Trileptal

Trileptal

oxcarbazepine

Manufacturer:

Novartis

Distributor:

Zuellig
Full Prescribing Info
Contents
Oxcarbazepine.
Description
Trileptal oral suspension also contains the following excipients: Saccharin, flavouring agents, vanillin, preservatives E200, E216 and E218.
Action
ATC Code: N03A F02.
Pharmacology: Mechanism of Action: The pharmacological activity of Trileptal (oxcarbazepine) is mediated principally by the MHD metabolite (monohydroxy derivative of oxcarbazepine). It is assumed that the mechanism of action of oxcarbazepine and MHD primarily lies in the blockade of voltage-sensitive sodium channels, which leads to stabilization of overly excitable neuronal membranes, inhibition of repetitive neuronal discharges and slowing down of the synaptic propagation of excitatory impulses. An increased inflow of potassium and the modulation of high-voltage-activated calcium channels may also contribute to the anticonvulsant effect of the drug. No significant interactions with brain neurotransmitter or modulator receptor sites have been found.
Pharmacodynamics: Oxcarbazepine and its active metabolite MHD are effective antiepileptics in animals. They protect rodents from generalized tonic-clonic seizures and, to a lesser extent, from clonic epileptic seizures, and they suppress or reduce the frequency of chronic recurrent partial seizures in rhesus monkeys with aluminum implants. No development of tolerance (ie, reduction in anticonvulsant activity) was observed in the treatment of tonic-clonic seizures when mice and rats were treated daily for 5 days and 4 weeks, respectively, with oxcarbazepine or MHD.
Clinical Efficacy: Trileptal is used as an antiepileptic either alone or in combination with other drugs, and can replace other antiepileptic drugs if the latter provide inadequate control of seizures.
Pharmacokinetics: Absorption: Oxcarbazepine is rapidly absorbed from the gastrointestinal tract. At least 95% is absorbed following administration of the film-coated tablets and the oral suspension. The active substance undergoes rapid and extensive metabolism to the pharmacologically active metabolite 10,11-dihydro-10-hydroxy-carbamazepine (monohydroxy derivative, MHD).
In healthy male volunteers, the mean Cmax of MHD, following a single dose of 600 mg Trileptal film-coated tablets taken on an empty stomach was 31.5 micromol/L and the corresponding tmax was 5 hrs.
Following a single dose of 600 mg Trileptal oral suspension taken on an empty stomach, the mean Cmax was 24.9 micromol/L and the (median) tmax 6 hrs in healthy male volunteers.
During repeated administration, the suspension and tablet formulations are bioequivalent.
Food does not affect either the extent or the rate of oxcarbazepine absorption, and Trileptal may thus be taken with or without food.
Distribution: The apparent distribution volume of MHD is 49 L. About 40% of MHD is bound to serum proteins, in particular albumin. Within the relevant therapeutic range, binding was not dependent on serum concentration. Oxcarbazepine and MHD do not bind to α-1 acid glycoproteins.
Oxcarbazepine and its active metabolite (MHD) cross the placental barrier. Neonatal and maternal plasma MHD concentrations were similar in one case.
In a mass balance study in humans, unchanged oxcarbazepine accounted for only 2% of total radioactivity in the serum, while about 70% was attributable to MHD, with the rest being associated with minor metabolites that were quickly eliminated.
MHD reaches steady state serum concentrations within 2-3 days in patients given Trileptal twice daily. The pharmacokinetics of MHD at steady state are linear and there is a linear relationship between levels of MHD and dosage at daily doses of 300-2400 mg.
Metabolism: Cytosolic enzymes in the liver rapidly convert oxcarbazepine to MHD, which is primarily responsible for the pharmacological effect of Trileptal. MHD is further metabolized by conjugation with glucuronic acid. Small amounts (4% of the dose) are oxidized to the pharmacologically inactive metabolite 10,11-dihydroxy derivative (DHD).
Elimination: Oxcarbazepine is primarily excreted via the kidney, principally in the form of metabolites. More than 95% of the dose is present in the urine, with <1% as unchanged oxcarbazepine. Less than 4% of the administered dose is excreted in the faeces. About 80% of the dose is excreted in the urine either as MHD glucuronide (49%) or as unchanged MHD (27%); inactive DHD represents about 3% of the dose and the conjugate of oxcarbazepine about 13%.
Oxcarbazepine is rapidly eliminated from the serum with a half-life between 1.3-2.3 hrs. In contrast, the mean serum half-life of MHD is 9.3±1.8 hrs.
