Trileptal 300mg. 600mg FC tablets

TRILEPTAL is indicated for the treatment of partial seizures with or without secondary generalised seizures and generalised tonic-clonic seizures, in adults and in children aged 1 month and above.

TRILEPTAL may be used as monotherapy or adjunctive therapy in adults and in children of 1 month of age and above.

TRILEPTAL is suitable for use either as monotherapy or in combination with other anti-epileptic medicinal products. In mono- and adjunctive therapy, treatment with TRILEPTAL is initiated with a clinically effective dose given in two divided doses. The dose may be increased depending on the clinical response of the patient. When other antiepileptic medicinal products (AEMPs) are replaced by TRILEPTAL, the dose of the concomitant AEMP(s) should be reduced gradually on initiation of TRILEPTAL therapy. In adjunctive therapy, as the total antiepileptic medicinal products load of the patient is increased, the dose of concomitant AEMP(s) may need to be reduced and/or the TRILEPTAL dose increased more slowly (see section 4.5).

TRILEPTAL can be taken with or without food.

Method of administration:

The following dosing recommendations apply to all patients, in the absence of impaired renal function (see section 5.2).

Drug plasma level monitoring is not necessary to optimise TRILEPTAL therapy. The tablets are scored and can be broken in two halves in order to make it easier for the patients to swallow the tablet.

Therapeutic drug monitoring

The therapeutic effect of oxcarbazepine is primarily exerted through the active metabolite 10-monohydroxy derivative (MHD) of oxcarbazepine (see section 5). Plasma level monitoring of oxcarbazepine or MHD is not routinely warranted. However, plasma level monitoring of MHD may be considered during TRILEPTAL therapy 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 section 4.2)
• pregnancy (see section 4.6)
• concomitant use of liver enzyme-inducing drugs (see section 4.5)

If any of these situations apply, the dose of TRILEPTAL may be adjusted (based on plasma levels measured 2 - 4 hours post dose) to maintain peak MHD plasma levels < 35 mg/L.

Adults:

Monotherapy and adjunctive therapy:

Initial dose TRILEPTAL should be initiated with a dose of 600 mg/day (8 - 10 mg/kg/day) given in 2 divided doses.

Maintenance dose Good therapeutic effects are seen at doses between 600 mg/day and 2400 mg/day. If clinically indicated, the dose may be increased by a maximum of 600 mg/day increments at approximately weekly intervals from the starting dose to achieve the desired clinical response.

Maximum recommended dose In a controlled hospital setting, dose increases up to 2400 mg/day have been achieved over 48 hours. Most adult patients are controlled on dosages of 900 - 1200 mg/day.

Daily doses from 600 to 2400 mg/day have been shown to be effective in a controlled adjunctive therapy trial, although most patients were not able to tolerate the 2400 mg/day dose without reduction of concomitant anti-epileptic drugs, mainly because of CNS-related adverse events. Daily doses above 2400 mg/day have not been studied systematically in clinical trials.

Elderly (65 years or above): Dosages in the elderly may need to be reduced based on decreased renal function. Close monitoring of sodium levels is required in patients at risk of hyponatremia (see section 4.4).

Children:

Initial dose In mono- and adjunctive therapy, TRILEPTAL should be initiated with a dose of 8 - 10 mg/kg/day given in 2 divided doses.

Maintenance dose The target maintenance dose of TRILEPTAL for adjunctive therapy is 30 - 46 mg/kg/day and should be achieved over two weeks. In an adjunctive therapy trial in paediatric patients (aged 3 to 17 years), in which the intention was to reach a target daily dose of 46 mg/kg/day, the median daily dose was 31 mg/kg/day with a range of 6 to 51 mg/kg/day. In an adjunctive therapy trial in paediatric patients (aged 1 month to less than 4 years) in which the intention was to reach a target daily dose of 60 mg/kg/day, 56 % of patients reached a final dose of at least 55 mg/kg/day.

