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Black Box Warning
WARNING 1. APLASTIC ANEMIA :
See full prescribing information for complete Boxed Warning.
WARNING 1. APLASTIC ANEMIA:
THE USE OF FELBATOL® (felbamate) IS ASSOCIATED WITH A MARKED INCREASE IN THE INCIDENCE OF APLASTIC ANEMIA. ACCORDINGLY, FELBATOL® SHOULD ONLY BE USED IN PATIENTS WHOSE EPILEPSY IS SO SEVERE THAT THE RISK OF APLASTIC ANEMIA IS DEEMED ACCEPTABLE IN LIGHT OF THE BENEFITS CONFERRED BY ITS USE (SEE INDICATIONS). ORDINARILY, A PATIENT SHOULD NOT BE PLACED ON AND/OR CONTINUED ON FELBATOL® WITHOUT CONSIDERATION OF APPROPRIATE EXPERT HEMATOLOGIC CONSULTATION.
AMONG FELBATOL® TREATED PATIENTS, APLASTIC ANEMIA (PANCYTOPENIA IN THE PRESENCE OF A BONE MARROW LARGELY DEPLETED OF HEMATOPOIETIC PRECURSORS) OCCURS AT AN INCIDENCE THAT MAY BE MORE THAN A 100 FOLD GREATER THAN THAT SEEN IN THE UNTREATED POPULATION (I.E., 2 TO 5 PER MILLION PERSONS PER YEAR). THE RISK OF DEATH IN PATIENTS WITH APLASTIC ANEMIA GENERALLY VARIES AS A FUNCTION OF ITS SEVERITY AND ETIOLOGY; CURRENT ESTIMATES OF THE OVERALL CASE FATALITY RATE ARE IN THE RANGE OF 20 TO 30%, BUT RATES AS HIGH AS 70% HAVE BEEN REPORTED IN THE PAST.
THERE ARE TOO FEW FELBATOL® ASSOCIATED CASES, AND TOO LITTLE KNOWN ABOUT THEM TO PROVIDE A RELIABLE ESTIMATE OF THE SYNDROME'S INCIDENCE OR ITS CASE FATALITY RATE OR TO IDENTIFY THE FACTORS, IF ANY, THAT MIGHT CONCEIVABLY BE USED TO PREDICT WHO IS AT GREATER OR LESSER RISK.
IN MANAGING PATIENTS ON FELBATOL®, IT SHOULD BE BORNE IN MIND THAT THE CLINICAL MANIFESTATION OF APLASTIC ANEMIA MAY NOT BE SEEN UNTIL AFTER A PATIENT HAS BEEN ON FELBATOL® FOR SEVERAL MONTHS (E.G., ONSET OF APLASTIC ANEMIA AMONG FELBATOL® EXPOSED PATIENTS FOR WHOM DATA ARE AVAILABLE HAS RANGED FROM 5 TO 30 WEEKS). HOWEVER, THE INJURY TO BONE MARROW STEM CELLS THAT IS HELD TO BE ULTIMATELY RESPONSIBLE FOR THE ANEMIA MAY OCCUR WEEKS TO MONTHS EARLIER. ACCORDINGLY, PATIENTS WHO ARE DISCONTINUED FROM FELBATOL® REMAIN AT RISK FOR DEVELOPING ANEMIA FOR A VARIABLE, AND UNKNOWN, PERIOD AFTERWARDS.
IT IS NOT KNOWN WHETHER OR NOT THE RISK OF DEVELOPING APLASTIC ANEMIA CHANGES WITH DURATION OF EXPOSURE. CONSEQUENTLY, IT IS NOT SAFE TO ASSUME THAT A PATIENT WHO HAS BEEN ON FELBATOL® WITHOUT SIGNS OF HEMATOLOGIC ABNORMALITY FOR LONG PERIODS OF TIME IS WITHOUT RISK.
IT IS NOT KNOWN WHETHER OR NOT THE DOSE OF FELBATOL® AFFECTS THE INCIDENCE OF APLASTIC ANEMIA.
IT IS NOT KNOWN WHETHER OR NOT CONCOMITANT USE OF ANTIEPILEPTIC DRUGS AND/OR OTHER DRUGS AFFECTS THE INCIDENCE OF APLASTIC ANEMIA.
APLASTIC ANEMIA TYPICALLY DEVELOPS WITHOUT PREMONITORY CLINICAL OR LABORATORY SIGNS, THE FULL BLOWN SYNDROME PRESENTING WITH SIGNS OF INFECTION, BLEEDING, OR ANEMIA. ACCORDINGLY, ROUTINE BLOOD TESTING CANNOT BE RELIABLY USED TO REDUCE THE INCIDENCE OF APLASTIC ANEMIA, BUT, IT WILL, IN SOME CASES, ALLOW THE DETECTION OF THE HEMATOLOGIC CHANGES BEFORE THE SYNDROME DECLARES ITSELF CLINICALLY. FELBATOL® SHOULD BE DISCONTINUED IF ANY EVIDENCE OF BONE MARROW DEPRESSION OCCURS.
2. HEPATIC FAILURE :
EVALUATION OF POSTMARKETING EXPERIENCE SUGGESTS THAT ACUTE LIVER FAILURE IS ASSOCIATED WITH THE USE OF FELBATOL®. THE REPORTED RATE IN THE U.S. HAS BEEN ABOUT 6 CASES OF LIVER FAILURE LEADING TO DEATH OR TRANSPLANT PER 75,000 PATIENT YEARS OF USE. THIS RATE IS AN UNDERESTIMATE BECAUSE OF UNDER REPORTING, AND THE TRUE RATE COULD BE CONSIDERABLY GREATER THAN THIS. FOR EXAMPLE, IF THE REPORTING RATE IS 10%, THE TRUE RATE WOULD BE ONE CASE PER 1,250 PATIENT YEARS OF USE.