Special Populations: Elderly Patients: Following administration of single (300 mg) and multiple (600 mg/day) doses of Trileptal, maximum serum concentrations and AUC values of MHD were 30-60% higher in older (60-82 years) than in younger (18-32 years) volunteers.
Comparisons of creatinine clearance in younger and older volunteers indicate that the difference was caused by age-related reduction of creatinine clearance. No special dose recommendations are necessary in patients with normal renal function since therapeutic doses are individually titrated (see Dosage & Administration).
Children: Weight-adjusted MHD clearance decreases as age and weight increase and gradually approaches that of adults. Mean weight-adjusted clearance in children 1 month to <4 years is 93% higher than in adults. Therefore, MHD exposure in these children is expected to be about half that of adults when treated with a similar weight-adjusted dose. Mean weight-adjusted clearance in children 4-12 years is 43% higher than in adults. MHD exposure in these children is therefore expected to be about 2/3 that of adults when treated with a similar weight-adjusted dose.
As weight increases, for patients ≥13 years, weight-adjusted MHD clearance is expected to reach that of adults.
Sex: No sex-specific differences were observed in children, adults or elderly patients.
Impaired Hepatic Function: The pharmacokinetics and metabolism of oxcarbazepine and MHD were investigated following administration of single oral doses of 900 mg in healthy volunteers and patients with impaired liver function. A slight to moderate impairment of liver function had no effect on the pharmacokinetics of oxcarbazepine or MHD. Trileptal has not been studied in patients with severe hepatic impairment.
Impaired Renal Function:
There is a linear correlation between creatinine clearance and renal clearance of MHD. Following oral administration of single 300 mg doses of Trileptal in patients with renal impairment (creatinine clearance <30 mL/min), the elimination half-life of MHD is extended by 60-90% (16-19 hrs), with a corresponding doubling of AUC.
Toxicology: Preclinical Data: Preclinical data indicate no special hazard for humans based on repeated-dose toxicity, safety pharmacology and genotoxicity studies with oxcarbazepine and the pharmacologically active metabolite monohydroxy derivate (MHD).
Evidence of nephrotoxicity was noted in repeated-dose toxicity rat studies but not in dog or mouse studies. As there are no reports of such changes in patients, the clinical relevance of this finding in rats remains unknown.
Immunostimulatory tests in mice showed that MHD (and to a lesser extent, oxcarbazepine) can induce a delayed hypersensitivity reaction.
Reproductive Toxicity: Animal studies revealed effects eg, increases in the incidence of embryo mortality and some delay in antenatal and/or postnatal growth at maternally toxic dose levels. In 1 of the 8 embryotoxicity studies conducted with either oxcarbazepine or the pharmacologically active metabolite (MHD), there was an increase in rat fetal malformations at a dose which also showed maternal toxicity (see Use in pregnancy & lactation under Precautions).
Carcinogenicity: In carcinogenicity studies, liver (rats and mice), testicular and female genital tract granular cell (rats) tumours were induced in treated animals. The occurrence of liver tumours was most likely a consequence of the induction of hepatic microsomal enzymes, an inductive effect which, although it cannot be entirely excluded, is weak or absent in patients treated with Trileptal. Testicular tumours may have been induced by elevated luteinizing hormone concentrations. Due to the absence of such an increase in humans, these tumours are considered to be of no clinical relevance. A dose-related increase in the incidence of granular cell tumours of the female genital tract (cervix and vagina) was noted in the rat carcinogenicity study with MHD. These effects occurred at exposure levels comparable to the anticipated clinical exposure. The mechanism for the development of these tumours has not been elucidated. Thus, the clinical relevance of these findings is not known.
Indications/Uses
Treatment of partial seizures (with or without secondary generalized tonic-clonic seizures) and generalized tonic-clonic seizures.
Trileptal is used in adults and in children ≥1 month.
Dosage/Direction for Use
Dosage: The following dosage recommendations apply to all patients who do not have impaired renal function. Serum level monitoring is not necessary for optimization of Trileptal therapy (see Pharmacokinetics under Actions).
Adults: Monotherapy: Initially, at a daily dose of 600 mg (8-10 mg/kg/day) given in 2 divided doses. The daily dose may be increased at 1-week intervals, in increments not exceeding 600 mg, in order to achieve the desired effect. The maintenance dose ranges from 600-2400 mg/day, with most patients responding to a dose of 900 mg/day.
