TRILEPTAL- oxcarbazepine tablet, film coated

Trileptal by

Drug Labeling and Warnings

Trileptal by is a Prescription medication manufactured, distributed, or labeled by PD-Rx Pharmaceuticals, Inc.. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

• HIGHLIGHTS OF PRESCRIBING INFORMATION

  These highlights do not include all the information needed to use TRILEPTAL safely and effectively. See full prescribing information for TRILEPTAL.
  
  TRILEPTAL ® (oxcarbazepine) film-coated tablets, for oral use
  
  Initial U.S. Approval: 2000

  INDICATIONS AND USAGE

  TRILEPTAL is indicated for:

  • Adults: Monotherapy or adjunctive therapy in the treatment of partial-onset seizures
    
  • Pediatrics:
    - Monotherapy in the treatment of partial-onset seizures in children 4–16 years
    - Adjunctive therapy in the treatment of partial-onset seizures in children 2–16 years ( 1)

  DOSAGE AND ADMINISTRATION

  Adults:  initiate with a dose of 600 mg/day, given twice-a-day

  • Adjunctive Therapy: Maximum increment of 600 mg/day at approximately weekly intervals. The recommended daily dose is 1200 mg/day ( 2.1)
    
  • Conversion to Monotherapy: withdrawal concomitant over 3 to 6 weeks; reach maximum dose of TRILEPTAL in 2 to 4 weeks with increments of 600 mg/day at weekly intervals to a recommended daily dose of 2400 mg/day ( 2.2)
    
  • Initiation of Monotherapy: Increments of 300 mg/day every third day to a dose of 1200 mg/day ( 2.3)
    
  • Initiate at one-half the usual starting dose and increase slowly in patients with a creatinine clearance < 30 mL/min ( 2.7)

  Pediatrics: initiation with 8 to 10 mg/kg/day, given twice-a-day. For patients aged 2 to < 4 years and under 20 kg, a starting dose of 16 to 20 mg/kg/day may be considered. Recommended daily dose is dependent upon patient weight.

  • Adjunctive Patients (Aged 2–16 Years): For patients aged 4 to 16 years, target maintenance dose should be achieved over 2 weeks ( 2.4). For patients aged 2 to < 4 years, maximum maintenance dose should be achieved over 2 to 4 weeks and should not to exceed 60 mg/kg/day ( 2.4)
    
  • Conversion to Monotherapy for Patients (Aged 4–16 Years): Maximum increment of 10 mg/kg/day at weekly intervals, concomitant antiepileptic drugs can be completely withdrawn over 3 to 6 weeks ( 2.5)
    
  • Initiation of Monotherapy for Patients (Aged 4–16 Years): Increments of 5 mg/kg/day every third day ( 2.6)

  DOSAGE FORMS AND STRENGTHS

  • Film-coated tablets: 150 mg, 300 mg and 600 mg ( 3)
    
  • Oral suspension: 300 mg/5 mL (60 mg/mL) ( 3)

  CONTRAINDICATIONS

  Known hypersensitivity to oxcarbazepine or to any of its components, or to eslicarbazepine acetate ( 4, 5.2)

  WARNINGS AND PRECAUTIONS

  • Hyponatremia: Monitor serum sodium levels ( 5.1)
    
  • Cross Hypersensitivity Reaction to Carbamazepine: Discontinue immediately if hypersensitivity occurs ( 5.3)
    
  • Serious Dermatological Reactions: If occurs, consider discontinuation ( 5.4)
    
  • Suicidal Behavior and Ideation: Monitor for suicidal thoughts/behavior ( 5.5)
    
  • Withdrawal of AEDs:  Withdraw TRILEPTAL  gradually ( 5.6)
    
  • Cognitive/Neuropsychiatric Adverse Reactions: May cause cognitive dysfunction, somnolence, and coordination abnormalities. Use caution when operating machinery ( 5.7)
    
  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity: Monitor and discontinue if another cause cannot be established ( 5.8)
    
  • Hematologic Events: Consider discontinuing ( 5.9)
    
  • Seizure Control During Pregnancy: Active metabolite may decrease ( 5.10)
    
  • Risk of Seizure Aggravation: Discontinue if occurs ( 5.11)

  ADVERSE REACTIONS

  The most common (≥ 10% more than placebo for adjunctive or low dose for monotherapy) adverse reactions in adults and pediatrics were: dizziness, somnolence, diplopia, fatigue, nausea, vomiting, ataxia, abnormal vision, headache, nystagmus, tremor, and abnormal gait. ( 6.1)

  
  

  To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

  DRUG INTERACTIONS

  • Phenytoin: Increased phenytoin levels. Reduced dose of phenytoin may be required ( 7.1)
    
  • Carbamazepine, Phenytoin, and Phenobarbital: Decreased plasma levels of MHD (the active metabolite). Dose adjustments may be necessary ( 7.1)
    
  • Oral Contraceptive: TRILEPTAL may decrease the effectiveness of hormonal contraceptives ( 7.3)

  USE IN SPECIFIC POPULATIONS

  • Pregnancy: May cause fetal harm ( 8.1)

  See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

  Revised: 1/2019

• Table of Contents

  FULL PRESCRIBING INFORMATION: CONTENTS*

  1       INDICATIONS AND USAGE

  2       DOSAGE AND ADMINISTRATION

  2.1       Adjunctive Therapy for Adults

  2.2       Conversion to Monotherapy for Adults

  2.3       Initiation of Monotherapy for Adults

  2.4       Adjunctive Therapy for Pediatric Patients (Aged 2–16 Years) 

  2.5       Conversion to Monotherapy for Pediatric Patients (Aged 4–16 Years) 

  2.6       Initiation of Monotherapy for Pediatric Patients (Aged 4–16 Years) 

  2.7       Dosage Modification for Patients with Renal Impairment

  2.8       Administration Information

  3       DOSAGE FORMS AND STRENGTHS

  4       CONTRAINDICATIONS

  5       WARNINGS AND PRECAUTIONS

  5.1        Hyponatremia 

  5.2       Anaphylactic Reactions and Angioedema

  5.3       Cross Hypersensitivity Reaction to Carbamazepine 

  5.4       Serious Dermatological Reactions

  5.5       Suicidal Behavior and Ideation

  5.6       Withdrawal of AEDs

  5.7       Cognitive/Neuropsychiatric Adverse Reactions

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

  5.9       Hematologic Events

  5.10       Seizure Control During Pregnancy

  5.11       Risk of Seizure Aggravation

  6       ADVERSE REACTIONS

  6.1       Clinical Trials Experience

  6.2       Postmarketing Experience

  7       DRUG INTERACTIONS

  7.1       Effect of TRILEPTAL on Other Drugs

  7.2       Effect of Other Drugs on TRILEPTAL

  7.3       Hormonal Contraceptives

  8       USE IN SPECIFIC POPULATIONS

  8.1       Pregnancy

  8.2       Lactation

  8.3       Females and Males of Reproductive Potential

  8.4       Pediatric Use

  8.5       Geriatric Use 

  8.6       Renal Impairment 

  9       DRUG ABUSE AND DEPENDENCE

  9.2       Abuse

  9.3       Dependence

  10       OVERDOSAGE

  10.1       Human Overdose Experience

  10.2       Treatment and Management

  11       DESCRIPTION

  12       CLINICAL PHARMACOLOGY

  12.1       Mechanism of Action

  12.2       Pharmacodynamics

  12.3       Pharmacokinetics

  13       NONCLINICAL TOXICOLOGY

  13.1       Carcinogenesis, Mutagenesis, Impairment of Fertility

  14       CLINICAL STUDIES

  14.1       TRILEPTAL Monotherapy Trials

  14.2       TRILEPTAL Adjunctive Therapy Trials

  16       HOW SUPPLIED/STORAGE AND HANDLING

  17       PATIENT COUNSELING INFORMATION

  * Sections or subsections omitted from the full prescribing information are not listed.

1       INDICATIONS AND USAGE

TRILEPTAL is indicated for use as monotherapy or adjunctive therapy in the treatment of partial-onset seizures in adults and as monotherapy in the treatment of partial-onset seizures in pediatric patients aged 4 years and above, and as adjunctive therapy in pediatric patients aged 2 years and above with partial-onset seizures.

