Felbamate

INDICATIONS AND USAGE Felbamate Tablets USP are not indicated as a first line antiepileptic treatment (see WARNINGS ). Felbamate Tablets USP are 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 Tablets USP 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 tablets have been studied as monotherapy and adjunctive therapy in adults and as adjunctive therapy in children with seizures associated with Lennox-Gastaut syndrome. As felbamate tablets are 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 tablets have not been systematically evaluated as initial monotherapy. Initiate felbamate tablets 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 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 therapy. At week 2, increase the felbamate tablets 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 dosage up to 3600 mg/day and continue to reduce the dosage of other AEDs as clinically indicated. Adjunctive Therapy: Felbamate tablets 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 tablets by 1200 mg/day increments at weekly intervals to 3600 mg/day. Most side effects seen during felbamate tablets 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 Tablets 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 conversion guidelines may result in a felbamate tablets 3600 mg/day dose within 3 weeks, in some patients titration to a 3600 mg/day felbamate tablets 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 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 by 15 mg/kg/day increments at weekly intervals to 45 mg/kg/day. Most side effects seen during felbamate tablets adjunctive therapy resolve as the dosage of concomitant AEDs is decreased.

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 Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1.0 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 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.

Drug Interactions: The drug interaction data described in this section were obtained from controlled clinical trials and studies involving otherwise healthy adults with epilepsy. Use in Conjunction with Other Antiepileptic Drugs (see DOSAGE AND ADMINISTRATION ): The addition of felbamate to antiepileptic drugs (AEDs) affects the steady-state plasma concentrations of AEDs. The net effect of these interactions is summarized in Table 2: *Not administered but an active metabolite of carbamazepine. **No significant effect. Table 2 Steady-State Plasma Concentrations of Felbamate When Coadministered With Other AEDs AED Coadministered AED Concentration Felbamate Concentration Phenytoin ↑ ↓ Valproate ↑ ↔** Carbamazepine (CBZ) *CBZ epoxide ↓ ↑ ↓ Phenobarbital ↑ ↓ Specific Effects of Felbamate on Other Antiepileptic Drugs: Phenytoin: Felbamate causes an increase in steady-state phenytoin plasma concentrations. In 10 otherwise healthy subjects with epilepsy ingesting phenytoin, the steady-state trough (C min ) phenytoin plasma concentration was 17±5 micrograms/mL. The steady-state C min increased to 21±5 micrograms/mL when 1200 mg/day of felbamate was coadministered. Increasing the felbamate dose to 1800 mg/day in six of these subjects increased the steady-state phenytoin C min to 25±7 micrograms/mL. In order to maintain phenytoin levels, limit adverse experiences, and achieve the felbamate dose of 3600 mg/day, a phenytoin dose reduction of approximately 40% was necessary for eight of these 10 subjects. In a controlled clinical trial, a 20% reduction of the phenytoin dose at the initiation of felbamate therapy resulted in phenytoin levels comparable to those prior to felbamate administration. Carbamazepine: Felbamate causes a decrease in the steady-state carbamazepine plasma concentrations and an increase in the steady-state carbamazepine epoxide plasma concentration. In nine otherwise healthy subjects with epilepsy ingesting carbamazepine, the steady-state trough (C min ) carbamazepine concentration was 8±2 micrograms/mL. The carbamazepine steady-state C min decreased 31% to 5±1 micrograms/mL when felbamate (3000 mg/day, divided into three doses) was coadministered. Carbamazepine epoxide steady-state C min concentrations increased 57% from 1.0±0.3 to 1.6±0.4 micrograms/mL with the addition of felbamate. In clinical trials, similar changes in carbamazepine and carbamazepine epoxide were seen. Valproate: Felbamate causes an increase in steady-state valproate concentrations. In four subjects with epilepsy ingesting valproate, the steady-state trough (C min ) valproate plasma concentration was 63±16 micrograms/mL. The steady-state C min increased to 78±14 micrograms/mL when 1200 mg/day of felbamate was coadministered. Increasing the felbamate dose to 2400 mg/day increased the steady-state valproate C min to 96±25 micrograms/mL. Corresponding values for free valproate C min concentrations were 7±3, 9±4, and 11±6 micrograms/mL for 0, 1200, and 2400 mg/day felbamate, respectively. The ratios of the AUCs of unbound valproate to the AUCs of the total valproate were 11.1%, 13.0%, and 11.5%, with coadministration of 0, 1200, and 2400 mg/day of felbamate, respectively. This indicates that the protein binding of valproate did not change appreciably with increasing doses of felbamate. Phenobarbital: Coadministration of felbamate with phenobarbital causes an increase in phenobarbital plasma concentrations. In 12 otherwise healthy male volunteers ingesting phenobarbital, the steady-state trough (C min ) phenobarbital concentration was 14.2 micrograms/mL. The steady-state C min concentration increased to 17.8 micrograms/mL when 2400 mg/day of felbamate was coadministered for one week. Effects of Other Antiepileptic Drugs on Felbamate: Phenytoin: Phenytoin causes an approximate doubling of the clearance of felbamate at steady-state and, therefore, the addition of phenytoin causes an approximate 45% decrease in the steady-state trough concentrations of fel…

Pregnancy: Pregnancy Category C. The incidence of malformations was not increased compared to control in offspring of rats or rabbits given doses up to 13.9 times (rat) and 4.2 times (rabbit) the human daily dose on a mg/kg basis, or 3 times (rat) and less than 2 times (rabbit) the human daily dose on a mg/m 2 basis. However, in rats, there was a decrease in pup weight and an increase in pup deaths during lactation. The cause for these deaths is not known. The no effect dose for rat pup mortality was 6.9 times the human dose on a mg/kg basis or 1.5 times the human dose on a mg/m 2 basis. Placental transfer of felbamate occurs in rat pups. There are, however, no studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. To provide information regarding the effects of in utero exposure to felbamate, physicians are advised to recommend that pregnant patients taking felbamate enroll in the NAAED Pregnancy Registry. This can be done by calling the toll free number 1-888-233-2334, and must be done by patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/ .

Nursing Mothers: Felbamate has been detected in human milk. The effect on the nursing infant is unknown (see Pregnancy section).

ADVERSE REACTIONS To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-855-204-1431 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 (1.0%). 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 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 Weight Decrease Face Edema 6.9 3.4 3.4 4.0 0 0 Central Nervous System Insomnia Headache Anxiety 8.6 6.9 5.2 4.0 18.0 2.0 Dermatological Acne Rash 3.4 3.4 0 0 Digestive Dyspepsia Vomiting Constipation Diarrhea SGPT Increased 8.6 8.6 6.9 5.2 5.2 2.0 2.0 2.0 0 2.0 Metabolic/Nutritional Hypophosphatemia 3.4 0 Respiratory Upper Respiratory Tract Infection Rhinitis 8.6 6.9 4.0 0 Special Senses Diplopia Otitis Media 3.4 3.4 4.0 0 Urogenital Intramenstrual Bleeding Urinary Tract Infection 3.4 3.4 0 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 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 experienc…