Controlled studies with monotherapy in patients not previously treated with antiepileptics have shown the efficacy of a daily dose of 1200 mg. In hard-to-treat patients who have been switched from other antiepileptics to monotherapy with Trileptal, a daily dose of 2400 mg has proven effective.
Combination Therapy: Treatment with Trileptal may be initiated at a daily dose of 600 mg (8-10 mg/kg/day), given in 2 divided doses. The daily dose may be increased at 1-week intervals, in increments not exceeding 600 mg, in order to achieve the desired effect. The maintenance dose ranges from 600-2400 mg/day.
A controlled study with combination therapy has shown daily doses of 600-2400 mg to be effective. However, most patients did not tolerate a daily dose of 2400 mg without a reduction in the dose of the other concurrently administered antiepileptics, primarily due to adverse effects involving the central nervous system.
Daily doses >2400 mg were not systematically investigated.
Children ≥1 month: In monotherapy and combination therapy, treatment should be initiated at a dose of 8-10 mg/kg/day, given in 2 divided doses.
If clinically indicated, the daily dose may be increased at 1-week intervals, in increments not exceeding 10 mg/kg/day, up to a maximum daily dose of 60 mg/kg, in order to achieve the desired effect (see Pharmacokinetics under Actions).
In both combination therapy and monotherapy, clearance (L/hr/kg), based on body weight, decreases with age such that children from 1 month to <4 years may require twice as high a dose of oxcarbazepine per body weight as adults; children 4-12 years may require a dose of oxcarbazepine per body weight that is 50% higher than that in adults (see Pharmacokinetics under Actions).
In children 1 month to <4 years, the influence of enzyme-inducing antiepileptics on weight-normalized clearance appears higher than in older children. Children 1 month to <4 years receiving combination therapy with enzyme-inducing antiepileptics may require a dose (by body weight) of oxcarbazepine about 60% higher than the dose needed with either as monotherapy or combination therapy with non-enzyme-inducing antiepileptics. Older children (≥4 years) receiving enzyme-inducing antiepileptics may require only a slightly higher dose than their counterparts on monotherapy.
Trileptal is intended for use in children ≥1 month. There have been no controlled clinical studies in children aged <1 month.
The dosage recommendations previously mentioned are based on doses used in all age groups (adults, elderly patients and children) during clinical trials. However, lower starting doses may also be used where appropriate.
Elderly: Dose adjustment is recommended in elderly patients with impaired renal function. For patients at risk for hyponatremia (see Precautions).
Impaired Hepatic Function: No dose adjustment is required in patients with mild to moderate hepatic impairment. Trileptal has not been studied in patients with severe hepatic impairment. Caution is therefore required when giving Trileptal to patients with severe hepatic impairment (see Pharmacokinetics under Actions).
Impaired Renal Function: In patients with renal impairment (creatinine clearance <30 mL/min), Trileptal therapy should be initiated at half the usual starting dose (300 mg/day) and increased at intervals of not <1 week until the desired clinical response is achieved (see Pharmacokinetics under Actions). Patients with renal impairment must be closely monitored when doses are increased.
Administration: Trileptal is suitable for use either alone or in combination with other antiepileptic drugs. In both monotherapy and combination therapy, treatment with Trileptal should be initiated at a clinically effective dose, given as 2 divided doses per day. The dose may be increased depending on the patient's clinical response. In the event of combination therapy, it may be necessary to reduce the dose of the other antiepileptic and/or to increase the dose of Trileptal more slowly (see Interactions), due to the increase in the patient's total antiepileptic dose.
Trileptal may be taken with or without food.
The tablets are scored and can be broken in half to facilitate administration for the patient.
The oral suspension is available for younger children who are unable to swallow the tablets or in whom the prescribed dose cannot be attained using the tablets.
The bottle containing the oral suspension must be shaken well before use. The prescribed amount of solution should then be withdrawn from the bottle immediately. The amount should be rounded up to the nearest 0.5 mL if the 10 mL dosing syringe is being used (supplied with the 250 mL bottle for adults and older children) and to the nearest 0.1 mL if the 1 mL dosing syringe is being used (supplied with the 100 mL bottle for younger children).
The oral suspension may be swallowed directly from the dosing syringe or stirred into a small glass of water immediately before ingestion. After each use, the bottle must be closed and the outside of the dosing syringe wiped clean with a clean, dry tissue.
Trileptal film-coated tablets and oral suspension may be interchanged at equal doses.
