Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: 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
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 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.
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.
If Zebinix is to be discontinued it is recommended to withdraw it gradually to minimise the potential of increased seizure frequency.
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 If signs and symptoms suggestive of these reactions appear, Zebinix should be withdrawn immediately and an alternative treatment considered (as appropriate).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 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.
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 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.
Prolongations in PR interval have been observed in clinical studies with eslicarbazepine acetate. Caution should be exercised in patients with medical conditions (e.g. low levels of thyroxine, cardiac conduction abnormalities), or when taking concomitant medicinal products known to be associated with PR prolongation.
Caution should be exercised in the treatment of patients with renal impairment and the dose should be adjusted according to creatinine clearance (see section 4.2). In patients with CLCR <30 ml/min use is not recommended due to insufficient data.
As clinical data are limited in patients with mild to moderate hepatic impairment and pharmacokinetic and clinical data are missing in patients with severe hepatic impairment, 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.
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).
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 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.
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.
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.
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.
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.
Concomitant use of eslicarbazepine acetate with oxcarbazepine is not recommended because this may cause overexposure to the active metabolites.
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).
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.
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.
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 Rwarfarin 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.
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 Pglycoprotein.
Based on a structural relationship of eslicarbazepine acetate to tricyclic antidepressants, an interaction between eslicarbazepine acetate and MAOIs is theoretically possible.
It has been shown that in the offspring of women with epilepsy using an antiepileptic treatment, 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. Specialist medical advice regarding the potential risk to a foetus caused by both seizures and antiepileptic treatment should be given to all women of child-bearing potential taking antiepileptic treatment, and especially to women planning pregnancy and women who are pregnant. Sudden discontinuation of antiepileptic drug (AED) therapy should be avoided as this may lead to seizures that could have serious consequences for the woman and the unborn child. Monotherapy is preferred for treating epilepsy in pregnancy whenever possible because therapy with multiple 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 treatment has been observed. There is no data available for eslicarbazepine acetate on this risk.
Women of childbearing potential should use effective contraception during treatment with eslicarbazepine acetate. 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. Women of childbearing 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 complementary forms of contraception including a barrier method should be used. Individual circumstances should be evaluated in each case, involving the patient in the discussion, when choosing the contraception method.
There is limited amount of data from the use of eslicarbazepine acetate in pregnant women. Studies in animals have shown reproductive toxicity (see Fertility section 5.3). A risk in humans (including of major congenital malformations, neurodevelopmental disorders and other reproductive toxic effects) is unknown.
Eslicarbazepine acetate should not be used during pregnancy unless the benefit is judged to outweigh the 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 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.
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 breastfeeding should be discontinued during treatment with eslicarbazepine acetate.
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).
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.
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).
Adverse reactions associated with eslicarbazepine acetate obtained from clinical studies and postmarketing 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 | ||
| Immune system disorders | Hypersensitivity | |||
| Endocrine disorders | Hypothyroidism | |||
| Metabolism and nutrition disorders | Hyponatraemia, decreased appetite | Electrolyte imbalance, dehydration, hypochloraemia | Inappropriate ADH secretion like syndrome with signs and symptoms of lethargy, nausea, dizziness, decrease in serum (blood) osmolality, vomiting, headache, confusional state or other neurological signs and symptoms | |
| 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 | ||
| 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 | ||
| Investigations | Weight increased | Blood pressure decreased, weight decreased, blood pressure increased, blood sodium decreased, blood chloride decreased, osteocalcin increased, haematocrit decreased, haemoglobin decreased, hepatic enzymes increased | ||
| Injury, poisoning and procedural complications | Drug toxicity, fall, thermal burn |
In patients concomitantly treated with carbamazepine and eslicarbazepine acetate in placebocontrolled 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.
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.
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.
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 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.
Not applicable.
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