Felbatol Information
Felbatol (Felbamate) Warning
AMONG Felbatol (Felbamate) ® TREATED PATIENTS, APLASTIC ANEMIA
(PANCYTOPENIA IN THE PRESENCE OF A BONE MARROW LARGELY DEPLETED OF
HEMATOPOIETIC PRECURSORS) OCCURS AT AN INCIDENCE THAT MAY BE MORE THAN A
100 FOLD GREATER THAN THAT SEEN IN THE UNTREATED POPULATION (I.E., 2 TO
5 PER MILLION PERSONS PER YEAR). THE RISK OF DEATH IN PATIENTS WITH
APLASTIC ANEMIA GENERALLY VARIES AS A FUNCTION OF ITS SEVERITY AND
ETIOLOGY; CURRENT ESTIMATES OF THE OVERALL CASE FATALITY RATE ARE IN THE
RANGE OF 20 TO 30%, BUT RATES AS HIGH AS 70% HAVE BEEN
REPORTED IN THE PAST.
THERE ARE TOO FEW Felbatol (Felbamate) ® ASSOCIATED CASES, AND TOO
LITTLE KNOWN ABOUT THEM TO PROVIDE A RELIABLE ESTIMATE OF THE SYNDROME'S
INCIDENCE OR ITS CASE FATALITY RATE OR TO IDENTIFY THE FACTORS, IF ANY,
THAT MIGHT CONCEIVABLY BE USED TO PREDICT WHO IS AT GREATER OR LESSER
RISK.
IN MANAGING PATIENTS ON Felbatol (Felbamate) ®, IT SHOULD BE BORNE IN
MIND THAT THE CLINICAL MANIFESTATION OF APLASTIC ANEMIA MAY NOT BE SEEN
UNTIL AFTER A PATIENT HAS BEEN ON Felbatol (Felbamate) ® FOR SEVERAL MONTHS
(E.G., ONSET OF APLASTIC ANEMIA AMONG Felbatol (Felbamate) ® EXPOSED
PATIENTS FOR WHOM DATA ARE AVAILABLE HAS RANGED FROM 5 TO 30 WEEKS).
HOWEVER, THE INJURY TO BONE MARROW STEM CELLS THAT IS HELD TO BE
ULTIMATELY RESPONSIBLE FOR THE ANEMIA MAY OCCUR WEEKS TO MONTHS EARLIER.
ACCORDINGLY, PATIENTS WHO ARE DISCONTINUED FROM Felbatol (Felbamate) ®
REMAIN AT RISK FOR DEVELOPING ANEMIA FOR A VARIABLE, AND UNKNOWN, PERIOD
AFTERWARDS.
IT IS NOT KNOWN WHETHER OR NOT THE RISK OF DEVELOPING APLASTIC
ANEMIA CHANGES WITH DURATION OF EXPOSURE. CONSEQUENTLY, IT IS NOT SAFE
TO ASSUME THAT A PATIENT WHO HAS BEEN ON Felbatol (Felbamate) ® WITHOUT
SIGNS OF HEMATOLOGIC ABNORMALITY FOR LONG PERIODS OF TIME IS WITHOUT
RISK.
IT IS NOT KNOWN WHETHER OR NOT THE DOSE OF Felbatol (Felbamate) ®
AFFECTS THE INCIDENCE OF APLASTIC ANEMIA.
IT IS NOT KNOWN WHETHER OR NOT CONCOMITANT USE OF ANTIEPILEPTIC
DRUGS AND/OR OTHER DRUGS AFFECTS THE INCIDENCE OF APLASTIC ANEMIA.
APLASTIC ANEMIA TYPICALLY DEVELOPS WITHOUT PREMONITORY CLINICAL
OR LABORATORY SIGNS, THE FULL BLOWN SYNDROME PRESENTING WITH SIGNS OF
INFECTION, BLEEDING, OR ANEMIA. ACCORDINGLY, ROUTINE BLOOD TESTING
CANNOT BE RELIABLY USED TO REDUCE THE INCIDENCE OF APLASTIC ANEMIA, BUT,
IT WILL, IN SOME CASES, ALLOW THE DETECTION OF THE HEMATOLOGIC CHANGES
BEFORE THE SYNDROME DECLARES ITSELF CLINICALLY. Felbatol (Felbamate) ®
SHOULD BE DISCONTINUED IF ANY EVIDENCE OF BONE MARROW DEPRESSION OCCURS.
