ZEBINIX 800mg tablets medication leaflet

Zebinix 800 mg tablets

Each tablet contains 800 mg of eslicarbazepine acetate.

For the full list of excipients, see section 6.1.

Tablet.

White oblong tablets, engraved ‘ESL 800’on one side and scored on the other side, with a length of 19mm. The tablet can be divided into equal doses.

Zebinix is indicated as:

* monotherapy in the treatment of partial-onset seizures, with or without secondary generalisation, inadults with newly diagnosed epilepsy;

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

Zebinix may be taken as monotherapy or added to existing anticonvulsant therapy. The recommendedstarting dose is 400 mg once daily which should be increased to 800 mg once daily after one or twoweeks. Based on individual response, the dose may be increased to 1,200 mg once daily Somepatients on monotherapy regimen may benefit from a dose of 1,600 mg once daily (see section 5.1).

Elderly (over 65 years of age)

No dose adjustment is needed in the elderly population provided that the renal function is notdisturbed. Due to very limited data on the 1,600 mg monotherapy regimen in the elderly, this dose isnot recommended for this population.

Caution should be exercised in the treatment of patients, adult and children above 6 years of age, withrenal 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 or400 mg (or 10 mg/kg in children above 6 years) every other day for 2 weeks followed by a oncedaily dose of 400 mg (or 10 mg/kg in children above 6 years). However, based on individualresponse, the dose may be increased.

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

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 hepaticimpairment (see sections 4.4 and 5.2) and use in these patients is, therefore, not recommended.

Children above 6 years of age

The recommended starting dose is 10 mg/kg/day once daily. Dosage should be increased in weekly orbi-weekly increments of 10 mg/kg/day up to 30 mg/kg/daybased on individual response. the maximumdose 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 beenestablished. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendationon a posology can be made.

Oral use.

Zebinix may be taken with or without food.

For patients who are unable to swallow whole tablets, the tablets may be crushed and mixed withwater or soft foods, such as apple sauce, immediately prior to use and administered orally.

Switching preparations

Based on comparative bioavailability data for the tablet and the suspension formulations, switchingpatients from one formulation to the other can be done.

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.

Suicidal ideation

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic activesubstances in several indications. A meta-analysis of randomised placebo-controlled trials ofantiepileptic medicinal products has also shown a small increased risk of suicidal ideation andbehaviour. The mechanism of this risk is not known and the available data do not exclude thepossibility of an increased risk for eslicarbazepine acetate. Therefore patients should be monitored forsigns of suicidal ideation and behaviours and appropriate treatment should be considered. Patients (andcaregivers of patients) should be advised to seek medical advice should signs of suicidal ideation orbehaviour emerge.

Eslicarbazepine acetate has been associated with some central nervous system adverse reactions, suchas dizziness and somnolence, which could increase the occurrence of accidental injury.

If Zebinix is to be discontinued it is recommended to withdraw it gradually to minimise the potentialof increased seizure frequency.

Rash developed as an adverse reaction in 1.2% of total population treated with Zebinix in clinicalstudies in epileptic patients. Urticaria and angioedema cases have been reported in patients taking

Zebinix. Angioedema in the context of hypersensitivity/anaphylactic reaction associated withlaryngeal oedema can be fatal. If signs or symptoms of hypersensitivity develop, eslicarbazepineacetate must be discontinued immediately and alternative treatment should be initiated.

Severe cutaneous adverse reactions (SCARS) including Stevens-Johnson syndrome (SJS)/toxicepidermal 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 Zebinixtreatment. At the time of prescription patients should be advised of the signs and symptoms andmonitored 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). Ifthe patients have developed such reactions, treatment with Zebinix must not be restarted in thesepatients 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 associatedwith 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 thatof carbamazepine, and it is possible that patients who are positive for HLA-B*1502 may also be at riskfor SJS after treatment with eslicarbazepine acetate. The prevalence of HLA-B*1502 carrier is about10% in Han Chinese and Thai populations. Whenever possible, these individuals should be screenedfor this allele before starting treatment with carbamazepine or chemically-related active substances. Ifpatients of these ethnic origins are tested positive for HLA- B*1502 allele, the use of eslicarbazepineacetate 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 Philippinesand Malaysia), testing genetically at risk populations for the presence of HLA- B*1502 may beconsidered.

