Included as part of the PRECAUTIONS section.
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
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 Cross Hypersensitivity Reaction To Carbamazepine].
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 Hyponatremia and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ
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
The reporting rate of TEN and SJS associated with
TRILEPTAL use, which is generally accepted to be an underestimate due to
underreporting, exceeds the background incidence rate estimates by a factor of
3- to 10-fold. Estimates of the background incidence rate for these serious
skin reactions in the general population range between 0.5 to 6 cases per
million-person years. Therefore, if a patient develops a skin reaction while
taking TRILEPTAL, consideration should be given to discontinuing TRILEPTAL use
and prescribing another antiepileptic medication.
Association With HLA-B*1502
Patients carrying the HLA-B*1502 allele may be at
increased risk for SJS/TEN with Trileptal treatment.
Human Leukocyte Antigen (HLA) allele B*1502 increases the
risk for developing SJS/TEN in patients treated with carbamazepine. The
chemical structure of Trileptal is similar to that of carbamazepine. Available
clinical evidence, and data from nonclinical studies showing a direct
interaction between Trileptal and HLA-B*1502 protein, suggest that the
HLA-B*1502 allele may also increase the risk for SJS/TEN with Trileptal.
The frequency of HLA-B*1502 allele ranges from 2 to 12%
in Han Chinese populations, is about 8% in Thai populations, and above 15% in
the Philippines and in some Malaysian populations. Allele frequencies up to
about 2% and 6% have been reported in Korea and India, respectively. The
frequency of the HLA-B*1502 allele is negligible in people from European
descent, several African populations, indigenous peoples of the Americas,
Hispanic populations, and in Japanese (<1%).
Testing for the presence of the HLA-B*1502 allele should
be considered in patients with ancestry in genetically at-risk populations, prior
to initiating treatment with Trileptal. The use of Trileptal should be avoided
in patients positive for HLA-B*1502 unless the benefits clearly outweigh the
risks. Consideration should also be given to avoid the use of other drugs
associated with SJS/TEN in HLAB* 1502 positive patients, when alternative
therapies are otherwise equally acceptable. Screening is not generally
recommended in patients from populations in which the prevalence of HLAB* 1502
is low, or in current Trileptal users, as the risk of SJS/TEN is largely
confined to the first few months of therapy, regardless of HLA B*1502 status.
The use of HLA-B*1502 genotyping has important
limitations and must never substitute for appropriate clinical vigilance and
patient management. The role of other possible factors in the development of,
and morbidity from, SJS/TEN, such as antiepileptic drug (AED) dose, compliance,
concomitant medications, comorbidities, and the level of dermatologic
monitoring have not been well characterized.
Suicidal Behavior And Ideation
Antiepileptic drugs (AEDs), including TRILEPTAL, increase
the risk of suicidal thoughts or behavior in patients taking these drugs for
any indication. Patients treated with any AED for any indication should be
monitored for the emergence or worsening of depression, suicidal thoughts or
behavior, and/or any unusual changes in mood or behavior.
Pooled analyses of 199 placebo-controlled clinical trials
(mono- and adjunctive therapy) of 11 different AEDs showed that patients
randomized to one of the AEDs had approximately twice the risk (adjusted Relative
Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to
patients randomized to placebo. In these trials, which had a median treatment
duration of 12 weeks, the estimated incidence rate of suicidal behavior or
ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among
16,029 placebo-treated patients, representing an increase of approximately one
case of suicidal thinking or behavior for every 530 patients treated. There
were 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.Â 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
Table 2: Risk by Indication for Antiepileptic Drugs in
the Pooled Analysis
||Placebo Patients with Events Per 1,000 Patients
||Drug Patients with Events Per 1,000 Patients
||Relative Risk:Incidence of Events in Drug Patients/Incidencein Placebo Patients
||Risk Difference: Additional Drug Patients with Events Per 1,000 Patients
The relative risk for suicidal thoughts or behavior was
higher in clinical trials for epilepsy than in clinical trials for psychiatric
or other conditions, but the absolute risk differences were similar for the epilepsy
and psychiatric indications.
Anyone considering prescribing TRILEPTAL or any other AED
must balance the risk of suicidal thoughts or behavior with the risk of
untreated illness. Epilepsy and many other illnesses for which AEDs are
prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal thoughts and
behavior emerge during treatment, the prescriber needs to consider whether the
emergence of these symptoms in any given patient may be related to the illness
Patients, their caregivers, and families should be
informed that AEDs increase the risk of suicidal thoughts and behavior and
should be advised of the need to be alert for the emergence or worsening of the
signs and symptoms of depression, any unusual changes in mood or behavior, or
the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
Behaviors of concern should be reported immediately to healthcare providers.
Withdrawal Of AEDs
As with most antiepileptic drugs, TRILEPTAL should
generally be withdrawn gradually because of the risk of increased seizure
frequency and status epilepticus [see DOSAGE AND ADMINISTRATION and Clinical
Studies]. But if withdrawal is needed because of a serious adverse event,
rapid discontinuation can be considered.