2       DOSAGE AND ADMINISTRATION

2.1       Adjunctive Therapy for Adults

Initiate TRILEPTAL with a dose of 600 mg/day, given twice-a-day. If clinically indicated, the dose may be increased by a maximum of 600 mg/day at approximately weekly intervals; the maximum recommended daily dose is 1200 mg/day. Daily doses above 1200 mg/day show somewhat greater effectiveness in controlled trials, but most patients were not able to tolerate the 2400 mg/day dose, primarily because of CNS effects.

Dosage adjustment is recommended with concomitant use of strong CYP3A4 enzyme inducers or UGT inducers, which include certain antiepileptic drugs (AEDs) [ see Drug Interactions (7.1, 7.2)].

2.2       Conversion to Monotherapy for Adults

Patients receiving concomitant AEDs may be converted to monotherapy by initiating treatment with TRILEPTAL at 600 mg/day (given in a twice-a-day regimen) while simultaneously initiating the reduction of the dose of the concomitant AEDs. The concomitant AEDs should be completely withdrawn over 3 to 6 weeks, while the maximum dose of TRILEPTAL should be reached in about 2 to 4 weeks. TRILEPTAL may be increased as clinically indicated by a maximum increment of 600 mg/day at approximately weekly intervals to achieve the maximum recommended daily dose of 2400 mg/day. A daily dose of 1200 mg/day has been shown in one study to be effective in patients in whom monotherapy has been initiated with TRILEPTAL. Patients should be observed closely during this transition phase.

2.3       Initiation of Monotherapy for Adults

Patients not currently being treated with AEDs may have monotherapy initiated with TRILEPTAL. In these patients, initiate TRILEPTAL at a dose of 600 mg/day (given a twice-a-day); the dose should be increased by 300 mg/day every third day to a dose of 1200 mg/day. Controlled trials in these patients examined the effectiveness of a 1200 mg/day dose; a dose of 2400 mg/day has been shown to be effective in patients converted from other AEDs to TRILEPTAL monotherapy (see above).

2.4       Adjunctive Therapy for Pediatric Patients (Aged 2–16 Years) 

In pediatric patients aged 4–16 years, initiate TRILETPAL at a daily dose of 8 to 10 mg/kg generally not to exceed 600 mg/day, given twice-a-day. The target maintenance dose of TRILEPTAL should be achieved over 2 weeks, and is dependent upon patient weight, according to the following chart:

      20 to 29 kg–900 mg/day

      29.1 to 39 kg–1200 mg/day

      > 39 kg–1800 mg/day

In the clinical trial, in which the intention was to reach these target doses, the median daily dose was 31 mg/kg with a range of 6 to 51 mg/kg.

In pediatric patients aged 2 to < 4 years, initiate TRILEPTAL at a daily dose of 8 to 10 mg/kg generally not to exceed 600 mg/day, given twice-a-day. For patients less than 20 kg, a starting dose of 16 to 20 mg/kg may be considered [ see Clinical Pharmacology (12.3)]. The maximum maintenance dose of TRILEPTAL should be achieved over 2 to 4 weeks and should not exceed 60 mg/kg/day in a twice-a-day regimen.

In the clinical trial in pediatric patients (2 to 4 years of age), in which the intention was to reach the target dose of 60 mg/kg/day, 50% of patients reached a final dose of at least 55 mg/kg/day.

Under adjunctive therapy (with and without enzyme-inducing AEDs), when normalized by body weight, apparent clearance (L/hr/kg) decreased when age increased such that children 2 to < 4 years of age may require up to twice the oxcarbazepine dose per body weight compared to adults; and children 4 to ≤ 12 years of age may require a 50% higher oxcarbazepine dose per body weight compared to adults.

Dosage adjustment is recommended with concomitant use of strong CYP3A4 enzyme inducers or UGT inducers, which include certain antiepileptic drugs (AEDs) [ see Drug Interactions (7.1, 7.2)].

2.5       Conversion to Monotherapy for Pediatric Patients (Aged 4–16 Years) 

Patients receiving concomitant AEDs may be converted to monotherapy by initiating treatment with TRILEPTAL at approximately 8 to 10 mg/kg/day given twice-a-day, while simultaneously initiating the reduction of the dose of the concomitant AEDs. The concomitant AEDs can be completely withdrawn over 3 to 6 weeks, while TRILEPTAL may be increased as clinically indicated by a maximum increment of 10 mg/kg/day at approximately weekly intervals to achieve the recommended daily dose. Patients should be observed closely during this transition phase.

The recommended total daily dose of TRILEPTAL is shown in Table 1.

2.6       Initiation of Monotherapy for Pediatric Patients (Aged 4–16 Years) 

Patients not currently being treated with AEDs may have monotherapy initiated with TRILEPTAL. In these patients, initiate TRILEPTAL at a dose of 8 to 10 mg/kg/day given twice-a-day. The dose should be increased by 5 mg/kg/day every third day to the recommended daily dose shown in the table below.

Table 1: Range of Maintenance Doses of TRILEPTAL for Pediatrics by Weight During Monotherapy

	From	To
Weight in kg	Dose (mg/day)	Dose (mg/day)
20	600	900
25	900	1200
30	900	1200
35	900	1500
40	900	1500
45	1200	1500
50	1200	1800
55	1200	1800
60	1200	2100
65	1200	2100
70	1500	2100

2.7       Dosage Modification for Patients with Renal Impairment

In patients with impaired renal function (creatinine clearance < 30 mL/min), initiate TRILEPTAL at one-half the usual starting dose (300 mg/day, given twice-a-day), and increase slowly to achieve the desired clinical response [ see Clinical Pharmacology  (12.3)].

2.8       Administration Information

TRILEPTAL can be taken with or without food [ see Clinical Pharmacology (12.3)].

Before using TRILEPTAL oral suspension, shake the bottle well and prepare the dose immediately afterwards. The prescribed amount of oral suspension should be withdrawn from the bottle using the oral dosing syringe supplied. 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. After each use, close the bottle and rinse the syringe with warm water, and allow it to dry thoroughly.

TRILEPTAL oral suspension and TRILEPTAL film-coated tablets may be interchanged at equal doses. 

3       DOSAGE FORMS AND STRENGTHS

Film-coated Tablets:

• 150 mg: pale grey-green, ovaloid, slightly biconvex, scored on both sides. Imprinted with T/D on one side and C/G on the other side. 
  
• 300 mg: yellow, ovaloid, slightly biconvex, scored on both sides. Imprinted with TE/TE on one side and CG/CG on the other side.
  
• 600 mg: light pink, ovaloid, slightly biconvex, scored on both sides. Imprinted with TF/TF on one side and CG/CG on the other side.

Oral Suspension: 

• 300 mg/5 mL (60 mg/mL): off-white to slightly brown or slightly red suspension.

4       CONTRAINDICATIONS

TRILEPTAL is contraindicated in patients with a known hypersensitivity to oxcarbazepine or to any of its components, or to eslicarbazepine acetate [ see Warnings and Precautions (5.2, 5.3)].

5       WARNINGS AND PRECAUTIONS

5.1        Hyponatremia 

Clinically significant hyponatremia (sodium < 125 mmol/L) can develop during TRILEPTAL use. In the 14 controlled epilepsy studies, 2.5% of TRILEPTAL-treated patients (38/1524) 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 3 months of treatment with TRILEPTAL, although there were patients who first developed a serum sodium < 125 mmol/L more than 1 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 and syndrome of inappropriate antidiuretic hormone secretion (SIADH) have been reported during postmarketing 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 (e.g., 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).

5.2       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 Warnings and Precautions (5.3)].

5.3       Cross Hypersensitivity Reaction to Carbamazepine 

Approximately 25% to 30% of patients who have had hypersensitivity reactions to carbamazepine 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 Warnings and Precautions (5.2, 5.8)].

5.4       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 HLAB*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 HLA-B*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.

5.5       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 4 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 to 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 1000 Patients	Drug Patients With Events Per 1000 Patients	Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients	Risk Difference: Additional Drug Patients with Events Per 1000 Patients
Epilepsy	1.0	3.4	3.5	2.4
Psychiatric	5.7	8.5	1.5	2.9
Other	1.0	1.8	1.9	0.9
Total	2.4	4.3	1.8	1.9

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.

