Felbamate 600 mg/5mL Suspension, 237 mL — NDC 65162-686-88 (Billing 65162-0686-88)

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

2.4Psychiatric 5.7 8.5 1.5

2.9Other 1 1.8 1.9

0.9Total 2.4 4.3 1.8

1.9The 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.

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… [Excerpted — this section continues on DailyMed.]

PRECAUTIONS Dosage Adjustment in the Renally Impaired: A study in otherwise healthy individuals with renal dysfunction indicated that prolonged half-life and reduced clearance of felbamate are associated with diminishing renal function. Felbamate should be used with caution in patients with renal dysfunction (see DOSAGE AND ADMINISTRATION ) . Information for Patients: Patients should be informed that the use of felbamate is associated with aplastic anemia and hepatic failure, potentially fatal conditions acutely or over a long term.

The physician should obtain written acknowledgment prior to initiation of felbamate therapy (see PATIENT/PHYSICIAN ACKNOWLEDGMENT FORM section). Patients should be instructed to read the Medication Guide supplied as required by law when felbamate is dispensed. The complete text of the Medication Guide is reprinted at the end of this document.

Aplastic anemia in the general population is relatively rare. The absolute risk for the individual patient is not known with any degree of reliability, but patients on felbamate may be at more than a 100 fold greater risk for developing the syndrome than the general population. The long term outlook for patients with aplastic anemia is variable.

Although many patients are apparently cured, others require repeated transfusions and other treatments for relapses, and some, although surviving for years, ultimately develop serious complications that sometimes prove fatal (e.g., leukemia). At present there is no way to predict who is likely to get aplastic anemia, nor is there a documented effective means to monitor the patient so as to avoid and/or reduce the risk. Patients with a history of any blood dyscrasia should not receive felbamate.

Patients should be advised to be alert for signs of infection, bleeding, easy bruising, or signs of anemia (fatigue, weakness, lassitude, etc.) and should be advised to report to the physician immediately if any such signs or symptoms appear. Hepatic failure in the general population is relatively rare. The absolute risk for an individual patient is not known with any degree of reliability but patients on felbamate are at a greater risk for developing hepatic failure than the general population.

At present, there is no way to predict who is likely to develop hepatic failure, however, patients with a history of hepatic dysfunction should not be started on felbamate. Patients should be advised to follow their physician's directives for liver function testing both before starting felbamate and at frequent intervals while taking felbamate. Patients should be advised to be alert for signs of liver dysfunction (jaundice, anorexia, gastrointestinal complaints, malaise, etc.) and to report them to their doctor immediately if they should occur.

Laboratory Tests: Full hematologic evaluations should be performed before felbamate therapy, frequently during therapy, and for a significant period of time after discontinuation of felbamate therapy. While it might appear prudent to perform frequent CBCs in patients continuing on felbamate, there is no evidence that such monitoring will allow early detection of marrow suppression before aplastic anemia occurs (see Boxed Warnings ). Complete pretreatment blood counts, including platelets and reticulocytes should be obtained as a baseline.

If any hematologic abnormalities are detected during the course of treatment, immediate consultation with a hematologist is advised. Felbamate should be discontinued if any evidence of bone marrow depression occurs. See Box Warnings for recommended monitoring of serum transaminases.

If significant, confirmed liver abnormalities are detected during the course of felbamate treatment, felbamate should be discontinued immediately with continued liver function monitoring until values return to normal (see PATIENT/PHYSICIAN ACKNOWLEDGMENT FORM ). Suicidal Thinking and Behavior: Patients, their caregivers, and families should be counseled that AEDs, including felbamate,… [Excerpted — this section continues on DailyMed.]

DRUG ABUSE AND DEPENDENCE Abuse: Abuse potential was not evaluated in human studies. Dependence: 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.