outer carton of multipacks (including blue box) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
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. PHARMACEUTICAL FORM AND CONTENTS 
 
Multipack: 180 (2 packs of 90) tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



110 

 
BIAL-Portela & Cª, S.A. 
À Av. da Siderurgia Nacional 
4745-457 S. Mamede do Coronado 
Portugal 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/514/025-026 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
zebinix 800 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
(only for outer packaging) 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
(only for outer packaging) 
 



111 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
Intermediate carton of multipacks (without blue box) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
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. PHARMACEUTICAL FORM AND CONTENTS 
 
90 tablets. Component of a multipack. Not to be sold separatley. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

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



112 

 
BIAL-Portela & Cª, S.A. 
À Av. da Siderurgia Nacional 
4745-457 S. Mamede do Coronado 
Portugal 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/514/025-026 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
zebinix 800 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 
 
 



113 

 
PARTICULARS TO APPEAR ON  THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
Outer carton / bottle 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Zebinix 50 mg/ml oral suspension  
Eslicarbazepine acetate 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ml of oral suspension contains 50 mg of eslicarbazepine acetate 
 
 
3. LIST OF EXCIPIENTS 
 
Contains methyl parahydroxybenzoate (E218) and sulphites 
See leaflet for further information  
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
oral suspension 
 
200 ml bottle 
oral syringe (10 ml) (outer pack only) 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use  
Oral use 
Shake well before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
After first opening, oral suspension may be used for up to 2 months 
Open date: ---/---/--- 



114 

 
 
9. SPECIAL STORAGE CONDITIONS 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 
 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
BIAL-Portela & Cª, S.A. 
À Av. da Siderurgia Nacional 
4745-457 S. Mamede do Coronado 
Portugal 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/09/514/024 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
zebinix 50 mg/ml 
 
(outer pack only) 
 
 

17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
(only for outer packaging) 
 
 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
(only for outer packaging) 



115 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



116 

Package leaflet: Information for the user 
 

Zebinix 200 mg tablets 
Eslicarbazepine acetate 

 
Read all of this leaflet carefully before you or your child start taking this medicine because it 

contains important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

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

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Zebinix is and what it is used for 
2. What you need to know before you take Zebinix 
3. How to take Zebinix 
4. Possible side effects 
5. How to store Zebinix 
6. Contents of the pack and other information 
 
 
1. What Zebinix is and what it is used for 
 
Zebinix contains the active substance eslicarbazepine acetate. 
Zebinix belongs to a group of medicines called antiepileptics used to treat epilepsy, a condition where 
someone has repeated seizures or fits.  
 
Zebinix is used: 

• on its own (monotherapy) in adult patients with newly diagnosed epilepsy 
 

• with other antiepileptic medicines (adjunctive therapy), in adult, adolescents and children 
patients above 6 years of age who are 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. What you need to know before you take Zebinix 
 
Do not take Zebinix: 

• if you are allergic to eslicarbazepine acetate, to other carboxamide derivatives (e.g. 
carbamazepine or oxcarbazepine, medicines used to treat epilepsy) or to any of the other 
ingredients of this medicine (listed in section 6); 

• if you suffer from a certain type of heart rhythm disorder (second or third degree 
atrioventricular (AV) block). 

 
Warnings and precautions 
 
Talk to your doctor or pharmacist before taking Zebinix. 
 
Contact your doctor immediately: 

• if you have blistering or peeling of the skin and/or mucous membranes, rash, swallowing or 
breathing problems, swelling of your lips, face, eyelids, throat or tongue. These could be signs 
of an allergic reaction.  



117 

• if 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. 

• if you have liver problems. Zebinix is not recommended in patients with severe liver problems. 
• if 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. 

• if you suffer from a heart disease such as heart failure or heart attack, or have any heart rhytm 
disorder. 

• if you suffer from seizures that begin with a widespread electric discharge that involves both 
sides of the brain.  

 
A small number of people being treated with antiepileptics have had thoughts of harming or killing 
themselves. If at any time you have these thoughts, when taking Zebinix, contact your doctor 
immediately. 
 
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, such as fall. 
 
Take special care with Zebinix: 
Serious and potentially life-threatening skin reactions including Stevens-Johnson syndrome/toxic 
epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS) have been 
reported in post-marketing experience in patients treated with Zebinix.  
If you develop a serious rash or another skin symptoms (see section 4), stop taking Zebinix and 
contact your doctor or seek medical attention immediately. 
 
In patients of Han Chinese or Thai origin the risk of serious skin reactions associated with 
carbamazepine or chemically-related compounds may be predicted by testing a blood sample of these 
patients. Your doctor should be able to advise if a blood test is necessary before taking Zebinix. 
 
Children 
Zebinix is not to be given to children aged 6 years and below. 
 
Other medicines and Zebinix 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This is just in case any of them interfere with how Zebinix works or how Zebinix interferes 
with their effect.  
Tell your doctor if you are taking: 
• phenytoin (a medicine used to treat epilepsy) since your dose may need to be adjusted; 
• carbamazepine (a medicine used to treat epilepsy) since your dose may have to be adjusted and the 

following side effects of Zebinix may occur in higher frequency: seeing double, abnormal 
coordination and dizziness; 

• hormonal contraceptives (such as the contraceptive pill) since Zebinix may make these less 
effective; 

• simvastatin (a medicine used to lower cholesterol levels) since your dose may have to be adjusted; 
• rosuvastatin, a medicine used to lower cholesterol level; 
• the blood thinner - warfarin; 
• tricyclic antidepressants e.g. amitriptyline; 
• 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. 
 
See ‘Pregnancy and breast-feeding’ section for advice about contraception. 
 



118 

Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
There are no data from the use of eslicarbazepine acetate in pregnant women. Research has shown an 
increased risk of birth defects in children of women taking antiepileptic medicines. On the other hand, 
effective antiepileptic 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. 
 
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. 
 
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. 
 
 
3. How to take Zebinix 
 
Always take this medicine exactly as your doctor has told you.  Check with your doctor or pharmacist 
if you are not sure. 
 
Adults 
 
Dose when you start treatment 
400 mg 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 1,200 mg once daily. If you 
are taking Zebinix on its own your doctor may consider you can benefit of a dose of 1,600 mg once 
daily. 
 
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. 
 
Elderly (over 65 years of age) 
If you are elderly and taking Zebinix on its own the dose of 1,600 mg is not a suitable dose for you. 
 
Children above 6 years of age 
 
Dose when you start treatment 
The starting dose is 10 mg per kg body weight taken once a day for one or two weeks, before 
increasing to the maintenance dose.  
 
Maintenance dose 
Depending on the response to Zebinix, the dose may be increased by 10 mg per kg body weight, at 
intervals of one or two weeks, up to 30 mg per kg body weight. The maximum dose is 1,200 mg once 
daily. 
 
Children with ≥60 kg 
Children with 60 kg or more body weight should take the same dose as adults. 



119 

 
Other form of this medicine, like oral suspension, maybe more suitable for children. Ask your doctor 
or pharmacist. 
 
Method and route of administration 
Zebinix is for oral use. Swallow the tablet with a glass of water.  
Zebinix tablets may be taken with or without food. 
 
If you take more Zebinix than you should 
If you accidently take more Zebinix than you should, you are potentially at risk of having more 
seizures; or you may feel like your heart beat is irregular or faster. Contact a doctor or go to a hospital 
immediately if you experience any of the above symptoms. 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 a forgotten dose. 
 
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. 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 medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine 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: 
• blistering or peeling of the skin and/or mucous membranes, rash, swallowing or breathing 

problems, swelling of your lips, face, eyelids, throat or tongue. These could be signs of an allergic 
reaction.  

 
Very common (may affect more than 1 in 10 people) side effects are: 
• Feeling dizzy or sleepy.  
 
Common (may affect up to 1 in 10 people) 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; 
• Skin rash; 
• Blood tests showing that you have low levels of sodium in your blood; 
• Decrease of appetite; 
• Difficulty in sleeping; 
• Difficulty in coordinating movements (ataxia); 
• Weight increase. 
 



