ADVERSE REACTIONS
To report SUSPECTED ADVERSE REACTIONS, contact
Meda Pharmaceuticals Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088
or
www.fda.gov/medwatch.
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 patients who received
Felbatol® monotherapy at dosages of 3600 mg/day in double-blind
controlled trials. Table 3 presents reported adverse events that were
classified using standard WHO-based dictionary terminology.
Table 3 Adults Treatment-Emergent Adverse Event Incidence in
Controlled Monotherapy Trials
| *3600 mg/day;** 15 mg/kg/day |
| |
Felbatol®* (N=58) |
Low Dose Valproate** (N=50) |
| Body System Event |
% |
% |
Body as a
Whole
Fatigue
Weight
Decrease
Face Edema |
6.9
3.4
3.4 |
4.0
0
0 |
Central Nervous
System
Insomnia
Headache
Anxiety |
8.6
6.9
5.2 |
4.0
18.0
2.0 |
Dermatological
Acne
Rash |
3.4
3.4 |
0
0 |
Digestive
Dyspepsia
Vomiting
Constipation
Diarrhea
SGPT
Increased |
8.6
8.6
6.9
5.2
5.2 |
2.0
2.0
2.0
0
2.0 |
Metabolic/Nutritional
Hypophosphatemia |
3.4 |
0 |
Respiratory
Upper Respiratory Tract
Infection
Rhinitis |
8.6
6.9 |
4.0
0 |
Special
Senses
Diplopia
Otitis
Media |
3.4
3.4 |
4.0
0 |
Urogenital
Intramenstrual
Bleeding
Urinary Tract Infection |
3.4
3.4 |
0
2.0 |
Incidence in Controlled Add-On Clinical
Studies in Adults:
Table 4 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.
Table 4 Adults Treatment-Emergent Adverse Event Incidence in
Controlled Add-On Trials
| |
Felbatol® |
Placebo |
| (N=114) |
(N=43) |
| Body System/Event |
% |
% |
Body as a
Whole
Fatigue
Fever
Chest
Pain |
16.8
2.6
2.6 |
7.0
4.7
0 |
Central Nervous
System
Headache
Somnolence
Dizziness
Insomnia
Nervousness
Tremor
Anxiety
Gait
Abnormal
Depression
Paraesthesia
Ataxia
Mouth
Dry
Stupor |
36.8
19.3
18.4
17.5
7.0
6.1
5.3
5.3
5.3
3.5
3.5
2.6
2.6 |
9.3
7.0
14.0
7.0
2.3
2.3
4.7
0
0
2.3
0
0
0 |
Dermatological
Rash |
3.5 |
4.7 |
Digestive
Nausea
Anorexia
Vomiting
Dyspepsia
Constipation
Diarrhea
Abdominal
Pain
SGPT Increased |
34.2
19.3
16.7
12.3
11.4
5.3
5.3
3.5 |
2.3
2.3
4.7
7.0
2.3
2.3
0
0 |
Musculoskeletal
Myalgia |
2.6 |
0 |
Respiratory
Upper Respiratory Tract
Infection
Sinusitis
Pharyngitis |
5.3
3.5
2.6 |
7.0
0
0 |
Special
Senses
Diplopia
Taste
Perversion
Vision Abnormal |
6.1
6.1
5.3 |
0
0
2.3 |
Children
Incidence in a Controlled Add-On Trial in
Children with Lennox-Gastaut Syndrome:
Table 5
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.
Table 5 Children Treatment-Emergent Adverse Event Incidence in
Controlled Add-On Lennox-Gastaut Trials
| |
Felbatol® |
Placebo |
| (N=31) |
(N=27) |
| Body System/Event |
% |
% |
Body as a
Whole
Fever
Fatigue
Weight
Decrease
Pain |
22.6
9.7
6.5
6.5 |
11.1
3.7
0
0 |
Central Nervous
System
Somnolence
Insomnia
Nervousness
Gait
Abnormal
Headache
Thinking
Abnormal
Ataxia
Urinary
Incontinence
Emotional
Lability
Miosis |
48.4
16.1
16.1
9.7
6.5
6.5
6.5
6.5
6.5
6.5 |
11.1
14.8
18.5
0
18.5
3.7
3.7
7.4
0
0
|
Dermatological
Rash |
9.7 |
7.4 |
Digestive
Anorexia
Vomiting
Constipation
Hiccup
Nausea
Dyspepsia |
54.8
38.7
12.9
9.7
6.5
6.5 |
14.8
14.8
0
3.7
0
3.7
|
Hematologic
Purpura
Leukopenia |
12.9
6.5 |
7.4
0 |
Respiratory
Upper Respiratory Tract
Infection
Pharyngitis
Coughing |
45.2
9.7
6.5 |
25.9
3.7
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 de pointes,
cardiac failure, hypotension, hypertension, flushing, thrombophlebitis,
ischemic necrosis, gangrene, peripheral ischemia, bradycardia,
Henoch-Sch¶nlein 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, leukemia, including
myelogenous leukemia, and lymphoma, including T-cell and B-cell
lymphoproliferative disorders.
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 Senses:
hemianopsia, decreased hearing, conjunctivitis.
Urogenital: menstrual
disorder, acute renal failure, hepatorenal syndrome, hematuria, urinary
retention, nephrosis, vaginal hemorrhage, abnormal renal function,
dysuria, placental disorder.
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