Felbamate

INDICATIONS AND USAGE Felbamate oral suspension, USP is not indicated as a first line antiepileptic treatment (see Warnings ). Felbamate oral suspension is recommended for use only in those patients who respond inadequately to alternative treatments and whose epilepsy is so severe that a substantial risk of aplastic anemia and/or liver failure is deemed acceptable in light of the benefits conferred by its use. If these criteria are met and the patient has been fully advised of the risk, and has provided written acknowledgement, felbamate can be considered for either monotherapy or adjunctive therapy in the treatment of partial seizures, with and without generalization, in adults with epilepsy and as adjunctive therapy in the treatment of partial and generalized seizures associated with Lennox-Gastaut syndrome in children.

DOSAGE AND ADMINISTRATION 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 to 33% to minimize side effects (see Drug Interactions subsection). Dosage Adjustment in the Renally Impaired 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. Table 6 Dosage Table (adults) WEEK 1 WEEK 2 WEEK 3 Dosage reduction of concomitant AEDs REDUCE original dose by 20 to 33% See Adjunctive and Conversion to Monotherapy sections. REDUCE original dose by up to an additional 1/3 REDUCE as clinically indicated Felbamate Dosage 1200 mg/day Initial dose 2400 mg/day Therapeutic dosage range 3600 mg/day Therapeutic dosage range While the above felbamate conversion guidelines may result in a felbamate 3600 mg/day dose within 3 weeks, in some patients titration to a 3600 mg/day felbamate 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 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.

ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, contact Taro at 1-866-923-4914 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 3600 mg/day; (N=58) Low Dose Valproate 15 mg/kg/day (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 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 Lennox-Gastaut 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.

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 and suspension were each 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; the effect of food on absorption of the suspension has not been evaluated. 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.