Felbamate (Page 3 of 5)

ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

The most common adverse reactions seen in association with felbamate in adults during monotherapy are anorexia, vomiting, insomnia, nausea and headache. The most common adverse reactions seen in association with felbamate in adults during adjunctive therapy are anorexia, vomiting, insomnia, nausea, dizziness, somnolence and headache.

The most common adverse reactions seen in association with 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%). 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 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 felbamate 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
Felbamate* (N=58) Low Dose Valproate** (N=50)
Body System Event % %
Body as a Whole
Fatigue 6.9 4
Weight Decrease 3.4 0
Face Edema 3.4 0
Central Nervous System
Insomnia 8.6 4
Headache 6.9 18
Anxiety 5.2 2
Dermatological
Acne 3.4 0
Rash 3.4 0
Digestive
Dyspepsia 8.6 2
Vomiting 8.6 2
Constipation 6.9 2
Diarrhea 5.2 0
SGPT Increased 5.2 2
Metabolic/Nutritional
Hypophosphatemia 3.4 0
Respiratory
Upper Respiratory Tract Infection 8.6 4
Rhinitis 6.9 0
Special Senses
Diplopia 3.4 4
Otitis Media 3.4 0
Urogenital
Intramenstrual Bleeding 3.4 0
Urinary Tract Infection 3.4 2
*3600 mg/day, ** 15 mg/kg/day

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 felbamate 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
Felbamate Placebo
(N=114) (N=43)
Body System/Event % %
Body as a Whole
Fatigue 16.8 7
Fever 2.6 4.7
Chest Pain 2.6 0
Central Nervous System
Headache 36.8 9.3
Somnolence 19.3 7
Dizziness 18.4 14
Insomnia 17.5 7
Nervousness 7 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
Constipation 11.4 2.3
Diarrhea 5.3 2.3
Abdominal Pain 5.3 0
SGPT Increased 3.5 0
Musculoskeletal
Myalgia 2.6 0
Respiratory
Upper Respiratory Tract Infection 5.3 7
Sinusitis 3.5 0
Pharyngitis 2.6 0
Special Senses
Diplopia 6.1 0
Taste Perversion 6.1 0
Vision Abnormal 5.3 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 felbamate 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 Lenox Trials
Felbamate Placebo
(N=31) (N=27)
Body System/Event % %
Body as a Whole
Fever 22.6 11.1
Fatigue 9.7 3.7
Weight Decrease 6.5 0
Pain 6.5 0
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 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 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 felbamate 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 to 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 felbamate.

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 felbamate (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-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, 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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