The prescription for Trileptal oral suspension should be given in mL which is shown in the following conversion of mg to mL: 10 mg=0.2 mL; 20 mg=0.3 mL; 30 mg=0.5 mL; 40 mg=0.7 mL; 50 mg=0.8 mL; 60 mg=1 mL; 70 mg=1.2 mL; 80 mg=1.3 mL; 90 mg=1.5 mL; 100 mg=1.7 mL; 200 mg=3.3 mL; 300 mg=5 mL; 400 mg=6.7 mL; 500 mg=8.3 mL; 600 mg=10 mL; 700 mg=11.7 mL; 800 mg=13.3 mL; 900 mg=15 mL; 1000 mg=16.7 mL.
Overdosage
Isolated cases of overdose have been reported. The maximum dose taken was 24 g. Symptomatic treatment was given and all patients recovered.
Signs and Symptoms: Overdosage leads to symptoms eg, drowsiness, lightheadedness, nausea, vomiting, hyperkinesia, hyponatraemia, ataxia and nystagmus.
Management: There is no specific antidote. Appropriate symptomatic and supportive treatment should be given. Removal of the drug by gastric lavage and/or inactivation of the drug through administration of activated charcoal should be considered. Monitoring of vital functions is recommended with particular attention being paid to cardiac conduction disturbances, electrolyte disturbances and respiratory problems.
Contraindications
Known hypersensitivity to oxcarbazepine or any of the excipients of Trileptal.
Special Precautions
Patients who have had hypersensitivity reactions to carbamazepine should be informed that hypersensitivity reactions (eg, severe skin reactions) may also occur during treatment with Trileptal at a cross-reaction rate of 25-30% (see Adverse Reactions).
Hypersensitivity reactions, including multi-organ hypersensitivity reactions, may also occur in patients without a history of hypersensitivity to carbamazepine. Such reactions may affect the skin, liver, blood, lymphatic system or other organs, either individually or in the context of a systemic reaction (see Adverse Reactions). As a matter of principle, Trileptal should be withdrawn immediately at the first sign of a hypersensitivity reaction.
There have been very rare reports of severe skin reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis (drug-induced Lyell's syndrome) and erythema multiforme, in association with the use of Trileptal. Patients with such reactions may require hospitalization, as these conditions may be life-threatening and, in very rare cases, fatal. Trileptal-associated cases have occurred in both adults and children. The median time to onset was 19 days. There have been several isolated reports of recurrence of a severe skin reaction following reintroduction of Trileptal.
If a patient develops a skin reaction while using Trileptal, consideration should be given to discontinuing Trileptal and prescribing another antiepileptic medication.
Multi-organ hypersensitivity reactions have occurred very soon after initiation of treatment with Trileptal in adults and children (usually within the first 3 weeks, but possibly later as well). Although few reports have been issued, some patients have been hospitalized and, in isolated cases, the condition of such patients has been considered life-threatening. The symptoms of this disorder have varied. Patients have typically presented with fever and rash, with concurrent involvement of other organ systems, but these have not been the only symptoms. Others have included lymphadenopathy, hepatitis, abnormal liver function tests, haematological anomalies (eg, eosinophilia, thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepatorenal syndrome, arthralgia, and asthenia. Since the manifestations of the disorder are variable, there may also be symptoms, not mentioned here, affecting other organ systems. If multi-organ hypersensitivity is suspected, Trileptal should be withdrawn and alternative treatment initiated.
There have been no reports of cross-reactions with other medicinal products associated with multi-organ hypersensitivity. However, experience with such products indicates that such cross-reactions are possible.
In up to 2.7% of patients treated with Trileptal, serum sodium levels fell below 125 mmol/L. As a rule, this was asymptomatic and did not require any change in treatment. If clinical intervention is considered, experience from clinical trials shows that the serum sodium level normalizes to the baseline value as soon as the dose of Trileptal is reduced, Trileptal is withdrawn, or the patient is given conservative treatment (eg, restricted fluid intake). In patients with preexisting renal disease who require high fluid intake, patients with preexisting low sodium levels and patients being treated concurrently either with drugs that lower sodium levels (eg, diuretics, desmopressin) or with NSAIDs (eg, indomethacin), serum sodium levels should be determined before initiating therapy. Thereafter, serum sodium levels should be determined after about 2 weeks to begin with, then either at monthly intervals, or in accordance with clinical requirements, during the 1st 3 months of treatment. The above risk factors apply in particular to elderly patients. The same approach for monitoring of serum sodium levels should be followed if treatment with a sodium-lowering drug is started in a patient receiving Trileptal. Determination of serum sodium should generally be considered if clinical signs or hyponatremia occur during treatment with Trileptal. Otherwise, serum sodium may be assessed as part of routine monitoring of laboratory parameters.