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 carbamazepineinduced cutaneous adverse drug reactions including SJS, TEN, Drug rash with eosinophilia (DRESS),or less severe acute generalized exanthematous pustulosis (AGEP) and maculopapular rash in peopleof European descent and the Japanese.

The frequency of the HLA-A*3101 allele varies widely between ethnic populations. HLA-A*3101allele 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 cutaneousreactions (mostly less severe) from 5.0% in general population to 26.0% among subjects of Europeanancestry, 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 startingcarbamazepine 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 arethought 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 symptomslike worsening of seizures, confusion, decreased consciousness. Frequency of hyponatraemiaincreased with increasing eslicarbazepine acetate dose. In patients with pre-existing renal diseaseleading to hyponatraemia, or in patients concomitantly treated with medicinal products which maythemselves lead to hyponatraemia (e.g. diuretics, desmopressin, carbamazepine), serum sodium levelsshould be examined before and during treatment with eslicarbazepine acetate. Furthermore, serumsodium levels should be determined if clinical signs of hyponatraemia occur. Apart from this, sodiumlevels should be determined during routine laboratory examination. If clinically-relevanthyponatraemia 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, cardiacconduction abnormalities), or when taking concomitant medicinal products known to be associatedwith PR prolongation.

Caution should be exercised in the treatment of patients with renal impairment and the dose should beadjusted according to creatinine clearance (see section 4.2). In patients with CLCR <30 ml/min use isnot recommended due to insufficient data.

As clinical data are limited in patients with mild to moderate hepatic impairment and pharmacokineticand clinical data are missing in patients with severe hepatic impairment, eslicarbazepine acetate shouldbe used with caution in patients with mild to moderate hepatic impairment and is not recommended inpatients with severe hepatic impairment.

Interaction studies have only been performed in adults.

Eslicarbazepine acetate is extensively converted to eslicarbazepine, which is mainly eliminated byglucuronidation. In vitro eslicarbazepine is a weak inducer of CYP3A4 and UDP-glucuronyltransferases. In vivo eslicarbazepine showed an inducing effect on the metabolism of medicinalproducts that are mainly eliminated by metabolism through CYP3A4 (e.g. Simvastatin). Thus, anincrease in the dose of the medicinal products that are mainly metabolised through CYP3A4 may berequired, when used concomitantly with eslicarbazepine acetate. Eslicarbazepine in vivo may have aninducing effect on the metabolism of medicinal products that are mainly eliminated by conjugationthrough the UDP-glucuronyl transferases. When initiating or discontinuing treatment with Zebinix orchanging the dose, it may take 2 to 3 weeks to reach the new level of enzyme activity. This time delaymust be taken into account when Zebinix is being used just prior to or in combination with othermedicinal products that require dose adjustment when co-administered with Zebinix. Eslicarbazepinehas inhibiting properties with respect to CYP2C19. Thus, interactions can arise when co-administeringhigh 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 oncedaily and carbamazepine 400 mg twice daily resulted in an average decrease of 32% in exposure to theactive metabolite eslicarbazepine, most likely caused by an induction of glucuronidation. No change inexposure to carbamazepine or its metabolite carbamazepine-epoxide was noted. Based on individualresponse, the dose of eslicarbazepine acetate may need to be increased if used concomitantly withcarbamazepine. Results from patient studies showed that concomitant treatment increased the risk ofthe following adverse reactions: diplopia, abnormal coordination and dizziness. The risk of increase ofother specific adverse reactions caused by co-administration of carbamazepine and eslicarbazepineacetate cannot be excluded.

In a study in healthy subjects, concomitant administration of eslicarbazepine acetate 1,200 mg oncedaily 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 of31-35% in exposure to phenytoin, most likely caused by an inhibition of CYP2C19. Based onindividual response, the dose of eslicarbazepine acetate may need to be increased and the dose ofphenytoin may need to be decreased.

Lamotrigine

Glucuronidation is the major metabolic pathway for both eslicarbazepine and lamotrigine andtherefore, an interaction could be expected. A study in healthy subjects with eslicarbazepine acetate1,200 mg once daily showed a minor average pharmacokinetic interaction (exposure of lamotriginedecreased 15%) between eslicarbazepine acetate and lamotrigine and consequently no doseadjustments are required. However, due to inter-individual variability, the effect may be clinicallyrelevant in some individuals.

