Trileptal

— THERAPEUTIC CATEGORIES —
  • Seizure disorders
PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Trileptal Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Oxcarbazepine 150mg, 300mg, 600mg; tabs.

    Pharmacological Class

    Dibenzazepine.

    See Also

    How Supplied

    Tabs—100; Susp—250mL (w. dosing syringe)

    How Supplied

    150 mg Film-Coated Tablets

    • Pale grey-green, ovaloid, slightly biconvex, scored on both sides. Imprinted with T/D on one side and C/G on the other side.

    • Bottle of 100.

    300 mg Film-Coated Tablets

    • Yellow, ovaloid, slightly biconvex, scored on both sides. Imprinted with TE/TE on one side and CG/CG on the other side. 

    • Bottle of 100.

    600 mg Film-Coated Tablets

    • Light pink, ovaloid, slightly biconvex, scored on both sides. Imprinted with TF/TF on one side and CG/CG on the other side.

    • Bottle of 100.

    Storage

    • Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. 

    Manufacturer

    Novartis Pharmaceuticals Corp

    Mechanism of Action

    The pharmacological activity of Trileptal is primarily exerted through the 10-monohydroxy metabolite (MHD) of oxcarbazepine. The precise mechanism by which oxcarbazepine and MHD exert their anti-seizure effect is unknown; however, in vitro electrophysiological studies indicate that they produce blockade of voltage-sensitive sodium channels, resulting in stabilization of hyperexcited neural membranes, inhibition of repetitive neuronal firing, and diminution of propagation of synaptic impulses. In addition, increased potassium conductance and modulation of high-voltage activated calcium channels may contribute to the anticonvulsant effects of the drug.

    Trileptal Indications

    Indications

    Monotherapy in partial seizures in adults and children ≥4yrs of age. Adjunctive therapy in partial seizures in adults and children ≥2yrs of age.

    Trileptal Dosage and Administration

    Adult

    Give in two equally divided doses. Monotherapy: initially 600mg/day; increase by 300mg/day every 3rd day to 1.2g/day. Adjunctive therapy: initially 600mg/day; may increase by up to 600mg/day at weekly intervals to 1.2g/day. Converting to monotherapy: initially 600mg/day; increase by 600mg/day at weekly intervals to usual max of 2.4g/day; attempt to reach oxcarbazepine max dose in 2–4 weeks while withdrawing other AED over 3–6 weeks (reduce dose of other AED when starting oxcarbazepine). Renal impairment (CrCl <30mL/min): reduce initial dose by ½ and titrate more slowly. Concomitant strong CYP3A4 or UGT inducers: may need oxcarbazepine dose adjustment; monitor.

    Children

    Give in two equally divided doses. Monotherapy: <4yrs: not established. 4–16yrs: initially 8–10mg/kg per day; increase by 5mg/kg per day every 3rd day to max dose (varies with weight; see full labeling). Adjunctive therapy: <2yrs: not established. 2–16yrs: initially 8–10mg/kg per day; usual max 600mg/day; target maintenance doses (attain over 2 weeks): <20kg: initially 16–20mg/kg per day; max 60mg/kg per day; 20–29kg: 900mg/day; 29.1–39kg: 1.2g/day; >39kg: 1.8g/day. Converting to monotherapy (4–16yrs): initially 8–10mg/kg per day; increase by 10mg/kg per day at weekly intervals to max dose (see full labeling) while withdrawing other AED over 3–6 weeks (reduce dose of other AED when starting oxcarbazepine). Renal impairment (CrCl <30mL/min): reduce initial dose by ½ and titrate more slowly. Concomitant strong CYP3A4 or UGT inducers: may need oxcarbazepine dose adjustment; monitor.

    Renal Impairment

    • Dose adjustment is recommended for renally impaired patients (CLcr <30 mL/min).

    Other Modifications

    Females and Males of Reproductive Potential 

    • Contraception: Advise women of reproductive potential taking Trileptal who are using a contraceptive containing ethinyl estradiol or levonorgestrel to use additional or alternative non-hormonal birth control.

     

    Trileptal Contraindications

    Contraindications

    Hypersensitivity to eslicarbazepine.