Maximum recommended dose If clinically indicated, the dose may be increased by a maximum of 10 mg/kg/day increments at approximately weekly intervals from the starting dose to a maximum daily dose of 60 mg/kg/day, to achieve the desired clinical response.

Effect of weight adjusted MHD clearance on paediatric dosage Under adjunctive therapy and monotherapy, when normalised by body weight, apparent clearance (L/hr/kg) decreased with age such that children 1 month to less than 4 years of age may require twice the TRILEPTAL dose per body weight compared to adults; and children 4 to 12 years of age may require a 50 % higher oxcarbazepine dose per body weight compared to adults (see section 5.2).

For children 1 month to less than 4 years of age, the influence of enzyme-inducing antiepileptic medicinal products on their weight-normalised apparent clearance appeared higher compared to older children.

Effect of concomitant enzyme-inducing antiepileptic drugs on paediatric dosage For children 1 month to less than 4 years of age, about 60 % higher TRILEPTAL dose per body weight may be required for adjunctive therapy on enzyme-inducing antiepileptic medicinal products relative to monotherapy or adjunctive therapy with non-enzyme-inducing antiepileptic medicinal products. For older children on enzyme-inducing antiepileptic medicinal products, only a slightly higher dose per body weight may be required than their counterparts on monotherapy.

TRILEPTAL has not been studied in controlled clinical trials in children below 1 month of age.

Patients with hepatic impairment: No dosage adjustment is required for patients with mild to moderate hepatic impairment. TRILEPTAL has not been studied in patients with severe hepatic impairment, therefore, caution should be exercised when dosing severely impaired patients (see section 5.2).

Patients with renal impairment: In patients with impaired renal function (creatinine clearance less than 30 mL/min) TRILEPTAL therapy should be initiated at half the usual starting dose (300 mg/day) and increased slowly to achieve the desired clinical response (see section 5.2).

Known hypersensitivity to oxcarbazepine or eslicarbazepine or to any of the excipients.

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 medication 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 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). If signs and symptoms suggestive of hypersensitivity reactions (e.g. severe skin reactions) occur, TRILEPTAL should be withdrawn immediately.

Dermatological effects: Serious dermatological reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyellu2019s syndrome) and erythema multiforme, have been reported in association with TRILEPTAL use. Patients with serious dermatological reactions may require hospitalisation, 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. Should a patient develop a skin reaction with TRILEPTAL, consideration should be given to discontinuing TRILEPTAL and prescribing another anti-epileptic medication. Patients should be made aware of early toxic signs of the above-mentioned reactions, e.g. fever, rash, lesions in the mouth, bruising, purpura. They should be advised to contact their doctor immediately if such a reaction appears.

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

Withdrawal: TRILEPTAL should be withdrawn gradually to minimise the potential of increased seizure frequency. If TRILEPTAL has to be discontinued abruptly, e.g. owing to severe adverse reactions, the change-over to another anti-epileptic preparation should be effected under cover of suitable medication (e.g. diazepam i.v.; rectal; phenytoin i.v.) and under close supervision.

TRILEPTAL should be given only under medical supervision.

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. If clinical intervention is considered, 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 or in patients treated concomitantly with sodium-lowering medicinal products (e.g. diuretics, medicinal products associated with inappropriate ADH secretion), 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 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 should be checked. If hyponatraemia is observed, water restriction is an important counter-measurement. As TRILEPTAL may lead to impairment of cardiac conduction, patients with pre-existing conduction disturbances (e.g. AV-block, dysrhythmia) should be followed carefully.

If during treatment, low or decreased white blood cell or platelet counts are observed, the complete blood count and the patient should be monitored closely. TRILEPTAL should be discontinued if any evidence of significant bone-marrow depression appears.

Hypothyroidism: Hypothyroidism is a very rare adverse drug reaction of oxcarbazepine. Considering the importance of thyroid hormones in childrenu2019s development after birth, it is advisable to perform a thyroid function test before the start of TRILEPTAL therapy in the paediatric age group, especially in children aged two years or below. Thyroid function monitoring is recommended in the paediatric age group while on TRILEPTAL therapy.

