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 As a matter of principle, Trileptal should be withdrawn immediately at the first sign of a hypersensitivity reaction.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 If multi-organ hypersensitivity is suspected, Trileptal should be withdrawn and alternative treatment initiated.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.