A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Felbatol Side Effects, and Drug Interactions - Felbamate
Felbatol Side Effects, and Drug Interactions - Felbamate
SIDE EFFECTS
The most common adverse reactions seen in association with Felbatol®
(felbamate) in adults during monotherapy are anorexia, vomiting, insomnia,
nausea, and headache.The most common adverse reactions seen in association
with Felbatol® in adults during adjunctive therapy are
anorexia, vomiting, insomnia, nausea, dizziness, somnolence, and headache.
The most common adverse reactions seen in association with Felbatol®
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 %).
INCIDENCE IN CLINICAL TRIALS
The prescriber should be aware that the figures cited in the following
table cannot be used to predict the incidence of side effects in the course
of usual medical practice where patient characteristics and other factors
differ from those which prevailed in the clinical trials. Similarly, the
cited frequencies cannot be compared with figures obtained from other
clinical investigations involving different investigators, treatments,
and uses including the use of Felbatol® (felbamate) as
adjunctive therapy where the incidence of adverse events may be higher
due to drug interactions. The cited figures, however, do provide the prescribing
physician with some basis for estimating the relative contribution of
drug and nondrug factors to the side effect incidence rate in the population
studied.
Adults
Incidence in Controlled Clinical Trials — Monotherapy Studies In
Adults
The table that follows enumerates adverse events that occurred at an
incidence of 2% or more among 58 adult patents who received Felbatol®
monotherapy at dosages of 3600 mg/day in double-blind controlled trials.
Reported adverse events were classified using standard WHO-based dictionary
terminology.
Adults
Treatment-Emergent Adverse Event
Incidence in Controlled Monotherapy Trials |
|
Body System/Event
|
Felbatol®* |
Low Dose
Valproate** |
| (N=58) |
(N=50) |
| % |
% |
| Body as a Whole |
| Fatigue |
6.9 |
4.0 |
| Weight Decrease |
3.4 |
0 |
| Face Edema |
3.4 |
0 |
| Central Nervous System |
| Insomnia
|
8.6 |
4.0 |
| Headache |
6.9 |
18.0 |
| Anxiety |
5.2 |
2.0 |
| Dermatological |
| Acne
|
3.4 |
0 |
| Rash |
3.4 |
0 |
| Digestive |
| Dyspepsia |
8.6 |
2.0 |
| Vomiting |
8.6 |
2.0 |
| Constipation |
6.9 |
2.0 |
| Diarrhea |
5.2 |
0 |
| SGPT Increased |
5.2 |
2.0 |
| Metabolic/Nutritional |
| Hypophosphatemia |
3.4 |
0 |
| Respiratory |
| Upper Respiratory Tract Infection |
8.6 |
4.0 |
| Rhinitis |
6.9 |
0 |
| Special Senses |
| Diplopia |
3.4 |
4.0 |
| Otitis Media |
3.4 |
0 |
| Urogenital |
| Intramenstrual Bleeding |
3.4 |
0 |
| Urinary Tract Infection |
3.4 |
2.0 |
*3600 mg/day: ** 15 mg/kg/day
Incidence in Controlled Add-On Clinical Studies in Adults
The table that follows enumerates adverse events that occurred at an
incidence of 2% or more among 114 adult patients who received Felbatol®
adjunctive therapy in add-on controlled trials at dosages up to 3600 mg/day.
Reported adverse events were classified using standard WHO-based dictionary
terminology.
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.