Hepatic function: Cases of hepatitis have been reported, which in most of the cases resolved favourably. In case of suspected hepatitis, discontinuation of TRILEPTAL should be considered. Caution should be exercised when treating patients with severe hepatic impairment (see section 4.2).

Haematological effects: Agranulocytosis, aplastic anaemia and pancytopenia have been reported in patients treated with TRILEPTAL during post-marketing experience (see section 4.8). However, due to the very low incidence of these conditions and confounding factors (e.g. underlying disease, concomitant medication), causality cannot be established. Discontinuation of the medicine should be considered if any evidence of significant bone marrow depression develops.

Suicidal ideation and behaviour: Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications. A meta-analysis of randomised placebo-controlled trials of antiepileptic medicines, including TRILEPTAL, has shown a small increased risk of suicidal ideation and behaviour. The mechanism of this risk is not known. Therefore, patients should be monitored for signs of suicidal ideation and behaviour 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. Patients with renal dysfunction and elderly patients should be carefully monitored as they are at higher risk of adverse reactions (see section 5.2). TRILEPTAL has a low enzyme-inducing potential. If, in patients on adjunctive therapy, carbamazepine or other antiepileptics with enzyme-inducing properties are withdrawn and replaced by TRILEPTAL, serum concentrations of the concurrent antiepileptic medicine should be monitored to avoid possible toxicity; it may be necessary to reduce the dosage of the antiepileptic co-medication (see section 4.5).

In vitro and in vivo studies demonstrate that TRILEPTAL has a low potential for interactions with other medicines.

Enzyme inhibition: TRILEPTAL was evaluated in human liver microsomes to determine its capacity to inhibit the major cytochrome P450 enzymes responsible for the metabolism of other medicinal products. The results demonstrate that TRILEPTAL and its pharmacologically active metabolite (the monohydroxy derivative, MHD) have little or no capacity to function as inhibitors for most of the human cytochrome P450 enzymes evaluated (CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11) with the exception of CYP2C19. Therefore, interactions could arise when co-administering high doses of TRILEPTAL with medicinal products that are metabolised by CYP2C19 (e.g. phenobarbitone, phenytoin). In some patients treated with TRILEPTAL and medicinal products metabolised via CYP2C19 a reduction of the co-administered medicinal product might be necessary.

Enzyme induction: In vitro, the UDP-glucuronyl transferase level was increased, indicating induction of this enzyme. An increase of 22 % with MHD and 47 % with TRILEPTAL were observed. TRILEPTAL and MHD are weak inducers of UDP-glucuronyl transferase and therefore, in vivo they are unlikely to have an effect on medicinal products which are mainly eliminated by conjugation through the UDP-glucuronyl transferases (e.g. valproic acid, lamotrigine). Even in view of the weak induction potential of TRILEPTAL and MHD, a higher dose of concomitantly used medicinal products which are metabolised via CYP3A4 or via conjugation (UDPGT) may be necessary. In case of discontinuation of TRILEPTAL therapy, a dose reduction of the concomitant medication may be necessary.

Induction studies conducted with human hepatocytes confirmed TRILEPTAL and MHD as weak inducers of isoenzymes of the 2B and 3A4 CYP sub-family. The induction potential of TRILEPTAL / MHD on other CYP isoenzymes is not known.

TRILEPTAL and MHD induce in vitro and in vivo, a subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists, oral contraceptives, and antiepileptic medicinal products (e.g. carbamazepine) resulting in a lower plasma concentration of these medicinal products (see below). Such level of decrease in plasma concentrations may also be observed in other medicines mainly metabolised by CYP3A4 and CYP3A5, for example immunosuppressants (e.g. ciclosporin).