OF THE CASES REPORTED, ABOUT 67% RESULTED IN DEATH OR
LIVER TRANSPLANTATION, USUALLY WITHIN 5 WEEKS OF THE ONSET OF SIGNS AND
SYMPTOMS OF LIVER FAILURE. THE EARLIEST ONSET OF SEVERE HEPATIC
DYSFUNCTION FOLLOWED SUBSEQUENTLY BY LIVER FAILURE WAS 3 WEEKS AFTER
INITIATION OF Felbatol (Felbamate) ®. ALTHOUGH SOME REPORTS DESCRIBED DARK
URINE AND NONSPECIFIC PRODROMAL SYMPTOMS (E.G., ANOREXIA, MALAISE, AND
GASTROINTESTINAL SYMPTOMS), IN OTHER REPORTS IT WAS NOT CLEAR IF ANY
PRODROMAL SYMPTOMS PRECEDED THE ONSET OF JAUNDICE.
IT IS NOT KNOWN WHETHER OR NOT THE RISK OF DEVELOPING HEPATIC
FAILURE CHANGES WITH DURATION OF EXPOSURE.
IT IS NOT KNOWN WHETHER OR NOT THE DOSAGE OF Felbatol (Felbamate) ®
AFFECTS THE INCIDENCE OF HEPATIC FAILURE.
IT IS NOT KNOWN WHETHER CONCOMITANT USE OF OTHER ANTIEPILEPTIC
DRUGS AND/OR OTHER DRUGS AFFECT THE INCIDENCE OF HEPATIC FAILURE.
Felbatol (Felbamate) ® SHOULD NOT BE PRESCRIBED FOR ANYONE WITH A
HISTORY OF HEPATIC DYSFUNCTION.
TREATMENT WITH Felbatol (Felbamate) ® SHOULD BE INITIATED ONLY IN
INDIVIDUALS WITHOUT ACTIVE LIVER DISEASE AND WITH NORMAL BASELINE SERUM
TRANSAMINASES. IT HAS NOT BEEN PROVED THAT PERIODIC SERUM TRANSAMINASE
TESTING WILL PREVENT SERIOUS INJURY BUT IT IS GENERALLY BELIEVED THAT
EARLY DETECTION OF DRUG-INDUCED HEPATIC INJURY ALONG WITH IMMEDIATE
WITHDRAWAL OF THE SUSPECT DRUG ENHANCES THE LIKELIHOOD FOR RECOVERY.
THERE IS NO INFORMATION AVAILABLE THAT DOCUMENTS HOW RAPIDLY PATIENTS
CAN PROGRESS FROM NORMAL LIVER FUNCTION TO LIVER FAILURE, BUT OTHER
DRUGS KNOWN TO BE HEPATOTOXINS CAN CAUSE LIVER FAILURE RAPIDLY (E.G.,
FROM NORMAL ENZYMES TO LIVER FAILURE IN 2-4 WEEKS). ACCORDINGLY,
MONITORING OF SERUM TRANSAMINASE LEVELS (AST AND ALT) IS RECOMMENDED AT
BASELINE AND PERIODICALLY THEREAFTER. WHILE THE MORE FREQUENT THE
MONITORING THE GREATER THE CHANCES OF EARLY DETECTION, THE PRECISE
SCHEDULE FOR MONITORING IS A MATTER OF CLINICAL JUDGEMENT.
Felbatol (Felbamate) ® SHOULD BE DISCONTINUED IF EITHER SERUM AST OR
SERUM ALT LEVELS BECOME INCREASED ≥ 2 TIMES THE UPPER LIMIT OF
NORMAL, OR IF CLINICAL SIGNS AND SYMPTOMS SUGGEST LIVER FAILURE (SEE
). PATIENTS WHO DEVELOP EVIDENCE OF
HEPATOCELLULAR INJURY WHILE ON Felbatol (Felbamate) ® AND ARE WITHDRAWN FROM
THE DRUG FOR ANY REASON SHOULD BE PRESUMED TO BE AT INCREASED RISK FOR
LIVER INJURY IF Felbatol (Felbamate) ® IS REINTRODUCED. ACCORDINGLY, SUCH
PATIENTS SHOULD NOT BE CONSIDERED FOR RE-TREATMENT.
