Special Warning : אזהרת שימוש

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

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 If signs and symptoms suggestive of these reactions appear, Zebinix should be withdrawn immediately and an alternative treatment considered (as appropriate).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 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.

Effects on Driving

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.