Patients with heart failure should have their weight monitored on a regular basis in order to determine if there has been any fluid retention. In the event of fluid retention or deterioration in cardiac function, serum sodium should be checked. Fluid restriction is an important method of treatment if hyponatremia is determined.
There have been very rare cases of impaired cardiac conduction during treatment with oxcarbazepine and patients with preexisting disorders of cardiac conduction (eg, atrioventricular block, arrhythmias) should therefore be closely monitored.
Very rare cases of hepatitis have been reported, which in most cases resolved favourably. If hepatic impairment is suspected, liver function should be checked and discontinuation of Trileptal considered.
As with other antiepileptics, abrupt discontinuation of Trileptal should be avoided. Dosage should be reduced gradually to minimize the risk of precipitating seizures (ie, seizure exacerbation or status epilepticus). If Trileptal does have to be discontinued abruptly eg, owing to severe adverse reactions, the switch to an alternative antiepileptic drug should be effected under cover of a suitable drug (eg, diazepam IV, rectal; phenytoin IV) and under close supervision.
Oxcarbazepine has less enzyme-inducing potential than carbamazepine. Under certain conditions, the dosage of the concurrently administered antiepileptic may have to be lowered (see Other Antiepileptics under Interactions).
Female patients of childbearing age should be told that concurrent use of Trileptal and hormonal contraceptives leads to loss of contraceptive efficacy (see Interactions). Additional non-hormonal contraceptives should be recommended to female patients treated with Trileptal.
Patients receiving Trileptal should avoid alcohol intake due to the risk of an additive sedative effect.
Trileptal oral suspension contains ethanol (<100 mg in the maximum ingested dose of 2400 mg). It also contains parabenes, which may cause allergic reactions (possibly delayed). The suspension also contains sorbitol and should therefore not be given to patients with rare hereditary problems of fructose intolerance.
Suicidal Ideation and 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 drugs 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.
Association with HLA-B*1502: There is growing evidence that different Human Leukocyte Antigen (HLA) alleles play a role in association with adverse cutaneous reactions in predisposed patients. As the chemical structure of oxcarbazepine is similar to that of carbamazepine, there is a possibility that patients carrying the HLA-B*1502 allele also have an increased risk of SJS/TEN skin reactions with oxcarbazepine.
The frequency of HLA-B*1502 allele ranges from 2-12% in Han Chinese populations and is about 8% in Thai populations, and >15% in the Philippines and some Malaysian populations. Allele frequencies up to about 2% and 6% have been reported in Korea and India, respectively. The frequency of the HLA-B*1502 allele is negligible in persons from European descent, several African populations, indigenous peoples of the Americas, Hispanic populations sampled and in Japanese (<1%).
The allele frequencies listed here represent the percentage of chromosomes in the specified population that carry the allele of interest, meaning that the percentage of patients who carry a copy of the allele on at least one of their 2 chromosomes (ie, the carrier frequency) is nearly twice as high as the allele frequency. Therefore, the percentage of patients who may be at risk is nearly twice the allele frequency.
Testing for the presence of the HLA-B*1502 allele should be considered in patients with ancestry in genetically at-risk populations, prior to initiating treatment with Trileptal. The use of Trileptal should be avoided in tested patients who are found to be positive for HLA-B*1502 unless the benefits clearly outweigh the risks. HLA-B*1502 may be a risk factor for the development of SJS/TEN in Chinese patients taking other anti-epileptic drugs (AED) associated with SJS/TEN. Consideration should therefore be given to avoid use of other drugs associated with SJS/TEN in HLA-B*1502 positive patients, when alternative therapies are otherwise equally acceptable. Screening is not generally recommended in patients from populations in which the prevalence of HLA-B*1502 is low or in current Trileptal users, as the risk of SJS/TEN is largely confined to the 1st few months of therapy, regardless of HLA-B*1502 status.
