or ideation among 27,863 aed-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. there were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. the increased risk of suicidal thoughts or behavior with aeds was observed as early as one week after starting drug treatment with aeds and persisted for the duration of treatment assessed. because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. the risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. the finding of increased risk with aeds of varying mechanisms of action and across a range of indications suggests that the risk applies to all aeds used for any indication. the risk did not vary substantially by age (5 to 100 years) in the clinical trials analyzed. table 1 shows absolute and relative risk by indication for all evaluated aeds. table 1 risk by indication for antiepileptic drugs in the pooled analysis indication placebo patients with events per 1000 patients drug patients with events per 1000 patients relative risk: incidence of events in drug patients/incidencein placebo patients risk difference: additional drug patients with events per 1000 patients epilepsy 1 3.4 3.5 2.4 psychiatric 5.7 8.5 1.5 2.9 other 1 1.8 1.9 0.9 total 2.4 4.3 1.8 1.9 the relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. anyone considering prescribing felbamate or any other aed must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. epilepsy and many other illnesses for which aeds are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. patients, their caregivers, and families should be informed that aeds increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. behaviors of concern should be reported immediately to healthcare providers.

als evaluating its use as both monotherapy and adjunctive therapy. monotherapy: (initial therapy) felbamate tablets, usp have not been systematically evaluated as initial monotherapy. initiate felbamate tablets, usp 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 tablets, usp 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 tablets, usp therapy. at week 2, increase the felbamate tablets, usp 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 tablets, usp dosage up to 3600 mg/day and continue to reduce the dosage of other aeds as clinically indicated. adjunctive therapy: felbamate tablets, usp 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, usp by 1200 mg/day increments at weekly intervals to 3600 mg/day. most side effects seen during felbamate tablets, usp adjunctive therapy resolve as the dosage of concomitant aeds is decreased. table 6 dosage table (adults) dosage reduction of concomitant aeds week 1 reduce original dose by 20% to 33%* week 2 reduce original dose by up to an additional 1/3* week 3 reduce as clinically indicated felbamate tablet, usp dosage 1200 mg/day initial dose 2400 mg/day therapeutic dosage range 3600 mg/day therapeutic dosage range *see adjunctive and conversion to monotherapy sections. while the above felbamate tablets, usp conversion guidelines may result in a felbamate tablet, usp 3600 mg/day dose within 3 weeks, in some patients titration to a 3600 mg/day felbamate tablets, usp dose has been achieved in as little as 3 days with appropriate adjustment of other aeds. children with lennox-gastaut syndrome (ages 2 to 14 years) adjunctive therapy: felbamate tablets, usp 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 tablets, usp by 15 mg/kg/day increments at weekly intervals to 45 mg/kg/day. most side effects seen during felbamate tablets, usp adjunctive therapy resolve as the dosage of concomitant aeds is decreased.

der 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.