120 

Uncommon (may affect up to 1 in 100 people) side effects are: 
• Clumsiness; 
• Allergy; 
• Constipation; 
• Seizures; 
• Underactive thyroid gland. Symptoms include decreased level of thyroid hormone levels (seen in 

blood tests), cold intolerance, large tongue, thin and brittle fingernails or hair and low body 
temperature; 

• Liver problems; 
• High blood pressure or severe increase in blood pressure; 
• Low blood pressure or a fall in blood pressure on standing up; 
• Blood tests showing that you have low levels of salts (including chloride) in your blood or a 

reduction in red blood cells; 
• Dehydration; 
• Eye movement changes, fuzzy vision or red eye; 
• Having falls; 
• Thermal burn; 
• 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; 
• Agitation; 
• Attention deficit/ hyperactivity disorder; 
• Irritability; 
• Mood changes or hallucinations; 
• Difficulty in speaking; 
• Nosebleed; 
• Chest pain; 
• Tingling and/or feeling numb in any part of your body; 
• Migraine; 
• Burning sensation; 
• Abnormal sense of touch; 
• Disturbances in the sense of smell; 
• Ringing in the ears; 
• Hearing difficulty; 
• Swelling in your legs and arms; 
• Heart burn, stomach upset, abdominal pain, abdominal bloating and discomfort or dry mouth; 
• Charcoal (dark) stool; 
• Inflamed gums or toothache; 
• Sweating or having dry skin; 
• Itching; 
• Skin changes (e.g. red skin); 
• Hair loss; 
• Urinary tract infection; 
• Feeling generally weak, unwell or having chills; 
• Weight loss; 
• Muscle pain, pain in limbs, muscular weakness; 
• Bone metabolism disorder; 
• Increased bone proteins; 
• Flushing, cold limbs; 
• Slower or irregular heart beat; 
• Feeling extremely sleepy; 
• Sedation; 
• Neurological movement disorder where your muscles contract causing twisting and repetitive 

movements or abnormal postures. Symptoms include tremors, pain, cramping; 



121 

• Medicine toxicity; 
• Anxiety. 
 
Not known (frequency cannot be estimated from available data) side effects are: 
• Reduction in blood platelets which increases risk of bleeding or bruising; 
• Severe pain in the back and stomach (caused by inflamation of the pancreas); 
• Reduction in white blood cells which makes infections more likely; 
• Reddish target-like macules or circular patches often with central blisters on the trunk, skin 

peeling, ulcers of mouth, throat, nose, genitals and eyes, red and swollen eyes and can be preceded 
by fever and/or flu-like symptoms (Stevens-Johnson syndrome/toxic epidermal necrolysis); 

• Initially flu-like symptoms, rash on the face then widespread rash, high body temperature, liver 
enzyme elevations, blood abnormalities (eosinophilia), enlarged lymph nodes and other body 
organs involvement (Drug Reaction with Eosinophilia and Systemic Symptoms which is also 
known as DRESS or drug hypersensitivity syndrome); 

• Serious allergic reaction which causes swelling of the face, throat, hand, feet, ankles, or lower 
legs; 

• Urticaria (skin rash with itching). 
•  
 
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. 
 
There have been reports of bone disorders including osteopenia and osteoporosis (thinning of the 
bone) and fractures with structurally related antiepileptics medicines like carbamazepine and 
oxcarbazepine. Check with your doctor or pharmacist, if you are on long-term antiepileptic treatment, 
have a history of osteoporosis, or take steroids. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Zebinix 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date, which is stated on the blister, 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. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6.  Contents of the pack and other information  
 
What Zebinix contains 
• The active substance is eslicarbazepine acetate. Each tablet contains 200 mg of eslicarbazepine 

acetate. 
• The other ingredients are povidone K29/32, croscarmellose sodium and magnesium stearate. 
 

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


122 

What Zebinix looks like and contents of the pack 
Zebinix 200 mg tablets are white and oblong. The tablets have ‘ESL 200’engraved on one side and are 
scored on the other side, with a length of 11 mm. The tablet can be divided into equal doses.  
 
The tablets are packaged in blisters in cardboard boxes containing 20 or 60 tablets, and in HDPE 
bottles with child resistant closure in cardboard boxes containing 60 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) 2 502 58 04 
 

Luxembourg/Luxemburg 
Eisai Europe Ltd. 
Tél/Tel: + 32 (0) 2 502 58 04 
(Belgique/Belgien) 
 

България 
BIAL-Portela & Cª., S.A. 
Teл.: + 351 22 986 61 00 
(Португалия) 
 

Magyarország 
Eisai Ltd 
Tel.: + 44 (0)845 676 1400 
(Nagy-Britannia) 
 

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 B.V. 
Tél/Tel: + 31 (0) 900 575 3340 
 

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) 
 



123 

España 
Laboratorios BIAL, S.A. 
Tel: + 34 91 562 41 96  
 

Portugal 
BIAL-Portela & Cª., S.A. 
Tel.: + 351 22 986 61 00 
 

France 
Eisai SAS 
Tél: + (33) 1 47 67 00 05 
 
Hrvatska  
BIAL-Portela & Cª, S.A. 
Tel: + 351 22 986 61 00 
(Portugal) 
 

România 
BIAL-Portela & Cª, S.A. 
Tel: + 351 22 986 61 00 
(Portugalia) 
 

Ireland 
Eisai GmbH 
Tel: + 49 (0) 69 66 58 50 
 

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) 
 

 

Lietuva 
BIAL-Portela & Cª, S.A. 
Tel: + 351 22 986 61 00 
(Portugalija) 
 
 

 

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

http://www.ema.europa.eu/


124 

Package leaflet: Information for the user 
 

Zebinix 400 mg tablets 
Eslicarbazepine acetate 

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

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

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet  
1. What Zebinix is and what it is used for 
2. What you need to know before you take Zebinix 
3. How to take Zebinix 
4. Possible side effects 
5. How to store Zebinix 
6. Contents of the pack and other information 
 
 
1. What Zebinix is and what it is used for 
 
Zebinix contains the active substance eslicarbazepine acetate. 
Zebinix belongs to a group of medicines called antiepileptics used to treat epilepsy, a condition where 
someone has repeated seizures or fits.  
 
Zebinix is used: 

• on its own (monotherapy) in adult patients with newly diagnosed epilepsy 
 

• with other antiepileptic medicines (adjunctive therapy), in adult, adolescents and children 
patients above 6 years of age, who are 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. What you need to know before you take Zebinix 
 
Do not take Zebinix: 

• if you are allergic to eslicarbazepine acetate, to other carboxamide derivatives (e.g. 
carbamazepine or oxcarbazepine, medicines used to treat epilepsy) or to any of the other 
ingredients of this medicine (listed in section 6); 

• if you suffer from a certain type of heart rhythm disorder (second or third degree 
atrioventricular (AV) block). 

 
Warnings and precautions  
 
Talk to your doctor or pharmacist before taking Zebinix. 
 
Contact your doctor immediately: 

• if you have blistering or peeling of the skin and/or mucous membranes, rash, swallowing or 
breathing problems, swelling of your lips, face, eyelids, throat or tongue. These could be signs 
of an allergic reaction.  



125 

• if 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. 

• if you have liver problems. Zebinix is not recommended in patients with severe liver problems. 
• if 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. 

• if you suffer from a heart disease such as heart failure or heart attack, or have any heart rhytm 
disorder. 

• if you suffer from seizures that begin with a widespread electric discharge that involves both 
sides of the brain. 

 
A small number of people being treated with antiepileptics have had thoughts of harming or killing 
themselves. If at any time you have these thoughts, when taking Zebinix, contact your doctor 
immediately. 
 
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, such as fall. 
 
Take special care with Zebinix: 
Serious and potentially life-threatening skin reactions including Stevens-Johnson syndrome/toxic 
epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS) have been 
reported in post-marketing experience in patients treated with Zebinix.  
If you develop a serious rash or another skin symptoms (see section 4), stop taking Zebinix and 
contact your doctor or seek medical attention immediately. 
In patients of Han Chinese or Thai origin the risk of serious skin reactions associated with 
carbamazepine or chemically-related compounds may be predicted by testing a blood sample of these 
patients. Your doctor should be able to advise if a blood test is necessary before taking Zebinix. 
 