Felbatol (Felbamate) Description
Felbatol (Felbamate) ® (felbamate) is an antiepileptic available as
400 mg and 600 mg tablets and as a 600 mg/5 mL suspension for oral
administration. Its chemical name is 2-phenyl-1,3-propanediol
dicarbamate.
Felbamate is a white to off-white crystalline powder with a
characteristic odor. It is very slightly soluble in water, slightly
soluble in ethanol, sparingly soluble in methanol, and freely soluble in
dimethyl sulfoxide. The molecular weight is 238.24; felbamate's
molecular formula is C H N O
; its structural formula is:
The inactive ingredients for Felbatol (Felbamate) ® (felbamate)
Tablets 400 mg and 600 mg are starch, microcrystalline cellulose,
croscarmellose sodium, lactose, magnesium stearate, FD&C Yellow
No. 6, D&C Yellow No. 10, and FD&C Red No. 40 (600 mg
tablets only). The inactive ingredients for Felbatol (Felbamate) ®
(felbamate) Oral Suspension 600 mg/5 mL are sorbitol, glycerin,
microcrystalline cellulose, carboxymethylcellulose sodium, simethicone,
polysorbate 80, methylparaben, saccharin sodium, propylparaben,
FD&C Yellow No. 6, FD&C Red No. 40, flavorings, and
purified water.
Felbatol (Felbamate) Clinical Pharmacology
The mechanism by which felbamate exerts its
anticonvulsant activity is unknown, but in animal test systems
designed to detect anticonvulsant activity, felbamate has
properties in common with other marketed anticonvulsants.
Felbamate is effective in mice and rats in the maximal
electroshock test, the subcutaneous pentylenetetrazol seizure
test, and the subcutaneous picrotoxin seizure test. Felbamate
also exhibits anticonvulsant activity against seizures induced
by intracerebroventricular administration of glutamate in rats
and N-methyl-D,L-aspartic acid in mice. Protection against
maximal electroshock-induced seizures suggests that felbamate
may reduce seizure spread, an effect possibly predictive of
efficacy in generalized tonic-clonic or partial seizures.
Protection against pentylenetetrazol-induced seizures suggests
that felbamate may increase seizure threshold, an effect
considered to be predictive of potential efficacy in absence
seizures.
Receptor-binding studies indicate that felbamate has weak inhibitory
effects on GABA-receptor binding, benzodiazepine receptor
binding, and is devoid of activity at the MK-801 receptor
binding site of the NMDA receptor-ionophore complex. However,
felbamate does interact as an antagonist at the
strychnine-insensitive glycine recognition site of the NMDA
receptor-ionophore complex. Felbamate is not effective in
protecting chick embryo retina tissue against the neurotoxic
effects of the excitatory amino acid agonists NMDA, kainate, or
quisqualate .
The monocarbamate, p-hydroxy, and 2-hydroxy metabolites
were inactive in the maximal electroshock-induced seizure test
in mice. The monocarbamate and p-hydroxy metabolites had only
weak (0.2 to 0.6) activity compared with felbamate in the
subcutaneous pentylenetetrazol seizure test. These metabolites
did not contribute significantly to the anticonvulsant action of
felbamate.
The numbers in the pharmacokinetic section are mean
± standard deviation.
Felbamate is well-absorbed after oral administration.
Over 90% of the radioactivity after a dose of 1000 mg
C felbamate was found in the urine. Absolute
bioavailability (oral vs. parenteral) has not been measured. The
tablet and suspension were each shown to be bioequivalent to the
capsule used in clinical trials, and pharmacokinetic parameters
of the tablet and suspension are similar. There was no effect of
food on absorption of the tablet; the effect of food on
absorption of the suspension has not been evaluated.
Following oral administration, felbamate is the
predominant plasma species (about 90% of plasma
radioactivity). About 40-50% of absorbed dose appears
unchanged in urine, and an additional 40% is present as
unidentified metabolites and conjugates. About 15% is
present as parahydroxyfelbamate, 2-hydroxyfelbamate, and
felbamate monocarbamate, none of which have significant
anticonvulsant activity.