    Trileptal Boxed Warnings

    Not Applicable

    Trileptal Warnings/Precautions

    Warnings/Precautions

    Risk of hyponatremia; monitor if signs/symptoms occur. Carbamazepine allergy. Discontinue if anaphylaxis or angioedema occurs; do not rechallenge. Evaluate for presence of HLA-B*1502 (esp. in Asians); if present, avoid oxcarbazepine use; increased risk of severe dermatological reactions. Suicidal behavior and ideation (monitor). Discontinue if DRESS/multi-organ hypersensitivity or seizure aggravation occurs. Monitor for seizures during pregnancy and through the postpartum period. Renal impairment. Avoid abrupt cessation. Elderly. Pregnancy. Nursing mothers.

    Warnings/Precautions

    Hyponatremia

    • Clinically significant hyponatremia (sodium <125 mmol/L) can develop during Trileptal 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.

    • Consider measuring serum sodium levels for patients during maintenance treatment with Trileptal, especially if the patient is receiving other medications that are known to decrease serum sodium levels or if symptoms possibly indicating hyponatremia develop.

    Anaphylactic Reactions and Angioedema

    • Discontinue if anaphylaxis or angioedema develops and initiate alternative treatment. Do not rechallenge these patients with Trileptal.

    Cross Hypersensitivity Reaction to Carbamazepine

    • Approximately 25% to 30% of patients who have had hypersensitivity reactions to carbamazepine will experience hypersensitivity reactions with Trileptal.

    • Discontinue immediately if signs or symptoms of hypersensitivity develop.

    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. Recurrence of the serious skin reactions following rechallenge with Trileptal has also been reported.  

    • Consider discontinuing and prescribe another antiepileptic medication if a patient develops a skin reaction while taking Trileptal.

    • Association with HLA-B*1502

      • Increased risk of severe dermatological reactions (SJS/TEN) in patients with HLA-B*1502 (esp. in Asians); evaluate for presence of the HLA-B*1502 allele.

      • Avoid use of Trileptal in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. 

    Suicidal Behavior and Ideation 

    • Increased risk for suicidal thoughts or behavior in patients taking Trileptal. These risks are observed as early as 1 week after starting and persisted for the duration of treatment. 

    • Monitor for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

    • Report behaviors of concern immediately to healthcare providers.

    Withdrawal of AEDs

    • Avoid abrupt cessation. Withdraw gradually due to the increased risk for seizure frequency and status epilepticus.

    • Consider rapid discontinuation if withdrawal is needed due to a serious adverse event.

    Cognitive/Neuropsychiatric Adverse Reactions

    • Monitor patients for cognitive/neuropsychiatric adverse reactions and advise 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.  

    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity

    • Discontinue if DRESS/multi-organ hypersensitivity or seizure aggravation occurs. 

    Hematologic Events

    • 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 develops. 

    Seizure Control During Pregnancy  

    • Monitor closely for seizures during pregnancy and through the postpartum period.

    Risk of Seizure Aggravation 

    • Exacerbation of or new onset primary generalized seizures has been reported. 

    • The risk of aggravation of primary generalized seizures is seen especially in children but may also occur in adults. 

    • Discontinue if seizure aggravation occurs.

    Pregnancy Considerations

    Pregnancy Exposure Registry

    • There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to AEDs, such as Trileptal, during pregnancy. Encourage women who are taking Trileptal during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/.

    Risk Summary 

    • No adequate data on the developmental risks associated with the use of Trileptal in pregnant women.

    • Data on a limited number of pregnancies from pregnancy registries suggest that Trileptal monotherapy use is associated with congenital malformations (eg, craniofacial defects such as oral clefts, and cardiac malformations such as ventricular septal defects).

    Clinical Considerations

    • An increase in seizure frequency may occur during pregnancy because of altered levels of the active metabolite of oxcarbazepine. 

    • Monitor patients carefully during pregnancy and through the postpartum period.

    Nursing Mother Considerations

    Risk Summary

    • Consider the developmental and health benefits of breastfeeding with the mother’s clinical need for Trileptal and any potential adverse effects on the breastfed infant from Trileptal or from the underlying maternal condition.

    Pediatric Considerations

    • Safety and effectiveness for use as adjunctive therapy for partial-onset seizures in pediatric patients below the age of 2 have not been established.

    • Safety and effectiveness for use as monotherapy for partial-onset seizures in pediatric patients below the age of 4 have not been established.

    Geriatric Considerations

    • Close monitoring of sodium levels is required in elderly patients at risk for hyponatremia.

    Renal Impairment Considerations

    • Dose adjustment is recommended for renally impaired patients (CLcr <30 mL/min).