Children 
Zebinix is not to be given to children aged 6 years and below. 
 
Other medicines and Zebinix 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This is just in case any of them interfere with how Zebinix works or how Zebinix interferes 
with their effect. 
Tell your doctor if you are taking: 
•  phenytoin (a medicine used to treat epilepsy) since your dose may need to be adjusted; 
• carbamazepine (a medicine used to treat epilepsy) since your dose may have to be adjusted and the 

following side effects of Zebinix may occur in higher frequency: seeing double, abnormal 
coordination and dizziness; 

• hormonal contraceptives (such as the contraceptive pill) since Zebinix may make these less 
effective; 

• simvastatin (a medicine used to lower cholesterol levels) since your dose may have to be adjusted; 
• rosuvastatin, a medicine used to lower cholesterol level; 
• the blood thinner - warfarin; 
• tricyclic antidepressants e.g. amitriptyline; 
• 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. 
 
See ‘Pregnancy and breast-feeding’ section for advice about contraception. 
 
Pregnancy and breast-feeding 



126 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
There are no data from the use of eslicarbazepine acetate in pregnant women. Research has shown an 
increased risk of birth defects in children of women taking antiepileptic medicines. On the other hand, 
effective antiepileptic 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. 
 
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. 
 
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. 
 
3. How to take Zebinix 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Adults 
 
Dose when you start treatment 
400 mg 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 1,200 mg once daily. If you 
are taking Zebinix on its own your doctor may consider you can benefit of a dose of 1,600 mg once 
daily. 
 
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. 
 
Elderly (over 65 years of age) 
If you are elderly and taking Zebinix on its own the dose of 1,600 mg is not a suitable dose for you. 
 
Children above 6 years of age 
 
Dose when you start treatment 
The starting dose is 10 mg per kg body weight taken once a day for one or two weeks, before 
increasing to the maintenance dose.  
 
Maintenance dose 
Depending on the response to Zebinix, the dose may be increased by 10 mg per kg body weight, at 
intervals of one or two weeks, up to 30 mg per kg body weight. The maximum is  1,200 mg once 
daily. 
 
Children with ≥60 kg 
Children with 60 kg or more body weight should take the same dose as adults. 
 



127 

Other form of this medicine, like oral suspension, maybe more suitable for children. Ask your doctor 
or pharmacist. 
 
Method and route of administration 
Zebinix is for oral use. Swallow the tablet with a glass of water.  
Zebinix tablets may be taken with or without food. 
 
The score line is only there to help you break the tablet if you have difficulty swallowing it whole. 
 
If you take more Zebinix than you should 
If you accidently take more Zebinix than you should, you are potentially at risk of having more 
seizures; or you may feel like your heart beat is irregular or faster. Contact a doctor or go to a hospital 
immediately if you experience any of the above symptoms. 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 a forgotten dose. 
 
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. 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 medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine 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: 
• blistering or peeling of the skin and/or mucous membranes, rash, swallowing or breathing 

problems, swelling of your lips, face, eyelids, throat or tongue. These could be signs of an allergic 
reaction. 

 
Very common (may affect more than 1 in 10 people) side effects are: 
• Feeling dizzy or sleepy.  
 
Common (may affect up to 1 in 10 people) 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; 
• Skin rash; 
• Blood tests showing that you have low levels of sodium in your blood; 
• Decrease of appetite; 
• Difficulty in sleeping; 
• Difficulty in coordinating movements (ataxia); 



128 

• Weight increase. 
 
Uncommon (may affect up to 1 in 100 people) side effects are: 
• Clumsiness; 
• Allergy; 
• Constipation; 
• Seizures; 
• Underactive thyroid gland. Symptoms include decreased level of thyroid hormone levels (seen in 

blood tests), cold intolerance, large tongue, thin and brittle fingernails or hair and low body 
temperature; 

• Liver problems; 
• High blood pressure or severe increase in blood pressure;  
• Low blood pressure or a fall in blood pressure on standing up; 
• Blood tests showing that you have low levels of salts (including chloride)  in your blood or a 

reduction in red blood cells; 
• Dehydration; 
• Eye movement changes, fuzzy vision or red eye; 
• Having falls; 
• Thermal burn; 
• 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; 
• Agitation; 
• Attention deficit/ hyperactivity disorder; 
• Irritability; 
• Mood changes or hallucinations; 
• Difficulty in speaking; 
• Nosebleed; 
• Chest pain; 
• Tingling and/or feeling numb in any part of your body; 
• Migraine; 
• Burning sensation; 
• Abnormal sense of touch; 
• Disturbances in the sense of smell; 
• Ringing in the ears; 
• Hearing difficulty; 
• Swelling in your legs and arms; 
• Heart burn, stomach upset, abdominal pain, abdominal bloating and discomfort or dry mouth; 
• Charcoal (dark) stool; 
• Inflamed gums or toothache; 
• Sweating or having dry skin; 
• Itching; 
• Skin changes (e.g. red skin); 
• Hair loss; 
• Urinary tract infection; 
• Feeling generally weak, unwell or having chills; 
• Weight loss; 
• Muscle pain, pain in limbs, muscular weakness; 
• Bone metabolism disorder; 
• Increased bone proteins; 
• Flushing, cold limbs; 
• Slower or irregular heart beat; 
• Feeling extremely sleepy; 
• Sedation; 



129 

• Neurological movement disorder where your muscles contract causing twisting and repetitive 
movements or abnormal postures. Symptoms include tremors, pain, cramping; 

• Medicine toxicity; 
• Anxiety. 
 
Not known (frequency cannot be estimated from available data) side effects are: 
• Reduction in blood platelets which increases risk of bleeding or bruising; 
• Severe pain in the back and stomach (caused by inflamation of the pancreas); 
• Reduction in white blood cells which makes infections more likely; 
• Reddish target-like macules or circular patches often with central blisters on the trunk, skin 

peeling, ulcers of mouth, throat, nose, genitals and eyes, red and swollen eyes and can be preceded 
by fever and/or flu-like symptoms (Stevens-Johnson syndrome/toxic epidermal necrolysis); 

• Initially flu-like symptoms, rash on the face then widespread rash, high body temperature, liver 
enzyme elevations, blood abnormalities (eosinophilia), enlarged lymph nodes and other body 
organs involvement (Drug Reaction with Eosinophilia and Systemic Symptoms which is also 
known as DRESS or drug hypersensitivity syndrome); 

• Serious allergic reaction which causes swelling of the face, throat, hand, feet, ankles, or lower 
legs; 

• Urticaria (skin rash with itching). 
•  
 
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. 
 
There have been reports of bone disorders including osteopenia and osteoporosis (thinning of the 
bone) and fractures with structurally related antiepileptics medicines like carbamazepine and 
oxcarbazepine. Check with your doctor or pharmacist, if you are on long-term antiepileptic treatment, 
have a history of osteoporosis, or take steroids. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Zebinix 
 
Keep this medicine out of the sight and  reach of children. 
 
Do not use this medicine after the expiry date, which is stated on the blister 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. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What 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. 

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


130 

 
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, with a diameter of 11 mm.  
 