Binding of felbamate to human plasma protein was
independent of felbamate concentrations between 10 and 310
micrograms/mL. Binding ranged from 22% to 25%,
mostly to albumin, and was dependent on the albumin
concentration.
Felbamate is excreted with a terminal half-life of 20-23
hours, which is unaltered after multiple doses. Clearance after
a single 1200 mg dose is 26±3 mL/hr/kg, and after
multiple daily doses of 3600 mg is 30±8 mL/hr/kg. The
apparent volume of distribution was 756±82 mL/kg after
a 1200 mg dose. Felbamate Cmax and AUC are proportionate to dose
after single and multiple doses over a range of 100-800 mg
single doses and 1200-3600 mg daily doses. Cmin (trough) blood
levels are also dose proportional. Multiple daily doses of 1200,
2400, and 3600 mg gave Cmin values of 30±5,
55±8, and 83±21 micrograms/mL (N=10 patients).
Linear and dose proportional pharmacokinetics were also observed
at doses above 3600 mg/day up to the maximum dose studied of
6000 mg/day. Felbamate gave dose proportional steady-state peak
plasma concentrations in children age 4-12 over a range of 15,
30, and 45 mg/kg/day with peak concentrations of 17, 32, and 49
micrograms/mL.
The effects of race and gender on felbamate
pharmacokinetics have not been systematically evaluated, but
plasma concentrations in males (N=5) and females (N=4) given
felbamate have been similar. The effects of felbamate kinetics
on hepatic functional impairment have not been evaluated.
Renal Impairment:
2. The only other change in vital signs was
a mean decrease of approximately 1 respiration per minute in
respiratory rate during adjunctive therapy in children. In
adults, statistically significant mean reductions in body weight
were observed during felbamate monotherapy and adjunctive
therapy. In children, there were mean decreases in body weight
during adjunctive therapy and monotherapy; however, these mean
changes were not statistically significant. These mean
reductions in adults and children were approximately 5% of the
mean weights at baseline.
Felbatol (Felbamate) Clinical Studies
The results of controlled clinical trials established the
efficacy of Felbatol (Felbamate) ® (felbamate) as monotherapy and adjunctive
therapy in adults with partial-onset seizures with or without secondary
generalization and in partial and generalized seizures associated with
Lennox-Gastaut syndrome in children.
Felbatol (Felbamate) ® (3600 mg/day given QID) and low-dose
valproate (15 mg/kg/day) were compared as monotherapy during a
112-day treatment period in a multicenter and a single-center
double-blind efficacy trial. Both trials were conducted
according to an identical study design. During a 56-day baseline
period, all patients had at least four partial-onset seizures
per 28 days and were receiving one antiepileptic drug at a
therapeutic level, the most common being carbamazepine. In the
multicenter trial, baseline seizure frequencies were 12.4 per 28
days in the Felbatol (Felbamate) ® group and 21.3 per 28 days in the
low-dose valproate group. In the single-center trial, baseline
seizure frequencies were 18.1 per 28 days in the
Felbatol (Felbamate) ® group and 15.9 per 28 days in the low-dose
valproate group. Patients were converted to monotherapy with
Felbatol (Felbamate) ® or low-dose valproic acid during the first 28
days of the 112-day treatment period. Study endpoints were
completion of 112 study days or fulfilling an escape criterion.
Criteria for escape relative to baseline were: (1) twofold
increase in monthly seizure frequency, (2) twofold increase in
highest 2-day seizure frequency, (3) single generalized
tonic-clonic seizure (GTC) if none occurred during baseline, or
(4) significant prolongation of GTCs. The primary efficacy
variable was the number of patients in each treatment group who
met escape criteria.
In the multicenter trial, the percentage of patients who
met escape criteria was 40% (18/45) in the
Felbatol (Felbamate) ® group and 78% (39/50) in the low-dose
valproate group. In the single-center trial, the percentage of
patients who met escape criteria was 14% (3/21) in the
Felbatol (Felbamate) ® group and 90% (19/21) in the low-dose
valproate group. In both trials, the difference in the
percentage of patients meeting escape criteria was statistically
significant (P<.001) in favor of Felbatol (Felbamate) ®.
These two studies by design were intended to demonstrate the
effectiveness of Felbatol (Felbamate) ® monotherapy. The studies
were not designed or intended to demonstrate comparative
efficacy of the two drugs. For example, valproate was not used
at the maximally effective dose.