Topiramate

In a study in healthy subjects, concomitant administration of eslicarbazepine acetate 1,200 mg oncedaily and topiramate showed no significant change in exposure to eslicarbazepine but an 18% decreasein exposure to topiramate, most likely caused by a reduced bioavailability of topiramate. No doseadjustment is required.

Valproate and levetiracetam

A population pharmacokinetics analysis of phase III studies in epileptic adult patients indicated thatconcomitant administration with valproate or levetiracetam did not affect the exposure toeslicarbazepine but this has not been verified by conventional interaction studies.

Oxcarbazepine

Concomitant use of eslicarbazepine acetate with oxcarbazepine is not recommended because this maycause overexposure to the active metabolites.

Other medicinal products

Administration of eslicarbazepine acetate 1,200 mg once daily to female subjects using a combinedoral contraceptive showed an average decrease of 37% and 42% in systemic exposure tolevonorgestrel 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 simvastatinwhen co-administered with eslicarbazepine acetate 800 mg once daily, most likely caused by aninduction of CYP3A4. An increase of the simvastatin dose may be required when used concomitantlywith eslicarbazepine acetate.

There was an average decrease of 36-39% in systemic exposure in healthy subjects whenco-administered with eslicarbazepine acetate 1,200 mg once daily. The mechanism for this reductionis unknown, but could be due to interference of transporter activity for rosuvastatin alone or incombination with induction of its metabolism. Since the relationship between exposure and drugactivity is unclear, the monitoring of response to therapy (e.g., cholesterol levels) is recommended.

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 theinteraction, special attention on monitoring of INR should be performed the first weeks after initiationor ending concomitant treatment of warfarin and eslicarbazepine acetate.

A study in healthy subjects showed no effect of eslicarbazepine acetate 1,200 mg once daily ondigoxin 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 interactionbetween eslicarbazepine acetate and MAOIs is theoretically possible.

Risk related to epilepsy and antiepileptic medicinal products in general

It has been shown that in the offspring of women with epilepsy using an antiepileptic treatment, theprevalence of malformations is two to three times greater than the rate of approximately 3% in thegeneral population. Most frequently reported are cleft lip, cardiovascular malformations and neuraltube defects. Specialist medical advice regarding the potential risk to a foetus caused by both seizuresand antiepileptic treatment should be given to all women of child-bearing potential taking antiepileptictreatment, and especially to women planning pregnancy and women who are pregnant. Suddendiscontinuation of antiepileptic drug (AED) therapy should be avoided as this may lead to seizuresthat could have serious consequences for the women and the unborn child.

Monotherapy is preferred for treating epilepsy in pregnancy whenever possible because therapy withmultiple AEDs could be associated with a higher risk of congenital malformations than monotherapy,depending on the associated AEDs.

Neurodevelopmental disorders in children of mothers with epilepsy using an antiepileptic treatmenthas been observed. There is no data available for eslicarbazepine acetate on this risk.

Women of childbearing potential should use effective contraception during treatment witheslicarbazepine acetate. Eslicarbazepine acetate adversely interacts with oral contraceptives.

Therefore, an alternative, effective and safe method of contraception should be used during treatmentand up to the end of the current menstrual cycle after treatment has been stopped. Women ofchildbearing potential should be counselled regarding the use of other effective contraceptive methods.

At least one effective method of contraception (such as an intra-uterine device) or two complementaryforms of contraception including a barrier method should be used. Individual circumstances should beevaluated in each case, involving the patient in the discussion, when choosing the contraceptionmethod.

Risk related to eslicarbazepine acetate

There is limited amount of data from the use of eslicarbazepine acetate in pregnant women. Studies inanimals have shown reproductive toxicity (see Fertility section 5.3). ). A risk in humans (including ofmajor congenital malformations, neurodevelopmental disorders and other reproductive toxic effects) isunknown.

Eslicarbazepine acetate should not be used during pregnancy unless the benefit is judged to outweighthe risk following careful consideration of alternative suitable treatment options.

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 monotherapywhenever possible should be preferred at least during the first three months of pregnancy. Patientsshould be counselled regarding the possibility of an increased risk of malformations and given theopportunity to antenatal screening.

Monitoring and prevention

Antiepileptic medicinal products may contribute to folic acid deficiency, a possible contributory causeof foetal abnormality. Folic acid supplementation is recommended before and during pregnancy. Asthe efficacy of this supplementation is not proven, a specific antenatal diagnosis can be offered evenfor 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. Asa precaution, vitamin K1 should be administered as a preventive measure in the last few weeks ofpregnancy and to the newborn.