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) 2 502 58 04 
 

Luxembourg/Luxemburg 
Eisai Europe Ltd. 
Tél/Tel: + 32 (0) 2 502 58 04 
(Belgique/Belgien) 
 

България 
BIAL-Portela & Cª., S.A. 
Teл.: + 351 22 986 61 00 
(Португалия) 
 

Magyarország 
Eisai Ltd 
Tel.: + 44 (0) 845 676 1400 
(Nagy-Britannia) 
 

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 B.V. 
Tél/Tel: + 31 (0) 900 575 3340 
 

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) 
 



131 

España 
Laboratorios BIAL, S.A. 
Tel: + 34 91 562 41 96  
 

Portugal 
BIAL-Portela & Cª., S.A. 
Tel.: + 351 22 986 61 00 
 

France 
Eisai SAS 
Tél: + (33) 1 47 67 00 05 
 
Hrvatska  
BIAL-Portela & Cª, S.A. 
Tel: + 351 22 986 61 00 
(Portugal) 
 

România 
BIAL-Portela & Cª, S.A. 
Tel: + 351 22 986 61 00 
(Portugalia) 
 

Ireland 
Eisai GmbH 
Tel: + 49 (0) 69 66 58 50 
 

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) 
 

 

Lietuva 
BIAL-Portela & Cª, S.A. 
Tel: + 351 22 986 61 00 
(Portugalija) 
 

 

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

http://www.ema.europa.eu/


132 

Package leaflet: Information for the user 
 

Zebinix 600 mg tablets 
Eslicarbazepine acetate 

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

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

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet  
1. What Zebinix is and what it is used for 
2. What you need to know before you take Zebinix 
3. How to take Zebinix 
4. Possible side effects 
5. How to store Zebinix 
6. Contents of the pack and other information 
 
 
1 What Zebinix is and what it is used for 
 
Zebinix contains the active substance eslicarbazepine acetate. 
Zebinix belongs to a group of medicines called antiepileptics used to treat epilepsy, a condition where 
someone has repeated seizures or fits.  
 
Zebinix is used: 

• on its own (monotherapy) in adult patients with newly diagnosed epilepsy 
 

• with other antiepileptic medicines (adjunctive therapy), in adult, adolescents and children 
patients above 6 years of age, who are 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 What you need to know before you take Zebinix 
 
Do not take Zebinix: 

• if you are allergic to eslicarbazepine acetate, to other carboxamide derivatives (e.g. 
carbamazepine or oxcarbazepine, medicines used to treat epilepsy) or to any of the other 
ingredients of this medicine (listed in section 6); 

• if you suffer from a certain type of heart rhythm disorder (second or third degree 
atrioventricular (AV) block). 

 
Warnings and precautions  
 
Talk to your doctor or pharmacist before taking Zebinix. 
 
Contact your doctor immediately: 

• if you have blistering or peeling of the skin and/or mucous membranes, rash, swallowing or 
breathing problems, swelling of your lips, face, eyelids, throat or tongue. These could be signs 
of an allergic reaction. 



133 

• if 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. 

• if you have liver problems. Zebinix is not recommended in patients with severe liver problems. 
• if 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. 

• if you suffer from a heart disease such as heart failure or heart attack, or have any heart rhytm 
disorder. 

• if you suffer from seizures that begin with a widespread electric discharge that involves both 
sides of the brain. 

 
A small number of people being treated with antiepileptics have had thoughts of harming or killing 
themselves. If at any time you have these thoughts, when taking Zebinix, contact your doctor 
immediately. 
 
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, such as fall. 
 
Take special care with Zebinix: 
Serious and potentially life-threatening skin reactions including Stevens-Johnson syndrome/toxic 
epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS) have been 
reported in post-marketing experience in patients treated with Zebinix.  
If you develop a serious rash or another skin symptoms (see section 4), stop taking Zebinix and 
contact your doctor or seek medical attention immediately. 
In patients of Han Chinese or Thai origin the risk of serious skin reactions associated with 
carbamazepine or chemically-related compounds may be predicted by testing a blood sample of these 
patients. Your doctor should be able to advise if a blood test is necessary before taking Zebinix. 
 
Children 
Zebinix is not to be given to children aged 6 years and below. 
 
Other medicines and Zebinix 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This is just in case any of them interfere with how Zebinix works or how Zebinix interferes 
with their effect. 
Tell your doctor if you are taking: 
•  phenytoin (a medicine used to treat epilepsy) since your dose may need to be adjusted; 
• carbamazepine (a medicine used to treat epilepsy) since your dose may have to be adjusted and the 

following side effects of Zebinix may occur in higher frequency: seeing double, abnormal 
coordination and dizziness; 

• hormonal contraceptives (such as the contraceptive pill) since Zebinix may make these less 
effective; 

• simvastatin (a medicine used to lower cholesterol levels) since your dose may have to be adjusted; 
• rosuvastatin, a medicine used to lower cholesterol level; 
• the blood thinner - warfarin; 
• tricyclic antidepressants e.g. amitriptyline; 
• 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. 
 
See ‘Pregnancy and breast-feeding’ section for advice about contraception. 
 
Pregnancy and breast-feeding 



134 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
There are no data from the use of eslicarbazepine acetate in pregnant women. Research has shown an 
increased risk of birth defects in children of women taking antiepileptic medicines. On the other hand, 
effective antiepileptic 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. 
 
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. 
 
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. 
 
 
3 How to take Zebinix 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Adults 
 
Dose when you start treatment 
400 mg 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 1,200 mg once daily. If you 
are taking Zebinix on its own your doctor may consider you can benefit of a dose of 1,600 mg once 
daily. 
 
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. 
 
Elderly (over 65 years of age) 
If you are elderly and taking Zebinix on its own the dose of 1,600 mg is not a suitable dose for you. 
 
Children above 6 years of age 
 
Dose when you start treatment 
The starting dose is 10 mg per kg body weight taken once a day for one or two weeks, before 
increasing to the maintenance dose.  
 
Maintenance dose 
Depending on the response to Zebinix, the dose may be increased by 10 mg per kg body weight, at 
intervals of one or two weeks, up to 30 mg per kg body weight. The maximum dose is 1,200 mg once 
daily. 
 
Children with ≥60 kg 
Children with 60 kg or more body weight should take the same dose as adults. 
 



135 

Other form of this medicine, like oral suspension, maybe more suitable for children. Ask your doctor 
or pharmacist. 
 
Method and route of administration 
Zebinix is for oral use. Swallow the tablet with a glass of water.  
Zebinix tablets may be taken with or without food. 
 
The tablet can be divided into equal doses. 
 
If you take more Zebinix than you should 
If you accidently take more Zebinix than you should, you are potentially at risk of having more 
seizures; or you may feel like your heart beat is irregular or faster. Contact a doctor or go to a hospital 
immediately if you experience any of the above symptoms. 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 a forgotten dose. 
 
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. 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 medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine 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: 
• blistering or peeling of the skin and/or mucous membranes, rash, swallowing or breathing 

problems, swelling of your lips, face, eyelids, throat or tongue. These could be signs of an allergic 
reaction.  

 
Very common (may affect more than 1 in 10 people) side effects are: 
• Feeling dizzy or sleepy.  
 
Common (may affect up to 1 in 10 people) 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; 
• Skin rash; 
• Blood tests showing that you have low levels of sodium in your blood; 
• Decrease of appetite; 
• Difficulty in sleeping; 
• Difficulty in coordinating movements (ataxia); 



136 

• Weight increase. 
 
Uncommon (may affect up to 1 in 100 people) side effects are: 
• Clumsiness; 
• Allergy; 
• Constipation; 
• Seizures; 
• Underactive thyroid gland. Symptoms include decreased level of thyroid hormone levels (seen in 

blood tests), cold intolerance, large tongue, thin and brittle fingernails or hair and low body 
temperature; 

• Liver problems; 
• High blood pressure or severe increase in blood pressure;  
• Low blood pressure or a fall in blood pressure on standing up; 
• Blood tests showing that you have low levels of salts (including chloride) in your blood or a 

reduction in red blood cells; 
• Dehydration; 
• Eye movement changes, fuzzy vision or red eye; 
• Having falls; 
• Thermal burn; 
• 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; 
• Agitation; 
• Attention deficit/ hyperactivity disorder; 
• Irritability; 
• Mood changes or hallucinations; 
• Difficulty in speaking; 
• Nosebleed; 
• Chest pain; 
• Tingling and/or feeling numb in any part of your body; 
• Migraine; 
• Burning sensation; 
• Abnormal sense of touch; 
• Disturbances in the sense of smell; 
• Ringing in the ears; 
• Hearing difficulty; 
• Swelling in your legs and arms; 
• Heart burn, stomach upset, abdominal pain, abdominal bloating and discomfort or dry mouth; 
• Charcoal (dark) stool; 
• Inflamed gums or toothache; 
• Sweating or having dry skin; 
• Itching; 
• Skin changes (e.g. red skin); 
• Hair loss; 
• Urinary tract infection; 
• Feeling generally weak, unwell or having chills; 
• Weight loss; 
• Muscle pain, pain in limbs, muscular weakness; 
• Bone metabolism disorder; 
• Increased bone proteins; 
• Flushing, cold limbs; 
• Slower or irregular heart beat; 
• Feeling extremely sleepy; 
• Sedation; 



137 

• Neurological movement disorder where your muscles contract causing twisting and repetitive 
movements or abnormal postures. Symptoms include tremors, pain, cramping; 

• Medicine toxicity; 
• Anxiety. 
 
