WARNINGS
See Boxed Warning regarding aplastic anemia and hepatic
failure. Antiepileptic drugs should not be suddenly discontinued
because of the possibility of increasing seizure frequency.
Suicidal Behavior and
Ideation
Antiepileptic drugs (AEDs) including Felbatol
®, 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 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 1 shows absolute and relative risk by indication for all
evaluated AEDs.
Table 1 Risk by Indication for Antiepileptic Drugs in the
Pooled Analysis
Indication |
Placebo Patients with Events Per 1000
Patients |
Drug Patients with Events Per 1000
Patients |
Relative Risk: Incidence of Events in
Drug Patients/Incidence in Placebo Patients |
Risk Difference: Additional
Drug Patients with Events Per 1000 Patients |
Epilepsy |
1.0 |
3.4 |
3.5 |
2.4 |
Psychiatric |
5.7 |
8.5 |
1.5 |
2.9 |
Other |
1.0 |
1.8 |
1.9 |
0.9 |
Total |
2.4 |
4.3 |
1.8 |
1.9 |
The relative risk for suicidal thoughts or behavior was higher in
clinical trials for epilepsy than in clinical trials for psychiatric or
other conditions, but the absolute risk differences were similar for the
epilepsy and psychiatric indications.
Anyone considering prescribing Felbatol or any other AED must
balance the risk of suicidal thoughts or behavior with the risk of
untreated illness. Epilepsy and many other illnesses for which AEDs are
prescribed are themselves associated with morbidity and mortality and an
increased risk of suicidal thoughts and behavior. Should suicidal
thoughts and behavior emerge during treatment, the prescriber needs to
consider whether the emergence of these symptoms in any given patient
may be related to the illness being treated.
Patients, their caregivers, and families should be informed that
AEDs increase the risk of suicidal thoughts and behavior and should be
advised of the need to be alert for the emergence or worsening of the
signs and symptoms of depression, any unusual changes in mood or
behavior, or the emergence of suicidal thoughts, behavior, or thoughts
about self-harm. Behaviors of concern should be reported immediately to
healthcare providers.
PRECAUTIONS
Dosage Adjustment in the
Renally Impaired: A study in otherwise healthy
individuals with renal dysfunction indicated that prolonged
half-life and reduced clearance of felbamate are associated with
diminishing renal function. Felbamate should be used with
caution in patients with renal dysfunction (see
DOSAGE AND ADMINISTRATION).
Information for
Patients: Patients should be informed that the use of
Felbatol® is associated with aplastic anemia and
hepatic failure, potentially fatal conditions acutely or over a
long term.
The physician should obtain written acknowledgement
prior to initiation of Felbatol® therapy (see
PATIENT/PHYSICIAN ACKNOWLEDGMENT FORM
section).
Patients should be instructed to read the Medication Guide supplied as required by law when
Felbatol® is dispensed. The complete text of the Medication Guide is reprinted at the end of
this document.
Aplastic anemia
in the general population is relatively rare. The absolute risk
for the individual patient is not known with any degree of
reliability, but patients on Felbatol® may be at more
than a 100 fold greater risk for developing the syndrome than
the general population.
The long term outlook for patients with aplastic anemia
is variable. Although many patients are apparently cured, others
require repeated transfusions and other treatments for relapses,
and some, although surviving for years, ultimately develop
serious complications that sometimes prove fatal (e.g.,
leukemia).
At present there is no way to predict who is likely to
get aplastic anemia, nor is there a documented effective means
to monitor the patient so as to avoid and/or reduce the risk.
Patients with a history of any blood dyscrasia should not
receive Felbatol®.
Patients should be advised to be alert for signs of
infection, bleeding, easy bruising, or signs of anemia (fatigue,
weakness, lassitude, etc.) and should be advised to report to
the physician immediately if any such signs or symptoms appear.
Hepatic failure
in the general population is relatively rare. The absolute risk
for an individual patient is not known with any degree of
reliability but patients on Felbatol® are at a greater
risk for developing hepatic failure than the general population.
At present, there is no way to predict who is likely to
develop hepatic failure, however, patients with a history of
hepatic dysfunction should not be started on Felbatol®.