A double-blind, placebo-controlled crossover trial
consisted of two 10-week outpatient treatment periods. Patients
with refractory partial-onset seizures who were receiving
phenytoin and carbamazepine at therapeutic levels were
administered Felbatol (Felbamate) ® (felbamate) as add-on therapy at
a starting dosage of 1400 mg/day in three divided doses, which
was increased to 2600 mg/day in three divided doses. Among the
56 patients who completed the study, the baseline seizure
frequency was 20 per month. Patients treated with
Felbatol (Felbamate) ® had fewer seizures than patients treated with
placebo for each treatment sequence. There was a 23%
(P=.018) difference in percentage seizure frequency reduction in
favor of Felbatol (Felbamate) ®.
Felbatol (Felbamate) ® 3600 mg/day given QID and placebo were
compared in a 28-day double-blind add-on trial in patients who
had their standard antiepileptic drugs reduced while undergoing
evaluations for surgery of intractable epilepsy. All patients
had confirmed partial-onset seizures with or without
generalization, seizure frequency during surgical evaluation not
exceeding an average of four partial seizures per day or more
than one generalized seizure per day, and a minimum average of
one partial or generalized tonic-clonic seizure per day for the
last 3 days of the surgical evaluation. The primary efficacy
variable was time to fourth seizure after randomization to
treatment with Felbatol (Felbamate) ® or placebo. Thirteen
(46%) of 28 patients in the Felbatol (Felbamate) ® group
versus 29 (88%) of 33 patients in the placebo group
experienced a fourth seizure. The median times to fourth seizure
were greater than 28 days in the Felbatol (Felbamate) ® group and 5
days in the placebo group. The difference between
Felbatol (Felbamate) ® and placebo in time to fourth seizure was
statistically significant (P=.002) in favor of
Felbatol (Felbamate) ®.
In a 70-day double-blind, placebo-controlled add-on trial
in the Lennox-Gastaut syndrome, Felbatol (Felbamate) ® 45 mg/kg/day
given QID was superior to placebo in controlling the multiple
seizure types associated with this condition. Patients had at
least 90 atonic and/or atypical absence seizures per month while
receiving therapeutic dosages of one or two other antiepileptic
drugs. Patients had a past history of using an average of eight
antiepileptic drugs. The most commonly used antiepileptic drug
during the baseline period was valproic acid. The frequency of
all types of seizures during the baseline period was 1617 per
month in the Felbatol (Felbamate) ® group and 716 per month in the
placebo group. Statistically significant differences in the
effect on seizure frequency favored Felbatol (Felbamate) ® over
placebo for total seizures (26% reduction vs. 5%
increase, P<.001), atonic seizures (44% reduction
vs. 7% reduction, P=.002), and generalized tonic-clonic
seizures (40% reduction vs. 12% increase,
P=.017). Parent/guardian global evaluations based on impressions
of quality of life with respect to alertness, verbal
responsiveness, general well-being, and seizure control
significantly (P<.001) favored Felbatol (Felbamate) ® over
placebo.
When efficacy was analyzed by gender in four
well-controlled trials of felbamate as adjunctive and
monotherapy for partial-onset seizures and Lennox-Gastaut
syndrome, a similar response was seen in 122 males and 142
females.
Felbatol (Felbamate) Indications And Usage
Felbatol (Felbamate) ® is not indicated as a first line antiepileptic
treatment (see ). Felbatol (Felbamate) ® is recommended for use only in those
patients who respond inadequately to alternative treatments and whose
epilepsy is so severe that a substantial risk of aplastic anemia and/or
liver failure is deemed acceptable in light of the benefits conferred by
its use.
If these criteria are met and the patient has been fully advised
of the risk, and has provided written acknowledgement,
Felbatol (Felbamate) ® can be considered for either monotherapy or
adjunctive therapy in the treatment of partial seizures, with and
without generalization, in adults with epilepsy and as adjunctive
therapy in the treatment of partial and generalized seizures associated
with Lennox-Gastaut syndrome in children.
Felbatol (Felbamate) Contraindications
Felbatol (Felbamate) ® is contraindicated in patients with known
hypersensitivity to Felbatol (Felbamate) ®, its ingredients, or known
sensitivity to other carbamates. It should not be used in patients with
a history of any blood dyscrasia or hepatic dysfunction.