It is unknown whether eslicarbazepine acetate is excreted in human milk. Animal studies have shownexcretion 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.

There are no data on the effects of eslicarbazepine acetate on human fertility. Studies in animals haveshown impairment of fertility after treatment with eslicarbazepine acetate (see section 5.3).

Zebinix has minor to moderate influence on the ability to drive and use machines. Some patients mightexperience 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 ordriving may be impaired and they are recommended not to do so until it has been established that theirability to perform such activities is not affected.

In clinical studies (adjunctive therapy treatment and monotherapy), 2,434 patients with partial-onsetseizures 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 thefirst weeks of treatment with eslicarbazepine acetate.

The risks that have been identified for Zebinix are mainly class-based, dose-dependent undesirableeffects. The most common treatment-emergent adverse reactions reported, in placebo controlledadjunctive therapy studies with adult epileptic patients and in an active controlled monotherapy studycomparing eslicarbazepine acetate with carbamazepine controlled release, were dizziness, somnolence,headache, and nausea. The majority of adverse reactions were reported in <3% of subjects in anytreatment group.

Severe cutaneous adverse reactions (SCARS), including Stevens-Johnson syndrome (SJS)/toxicepidermal 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).

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 (frequencycannot be estimated from available data). Within each frequency category, adverse reactions arepresented in order of decreasing seriousness.

Table 1: Treatment emergent adverse reactions associated with Zebinix obtained from in clinicalstudies and post-marketing surveillance

System Organ Very Common Uncommon Not known

Class common

Blood and Anaemia Thrombocytopenia,lymphatic leukopeniasystem disorders

Immune system Hypersensitivitydisorders

Endocrine Hypothyroidismdisorders

Metabolism and Hyponatraemia, Electrolyte Inappropriate ADHnutrition decreased imbalance, secretion likedisorders appetite dehydration, syndrome withhypochloraemia signs andsymptoms oflethargy, nausea,dizziness, decreasein serum (blood)osmolality,vomiting,headache,confusional state orother neurologicalsigns andsymptoms

Psychiatric Insomnia Psychoticdisorders disorder, apathy,depression,nervousness,agitation,irritability,attention deficit/hyperactivitydisorder,confusionalstate, moodswings, crying,psychomotorretardation,anxiety

Nervous system Dizziness, Headache, Coordinationdisorders somnolence disturbance in abnormal,attention, memorytremor, ataxia, impairment,balance disorder amnesia,hypersomnia,sedation,aphasia,dysaesthesia,dystonia,lethargy,parosmia,cerebellarsyndrome,convulsion,peripheralneuropathy,nystagmus,speech disorder,dysarthria,burningsensation,paraesthesia,migraine

Eye disorders Diplopia, vision Visualblurred impairment,oscillopsia,binocular eyemovementdisorder, ocularhyperaemia

Ear and Vertigo Hypoacusis,labyrinth tinnitusdisorders

Cardiac Palpitations,disorders bradycardia

Vascular Hypertensiondisorders (includinghypertensivecrisis),hypotension,orthostatichypotension,flushing,peripheralcoldness

Respiratory, Epistaxis, chestthoracic and painmediastinaldisorders

Gastrointestinal Nausea, Constipation, Pancreatitisdisorders vomiting, dyspepsia,diarrhoea gastritis,abdominal pain,dry mouth,abdominaldiscomfort,abdominaldistension,gingivitis ,melaena,toothache

Hepatobiliary Liver disorderdisorders

Skin and Rash Alopecia, dry Toxic epidermalsubcutaneous skin, necrolysis, Stevens-tissue disorders hyperhidrosis, Johnson syndrome,erythema, skin drug reaction withdisorder, eosinophilia andpruritus, systemic symptomsdermatitis (DRESS),allergic angioedema,urticaria

Musculoskeletal Myalgia, boneand connective metabolismtissue disorders disorder,muscularweakness, painin extremity

Renal and Urinary tracturinary infectiondisorders

General Fatigue, gait Malaise, chills,disorders and disturbance, oedemaadministration asthenia peripheralsite conditions

Investigations Weight Blood pressureincreased decreased,weightdecreased, bloodpressureincreased, bloodsodiumdecreased, bloodchloridedecreased,osteocalcinincreased,haematocritdecreased,haemoglobindecreased,hepatic enzymesincreased

Injury, Drug toxicity,poisoning and fall, thermalprocedural burncomplications

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 withconcomitant carbamazepine, 2.4% of subjects without concomitant carbamazepine), abnormalcoordination (6.7% with concomitant carbamazepine, 2.7% without concomitant carbamazepine), anddizziness (30.0% with concomitant carbamazepine, 11.5% without concomitant carbamazepine), seesection 4.5.