Antiepileptic medicinal products: Potential interactions between TRILEPTAL and other antiepileptic medicinal products (AEMPs) 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 products interactions with TRILEPTAL In vivo, the plasma levels of phenytoin increased by up to 40 %, when TRILEPTAL was given at doses above 1200 mg/day. Therefore, when using doses of TRILEPTAL greater than 1200 mg/day during adjunctive therapy, a decrease in the dose of phenytoin may be required. The increase of phenobarbitone level, however, is small (15 %) when given 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 levels of MHD (29 u2013 49 %). No auto-induction has been observed with TRILEPTAL.

Pregnancy: Data on a limited number of pregnancies indicate that TRILEPTAL may cause serious birth defects (e.g. cleft palate) when administered during pregnancy. In animal studies, increased embryo mortality, delayed growth and malformations were observed. Taking these data into consideration:

• If women receiving TRILEPTAL become pregnant, plan to become pregnant, or if the need to initiate treatment with TRILEPTAL arises during pregnancy, the medicinal productsu2019 potential benefits must be carefully weighed against the potential risk of foetal malformations. (e.g. cleft palate). This is particularly important during the first three months of pregnancy.
• Minimum effective doses should be given.
• In women of childbearing age, TRILEPTAL should be administered as monotherapy, whenever possible.
• Patients should be counselled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening.
• During pregnancy, antiepileptic treatment must not be interrupted, since the aggravation of the illness is detrimental to both the mother and the foetus.

Monitoring and prevention: Antiepileptic medicinal products such as TRILEPTAL may contribute to folic acid deficiency, a possible contributory cause of foetal abnormality. Folic acid supplementation is recommended before and during pregnancy. Due to physiological changes during pregnancy, plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxyderivative (MHD), may gradually decrease throughout pregnancy. It is recommended that clinical response should be monitored carefully in women receiving TRILEPTAL treatment during pregnancy and determination of changes in MHD plasma concentrations should be considered to ensure that adequate seizure control is maintained throughout pregnancy. Postpartum MHD plasma levels may also be considered for monitoring especially in the event that medication was increased during pregnancy.

In the newborn child: Bleeding disorders in the newborn caused by antiepileptic agents have been reported. As a precaution, vitamin K 1 should be administered as a preventive measure in the last few weeks of pregnancy and to the newborn.

TRILEPTAL and its active metabolite (MHD) cross the placenta. Neonatal and maternal plasma MHD concentrations were similar in one case.

Lactation: TRILEPTAL and its active metabolite are excreted in breast milk. A milk-to-plasma concentration ratio of 0,5 were found for both. The effects on the infant exposed to TRILEPTAL by this route are unknown. Therefore, breastfeeding while taking TRILEPTAL is not recommended.

Infertility: There are no human data on fertility. In rats, fertility in both sexes was unaffected by oxcarbazepine or MHD at oral doses up to 150 and 450 mg/kg/day, respectively. However, disruption of oestrous cyclicity and reduced numbers of corpora lutea, implantations and live embryos were observed in female animals at the highest dose of MHD.

Adverse reactions such as dizziness, somnolence, ataxia, diplopia, blurred vision, visual disturbances, hyponatremia and depressed level of consciousness were reported with TRILEPTAL (for the complete list of Undesirable effects, 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.

The most commonly reported adverse reactions are somnolence, headache, dizziness, diplopia, nausea, vomiting and fatigue occurring in more than 10 % of patients. In clinical trials, adverse events (AEs) were generally mild to moderate in severity, of transient nature and occurred predominantly at the start of treatment. The analysis of the undesirable effect profile by body system is based on AEs from clinical trials assessed as related to TRILEPTAL. In addition, clinically meaningful reports on adverse experiences from named patient programs and post-marketing experience were taken into account. Adverse reactions are ranked under heading of frequency, the most frequent first, using the following convention: very common: ( u2265 1/10); common: ( u2265 1/100 - <1/10); uncommon: ( u2265 1/1,000 - <1/100); rare: ( u2265 1/10,000 - <1/1,000); very rare: (<1/10,000), including isolated reports.