Felbatol (Felbamate) Warnings
See regarding aplastic anemia and hepatic
failure. Antiepileptic drugs should not be suddenly discontinued
because of the possibility of increasing seizure frequency.
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.
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 (Felbamate) 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.
Felbatol (Felbamate) Precautions
Dosage Adjustment in the
Renally Impaired:
Information for
Patients:
The physician should obtain written acknowledgement
prior to initiation of Felbatol (Felbamate) ® therapy (see section).
Patients should be instructed to read the Medication Guide supplied as required by law when
Felbatol (Felbamate) ® is dispensed. The complete text of the Medication Guide is reprinted at the end of
this document.
Aplastic anemia
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 (Felbamate) ®.
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
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 (Felbamate) ®.
Patients should be advised to follow their physician's
directives for liver function testing both before starting
Felbatol (Felbamate) ® (felbamate) and at frequent intervals while
taking Felbatol (Felbamate) ®.
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.
See for recommended monitoring of serum
transaminases. If significant, confirmed liver abnormalities are
detected during the course of Felbatol (Felbamate) ® treatment,
Felbatol (Felbamate) ® should be discontinued immediately with
continued liver function monitoring until values return to
normal. (see ).
Suicidal Thinking and
Behavior:
Pregnancy:
Drug Interactions:
Use in Conjunction with Other
Antiepileptic Drugs (see ):
The addition of
Felbatol (Felbamate) ® to antiepileptic drugs (AEDs) affects the
steady-state plasma concentrations of AEDs.
In a controlled clinical trial, a 20% reduction
of the phenytoin dose at the initiation of Felbatol (Felbamate) ®
therapy resulted in phenytoin levels comparable to those prior
to Felbatol (Felbamate) ® administration.
Carbamazepine:
In clinical trials, similar changes in carbamazepine and
carbamazepine epoxide were seen.
Valproate:
Phenobarbital:
Carbamazepine:
Valproate:
Phenobarbital:
Effects of Antacids on
Felbatol (Felbamate) ®:
Effects of Erythromycin on
Felbatol (Felbamate) ®:
Effects of Felbatol (Felbamate) ®
on Low-Dose Combination Oral Contraceptives:
Drug/Laboratory Test
Interactions:
Carcinogenesis, Mutagenesis,
Impairment of Fertility:
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/m 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 /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/m
basis.
Pregnancy: Pregnancy Category
C.
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 (Felbamate) ®, physicians are advised to
recommend that pregnant patients taking Felbatol (Felbamate) 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:
Nursing Mothers:
Pediatric Use:
Geriatric Use:
Felbatol (Felbamate) Adverse Reactions
The most common adverse reactions seen in association with
Felbatol (Felbamate) ® (felbamate) in adults during monotherapy are
anorexia, vomiting, insomnia, nausea, and headache. The most common
adverse reactions seen in association with Felbatol (Felbamate) ® in adults
during adjunctive therapy are anorexia, vomiting, insomnia, nausea,
dizziness, somnolence, and headache.
The most common adverse reactions seen in association with
Felbatol (Felbamate) ® in children during adjunctive therapy are anorexia,
vomiting, insomnia, headache, and somnolence.
The dropout rate because of adverse experiences or intercurrent
illnesses among adult felbamate patients was 12 percent (120/977). The
dropout rate because of adverse experiences or intercurrent illnesses
among pediatric felbamate patients was six percent (22/357). In adults,
the body systems associated with causing these withdrawals in order of
frequency were: digestive (4.3%), psychological (2.2%),
whole body (1.7%), neurological (1.5%), and
dermatological (1.5%). In children, the body systems associated
with causing these withdrawals in order of frequency were: digestive
(1.7%), neurological (1.4%), dermatological
(1.4%), psychological (1.1%), and whole body
(1.0%). In adults, specific events with an incidence of
1% or greater associated with causing these withdrawals, in
order of frequency were: anorexia (1.6%), nausea (1.4%),
rash (1.2%), and weight decrease (1.1%). In children,
specific events with an incidence of 1% or greater associated
with causing these withdrawals, in order of frequency was rash
(1.1%).
