Felbamate

INDICATIONS AND USAGE Felbamate oral suspension 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 acknowledgment, felbamate oral suspension 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 oral suspension 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 oral suspension 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 oral suspension has not been systematically evaluated as initial monotherapy. Initiate felbamate oral suspension 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 oral suspension 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 oral suspension therapy. At week 2, increase the felbamate oral suspension 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 oral suspension dosage up to 3600 mg/day and continue to reduce the dosage of other AEDs as clinically indicated. Adjunctive Therapy: Felbamate oral suspension 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 oral suspension by 1200 mg/day increments at weekly intervals to 3600 mg/day. Most side effects seen during felbamate oral suspension 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 Oral Suspension 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 oral suspension conversion guidelines may result in a felbamate oral suspension 3600 mg/day dose within 3 weeks, in some patients titration to a 3600 mg/day felbamate oral suspension, 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 oral suspension 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 oral suspension by 15 mg/kg/day increments at weekly intervals to 45 mg/kg/day. Most side effect…

WARNINGS See Boxed Warning regarding aplastic anemia and hepatic failure. Antiepileptic drugs should not be suddenly discontinued because of the possibility of increasing seizure frequency. Suicidal Behavior and Ideation Antiepileptic drugs (AEDs) including felbamate, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior 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 Patientswith Events Per 1000 Patients Drug Patients with Events Per1000 Patients Relative Risk:Incidence ofEvents in DrugPatients/Incidencein Placebo Patients Risk Difference:Additional DrugPatients withEvents Per 1000Patients 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.

CONTRAINDICATIONS Felbamate oral suspension is contraindicated in patients with known hypersensitivity to felbamate, its ingredients, or known sensitivity to other carbamates. It should not be used in patients with a history of any blood dyscrasia or hepatic dysfunction.

ADVERSE REACTIONS 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 …