Oxcarbazepine

The interaction between oxcarbazepine and MAOIs is theoretically possible based on a structural relationship of oxcarbazepine to tricyclic antidepressants.

In vitro, oxcarbazepine and MHD are weak inducers of UDP-glucuronyl transferases (effects on specific enzymes in this family are not known). Therefore, in vivo oxcarbazepine and MHD may have a small inducing effect on the metabolism of medicinal products which are mainly eliminated by conjugation through the UDP-glucuronyl transferases. When initiating treatment with oxcarbazepine or changing the dose, it may take 2 to 3 weeks to reach the new level of induction.

Oxcarbazepine and MHD inhibit CYP2C19. Therefore, interactions could arise when co-administering high doses of oxcarbazepine with medicinal products that are mainly metabolised by CYP2C19 (e.g. phenytoin). Phenytoin plasma levels increased by up to 40% when oxcarbazepine was given at doses above 1,200 mg/day. In this case, a reduction of co-administered phenytoin may be required.

Oxcarbazepine and its pharmacologically active metabolite (the monohydroxy derivative, MHD) are weak inducers in vitro and in vivo of the cytochrome P450 enzymes CYP3A4 and CYP3A5 responsible for the metabolism of a very large number of medicines, for example, immunosuppressants (e.g. ciclosporin, tacrolimus), oral contraceptives, and some other antiepileptic medicinal products (e.g. carbamazepine) resulting in a lower plasma concentration of these medicinal products (see table below summarizing results with other antiepileptic medicinal products).

Summary of antiepileptic medicinal product interactions with oxcarbazepine:

In patients with impaired renal function (creatinine clearance less than 30 ml/min) oxcarbazepine therapy should be initiated at half the usual starting dose (300 mg/day) and increased, in at least weekly intervals, to achieve the desired clinical response.

Dose escalation in renally impaired patients may require more careful observation.

Caution should be exercised if alcohol is taken in combination with oxcarbazepine therapy, due to a possible additive sedative effect.

Strong inducers of cytochrome P450 enzymes and/or UGT (i.e. rifampicin, carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma/serum levels of MHD (29-49%) in adults; in children 4 to 12 years of age, MHD clearance increased by approximately 35% when given one of the three enzyme-inducing antiepileptic medicinal products compared to monotherapy. Concomitant therapy of oxcarbazepine and lamotrigine has been associated with an increased risk of adverse events (nausea, somnolence, dizziness and headache). When one or several antiepileptic medicinal products are concurrently administered with oxcarbazepine, a careful dose adjustment and/or plasma level monitoring may be considered on a case by case basis, notably in paediatric patients treated concomitantly with lamotrigine.

Oxcarbazepine has not been studied in patients with severe hepatic impairment, therefore, caution should be exercised when dosing severely impaired patients.

Female patients of childbearing age should be warned that the concurrent use of oxcarbazepine with hormonal contraceptives may render this type of contraceptive ineffective. Additional non-hormonal forms of contraception are recommended when using oxcarbazepine.

Oxcarbazepine was shown to have an influence on the two components, ethinylestradiol (EE) and levonorgestrel (LNG), of an oral contraceptive. The mean AUC values of EE and LNG were decreased by 48-52% and 32-52% respectively.

The combination of lithium and oxcarbazepine might cause enhanced neurotoxicity.

In patients with pre-existing renal conditions associated with low sodium levels (e.g. inappropriate ADH secretion like syndrome) or in patients treated concomitantly with sodium-lowering medicinal products (e.g. diuretics, desmopressin) as well as NSAIDs (e.g. indometacin), serum sodium levels should be measured prior to initiating therapy. Thereafter, serum sodium levels should be measured after approximately two weeks and then at monthly intervals for the first three months during therapy, or according to clinical need. These risk factors may apply especially to elderly patients. For patients on oxcarbazepine therapy when starting on sodium-lowering medicinal products, the same approach for sodium checks should be followed. In general, if clinical symptoms suggestive of hyponatraemia occur on oxcarbazepine therapy, serum sodium measurement may be considered. Other patients may have serum sodium levels assessed as part of their routine laboratory studies.