receptor-binding studies in vitro indicate that felbamate has weak inhibitory effects on gaba-receptor binding, benzodiazepine receptor binding, and is devoid of activity at the mk-801 receptor binding site of the nmda receptor-ionophore complex. however, felbamate does interact as an antagonist at the strychnine-insensitive glycine recognition site of the nmda receptor-ionophore complex. felbamate is not effective in protecting chick embryo retina tissue against the neurotoxic effects of the excitatory amino acid agonists nmda, kainate, or quisqualate in vitro. the monocarbamate, p-hydroxy, and 2-hydroxy metabolites were inactive in the maximal electroshock-­induced seizure test in mice. the monocarbamate and p-hydroxy metabolites had only weak (0.2 to 0.6) activity compared with felbamate in the subcutaneous pentylenetetrazol seizure test. these metabolites did not contribute significantly to the anticonvulsant action of felbamate. pharmacokinetics: the numbers in the pharmacokinetic section are mean ± standard deviation. felbamate is well-absorbed after oral administration. over 90% of the radioactivity after a dose of 1000 mg 14 c felbamate was found in the urine. absolute bioavailability (oral vs. parenteral) has not been measured. the tablet was shown to be bioequivalent to the capsule used in clinical trials, and pharmacokinetic parameters of the tablet and suspension are similar. there was no effect of food on absorption of the tablet. following oral administration, felbamate is the predominant plasma species (about 90% of plasma radioactivity). about 40% to 50% of absorbed dose appears unchanged in urine, and an additional 40% is present as unidentified metabolites and conjugates. about 15% is present as parahydroxyfelbamate, 2­-hydroxyfelbamate, and felbamate monocarbamate, none of which have significant anticonvulsant activity. binding of felbamate to human plasma protein was independent of felbamate concentrations between 10 and 310 micrograms/ml. binding ranged from 22% to 25%, mostly to albumin, and was dependent on the albumin concentration. felbamate is excreted with a terminal half-life of 20 to 23 hours, which is unaltered after multiple doses. clearance after a single 1200 mg dose is 26±3 ml/hr/kg, and after multiple daily doses of 3600 mg is 30±8 ml/hr/kg. the apparent volume of distribution was 756±82 ml/kg after a 1200 mg dose. felbamate c max and auc are proportionate to dose after single and multiple doses over a range of 100 to 800 mg single doses and 1200 to 3600 mg daily doses. c min (trough) blood levels are also dose proportional. multiple daily doses of 1200, 2400 and 3600 mg gave c min values of 30±5, 55±8 and 83±21 micrograms/ml (n=10 patients). linear and dose proportional pharmacokinetics were also observed at doses above 3600 mg/day up to the maximum dose studied of 6000 mg/day. felbamate gave dose proportional steady-state peak plasma concentrations in children age 4 to 12 over a range of 15, 30 and 45 mg/kg/day with peak concentrations of 17, 32 and 49 micrograms/ml. the effects of race and gender on felbamate pharmacokinetics have not been systematically evaluated, but plasma concentrations in males (n=5) and females (n=4) given felbamate have been similar. the effects of felbamate kinetics on hepatic functional impairment have not been evaluated. renal impairment: felbamate's single dose monotherapy pharmacokinetic parameters were evaluated in 12 otherwise healthy individuals with renal impairment. there was a 40% to 50% reduction in total body clearance and 9 to 15 hours prolongation of half-life in renally impaired subjects compared to that in subjects with normal renal function. reduced felbamate clearance and a longer half-life were associated with diminishing renal function. pharmacodynamics: typical physiologic responses: 1. cardiovascular: in adults, there is no effect of felbamate on blood pressure. small but statistically significant mean increases in heart rate were seen during adjunctive therapy and monotherapy; however, these mean increases of up to 5 bpm were not clinically significant. in children, no clinically relevant changes in blood pressure or heart rate were seen during adjunctive therapy or monotherapy with felbamate. 2. other physiologic effects: the only other change in vital signs was a mean decrease of approximately 1 respiration per minute in respiratory rate during adjunctive therapy in children. in adults, statistically significant mean reductions in body weight were observed during felbamate monotherapy and adjunctive therapy. in children, there were mean decreases in body weight during adjunctive therapy and monotherapy; however, these mean changes were not statistically significant. these mean reductions in adults and children were approximately 5% of the mean weights at baseline. clinical studies the results of controlled clinical trials established the efficacy of felbamate as monotherapy and adjunctive therapy in adults with partial-onset seizures with or without secondary generalization and in partial and generalized seizures associated with lennox-gastaut syndrome in children. felbamate monotherapy trials in adults felbamate (3600 mg/day given qid) and low-dose valproate (15 mg/kg/day) were compared as monotherapy during a 112-day treatment period in a