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To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.eov/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

  Felbatol®*
(N=58)
Low Dose Valproate**
(N=50)
Body System Event % %
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

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

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
  Abdominal 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
  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 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

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 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 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: GOT 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-Schonlein 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.

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.