Included as part of the PRECAUTIONS section.
Clinically significant hyponatremia (sodium < 125
mmol/L) may develop during Oxtellar XR® use. Serum sodium levels
less than 125 mmol/L have occurred in immediate-release oxcarbazepine-treated
patients generally in the first three months of treatment. However, clinically
significant hyponatremia may develop more than a year after initiating therapy.
Most immediate-release oxcarbazepine-treated patients who
developed hyponatremia were asymptomatic in clinical trials. However, some of
these patients had their dose reduced, discontinued, or had their fluid intake
restricted for hyponatremia. Serum sodium levels returned toward normal when
the dosage was reduced or discontinued, or when the patient was treated
conservatively (e.g., fluid restriction). Post-marketing cases of symptomatic
hyponatremia have been reported during post-marketing use of immediate-release
Among treated patients in a controlled trial of
adjunctive therapy with Oxtellar XR®in 366 adults with complex
partial seizures, 1 patient receiving 2400 mg experienced a severe reduction in
serum sodium (117 mEq/L) requiring discontinuation from treatment, while 2
other patients receiving 1200 mg experienced serum sodium concentrations low
enough (125 and 126 mEq/L) to require discontinuation from treatment. The
overall incidence of clinically significant hyponatremia in patients treated
with Oxtellar XR®was 1.2%, although slight shifts in serum sodium
concentrations from Normal to Low ( < 135 mEq/L) were observed for the 2400 mg
(6.5%) and 1200 mg (9.8%) groups compared to placebo (1.7%).Measure serum
sodium concentrations if patients develop symptoms of hyponatremia (e.g.,
nausea, malaise, headache, lethargy, confusion, obtunded consciousness, or
increase in seizure frequency or severity). Consider measurement of serum
sodium concentrations during treatment with Oxtellar XR®,
particularly if the patient receives concomitant medications known to decrease
serum sodium levels (for example, drugs associated with inappropriate ADH
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 immediate-release oxcarbazepine. Angioedema
associated with laryngeal edema can be fatal. If a patient develops any of
these reactions after treatment with Oxtellar XR®, discontinue the
drug and initiate an alternative treatment. Do not rechallenge these patients
with Oxtellar XR®.
Hypersensitivity Reactions In Patients With Hypersensitivity
Inform patients who have had hypersensitivity reactions
to carbamazepine that approximately 25%-30% of them will experience
hypersensitivity reactions with Oxtellar XR®. Question patients
about any prior adverse reactions with carbamazepine. Patients with a history
of hypersensitivity reactions to carbamazepine should ordinarily be treated
with Oxtellar XR® only if the potential benefit justifies the
potential risk. Discontinue Oxtellar XR® immediately if signs or
symptoms of hypersensitivity develop [see Hematologic Reactions].
Serious Dermatological Reactions
Serious dermatological reactions, including
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have
occurred in both children and adults treated with immediate-release
oxcarbazepine use. The median time of onset for reported cases was 19 days.
Such serious skin reactions may be life threatening, and some patients have
required hospitalization with very rare reports of fatal outcome. Recurrence of
the serious skin reactions following rechallenge with immediate-release
oxcarbazepine has also been reported.
The reporting rate of TEN and SJS associated with
immediate-release oxcarbazepine 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 Oxtellar XR®, consider discontinuing
Oxtellar XR® use and prescribing another AED.
Association with HLA-B*1502
Patients carrying the HLA-B*1502 allele may be at
increased risk for SJS/TEN with Oxtellar XR® treatment.
Human Leukocyte Antigen (HLA) allele B*1502 increases the
risk for developing SJS/TEN in patients treated with carbamazepine. The
chemical structures of immediate release oxcarbazepine and Oxtellar XR are
similar to that of carbamazepine. Available clinical evidence, and data from
nonclinical studies showing a direct interaction between immediate release
oxcarbazepine and HLA-B*1502 protein, suggest that the HLAB*1502 allele may
also increase the risk for SJS/TEN with Oxtellar XR®.
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 Oxtellar XR® . The use of
Oxtellar XR® 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 Oxtellar XR 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 Oxtellar XR®,
increase the risk of suicidal thoughts or behavior in patients taking these
drugs for any indication. Monitor patients treated with any AED for any
indication 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 four 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 (5-100 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
||Placebo Patients with Events per 1,000 Patients
||Drug Patients with Events per 1,000 Patients
||Relative Risk: Incidence of Events in Drug Patients/Incidence in 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
Oxtellar XR® 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 Oxtellar XR® treatment, the prescriber needs to consider whether the emergence of
these symptoms in any given patient may be related to the illness being
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
Withdrawal Of AEDs
As with all AEDs, Oxtellar XR® should be
withdrawn gradually to minimize the potential of increased seizure frequency.