Not known (frequency cannot be estimated from available data) side effects are: 
• Reduction in blood platelets which increases risk of bleeding or bruising; 
• Severe pain in the back and stomach (caused by inflamation of the pancreas); 
• Reduction in white blood cells which makes infections more likely; 
• Reddish target-like macules or circular patches often with central blisters on the trunk, skin 

peeling, ulcers of mouth, throat, nose, genitals and eyes, red and swollen eyes and can be preceded 
by fever and/or flu-like symptoms (Stevens-Johnson syndrome/toxic epidermal necrolysis); 

• Initially flu-like symptoms, rash on the face then widespread rash, high body temperature, liver 
enzyme elevations, blood abnormalities (eosinophilia), enlarged lymph nodes and other body 
organs involvement (Drug Reaction with Eosinophilia and Systemic Symptoms which is also 
known as DRESS or drug hypersensitivity syndrome); 

• Serious allergic reaction which causes swelling of the face, throat, hand, feet, ankles, or lower 
legs; 

• Urticaria (skin rash with itching). 
•  
 
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. 
 
There have been reports of bone disorders including osteopenia and osteoporosis (thinning of the 
bone) and fractures with structurally related antiepileptics medicines like carbamazepine and 
oxcarbazepine. Check with your doctor or pharmacist, if you are on long-term antiepileptic treatment, 
have a history of osteoporosis, or take steroids. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Zebinix 
 
Keep this medicine out of the sight and  reach of children. 
 
Do not use this medicine after the expiry date, which is stated on the blister 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. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What 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. 

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


138 

 
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, with a length of 17.3 mm. The tablet can be divided into equal doses. 
 
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) 2 502 58 04 
 

Luxembourg/Luxemburg 
Eisai Europe Ltd. 
Tél/Tel: + 32 (0) 2 502 58 04 
(Belgique/Belgien) 
 

България 
BIAL-Portela & Cª., S.A. 
Teл.: + 351 22 986 61 00 
(Португалия) 
 

Magyarország 
Eisai Ltd 
Tel.: + 44 (0)845 676 1400 
(Nagy-Britannia) 

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 B.V. 
Tél/Tel: + 31 (0) 900 575 3340 
 

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) 
 



139 

España 
Laboratorios BIAL, S.A. 
Tel: + 34 91 562 41 96  
 

Portugal 
BIAL-Portela & Cª., S.A. 
Tel.: + 351 22 986 61 00 
 

France 
Eisai SAS 
Tél: + (33) 1 47 67 00 05 
 
Hrvatska 
BIAL-Portela & Cª, S.A. 
Tel: + 351 22 986 61 00 
(Portugal) 
 

România 
BIAL-Portela & Cª, S.A. 
Tel: + 351 22 986 61 00 
(Portugalia) 
 

Ireland 
Eisai GmbH 
Tel: + 49 (0) 69 66 58 50 
 

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) 
 

 

Lietuva 
BIAL-Portela & Cª, S.A. 
Tel: + 351 22 986 61 00 
(Portugalija) 
 

 

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

http://www.ema.europa.eu/


140 

Package leaflet: Information for the user 
 

Zebinix 800 mg tablets 
Eslicarbazepine acetate 

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

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

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet  
1. What Zebinix is and what it is used for 
2. What you need to know before you take Zebinix 
3. How to take Zebinix 
4. Possible side effects 
5. How to store Zebinix 
6. Contents of the pack and other information 
 
 
1. What Zebinix is and what it is used for 
 
Zebinix contains the active substance eslicarbazepine acetate. 
Zebinix belongs to a group of medicines called antiepileptics used to treat epilepsy, a condition where 
someone has repeated seizures or fits.  
 
Zebinix is used: 

• on its own (monotherapy) in adult patients with newly diagnosed epilepsy 
 

• with other antiepileptic medicines (adjunctive therapy), in adult, adolescents and children 
patients above 6 years of age, who are 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. What you need to know before you take Zebinix 
 
Do not take Zebinix: 

• if you are allergic to eslicarbazepine acetate, to other carboxamide derivatives (e.g. 
carbamazepine or oxcarbazepine, medicines used to treat epilepsy) or to any of the other 
ingredients of this medicine (listed in section 6); 

• if you suffer from a certain type of heart rhythm disorder (second or third degree 
atrioventricular (AV) block). 

 
Warnings and precautions  
Talk to your doctor or pharmacist before taking Zebinix. 
 
Contact your doctor immediately: 

• if you have blistering or peeling of the skin and/or mucous membranes, rash, swallowing or 
breathing problems, swelling of your lips, face, eyelids, throat or tongue. These could be signs 
of an allergic reaction.  



141 

• if 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. 

• if you have liver problems. Zebinix is not recommended in patients with severe liver problems. 
• if 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. 

• if you suffer from a heart disease such as heart failure or heart attack, or have any heart rhytm 
disorder. 

• if you suffer from seizures that begin with a widespread electric discharge that involves both 
sides of the brain. 

 
A small number of people being treated with antiepileptics have had thoughts of harming or killing 
themselves. If at any time you have these thoughts, when taking Zebinix, contact your doctor 
immediately. 
 
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, such as fall. 
 
Take special care with Zebinix: 
Serious and potentially life-threatening skin reactions including Stevens-Johnson syndrome/toxic 
epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS) have been 
reported in post-marketing experience in patients treated with Zebinix.  
If you develop a serious rash or another skin symptoms (see section 4), stop taking Zebinix and 
contact your doctor or seek medical attention immediately. 
 
In patients of Han Chinese or Thai origin the risk of serious skin reactions associated with 
carbamazepine or chemically-related compounds may be predicted by testing a blood sample of these 
patients. Your doctor should be able to advise if a blood test is necessary before taking Zebinix. 
 
Children 
Zebinix is not to be given to children aged 6 years and below. 
 
Other medicines and Zebinix 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This is just in case any of them interfere with how Zebinix works or how Zebinix interferes 
with their effect. 
Tell your doctor if you are taking: 
• phenytoin (a medicine used to treat epilepsy) since your dose may need to be adjusted; 
• carbamazepine (a medicine used to treat epilepsy) since your dose may have to be adjusted and the 

following side effects of Zebinix may occur in higher frequency: seeing double, abnormal 
coordination and dizziness; 

• hormonal contraceptives (such as the contraceptive pill) since Zebinix may make these less 
effective; 

• simvastatin (a medicine used to lower cholesterol levels) since your dose may have to be adjusted; 
• rosuvastatin, a medicine used to lower cholesterol level; 
• the blood thinner - warfarin; 
• tricyclic antidepressants e.g. amitriptyline; 
• 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. 
 
See ‘Pregnancy and breast-feeding’ section for advice about contraception. 
 



142 

Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
There are no data from the use of eslicarbazepine acetate in pregnant women. Research has shown an 
increased risk of birth defects in children of women taking antiepileptic medicines. On the other hand, 
effective antiepileptic 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. 
 
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. 
 
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. 
 
 
3. How to take Zebinix 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Adults 
 
Dose when you start treatment 
400 mg 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 1,200 mg once daily. If you 
are taking Zebinix on its own your doctor may consider you can benefit of a dose of 1,600 mg once 
daily. 
 
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. 
 
Elderly (over 65 years of age) 
If you are elderly and taking Zebinix on its own the dose of 1,600 mg is not a suitable dose for you. 
 