Blood and lymphatic system disorders

• Uncommon Leucopenia.
• Very rare Bone marrow depression, aplastic anaemia, agranulocytosis, pancytopenia, thrombocytopenia, neutropenia.

Immune system disorders

• Very rare Anaphylactic 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); muscle and joints (e.g. joint swelling, myalgia, arthralgia); nervous system (e.g. hepatic encephalopathy); kidney (e.g. renal failure, nephritis interstitial, proteinurea; lungs (e.g. pulmonary oedema, asthma, bronchospasms, interstitial lung disease, dyspnoea); angioedema.

Endocrine disorders

• Common Weight increased.
• Very rare Hypothyroidism.

Metabolism and nutrition disorders

• Common Hyponatraemia.
• Very rare Hyponatraemia 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), vomiting, and nausea, folic acid deficiency and hypothyroidism.

Psychiatric disorders

• Common Agitation (e.g. nervousness), affect lability, confusional state, depression, apathy.

Nervous system disorders

• Very common Somnolence, headache, dizziness.
• Common Ataxia, tremor, nystagmus, disturbance in attention, amnesia.

Eye disorders

• Very common Diplopia.
• Common Vision blurred, visual disturbance.

Ear and labyrinth disorders

• Common Vertigo.

Cardiac disorders

• Very rare Atrioventricular block, dysrhythmia.

Vascular disorders

• Very rare Hypertension.

Gastrointestinal disorders

• Very common Vomiting, nausea.
• Common Diarrhoea, abdominal pain, constipation.
• Very rare Pancreatitis and/or lipase and/or amylase increase.

Hepato-biliary disorders

• Very rare Hepatitis.

Skin and subcutaneous tissue disorders

• Common Rash, alopecia, acne.
• Uncommon Urticaria.
• Very rare Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyellu2019s syndrome), angioedema, erythema multiforme.

Musculoskeletal, connective tissue and bone disorders

• Very rare Systemic lupus erythematosus.

General disorders and administration site conditions

• Very common Fatigue.
• Common Asthenia.

Investigations

• Uncommon Hepatic enzymes increased, blood alkaline phosphatase increased.
• Very rare Amylase increase, Lipase increase.

u2217 according to CIOMS III frequency classification In clinical trials in children aged 1 month to less than 4 years, the most commonly reported adverse reaction was somnolence occurring in approximately 11 % of patients. Adverse reactions occurring at an incidence of u2265 1 % - < 10 % (common) were: ataxia, irritability, vomiting, lethargy, fatigue, nystagmus, tremor, decreased appetite, and blood uric acid increased.

Post-Marketing reported Side-Effects The following adverse drug reactions have been derived from post-marketing experience with TRILEPTAL via spontaneous case reports and literature cases. It is not possible to reliably estimate their frequency. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

Metabolism and nutrition disorders: Inappropriate ADH secretion like syndrome with signs and symptoms of lethargy, nausea, dizziness, decrease in serum (blood) osmolality, vomiting, headache, confusional state or other neurological signs and symptoms.

Immune system disorders: Drug Rash with Eosinophilia and Systemic Symptoms (DRESS).

Skin and subcutaneous tissue disorders: Acute Generalised Exanthematous Pustulosis (AGEP).

Injury, poisoning and procedural complications: Fall.

Nervous system disorders: Speech disorders (including dysarthria); more frequent during up titration of TRILEPTAL dose.

Musculoskeletal, connective tissue and bone disorders: There have been reports of decreased bone mineral density, osteopenia, osteoporosis and fractures in patients on long-term therapy with TRILEPTAL. The mechanism by which oxcarbazepine affects bone metabolism has not been identified.

Symptoms of overdose include somnolence, dizziness, nausea, vomiting, hyperkinesia, hyponatraemia, ataxia and nystagmus. There is no specific antidote. Treatment is symptomatic and supportive. Removal of the medicine by gastric lavage and/or inactivation by administering activated charcoal should be considered.