multicenter and a single-center double-blind efficacy trial. both trials were conducted according to an identical study design. during a 56-day baseline period, all patients had at least four partial-onset seizures per 28 days and were receiving one antiepileptic drug at a therapeutic level, the most common being carbamazepine. in the multicenter trial, baseline seizure frequencies were 12.4 per 28 days in the felbamate group and 21.3 per 28 days in the low-dose valproate group. in the single-center trial, baseline seizure frequencies were 18.1 per 28 days in the felbamate group and 15.9 per 28 days in the low-dose valproate group. patients were converted to monotherapy with felbamate or low-dose valproic acid during the first 28 days of the 112-day treatment period. study endpoints were completion of 112 study days or fulfilling an escape criterion. criteria for escape relative to baseline were: (1) twofold increase in monthly seizure frequency, (2) twofold increase in highest 2-day seizure frequency, (3) single generalized tonic-clonic seizure (gtc) if none occurred during baseline, or (4) significant prolongation of gtcs. the primary efficacy variable was the number of patients in each treatment group who met escape criteria. in the multicenter trial, the percentage of patients who met escape criteria was 40% (18/45) in the felbamate group and 78% (39/50) in the low-dose valproate group. in the single-center trial, the percentage of patients who met escape criteria was 14% (3/21) in the felbamate group and 90% (19/21) in the low-dose valproate group. in both trials, the difference in the percentage of patients meeting escape criteria was statistically significant (p<.001) in favor of felbamate. these two studies by design were intended to demonstrate the effectiveness of felbamate monotherapy. the studies were not designed or intended to demonstrate comparative efficacy of the two drugs. for example, valproate was not used at the maximally effective dose. felbamate adjunctive therapy trials in adults a double-blind, placebo-controlled crossover trial consisted of two 10-week outpatient treatment periods. patients with refractory partial-onset seizures who were receiving phenytoin and carbamazepine at therapeutic levels were administered felbamate as add-on therapy at a starting dosage of 1400 mg/day in three divided doses, which was increased to 2600 mg/day in three divided doses. among the 56 patients who completed the study, the baseline seizure frequency was 20 per month. patients treated with felbamate had fewer seizures than patients treated with placebo for each treatment sequence. there was a 23% (p=.018) difference in percentage seizure frequency reduction in favor of felbamate. felbamate 3600 mg/day given qid and placebo were compared in a 28-day double-blind add-on trial in patients who had their standard antiepileptic drugs reduced while undergoing evaluations for surgery of intractable epilepsy. all patients had confirmed partial-onset seizures with or without generalization, seizure frequency during surgical evaluation not exceeding an average of four partial seizures per day or more than one generalized seizure per day, and a minimum average of one partial or generalized tonic­clonic seizure per day for the last 3 days of the surgical evaluation. the primary efficacy variable was time to fourth seizure after randomization to treatment with felbamate or placebo. thirteen (46%) of 28 patients in the felbamate group versus 29 (88%) of 33 patients in the placebo group experienced a fourth seizure. the median times to fourth seizure were greater than 28 days in the felbamate group and 5 days in the placebo group. the difference between felbamate and placebo in time to fourth seizure was statistically significant (p=.002) in favor of felbamate. felbamate adjunctive therapy trial in children with lennox-gastaut syndrome in a 70-day double-blind, placebo-controlled add-on trial in the lennox-gastaut syndrome, felbamate 45 mg/kg/day given qid was superior to placebo in controlling the multiple seizure types associated with this condition. patients had at least 90 atonic and/or atypical absence seizures per month while receiving therapeutic dosages of one or two other antiepileptic drugs. patients had a past history of using an average of eight antiepileptic drugs. the most commonly used antiepileptic drug during the baseline period was valproic acid. the frequency of all types of seizures during the baseline period was 1617 per month in the felbamate group and 716 per month in the placebo group. statistically significant differences in the effect on seizure frequency favored felbamate over placebo for total seizures (26% reduction vs 5% increase, p<.001), atonic seizures (44% reduction vs 7% reduction, p=.002), and generalized tonic-clonic seizures (40% reduction vs 12% increase, p=.017). parent/guardian global evaluations based on impressions of quality of life with respect to alertness, verbal responsiveness, general well-being, and seizure control significantly (p<.001) favored felbamate over placebo. when efficacy was analyzed by gender in four well-controlled trials of felbamate as adjunctive and monotherapy for partial-onset seizures and lennox-gastaut syndrome, a similar response was seen in 122 males and 142 females.