Multi-organ hypersensitivity reactions have occurred in
close temporal association (median time to detection 13 days: range 4-60) to
the initiation of immediate-release oxcarbazepine therapy in adult and
pediatric patients. Although there have been a limited number of reports, many
of these cases resulted in hospitalization and some were life-threatening.
Signs and symptoms of this disorder were diverse; however, patients typically,
although not exclusively, presented with fever and rash associated with other
organ system involvement. These included the following: hematologic and
lymphatic (e.g., eosinophilia, thrombocytopenia, lymphadenopathy, leukopenia,
neutropenia, splenomegaly), hepatobiliary (e.g., hepatitis, liver function test
abnormalities), renal (e.g., proteinuria, nephritis, oliguria, renal failure),
muscles and joints (e.g., joint swelling, myalgia, arthralgia, asthenia),
nervous system (e.g., hepatic encephalopathy), respiratory (e.g., dyspnea,
pulmonary edema, asthma, bronchospasm, interstitial lung disease), hepatorenal
syndrome, pruritus, and angioedema. Because the disorder is variable in its
expression, other organ system symptoms and signs, not noted here, may occur.
If this reaction is suspected, discontinue Oxtellar XR®and initiate
an alternative treatment.
Rare reports of pancytopenia, agranulocytosis, and
leukopenia have been seen in patients treated with immediate-release
oxcarbazepine during post-marketing experience. Discontinuation of Oxtellar XR® should be considered if any evidence of these hematologic reactions
Risk Of Seizures In The Pregnant Patient
Due to physiological changes during pregnancy, plasma
concentrations of the active metabolite of oxcarbazepine, the 10-monohydroxy
derivative (MHD), may gradually decrease throughout pregnancy. Monitor patients
carefully during pregnancy and through the postpartum period because MHD
concentrations may increase after delivery.
Laboratory data from clinical trials suggest that
immediate-release oxcarbazepine may be associated with decreases in T4, without
changes in T3 or TSH.
Patient Counseling Information
See FDA-Approved patient labeling (Medication Guide).
Inform patients and caregivers of the availability of a
Medication Guide. Instruct patients and caregivers to read the Medication Guide
prior to taking Oxtellar XR®.
- Advise patients to take the tablet whole with water or
other liquid, and not to cut, chew or crush the tablet. Cutting, chewing or
crushing Oxtellar XR® tablet could affect its performance.
- Advise patients to take Oxtellar XR® on an
empty stomach. This means they should take Oxtellar XR® at least one
hour before food or at least two hours after food [see CLINICAL PHARMACOLOGY].
- Advise patients that Oxtellar XR® may reduce
serum sodium concentrations especially if they are taking other medications
that can lower sodium. Advise 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 may occur during
treatment with Oxtellar XR®. Advise patients to immediately report
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].
- Inform patients who have exhibited hypersensitivity
reactions to carbamazepine that approximately 25%-30% of these patients may
also experience hypersensitivity reactions with Oxtellar XR®. If
patients experience a hypersensitivity reaction while taking Oxtellar XR®,
advise them to consult with their physician immediately [see WARNINGS AND
- Advise patients that serious skin reactions have been
reported in association with immediate-release oxcarbazepine. If patients
experience a skin reaction while taking Oxtellar XR®, advise
patients to consult with their physician immediately [see WARNINGS AND
- Instruct patients that a fever associated with other
organ system involvement (rash, lymphadenopathy, etc.) occurring during
treatment with Oxtellar XR® may be drug-related and advise them to
consult their physician immediately [see WARNINGS AND PRECAUTIONS].
- Advise patients that there have been rare reports of
blood disorders reported in patients treated with immediate-release
oxcarbazepine. Instruct patients to immediately consult with their physician if
they experience symptoms suggestive of blood disorders during treatment with
Oxtellar XR® [see WARNINGS AND PRECAUTIONS].
- Warn female patients of childbearing age that the
concurrent use of Oxtellar XR®with hormonal contraceptives may
render this method of contraception less effective [see DRUG INTERACTIONS].