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential 

    • Contraception: Advise women of reproductive potential taking Trileptal who are using a contraceptive containing ethinyl estradiol or levonorgestrel to use additional or alternative non-hormonal birth control.

     

    Trileptal Pharmacokinetics

    Absorption

    • Median time to peak concentration (tmax) for Trileptal tablets: 4.5 (range, 3 to 13) hours.

    • Median tmax for Trileptal oral suspension: 6 hours.

    • Steady-state plasma concentrations are reached within 2 to 3 days.

    Distribution

    • Apparent volume of distribution: 49 L.

    • Approximately 40% of MHD is bound to serum proteins, predominantly to albumin.

    Metabolism

    Hepatic.

    Elimination

    • Renal (>95%), fecal (<4%).

    • Half-life: ~2 hours (oxcarbazepine); ~9 hours (MHD).

    Trileptal Interactions

    Interactions

    Monitor plasma levels of other AEDs (esp. during titration) and adjust if needed; withdraw gradually. Doses >1200mg/day may potentiate concomitant phenytoin; monitor levels and may need to decrease phenytoin dose. Antagonized by strong CYP3A4 or UGT inducers (eg, rifampin, carbamazepine, phenytoin, phenobarbital); see Adults. May decrease effectiveness of hormonal contraceptives containing ethinyl-estradiol or levonorgestrel; use additional or alternative non-hormonal methods. Caution with other drugs that cause hyponatremia. CNS depression potentiated with alcohol, other CNS depressants. May affect thyroid (T4) tests.

    Trileptal Adverse Reactions

    Adverse Reactions

    Dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision or gait, headache, nystagmus, tremor; rash (may be serious, eg, Stevens-Johnson syndrome, toxic epidermal necrolysis), cognitive/neuropsychiatric reactions (monitor), hyponatremia; rare: pancytopenia, agranulocytosis, leukopenia (discontinue if occurs), DRESS; also: patients <4yrs: infections and infestations.

    Trileptal Clinical Trials

    Clinical Trials

    Trileptal Monotherapy Trials 

    • The efficacy of Trileptal as monotherapy was also evaluated in a randomized, controlled, rater-blind, multicenter study in pediatric patients. Results showed that there was not a statistically significant difference between low and high dose Trileptal treatment groups.

    • In a placebo-controlled trial, Trileptal was evaluated in 102 patients 11 to 62 years of age with refractory partial-onset seizures who had completed an inpatient evaluation for epilepsy surgery. Eligible patients were required to have 2 to 10 partial-onset seizures within 48 hours prior to randomization. Patients were randomly assigned to receive placebo or Trileptal 1500 mg/day on Day 1 and 2400 mg/day thereafter for an additional 9 days, or until exit criteria occurred. Results showed that there was a statistically significant difference in favor of Trileptal.

    • In a second placebo-controlled trial, Trileptal was evaluated in 67 patients with newly-diagnosed and recent-onset partial seizures. Patients were randomly assigned to placebo or Trileptal initiated at 300 mg twice a day and titrated to 1200 mg/day in 6 days, then maintenance treatment for 84 days. Results showed that there was a statistically significant difference in favor of Trileptal (P =.046).

    • In a third trial, Trileptal monotherapy at 2400 mg/day was substituted for carbamazepine in 143 patients 12 to 65 years of age whose partial-onset seizures were inadequately controlled on carbamazepine (CBZ) monotherapy at a stable dose of 800 to 1600 mg/day, and maintained this Trileptal dose for 56 days (baseline phase). The difference between the curves was statistically significant in favor of the Trileptal 2400 mg/day group (P =.0001).  

    • A fourth monotherapy substitution trial was conducted in 87 patients 11 to 66 years of age whose seizures were inadequately controlled on 1 or 2 AEDs. Patients were randomly assigned to either Trileptal 2400 mg/day or 300 mg/day and their standard AED regimen(s) were eliminated over the first 6 weeks of double-blind therapy. Double-blind treatment continued for another 84 days (total double-blind treatment of 126 days) or until 1 of the 4 exit criteria described for the previous study occurred. The results were statistically significant in favor of the Trileptal 2400 mg/day group (14/34; 41.2%) compared to the Trileptal 300 mg/day group (42/45; 93.3%) (P <.0001). The time to meeting one of the exit criteria was also statistically significant in favor of the Trileptal 2400 mg/day group (P =.0001).

