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 1/100-1/1000 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.
Dermatological:Frequent: Pruritus; Infrequent: urticaria, bullous eruption; Rare: buccal mucous membrane swelling, Stevens-Johnson Syndrome.
Special Senses:Rare: Photosensitivity allergic reaction.
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.
Abuse potential was not evaluated in human studies.
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.
Four subjects inadvertently received 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 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.
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 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 Drug Interactions subsection).
Felbamate should be used with caution in patients with renal dysfunction. In the renally impaired, starting and maintenance doses should be reduced by one-half (see CLINICAL PHARMACOLOGY / Pharmacokinetics and PRECAUTIONS ). Adjunctive therapy with medications which affect felbamate plasma concentrations, especially AEDs, may warrant further reductions in felbamate daily doses in patients with renal dysfunction.
Adults (14 years of age and over)The majority of patients received 3600 mg/day in clinical trials evaluating its use as both monotherapy and adjunctive therapy.
Monotherapy: (Initial therapy) Felbamate has not been systematically evaluated as initial monotherapy. Initiate Felbamate at 1200 mg/day in divided doses three or four times daily. The prescriber is advised to titrate previously untreated patients under close clinical supervision, increasing the dosage in 600-mg increments every 2 weeks to 2400 mg/day based on clinical response and thereafter to 3600 mg/day if clinically indicated.
Conversion to Monotherapy: Initiate Felbamate at 1200 mg/day in divided doses three or four times daily. Reduce the dosage of concomitant AEDs by one-third at initiation of Felbamate therapy. At week 2, increase the Felbamate dosage to 2400 mg/day while reducing the dosage of other AEDs up to an additional one-third of their original dosage. At week 3, increase the Felbamate dosage up to 3600 mg/day and continue to reduce the dosage of other AEDs as clinically indicated.
Adjunctive Therapy: Felbamate should be added at 1200 mg/day in divided doses three or four times daily while reducing present AEDs by 20% in order to control plasma concentrations of concurrent phenytoin, valproic acid, phenobarbital, and carbamazepine and its metabolites. Further reductions of the concomitant AEDs dosage may be necessary to minimize side effects due to drug interactions. Increase the dosage of Felbamate by 1200 mg/day increments at weekly intervals to 3600 mg/day. Most side effects seen during Felbamate adjunctive therapy resolve as the dosage of concomitant AEDs is decreased.
|*See Adjunctive and Conversion to Monotherapy sections.|
Dosage reduction of concomitant AEDs
REDUCE original dose by20–33%*
REDUCE original dose byup to an additional 1/3*
1200 mg/day Initial dose
2400 mg/dayTherapeutic dosage range
3600 mg/dayTherapeutic dosage range
Children with Lennox-Gastaut Syndrome (Ages 2-14 years)
Adjunctive Therapy: Felbamate should be added at 15 mg/kg/day in divided doses three or four times daily while reducing present AEDs by 20% in order to control plasma levels of concurrent phenytoin, valproic acid, phenobarbital, and carbamazepine and its metabolites. Further reductions of the concomitant AEDs dosage may be necessary to minimize side effects due to drug interactions. Increase the dosage of Felbamate by 15 mg/kg/day increments at weekly intervals to 45 mg/kg/day. Most side effects seen during Felbamate adjunctive therapy resolve as the dosage of concomitant AEDs is decreased.
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