Patients should be advised to follow their physician's
directives for liver function testing both before starting
Felbatol® (felbamate) and at frequent intervals while
taking Felbatol®.
Patients should be advised to be alert for signs of liver
dysfunction (jaundice, anorexia, gastrointestinal complaints,
malaise, etc.) and to report them to their doctor immediately if
they should occur.
Laboratory Tests:
Full hematologic
evaluations should be performed before
Felbatol® therapy, frequently during therapy, and for a
significant period of time after discontinuation of
Felbatol® therapy. While it might appear prudent to
perform frequent CBCs in patients continuing on
Felbatol®, there is no evidence that such monitoring
will allow early detection of marrow suppression before aplastic
anemia occurs. (See
Boxed Warnings). Complete pretreatment blood counts, including
platelets and reticulocytes should be obtained as a baseline. If
any hematologic abnormalities are detected during the course of
treatment, immediate consultation with a hematologist is
advised. Felbatol® should be discontinued if any
evidence of bone marrow depression occurs.
See Box
Warnings for recommended monitoring of serum
transaminases. If significant, confirmed liver abnormalities are
detected during the course of Felbatol® treatment,
Felbatol® should be discontinued immediately with
continued liver function monitoring until values return to
normal. (see
PATIENT/PHYSICIAN ACKNOWLEDGMENT FORM).
Suicidal Thinking and
Behavior: Patients, their caregivers, and families
should be counseled that AEDs, including Felbatol®, 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.
Pregnancy: Patients
should be encouraged 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
Pregnancy
section).
Drug Interactions:
The drug interaction data described in this section were
obtained from controlled clinical trials and studies involving
otherwise healthy adults with epilepsy.
Use in Conjunction with Other
Antiepileptic Drugs (see DOSAGE
AND ADMINISTRATION):
The addition of
Felbatol® to antiepileptic drugs (AEDs) affects the
steady-state plasma concentrations of AEDs. The
net effect of these interactions is summarized in Table 2:
Table 2 Steady-State Plasma Concentrations of Felbatol
When Coadministered With Other AEDs
*Not administered but an
active metabolite of carbamazepine. |
**No significant
effect. |
AED Coadministered |
AED Concentration |
Felbatol® Concentration |
Phenytoin |
↑ |
↓ |
Valproate |
↑ |
↔** |
Carbamazepine (CBZ) *CBZ epoxide |
↓ ↑ |
↓ |
Phenobarbital |
↑ |
↓ |
Specific Effects of
Felbatol® on Other Antiepileptic Drugs:
Phenytoin:
Felbatol® causes an increase in steady-state phenytoin
plasma concentrations. In 10 otherwise healthy subjects with
epilepsy ingesting phenytoin, the steady-state trough (Cmin)
phenytoin plasma concentration was 17±5 micrograms/mL.
The steady-state Cmin increased to 21±5 micrograms/mL
when 1200 mg/day of felbamate was coadministered. Increasing the
felbamate dose to 1800 mg/day in six of these subjects increased
the steady-state phenytoin Cmin to 25±7 micrograms/mL.
In order to maintain phenytoin levels, limit adverse
experiences, and achieve the felbamate dose of 3600 mg/day, a
phenytoin dose reduction of approximately 40% was
necessary for eight of these 10 subjects.
In a controlled clinical trial, a 20% reduction
of the phenytoin dose at the initiation of Felbatol®
therapy resulted in phenytoin levels comparable to those prior
to Felbatol® administration.
Carbamazepine: Felbatol® causes a decrease
in the steady-state carbamazepine plasma concentrations and an
increase in the steady-state carbamazepine epoxide plasma
concentration. In nine otherwise healthy subjects with epilepsy
ingesting carbamazepine, the steady-state trough (Cmin)
carbamazepine concentration was 8±2 micrograms/mL. The
carbamazepine steady-state Cmin decreased 31% to
5±1 micrograms/mL when felbamate (3000 mg/day, divided
into three doses) was coadministered. Carbamazepine epoxide
steady-state Cmin concentrations increased 57% from
1.0±0.3 to 1.6±0.4 micrograms/mL with the
addition of felbamate.