5.6       Withdrawal of AEDs

As with most antiepileptic drugs, TRILEPTAL should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus [ see Dosage and Administration (2.4) and Clinical Studies (14)]. But if withdrawal is needed because of a serious adverse event, rapid discontinuation can be considered.

5.7       Cognitive/Neuropsychiatric Adverse Reactions

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

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.

Adult Patients

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 reaction. 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 7 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 2 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 reactions 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.

Pediatric Patients

A study was conducted in pediatric patients (3 to 17 years old) with inadequately controlled partial-onset seizures in which TRILEPTAL was added to existing AED therapy (up to 2 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 reaction 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.

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

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multi-organ hypersensitivity, has occurred with TRILEPTAL.  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. Eosinophilia is often present. This disorder is variable in its expression, and other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity (e.g., fever, lymphadenopathy) may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. TRILEPTAL should be discontinued if an alternative etiology for the signs or symptoms cannot be established.

5.9       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.

5.10       Seizure Control During Pregnancy

Due to physiological changes during pregnancy, plasma levels of the active metabolite of oxcarbazepine, the 10-monohydroxy 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. 

5.11       Risk of Seizure Aggravation

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.

6       ADVERSE REACTIONS

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

• Hyponatremia [see Warnings and Precautions (5.1)]
  
• Anaphylactic Reactions and Angioedema [see Warnings and Precautions (5.2)]
  
• Cross Hypersensitivity Reaction to Carbamazepine [see Warnings and Precautions (5.3)]
  
• Serious Dermatological Reactions [see Warnings and Precautions (5.4)]
  
• Suicidal Behavior and Ideation [see Warnings and Precautions (5.5)]
  
• Cognitive/Neuropsychiatric Adverse Reactions  [see Warnings and Precautions (5.7)]
  
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ Hypersensitivity [see Warnings and Precautions (5.8)]
  
• Hematologic Events [see Warnings and Precautions (5.9)]

6.1       Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Most Common Adverse Reactions in All Clinical Studies

Adjunctive Therapy/Monotherapy in Adults Previously Treated with Other AEDs

The most common (≥ 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.

Approximately 23% of these 1537 adult patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: dizziness (6.4%), diplopia (5.9%), ataxia (5.2%), vomiting (5.1%), nausea (4.9%), somnolence (3.8%), headache (2.9%), fatigue (2.1%), abnormal vision (2.1%), tremor (1.8%), abnormal gait (1.7%), rash (1.4%), and hyponatremia (1.0%).

Monotherapy in Adults Not Previously Treated With Other AEDs

The most common (≥ 5%) adverse reactions with TRILEPTAL in these patients were similar to those in previously treated patients.

Approximately 9% of these 295 adult patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: dizziness (1.7%), nausea (1.7%), rash (1.7%), and headache (1.4%).

Adjunctive Therapy/Monotherapy in Pediatric Patients 4 Years Old and Above Previously Treated With Other AEDs

The most common (≥ 5%) adverse reactions with TRILEPTAL in these patients were similar to those seen in adults.

Approximately 11% of these 456 pediatric patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: somnolence (2.4%), vomiting (2.0%), ataxia (1.8%), diplopia (1.3%), dizziness (1.3%), fatigue (1.1%), and nystagmus (1.1%).

Monotherapy in Pediatric Patients 4 Years Old and Above Not Previously Treated With Other AEDs

The most common (≥ 5%) adverse reactions with TRILEPTAL in these patients were similar to those in adults.

Approximately 9.2% of 152 pediatric patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated (≥ 1%) with discontinuation were rash (5.3%) and maculopapular rash (1.3%).

Adjunctive Therapy/Monotherapy in Pediatric Patients 1 Month to < 4 Years Old Previously Treated or Not Previously Treated with Other AEDs:

The most common (≥ 5%) adverse reactions with TRILEPTAL in these patients were similar to those seen in older children and adults except for infections and infestations which were more frequently seen in these younger children.

Approximately 11% of these 241 pediatric patients discontinued treatment because of an adverse reaction. The adverse reactions most commonly associated with discontinuation were: convulsions (3.7%), status epilepticus (1.2%), and ataxia (1.2%).

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. Note that in some of these monotherapy studies patients who dropped out during a preliminary tolerability phase are not included in the tables.

Table 3:  Adverse Reactions in a Controlled Clinical Study of Adjunctive Therapy with TRILEPTAL in Adults

	TRILEPTAL Dosage (mg/day)
Body System/; Adverse Reaction	TRILEPTAL 600; N = 163; %	TRILEPTAL; 1200; N = 171; %	TRILEPTAL; 2400; N = 126; %	Placebo; N = 166; %
Body as a Whole
Fatigue	15	12	15	7
Asthenia	6	3	6	5
Leg Edema	2	1	2	1
Increased Weight	1	2	2	1
Feeling Abnormal	0	1	2	0
Cardiovascular System
Hypotension	0	1	2	0
Digestive System
Nausea	15	25	29	10
Vomiting	13	25	36	5
Abdominal Pain	10	13	11	5
Diarrhea	5	6	7	6
Dyspepsia	5	5	6	2
Constipation	2	2	6	4
Gastritis	2	1	2	1
Metabolic and Nutritional Disorders
Hyponatremia	3	1	2	1
Musculoskeletal System
Muscle Weakness	1	2	2	0
Sprains and Strains	0	2	2	1
Nervous System
Headache	32	28	26	23
Dizziness	26	32	49	13
Somnolence	20	28	36	12
Ataxia	9	17	31	5
Nystagmus	7	20	26	5
Abnormal Gait	5	10	17	1
Insomnia	4	2	3	1
Tremor	3	8	16	5
Nervousness	2	4	2	1
Agitation	1	1	2	1
Abnormal Coordination	1	3	2	1
Abnormal EEG	0	0	2	0
Speech Disorder	1	1	3	0
Confusion	1	1	2	1
Cranial Injury NOS	1	0	2	1
Dysmetria	1	2	3	0
Abnormal Thinking	0	2	4	0
Respiratory System
Rhinitis	2	4	5	4
Skin and Appendages
Acne	1	2	2	0
Special Senses
Diplopia	14	30	40	5
Vertigo	6	12	15	2
Abnormal Vision	6	14	13	4
Abnormal Accommodation	0	0	2	0

Table 4:  Adverse Reactions in Controlled Clinical Studies of Monotherapy with TRILEPTAL in Adults Previously Treated with Other AEDs

Body System/; Adverse Reaction	TRILEPTAL; 2400 mg/day; N = 86; %	TRILEPTAL; 300 mg/day; N = 86; %
Body as a Whole
Fatigue	21	5
Fever	3	0
Allergy	2	0
Generalized Edema	2	1
Chest Pain	2	0
Digestive System
Nausea	22	7
Vomiting	15	5
Diarrhea	7	5
Dyspepsia	6	1
Anorexia	5	3
Abdominal Pain	5	3
Dry Mouth	3	0
Hemorrhage Rectum	2	0
Toothache	2	1
Hemic and Lymphatic System
Lymphadenopathy	2	0
Infections and Infestations
Viral Infection	7	5
Infection	2	0
Metabolic and Nutritional Disorders
Hyponatremia	5	0
Thirst	2	0
Nervous System
Headache	31	15
Dizziness	28	8
Somnolence	19	5
Anxiety	7	5
Ataxia	7	1
Confusion	7	0
Nervousness	7	0
Insomnia	6	3
Tremor	6	3
Amnesia	5	1
Aggravated Convulsions	5	2
Emotional Lability	3	2
Hypoesthesia	3	1
Abnormal Coordination	2	1
Nystagmus	2	0
Speech Disorder	2	0
Respiratory System
Upper Respiratory Tract Infection	10	5
Coughing	5	0
Bronchitis	3	0
Pharyngitis	3	0
Skin and Appendages
Hot Flushes	2	1
Purpura	2	0
Special Senses
Abnormal Vision	14	2
Diplopia	12	1
Taste Perversion	5	0
Vertigo	3	0
Earache	2	1
Ear Infection NOS	2	0
Urogenital and Reproductive System
Urinary Tract Infection	5	1
Micturition Frequency	2	1
Vaginitis	2	0