Many adverse experiences that occurred during adjunctive therapy
may be a result of drug interactions. Adverse experiences during
adjunctive therapy typically resolved with conversion to monotherapy, or
with adjustment of the dosage of other antiepileptic drugs.
Events are classified within body system categories and
enumerated in order of decreasing frequency using the following
definitions: frequent adverse events are defined as those occurring on
one or more occasions in at least 1/100 patients; infrequent adverse
events are those occurring in 1/100-1/1000 patients; and rare events are
those occurring in fewer than 1/1000 patients.
Event frequencies are calculated as the number of patients
reporting an event divided by the total number of patients (N=1334)
exposed to Felbatol (Felbamate) ®.
Felbatol (Felbamate) Drug Abuse And Dependence
Abuse:
Dependence:
Felbatol (Felbamate) Overdosage
Four subjects inadvertently received Felbatol (Felbamate) ®
(felbamate) as adjunctive therapy in dosages ranging from 5400 to 7200
mg/day for durations between 6 and 51 days. One subject who received
5400 mg/day as monotherapy for 1 week reported no adverse experiences.
Another subject attempted suicide by ingesting 12,000 mg of
Felbatol (Felbamate) ® in a 12-hour period. The only adverse experiences
reported were mild gastric distress and a resting heart rate of 100 bpm.
No serious adverse reactions have been reported. General supportive
measures should be employed if overdosage occurs. It is not known if
felbamate is dialyzable.
Felbatol (Felbamate) Dosage And Administration
Felbatol (Felbamate) ® (felbamate) has been studied as monotherapy
and adjunctive therapy in adults and as adjunctive therapy in children
with seizures associated with Lennox-Gastaut syndrome. As
Felbatol (Felbamate) ® is added to or substituted for existing AEDs, it is
strongly recommended to reduce the dosage of those AEDs in the range of
20-33% to minimize side effects (see subsection).
While the above Felbatol (Felbamate) ® conversion guidelines may
result in a Felbatol (Felbamate) ® 3600 mg/day dose within 3 weeks, in some
patients titration to a 3600 mg/day Felbatol (Felbamate) ® dose has been
achieved in as little as 3 days with appropriate adjustment of other
AEDs.
Felbatol (Felbamate) How Supplied
Felbatol (Felbamate) ® (felbamate) Tablets, 400 mg, are yellow,
scored, capsule-shaped tablets, debossed 0430 on one side and Felbatol (Felbamate)
400 on the other; available in bottles of 100 (NDC 0037-0430-01).
Felbatol (Felbamate) ® (felbamate) Tablets, 600 mg, are peach-colored,
scored, capsule-shaped tablets, debossed 0431 on one side and Felbatol (Felbamate)
600 on the other; available in bottles of 100 (NDC 0037-0431-01).
Felbatol (Felbamate) ® (felbamate) Oral Suspension, 600 mg/5 mL, is
peach-colored; available in 8 oz bottles (NDC 0037-0442-67) and 32 oz
bottles (NDC 0037-0442-17).
Shake suspension well before using. Store at controlled room
temperature 20°-25°C (68°-77°F).
Dispense in tight container.
MEDA Pharmaceuticals® MEDA Pharmaceuticals Inc.
Somerset, NJ 08873
IN-00431-18 Rev.
7/11
Felbatol (Felbamate) Patient/physician Acknowledgment Form
Felbatol (Felbamate) ® (felbamate) SHOULD NOT BE USED BY PATIENTS UNTIL THERE HAS BEEN A COMPLETE DISCUSSION OF THE RISKS.
All patients treated with Felbatol (Felbamate) should acknowledge that they understand the risks and other information about Felbatol (Felbamate) discussed below, and physicians should acknowledge this discussion.
IMPORTANT INFORMATION AND WARNING:
Felbatol (Felbamate) ®, taken by itself or with other prescription and/or non-prescription drugs, can result in a severe, potentially fatal blood abnormality ("aplastic anemia") and/or severe, potentially fatal liver damage.