PR interval

The use of eslicarbazepine acetate is associated with increase in the PR interval. Adverse reactionsassociated 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 lupuserythematosus or serious cardiac arrhythmias did not occur during the placebo-controlled studies ofthe epilepsy program with eslicarbazepine acetate. However, they have been reported withoxcarbazepine. Therefore, their occurrence after treatment with eslicarbazepine acetate cannot beexcluded.

There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures inpatients on long-term therapy with the structurally related antiepileptic drugs carbamazepine andoxcarbazepine. The mechanism by which bone metabolism is affected has not been identified.

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 treatedwith 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 agegroup from 6 to 11 years of age, the most common adverse reaction observed in more than twopatients 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 6years and below has not yet been established.

The safety profile of eslicarbazepine acetate was generally similar between adult and paediatricpatients, except for agitation (common, 1.3%) and abdominal pain (common, 2.1%) which were morecommon in children than in adults. Dizziness; somnolence; vertigo; asthenia; gait disturbance; tremor;ataxia; balance disorder; vision blurred; diarrhoea; rash and hyponatraemia were less common inchildren than in adults. Dermatitis allergic (uncommon, 0.8%) was reported only in the paediatricpopulation.

Long-term safety data in the paediatric population obtained from open label extensions of the phase IIIstudy was consistent with the known safety profile of the product with no new findings of concern.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Symptoms observed after an overdose of eslicarbazepine acetate are primarily associated with centralnervous symptoms (e.g. seizures of all types, status epilepticus) and cardiac disorders (e.g. cardiacarrhythmia). There is no known specific antidote. Symptomatic and supportive treatment should beadministered as appropriate. Eslicarbazepine acetate metabolites can effectively be cleared byhaemodialysis, if necessary (see section 5.2).

Pharmacotherapeutic group: Antiepileptics, carboxamide derivatives, ATC code: N03AF04

The precise mechanisms of action of eslicarbazepine acetate are unknown. However, in vitroelectrophysiological studies indicate that both eslicarbazepine acetate and its metabolites stabilise theinactivated state of voltage-gated sodium channels, precluding their return to the activated state andthereby preventing repetitive neuronal firing.

Pharmacodynamic effect

Eslicarbazepine acetate and its active metabolites prevented the development of seizures in nonclinicalmodels predictive of anticonvulsant efficacy in man. In humans, the pharmacological activity ofeslicarbazepine acetate is primarily exerted through the active metabolite eslicarbazepine.

Adult population

The efficacy of eslicarbazepine acetate as adjunctive therapy has been demonstrated in four phase IIIdouble-blind placebo-controlled studies in 1,703 randomized adult patients with partial epilepsyrefractory to treatment with one to three concomitant antiepileptic medicinal products. Oxcarbazepineand felbamate were not allowed as concomitant medicinal products in these studies. Eslicarbazepineacetate was tested at doses of 400 mg (in -301 and -302 studies only), 800 mg and 1,200 mg, oncedaily. Eslicarbazepine acetate 800 mg once daily and 1,200 mg once daily were significantly moreeffective than placebo in reducing seizure frequency over a 12-week maintenance period. Thepercentage of subjects with ≥50% reduction (1581 analyzed) in seizure frequency in the phase IIIstudies was 19.3% for placebo, 20.8% for eslicarbazepine acetate 400 mg, 30.5% for eslicarbazepineacetate 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 patientswith newly diagnosed partial-onset seizures. Eslicarbazepine acetate was tested at once-daily doses of800 mg, 1,200 mg and 1,600 mg. The doses of the active comparator, carbamazepine controlledrelease, were 200 mg, 400 mg and 600 mg, twice-daily. All subjects were randomized to the lowestdose level and only if a seizure occurred subjects were to be escalated to the next dose level. From the815 randomized patients, 401 patients were treated with eslicarbazepine acetate once-daily [271patients (67.6%) remained at dose of 800 mg, 70 patients (17.5%) remained at dose of 1,200 mg and60 patients (15.0%) were treated with 1,600 mg]. In the primary efficacy analysis, in which drop-outswere considered as non-responders, 71.1% subjects were classified as seizure free in theeslicarbazepine acetate group and 75.6% in the carbamazepine controlled release group during the26 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 oftreatment with 64.7 % eslicarbazepine acetate subjects and 70.3 % carbamazepine controlled releasesubjects 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-Meieranalysis and Cox regression), the Kaplan-Meier estimates of seizure risk at the end of the evaluationperiod was 0.06 with carbamazepine and 0.12 with eslicarbazepine acetate and by the end of 1 yearwith 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 efficacywas 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 acetatewas tested at doses of 1,200 mg and 1,600 mg once-daily. Seizure-free rates during the entire 10-weekmonotherapy 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.