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

Body System/; Adverse Reaction	TRILEPTAL; N = 55; %	Placebo; N = 49; %
Body as a Whole
Falling Down NOS	4	0
Digestive System
Nausea	16	12
Diarrhea	7	2
Vomiting	7	6
Constipation	5	0
Dyspepsia	5	4
Musculoskeletal System
Back Pain	4	2
Nervous System
Dizziness	22	6
Headache	13	10
Ataxia	5	0
Nervousness	5	2
Amnesia	4	2
Abnormal Coordination	4	2
Tremor	4	0
Respiratory System
Upper Respiratory Tract Infection	7	0
Epistaxis	4	0
Infection Chest	4	0
Sinusitis	4	2
Skin and Appendages
Rash	4	2
Special Senses
Vision Abnormal	4	0

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

Body System/; Adverse Reaction	TRILEPTAL; N = 171; %	Placebo; N = 139; %
Body as a Whole
Fatigue	13	9
Allergy	2	0
Asthenia	2	1
Digestive System
Vomiting	33	14
Nausea	19	5
Constipation	4	1
Dyspepsia	2	0
Nervous System
Headache	31	19
Somnolence	31	13
Dizziness	28	8
Ataxia	13	4
Nystagmus	9	1
Emotional Lability	8	4
Abnormal Gait	8	3
Tremor	6	4
Speech Disorder	3	1
Impaired Concentration	2	1
Convulsions	2	1
Involuntary Muscle Contractions	2	1
Respiratory System
Rhinitis	10	9
Pneumonia	2	1
Skin and Appendages
Bruising	4	2
Increased Sweating	3	0
Special Senses
Diplopia	17	1
Abnormal Vision	13	1
Vertigo	2	0

Other Events Observed in Association with the Administration of TRILEPTAL

In the paragraphs that follow, the adverse reactions, other than those in the preceding tables or text, that occurred in a total of 565 children and 1574 adults exposed to TRILEPTAL and that are reasonably likely to be related to drug use are presented. Events common in the population, events reflecting chronic illness and events likely to reflect concomitant illness are omitted particularly if minor. They are listed in order of decreasing frequency. Because the reports cite events observed in open label and uncontrolled trials, the role of TRILEPTAL in their causation cannot be reliably determined.

Body as a Whole: fever, malaise, pain chest precordial, rigors, weight decrease

Cardiovascular System: bradycardia, cardiac failure, cerebral hemorrhage, hypertension, hypotension postural, palpitation, syncope, tachycardia

Digestive System: appetite increased, blood in stool, cholelithiasis, colitis, duodenal ulcer, dysphagia, enteritis, eructation, esophagitis, flatulence, gastric ulcer, gingival bleeding, gum hyperplasia, hematemesis, hemorrhage rectum, hemorrhoids, hiccup, mouth dry, pain biliary, pain right hypochondrium, retching, sialoadenitis, stomatitis, stomatitis ulcerative

Hematologic and Lymphatic System: thrombocytopenia

Laboratory Abnormality: gamma-GT increased, hyperglycemia, hypocalcemia, hypoglycemia, hypokalemia, liver enzymes elevated, serum transaminase increased

Musculoskeletal System: hypertonia muscle

Nervous System: aggressive reaction, amnesia, anguish, anxiety, apathy, aphasia, aura, convulsions aggravated, delirium, delusion, depressed level of consciousness, dysphonia, dystonia, emotional lability, euphoria, extrapyramidal disorder, feeling drunk, hemiplegia, hyperkinesia, hyperreflexia, hypoesthesia, hypokinesia, hyporeflexia, hypotonia, hysteria, libido decreased, libido increased, manic reaction, migraine, muscle contractions involuntary, nervousness, neuralgia, oculogyric crisis, panic disorder, paralysis, paroniria, personality disorder, psychosis, ptosis, stupor, tetany

Respiratory System: asthma, dyspnea, epistaxis, laryngismus, pleurisy

Skin and Appendages: acne, alopecia, angioedema, bruising, dermatitis contact, eczema, facial rash, flushing, folliculitis, heat rash, hot flushes, photosensitivity reaction, pruritus genital, psoriasis, purpura, rash erythematous, rash maculopapular, vitiligo, urticaria

Special Senses: accommodation abnormal, cataract, conjunctival hemorrhage, edema eye, hemianopia, mydriasis, otitis externa, photophobia, scotoma, taste perversion, tinnitus, xerophthalmia

Surgical and Medical Procedures: procedure dental oral, procedure female reproductive, procedure musculoskeletal, procedure skin

Urogenital and Reproductive System: dysuria, hematuria, intermenstrual bleeding, leukorrhea, menorrhagia, micturition frequency, pain renal, pain urinary tract, polyuria, priapism, renal calculus

Other: Systemic lupus erythematosus

Laboratory Tests

Serum sodium levels below 125 mmol/L have been observed in patients treated with TRILEPTAL [ see Warnings and Precautions  (5.1)]. 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 T 4, without changes in T 3 or TSH.

6.2       Postmarketing Experience

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 [ see Warnings and Precautions (5.8)]

Cardiovascular System: atrioventricular block

Immune System Disorders: anaphylaxis [ see Warnings and Precautions (5.2)]

Digestive System: pancreatitis and/or lipase and/or amylase increase

Hematologic and Lymphatic Systems: aplastic anemia [ see Warnings and Precautions (5.9)]

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

Skin and Subcutaneous Tissue Disorders: erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis [ see Warnings and Precautions (5.4)], Acute Generalized Exanthematous Pustulosis (AGEP)

Musculoskeletal, Connective Tissue and Bone Disorders: There have been reports of decreased bone mineral density, osteoporosis and fractures in patients on long-term therapy with TRILEPTAL.

Injury, Poisoning, and Procedural Complications: fall

Nervous System Disorders: dysarthria

7       DRUG INTERACTIONS

7.1       Effect of TRILEPTAL on Other Drugs

Phenytoin levels have been shown to increase with concomitant use of TRILEPTAL at doses greater than 1200 mg/day [see Clinical Pharmacology (12.3)]. 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

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%)   [see Clinical Pharmacology (12.3)]. 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.

7.3       Hormonal Contraceptives

Concurrent use of TRILEPTAL with hormonal contraceptives may render these contraceptives less effective [see Use in Specific Populations (8.3) and Clinical Pharmacology (12.3)]. Studies with other oral or implant contraceptives have not been conducted.

8       USE IN SPECIFIC POPULATIONS

8.1       Pregnancy

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

There are no adequate data on the developmental risks associated with the use of TRILEPTAL in pregnant women; however, TRILEPTAL is closely related structurally to carbamazepine, which is considered to be teratogenic in humans. Data on a limited number of pregnancies from pregnancy registries suggest that TRILEPTAL monotherapy use is associated with congenital malformations (e.g., craniofacial defects such as oral clefts, and cardiac malformations such as ventricular septal defects). 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 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown.

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 [see Warnings and Precautions (5.10)].

Data

Human Data

Data from published registries have reported craniofacial defects such as oral clefts and cardiac malformations such as ventricular septal defects in children with prenatal oxcarbazepine exposure.

Animal Data

When pregnant rats were given oxcarbazepine (0, 30, 300, or 1000 mg/kg/day) 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 MRHD on a mg/m 2 basis). Increased embryofetal death and decreased fetal body weights were seen at the high dose. Doses ≥300 mg/kg/day 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 (0, 20, 100, or 200 mg/kg/day) during organogenesis, embryofetal mortality was increased at the highest dose (1.5 times the MRHD on a mg/m 2 basis). This dose produced only minimal maternal toxicity.

In a study in which female rats were dosed orally with oxcarbazepine (0, 25, 50, or 150 mg/kg/day) 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 (less than the MRHD on a mg/m 2 basis). Oral administration of MHD (0, 25, 75, or 250 mg/kg/day) 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/m 2 basis).