Children above 6 years of age 
 
Dose when you start treatment 
The starting dose is 10 mg per kg body weight taken once a day for one or two weeks, before 
increasing to the maintenance dose.  
 
Maintenance dose 
Depending on the response to Zebinix, the dose may be increased by 10 mg per kg body weight, at 
intervals of one one or two weeks, up to 30 mg per kg body weight. The maximum dose is 1,200 mg 
once daily. 
 
Children ≥60 kg 
Children with 60 kg or more body weight should take the same dose as adults. 



143 

 
Other form of this medicine, like oral suspension, maybe more suitable for children. Ask your doctor 
or pharmacist. 
 
Method and route of administration 
Zebinix is for oral use. Swallow the tablet with a glass of water.  
Zebinix tablets may be taken with or without food. 
 
The tablet can be divided into equal doses. 
 
If you take more Zebinix than you should 
If you accidently take more Zebinix than you should, you are potentially at risk of having more 
seizures; or you may feel like your heart beat is irregular or faster. Contact a doctor or go to a hospital 
immediately if you experience any of the above symptoms. 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 a forgotten dose. 
 
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. 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 medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine 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: 
• blistering or peeling of the skin and/or mucous membranes, rash, swallowing or breathing 

problems, swelling of your lips, face, eyelids, throat or tongue. These could be signs of an allergic 
reaction.  

 
Very common (may affect more than 1 in 10 people) side effects are: 
• Feeling dizzy or sleepy.  
 
Common (may affect up to 1 in 10 people) 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; 
• Skin rash; 
• Blood tests showing that you have low levels of sodium in your blood; 
• Decrease of appetite; 
• Difficulty in sleeping; 
• Difficulty in coordinating movements (ataxia); 



144 

• Weight increase. 
 
Uncommon (may affect up to 1 in 100 people) side effects are: 
• Clumsiness; 
• Allergy; 
• Constipation; 
•  Seizures; 
• Underactive thyroid gland. Symptoms include decreased level of thyroid hormone levels (seen in 

blood tests), cold intolerance, large tongue, thin and brittle fingernails or hair and low body 
temperature; 

• Liver problems; 
• High blood pressure or severe increase in blood pressure;  
• Low blood pressure or a fall in blood pressure on standing up; 
• Blood tests showing that you have low levels of salts (including chloride) in your blood or a 

reduction in red blood cells; 
• Dehydration; 
• Eye movement changes, fuzzy vision or red eye; 
• Having falls; 
• Thermal burn; 
• 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; 
• Agitation; 
• Attention deficit/ hyperactivity disorder; 
• Irritability; 
• Mood changes or hallucinations; 
• Difficulty in speaking; 
• Nosebleed; 
• Chest pain; 
• Tingling and/or feeling numb in any part of your body; 
• Migraine; 
• Burning sensation; 
• Abnormal sense of touch; 
• Disturbances in the sense of smell; 
• Ringing in the ears; 
• Hearing difficulty; 
• Swelling in your legs and arms; 
• Heart burn, stomach upset, abdominal pain, abdominal bloating and discomfort or dry mouth; 
• Charcoal (dark) stool; 
• Inflamed gums or toothache; 
• Sweating or having dry skin; 
• Itching; 
• Skin changes (e.g. red skin); 
• Hair loss; 
• Urinary tract infection; 
• Feeling generally weak, unwell or having chills; 
• Weight loss; 
• Muscle pain, pain in limbs, muscular weakness; 
• Bone metabolism disorder; 
• Increased bone proteins; 
• Flushing, cold limbs; 
• Slower or irregular heart beat; 
• Feeling extremely sleepy; 
• Sedation; 



145 

• Neurological movement disorder where your muscles contract causing twisting and repetitive 
movements or abnormal postures. Symptoms include tremors, pain, cramping; 

• Medicine toxicity; 
• Anxiety. 
 
Not known (frequency cannot be estimated from available data) side effects are: 
• Reduction in blood platelets which increases risk of bleeding or bruising; 
• Severe pain in the back and stomach (caused by inflamation of the pancreas); 
• Reduction in white blood cells which makes infections more likely; 
• Reddish target-like macules or circular patches often with central blisters on the trunk, skin 

peeling, ulcers of mouth, throat, nose, genitals and eyes, red and swollen eyes and can be preceded 
by fever and/or flu-like symptoms (Stevens-Johnson syndrome/toxic epidermal necrolysis); 

• Initially flu-like symptoms, rash on the face then widespread rash, high body temperature, liver 
enzyme elevations, blood abnormalities (eosinophilia), enlarged lymph nodes and other body 
organs involvement (Drug Reaction with Eosinophilia and Systemic Symptoms which is also 
known as DRESS or drug hypersensitivity syndrome); 

• Serious allergic reaction which causes swelling of the face, throat, hand, feet, ankles, or lower 
legs; 

• Urticaria (skin rash with itching). 
 
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. 
 
There have been reports of bone disorders including osteopenia and osteoporosis (thinning of the 
bone) and fractures with structurally related antiepileptics medicines like carbamazepine and 
oxcarbazepine. Check with your doctor or pharmacist, if you are on long-term antiepileptic treatment, 
have a history of osteoporosis, or take steroids. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Zebinix 
 
Keep this medicine out of the sight and  reach of children. 
 
Do not use this medicine after the expiry date, which is stated on the blister 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. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What 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. 
 

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146 

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, with a length of 19 mm. The tablet can be divided into equal doses. 
 
The tablets are packaged in blisters in cardboard boxes containing 20, 30, 60 or 90 tablets or in 
multipacks containing 180 (2x90) 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) 2 502 58 04 
 

Luxembourg/Luxemburg 
Eisai Europe Ltd. 
Tél/Tel: + 32 (0) 2 502 58 04 
(Belgique/Belgien) 
 

България 
BIAL-Portela & Cª., S.A. 
Teл.: + 351 22 986 61 00 
(Португалия) 
 

Magyarország 
Eisai Ltd 
Tel.: + 44 (0)845 676 1400 
(Nagy-Britannia) 
 

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 B.V. 
Tél/Tel: + 31 (0) 900 575 3340 
 

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) 
 



147 

España 
Laboratorios BIAL, S.A. 
Tel: + 34 91 562 41 96  
 

Portugal 
BIAL-Portela & Cª., S.A. 
Tel.: + 351 22 986 61 00 
 

France 
Eisai SAS 
Tél: + (33) 1 47 67 00 05 
 
Hrvatska 
BIAL-Portela & Cª, S.A. 
Tel: + 351 22 986 61 00 
(Portugal) 
 
  

 

România 
BIAL-Portela & Cª, S.A. 
Tel: + 351 22 986 61 00 
(Portugalia) 
 

Ireland 
Eisai GmbH 
Tel: + 49 (0) 69 66 58 50 
 

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) 
 

 

Lietuva 
BIAL-Portela & Cª, S.A. 
Tel: + 351 22 986 61 00 
(Portugalija) 
 

 

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

http://www.ema.europa.eu/


148 

Package leaflet: Information for the user 
 

Zebinix 50 mg/ml oral suspension  
Eslicarbazepine acetate 

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

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

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
1. What Zebinix is and what it is used for 
2. What you need to know before you take Zebinix 
3. How to take Zebinix 
4. Possible side effects 
5. How to store Zebinix 
6. Contents of the pack and other information 
 
 
1. What Zebinix is and what it is used for 
 
Zebinix contains the active substance eslicarbazepine acetate. 
Zebinix belongs to a group of medicines called antiepileptics used to treat epilepsy, a condition where 
someone has repeated seizures or fits.  
 
Zebinix is used: 

• on its own (monotherapy) in adult patients with newly diagnosed epilepsy 
 
• with other antiepileptic medicines (adjunctive therapy), in adult, adolescents and children 
patients above 6 years of age,  whoare 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. What you need to know before you take Zebinix 
 
Do not take Zebinix: 

• if you are allergic to eslicarbazepine acetate, to other carboxamide derivatives (e.g. 
carbamazepine or oxcarbazepine, medicines used to treat epilepsy) or to any of the other 
ingredients of this medicine (listed in section 6); 

• if you suffer from a certain type of heart rhythm disorder (second or third degree 
atrioventricular (AV) block). 

