Epilim - Pregnancy and lactation warning - Summary of Product Characteristics

http://www.medicines.org.uk/EMC/medicine/6781/SPC/Epilim+500+Enteric+Coated/


4.6 Pregnancy and lactation


Women of childbearing potential should not be started on Epilim without specialist neurological advice.



Adequate counselling should be made available to all women with epilepsy of childbearing potential regarding the risks associated with pregnancy because of the potential teratogenic risk to the foetus (See also section 4.6.1).Women who are taking Epilim and who may become pregnant should receive specialist neurological advice and the benefits of its use should be weighed against the risks.



Epilim is the antiepileptic of choice in patients with certain types of epilepsy such as generalised epilepsy ± myoclonus/photosensitivity. For partial epilepsy, Epilim should be used only in patients resistant to other treatment.



If pregnancy is planned, consideration should be given to cessation of Epilim treatment, if appropriate.



When Epilim treatment is deemed necessary, precautions to minimize the potential teratogenic risk should be followed. (See also section 4.6.1 paragraph entitled “In view of the above”)





4.6.1 Pregnancy



- Risk associated with epilepsy and antiepileptics



In offspring born to mothers with epilepsy receiving any anti-epileptic treatment, the overall rate of malformations has been demonstrated to be higher than the rate (approximately 3 %) reported in the general population. An increased number of children with malformations have been reported in cases of multiple drug therapy. Malformations most frequently encountered are cleft lip and cardio-vascular malformations.



No sudden discontinuation in the anti-epileptic therapy should be undertaken as this may lead to breakthrough seizures which could have serious consequences for both the mother and the foetus.



Antiepileptic drugs should be withdrawn under specialist supervision.





- Risk associated with seizures



During pregnancy, maternal tonic clonic seizures and status epilepticus with hypoxia carry a particular risk of death for mother and the unborn child.





- Risk associated with valproate



In animals: teratogenic effects have been demonstrated in the mouse, rat and rabbit.



There is animal experimental evidence that high plasma peak levels and the size of an individual dose are associated with neural tube defects.



In humans: Available data suggest an increased incidence of minor or major malformations including neural tube defects, cranio-facial defects, malformations of the limbs, cardiovascular malformations, hypospadias and multiple anomalies involving various body systems in offspring born to mothers with epilepsy treated with valproate. The data suggest that the use of valproate is associated with a greater risk of certain types of these malformations (in particular neural tube defects) than some other anti-epileptic drugs.



Both valproate monotherapy and valproate as part of polytherapy are associated with abnormal pregnancy outcome. Available data suggest that antiepileptic polytherapy including sodium valproate is associated with a higher risk of abnormal pregnancy outcome than sodium valproate monotherapy.



Data have suggested an association between in-utero exposure to valproate and the risk of developmental delay (frequently associated with dysmorphic features), particularly of verbal IQ. However, the interpretation of the observed findings in offspring born to mothers with epilepsy treated with sodium valproate remains uncertain, in the view of possible confounding factors such as low maternal IQ, genetic, social, environmental factors and poor maternal seizure control during pregnancy.



Autism spectrum disorders have also been reported in children exposed to valproate in utero.





- In view of the above data



When a woman is planning pregnancy, this provides an opportunity to review the need for anti-epileptic treatment. Women of child-bearing potential should be informed of the risks and benefits of the use of Epilim during pregnancy. Specialist advice is required and physicians are strongly encouraged to discuss reproductive issues with their patients before Epilim is prescribed for the first time or a woman already treated with Epilim is planning a pregnancy.



Folate supplementation, prior to pregnancy, has been demonstrated to reduce the incidence of neural tube defects in the offspring of women at high risk. Although no direct evidence exists of such effects in women receiving anti-epileptic drugs, women should be advised to start taking folic acid supplementation (5mg) as soon as contraception is discontinued.



The available evidence suggests that anticonvulsant monotherapy is preferred. Dosage should be reviewed before conception and the lowest effective dose used, in divided doses, as abnormal pregnancy outcome tends to be associated with higher total daily dosage and with the size of an individual dose. The incidence of neural tube defects rises with increasing dosage, particularly above 1000mg daily. The administration in several divided doses over the day and the use of a prolonged release formulation is preferable in order to avoid high peak plasma levels.



During pregnancy, Epilim anti-epileptic treatment should not be discontinued without reassessment of the benefit/risk.



Nevertheless, specialised prenatal monitoring should be instituted in order to detect the possible occurrence of a neural tube defect or any other malformation. Pregnancies should be carefully screened by ultrasound, and other techniques if appropriate (see Section 4.4 Special Warnings and Precautions for use).





- Risk in the neonate



Very rare cases of haemorrhagic syndrome have been reported in neonates whose mothers have taken Epilim during pregnancy. This haemorrhagic syndrome is related to hypofibrinogenemia; afibrinogenemia has also been reported and may be fatal. These are possibly associated with a decrease of coagulation factors. However, this syndrome has to be distinguished from the decrease of the vitamin-K factors induced by phenobarbital and other anti-epileptic enzyme inducing drugs.



Therefore, platelet count, fibrinogen plasma level, coagulation tests and coagulation factors should be investigated in neonates.





4.6.2 Lactation





Excretion of Epilim in breast milk is low, with a concentration between 1 % to 10 % of total maternal serum levels. Although there appears to be no contra-indication to breastfeeding, physicians are advised that in any individual case, consideration should be given to the safety profile of Epilim, specifically haematological disorders (see section 4.8 Undesirable Effects).