8.2       Lactation

Risk Summary

Oxcarbazepine and its active metabolite (MHD) are present in human milk after TRILEPTAL administration. The effects of oxcarbazepine and its active metabolite (MHD) on the breastfed infant or on milk production are unknown. The developmental and health benefits of breastfeeding should be considered along 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.

8.3       Females and Males of Reproductive Potential

Contraception

Use of TRILEPTAL with hormonal contraceptives containing ethinylestradiol or levonorgestrel is associated with decreased plasma concentrations of these hormones and may result in a failure of the therapeutic effect of the oral contraceptive drug. Advise women of reproductive potential taking TRILEPTAL who are using a contraceptive containing ethinylestradiol or levonorgestrel to use additional or alternative non-hormonal birth control [see Drug interactions (7.3) and Clinical Pharmacology (12.3)].

8.4       Pediatric Use

TRILEPTAL is indicated for use as adjunctive therapy for partial-onset seizures in patients aged 2 to 16 years.

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

TRILEPTAL is also indicated as monotherapy for partial-onset seizures in patients aged 4 to 16 years.

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

TRILEPTAL has been given to 898 patients between the ages of 1 month to 17 years in controlled clinical trials (332 treated as monotherapy) and about 677 patients between the ages of 1 month to 17 years in other trials [ see Warnings and Precautions (5.11), Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

8.5       Geriatric Use 

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 to 82 years of age), the maximum plasma concentrations and AUC values of MHD were 30% to 60% higher than in younger volunteers (18 to 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. Close monitoring of sodium levels is required in elderly patients at risk for hyponatremia [ see Warnings and Precautions (5.1)]. 

8.6       Renal Impairment 

Dose adjustment is recommended for renally impaired patients (CLcr <30 mL/min) [ see Dosage and Administration (2.7) and Clinical Pharmacology (12.3)]. 

9       DRUG ABUSE AND DEPENDENCE

9.2       Abuse

The abuse potential of TRILEPTAL has not been evaluated in human studies.

9.3       Dependence

Intragastric injections of oxcarbazepine to 4 cynomolgus monkeys demonstrated no signs of physical dependence as measured by the desire to self-administer oxcarbazepine by lever pressing activity.

10       OVERDOSAGE

10.1       Human Overdose Experience

Isolated cases of overdose with TRILEPTAL have been reported. The maximum dose taken was approximately 48,000 mg. All patients recovered with symptomatic treatment. Nausea, vomiting, somnolence, aggression, agitation, hypotension, and tremor each occurred in more than one patient. Coma, confusional state, convulsion, dyscoordination, depressed level of consciousness, diplopia, dizziness, dyskinesia, dyspnea, QT prolongation, headache, miosis, nystagmus, overdose, decreased urine output, and blurred vision also occurred. 

10.2       Treatment and Management

There is no specific antidote. Symptomatic and supportive treatment should be administered as appropriate. Removal of the drug by gastric lavage and/or inactivation by administering activated charcoal should be considered.

11       DESCRIPTION

TRILEPTAL is an antiepileptic drug available as 150 mg, 300 mg, and 600 mg film-coated tablets for oral administration. TRILEPTAL is also available as a 300 mg/5 mL (60 mg/mL) oral suspension. Oxcarbazepine is 10,11-Dihydro-10-oxo-5 H-dibenz[b, f]azepine-5-carboxamide, and its structural formula is:

Oxcarbazepine is a white to faintly orange crystalline powder. It is slightly soluble in chloroform, dichloromethane, acetone, and methanol and practically insoluble in ethanol, ether and water. Its molecular weight is 252.27 g/mol.

TRILEPTAL film-coated tablets contain the following inactive ingredients: colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, iron oxide, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.

TRILEPTAL oral suspension contains the following inactive ingredients: ascorbic acid; dispersible cellulose; ethanol; macrogol stearate; methyl parahydroxybenzoate; propylene glycol; propyl parahydroxybenzoate; purified water; sodium saccharin; sorbic acid; sorbitol; yellow-plum-lemon aroma.

12       CLINICAL PHARMACOLOGY

12.1       Mechanism of Action

The pharmacological activity of TRILEPTAL is primarily exerted through the 10-monohydroxy metabolite (MHD) of oxcarbazepine [ see Clinical Pharmacology (12.3)]. 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. These actions are thought to be important in the prevention of seizure spread in the intact brain. In addition, increased potassium conductance and modulation of high-voltage activated calcium channels may contribute to the anticonvulsant effects of the drug. No significant interactions of oxcarbazepine or MHD with brain neurotransmitter or modulator receptor sites have been demonstrated.

12.2       Pharmacodynamics

Oxcarbazepine and its active metabolite (MHD) exhibit anticonvulsant properties in animal seizure models. They protected rodents against electrically induced tonic extension seizures and, to a lesser degree, chemically induced clonic seizures, and abolished or reduced the frequency of chronically recurring focal seizures in Rhesus monkeys with aluminum implants. No development of tolerance (i.e., attenuation of anticonvulsive activity) was observed in the maximal electroshock test when mice and rats were treated daily for 5 days and 4 weeks, respectively, with oxcarbazepine or MHD.

12.3       Pharmacokinetics

Following oral administration of TRILEPTAL tablets, oxcarbazepine is completely absorbed and extensively metabolized to its pharmacologically active 10-monohydroxy metabolite (MHD). In a mass balance study in people, only 2% of total radioactivity in plasma was due to unchanged oxcarbazepine, with approximately 70% present as MHD, and the remainder attributable to minor metabolites.

The half-life of the parent is about 2 hours, while the half-life of MHD is about 9 hours, so that MHD is responsible for most antiepileptic activity.

Absorption

Based on MHD concentrations, TRILEPTAL tablets and suspension were shown to have similar bioavailability.

After single-dose administration of TRILEPTAL tablets to healthy male volunteers under fasted conditions, the median t max was 4.5 (range 3 to 13) hours. After single-dose administration of TRILEPTAL oral suspension to healthy male volunteers under fasted conditions, the median t max was 6 hours.

Steady-state plasma concentrations of MHD are reached within 2 to 3 days in patients when TRILEPTAL is given twice a day. At steady state the pharmacokinetics of MHD are linear and show dose proportionality over the dose range of 300 to 2400 mg/day.

Food has no effect on the rate and extent of absorption of oxcarbazepine from TRILEPTAL tablets. Although not directly studied, the oral bioavailability of the TRILEPTAL suspension is unlikely to be affected under fed conditions. Therefore, TRILEPTAL tablets and suspension can be taken with or without food.

Distribution

The apparent volume of distribution of MHD is 49 L.

Approximately 40% of MHD is bound to serum proteins, predominantly to albumin. Binding is independent of the serum concentration within the therapeutically relevant range. Oxcarbazepine and MHD do not bind to alpha-1-acid glycoprotein.

Metabolism and Excretion

Oxcarbazepine is rapidly reduced by cytosolic enzymes in the liver to its 10-monohydroxy metabolite, MHD, which is primarily responsible for the pharmacological effect of TRILEPTAL. MHD is metabolized further by conjugation with glucuronic acid. Minor amounts (4% of the dose) are oxidized to the pharmacologically inactive 10,11-dihydroxy metabolite (DHD).

Oxcarbazepine is cleared from the body mostly in the form of metabolites which are predominantly excreted by the kidneys. More than 95% of the dose appears in the urine, with less than 1% as unchanged oxcarbazepine. Fecal excretion accounts for less than 4% of the administered dose. Approximately 80% of the dose is excreted in the urine either as glucuronides of MHD (49%) or as unchanged MHD (27%); the inactive DHD accounts for approximately 3% and conjugates of MHD and oxcarbazepine account for 13% of the dose.

The half-life of the parent is about 2 hours, while the half-life of MHD is about 9 hours.

Specific Populations

Geriatrics

Following administration of single (300 mg) and multiple (600 mg/day) doses of TRILEPTAL to elderly volunteers (60 to 82 years of age), the maximum plasma concentrations and AUC values of MHD were 30% to 60% higher than in younger volunteers (18 to 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.