Adults
Treatment-Emergent Adverse Event
Incidence in Controlled Add-On Trials |
|
Body System/Event
|
Felbatol® |
Placebo |
| (N=114) |
(N=43) |
| % |
% |
| Body as a Whole |
| Fatigue |
16.8 |
7.0 |
| Fever |
2.6 |
4.7 |
| Chest Pain |
2.6 |
0 |
| Central Nervous System |
|
Headache
|
36.8 |
9.3 |
| Somnolence |
19.3 |
7.0 |
| Dizziness |
18.4 |
14.0 |
| Insomnia |
17.5 |
7.0 |
| Nervousness |
7.0 |
2.3 |
| Tremor |
6.1 |
2.3 |
| Anxiety |
5.3 |
4.7 |
| Gait Abnormal |
5.3 |
0 |
| Depression |
5.3 |
0 |
| Paraesthesia |
3.5 |
2.3 |
| Ataxia |
3.5 |
0 |
| Mouth Dry |
2.6 |
0 |
| Stupor |
2.6 |
0 |
| Dermatological |
|
Rash
|
3.5 |
4.7 |
| Digestive |
| Nausea |
34.2 |
2.3 |
| Anorexia |
19.3 |
2.3 |
| Vomiting |
16.7 |
4.7 |
| Dyspepsia |
12.3 |
7.0 |
| Constipation |
11.4 |
2.3 |
| Diarrhea |
5.3 |
2.3 |
| Abnormal Pain |
5.3 |
0 |
| SGPT Increased |
3.5 |
0 |
| Musculoskeletal |
| Myalgia |
2.6 |
0 |
| Respiratory |
| Upper Respiratory Tract Infection |
5.3 |
7.0 |
| Sinusitis |
3.5 |
0 |
| Pharyngitis |
2.6 |
0 |
| Special Senses |
| Diplopia |
6.1 |
0 |
| Test Perversion |
6.1 |
0 |
| Vision Abnormal |
5.3 |
2.3 |
Children
Incidence in a Controlled Add-On Trial in Children with Lennox-Gastaut
Syndrome
The table that follows enumerates adverse events that occurred more than
once among 31 pediatric patients who received Felbatol®
up to 45 mg/kg/day or a maximum of 3600 mg/day. Reported adverse events
were classified using standard WHO-based dictionary terminology.
Children
Treatment-Emergent Adverse Event
Incidence in Controlled Add-On Lennox-Gastaut Trials |
|
Body System/Event
|
Felbatol® |
Placebo |
| (N=31) |
(N=27) |
| % |
% |
| Body as a Whole |
| Fever |
22.6 |
11.1 |
| Fatigue |
9.7 |
3.7 |
| Weight Decrease |
6.5 |
|
| Pain |
6.5 |
|
| Central Nervous System |
|
Somnolence
|
48.4 |
11.1 |
| Insomnia |
16.1 |
14.8 |
| Nervousness |
16.1 |
18.5 |
| Gait Abnormal |
9.7 |
0 |
| Headache |
6.5 |
18.5 |
| Thinking Abnormal |
6.5 |
3.7 |
| Ataxia |
6.5 |
3.7 |
| Urinary Incontinence |
6.5 |
7.4 |
| Emotional Lability |
6.5 |
0 |
| Miosis |
6.5 |
0 |
| Dermatological |
|
Rash
|
9.7 |
7.4 |
| Digestive |
| Anorexia |
54.8 |
14.8 |
| Vomiting |
38.7 |
14.8 |
| Constipation |
12.9 |
0 |
| Hiccup |
9.7 |
3.7 |
| Nausea |
6.5 |
0 |
| Dyspepsia |
6.5 |
3.7 |
| Hematologic |
| Purpura |
12.9 |
7.4 |
| Leukopenia |
6.5 |
0 |
| Respiratory |
| Upper Respiratory Tract Infection |
45.2 |
25.9 |
| Pharyngitis |
9.7 |
3.7 |
| Coughing |
6.5 |
0 |
| Special Senses |
| Otitis Media |
9.7 |
0 |
Other Events Observed in Association with the Administration of Felbatol®
(felbamate)
In the paragraphs that follow, the adverse clinical events, other than
those in the preceding tables that occurred in a total of 977 adults and
357 children exposed to Felbatol® (felbamate) and that
are reasonably associated with its use are presented. They are listed
in order of decreasing frequency. Because the reports cite events observed
in open-label and uncontrolled studies, the role of Felbatol®
in their causation cannot be reliably determined.
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®.
Body as a Whole: Frequent: Weight increase, asthenia, malaise,
influenza-like symptoms; Rare: anaphylactoid reaction, Chest pain
substernal.
Cardiovascular: Frequent: Palpitation, tachycardia; Rare:
supraventricular tachycardia.
Central Nervous System: Frequent: Agitation, psychological
disturbance, aggressive reaction; Infrequent: hallucination, euphoria,
suicide attempt, migraine.
Digestive: Frequent: SGOT increased; Infrequent:
esophagitis, appetite increased; Rare: GGT elevated.
Hematologic: Infrequent: Lymphadenopathy, leukopenia, leukocytosis,
thrombocytopenia, granulocytopenia; Rare: antinuclear factor test
positive, qualitative platelet disorder, agranulocytosis.