Additional non-hormonal forms of contraception are recommended when using
- Counsel patients, their caregivers, and families that
AEDs, including Oxtellar XR® , may increase the risk of suicidal
thoughts and behavior and that they 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.
Advise them to immediately report behaviors of concern to healthcare providers.
- Advise patients to exercise caution if alcohol is taken
in combination with Oxtellar XR® therapy, due to a possible additive
- Advise patients that Oxtellar XR® may cause
dizziness and somnolence. Accordingly, advise patients not to drive or operate
machinery until they have gained sufficient experience on Oxtellar XR®to
gauge whether it adversely affects their ability to drive or operate machinery.
- 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. To enroll, patients can call the toll free number 1-888-233-2334
[see Use In Specific Populations].
- Advise patients that they should call their healthcare
provider or poison control center (phone number 1-800-222-1222) if they take
too much Oxtellar XR®.
- Discuss with your patient what they should do if they
miss a dose.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
In two-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),
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.
Oxcarbazepine increased mutation frequencies in the Ames
test in vitro in the absence of metabolic activation in one of five bacterial
strains. 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 two times the MRHD on a mg/m² basis).
Use In Specific Populations
Oxtellar XR® plasma
concentrations may decrease during pregnancy [see WARNINGS AND
Pregnancy Category C
There are no adequate and
well-controlled clinical studies of Oxtellar XR®in pregnant women;
however, Oxtellar XR® is closely related structurally to
carbamazepine, which is considered to be teratogenic in humans. Given this
fact, and the results of the animal studies described, it is likely that
Oxtellar XR® is a human teratogen. Oxtellar XR® 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.
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 maximum
recommended human dose [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
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 mg/m² basis).
To provide information
regarding the effects of in utero exposure to Oxtellar XR® ,
physicians are advised to recommend that pregnant patients taking Oxtellar XR® enroll in the NAAED Pregnancy Registry. This can be done by calling the
toll free number 1-888233-2334, and must be done by patients themselves.
Information on the registry can also be found at the website
Labor And Delivery
The effect of Oxtellar XR® on labor and
delivery in humans has not been evaluated.
Oxcarbazepine and its active metabolite (MHD) are
excreted in human milk. A milk-toplasma concentration ratio of 0.5 was found
for both. Because of the potential for serious adverse reactions to Oxtellar XR® 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.
The short term safety and effectiveness of Oxtellar XR® in pediatric patients ages 6 to 16 years with partial onset seizures is
- An adequate and well-controlled short term safety and
efficacy study of Oxtellar XR® in adults that included
pharmacokinetic sampling [see Clinical Studies], A pharmacokinetic study
of Oxtellar XR® in pediatric patients ages 4 to 16 years [see CLINICAL
- Safety and efficacy studies with the immediate-release
formulation in adults and pediatric patients [see Clinical Studies and ADVERSE
- Oxtellar XR® is not approved for pediatric
patients less than 6 years of age because the size of the tablets are
inappropriate for younger children, and has not been studied in patients
younger than 4 years of age.
Following administration of single (300 mg) and multiple
(600 mg/day) doses of immediate-release oxcarbazepine to elderly volunteers
(60-82 years of age), the maximum plasma concentrations and AUC values of MHD
were 30%-60% higher than in younger volunteers (18-32 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.
Consider starting at a lower dose and lower titration [see DOSAGE AND
There is a linear correlation between creatinine
clearance and the renal clearance of MHD. [see CLINICAL PHARMACOLOGY and
DOSAGE AND ADMINISTRATION].
The pharmacokinetics of Oxtellar XR®has not
been evaluated in patients with renal impairment. In patients with severe renal
impairment (creatinine clearance < 30 mL/min) given immediate release
oxcarbazepine, the elimination half-life of MHD was prolonged with a
corresponding two-fold increase in AUC [see CLINICAL PHARMACOLOGY]. In
these patients initiate Oxtellar XR® at a lower starting dose and
increase, if necessary, at a slower than usual rate until the desired clinical
response is achieved [see DOSAGE AND ADMINISTRATION].
In patients with end-stage renal disease on dialysis, it
is recommended that immediate release oxcarbazepine be used instead of Oxtellar
The pharmacokinetics of oxcarbazepine and MHD has not
been evaluated in severe hepatic impairment, and therefore is not recommended
in these patients. [see CLINICAL PHARMACOLOGY].