Approved Drug Label (PDF)
5
Warnings and Precautions
Additions
and/or revisions underlined:
5.2
Serious Dermatologic Reactions
Serious dermatologic reactions including
Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) have
been reported in association with APTIOM use.
Serious and sometimes fatal dermatologic reactions, including TEN and
SJS, have also been reported … estimates by a factor of 3- to 10-fold. The
reporting rates for Aptiom have not been determined.
Risk factors for the development of
serious and potentially fatal dermatologic reactions with APTIOM use
have not been identified.
… Patients with a prior dermatologic
reaction with oxcarbazepine, carbamazepine, or APTIOM should ordinarily
not be treated with APTIOM.
5.5
Hyponatremia
Clinically significant hyponatremia
(sodium less than 125 mEq/L) can develop in patients taking APTIOM. Measurement
of serum sodium and chloride levels should be considered during maintenance
treatment with APTIOM, particularly if the patient is receiving other
medications known to decrease serum sodium levels, and should be performed if
symptoms of hyponatremia develop (e.g., nausea/vomiting, malaise, headache,
lethargy, confusion, irritability, muscle weakness/spasms, obtundation, or
increase in seizure frequency or severity).
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 APTIOM was discontinued because of hyponatremia generally experienced
normalization of serum sodium within a few days without additional treatment.
In the controlled adult adjunctive
epilepsy trials, 4/415 patients …
Concurrent hypochloremia was also
present in patients with hyponatremia. Hyponatremia
was also observed in adult monotherapy trials and in pediatric trials.
Depending on the severity …
Additions
and/or revisions underlined:
5.6
Neurological Adverse Reactions
Dizziness and Disturbance in Gait and
Coordination
… In controlled adult adjunctive
epilepsy trials, these …
… Nausea and vomiting also occurred with
these events. Adverse reactions related to dizziness and disturbance in
gait and coordination were also observed in adult monotherapy trials
and pediatric trials …
… The incidence of dizziness was greater
with the concomitant use of APTIOM and carbamazepine compared to the use of
APTIOM without carbamazepine in adult and pediatric trials. Therefore,
consider dosage …
Somnolence and Fatigue
… In the controlled adult adjunctive
epilepsy trials …
Somnolence and fatigue-related reactions
were also observed in adult monotherapy trials and in pediatric
trials.
Cognitive Dysfunction
APTIOM causes dose-dependent increases
in cognitive dysfunction-related events in adults (memory …
… In
the controlled adult adjunctive epilepsy trials …
… Cognitive dysfunction events were also
observed in adult monotherapy trials.
Visual Changes
… In the controlled adult
adjunctive epilepsy trials …
… APTIOM without carbamazepine (up to
16% vs. 6%, respectively). Similar adverse reactions related to visual
changes were also observed in adult monotherapy trials and in
pediatric trials.
5.7
Withdrawal of AEDs
As with all antiepileptic drugs, APTIOM
should be withdrawn gradually because of the risk of increased seizure
frequency and status epilepticus, but if withdrawal is needed because of a
serious adverse event, rapid discontinuation can be considered.
Newly
added subsection:
5.10
Hematologic Adverse Reactions
Rare cases of pancytopenia,
agranulocytosis, and leukopenia have been reported during postmarketing use in
patients treated with APTIOM. Discontinuation of APTIOM should be considered in
patients who develop pancytopenia, agranulocytosis, or leukopenia.
6
Adverse Reactions
The following adverse reactions are
described in more detail in the Warnings
and Precautions section of the label:
Addition
of the following:
6.1
Clinical Trials Experience
Additions
and/or revisions underlined:
Adult Patients
In monotherapy trials in patients …
Following
Table 4 Adverse Reactions Incidence in Pooled
Controlled Clinical Trials of Adjunctive Therapy in Adults (Events greater than
or equal to 2% of Patients in the APTIOM 800 mg or 1200 mg Dose Group and More
Frequent Than in the Placebo Group), addition of the following:
Pediatric Patients (4 to 17 Years of
Age)
Clinical studies of pediatric patients 4
to 17 years were conducted which support the safety and tolerability of APTIOM
for the treatment of partial-onset seizures.
Across studies in pediatric patients with partial-onset seizures, 393
patients ages 4 to 17 years received APTIOM, of whom 265 received APTIOM for at
least 1 year. Adverse reactions reported in clinical studies of pediatric
patients 4 to 17 years of age were similar to those seen in adult patients.
Newly
added subsection:
6.2
Postmarketing Experience
The following adverse reactions have
been identified during postapproval use of APTIOM. 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:
Hematologic and Lymphatic Systems:
leukopenia, agranulocytosis, thrombocytopenia, megaloblastic anemia, and
pancytopenia
Metabolism and Nutrition Disorders:
syndrome of inappropriate antidiuretic hormone secretion (SIADH)
7
Drug Interactions
Additions
and/or revisions underlined:
7.1
Other Antiepileptic Drugs
Several AEDs …
7.2
CYP2C19 Substrates
APTIOM can inhibit CYP2C19 … omeprazole).
Dose adjustment may be needed.
7.3
CYP3A4 Substrates
In
vivo studies
… simvastatin, lovastatin). Dose
adjustment of simvastatin and lovastatin may be needed if a clinically
significant change in lipids is noted.
7.4
Oral Contraceptives
Because concomitant use …
8
Use in Specific Populations
8.1 Pregnancy
PLLR
conversion; as below:
Pregnancy Exposure Registry
There is a pregnancy exposure registry
that monitors pregnancy outcomes in women exposed to AEDs, such as APTIOM,
during pregnancy. Encourage women who are taking APTIOM during pregnancy to
enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by
calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org.