PATIENT ACKNOWLEDGMENT:
My [My son, daughter, ward treatment with Felbatol (Felbamate) ® has been personally explained to me by Dr. The following points of information, among others, have been specifically discussed and made clear and I have had the opportunity to ask any questions concerning this information:
1. I, (Patient's Name), understand that Felbatol (Felbamate) ® is used to treat certain types of seizures and my physician has told me that I have this type(s) of seizures;INITIALS:
2. I understand that Felbatol (Felbamate) ® is being used because my seizures have not been satisfactorily treated with other antiepileptic drugs;INITIALS:
3. I understand that there is a serious risk that I could develop aplastic anemia and/or liver failure, both of which are potentially fatal, by using Felbatol (Felbamate) ®;INITIALS:
4. I understand that there are no laboratory tests which will predict if I am at an increased risk for one of the potentially fatal conditions;INITIALS:
5. I understand that I should have the recommended blood work before my treatment with Felbatol (Felbamate) ® is begun (baseline) and periodically thereafter as clinical judgement warrants. I understand that although this blood work may help detect if I develop one of these conditions, it may do so only after significant, irreversible and potentially fatal damage has already occurred;INITIALS:
6. If I am currently taking other antiepileptic drugs, I understand that the manufacturer of Felbatol (Felbamate) ® recommends that the dosage of these other drugs be decreased by a certain amount when Felbatol (Felbamate) ® is started; if my physician determines that this should not be done in my case, he/she has explained the reason(s) for this decision;INITIALS:
7. I understand that I must immediately report any unusual symptoms to Dr. and be especially aware of any rashes, easy bruising, bleeding, sore throats, fever, and/or dark urine; INITIALS:
8. I understand that antiepileptic drugs such as Felbatol (Felbamate) ® may increase the risk of suicidal thoughts and behavior. I understand that I must immediately report any unusual changes in mood or behavior, symptoms of depression or thoughts about self-harm to Dr.
INITIALS:
Revised: 7/11
MEDA Pharmaceuticals® MEDA Pharmaceuticals Inc.Somerset, New Jersey 08873-4120
Felbatol (Felbamate) Medication Guide
IS-00431-01 Rev. 7/11
Read this Medication Guide before you start taking Felbatol (Felbamate) and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.
Felbatol (Felbamate) can cause serious side effects, including:
Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
Stopping Felbatol (Felbamate) suddenly can cause serious problems. You should talk to your health care provider before stopping. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures.
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
Felbatol (Felbamate) is a prescription medicine used when other treatments have failed in:
Taking Felbatol (Felbamate) with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
The most common side effects of Felbatol (Felbamate) include:
These are not all the possible side effects of Felbatol (Felbamate) . For more information, ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Felbatol (Felbamate) for a condition for which it was not prescribed. Do not give Felbatol (Felbamate) to other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about Felbatol (Felbamate) . If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Felbatol (Felbamate) that is written for health professionals.
For more information, go to www. Felbatol (Felbamate) .com or call 1-800-526-3840.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
MEDA Pharmaceuticals Issued 7/11
MEDA Pharmaceuticals Inc., Somerset, NJ 08873-4120
Felbatol (Felbamate) is a registered trademark of Meda Pharmaceuticals Inc.
IS-00431-01 Rev. 7/11
Felbatol (Felbamate) Package Label - Principal Display Panel – -count Bottle, Mg Tablet
NDC 0037-0430-01
(felbamate) 400 mg Tablets
LB-024G5-09 Rev. 12/10
For full
prescribing information, see accompanying package insert.
Store at controlled room temperature 20°-25°C
(68°-77°F).
Dispense in a tight container.
Meda
Pharmaceuticals Inc. Somerset, New Jersey 08873-4120
Felbatol (Felbamate) Package Label - Principal Display Panel – -count Bottle, Mg Tablet
NDC 0037-0431-01
(felbamate) 600 mg Tablets
LB-024H5-09 Rev. 12/10
For full
prescribing information, see accompanying package insert.
Store at controlled room temperature 20°-25°C
(68°-77°F).
Dispense in a tight container.
Meda
Pharmaceuticals Inc. Somerset, New Jersey 08873-4120
Felbatol (Felbamate) Package Label - Principal Display Panel – Fl Oz ( Ml) Bottle, Mg
Suspension
NDC 0037-0442-67
(felbamate) Oral
Suspension Each 5 mL contains 600 mg felbamate
LB-024F5-10 Rev. 12/10
For full prescribing
information, see accompanying package insert. Store at
controlled room temperature 20°-25°C
(68°-77°F).
Dispense in a tight container.
Meda
Pharmaceuticals Inc. Somerset, New Jersey 08873-4120