All patients with cardiac insufficiency and secondary heart failure should have regular weight measurements to determine occurrence of fluid retention. In case of fluid retention or worsening of the cardiac condition, serum sodium levels should be checked. If hyponatraemia is observed, water restriction is an important counter-measurement. As oxcarbazepine may, very rarely, lead to impairment of cardiac conduction, patients with pre-existing conduction disturbances (e.g. atrioventricular-block, arrhythmia) should be followed carefully.

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 generalised 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%.

HLA-A*3101 allele – Other descents

The frequency of this allele is estimated to be less than 5% in the majority of Australian, Asian, African and North American populations with some exceptions within 5 to 12%. Frequency above 15% has been estimated in some ethnic groups in South America (Argentina and Brazil), North America (US Navajo and Sioux, and Mexico Sonora Seri) and Southern India (Tamil Nadu) and between 10% to 15% in other native ethnicities in these same regions.

Allele frequencies refer to the percentage of chromosomes in the population that carry a given allele. Since a person carries two copies of each chromosome, but even one copy of the HLA-A*3101 allele may be enough to increase the risk of SJS, the percentage of patients who may be at risk is nearly twice the allele frequency.

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.

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)/toxic epidermal necrolysis (TEN), when treated with carbamazepine. The chemical structure of oxcarbazepine 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/TEN after treatment with oxcarbazepine. There are some data that suggest that such an association exists for oxcarbazepine. 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 a chemically-related active substance. If patients of these origins are tested positive for HLA-B*1502 allele, the use of oxcarbazepine 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.

The prevalence of the HLA-B*1502 allele is negligible in e.g. European descent, African, Hispanic populations sampled, and in Japanese and Koreans (<1%).

Allele frequencies refer to the percentage of chromosomes in the population that carry a given allele. Since a person carries two copies of each chromosome, but even one copy of the HLA-B* 1502 allele may be enough to increase the risk of SJS, the percentage of patients who may be at risk is nearly twice the allele frequency.

Risk related to epilepsy and antiepileptic medicinal products in general

In the treated population, an increase in malformations has been noted with polytherapy, particularly in polytherapy including valproate.

Moreover, effective anti-epileptic therapy must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.

Risk related to oxcarbazepine

There is moderate amount of data on pregnant women (300-1000 pregnancy outcomes). However, the data on oxcarbazepine associated with congenital malformation is limited. There is no increase in the total rate of malformations with oxcarbazepine as compared with the rate observed in the general population (2-3%). Nevertheless, with this amount of data, a moderate teratogenic risk cannot be completely excluded. Study results related to the risk of neurodevelopmental disorders in children exposed to oxcarbazepine during pregnancy are conflicting and a risk cannot be excluded.

Data from an observational population-based registry study from the Nordic countries suggests an increased risk for children being born small for gestational age (SGA; defined as birth weight below the 10^th percentile for their sex and gestational age) following prenatal exposure to oxcarbazepine. The risk of SGA in children of women with epilepsy receiving oxcarbazepine was 15.2% compared with 10.9% in children of women with epilepsy not receiving an anti-seizure medication.

Taking these data into consideration:

• If women receiving oxcarbazepine become pregnant or plan to become pregnant, the use of this product 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. The potential for congenital abnormalities in the offspring of women treated with combination therapies is greater than those receiving monotherapy.
• During pregnancy, an effective antiepileptic oxcarbazepine treatment must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.

Monitoring and prevention

Some 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 proved, a specific antenatal diagnosis should be offered even for women with a supplementary treatment of folic acid.