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 3 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
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.
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
placebotreated 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.
A study was conducted in pediatric patients (3 to 17
years old) with inadequately controlled partial seizures in which TRILEPTAL was
added to existing AED therapy (up to 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.
Drug Reaction With Eosinophilia And Systemic Symptoms
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 lifethreatening. 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.
Rare reports of pancytopenia, agranulocytosis, and
leukopenia have been seen in patients treated with TRILEPTAL during
postmarketing experience. Discontinuation of the drug should be considered if
any evidence of these hematologic events develops.
Seizure Control During Pregnancy
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.
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.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Counsel patients that TRILEPTAL may be taken with or
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 and HOW SUPPLIED/Storage And Handling].
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].
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].
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
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].
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].
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 and ADVERSE REACTIONS].
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].
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].
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].Â 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.
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].
Carcinogenesis, Mutagenesis, Impairment Of Fertility
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/m²
basis. In rats, the incidence of hepatocellular carcinomas was increased in
females treated with oxcarbazepine at doses ≥25 mg/kg/day (0.1 times the
MRHD on a mg/m² basis), and incidences of hepatocellular adenomas and/or
carcinomas were increased in males and females treated with MHD at doses of 600
mg/kg/day (2.4 times the MRHD on a mg/m² basis) and ≥250 mg/kg/day (equivalent
to the MRHD on a mg/m² basis), respectively. There was an increase in the
incidence of benign testicular interstitial cell tumors in rats at 250 mg
oxcarbazepine/kg/day and at ≥250 mg MHD/kg/day, and an increase in the
incidence of granular cell tumors in the cervix and vagina in rats at 600 mg
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/m² basis).
Use In Specific Populations
TRILEPTAL levels may decrease during pregnancy [see WARNINGS
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 of pregnancies from pregnancy registries suggest congenital
malformations associated with TRILEPTAL monotherapy use (e.g., craniofacial
defects such as oral clefts and cardiac malformations such as ventricular
septal defects). TRILEPTAL should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
Increased incidences of fetal structural abnormalities
and other manifestations of developmental toxicity (embryolethality, growth
retardation) were observed in the offspring of animals treated with either oxcarbazepine
or its active 10-hydroxy metabolite (MHD) during pregnancy at doses similar to
the maximum recommended human dose (MRHD).
When pregnant rats were given oxcarbazepine (30, 300, or
1000 mg/kg) orally throughout the period of organogenesis, increased incidences
of fetal malformations (craniofacial, cardiovascular, and skeletal) and
variations were observed at the intermediate and high doses (approximately 1.2
and 4 times, respectively, the MRHD on a mg/m² basis). Increased embryofetal
death and decreased fetal body weights were seen at the high dose. Doses
≥300 mg/kg were also maternally toxic (decreased body weight gain,
clinical signs), but there is no evidence to suggest that teratogenicity was
secondary to the maternal effects.
In a study in which pregnant rabbits were orally
administered MHD (20, 100, or 200 mg/kg) during organogenesis, embryofetal
mortality was increased at the highest dose (1.5 times the MRHD on a mg/m²
basis). This dose produced only minimal maternal toxicity.
In a study in which female rats were dosed orally with
oxcarbazepine (25, 50, or 150 mg/kg) during the latter part of gestation and
throughout the lactation period, a persistent reduction in body weights and altered
behavior (decreased activity) were observed in offspring exposed to the highest
dose (0.6 times the MRHD on a mg/m² basis). Oral administration of MHD (25, 75,
or 250 mg/kg) to rats during gestation and lactation resulted in a persistent
reduction in offspring weights at the highest dose (equivalent to the MRHD on a
To provide information regarding the effects of in utero
exposure to TRILEPTAL, physicians are advised to recommend that pregnant
patients taking TRILEPTAL enroll in the NAAED Pregnancy Registry. This can be
done by calling the toll-free number 1-888-233-2334, and must be done by patients
themselves. Information on the registry can also be found at the website:
Oxcarbazepine and its active metabolite (MHD) are
excreted in human milk. A milk-to-plasma concentration ratio of 0.5 was found
for both. Because of the potential for serious adverse reactions to TRILEPTAL
in nursing infants, a decision should be made about whether to discontinue
nursing or to discontinue the drug in nursing women, taking into account the
importance of the drug to the mother.
TRILEPTAL is indicated for use as adjunctive therapy for
partial seizures in patients aged 2 to 16 years.
The safety and effectiveness for use as adjunctive
therapy for partial seizures in pediatric patients below the age of 2 have not
TRILEPTAL is also indicated as monotherapy for partial
seizures in patients aged 4 to 16 years.
The safety and effectiveness for use as monotherapy for
partial seizures in pediatric patients below the age of 4 have not been
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, ADVERSE REACTIONS, CLINICAL
PHARMACOLOGY, and Clinical Studies].
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
Dose adjustment is recommended for renally impaired
patients (CLcr <30 mL/min) [see DOSAGE AND ADMINISTRATION and CLINICAL