Drug Safety-related Labeling Changes (SrLC)

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TRILEPTAL (NDA-021014)

(OXCARBAZEPINE)

Safety-related Labeling Changes Approved by FDA Center for Drug Evaluation and Research (CDER)

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09/23/2025 (SUPPL-49)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

Additions and/or revisions underlined:

…

Risk Summary

Although TRILEPTAL is closely related structurally to carbamazepine, which is considered to be teratogenic in humans, available human data from published literature and ongoing pregnancy registry studies on use of oxcarbazepine during pregnancy have not demonstrated an increased prevalence of major congenital malformations with first trimester exposure. However, all published studies reviewed have important methodological limitations, including unmeasured confounding and a small number of exposed cases (see Data). There are risks to the mother and fetus associated with partial onset seizures (see Clinical Considerations). There are no data on the risks associated with the use of TRILEPTAL and miscarriage or other adverse maternal outcomes.

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 (MRHD).

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

Clinical Considerations

Disease-associated Maternal and/or Embryofetal Risk

Epilepsy, with or without exposure to antiepileptic drugs, has been associated with several adverse outcomes during pregnancy, including preeclampsia, preterm labor, antepartum and postpartum hemorrhage, placental abruption, poor fetal growth, prematurity, fetal death, and maternal mortality. The risk of maternal or fetal injury may be greatest for patients with untreated or poorly controlled convulsive seizures. Women with epilepsy who become pregnant should not abruptly discontinue antiepileptic drugs, including TRILEPTAL, due to the risk of status epilepticus or severe seizures, which may be life-threatening [see Warnings and Precautions (5.6)].

Maternal Adverse Reactions

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 [see Warnings and Precautions (5.10)].

Data

Human Data

Data from a published retrospective cohort study and ongoing pregnancy registry studies on the use of oxcarbazepine during pregnancy have not demonstrated an increased prevalence of major congenital malformations with first trimester exposure. A retrospective cohort study conducted in Nordic countries (Denmark, Finland, Iceland, Norway, and Sweden) from 1996-2020 found that there was no increased prevalence of major congenital malformations when pregnancies exposed to oxcarbazepine during the first trimester were compared to pregnancies exposed to lamotrigine (adjusted risk ratio =1.09; 95% CI 0.83 to 1.44; n pregnancies exposed to oxcarbazepine= 1,313, n exposed cases = 58). In an ongoing pregnancy registry that included data from over 40 countries from 1999 to 2022 and 443 pregnancies exposed to oxcarbazepine, oxcarbazepine exposure during the first trimester was not associated with major congenital malformations (adjusted odds ratio =1.09; 95% CI 0.56 to 2.13, n exposed cases = 10). However, there are important methodological limitations of these studies including unmeasured confounding factors and a small number of exposed cases in the registry.

…

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

MEDICATION GUIDE

Additions and/or revisions underlined:

…

Before taking TRILEPTAL, tell your healthcare provider about all your medical conditions, including if you:

…

• are pregnant or plan to become pregnant. It is not known if TRILEPTAL may harm your unborn baby. Tell your healthcare provider right away if you become pregnant while taking TRILEPTAL. You and your healthcare provider will decide if you should take TRILEPTAL while you are pregnant.

  …

  What are the possible side effects of TRILEPTAL?

  …

  The most common side effects of TRILEPTAL include:

• dizziness

• problems with vision

• sleepiness

• trembling

• double vision

• problems with walking and coordination (unsteadiness)

• tiredness

• nausea

• rash

• vomiting

• headache

  …

             

01/04/2019 (SUPPL-43)

Approved Drug Label (PDF)

8 Use in Specific Populations

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

PLLR Conversion; extensive changes. Please refer to label for complete information.

8.4 Pediatric Use

Addition of “-onset” to partial seizures (to read partial-onset seizures) throughout this sub-section.

11/17/2017 (SUPPL-41)

Approved Drug Label (PDF)

7 Drug Interactions

7.1 Effect of TRILEPTAL on Other Drugs

(Additions and/or revisions are underlined)

Phenytoin levels have been shown to increase with concomitant use of TRILEPTAL at doses greater than 1200 mg/day. Therefore, it is recommended that the plasma levels of phenytoin be monitored during the period of TRILEPTAL titration and dosage modification.   A decrease in the dose of phenytoin may be required.

7.2 Effect of Other Drugs on TRILEPTAL

(Additions and/or revisions are underlined)

Strong inducers of cytochrome P450 enzymes and/or inducers of UGT (e.g., rifampin,  carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma/serum levels of MHD, the active metabolite of TRILEPTAL (25% to 49%). If TRILEPTAL and strong CYP3A4 inducers or UGT inducers are administered concurrently, it is recommended that the plasma levels of MHD be monitored during the period of TRILEPTAL titration. Dose adjustment of TRILEPTAL may be required after initiation, dosage modification, or discontinuation of such inducers.