Risk Summary
Limited available data with APTIOM use
in pregnant women are insufficient to inform a drug-associated risk of adverse
developmental outcomes. In oral studies
conducted in pregnant mice, rats, and rabbits, eslicarbazepine acetate
demonstrated developmental toxicity, including increased incidence of
malformations (mice), embryolethality (rats), and fetal growth retardation (all
species), at clinically relevant doses (see
Data). Advise a pregnant woman of the potential risk to a fetus.
In the U.S. general population, the
estimated background risk of major birth defects and miscarriage in clinically
recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of
major birth defects and miscarriage for the indicated population is unknown.
Data
Animal
Data
When eslicarbazepine acetate was orally
administered (150, 350, 650 mg/kg/day) to pregnant mice throughout
organogenesis, increased incidences of fetal malformations was observed at all
doses and fetal growth retardation was observed at the mid and high doses. A
no-effect dose for adverse developmental effects was not identified. At the
lowest dose tested, plasma eslicarbazepine exposure (Cmax, AUC) is less than
that in humans at the maximum recommended human dose (MRHD, 1600 mg/day).
Oral administration of eslicarbazepine
acetate (40, 160, 320 mg/kg/day) to pregnant rabbits throughout organogenesis
resulted in fetal growth retardation and increased incidences of skeletal
variations at the mid and high doses. The no-effect dose (40 mg/kg/day) is less
than the MRHD on a mg/m2 basis.
Oral administration to pregnant rats
(65, 125, 250 mg/kg/day) throughout organogenesis resulted in embryolethality
at all doses, increased incidences of skeletal variations at the mid and high
doses, and fetal growth retardation at the high dose. The lowest dose tested
(65 mg/kg/day) is less than the MRHD on a mg/m2 basis.
When eslicarbazepine acetate was orally
administered to female mice during pregnancy and lactation (150, 350, 650
mg/kg/day), the gestation period was prolonged at the highest dose tested. In
offspring, a persistent reduction in offspring body weight and delayed physical
development and sexual maturation were observed at the mid and high doses. The
lowest dose tested (150 mg/kg/day) is less than the MRHD on a mg/m2 basis.
When eslicarbazepine acetate was orally
administered (65, 125, 250 mg/kg/day) to rats during pregnancy and lactation,
reduced offspring body weight was seen at the mid and high doses. Delayed sexual
maturation and a neurological deficit (decreased motor coordination) were
observed at the highest dose tested. The no-effect dose for adverse
developmental effects (65 mg/kg/day) is less than the MRHD on a mg/m2 basis.
The rat data are of uncertain relevance
to humans because of differences in metabolic profile between species.
8.2 Lactation
PLLR
conversion; as below:
Eslicarbazepine is present in human
milk. The effects of APTIOM on the breastfed infant or on milk production are
unknown. The developmental and health benefits of breastfeeding should be
considered along with the mother’s clinical need for APTIOM and any potential
adverse effects on the breastfed infant from APTIOM or from the underlying
maternal condition.
8.3 Females and Males of Reproductive Potential
PLLR
conversion; as below:
Contraception
Use of APTIOM with hormonal contraceptives containing
ethinyl estradiol or levonorgestrel is associated with lower plasma levels of
these hormones. Advise women of reproductive potential taking APTIOM who are
using a contraceptive containing ethinyl estradiol or levonorgestrel to use
additional or alternative non-hormonal birth control.
Infertility
Eslicarbazepine acetate was evaluated in
rats and mice for potential adverse impact on fertility of the parental and
first generation. In a fertility study in male and female mice, adverse
developmental outcomes were observed in embryos. In a fertility study in male and female rats,
impairment of female fertility by eslicarbazepine acetate was shown.
8.4 Pediatric Use
Additions
and/or revisions underlined:
Safety and effectiveness of APTIOM
have been established in the age groups 4 to 17 years. Use of APTIOM in these
age groups is supported by evidence from adequate and well-controlled studies
of APTIOM in adults with partial-onset seizures, pharmacokinetic data from
adult and pediatric patients, and safety data from clinical studies in 393
pediatric patients 4 to 17 years of age. Safety and effectiveness in
pediatric patients below the age of 4 years have not been established.
Animal Data
In a juvenile animal study … but not at
the end of a 2- month recovery period. Convulsions were seen at the
highest dose tested. A no-effect dose for adverse effects in juvenile dogs
was not identified. The lowest dose tested is less than the maximum
recommended pediatric dose (1200 mg/day) on a body surface area (mg/m2) basis.
A separate juvenile animal study was
conducted to assess possible adverse effects on the immune system.
Eslicarbazepine acetate (10, 40, 80 mg/kg/day) was orally administered to young
dogs for 17 weeks starting on postnatal day 21. No effects on the immune system
were observed.
17 PCI/PI/MG (Patient Counseling Information/Patient Information/Medication Guide)
PATIENT COUNSELING INFORMATION
Additions
and/or revisions underlined:
patients and caregivers has been updated throughout this section
APTIOM should only be taken
as prescribed.
Newly
added information:
Hematologic Adverse Reactions
Advise patients and caregivers that
there have been rare reports of blood disorders reported in patients treated
with APTIOM. Instruct patients to immediately consult with their physician if
they experience symptoms suggestive of blood disorders.
Get Email Alerts |
Guide