Metabolic/Nutritional: Infrequent: Hypokalemia, hyponatremia,
LDH increased, alkaline phosphatase increased, hypophosphatemia; Rare:
creatinine phosphokinase increased.
Musculoskeletal: Infrequent: Dystonia.
Dermatological: Frequent: Pruritus; Infrequent:
urticaria, bullous eruption; Rare: buccal mucous membrane swelling,
Stevens-Johnson Syndrome.
Special Senses: Rare: Photosensitivity, allergic reaction.
Postmarketing Adverse Event Reports
Voluntary reports of adverse events in patients taking Felbatol®
(usually in conjunction with other drugs) have been received since market
introduction and may have no causal relationship with the drug(s). These
include the following by body system:
Body as a Whole: neoplasm, sepsis, L.E. syndrome, SIDS, sudden
death, edema, hypothermia, rigors, hyperpyrexia.
Cardiovascular: atrial fibrillation, atrial arrhythmia, cardiac
arrest, torsade do pointes, cardiac failure, hypotension, hypertension,
flushing, thrombophlebitis, ischemic necrosis, gangrene, peripheral ischemia,
bradycardia, Henoch-Schönlein purpura (vasculitis).
Central & Peripheral Nervous System: delusion, paralysis, mononeuritis,
cerebrovascular disorder, cerebral edema, coma, manic reaction, encephalopathy,
paranoid reaction, nystagmus, choreoathetosis, extrapyramidal disorder,
confusion, psychosis, status epilepticus, dyskinesia, dysarthria, respiratory
depression, apathy, concentration impaired.
Dermatological: abnormal body odor, sweating, lichen planus, livedo
reticularis, alopecia, toxic epidermal necrolysis.
Digestive: (Refer to WARNINGS)
hepatitis, hepatic failure, G.I. hemorrhage, hyperammonemia, pancreatitis,
hematemesis, gastritis, rectal hemorrhage, flatulence, gingival bleeding,
acquired megacolon, ileus, intestinal obstruction, enteritis, ulcerative
stomatitis, glossitis, dysphagia, jaundice, gastric ulcer, gastric dilatation,
gastroesophageal reflux.
Fetal Disorders: fetal death, microcephaly, genital malformation,
anencephaly, encephalocele.
Hematologic: (Refer to WARNINGS)
increased and decreased prothrombin time, anemia, hypochromic anemia,
aplastic anemia, pancytopenia, hemolytic uremic syndrome, increased mean
corpuscular volume (mcv) with and without anemia, coagulation disorder,
embolism-limb, disseminated intravascular coagulation, eosinophilia, hemolytic
anemia.
Metabolic/Nutritional: hypernatremia, hypoglycemia, SIADH, hypomagnesemia,
dehydration, hyperglycemia, hypocalcemia.
Musculoskeletal: arthralgia, muscle weakness, involuntary muscle
contraction, rhabdomyolysis.
Respiratory: dyspnea, pneumonia, pneumonitis, hypoxia, epistaxis,
pleural effusion, respiratory insufficiency, pulmonary hemorrhage, asthma.
Special Sense: hemianopsia, decreased hearing, conjunctivitis.
Urogenital: menstrual disorder, acute renal failure, hepatorenal
syndrome, hematuria, urinary retention, nephrosis, vaginal hemorrhage,
abnormal renal function, dysuria, placental disorder.
DRUG ABUSE AND DEPENDENCE
Abuse
Abuse potential was not evaluated in human studies.
Dependence
Rats administered felbamate orally at doses 8.3 times the recommended
human dose 6 days each week for 5 consecutive weeks demonstrated no signs
of physical dependence as measured by weight loss following drug withdrawal
on day 7 of each week.
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 the following table:
| AED |
AED |
Felbatol® |
| Coadministered |
Concentration |
Concentration |
| Phenytoin |
Ó |
¯ |
| Valproate |
Ó |
«** |
| Carbamazepine (CBZ) |
¯ |
¯ |
| *CBZ epoxide |
Ó |
|
| Phenobarbital |
Ó |
¯ |
|
*Not administered, but an active metabolite of carbamazepine.
|
|
**No significant effect.
|
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 steadystate 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 steadystate 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, CI/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 mg
ethinyl estradiol and 75 mg
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.
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