 
Warnings and precautions 
 
Talk to your doctor or pharmacist before taking Zebinix. 
 
Contact your doctor immediately: 

• if you have blistering or peeling of the skin and/or mucous membranes, rash, swallowing or 
breathing problems, swelling of your lips, face, eyelids, throat or tongue. These could be signs 
of an allergic reaction.  



149 

• if 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. 

• if you have liver problems. Zebinix is not recommended in patients with severe liver problems. 
• if 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. 

• if you suffer from a heart disease such as heart failure or heart attack, or have any heart rhytm 
disorder. 

• if you suffer from seizures that begin with a widespread electric discharge that involves both 
sides of the brain.  

 
A small number of people being treated with antiepileptics have had thoughts of harming or killing 
themselves. If at any time you have these thoughts, when taking Zebinix, contact your doctor 
immediately. 
 
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, such as fall. 
 
Take special care with Zebinix: 
Serious and potentially life-threatening skin reactions including Stevens-Johnson syndrome/toxic 
epidermal necrolysis, drug reaction with eosinophilia and systemic symptoms (DRESS) have been 
reported in post-marketing experience in patients treated with Zebinix.  
If you develop a serious rash or another skin symptoms (see section 4), stop taking Zebinix and 
contact your doctor or seek medical attention immediately. 
 
In patients of Han Chinese or Thai origin the risk of serious skin reactions associated with 
carbamazepine or chemically-related compounds may be predicted by testing a blood sample of these 
patients. Your doctor should be able to advise if a blood test is necessary before taking Zebinix. 
 
Children 
Zebinix is not to be given to children aged 6 years and below. 
 
Other medicines and Zebinix 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. This is just in case any of them interfere with how Zebinix works or how Zebinix interferes 
with their effect.  
Tell your doctor if you are taking: 
• phenytoin (a medicine used to treat epilepsy) since your dose may need to be adjusted; 
• carbamazepine (a medicine used to treat epilepsy) since your dose may have to be adjusted and the 

following side effects of Zebinix may occur in higher frequency: seeing double, abnormal 
coordination and dizziness; 

• hormonal contraceptives (such as the contraceptive pill) since Zebinix may make these less 
effective; 

• simvastatin (a medicine used to lower cholesterol levels) since your dose may have to be adjusted; 
• rosuvastatin, a medicine used to lower cholesterol level; 
• the blood thinner - warfarin; 
• tricyclic antidepressants e.g. amitriptyline; 
• 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. 
 
See ‘Pregnancy and breast-feeding’ section for advice about contraception. 



150 

 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
There are no data from the use of eslicarbazepine acetate in pregnant women. Research has shown an 
increased risk of birth defects in children of women taking antiepileptic medicines. On the other hand 
effective antiepileptic 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. 
 
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. 
 
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. 
 
Zebinix contains methyl parahydroxybenzoate (E218) and sulphites  
Zebinix oral suspension contains methyl parahydroxybenzoate (E218) which may cause allergic 
reactions (possibly delayed) and sulphites which may rarely cause severe hypersensitivity reactions 
and bronchospasm. 
 
 
3. How to take Zebinix 
 
Always take this medicine exactly as your doctor has told you.  Check with your doctor or pharmacist 
if you are not sure. 
 
 
Adults 
 
Dose when you start treatment 
400 mg 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 1,200 mg once daily. If you 
are taking Zebinix on its own your doctor may consider you can benefit of a dose of 1,600 mg once 
daily. 
 
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. 
 
Elderly (over 65 years of age) 
If you are elderly and taking Zebinix on its own the dose of 1,600 mg is not a suitable dose for you. 
 
Children above 6 years of age 
 
Dose when you start treatment 
The starting dose is 10 mg per kg body weight taken once a day for one or two weeks, before 
increasing to the maintenance dose.  
 



151 

Maintenance dose 
Depending on the response to Zebinix, the dose may be increased by 10 mg per kg body weight, at 
intervals of one or two weeks, up to 30 mg per kg body weight. The maximum dose is 1,200 mg once 
daily. 
 
Children with ≥60 kg 
Children with 60 kg or more body weight should take the same dose as adults. 
 
Other form of this medicine, like oral suspension, maybe more suitable for children. Ask your doctor 
or pharmacist. 
 
Method and route of administration 
Zebinix is for oral use.  
Zebinix oral suspension may be taken with or without food. 
 
Shake well before use. 
 
Always use the oral syringe provided to take your medicine. 
 
Instructions for use: 
 
Step 1. Remove the bottle, the oral syringe and the bottle adapter from the box  
 
Step 2. Shake the bottle for at least 10 seconds and remove the child resistant closure by pushing it 
down and turning it counter-clockwise (to the left). 
 

 
 
Step 3. Insert the bottle adapter in the bottle neck opening. You may need to apply some pressure to 
insert it securely. Once inserted, the bottle adapter must not be removed from the bottle. The bottle can 
be closed with the closure with the bottle adapter still in place. 
 

 
 



152 

Step 4. To ease the process you should mark the desired volume in the syringe by moving the plunger. 
Insert the tip of the oral syringe into the bottle adapter opening, keeping the bottle upright. Push the 
plunger all the way down. This will create pressure inside the bottle that will help the dosing of the 
suspension, forcing it to leave from the bottle to the oral syringe. 
 

 
 
Step 5: Hold the oral syringe in place and turn the bottle upside down. 
Gently pull the plunger of the oral syringe to the desired volume. 
 

 
 
Step 6: If you see any air bubbles in the oral syringe, push the plunger upwards just far enough to 
completely push out any large air bubbles. Gently pull the plunger back downwards to the dose 
prescribed by your doctor. 
 

 
 
Step 7. Turn the bottle upright and remove the entire oral syringe from the bottle. Be careful, do not 
push the plunger down when removing the oral syringe from the bottle. 



153 

 
 
Step 8. Replace the closure on the bottle by turning it clock-wise (to the right). 
 

 
 
Step 9. Place the oral syringe into the mouth against the inside of the cheek. Press the plugger down 
slowly to release Zebinix into the mouth. 
 
Step 10: Rinse the empty oral syringe after each use into a glass of clean water. Repeat this cleaning 
process 3 times.  
Store the bottle and the oral syringe together in the carton until next use. 
 
If you take more Zebinix than you should 
If you accidently take more Zebinix than you should, you are potentially at risk of having more 
seizures; or you may feel like your heart beat is irregular or faster. Contact a doctor or go to a hospital 
immediately if you experience any of the above symptoms. 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 dose, take it as soon as you remember and carry on as usual. Do not take a 
double dose to make up for a forgotten dose. 
 
If you stop taking Zebinix 
Do not stop taking your oral suspension suddenly. If you do, you are at risk of having more seizures. 
Your doctor will decide how long you should take Zebinix. 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 medicine, ask your doctor or pharmacist. 
 
 



154 

4. Possible side effects 
 
Like all medicines, this medicine 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: 
• blistering or peeling of the skin and/or mucous membranes, rash, swallowing or breathing 

problems, swelling of your lips, face, eyelids, throat or tongue. These could be signs of an allergic 
reaction.  

 
Very common (may affect more than 1 in 10 people) side effects are: 
• Feeling dizzy or sleepy.  
 
Common (may affect up to 1 in 10 people) 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; 
• Skin rash; 
• Blood tests showing that you have low levels of sodium in your blood; 
• Decrease of appetite; 
• Difficulty in sleeping; 
• Difficulty in coordinating movements (ataxia); 
• Weight increase. 
 
