TRILEPTAL Film-coated tablet Ref.[50807] Active ingredients: Oxcarbazepine

Hypersensitivity

Class I (immediate) hypersensitivity reactions including rash, pruritus, urticaria, angioedema and reports of anaphylaxis have been received in the post-marketing period. Cases of anaphylaxis and angioedema involving the larynx, glottis, lips and eyelids have been reported in patients after taking the first or subsequent doses of Trileptal. If a patient develops these reactions after treatment with Trileptal, the drug should be discontinued and an alternative treatment started.

Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25-30% of these patients may experience hypersensitivity reactions (e.g. severe skin reactions) with Trileptal (see section 4.8).

Hypersensitivity reactions, including multi-organ hypersensitivity reactions, may also occur in patients without a history of hypersensitivity to carbamazepine. Such reactions can affect the skin, liver, blood and lymphatic system or other organs, either individually or together in the context of a systemic reaction (see section 4.8). In general, if signs and symptoms suggestive of hypersensitivity reactions occur, Trileptal should be withdrawn immediately.

Dermatological effects

Serious dermatological reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome) and erythema multiforme, have been reported very rarely in association with the use of Trileptal. Patients with serious dermatological reactions may require hospitalization, as these conditions may be life-threatening and very rarely be fatal. Trileptal associated cases occurred in both children and adults. The median time to onset was 19 days. Several isolated cases of recurrence of the serious skin reaction when rechallenged with Trileptal were reported. Patients who develop a skin reaction with Trileptal should be promptly evaluated and Trileptal withdrawn immediately unless the rash is clearly not drug related. In case of treatment withdrawal, consideration should be given to replacing Trileptal with other antiepileptic drug therapy to avoid withdrawal seizures. Trileptal should not be restarted in patients who discontinued treatment due to a hypersensitivity reaction (see section 4.3).

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)/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.

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 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%.

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.

Limitation of genetic screening

Genetic screening results must never substitute appropriate clinical vigilance and patient management. Many Asian patients positive for HLA-B*1502 and treated with Trileptal will not develop SJS/TEN, and patients negative for HLA-B*1502 of any ethnicity can still develop SJS/TEN. The same is true for HLA-A*3101 with respect to risk of SJS, TEN, DRESS, AGEP or maculopapular rash. The development of these severe cutaneous adverse reactions and its related morbidity due to other possible factors such as AED dose, compliance, concomitant medications, co-morbidities, and the level of dermatologic monitoring have not been studied.

Information for healthcare professionals

If testing for the presence of the HLA-B*1502 allele is performed, high-resolution “HLA-B*1502 genotyping” is recommended. The test is positive if either one or two HLA-B*1502 alleles are detected, and negative if no HLA-B*1502 alleles are detected. Similarly, if testing for the presence of the HLA-A*3101 allele is performed, high resolution “HLA-A*3101 genotyping” is recommended. The test is positive if either one or two HLA-A*3101 alleles are detected, and negative if no HLA-A*3101 alleles are detected.

Risk of seizure aggravation

Risk of seizure aggravation has been reported with Trileptal. The risk of seizure aggravation is seen especially in children but may also occur in adults. In case of seizure aggravation, Trileptal should be discontinued.

Hyponatraemia

Serum sodium levels below 125 mmol/l, usually asymptomatic and not requiring adjustment of therapy, have been observed in up to 2.7% of Trileptal treated patients. Experience from clinical trials shows that serum sodium levels returned towards normal when the Trileptal dosage was reduced, discontinued or the patient was treated conservatively (e.g. restricted fluid intake). 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 Trileptal 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 Trileptal therapy (see section 4.8), 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.

Hypothyroidism

Hypothyroidism is an adverse reaction (with “uncommon” frequency, see section 4.8) of oxcarbazepine. Considering the importance of thyroid hormones in children’s development after birth, thyroid function monitoring is recommended in the pediatric age group while on Trileptal therapy.

Hepatic function

Very rare cases of hepatitis have been reported, which in most cases resolved favourably. When a hepatic event is suspected, liver function should be evaluated and discontinuation of Trileptal should be considered. Caution should be exercised when treating patients with severe hepatic impairment (see section 4.2 and 5.2).

Renal function

In patients with impaired renal function (creatinine clearance less than 30 mL/min), caution should be exercised during Trileptal treatment especially with regard to the starting dose and up titration of the dose. Plasma level monitoring of MHD may be considered (see section 4.2 and 5.2).

Hematological effects

Rare reports of agranulocytosis, aplastic anemia and pancytopenia have been seen in patients treated with Trileptal during post-marketing experience (see section 4.8).

