CRIZEPINE

Epilepsies

In adults

· either as monotherapy;

· or in association with another anti-epileptic treatment;

· treatment of partial epilepsies with or without secondary generalization;

· treatment of generalized epilepsies: tonic-clonic seizures.

In children

· either as monotherapy;

· or in association with another anti-epileptic treatment;

· treatment of partial epilepsies with or without secondary generalization;

· treatment of generalized epilepsies: tonic-clonic seizures.

Psychiatry

· Prevention of relapses in the context of bipolar disorders, notably in patients presenting with relative resistance, contraindications or intolerance to lithium.

· Treatment of manic or hypomanic states.

Pain

· Treatment of trigeminal and glossopharyngeal neuralgias.

· Treatment of neuropathic pain in adults.

Pregnancy

Risks associated with anti-epileptic drugs in general

Specialised medical advice concerning the potential risks to the foetus caused by both epileptic seizures and anti-epileptic treatment must be given to all women of childbearing potential who are taking anti-epileptic treatment, in particular to women planning a pregnancy and to pregnant women.

Abrupt discontinuation of treatment with an anti-epileptic drug must be avoided as it may lead to seizures that are liable to have serious consequences for the woman and the unborn child.

Monotherapy should be preferred for the treatment of epilepsy during pregnancy, as far as possible.

Indeed, polytherapy with anti-epileptics may be associated with a higher risk of congenital malformations than monotherapy; this risk varies according to the co-administered anti-epileptics.

Risks related to carbamazepine

In the human species, carbamazepine crosses the placenta. Prenatal exposure to carbamazepine may increase the risks of congenital malformations and other adverse effects on development. In the human species, exposure to carbamazepine during pregnancy is associated with a frequency of major congenital malformations 2 to 3 times higher than that of the general population, which is 2 to 3 %. The most commonly encountered malformations are neural tube defects (spina bifida), craniofacial anomalies (including cleft lip/palate), cardiovascular malformations, hypospadias, finger hypoplasia, microcephaly and other anomalies involving different organs have been reported in children of women treated with carbamazepine during pregnancy. Data from an observational study based on population registries conducted in the Nordic countries suggest an increased risk of children born with small weight for gestational age (SGA; defined as a birth weight below the 10th percentile for sex and gestational age) after prenatal exposure to carbamazepine. The risk of SGA in children of epileptic women treated with carbamazepine was 12,8 %, versus 10,9 % in children of epileptic women not receiving anti-epileptic treatment. Specialised prenatal monitoring of these malformations and growth retardation is recommended.

Neurodevelopmental disorders have been reported in children born to epileptic women taking carbamazepine alone or in association with other anti-epileptics during pregnancy. Studies relating to the risk of neurodevelopmental disorders in children exposed to carbamazepine during pregnancy are contradictory and do not allow for the exclusion of a risk.

Carbamazepine must not be used during pregnancy, unless the benefit is judged to outweigh the risks after careful examination of the available therapeutic alternatives. The woman must be fully informed and understand the risks associated with taking carbamazepine during pregnancy.

Available data suggest that the risk of malformation associated with carbamazepine may be dose-dependent. If, based on a careful assessment of risks and benefits, no appropriate therapeutic alternative is available, and carbamazepine treatment is continued, monotherapy and the lowest effective dose of carbamazepine should be used and monitoring of plasma levels is recommended. Plasma concentration could be maintained in the lower part of the therapeutic range from 4 to 12 microgrammes/mL, provided that seizure control is maintained.

It has been reported that certain anti-epileptic drugs, such as carbamazepine, decrease serum folate levels. This deficiency may contribute to the increased incidence of congenital malformations in the offspring of treated women with epilepsy. Folic acid supplementation is recommended before and during pregnancy. In order to prevent bleeding disorders in the offspring, it has also been recommended to administer vitamin K1 to the mother during the last weeks of pregnancy, as well as to the newborn.

If a woman is planning a pregnancy, every effort should be made to switch to an appropriate alternative treatment before conception and before stopping contraception. If a woman becomes pregnant while taking carbamazepine, she should be referred to a specialist to reassess carbamazepine treatment and consider therapeutic alternatives.

Female children and adolescents, women of childbearing potential

Carbamazepine should not be used in women of childbearing potential, unless the potential benefit is judged to outweigh the risks after careful examination of available therapeutic alternatives. The woman must be fully informed and understand the risk of potential harm to the fetus if carbamazepine is taken during pregnancy and, consequently, the importance of planning a pregnancy. A pregnancy test in women of childbearing potential should be considered before starting carbamazepine treatment.

At the start of treatment, and once a year, the doctor ensures that carbamazepine treatment is the best option for the patient and signs a shared information attestation with her.

Women of childbearing potential must use effective contraception during treatment and for two weeks after stopping treatment. Due to the enzyme-inducing effect of carbamazepine, treatment with TEGRETOL may lead to failure of hormonal contraceptives (see section 4.5). Consequently, women of childbearing potential should be advised on the use of other effective contraceptive methods.

At least one effective method of contraception (such as an intrauterine device) or two complementary forms of contraception, including a mechanical method of contraception (for example a condom), must be used. Individual circumstances should be assessed in each case, involving the patient in the discussion, when choosing the method of contraception.

Prescribers must ensure that the parents / guardians of female children and adolescents treated with carbamazepine understand the need to contact a specialist as soon as first menstruation occurs (menarche). The patient and her parents / guardians should then receive complete information on the risks associated with in utero exposure to carbamazepine and on the need to use highly effective contraception as soon as necessary. The need to continue carbamazepine treatment must be reassessed and therapeutic alternatives must also be considered.

Before childbirth / In the newborn:

Enzyme-inducing antiepileptics can sometimes cause in the newborn of a treated mother:

· a hemorrhagic syndrome that can occur during childbirth or in the first days of life. Prevention by oral vitamin K1 in the mother in the month preceding childbirth and the administration of vitamin K1 by parenteral route (IM or slow IV) at birth, in the newborn, seem effective. A normal hemostasis profile in the mother does not allow for the elimination of hemostasis abnormalities in the newborn.

· disturbances of phosphocalcic metabolism and bone mineralization, which vitamin D supplementation of the mother during the 3rd trimester seems able to prevent.

Postnatal follow-up / In the child: in case of exposure during pregnancy, close monitoring of the neurobehavioral development of the child must be established and appropriate management must be put in place as soon as possible if necessary.

Breastfeeding

Breastfeeding is not recommended due to the non-negligible passage of carbamazepine into breast milk and the possibility of occurrence of hepatic disorders in breastfed newborns.

Fertility

Not applicable

TEGRETOL 200 mg, scored tablet has a moderate influence on the ability to drive vehicles and use machines.

Attention is drawn, particularly in vehicle drivers and machine users, to the risks associated with epileptic seizures, as well as the following adverse effects: dizziness, drowsiness, sensations of vertigo, ataxia, accommodation disorders, diplopia and blurred vision, associated with the use of carbamazepine.