Uncommon (may affect up to 1 in 100 people) side effects are: 
• Clumsiness; 
• Allergy; 
• Constipation; 
• Seizures; 
• Underactive thyroid gland. Symptoms include decreased level of thyroid hormone levels (seen in 

blood tests), cold intolerance, large tongue, thin and brittle fingernails or hair and low body 
temperature; 

• Liver problems; 
• High blood pressure or severe increase in blood pressure; 
• Low blood pressure or a fall in blood pressure on standing up; 
• Blood tests showing that you have low levels of salts (including chloride) in your blood or a 

reduction in red blood cells; 
• Dehydration; 
• Eye movement changes, fuzzy vision or red eye; 
• Having falls; 
• Thermal burn; 
• 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; 
• Agitation; 
• Attention deficit/ hyperactivity disorder; 
• Irritability; 
• Mood changes or hallucinations; 
• Difficulty in speaking; 
• Nosebleed; 



155 

• Chest pain; 
• Tingling and/or feeling numb in any part of your body; 
• Migraine; 
• Burning sensation; 
• Abnormal sense of touch; 
• Disturbances in the sense of smell; 
• Ringing in the ears; 
• Hearing difficulty; 
• Swelling in your legs and arms; 
• Heart burn, stomach upset, abdominal pain, abdominal bloating and discomfort or dry mouth; 
• Charcoal (dark) stool; 
• Inflamed gums or toothache; 
• Sweating or having dry skin; 
• Itching; 
• Skin changes (e.g. red skin); 
• Hair loss; 
• Urinary tract infection; 
• Feeling generally weak, unwell or having chills; 
• Weight loss; 
• Muscle pain, pain in limbs, muscular weakness; 
• Bone metabolism disorder; 
• Increased bone proteins; 
• Flushing, cold limbs; 
• Slower or irregular heart beat; 
• Feeling extremely sleepy; 
• Sedation; 
• Neurological movement disorder where your muscles contract causing twisting and repetitive 

movements or abnormal postures. Symptoms include tremors, pain, cramping; 
• Medicine toxicity; 
• Anxiety. 
 
Not known (frequency cannot be estimated from available data) side effects are: 
• Reduction in blood platelets which increases risk of bleeding or bruising; 
• Severe pain in the back and stomach (caused by inflamation of the pancreas); 
• Reduction in white blood cells which makes infections more likely; 
• Reddish target-like macules or circular patches often with central blisters on the trunk, skin 

peeling, ulcers of mouth, throat, nose, genitals and eyes, red and swollen eyes and can be preceded 
by fever and/or flu-like symptoms (Stevens-Johnson syndrome/toxic epidermal necrolysis); 

• Initially flu-like symptoms, rash on the face then widespread rash, high body temperature, liver 
enzyme elevations, blood abnormalities (eosinophilia), enlarged lymph nodes and other body 
organs involvement (Drug Reaction with Eosinophilia and Systemic Symptoms which is also 
known as DRESS or drug hypersensitivity syndrome); 

• Serious allergic reaction which causes swelling of the face, throat, hand, feet, ankles, or lower 
legs; 

• Urticaria (skin rash with itching). 
 
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. 
 
There have been reports of bone disorders including osteopenia and osteoporosis (thinning of the 
bone) and fractures with structurally related antiepileptics medicines like carbamazepine and 
oxcarbazepine. Check with your doctor or pharmacist, if you are on long-term antiepileptic treatment, 
have a history of osteoporosis, or take steroids. 
 



156 

Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Zebinix 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date, which is stated on the bottle and the carton after EXP. 
The expiry date refers to the last day of that month. 
 
Once you have opened the bottle, you must not use it longer than 2 months 
 
This medicine does not require any special storage conditions. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6.  Contents of the pack and other information  
 
What Zebinix contains 
• The active substance is eslicarbazepine acetate. Each ml of oral suspension contains 50 mg of 

eslicarbazepine acetate. 
The other ingredients are xanthan gum (E415), macrogol-100 stearate, methyl 
parahydroxybenzoate (E218), saccharin sodium (E954), flavour tutti-frutti artificial (contains 
maltodextrin, propylene glycol, natural and artificial flavouring, and gum acacia (E414), masking 
flavour (contains propylene glycol, water and natural and artificial flavouring) and purified water. 

 
What Zebinix looks like and contents of the pack 
Zebinix 50 mg/ml is an off-white to white oral suspension.  
 
The oral suspension is packaged in amber glass bottles with HDPE child resistant closures containing 
200 ml oral suspension, inside a cardboard box. Each cardboard box contains a 10 ml polypropylene 
graduated syringe with 0.2 ml graduations, and a copolymer push-in bottle adapter. 
 
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) 2 502 58 04 
 

Luxembourg/Luxemburg 
Eisai Europe Ltd. 
Tél/Tel: + 32 (0) 2 502 58 04 
(Belgique/Belgien) 
 

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


157 

България 
BIAL-Portela & Cª., S.A. 
Teл.: + 351 22 986 61 00 
(Португалия) 
 

Magyarország 
Eisai Ltd 
Tel.: + 44 (0)845 676 1400 
(Nagy-Britannia) 
 

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 B.V. 
Tél/Tel: + 31 (0) 900 575 3340 
 

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 
Laboratorios BIAL, S.A. 
Tel: + 34 91 562 41 96  

Portugal 
BIAL-Portela & Cª., S.A. 
Tel.: + 351 22 986 61 00 
 

France 
Eisai SAS 
Tél: + (33) 1 47 67 00 05 
 
Hrvatska  
BIAL-Portela & Cª, S.A. 
Tel: + 351 22 986 61 00 
(Portugal) 
 

România 
BIAL-Portela & Cª, S.A. 
Tel: + 351 22 986 61 00 
(Portugalia) 
 

Ireland 
Eisai GmbH 
Tel: + 49 (0) 69 66 58 50 
 
 

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) 
 



158 

Italia 
Eisai S.r.l. 
Tel: + 39 02 518 1401 
 

Suomi/Finland 
Eisai AB 
Puh/Tel: + 46 (0) 8 501 01 600 
(Ruotsi) 
 

Κύπρος 
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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) 
 

 

Lietuva 
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Tel: + 351 22 986 61 00 
(Portugalija) 
 
 

 

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

http://www.ema.europa.eu/


159 

 
 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Annex B  

(variation to centrally authorised medicinal products) 

 



160 

 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Annex IV 

Scientific conclusions and grounds for the variation to the terms of the marketing 
authorisation(s) 

 
 
 
 
 

 



161 

Scientific conclusions 

Taking into account the PRAC Assessment Report on the PSUR(s) for eslicarbazepine acetate, the 
scientific conclusions of CHMP are as follows:  

Weight gain 

Taking into account that more eslicarbazepine acetate-treated patients experienced weight increase 
than weight decrease during the open label extension of the Phase III studies the current labelling is 
not considered adequate. In addition, there are six post-marketing cases of ‘weight increase’ for 
which the causality was assessed as possibly related to eslicarbazepine acetate by the MAH. 
Considering that changes in body weight can influence the treatment decision and are of particular 
importance in epilepsy which itself may be associated with overweight/obesity this information 
should adequately be reflected in SmPC and PIL.  

Based on this outcome, update of section 4.8 of the SmPC to add ‘weight increased’ with the 
frequency common (calculation based on clinical trial data) is recommended.  

Overdose 

During the reporting period, the MAH detected a signal of overdose. Two clusters of ADRs were 
identified in context of overdose cases – epilepsy/seizures/status epilepticus and cardiac events, 
mainly arrhythmias. The information currently provided in section 4.9 of the SmPC is limited and 
does not reflect a potential cardiac risk of eslicarbazepine acetate overdose or the risk of seizure 
induction. Based on this outcome, update of section 4.9 to reflect new information from overdose 
cases is recommended. 

Therefore, in view of the data presented in the reviewed PSUR, the PRAC considered that changes to 
the product information of medicinal products containing eslicarbazepine acetate were warranted. 

The CHMP agrees with the scientific conclusions made by the PRAC. 

Grounds for the variation to the terms of the marketing authorisation(s) 

On the basis of the scientific conclusions for eslicarbazepine acetate the CHMP is of the opinion 
that the benefit-risk balance of the medicinal product(s) containing eslicarbazepine acetate is 
unchanged subject to the proposed changes to the product information 

The CHMP recommends that the terms of the marketing authorisation(s) should be varied. 

 

 
 

 

 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET
	Scientific conclusions and grounds for the variation to the terms of the marketing authorisation(s)