Discontinuation of the medicinal product should be considered if any evidence of significant bone marrow depression develops.

Suicidal behaviour

Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomized placebo controlled trials of antiepileptic medicines 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 oxcarbazepine.

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.

Hormonal contraceptives

Female patients of childbearing age should be warned that the concurrent use of Trileptal with hormonal contraceptives may render this type of contraceptive ineffective (see section 4.5). Additional non-hormonal forms of contraception are recommended when using Trileptal.

Alcohol

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

Withdrawal

As with all antiepileptic medicinal products, Trileptal should be withdrawn gradually to minimise the potential of increased seizure frequency.

Monitoring of plasma levels

Although correlations between dosage and plasma levels of oxcarbazepine, and between plasma levels and clinical efficacy or tolerability are rather tenuous, monitoring of the plasma levels may be useful in the following situations in order to rule out noncompliance or in situations where an alteration in MHD clearance is to be expected, including:

• changes in renal function (see renal impairment in section 4.2).
• pregnancy (see section 4.6 and 5).
• concomitant use of liver enzyme-inducing medicines (see section 4.5).

Enzyme induction

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 (see below), 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).

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 Trileptal or changing the dose, it may take 2 to 3 weeks to reach the new level of induction.

In case of discontinuation of Trileptal therapy, a dose reduction of the concomitant medications may be necessary and should be decided upon by clinical and/or plasma level monitoring. The induction is likely to gradually decrease over 2 to 3 weeks after discontinuation.

Hormonal contraceptives: Trileptal 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. Therefore, concurrent use of Trileptal with hormonal contraceptives may render these contraceptives ineffective (see section 4.4). Another reliable contraceptive method should be used.

Enzyme inhibition

Oxcarbazepine and MHD inhibit CYP2C19. Therefore, interactions could arise when co-administering high doses of Trileptal with medicinal products that are mainly metabolised by CYP2C19 (e.g. phenytoin). Phenytoin plasma levels increased by up to 40% when Trileptal was given at doses above 1,200 mg/day (see table below summarizing results with other anticonvulsants). In this case, a reduction of co-administered phenytoin may be required (see section 4.2).

Antiepileptic and enzyme inducing medicinal products

Potential interactions between Trileptal and other antiepileptic medicinal products were assessed in clinical studies. The effect of these interactions on mean AUCs and C_min are summarised in the following table.

Summary of antiepileptic medicinal product interactions with Trileptal:

Strong inducers of cytochrome P450 enzymes and/or UGT (i.e. rifampicin, carbamazepine, phenytoin and phenobarbitone) 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 Trileptal 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 Trileptal, 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.

No autoinduction has been observed with Trileptal.

Other medicinal product interactions

Cimetidine, erythromycin, viloxazine, warfarin and dextropropoxyphene had no effect on the pharmacokinetics of MHD.

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

Patients on tricyclic antidepressant therapy were included in clinical trials and no clinically relevant interactions have been observed.

The combination of lithium and oxcarbazepine might cause enhanced neurotoxicity.

Women of childbearing potential and contraceptive measures

Trileptal may result in a failure of the therapeutic effect of oral contraceptive medicines containing ethinylestradiol (EE) and levonorgestrel (LNG) (see section 4.4 and 4.5). Women of child bearing potential should be advised to use highly effective contraception (preferably non-hormonal; e.g. intrauterine implants) while on treatment with Trileptal.

Pregnancy

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 Trileptal 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.

Taking these data into consideration

• If women receiving Trileptal 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.
• 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 Trileptal 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.

Breast-feeding

Oxcarbazepine and its active metabolite (MHD) are excreted in human breast milk. A milk-to-plasma concentration ratio of 0.5 was found for both. The effects on the infant exposed to Trileptal by this route are not known. Therefore, Trileptal should not be used during breast-feeding.

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 (see section 5.3).

Trileptal 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 Trileptal (for complete list of ADRs see section 4.8), 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 Trileptal. In addition, clinically meaningful reports on adverse experiences from named patient programs and postmarketing experience were taken into account.

Adverse reactions (Table 1) 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).

Table 1. 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 Trileptal treated patients with frequency common (see section 4.4). 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 Trileptal, although there were patients who first developed a serum sodium level <125 mmol/l more than 1 year after initiation of therapy (see section 4.4).

Paediatric population

In general, the safety profile in children was similar to that observed in the adult population (see section 5.1).

Reporting of suspected adverse reactions

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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

Not applicable.