"The U.S. Food and Drug Administration today approved Aptiom (eslicarbazepine acetate) as an add-on medication to treat seizures associated with epilepsy.
Epilepsy is a brain disorder caused by abnormal or excessive activity in the brain"...
Clinically significant hyponatremia (sodium < 125 mmol/L) can develop during Trileptal use. In the 14 controlled epilepsy studies 2.5% of Trileptal-treated patients (38/1,524) had a sodium of less than 125 mmol/L at some point during treatment, compared to no such patients assigned placebo or active control (carbamazepine and phenobarbital for adjunctive and monotherapy substitution studies, and phenytoin and valproate for the monotherapy initiation studies). Clinically significant hyponatremia generally occurred during the first three months of treatment with Trileptal, although there were patients who first developed a serum sodium < 125 mmol/L more than one year after initiation of therapy. Most patients who developed hyponatremia were asymptomatic but patients in the clinical trials were frequently monitored and some had their Trileptal dose reduced, discontinued, or had their fluid intake restricted for hyponatremia. Whether or not these maneuvers prevented the occurrence of more severe events is unknown. Cases of symptomatic hyponatremia have been reported during post-marketing use. In clinical trials, patients whose treatment with Trileptal was discontinued due to hyponatremia generally experienced normalization of serum sodium within a few days without additional treatment.
Measurement of serum sodium levels should be considered for patients during maintenance treatment with Trileptal, particularly if the patient is receiving other medications known to decrease serum sodium levels (for example, drugs associated with inappropriate ADH secretion) or if symptoms possibly indicating hyponatremia develop (e.g., nausea, malaise, headache, lethargy, confusion, obtundation, or increase in seizure frequency or severity).
Anaphylactic Reactions And Angioedema
Rare 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. Angioedema associated with laryngeal edema can be fatal. If a patient develops any of these reactions after treatment with Trileptal, the drug should be discontinued and an alternative treatment started. These patients should not be rechallenged with the drug [see Patients with a Past History of Hypersensitivity Reaction to Carbamazepine].
Patients With A Past History Of Hypersensitivity Reaction To Carbamazepine
Patients who have had hypersensitivity reactions to carbamazepine should be informed that approximately 25%-30% of them will experience hypersensitivity reactions with Trileptal. For this reason patients should be specifically questioned about any prior experience with carbamazepine, and patients with a history of hypersensitivity reactions to carbamazepine should ordinarily be treated with Trileptal only if the potential benefit justifies the potential risk. If signs or symptoms of hypersensitivity develop, Trileptal should be discontinued immediately [see Anaphylactic Reactions And Angioedema].
Serious Dermatological Reactions
Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both children and adults in association with Trileptal use. Such serious skin reactions may be life threatening, and some patients have required hospitalization, with very rare reports of fatal outcome. The median time of onset for reported cases was 19 days after treatment initiation. Recurrence of the serious skin reactions following rechallenge with Trileptal has also been reported.
The reporting rate of TEN and SJS associated with Trileptal use, which is generally accepted to be an underestimate due to underreporting, exceeds the background incidence rate estimates by a factor of 3-to 10-fold. Estimates of the background incidence rate for these serious skin reactions in the general population range between 0.5 to 6 cases per million-person years. Therefore, if a patient develops a skin reaction while taking Trileptal, consideration should be given to discontinuing Trileptal use and prescribing another antiepileptic medication.
Association with HLA-B*1502
Patients carrying the HLA-B*1502 allele may be at increased risk for SJS/TEN with Trileptal treatment.
Human Leukocyte Antigen (HLA) allele B*1502 increases the risk for developing SJS/TEN in patients treated with carbamazepine. The chemical structure of Trileptal is similar to that of carbamazepine. Available clinical evidence, and data from nonclinical studies showing a direct interaction between Trileptal and HLA-B*1502 protein, suggest that the HLA-B*1502 allele may also increase the risk for SJS/TEN with Trileptal.
The frequency of HLA-B*1502 allele ranges from 2 to 12% in Han Chinese populations, is about 8% in Thai populations, and above 15% in the Philippines and in 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 people from European descent, several African populations, indigenous peoples of the Americas, Hispanic populations, and in Japanese ( < 1%).
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 patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Consideration should also be given to avoid the 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 HLAB*1502 is low, or in current Trileptal users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLA B*1502 status.
The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been well characterized.
Suicidal Behavior And Ideation
Antiepileptic drugs (AEDs), including Trileptal, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials (mono-and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.
The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.
Table 2 : Risk by Indication for Antiepileptic Drugs
in the Pooled Analysis
|Indication||Placebo Patients with Events Per 1,000 Patients||Drug Patients with Events Per 1,000 Patients||Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients||Risk Difference: Additional Drug Patients with Events Per 1,000 Patients|
The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.