Pediatrics

Weight-adjusted MHD clearance decreases as age and weight increases, approaching that of adults. The mean weight-adjusted clearance in children 2 years to < 4 years of age is approximately 80% higher on average than that of adults. Therefore, MHD exposure in these children is expected to be about one-half that of adults when treated with a similar weight-adjusted dose. The mean weight-adjusted clearance in children 4 to 12 years of age is approximately 40% higher on average than that of adults. Therefore, MHD exposure in these children is expected to be about three-quarters that of adults when treated with a similar weight-adjusted dose. As weight increases, for patients 13 years of age and above, the weight-adjusted MHD clearance is expected to reach that of adults.

Gender

No gender-related pharmacokinetic differences have been observed in children, adults, or the elderly.

Race

No specific studies have been conducted to assess what effect, if any, race may have on the disposition of oxcarbazepine.

Renal Impairment

There is a linear correlation between creatinine clearance and the renal clearance of MHD. When TRILEPTAL is administered as a single 300 mg dose in renally-impaired patients (creatinine clearance < 30 mL/min), the elimination half-life of MHD is prolonged to 19 hours, with a 2-fold increase in AUC [ see Dosage and Administration (2.7) and Use in Specific Populations (8.6)].

Hepatic Impairment

The pharmacokinetics and metabolism of oxcarbazepine and MHD were evaluated in healthy volunteers and hepatically-impaired subjects after a single 900-mg oral dose. Mild-to-moderate hepatic impairment did not affect the pharmacokinetics of oxcarbazepine and MHD [ see Dosage and Administration (2.8)].

Pregnancy

Due to physiological changes during pregnancy, MHD plasma levels may gradually decrease throughout pregnancy [ see Use in Specific Populations (8.1)].

Drug Interactions:

• In Vitro

Oxcarbazepine can inhibit CYP2C19 and induce CYP3A4/5 with potentially important effects on plasma concentrations of other drugs. In addition, several AEDs that are cytochrome P450 inducers can decrease plasma concentrations of oxcarbazepine and MHD. No autoinduction has been observed with TRILEPTAL.

Oxcarbazepine was evaluated in human liver microsomes to determine its capacity to inhibit the major cytochrome P450 enzymes responsible for the metabolism of other drugs. Results demonstrate that oxcarbazepine and its pharmacologically active 10-monohydroxy metabolite (MHD) have little or no capacity to function as inhibitors for most of the human cytochrome P450 enzymes evaluated (CYP1A2, CYP2A6, CYP2C9, CYP2D6, CYP2E1, CYP4A9 and CYP4A11) with the exception of CYP2C19 and CYP3A4/5. Although inhibition of CYP3A4/5 by oxcarbazepine and MHD did occur at high concentrations, it is not likely to be of clinical significance. The inhibition of CYP2C19 by oxcarbazepine and MHD can cause increased plasma concentrations of drugs that are substrates of CYP2C19, which is clinically relevant. 

In vitro, the UDP-glucuronyl transferase level was increased, indicating induction of this enzyme. Increases of 22% with MHD and 47% with oxcarbazepine were observed. As MHD, the predominant plasma substrate, is only a weak inducer of UDP-glucuronyl transferase, it is unlikely to have an effect on drugs that are mainly eliminated by conjugation through UDP-glucuronyl transferase (e.g., valproic acid, lamotrigine).

In addition, oxcarbazepine and MHD induce a subgroup of the cytochrome P450 3A family (CYP3A4 and CYP3A5) responsible for the metabolism of dihydropyridine calcium antagonists, oral contraceptives and cyclosporine resulting in a lower plasma concentration of these drugs.

As binding of MHD to plasma proteins is low (40%), clinically significant interactions with other drugs through competition for protein binding sites are unlikely.

• In Vivo

Other Antiepileptic Drugs

Potential interactions between TRILEPTAL and other AEDs were assessed in clinical studies. The effect of these interactions on mean AUCs and C min are summarized in Table 7 [ see Drug Interactions (7.1, 7.2)].

Table 7:  Summary of AED Interactions with TRILEPTAL

AED; Coadministered	Dose of AED; (mg/day)	TRILEPTAL Dose; (mg/day)	Influence of; TRILEPTAL on AED; Concentration; (Mean Change,; 90% Confidence; Interval)	Influence of; AED on MHD; Concentration; (Mean Change,; 90% Confidence; Interval)
Carbamazepine	400-2000	900	nc 1	40% decrease; [CI: 17% decrease,; 57% decrease]
Phenobarbital	100-150	600-1800	14% increase; [CI: 2% increase,; 24% increase]	25% decrease; [CI: 12% decrease,; 51% decrease]
Phenytoin	250-500	600-1800; > 1200-2400	nc 1,2; up to 40%; increase 3; [CI: 12% increase,; 60% increase]	30% decrease; [CI: 3% decrease,; 48% decrease]
Valproic acid	400-2800	600-1800	nc 1	18% decrease; [CI: 13% decrease,; 40% decrease]
Lamotrigine	200	1200	nc 1	nc 1

1nc denotes a mean change of less than 10%.

2Pediatrics.

3Mean increase in adults at high TRILEPTAL doses.

Hormonal Contraceptives

Coadministration of TRILEPTAL with an oral contraceptive has been shown to influence the plasma concentrations of the two hormonal components:, ethinylestradiol (EE) and levonorgestrel (LNG) [ see Drug Interactions (7.3)]. The mean AUC values of EE were decreased by 48% [90% CI: 22 to 65] in one study and 52% [90% CI: 38 to 52] in another study. The mean AUC values of LNG were decreased by 32% [90% CI: 20 to 45] in one study and 52% [90% CI: 42 to 52] in another study.

Other Drug Interactions

Calcium Antagonists: After repeated coadministration of TRILEPTAL, the AUC of felodipine was lowered by 28% [90% CI: 20 to 33]. Verapamil produced a decrease of 20% [90% CI: 18 to 27] of the plasma levels of MHD.

Cimetidine, erythromycin and dextropropoxyphene had no effect on the pharmacokinetics of MHD. Results with warfarin show no evidence of interaction with either single or repeated doses of TRILEPTAL.

13       NONCLINICAL TOXICOLOGY

13.1       Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In 2-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, which is less than the maximum recommended human dose (MRHD) on a mg/m 2 basis. In rats, the incidence of hepatocellular carcinomas was increased in females treated with oxcarbazepine at doses ≥ 25 mg/kg/day (less than the MRHD on a mg/m 2 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/m 2 basis) and ≥ 250 mg/kg/day (equivalent to the MRHD on a mg/m 2 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.

Mutagenesis

Oxcarbazepine increased mutation frequencies in the in vitro Ames test in the absence of metabolic activation. 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 study in which male and female rats were administered oxcarbazepine (0, 25, 75, and 150 mg/kg/day) orally prior to and during mating and continuing in females during gestation, no adverse effects on fertility or reproductive performance were observed. The highest dose tested is less than the MRHD on a mg/m 2 basis. In a fertility study in which rats were administered MHD (0, 50, 150, or 450 mg/kg/day) 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 2 times the MRHD on a mg/m 2 basis).

14       CLINICAL STUDIES

The effectiveness of TRILEPTAL as adjunctive and monotherapy for partial-onset seizures in adults, and as adjunctive therapy in children aged 2 to 16 years was established in seven multicenter, randomized, controlled trials.

The effectiveness of TRILEPTAL as monotherapy for partial-onset seizures in children aged 4 to 16 years was determined from data obtained in the studies described, as well as by pharmacokinetic/pharmacodynamic considerations.

14.1       TRILEPTAL Monotherapy Trials

Four randomized, controlled, double-blind, multicenter trials, conducted in a predominately adult population, demonstrated the efficacy of TRILEPTAL as monotherapy. Two trials compared TRILEPTAL to placebo and 2 trials used a randomized withdrawal design to compare a high dose (2400 mg) with a low dose (300 mg) of TRILEPTAL, after substituting TRILEPTAL 2400 mg/day for 1 or more antiepileptic drugs (AEDs). All doses were administered on a twice-a-day schedule. A fifth randomized, controlled, rater-blind, multicenter study, conducted in a pediatric population, failed to demonstrate a statistically significant difference between low and high dose TRILEPTAL treatment groups.