03/23/2017 (SUPPL-36)

Approved Drug Label (PDF)

4 Contraindications

(Additions and/or revisions are underlined)

TRILEPTAL is contraindicated in patients with a known hypersensitivity to oxcarbazepine or to any of its components, or to eslicarbazepine acetate.

5 Warnings and Precautions

5.1 Hyponatremia

(Additions and/or revisions are underlined)

…Cases of symptomatic hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported during postmarketing use…

5.11 Risk of Seizure Aggravation

(Newly added subsection)

Exacerbation of or new onset primary generalized seizures has been reported with TRILEPTAL. The risk of aggravation of primary generalized seizures is seen especially in children but may also occur in adults. In case of seizure aggravation, TRILEPTAL should be discontinued.

5.3 Cross Hypersensitivity Reaction to Carbamazepine

(Additions and/or revisions are underlined; subsection title revised)

Approximately 25% to 30% of patients who have had hypersensitivity reactions to carbamazepine will experience hypersensitivity reactions with TRILEPTAL…

5.6 Withdrawal of AEDs

(Additions and/or revisions are underlined)

As with most antiepileptic drugs, TRILEPTAL should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.

5.7 Cognitive/Neuropsychiatric Adverse Reactions

(Additions and/or revisions are underlined; subsection title revised)

Use of TRILEPTAL has been associated with central nervous system-related adverse reactions…

Patients should be monitored for these signs and symptoms and 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.

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

(Additions and/or revisions are underlined)

…Some of these events have been fatal or life-threatening. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection…

6 Adverse Reactions

(Additions and/or revisions are underlined)

The following serious adverse reactions are described below and elsewhere in the labeling:

• Hyponatremia

• Anaphylactic Reactions and Angioedema

• Cross Hypersensitivity Reaction to Carbamazepine

• Serious Dermatological Reactions

• Suicidal Behavior and Ideation

• Cognitive/Neuropsychiatric Adverse Reactions

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

• Hematologic Events

6.1 Clinical Trials Experience

(Additions and/or revisions are underlined)

Most Common Adverse Reactions in All Clinical Studies

The most common (greater than or equal to 10% more than placebo for adjunctive or low dose for monotherapy) adverse reactions with TRILEPTAL: dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, headache, nystagmus tremor, and abnormal gait.

 

Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Adults Previously Treated with Other AEDs

Table 3 lists adverse reactions that occurred in at least 2% of adult patients with epilepsy treated with TRILEPTAL or placebo as adjunctive treatment and were numerically more common in the patients treated with any dose of TRILEPTAL.

Table 4 lists adverse reactions in patients converted from other AEDs to either high-dose TRILEPTAL (2400 mg/day) or low-dose (300 mg/day) TRILEPTAL.

 

Table 3 Adverse Reactions in a Controlled Clinical Study of Adjunctive Therapy with TRILEPTAL in Adults (Table title has been revised)

Table 4 Adverse Reactions in Controlled Clinical Studies of Monotherapy with TRILEPTAL in Adults Previously Treated with Other AEDs (Table title has been revised)

 

Controlled Clinical Study of Monotherapy in Adults Not Previously Treated with Other AEDs

Table 5 lists adverse reactions in a controlled clinical study of monotherapy in adults not previously treated with other AEDs that occurred in at least 2% of adult patients with epilepsy treated with TRILEPTAL or placebo and were numerically more common in the patients treated with TRILEPTAL.

Table 5 Adverse Reactions in a Controlled Clinical Study of Monotherapy with TRILEPTAL in Adults Not Previously Treated with Other AEDs (Table title has been revised)

 

Controlled Clinical Studies of Adjunctive Therapy/Monotherapy in Pediatric Patients Previously Treated with Other AEDs

Table 6 lists adverse reactions that occurred in at least 2% of pediatric patients with epilepsy treated with TRILEPTAL or placebo as adjunctive treatment and were numerically more common in the patients treated with TRILEPTAL.

Table 6  Adverse Reactions in Controlled Clinical Studies of Adjunctive Therapy/Monotherapy with TRILEPTAL in Pediatric Patients Previously Treated with Other AEDs (Table title has been revised)

6.2 Postmarketing Experience

(Additions and/or revisions are underlined)

The following adverse reactions have been identified during postapproval use of TRILEPTAL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body as a Whole: multi-organ hypersensitivity disorders characterized by features such as rash, fever, lymphadenopathy, abnormal liver function tests, eosinophilia and arthralgia

Cardiovascular System: atrioventricular block

Immune System Disorders: anaphylaxis

Metabolism and Nutrition Disorders: hypothyroidism and syndrome of inappropriate antidiuretic hormone secretion (SIADH)

Injury, Poisoning, and Procedural Complications: fall

Nervous System Disorders: dysarthria

7 Drug Interactions

7.1 Antiepileptic Drugs

Table 7 Summary of AED Interactions with TRILEPTAL (Table has been revised; please refer to label)

8 Use in Specific Populations

8.1 Pregnancy

(Additions and/or revisions are underlined)

Clinical Considerations

TRILEPTAL levels may decrease during pregnancy.