Anyone considering prescribing Trileptal or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.
Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Withdrawal Of AEDs
As with all antiepileptic drugs, Trileptal should be withdrawn gradually to minimize the potential of increased seizure frequency.
Cognitive/Neuropsychiatric Adverse Events
Use of Trileptal has been associated with central nervous system-related adverse events. The most significant of these can be classified into three general categories: 1) cognitive symptoms including psychomotor slowing, difficulty with concentration, and speech or language problems, 2) somnolence or fatigue, and 3) coordination abnormalities, including ataxia and gait disturbances.
In one large, fixed-dose study, Trileptal was added to existing AED therapy (up to three concomitant AEDs). By protocol, the dosage of the concomitant AEDs could not be reduced as Trileptal was added, reduction in Trileptal dosage was not allowed if intolerance developed, and patients were discontinued if unable to tolerate their highest target maintenance doses. In this trial, 65% of patients were discontinued because they could not tolerate the 2400 mg/day dose of Trileptal on top of existing AEDs. The adverse events seen in this study were primarily CNS related and the risk for discontinuation was dose related.
In this trial, 7.1% of oxcarbazepine-treated patients and 4% of placebo-treated patients experienced a cognitive adverse event. The risk of discontinuation for these events was about 6.5 times greater on oxcarbazepine than on placebo. In addition, 26% of oxcarbazepine-treated patients and 12% of placebo-treated patients experienced somnolence. The risk of discontinuation for somnolence was about 10 times greater on oxcarbazepine than on placebo. Finally, 28.7% of oxcarbazepine-treated patients and 6.4% of placebo-treated patients experienced ataxia or gait disturbances. The risk for discontinuation for these events was about seven times greater on oxcarbazepine than on placebo.
In a single placebo-controlled monotherapy trial evaluating 2400 mg/day of Trileptal, no patients in either treatment group discontinued double-blind treatment because of cognitive adverse events, somnolence, ataxia, or gait disturbance.
In the two dose-controlled conversion to monotherapy trials comparing 2400 mg/day and 300 mg/day Trileptal, 1.1% of patients in the 2400 mg/day group discontinued double-blind treatment because of somnolence or cognitive adverse events compared to 0% in the 300 mg/day group. In these trials, no patients discontinued because of ataxia or gait disturbances in either treatment group.
A study was conducted in pediatric patients (3 to 17 years old) with inadequately controlled partial seizures in which Trileptal was added to existing AED therapy (up to two concomitant AEDs). By protocol, the dosage of concomitant AEDs could not be reduced as Trileptal was added. Trileptal was titrated to reach a target dose ranging from 30 mg/kg to 46 mg/kg (based on a patient's body weight with fixed doses for predefined weight ranges).
Cognitive adverse events occurred in 5.8% of oxcarbazepine-treated patients (the single most common event being concentration impairment, 4 of 138 patients) and in 3.1% of patients treated with placebo. In addition, 34.8% of oxcarbazepine-treated patients and 14.0% of placebo-treated patients experienced somnolence. (No patient discontinued due to a cognitive adverse event or somnolence.). Finally, 23.2% of oxcarbazepine-treated patients and 7.0% of placebo-treated patients experienced ataxia or gait disturbances. Two (1.4%) oxcarbazepine-treated patients and 1 (0.8%) placebo-treated patient discontinued due to ataxia or gait disturbances.
Multi-organ hypersensitivity reactions have occurred in close temporal association (median time to detection 13 days: range 4-60) to the initiation of Trileptal therapy in adult and pediatric patients. Although there have been a limited number of reports, many of these cases resulted in hospitalization and some were considered life threatening. Signs and symptoms of this disorder were diverse; however, patients typically, although not exclusively, presented with fever and rash associated with other organ system involvement. These may include hematologic and lymphatic (e.g., eosinophilia, thrombocytopenia, lymphadenopathy, leukopenia, neutropenia, splenomegaly), hepatobiliary (e.g., hepatitis, liver function test abnormalities), renal (e.g., proteinuria, nephritis, oliguria, renal failure), muscles and joints (e.g., joint swelling, myalgia, arthralgia, asthenia), nervous system (e.g., hepatic encephalopathy), respiratory (e.g., dyspnea, pulmonary edema, asthma, bronchospasm, interstitial lung disease), hepatorenal syndrome, pruritus, and angioedema. Because the disorder is variable in its expression, other organ system symptoms and signs, not noted here, may occur. If this reaction is suspected, Trileptal should be discontinued and an alternative treatment started. Although there are no case reports to indicate cross sensitivity with other drugs that produce this syndrome, the experience amongst drugs associated with multi-organ hypersensitivity would indicate this to be a possibility [see Patients with a Past History of Hypersensitivity Reaction to Carbamazepine].