Data from a limited number of women indicate that plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxy derivative (MHD), may gradually decrease throughout pregnancy. It is recommended that clinical response should be monitored carefully in women receiving oxcarbazepine treatment during pregnancy to ensure that adequate seizure control is maintained. Determination of changes in MHD plasma concentrations should be considered. If dosages have been increased during pregnancy, postpartum MHD plasma levels may also be considered for monitoring.

In the newborn child

Bleeding disorders in the newborn have been reported with hepatic inductor antiepileptic medicines. As a precaution, vitamin K1 should be administered as a preventive measure in the last few weeks of pregnancy and to the newborn.

Oxcarbazepine and its active metabolite (MHD) are excreted in human breast milk. Limited data indicate that the breastfed infants' MHD plasma concentrations are 0.2-0.8 μg/ml, corresponding to up to 5% of the maternal MHD plasma concentration. Although exposure appears to be low, a risk to the infant cannot be excluded. Therefore, a decision whether to breastfeed while using oxcarbazepine should take into consideration both the benefit of breastfeeding and the potential risk of side effects in the infant. If breastfed, the infant should be monitored for adverse effects such as drowsiness and poor weight gain.

Women of childbearing potential and contraceptive measures

Oxcarbazepine may result in a failure of the therapeutic effect of oral contraceptive medicines containing ethinylestradiol (EE) and levonorgestrel (LNG). Women of child bearing potential should be advised to use highly effective contraception (preferably non-hormonal; e.g. intrauterine implants) while on treatment with oxcarbazepine.

Fertility

There are no human data on fertility.

In rats, oxcarbazepine had no effects on fertility. Effects on reproductive parameters in female rats were observed for MHD at doses comparable to those in humans.

Oxcarbazepine has moderate influence on the ability to drive and use machines. Adverse reactions such as dizziness, somnolence, ataxia, diplopia, blurred vision, visual disturbances, hyponatremia and depressed level of consciousness were reported with oxcarbazepine, especially at the start of treatment or in connection with dose adjustments (more frequently during the up titration phase). Patients should therefore exercise due caution when driving a vehicle or operating machinery.

Summary of the safety profile

The most commonly reported adverse reactions are somnolence, headache, dizziness, diplopia, nausea, vomiting and fatigue occurring in more than 10% of patients.

The safety profile is based on adverse events from clinical trials assessed as related to oxcarbazepine. In addition, clinically meaningful reports on adverse experiences from named patient programs and postmarketing experience were taken into account.

Adverse reactions (table) are listed by MedDRA system organ class.

Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent first. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category, using the following convention (CIOMS III) is also provided for each adverse reaction: very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Adverse reactions:

Description of selected adverse reactions

^# Hypersensitivity (including multi-organ hypersensitivity) characterised by features such as rash, fever. Other organs or systems may be affected such as blood and lymphatic system (e.g. eosinophilia, thrombocytopenia, leucopenia, lymphadenopathy, splenomegaly), liver (e.g. hepatitis, abnormal liver function tests), muscles and joints (e.g. joint swelling, myalgia, arthralgia), nervous system (e.g. hepatic encephalopathy), kidneys (e.g. renal failure, nephritis interstitial, proteinuria), lungs (e.g. pulmonary oedema, asthma, bronchospasms, interstitial lung disease, dyspnea), angioedema.

^† Serum sodium levels below 125 mmol/l have been observed in up to 2.7% of oxcarbazepine treated patients with frequency common. In most cases, the hyponatriaemia is asymptomatic and does not require adjustment of therapy,

Very rarely, the hyponatraemia is associated with signs and symptoms such as seizures, encephalopathy, depressed level of consciousness, confusion, (see also Nervous system disorders for further undesirable effects), vision disorders (e.g. blurred vision), hypothyroidism, vomiting, and nausea. Low serum sodium levels generally occurred during the first 3 months of treatment with oxcarbazepine, although there were patients who first developed a serum sodium level <125 mmol/l more than 1 year after initiation of therapy.

Paediatric population

In general, the safety profile in children was similar to that observed in the adult population.