The safety and efficacy of eslicarbazepine acetate as adjunctive therapy for partial seizures in elderlypatients 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 %) issimilar to the general population enrolled in the double-blind epilepsy studies (66.8%). The mostfrequent 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 tractinfection (5.6%). A total of 50 of the 72 subjects starting the study completed the 26-week treatmentperiod 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.

The efficacy and safety of eslicarbazepine acetate as adjunctive therapy for partial-onset seizures inchildren was evaluated in one phase II study in children aged from 6 to 16 years (N=123) and onephase III study in children aged from 2 to 18 years (N=304). Both studies were double-blind andplacebo 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 inpart II and 2 years in part III) and Study 305 included 4 subsequent long-term, open-label extensionperiods (1 year in Parts II, III and IV and 2 years in Part V). Eslicarbazepine acetate was tested atdoses of 20 and 30 mg/kg/day, up to a maximum of 1,200 mg/day. The target dose was 30 mg/kg/dayin study 208 and 20 mg/kg/day in study 305. Doses could be adjusted based on tolerability andtreatment response.

In the double-blind period of the phase II study, evaluation of efficacy was a secondary objective. Theleast square mean reduction in standardised seizure frequency from baseline to maintenance periodwas 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 standardisedseizure 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 theeslicarbazepine 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 andabove 6 years, as well as by dose. In children above 6 years, 36 patients (35.0%) in the eslicarbazepineacetate group compared to 29 patients (30.2%) in the placebo group were responders (p=0.4759) andthe least square mean reduction in standardised seizure frequency was higher in the eslicarbazepineacetate group compared to placebo (-24.4% versus -10.5%); however, the difference of 13.9% was notstatistically significant (p=0.1040). A total of 39% patients in study 305 were up titrated to themaximum possible dose (30 mg/kg/day). Amongst these, when excluding patients aged 6 years andyounger, 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 subgroupanalyses 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 totalresponder rate was 46.7% (steadily increasing from 44.9% (weeks 1-4) to 57.5% (weeks > 40)). Thetotal 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 medianrelative 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 baselineperiod 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 standardisedseizure 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%) thanin 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-blindpart of the study. 14 patients (9.2%) completed open-label treatment with ESL through Part V. Themost common reason for withdrawal during any part of the study was sponsor request (30 patients inpart 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 toeslicarbazepine 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 partialonset seizures (see section 4.2 for information on paediatric use).

Eslicarbazepine acetate is extensively converted to eslicarbazepine. Plasma levels of eslicarbazepineacetate 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 theamount of metabolites recovered in urine corresponded to more than 90% of an eslicarbazepine acetatedose.

Bioavailability (AUC and Cmax) is comparable for eslicarbazepine administered orally as a crushedtablet mixed in apple sauce and administered with water compared to a whole tablet.

The binding of eslicarbazepine to plasma proteins is relatively low (<40%) and independent fromconcentration. In vitro studies have shown that plasma protein binding was not relevantly affected bythe presence of warfarin, diazepam, digoxin, phenytoin and tolbutamide. The binding of warfarin,diazepam, digoxin, phenytoin and tolbutamide was not significantly affected by the presence ofeslicarbazepine.

Eslicarbazepine acetate is rapidly and extensively biotransformed to its major active metaboliteeslicarbazepine by hydrolytic first-pass metabolism. The steady state plasma concentrations areattained after 4 to 5 days of once daily dosing, consistent with an effective half-life in the order of20-24 hours. In studies in healthy subjects and epileptic adult patients, the apparent half-life ofeslicarbazepine 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 conjugatesof 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 mediatedglucuronidation was observed.