Rare reports of pancytopenia, agranulocytosis, and leukopenia have been seen in patients treated with Trileptal during postmarketing experience. Discontinuation of the drug should be considered if any evidence of these hematologic events develop.
Seizure Control During Pregnancy
Due to physiological changes during pregnancy, plasma levels of the active metabolite of oxcarbazepine, the 10monohydroxy derivative (MHD), may gradually decrease throughout pregnancy. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period because MHD levels may return after delivery.
Serum sodium levels below 125 mmol/L have been observed in patients treated with Trileptal [see Hyponatremia]. Experience from clinical trials indicates that serum sodium levels return toward normal when the Trileptal dosage is reduced or discontinued, or when the patient was treated conservatively (e.g., fluid restriction).
Laboratory data from clinical trials suggest that Trileptal use was associated with decreases in T4, without changes in T3 or TSH.
Patient Counseling Information
Patients and caregivers should be informed of the availability of a Medication Guide, and they should be instructed to read the Medication Guide prior to taking Trileptal.
Patients should be advised that Trileptal may reduce the serum sodium concentrations especially if they are taking other medications that can lower sodium. Patients should be advised to report symptoms of low sodium like nausea, tiredness, lack of energy, confusion, and more frequent or more severe seizures [see WARNINGS AND PRECAUTIONS].
Anaphylactic reactions and angioedema may occur during treatment with Trileptal. Patients should be advised to report immediately signs and symptoms suggesting angioedema (swelling of the face, eyes, lips, tongue or difficulty in swallowing or breathing) and to stop taking the drug until they have consulted with their physician [see WARNINGS AND PRECAUTIONS].
Patients who have exhibited hypersensitivity reactions to carbamazepine should be informed that approximately 25%-30% of these patients may experience hypersensitivity reactions with Trileptal. Patients should be advised that if they experience a hypersensitivity reaction while taking Trileptal they should consult with their physician immediately [see WARNINGS AND PRECAUTIONS].
Patients should be advised that serious skin reactions have been reported in association with Trileptal. In the event a skin reaction should occur while taking Trileptal, patients should consult with their physician immediately [see WARNINGS AND PRECAUTIONS].
Patients should be instructed that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug related and should be reported to the physician immediately [see WARNINGS AND PRECAUTIONS].
Patients should be advised that there have been rare reports of blood disorders reported in patients treated with Trileptal. Patients should be instructed to immediately consult with their physician if they experience symptoms suggestive of blood disorders [see WARNINGS AND PRECAUTIONS].
Female patients of childbearing age should be warned that the concurrent use of Trileptal with hormonal contraceptives may render this method of contraception less effective [see DRUG INTERACTIONS]. Additional non-hormonal forms of contraception are recommended when using Trileptal.
Patients, their caregivers, and families should be counseled that AEDs, including Trileptal, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported immediately to healthcare providers.
Caution should be exercised if alcohol is taken in combination with Trileptal therapy, due to a possible additive sedative effect.
Patients should be advised that Trileptal may cause dizziness and somnolence. Accordingly, patients should be advised not to drive or operate machinery until they have gained sufficient experience on Trileptal to gauge whether it adversely affects their ability to drive or operate machinery.
Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 [see Use In Specific Populations].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In two-year carcinogenicity studies, oxcarbazepine was administered in the diet at doses of up to 100 mg/kg/day to mice and by gavage at doses of up to 250 mg/kg/day to rats, and the pharmacologically active 10-hydroxy metabolite (MHD) was administered orally at doses of up to 600 mg/kg/day to rats. In mice, a dose-related increase in the incidence of hepatocellular adenomas was observed at oxcarbazepine doses ≥ 70 mg/kg/day or approximately 0.1 times the maximum recommended human dose (MRHD) on a mg/m² basis. In rats, the incidence of hepatocellular carcinomas was increased in females treated with oxcarbazepine at doses ≥ 25 mg/kg/day (0.1 times the MRHD on a mg/m² basis), and incidences of hepatocellular adenomas and/or carcinomas were increased in males and females treated with MHD at doses of 600 mg/kg/day (2.4 times the MRHD on a mg/m² basis) and ≥ 250 mg/kg/day (equivalent to the MRHD on a mg/m² basis), respectively. There was an increase in the incidence of benign testicular interstitial cell tumors in rats at 250 mg oxcarbazepine/kg/day and at ≥ 250 mg MHD/kg/day, and an increase in the incidence of granular cell tumors in the cervix and vagina in rats at 600 mg MHD/kg/day.
