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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 TRILEPTAL®^ (oxcarbazepine) oral suspension Initial U.S. Approval: 2000
------------------------------RECENT MAJOR CHANGES------------------------------ Contraindications (4) 3/ Warnings and Precautions (5.1, 5.3, 5.6, 5.7, 5.8, 5.11) 3/
---------------------------INDICATIONS AND USAGE--------------------------------- TRILEPTAL is indicated for:
- Adults: Monotherapy or adjunctive therapy in the treatment of partial seizures
- Pediatrics:
- Monotherapy in the treatment of partial seizures in children 4–16 years
- Adjunctive therapy in the treatment of partial 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4–16 Years) Maximum increment of 10 mg/kg/day at weekly intervals, concomitant antiepileptic drugs can be completely withdrawn over 3 to 6 weeks (2.5)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 a 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, 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 fpr 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, 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. (7.2) --------------------------USE IN SPECIFIC POPULATIONS-----------------------
- Pregnancy: May cause fetal harm. (8.1 )
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide Revised: 3/
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– Years) 2.6 Initiation of Monotherapy for Pediatric Patients (Aged 4–16 Years) 2.7 Dosage Modification for Patients with Renal Impairment 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 Antiepileptic Drugs 7.2 Hormonal Contraceptives 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 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
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
TRILEPTAL is indicated for use as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and as monotherapy in the treatment of partial seizures in pediatric patients aged 4 years and above with epilepsy, and as adjunctive therapy in pediatric patients aged 2 years and above with partial 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. It is recommended that the patient be observed closely and plasma levels of the concomitant AEDs be monitored during the period of TRILEPTAL titration, as these plasma levels may be altered, especially at TRILEPTAL doses greater than 1200 mg/day [ see Drug Interactions (7.1) ].
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.
- 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 (38/1,524) had a sodium of less than 125 mmol/L at some point during treatment, compared to no such patients assigned placebo or active control (carbamazepine and phenobarbital for adjunctive and monotherapy substitution studies, and phenytoin and valproate for the monotherapy initiation studies). Clinically significant hyponatremia generally occurred during the first 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 HLA-B* 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-B1502 protein, suggest that the HLA-B1502 allele may also increase the risk for SJS/TEN with TRILEPTAL.
The frequency of HLA-B1502 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-B1502 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-B1502 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-B1502 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-B1502 positive patients, when alternative therapies are otherwise equally acceptable. Screening is not generally recommended in patients from populations in which the prevalence of HLAB 1502 is low, or in current TRILEPTAL users, as the risk of SJS/TEN is largely confined to the first few months of therapy, regardless of HLA B*1502 status.
The use of HLA-B*1502 genotyping has important limitations and must never substitute for appropriate clinical vigilance and patient management. The role of other possible factors in the development of, and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance, concomitant medications, comorbidities, and the level of dermatologic monitoring have not been well characterized.
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 Drug Patients with Relative Risk: Risk Difference: with Events Per Events Per 1,000 Incidence of Events Additional Drug 1,000 Patients Patients in Drug Patients with Events Patients/Incidence in Per 1,000 Patients Placebo Patients
Epilepsy 1.0 3.4 3.5 2.
Psychiatric 5.7 8.5 1.5 2.
Other 1.0 1.8 1.9 0.
Total 2.4 4.3 1.8 1.
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.
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 eventhough 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 1,537 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%), 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%), 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%), 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.
Abnormal
Table 4 Adverse Reactions in Controlled Clinical Studies of Monotherapy with TRILEPTAL in Adults Previously Treated with Other AEDs
TRILEPTAL TRILEPTAL
Adverse Reaction % %
- Abnormal Vision
- Accommodation
- Body System/ N=86 N= 2400 mg/day 300 mg/day
- Fatigue Body as a Whole
- Fever
- Allergy
- Generalized Edema
- Chest Pain
- Nausea Digestive System
- Vomiting
- Diarrhea
- Dyspepsia
- Anorexia
- Abdominal Pain
- Dry Mouth
- Hemorrhage Rectum
- Toothache
- Lymphadenopathy Hemic and Lymphatic System
- Viral Infection Infections and Infestations
- Infection
- Hyponatremia Metabolic and Nutritional Disorders
- Thirst
- Headache Nervous System
- Dizziness
- Somnolence
- Anxiety
- Ataxia
- Confusion
- Nervousness
- Insomnia
- Tremor
- Amnesia
- Aggravated Convulsions
- Emotional Lability
- Hypoesthesia
- Abnormal Coordination
- Nystagmus
- Speech Disorder
- Upper Respiratory Tract Infection Respiratory System
- Coughing
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/ TRILEPTAL Placebo Adverse Reaction N=55 N= % % 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
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 T4, 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 Antiepileptic Drugs
Potential interactions between TRILEPTAL and other AEDs were assessed in clinical studies. The effect of these interactions on mean AUCs and Cmin are summarized in Table 7.
Table 7 Summary of AED Interactions with TRILEPTAL
Influence of TRILEPTAL on Influence of AED AED on MHD Concentration Concentration
AED Dose of AED
TRILEPTAL
Dose
(Mean Change, 90% Confidence
(Mean Change, 90% Confidence Coadministered (mg/day) (mg/day) Interval) Interval)
Carbamazepine 400-2000 900 nc 1 40% decrease [CI: 17% decrease, 57% decrease]
Phenobarbital 100-150 600-1800 14% increase 25% decrease [CI: 2% increase, 24% increase]
[CI: 12% decrease, 51% decrease]
Phenytoin 250-500 600-
1200-
nc 1, 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 (^1) nc denotes a mean change of less than 10% (^2) Pediatrics (^3) Mean increase in adults at high TRILEPTAL doses
When using doses of TRILEPTAL greater than 1200 mg/day during adjunctive therapy, a decrease in the dose of phenytoin may be required.
Strong inducers of cytochrome P450 enzymes (i.e., carbamazepine, phenytoin and phenobarbital) have been shown to decrease the plasma levels of MHD (29% to 40%).
7.2 Hormonal Contraceptives
Concurrent use of TRILEPTAL with hormonal contraceptives may render these contraceptives less effective [see Clinical Pharmacology (12.3)]. Studies with other oral or implant contraceptives have not been conducted.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Clinical Considerations
TRILEPTAL levels may decrease during pregnancy [ see Warnings and Precautions (5.10) ].
Pregnancy Category C
Fetal Risk Summary
There are no adequate and well-controlled clinical studies of TRILEPTAL in pregnant women; however, TRILEPTAL is closely related structurally to carbamazepine, which is considered to be teratogenic in humans. Data on a limited number
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, 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, 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.
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.
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 antiseizure 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 (^) ma x 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 (^) ma x 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
For in vivo drug interactions [ see Drug Interactions (7) ]. 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). 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 or approximately 0.1 times 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 (0.1 times 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 fertility study in which rats were administered MHD (50, 150, or 450 mg/kg) orally prior to and during mating and early gestation, estrous cyclicity was disrupted and numbers of corpora lutea, implantations, and live embryos were reduced in females receiving the highest dose (approximately 2 times the MRHD on a mg/m^2 basis).
14 CLINICAL STUDIES
The effectiveness of TRILEPTAL as adjunctive and monotherapy for partial 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 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 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 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 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.
Figure 1 Kaplan-Meier Estimates of Exit Rate by Treatment Group
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.
Figure 2 Kaplan-Meier Estimates of First Seizure Event Rate by Treatment Group
A third trial substituted TRILEPTAL monotherapy at 2400 mg/day for carbamazepine in 143 patients (12 to 65 years of age) whose partial 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.