Eslicarbazepine acetate metabolites are eliminated from the systemic circulation primarily by renalexcretion, in the unchanged and glucuronide conjugate forms. In total, eslicarbazepine and itsglucuronide correspond to more than 90% of total metabolites excreted in urine, approximately twothirds in the unchanged form and one third as glucuronide conjugate.

The pharmacokinetics of eslicarbazepine acetate is linear and dose-proportional in the range400-1,200 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 withcreatinine clearance >60 ml/min (see section 4.2).

Eslicarbazepine acetate metabolites are eliminated from the systemic circulation primarily by renalexcretion. A study in adult patients with mild to severe renal impairment showed that clearance isdependent on renal function. During treatment with Zebinix dose adjustment is recommended inpatients, adult and children above 6 years of age with creatinine clearance <60 ml/min (see section4.2).

In children from 2 to 6 years of age, the use of eslicarbazepine acetate is not recommended. At this agethe intrinsic activity of the elimination process has not yet reached maturation.

Haemodialysis removes eslicarbazepine acetate metabolites from plasma.

The pharmacokinetics and metabolism of eslicarbazepine acetate were evaluated in healthy subjectsand moderately liver-impaired patients after multiple oral doses. Moderate hepatic impairment did notaffect the pharmacokinetics of eslicarbazepine acetate. No dose adjustment is recommended inpatients with mild to moderate liver impairment (see section 4.2).

The pharmacokinetics of eslicarbazepine acetate has not been evaluated in patients with severe hepaticimpairment.

Studies in healthy subjects and patients showed that pharmacokinetics of eslicarbazepine acetate werenot affected by gender.

Similar to adults, eslicarbazepine acetate is extensively converted to eslicarbazepine. Plasma levels ofeslicarbazepine 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 aneffect on volume of distribution and clearance. Furthermore, a role of age independently of weightwith regards to clearance of eslicarbazepine acetate could not be excluded, in particular for theyoungest 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 of27.5 mg/kg/day and 40 mg/kg/day are required in order to achieve exposures that are equivalent to thetherapeutic 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 between20 and 30 mg/kg/day in children above 6 years old and adults with 800 and 1200 mg ofeslicarbazepine acetate once-daily, respectively (see section 4.2).

Adverse reactions observed in animal studies occurred at exposure levels appreciably lower than theclinical exposure levels to eslicarbazepine (the principal and pharmacologically active metabolite ofeslicarbazepine acetate). Safety margins based on comparative exposure have thus not beenestablished.

Evidence of nephrotoxicity was observed in repeated dose-toxicity studies in the rat, but was not seenin studies in mice or dogs, and is consistent with an exacerbation of spontaneous chronic progressivenephropathy in this species.

Liver centrilobular hypertrophy was seen in repeated-dose toxicity studies in mice and rats and anincreased incidence of liver tumours was observed in the carcinogenicity study in mice; these findingsare consistent with an induction of hepatic microsomal enzymes, an effect which has not beenobserved in patients receiving eslicarbazepine acetate.

In repeat-dose studies in juvenile dogs, the toxicity profile was comparable to that observed in adultanimals. In the 10-month study decreases in bone mineral content, bone area and/or bone mineraldensity in lumbar vertebrae and/or femur were observed in high-dose female animals at exposurelevels 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 seenin the mouse fertility study may also indicate effects on female fertility, however, corpora lutea countswere not evaluated. Eslicarbazepine acetate was not teratogenic in the rat or rabbit, but did induceskeletal abnormalities in the mouse. Ossification delays, reduced foetal weights, an increase in minorskeletal and visceral anomalies were observed at maternal toxic doses in embryotoxicity studies inmice, rats and rabbits. A delay in the sexual development of the F1 generation was observed inperi/postnatal studies in mice and rats.

Povidone K 29/32

Croscarmellose sodium

Magnesium stearate

Not applicable.

5 years.

This medicinal product does not require any special storage conditions.

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 90tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

BIAL - Portela & Cª , SA

À Av. da Siderurgia Nacional 4745-457 S. Mamede do Coronado - Portugaltel: +351 22 986 61 00fax: +351 22 986 61 99e-mail: info@bial.com

EU/1/09/514/012-020

EU/1/09/514/025-026

Date of first authorisation: 21.04.2009

Date of latest renewal: 22.01.2014

Detailed information on this medicinal product is available on the website of the European Medicines

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