In clinical trials, similar changes in carbamazepine and
carbamazepine epoxide were seen.
Valproate:
Felbatol® causes an increase in steady-state valproate
concentrations. In four subjects with epilepsy ingesting
valproate, the steady-state trough (Cmin) valproate plasma
concentration was 63±16 micrograms/mL. The steady-state
Cmin increased to 78±14 micrograms/mL when 1200 mg/day
of felbamate was coadministered. Increasing the felbamate dose
to 2400 mg/day increased the steady-state valproate Cmin to
96±25 micrograms/mL. Corresponding values for free
valproate Cmin concentrations were 7±3, 9±4,
and 11±6 micrograms/mL for 0, 1200, and 2400 mg/day
Felbatol®, respectively. The ratios of the AUCs of
unbound valproate to the AUCs of the total valproate were
11.1%, 13.0%, and 11.5%, with
coadministration of 0, 1200, and 2400 mg/day of
Felbatol®, respectively. This indicates that the
protein binding of valproate did not change appreciably with
increasing doses of Felbatol®.
Phenobarbital: Coadministration of felbamate with
phenobarbital causes an increase in phenobarbital plasma
concentrations. In 12 otherwise healthy male volunteers
ingesting phenobarbital, the steady-state trough (Cmin)
phenobarbital concentration was 14.2 micrograms/mL. The
steady-state Cmin concentration increased to 17.8 micrograms/mL
when 2400 mg/day of felbamate was coadministered for one week.
Effects of Other
Antiepileptic Drugs on Felbatol®:
Phenytoin:
Phenytoin causes an approximate doubling of the clearance of
Felbatol® (felbamate) at steady-state and, therefore,
the addition of phenytoin causes an approximate 45%
decrease in the steady-state trough concentrations of
Felbatol® as compared to the same dose of
Felbatol® given as monotherapy.
Carbamazepine: Carbamazepine causes an approximate
50% increase in the clearance of Felbatol® at
steady-state and, therefore, the addition of carbamazepine
results in an approximate 40% decrease in the
steady-state trough concentrations of Felbatol® as
compared to the same dose of Felbatol® given as
monotherapy.
Valproate:
Available data suggest that there is no significant effect of
valproate on the clearance of Felbatol® at
steady-state. Therefore, the addition of valproate is not
expected to cause a clinically important effect on
Felbatol® (felbamate) plasma concentrations.
Phenobarbital: It appears that phenobarbital may
reduce plasma felbamate concentrations. Steady-state plasma
felbamate concentrations were found to be 29% lower than
the mean concentrations of a group of newly diagnosed subjects
with epilepsy also receiving 2400 mg of felbamate a day.
Effects of Antacids on
Felbatol®:
The rate and extent of
absorption of a 2400 mg dose of Felbatol® as
monotherapy given as tablets was not affected when
coadministered with antacids.
Effects of Erythromycin on
Felbatol®:
The coadministration of
erythromycin (1000 mg/day) for 10 days did not alter the
pharmacokinetic parameters of Cmax, Cmin, AUC, Cl/kg or tmax at
felbamate daily doses of 3000 or 3600 mg/day in 10 otherwise
healthy subjects with epilepsy.
Effects of Felbatol®
on Low-Dose Combination Oral Contraceptives:
A group of 24 nonsmoking, healthy white female volunteers
established on an oral contraceptive regimen containing 30
µg ethinyl estradiol and 75 µg gestodene for
at least 3 months received 2400 mg/day of felbamate from
midcycle (day 15) to midcycle (day 14) of two consecutive oral
contraceptive cycles. Felbamate treatment resulted in a
42% decrease in the gestodene AUC 0-24, but no
clinically relevant effect was observed on the pharmacokinetic
parameters of ethinyl estradiol. No volunteer showed hormonal
evidence of ovulation, but one volunteer reported intermenstrual
bleeding during felbamate treatment.
Drug/Laboratory Test
Interactions: There are no known interactions of
Felbatol® with commonly used laboratory
tests.