One placebo-controlled trial was conducted in 102 patients (11 to 62 years of age) with refractory partial-onset seizures who had completed an inpatient evaluation for epilepsy surgery. Patients had been withdrawn from all AEDs and were required to have 2 to 10 partial-onset seizures within 48 hours prior to randomization. Patients were randomized to receive either placebo or TRILEPTAL given as 1500 mg/day on Day 1 and 2400 mg/day thereafter for an additional 9 days, or until 1 of the following 3 exit criteria occurred: 1) the occurrence of a fourth partial-onset seizure, excluding Day 1, 2) 2 new-onset secondarily generalized seizures, where such seizures were not seen in the 1-year period prior to randomization, or 3) occurrence of serial seizures or status epilepticus. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria. There was a statistically significant difference in favor of TRILEPTAL (see Figure 1), p = 0.0001.

The second placebo-controlled trial was conducted in 67 untreated patients (8 to 69 years of age) with newly-diagnosed and recent-onset partial seizures. Patients were randomized to placebo or TRILEPTAL, initiated at 300 mg twice a day and titrated to 1200 mg/day (given as 600 mg twice a day) in 6 days, followed by maintenance treatment for 84 days. The primary measure of effectiveness was a between-group comparison of the time to first seizure. The difference between the 2 treatments was statistically significant in favor of TRILEPTAL (see Figure 2), p = 0.046.

A third trial substituted TRILEPTAL monotherapy at 2400 mg/day 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). Patients who were able to tolerate titration of TRILEPTAL to 2400 mg/day during simultaneous carbamazepine withdrawal were randomly assigned to either 300 mg/day of TRILEPTAL or 2400 mg/day TRILEPTAL. Patients were observed for 126 days or until 1 of the following 4 exit criteria occurred: 1) a doubling of the 28-day seizure frequency compared to baseline, 2) a 2-fold increase in the highest consecutive 2-day seizure frequency during baseline, 3) a single generalized seizure if none had occurred during baseline, or 4) a prolonged generalized seizure. The primary measure of effectiveness was a between-group comparison of the time to meet exit criteria. The difference between the curves was statistically significant in favor of the TRILEPTAL 2400 mg/day group (see Figure 3), p = 0.0001.

Another 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 randomized 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 primary measure of effectiveness was a between-group comparison of the percentage of patients meeting exit criteria. 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< 0.0001). The time to meeting one of the exit criteria was also statistically significant in favor of the TRILEPTAL 2400 mg/day group (see Figure 4), p = 0.0001.

A 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. Seizures were recorded through continuous video-EEG monitoring from Day 3 to Day 5. Patients either completed the 5-day treatment or met 1 of the 2 exit criteria: 1) three study-specific seizures (i.e., electrographic partial-onset seizures with a behavioral correlate), 2) a prolonged study-specific seizure. 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 = 0.904). The majority of patients from both dose groups completed the 5-day study without exiting.

Although this study failed to demonstrate an effect of oxcarbazepine as monotherapy in pediatric patients, several design elements, including the short treatment and assessment period, the absence of a true placebo, and the likely persistence of plasma levels of previously administered AEDs during the treatment period, make the results uninterpretable. For this reason, the results do not undermine the conclusion, based on pharmacokinetic/pharmacodynamic considerations, that oxcarbazepine is effective as monotherapy in pediatric patients 4 years old and older.

14.2       TRILEPTAL Adjunctive Therapy Trials

The effectiveness of TRILEPTAL as an adjunctive therapy for partial-onset seizures was established in 2 multicenter, randomized, double-blind, placebo-controlled trials, one in 692 patients (15 to 66 years of age) and one in 264 pediatric patients (3 to 17 years of age), and in one multicenter, rater-blind, randomized, age-stratified, parallel-group study comparing 2 doses of oxcarbazepine in 128 pediatric patients (1 month to < 4 years of age).

Patients in the 2 placebo-controlled trials were on 1 to 3 concomitant AEDs. In both of the trials, patients were stabilized on optimum dosages of their concomitant AEDs during an 8-week baseline phase. Patients who experienced at least 8 (minimum of 1 to 4 per month) partial-onset seizures during the baseline phase were randomly assigned to placebo or to a specific dose of TRILEPTAL in addition to their other AEDs.

In these studies, the dose was increased over a 2-week period until either the assigned dose was reached, or intolerance prevented increases. Patients then entered a 14- (pediatrics) or 24-week (adults) maintenance period.

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 = 0.0001 for all doses for both trials). The number of patients randomized to each dose, the median baseline seizure rate, and the median percentage seizure rate reduction for each trial are shown in Table 8. It is important to note that in the high-dose group in the study in adults, over 65% of patients discontinued treatment because of adverse events; only 46 (27%) of the patients in this group completed the 28-week study [ see Adverse Reactions (6)], an outcome not seen in the monotherapy studies.

Table 8:  Summary of Percentage Change in Partial-Onset Seizure Frequency from Baseline for Placebo-Controlled Adjunctive Therapy Trials

Trial	Treatment Group
		N		Baseline; Median; Seizure Rate*		Median; %; Reduction
1 (pediatrics)	TRILEPTAL	136		12.5		34.8 1
	Placebo	128		13.1		9.4
2 (adults)	TRILEPTAL 2400 mg/day	174		10.0		49.9 1
	TRILEPTAL 1200 mg/day	177		9.8		40.2 1
	TRILEPTAL 600 mg/day	168		9.6		26.4 1
	Placebo	173		8.6		7.6

1p = 0.0001.
*=number of seizures per 28 days.

Subset analyses of the antiepileptic efficacy of TRILEPTAL with regard to gender in these trials revealed no important differences in response between men and women. Because there were very few patients over the age of 65 years in controlled trials, the effect of the drug in the elderly has not been adequately assessed.

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 (N = 75).

16       HOW SUPPLIED/STORAGE AND HANDLING

Tablets

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 30……...NDC: 55289-007-30

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

17       PATIENT COUNSELING INFORMATION

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 [ see Dosage and Administration (2.8) and How Supplied/Storage and Handling (16)] .

Hyponatremia

Advise patients that TRILEPTAL may reduce the serum sodium concentrations especially if they are taking other medications that can lower sodium. Instruct patients to report symptoms of low sodium like nausea, tiredness, lack of energy, confusion, and more frequent or more severe seizures [ see Warnings and Precautions (5.1)].

Anaphylactic Reactions and Angioedema

Anaphylactic reactions and angioedema may occur during treatment with TRILEPTAL. Advise patients 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 (5.2)].

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. 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 (5.3)].

Serious Dermatological Reactions

Advise patients 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 (5.4)].

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 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  [see Warnings and Precautions (5.5)].

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 [see Warnings and Precautions (5.7) and Adverse Reactions (6)].

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 [ see Warnings and Precautions (5.8)].

Hematologic Events

Advise patients that there have been rare reports of blood disorders reported in patients treated with TRILEPTAL. Instruct patients to immediately consult with their physician if they experience symptoms suggestive of blood disorders [ see Warnings and Precautions (5.9)].

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 [see Drug Interactions (7.2) and Use in Specific Populations (8.1)]. 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 [ see Use in Specific Populations (8.1)].