Oxcarbazepine increased mutation frequencies in the Ames test in vitro in the absence of metabolic activation in one of five bacterial strains. Both oxcarbazepine and MHD produced increases in chromosomal aberrations and polyploidy in the Chinese hamster ovary assay in vitro in the absence of metabolic activation. MHD was negative in the Ames test, and no mutagenic or clastogenic activity was found with either oxcarbazepine or MHD in V79 Chinese hamster cells in vitro. Oxcarbazepine and MHD were both negative for clastogenic or aneugenic effects (micronucleus formation) in an in vivo rat bone marrow assay.
Impairment of Fertility
In a fertility study in which rats were administered MHD (50, 150, or 450 mg/kg) orally prior to and during mating and early gestation, estrous cyclicity was disrupted and numbers of corpora lutea, implantations, and live embryos were reduced in females receiving the highest dose (approximately two times the MRHD on a mg/m² basis).
Use In Specific Populations
Trileptal levels may decrease during pregnancy [see WARNINGS AND PRECAUTIONS].
Pregnancy Category C
There are no adequate and well-controlled clinical studies of Trileptal in pregnant women; however, Trileptal is closely related structurally to carbamazepine, which is considered to be teratogenic in humans. Given this fact, and the results of the animal studies described, it is likely that Trileptal is a human teratogen. Trileptal should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Increased incidences of fetal structural abnormalities and other manifestations of developmental toxicity (embryolethality, growth retardation) were observed in the offspring of animals treated with either oxcarbazepine or its active 10-hydroxy metabolite (MHD) during pregnancy at doses similar to the maximum recommended human dose.
When pregnant rats were given oxcarbazepine (30, 300, or 1000 mg/kg) orally throughout the period of organogenesis, increased incidences of fetal malformations (craniofacial, cardiovascular, and skeletal) and variations were observed at the intermediate and high doses (approximately 1.2 and 4 times, respectively, the maximum recommended human dose [MRHD] on a mg/m² basis). Increased embryofetal death and decreased fetal body weights were seen at the high dose. Doses ≥ 300 mg/kg were also maternally toxic (decreased body weight gain, clinical signs), but there is no evidence to suggest that teratogenicity was secondary to the maternal effects.
In a study in which pregnant rabbits were orally administered MHD (20, 100, or 200 mg/kg) during organogenesis, embryofetal mortality was increased at the highest dose (1.5 times the MRHD on a mg/m² basis). This dose produced only minimal maternal toxicity.
In a study in which female rats were dosed orally with oxcarbazepine (25, 50, or 150 mg/kg) during the latter part of gestation and throughout the lactation period, a persistent reduction in body weights and altered behavior (decreased activity) were observed in offspring exposed to the highest dose (0.6 times the MRHD on a mg/m² basis). Oral administration of MHD (25, 75, or 250 mg/kg) to rats during gestation and lactation resulted in a persistent reduction in offspring weights at the highest dose (equivalent to the MRHD on a mg/m² basis).
To provide information regarding the effects of in utero exposure to Trileptal, physicians are advised to recommend that pregnant patients taking Trileptal enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
Labor And Delivery
The effect of Trileptal on labor and delivery in humans has not been evaluated.
Oxcarbazepine and its active metabolite (MHD) are excreted in human milk. A milk-to-plasma concentration ratio of 0.5 was found for both. Because of the potential for serious adverse reactions to Trileptal in nursing infants, a decision should be made about whether to discontinue nursing or to discontinue the drug in nursing women, taking into account the importance of the drug to the mother.
Trileptal is indicated for use as adjunctive therapy for partial seizures in patients aged 2-16 years. Trileptal is also indicated as monotherapy for partial seizures in patients aged 4-16 years. Trileptal has been given to 898 patients between the ages of 1 month-17 years in controlled clinical trials (332 treated as monotherapy) and about 677 patients between the ages of 1 month-17 years in other trials [see ADVERSE REACTIONS for a description of the adverse events associated with Trileptal use in this population].
There were 52 patients over age 65 in controlled clinical trials and 565 patients over the age of 65 in other trials. Following administration of single (300 mg) and multiple (600 mg/day) doses of Trileptal in elderly volunteers (60-82 years of age), the maximum plasma concentrations and AUC values of MHD were 30%-60% higher than in younger volunteers (18-32 years of age). Comparisons of creatinine clearance in young and elderly volunteers indicate that the difference was due to age-related reductions in creatinine clearance.
In renally-impaired patients (creatinine clearance < 30 mL/min), the elimination half-life of MHD is prolonged with a corresponding two-fold increase in AUC [see CLINICAL PHARMACOLOGY]. Trileptal therapy should be initiated at one-half the usual starting dose and increased, if necessary, at a slower than usual rate until the desired clinical response is achieved.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 6/20/2014
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