Association with HLA-A*3101: Human Leukocyte Antigen (HLA)-A*3101 may be a risk factor for the development of cutaneous adverse drug reactions eg, SJS, TEN, DRESS, AGEP and maculopapular rash. The frequency of the HLA-A*3101 allele varies widely between ethnic populations and its frequency is about 2-5% in European populations and is about 10% in the Japanese population. The frequency of this allele is estimated to be <5% in the majority of Australian, Asian, African and North American populations with some exceptions within 5-12%. Frequency >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 10-15% in other native ethnicities in these same regions.
The allele frequencies listed here represent the percentage of chromosomes in the specified population that carry the allele of interest, meaning that the percentage of patients who carry a copy of the allele on at least 1 of their 2 chromosomes (ie, the carrier frequency) is nearly twice as high as the allele frequency. Therefore, the percentage of patients who may be at risk is nearly twice the allele frequency.
There is 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 generalized exanthematous pustulosis (AGEP) and maculopapular rash.
There are insufficient data to support a recommendation for testing the presence of HLA-A*3101 allele in patients, prior to initiating treatment with oxcarbazepine. Genetic screening is generally not recommended for any current Trileptal users, as the risk of SJS/TEN, AGEP, DRESS and maculopapular rash is largely confined to the first few months of therapy, regardless of HLA-A*3101 status.
Limitation of Genetic Screening: Genetic screening results must never substitute for 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. Similarly many patients positive for HLA-A*3101 and treated with Trileptal will not develop SJS, TEN, DRESS, AGEP or maculopapular rash and patients negative for HLA-A*3101 of any ethnicity can still develop these severe cutaneous adverse reactions. The role of other possible factors in the development of, and morbidity from, these severe cutaneous adverse reactions eg, AED dose, compliance, concomitant medications, co-morbidities, and the level of dermatologic monitoring have not been studied.
Information for the 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 1 or 2 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” respectively 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.
Effects on the Ability to Drive or Operate Machinery: Trileptal can cause dizziness and drowsiness (see Adverse Reactions), leading to impairment of the reactions. Particular caution is therefore required when driving or using machines.
Use in pregnancy & lactation: General Risk Associated with Epilepsy and Antiepileptic Drugs: The rate of malformations in the offspring of women with epilepsy has been shown to be 2-3 times higher than the rate of about 3% found in the general population. In treated women, an increase in malformations was primarily found in those given combination therapy. It was not possible to determine to what extent the specific treatment and/or the disease was responsible for this.
In addition, effective antiepileptic therapy should not be interrupted as aggravation of the disease is detrimental to both the mother and the fetus.
Risk Related to Oxcarbazepine: Data on administration in pregnant women are limited.
In animal studies, increased embryo mortality, delayed growth and malformations were observed with high maternally toxic doses (see Toxicology under Actions).
If a woman receiving Trileptal becomes pregnant or plans to become pregnant, or if Trileptal needs to be initiated during pregnancy, the need for Trileptal therapy must be reconsidered. This is particularly important during the first 3 months of pregnancy. The lowest effective dose should be given. In women of childbearing age, Trileptal should be given as monotherapy whenever possible and at least during the first 3 months of pregnancy. Patients should be counselled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening.
Effective antiepileptic therapy with oxcarbazepine must not be interrupted during pregnancy as aggravation of the disease is detrimental to both the mother and fetus.
Monitoring and Prevention: Folic acid deficiency may occur during pregnancy. Antiepileptics have been reported to aggravate this condition. Folic acid deficiency can contribute to an increased incidence of fetal malformations. Folic acid supplementation is therefore recommended before and during pregnancy.
Vitamin B12 deficiency should be ruled out or treated.
Lactation: Oxcarbazepine and its active metabolite MHD are excreted in breast milk.
Effects on the infant exposed to Trileptal are unknown. For this reason, Trileptal should not be given to women who are breastfeeding.
Use in children: Neonates: Antiepileptics have been reported to cause disturbances on coagulation in neonates. As a precaution, vitamin K1 should be considered as a preventive measure in the last few weeks of pregnancy.
In rare cases, antiepileptic therapy has been associated with neonatal hypocalcemia, resulting from difficulties in calcium phosphate metabolism and bone mineralization.
Use In Pregnancy & Lactation
General Risk Associated with Epilepsy and Antiepileptic Drugs: The rate of malformations in the offspring of women with epilepsy has been shown to be 2-3 times higher than the rate of about 3% found in the general population. In treated women, an increase in malformations was primarily found in those given combination therapy. It was not possible to determine to what extent the specific treatment and/or the disease was responsible for this.
In addition, effective antiepileptic therapy should not be interrupted as aggravation of the disease is detrimental to both the mother and the fetus.