Pregnancy Category C

 

Fetal Risk Summary

… Data on a limited number of pregnancies from pregnancy registries suggest congenital malformations associated with TRILEPTAL monotherapy use (e.g., craniofacial defects such as oral clefts and cardiac malformations such as ventricular septal defects)…

 

Data

Animal

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 (MRHD).

8.4 Pediatric Use

(Additions and/or revisions are underlined)

The safety and effectiveness for use as adjunctive therapy for partial seizures in pediatric patients below the age of 2 have not been established…

The safety and effectiveness for use as monotherapy for partial seizures in pediatric patients below the age of 4 have not been established.

8.5 Geriatric Use

(Additions and/or revisions are underlined)

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

8.6 Renal Impairment

(Additions and/or revisions are underlined)

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

17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)

17 PATIENT COUNSELING INFORMATION

(Additions and/or revisions are underlined)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Administration Information

Counsel patients that TRILEPTAL may be taken with or without food.

For TRILEPTAL oral suspension, advise patients to shake the bottle well and prepare the dose immediately afterwards using the oral dosing syringe supplied. Inform patients that TRILEPTAL oral suspension can be mixed in a small glass of water just prior to administration or, alternatively, may be swallowed directly from the syringe. Instruct patients to discard any unused TRILEPTAL oral suspension after 7 weeks of first opening the bottle.

Hyponatremia

…Instruct patients to report symptoms of low sodium like nausea, tiredness, lack of energy, confusion, and more frequent or more severe seizures.

Anaphylactic Reactions and Angioedema

Anaphylactic reactions and angioedema may occur during treatment with TRILEPTAL…

Cross Hypersensitivity Reaction to Carbamazepine

Inform patients who have exhibited hypersensitivity reactions to carbamazepine that approximately 25% to 30% of these patients may experience hypersensitivity reactions with TRILEPTAL…

Serious Dermatological Reactions

Advise patients that serious skin reactions have been reported in association with TRILEPTAL…

Suicidal Behavior and Ideation

Patients, their caregivers, and families should be counseled that AEDs, including TRILEPTAL, may increase the risk of suicidal thoughts and behavior…

Driving and Operating Machinery

Advise patients that TRILEPTAL may cause adverse reactions such as dizziness, somnolence, ataxia, visual disturbances, and depressed level of consciousness. Accordingly, 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.

Hematologic Events

Advise patients that there have been rare reports of blood disorders reported in patients treated with TRILEPTAL…

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…

Pregnancy Registry

Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant…

MEDICATION GUIDE

(Additions and/or revisions are underlined)

What is the most important information I should know about TRILEPTAL?

TRILEPTAL can cause serious side effects, including:

1. TRILEPTAL may cause the level of sodium in your blood to be low…

…Your healthcare provider may do blood tests to check your sodium levels during your treatment with TRILEPTAL.

 

What is TRILEPTAL?

It is not known if TRILEPTAL is safe and effective for use alone to treat partial seizures in children less than 4 years of age or for use with other medicines to treat partial seizures in children less than 2 years of age.

Do not take TRILEPTAL if you are allergic to TRILEPTAL or any of the other ingredients in TRILEPTAL, or to eslicarbazepine acetate. See the end of this Medication Guide for a complete list of ingredients in TRILEPTAL.

Before taking TRILEPTAL, tell your healthcare provider about all your medical conditions, including if you:

• are breastfeeding or plan to breastfeed. TRILEPTAL passes into breast milk. You and your healthcare provider should decide if you will take TRILEPTAL or breastfeed. You should not do both.

 

How should I take TRILEPTAL?

• Before taking TRILEPTAL oral suspension shake the bottle well and use the oral dosing syringe that comes with your oral suspension to measure the amount of medicine needed…

 

What are the possible side effects of TRILEPTAL?

TRILEPTAL may cause other serious side effects including:

• seizures that can happen more often or become worse, especially in children

 

How should I store TRILEPTAL?

• Store TRILEPTAL film-coated tablets and oral suspension at room temperature between 15°C to 30°C (59°F to 86°F)

• Keep TRILEPTAL film-coated tablets dry

 

What are the ingredients in TRILEPTAL?

Inactive ingredients:

• Film-coated tablets: colloidal silicon dioxide, crospovidone,…