    • Another monotherapy trial was conducted in 92 pediatric patients 1 month to 16 years of age with inadequately-controlled or new-onset partial seizures. Patients were hospitalized and randomized to either Trileptal 10 mg/kg/day or were titrated up to 40 to 60 mg/kg/day within 3 days while withdrawing the previous AED on the second day of Trileptal. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria in which the difference between the curves was not statistically significant (P =.904). The majority of patients from both dose groups completed the 5-day study without exiting.

     

    Trileptal Adjunctive Therapy Trials 

    • 2 multicenter, randomized, double-blind, placebo-controlled trials evaluated the efficacy of Trileptal as adjunctive therapy for partial-onset seizures in: 692 patients 15 to 66 years of age, and 264 pediatric patients 3 to 17 years of age. Patients were on 1 to 3 concomitant AEDs. Patients were randomly assigned to receive placebo or to a specific dose of Trileptal in addition to other AEDs.

    • In the adult trial, patients received fixed doses of 600, 1200 or 2400 mg/day. In the pediatric trial, patients received maintenance doses in the range of 30 to 46 mg/kg/day, depending on baseline weight. The primary measure of effectiveness in both trials was a between-group comparison of the percentage change in partial-onset seizure frequency in the double-blind treatment phase relative to baseline phase. This comparison was statistically significant in favor of Trileptal at all doses tested in both trials (P =.0001 for all doses for both trials). 

    • The third adjunctive therapy trial enrolled 128 pediatric patients (1 month to <4 years of age) with inadequately-controlled partial-onset seizures on 1 to 2 concomitant AEDs. Patients who experienced at least 2 study-specific seizures (i.e., electrographic partial-onset seizures with a behavioral correlate) during the 72-hour baseline period were randomly assigned to either Trileptal 10 mg/kg/day or were titrated up to 60 mg/kg/day within 26 days. Patients were maintained on their randomized target dose for 9 days and seizures were recorded through continuous video-EEG monitoring during the last 72 hours of the maintenance period. The primary measure of effectiveness in this trial was a between-group comparison of the change in seizure frequency per 24 hours compared to the seizure frequency at baseline. For the entire group of patients enrolled, this comparison was statistically significant in favor of Trileptal 60 mg/kg/day. In this study, there was no evidence that Trileptal was effective in patients below the age of 2 years.

    Trileptal Note

    Notes

    To enroll in the North American Antiepileptic Drug Pregnancy Registry call (888) 233-2334.

    Trileptal Patient Counseling

    Patient Counseling

    Hyponatremia

    • Advise patients to report symptoms of low sodium (eg, nausea, tiredness, lack of energy, confusion, and more frequent or more severe seizures.

    Anaphylactic Reactions and Angioedema

    • Advise patients to report immediately any signs and symptoms suggesting angioedema and to stop taking the drug until consulting a health care provider.

    Cross Hypersensitivity Reaction to Carbamazepine

    • Approximately 25% to 30% of patients who have had hypersensitivity reactions to carbamazepine will experience hypersensitivity reactions with Trileptal.

    • Advise patients to discontinue immediately if signs or symptoms of hypersensitivity develop.

    Serious Dermatological Reactions  

    • Consult a healthcare provider if a skin reaction occurs while taking Trileptal.  

    Suicidal Behavior and Ideation 

    • Increased risk for suicidal thoughts or behavior in patients taking Trileptal. Counsel patients, caregivers, and families for the risk for suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

    • Report behaviors of concern immediately to healthcare providers.

    Driving and Operating Machinery

    • Advise patients 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.

    Multi-Organ Hypersensitivity 

    • Instruct patients that a fever associated with other organ system involvement (e.g., rash, lymphadenopathy, hepatic dysfunction) may be drug-related and should be reported to their healthcare provider immediately.

    Cognitive/Neuropsychiatric Adverse Reactions

    • Monitor patients for cognitive/neuropsychiatric adverse reactions and advise 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.  

    Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity

    • Discontinue if DRESS/multi-organ hypersensitivity or seizure aggravation occurs. 

    Hematologic Events

    • Advise patients that there have been rare reports of blood disorders. Consult healthcare provider immediately if symptoms suggestive of blood disorders occur.

    Drug Interactions

    • Caution female patients of reproductive potential that the concurrent use of Trileptal with hormonal contraceptives may render this method of contraception less effective. Additional non-hormonal forms of contraception are recommended when using Trileptal. Caution should be exercised if alcohol is taken in combination with Trileptal, due to a possible additive sedative effect. 

    Pregnancy Registry  

    • Encourage patients 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.

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