Risk Related to Oxcarbazepine: Data on administration in pregnant women are limited.
In animal studies, increased embryo mortality, delayed growth and malformations were observed with high maternally toxic doses (see Toxicology under Actions).
If a woman receiving Trileptal becomes pregnant or plans to become pregnant, or if Trileptal needs to be initiated during pregnancy, the need for Trileptal therapy must be reconsidered. This is particularly important during the first 3 months of pregnancy. The lowest effective dose should be given. In women of childbearing age, Trileptal should be given as monotherapy whenever possible and at least during the first 3 months of pregnancy. Patients should be counselled regarding the possibility of an increased risk of malformations and given the opportunity of antenatal screening.
Effective antiepileptic therapy with oxcarbazepine must not be interrupted during pregnancy as aggravation of the disease is detrimental to both the mother and fetus.
Monitoring and Prevention: Folic acid deficiency may occur during pregnancy. Antiepileptics have been reported to aggravate this condition. Folic acid deficiency can contribute to an increased incidence of fetal malformations. Folic acid supplementation is therefore recommended before and during pregnancy.
Vitamin B12 deficiency should be ruled out or treated.
Lactation: Oxcarbazepine and its active metabolite MHD are excreted in breast milk.
Effects on the infant exposed to Trileptal are unknown. For this reason, Trileptal should not be given to women who are breastfeeding.
Adverse Reactions
The most commonly reported adverse effects, which occur in >10% of patients, are drowsiness, headache, dizziness, diplopia, nausea, vomiting and feeling of weakness.
In clinical trials, adverse effects were for the most part mild to moderately severe and were transient, occuring primarily at the start of treatment.
The assessment of the adverse effect profile for each body system is based on the adverse events ascribed to Trileptal in clinical trials. Clinically significant reports from the post-marketing phase have also been taken into account.
Estimated Frequency in Accordance with CIOMS III Classification: Very common (>1/10), common (>1/100 to <1/10), uncommon (>1/1000 to <1/100), rare (>1/10,000 to <1/1000), very rare (<1/10,000).
Blood and Lymphatic System Disorders: Uncommon: Leucopenia. Very Rare: Thrombocytopenia.
Metabolic and Nutritional Disturbances: Common: Hyponatremia under special clinical circumstances, and more frequently in elderly patients (see Precautions).
In very rare cases, clinically significant hyponatremia (Na <125 mmol/L) may develop in patients being treated with Trileptal. It has usually occurred during the 1st 3 months, but there have been patients whose serum sodium levels did not fall <125 mmol/L until >1 year after the start of treatment (see Precautions). There have also been reports of symptomatic hyponatremia with seizures, disorientation, reduced perception, encephalopathy (see also Nervous System Disorders as follows), visual disturbances (eg, blurred vision), vomiting, nausea and folic acid deficiency.
Under special clinical circumstances, a syndrome of inappropriate secretion of antidiuretic hormone (SIADH) may occur during treatment with Trileptal (see Precautions).
Psychiatric Disorders: Common: Confusional state, depression, apathy, restlessness (eg, nervousness), affect lability.
Nervous System Disorders: Very Common: Drowsiness (22.5%), headache (14.6%), lightheadedness (22.6%), dizziness (22.6%). Common: Ataxia, tremor, nystagmus, disturbances in attention, disturbances in memory.
Eye Disorders: Very Common: Diplopia (13.9%). Common: Blurred vision, disturbances of vision.
Cardiac Disorders: Very Rare: Arrhythmia, atrioventricular block.
Vascular Disorders: Hypertension.
Gastrointestinal Disorders: Very Common: Nausea (14.1%), vomiting (11.1%). Common: Diarrhoea, constipation, abdominal pain. Very Rare: Pancreatitis and/or increase in lipase and/or amylase.
Hepatobiliary Disorders: Uncommon: Elevated levels of transaminases and/or alkaline phosphatase. Very Rare: Hepatitis (see Precautions).
Skin: Common: Exanthema, alopecia and acne. Uncommon: Urticaria. Very rare: Angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis (drug-induced Lyell's syndrome) and erythema multiforme.
General Disorders: Very Common: Fatigue (12%). Common: Asthenia.