Carcinogenesis, Mutagenesis,
Impairment of Fertility: Carcinogenicity studies
were conducted in mice and rats. Mice received felbamate as a
feed admixture for 92 weeks at doses of 300, 600, and 1200 mg/kg
and rats were also dosed by feed admixture for 104 weeks at
doses of 30, 100, and 300 (males) or 10, 30, and 100 (females)
mg/kg. The maximum doses in these studies produced steady-state
plasma concentrations that were equal to or less than the
steady-state plasma concentrations in epileptic patients
receiving 3600 mg/day. There was a statistically significant
increase in hepatic cell adenomas in high-dose male and female
mice and in high-dose female rats. Hepatic hypertrophy was
significantly increased in a dose-related manner in mice,
primarily males, but also in females. Hepatic hypertrophy was
not found in female rats. The relationship between the
occurrence of benign hepatocellular adenomas and the finding of
liver hypertrophy resulting from liver enzyme induction has not
been examined. There was a statistically significant increase in
benign interstitial cell tumors of the testes in high-dose male
rats receiving felbamate. The relevance of these findings to
humans is unknown.
As a result of the synthesis process, felbamate could
contain small amounts of two known animal carcinogens, the
genotoxic compound ethyl carbamate (urethane) and the
nongenotoxic compound methyl carbamate. It is theoretically
possible that a 50 kg patient receiving 3600 mg of felbamate
could be exposed to up to 0.72 micrograms of urethane and 1800
micrograms of methyl carbamate. These daily doses are
approximately 1/35,000 (urethane) and 1/5,500 (methyl carbamate)
on a mg/kg basis, and 1/10,000 (urethane) and 1/1,600 (methyl
carbamate) on a mg/m2 basis, of the dose levels shown
to be carcinogenic in rodents. Any presence of these two
compounds in felbamate used in the lifetime carcinogenicity
studies was inadequate to cause tumors.
Microbial and mammalian cell assays revealed no evidence
of mutagenesis in the Ames Salmonella /microsome plate test, CHO/HGPRT
mammalian cell forward gene mutation assay, sister chromatid
exchange assay in CHO cells, and bone marrow cytogenetics assay.
Reproduction and fertility studies in rats showed no
effects on male or female fertility at oral doses of up to 13.9
times the human total daily dose of 3600 mg on a mg/kg basis, or
up to 3 times the human total daily dose on a mg/m2
basis.
Pregnancy: Pregnancy Category
C. The incidence of malformations was not
increased compared to control in offspring of rats or rabbits
given doses up to 13.9 times (rat) and 4.2 times (rabbit) the
human daily dose on a mg/kg basis, or 3 times (rat) and less
than 2 times (rabbit) the human daily dose on a mg/m
2 basis. However, in rats, there was a decrease in
pup weight and an increase in pup deaths during lactation. The
cause for these deaths is not known. The no effect dose for rat
pup mortality was 6.9 times the human dose on a mg/kg basis or
1.5 times the human dose on a mg/m 2 basis.
Placental transfer of felbamate occurs in rat pups. There
are, however, no studies in pregnant women. Because animal
reproduction studies are not always predictive of human
response, this drug should be used during pregnancy only if
clearly needed.
To provide information regarding the effects of in utero
exposure to Felbatol®, physicians are advised to
recommend that pregnant patients taking Felbatol 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 http://www.aedpregnancyregistry.org/.
Labor and Delivery:
The effect of felbamate on labor and delivery in humans is
unknown.
Nursing Mothers:
Felbamate has been detected in human milk. The effect on the
nursing infant is unknown (see
Pregnancy
section).
Pediatric Use: The
safety and effectiveness of Felbatol® in children other
than those with Lennox-Gastaut syndrome has not been
established.
Geriatric Use: No
systematic studies in geriatric patients have been conducted.
Clinical studies of Felbatol® did not include
sufficient numbers of patients aged 65 and over to determine
whether they respond differently from younger patients. Other
reported clinical experience has not identified differences in
responses between the elderly and younger patients. In general,
dosage selection for an elderly patient should be cautious,
usually starting at the low end of the dosing range, reflecting
the greater frequency of decreased hepatic, renal, or cardiac
function, and of concomitant disease or other drug
therapy.
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