T2019-01

MEDICATION GUIDE

This Medication Guide has been approved by the U.S. Food and Drug Administration	Revised: January 2019
MEDICATION GUIDE; TRILEPTAL (try-LĔP-tăl); (oxcarbazepine); film-coated tablets, for oral use; and; oral suspension
What is the most important information I should know about TRILEPTAL?; Do not stop taking TRILEPTAL without first talking to your healthcare provider. Stopping TRILEPTAL suddenly can cause serious problems.; TRILEPTAL can cause serious side effects, including: 1. TRILEPTAL may cause the level of sodium in your blood to be low. Symptoms of low blood sodium include:
nausea	confusion
tiredness (lack of energy)	more frequent or more severe seizures
headache
Similar symptoms that are not related to low sodium may occur from taking TRILEPTAL. You should tell your healthcare provider if you have any of these side effects and if they bother you or they do not go away.; Some other medicines can also cause low sodium in your blood. Be sure to tell your healthcare provider about all the other medicines that you are taking.; Your healthcare provider may do blood tests to check your sodium levels during your treatment with TRILEPTAL.; 2. TRILEPTAL may also cause allergic reactions or serious problems which may affect organs and other parts of your body like the liver or blood cells. You may or may not have a rash with these types of reactions.; Call your healthcare provider right away if you have any of the following:
swelling of your face, eyes, lips, or tongue	painful sores in the mouth or around your eyes
trouble swallowing or breathing	yellowing of your skin or eyes
a skin rash	unusual brusing or bleeding
hives	severe fatigue or weakness
fever, swollen glands, or sore throat that do not go away or come and go	severe muscle pain
	frequent infections or infections that do not go away
Many people who are allergic to carbamazepine are also allergic to TRILEPTAL. Tell your healthcare provider if you are allergic to carbamazepine.; 3. Like other antiepileptic drugs, TRILEPTAL may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.; Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:
thoughts about suicide or dying	trouble sleeping (insomnia)
attempts to commit suicide	new or worse irritability
new or worse depression	acting aggressive, being angry, or violent
new or worse anxiety	acting on dangerous impulses
feeling agitated or restless	an extreme increase in activity and talking (mania)
panic attacks	other unusual changes in behavior or mood
How can I watch for early symptoms of suicidal thoughts and actions?; Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.; Keep all follow-up visits with your healthcare provider as scheduled. Call your healthcare provider between visits as needed, especially if you are worried about symptoms.; Do not stop taking TRILEPTAL without first talking to a healthcare provider.; Stopping TRILEPTAL suddenly can cause serious problems.; Stopping a seizure medicine suddenly in a patient who has epilepsy may cause seizures that will not stop (status epilepticus). Suicidal thoughts or actions may be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
What is TRILEPTAL?; TRILEPTAL is a prescription medicine used: alone or with other medicines to treat partial-onset seizures in adults; alone to treat partial-onset seizures in children 4 years and older; with other medicines to treat partial-onset seizures in children 2 years and older It is not known if TRILEPTAL is safe and effective for use alone to treat partial-onset seizures in children less than 4 years of age or for use with other medicines to treat partial-onset 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.; Many people who are allergic to carbamazepine are also allergic to TRILEPTAL. Tell your healthcare provider if you are allergic to carbamazepine.
Before taking TRILEPTAL, tell your healthcare provider about all your medical conditions, including if you: have or have had suicidal thoughts or actions, depression or mood problems; have liver problems; have kidney problems; are allergic to carbamazepine. Many people who are allergic to carbamazepine are also allergic to TRILEPTAL.; use birth control medicine. TRILEPTAL may cause your birth control medicine to be less effective. Talk to your healthcare provider about the best birth control method to use.; are pregnant or plan to become pregnant. 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.; If you become pregnant while taking TRILEPTAL, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) Pregnancy Registry. The purpose of this registry is to collect information about the safety of antiepileptic medicine during pregnancy. You can enroll in this registry by calling 1-888-233-2334.; are breastfeeding or plan to breastfeed. TRILEPTAL passes into breast milk. Talk with your healthcare provider about the best way to feed your baby if you take TRILEPTAL. Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Taking TRILEPTAL with certain other medicines may cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.; Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist when you get a new medicine.
How should I take TRILEPTAL? Do not stop taking TRILEPTAL without talking to your healthcare provider. Stopping TRILEPTAL suddenly can cause serious problems, including seizures that will not stop (status epilepticus).; Take TRILEPTAL exactly as prescribed. Your healthcare provider may change your dose. Your healthcare provider will tell you how much TRILEPTAL to take.; Take TRILEPTAL 2 times a day.; Take TRILEPTAL with or without food.; 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. TRILEPTAL oral suspension can be mixed in a small glass of water, or swallowed directly from the syringe. Clean the syringe with warm water and let it dry after each use.; If you take too much TRILEPTAL, call your healthcare provider right away.
What should I avoid while taking TRILEPTAL? Do not drive or operate machinery until you know how TRILEPTAL affects you. TRILEPTAL may slow your thinking and motor skills.; Do not drink alcohol or take other drugs that make you sleepy or dizzy while taking TRILEPTAL until you talk to your healthcare provider. TRILEPTAL taken with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
What are the possible side effects of TRILEPTAL?; See “ What is the most important information I should know about TRILEPTAL?”; TRILEPTAL may cause other serious side effects including: trouble concentrating; problems with your speech and language; feeling confused; feeling sleepy and tired; trouble with walking and coordination; seizures that can happen more often or become worse, especially in children Get medical help right away if you have any of the symptoms listed above or listed in “What is the most important information I should know about TRILEPTAL?”; The most common side effects of TRILEPTAL include:
dizziness	problems with vision
sleepiness	trembling
double vision	problems with walking and coordination (unsteadiness)
tiredness	rash
nausea
vomiting
These are not all the possible side effects of TRILEPTAL. Tell your healthcare provider if you have any side effect that bothers you or that does not go away.; Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
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.; Keep TRILEPTAL oral suspension in the original container and use within 7 weeks of first opening the bottle. Shake well before using. Keep TRILEPTAL and all medicines out of the reach of children.
General Information about the safe and effective use of TRILEPTAL.; Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use TRILEPTAL for a condition for which it was not prescribed. Do not give TRILEPTAL to other people, even if they have the same symptoms that you have. It may harm them.; You can ask your pharmacist or healthcare provider for information about TRILEPTAL that is written for health professionals.
What are the ingredients in TRILEPTAL?; Active ingredient: oxcarbazepine; Inactive ingredients: Film-coated tablets: colloidal silicon dioxide, crospovidone, hydroxypropyl methylcellulose, iron oxide, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc and titanium dioxide.; Oral suspension: ascorbic acid, dispersible cellulose, ethanol, macrogol stearate, methyl parahydroxybenzoate, propylene glycol, propyl parahydroxybenzoate, purified water, sodium saccharin, sorbic acid, sorbitol, yellow-plum-lemon aroma. Distributed by: Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936.; © Novartis; T2019-02; For more information, go to www.pharma.us.novartis.com or call 1-888-669-6682.

PRINCIPAL DISPLAY PANEL

PRINCIPAL DISPLAY PANEL

Package Label – 300 mg

Rx Only             NDC: 0078-0337-05

Trileptal ® (oxcarbazepine)

PHARMACIST: DISPENSE WITH MEDICATION
GUIDE ATTACHED OR PROVIDED SEPARATELY.

INGREDIENTS AND APPEARANCE

TRILEPTAL 
oxcarbazepine tablet, film coated

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC: 55289-007(NDC:0078-0337)
Route of Administration	ORAL

Active Ingredient/Active Moiety
Ingredient Name	Basis of Strength	Strength
OXCARBAZEPINE (UNII: VZI5B1W380) (OXCARBAZEPINE - UNII:VZI5B1W380)	OXCARBAZEPINE	300 mg

Inactive Ingredients
Ingredient Name	Strength
CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U)
CROSPOVIDONE (UNII: 68401960MK)
HYPROMELLOSES (UNII: 3NXW29V3WO)
MAGNESIUM STEARATE (UNII: 70097M6I30)
TITANIUM DIOXIDE (UNII: 15FIX9V2JP)
SILICON DIOXIDE (UNII: ETJ7Z6XBU4)
TALC (UNII: 7SEV7J4R1U)
POLYETHYLENE GLYCOL (UNII: 3WJQ0SDW1A)
FERRIC OXIDE YELLOW (UNII: EX438O2MRT)
WATER (UNII: 059QF0KO0R)

Product Characteristics
Color	yellow	Score	2 pieces
Shape	OVAL	Size	15mm
Flavor		Imprint Code	TE;TE;CG;CG
Contains

Packaging
#	Item Code	Package Description	Marketing Start Date	Marketing End Date
1	NDC: 55289-007-30	30 in 1 BOTTLE, PLASTIC; Type 0: Not a Combination Product	03/17/2011

Marketing Information
Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
NDA	NDA021014	01/30/2000

Labeler - PD-Rx Pharmaceuticals, Inc. (156893695)

Registrant - PD-Rx Pharmaceuticals, Inc. (156893695)

Establishment
Name	Address	ID/FEI	Business Operations
PD-Rx Pharmaceuticals, Inc.		156893695	repack(55289-007)