Other Disorders: Very Common: Feeling of weakness (12%). Very Rare: Systemic lupus erythematosus, hypersensitivity (including multi-organ hypersensitivity) characterized by rash, fever. Other organs or systems may be affected eg, blood and lymphatic system (eg, eosinophilia, thrombocytopenia, leucopenia, lymphadenopathy, splenomegaly), liver (eg, abnormal liver function tests, hepatitis), muscles and joints (eg, joint swelling, myalgia, arthralgia), nervous system (eg, hepatic encephalopathy), kidney (eg, proteinuria, interstitial nephritis, renal failure), lungs (eg, dyspnea, pulmonary edema, asthma, bronchospasms, interstitial lung disease); angioedema and anaphylactic reactions (see Precautions).
In clinical studies in children aged from 1 month to <4 years, the most frequently reported adverse effect was drowsiness, which occurred in approximately 11% of patients. Adverse effects occurring with a frequency of ≥1% to <10% (common) were ataxia, excitation, vomiting, lethargy, fatigue, nystagmus, tremor, decreased appetite and increased blood uric acid.
Adverse Drug Reactions from Spontaneous Reports and Literature Cases (Frequency Not Known): The following adverse drug reactions have been derived from post-marketing experience with Trileptal via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. 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.
Immune System Disorders: Drug Rash with Eosinophilia and Systemic Symptoms (DRESS).
Skin and Subcutaneous Tissue Disorders: Acute Generalized Exanthematous Pustulosis (AGEP).
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.
Drug Interactions
Enzyme Inhibition: Oxcarbazepine and its pharmacologically active metabolite (MHD) inhibits CYP2C19. Interactions are thus possible if high doses of Trileptal are administered together with drugs metabolized by CYP2C19 (eg, phenytoin). Plasma levels of phenytoin increased by up to 40% when Trileptal was given at doses exceeding 1200 mg/day (see table). In such cases, it may be necessary to reduce the concomitantly administered dose of phenytoin (see Dosage & Administration).
Enzyme Induction: In vitro and in vivo, oxcarbazepine and MHD are weak inducers of cytochrome CYP3A4 and CYP3A5, which are primarily responsible for the metabolism of eg, dihydropyridine calcium channel blockers (eg, felodipine), immunosuppressants (eg, ciclosporin, tacrolimus), oral contraceptives (see as follows) and some other antiepileptics (eg, carbamazepine). This results in lower serum levels of these drugs (see table).
In vitro, oxcarbazepine and MHD are weak inducers of UDP-glucuronyl transferase (nonspecific UGT enzyme study). They therefore seem unlikely to have a clinically relevant effect in vivo on drugs that are mainly eliminated by conjugation via UDP glucuronyl transferases.
Even in view of the weak induction potential of oxcarbazepine and MHD, dose reduction of the concurrently administered drug may be necessary on discontinuation of Trileptal; this should be decided on the basis of clinical monitoring and determination of plasma levels.
Hormonal Contraceptives: Trileptal has been shown to affect ethinyloestradiol and levonorgestrel, the 2 components of a hormonal contraceptive. Mean AUC for ethinyloestradiol and levonorgestrel was lowered by 48-52% and 32-52%, respectively. Concurrent use with Trileptal may therefore render hormonal contraceptives ineffective (see Precautions). An alternative reliable method of contraception should therefore be used.
Other Antiepileptics: Possible interactions between Trileptal and other antiepileptics were investigated in clinical trials.
It was possible to show that strong inducers of cytochrome P450 (eg, carbamazepine, phenytoin and phenobarbital) lower plasma concentrations of MHD (29-40%).
In the event of concomitant administration of >1 antiepileptics with oxcarbazepine, careful dose adjustment and/or monitoring of plasma levels should be considered on an individual basis.
Effects on mean AUC and Cmin are summarized in the table.

Click on icon to see table/diagram/image

No autoinduction has been observed with Trileptal.
Other Drug Interactions: Cimetidine, erythromycin, viloxazine and dextropropoxyphene had no effect on the pharmacokinetics of MHD.
Patients treated with tricyclic antidepressants were included in the clinical trials; no clinically relevant interactions were observed.
Combining lithium with oxcarbazepine may lead to increased neurotoxicity.
Storage
The FC tablets should be protected from moisture and should not be stored above 30°C.
The suspension should be protected from light and should not be stored above 30°C. Once the bottle is opened, the suspension should not be used for >7 weeks.
MIMS Class
ATC Classification
N03AF02 - oxcarbazepine ; Belongs to the class of carboxamide derivatives antiepileptic.
Presentation/Packing
FC tab (scored on both sides) 300 mg x 50's. 600 mg x 50's. Susp 60 mg/mL x 250 mL.
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