OF THE CASES REPORTED, ABOUT 67% RESULTED IN DEATH OR LIVER TRANSPLANTATION, USUALLY WITHIN 5 WEEKS OF THE ONSET OF SIGNS AND SYMPTOMS OF LIVER FAILURE. THE EARLIEST ONSET OF SEVERE HEPATIC DYSFUNCTION FOLLOWED SUBSEQUENTLY BY LIVER FAILURE WAS 3 WEEKS AFTER INITIATION OF FELBATOL®. ALTHOUGH SOME REPORTS DESCRIBED DARK URINE AND NONSPECIFIC PRODROMAL SYMPTOMS (E.G., ANOREXIA, MALAISE, AND GASTROINTESTINAL SYMPTOMS), IN OTHER REPORTS IT WAS NOT CLEAR IF ANY PRODROMAL SYMPTOMS PRECEDED THE ONSET OF JAUNDICE.
IT IS NOT KNOWN WHETHER OR NOT THE RISK OF DEVELOPING HEPATIC FAILURE CHANGES WITH DURATION OF EXPOSURE.
IT IS NOT KNOWN WHETHER OR NOT THE DOSAGE OF FELBATOL® AFFECTS THE INCIDENCE OF HEPATIC FAILURE.
IT IS NOT KNOWN WHETHER CONCOMITANT USE OF OTHER ANTIEPILEPTIC DRUGS AND/OR OTHER DRUGS AFFECT THE INCIDENCE OF HEPATIC FAILURE.
FELBATOL® SHOULD NOT BE PRESCRIBED FOR ANYONE WITH A HISTORY OF HEPATIC DYSFUNCTION.
TREATMENT WITH FELBATOL® SHOULD BE INITIATED ONLY IN INDIVIDUALS WITHOUT ACTIVE LIVER DISEASE AND WITH NORMAL BASELINE SERUM TRANSAMINASES. IT HAS NOT BEEN PROVED THAT PERIODIC SERUM TRANSAMINASE TESTING WILL PREVENT SERIOUS INJURY BUT IT IS GENERALLY BELIEVED THAT EARLY DETECTION OF DRUG-INDUCED HEPATIC INJURY ALONG WITH IMMEDIATE WITHDRAWAL OF THE SUSPECT DRUG ENHANCES THE LIKELIHOOD FOR RECOVERY. THERE IS NO INFORMATION AVAILABLE THAT DOCUMENTS HOW RAPIDLY PATIENTS CAN PROGRESS FROM NORMAL LIVER FUNCTION TO LIVER FAILURE, BUT OTHER DRUGS KNOWN TO BE HEPATOTOXINS CAN CAUSE LIVER FAILURE RAPIDLY (E.G., FROM NORMAL ENZYMES TO LIVER FAILURE IN 2-4 WEEKS). ACCORDINGLY, MONITORING OF SERUM TRANSAMINASE LEVELS (AST AND ALT) IS RECOMMENDED AT BASELINE AND PERIODICALLY THEREAFTER. WHILE THE MORE FREQUENT THE MONITORING THE GREATER THE CHANCES OF EARLY DETECTION, THE PRECISE SCHEDULE FOR MONITORING IS A MATTER OF CLINICAL JUDGEMENT.
FELBATOL® SHOULD BE DISCONTINUED IF EITHER SERUM AST OR SERUM ALT LEVELS BECOME INCREASED ≥ 2 TIMES THE UPPER LIMIT OF NORMAL, OR IF CLINICAL SIGNS AND SYMPTOMS SUGGEST LIVER FAILURE (SEE PRECAUTIONS). PATIENTS WHO DEVELOP EVIDENCE OF HEPATOCELLULAR INJURY WHILE ON FELBATOL® AND ARE WITHDRAWN FROM THE DRUG FOR ANY REASON SHOULD BE PRESUMED TO BE AT INCREASED RISK FOR LIVER INJURY IF FELBATOL® IS REINTRODUCED. ACCORDINGLY, SUCH PATIENTS SHOULD NOT BE CONSIDERED FOR RE-TREATMENT.
Overview
Felbamate is a antiepileptic that is FDA approved for 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. There is a Black Box Warning for this drug as shown here. Common adverse reactions include anorexia, vomiting, insomnia, nausea, and headache.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
Felbatol® is not indicated as a first line antiepileptic treatment (see WARNINGS). Felbatol® 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, Felbatol® 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
Felbatol® (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 Felbatol® is added to or substituted for existing AEDs, it is strongly recommended to reduce the dosage of those AEDs in the range of 20-33% 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) Felbatol® (felbamate) has not been systematically evaluated as initial monotherapy. Initiate Felbatol® 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 Felbatol® at 1200 mg/day in divided doses three or four times daily. Reduce the dosage of concomitant AEDs by one-third at initiation of Felbatol® therapy. At week 2, increase the Felbatol® 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 Felbatol® dosage up to 3600 mg/day and continue to reduce the dosage of other AEDs as clinically indicated.
Adjunctive Therapy: Felbatol® 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 Felbatol® by 1200 mg/day increments at weekly intervals to 3600 mg/day. Most side effects seen during Felbatol® adjunctive therapy resolve as the dosage of concomitant AEDs is decreased.
While the above Felbatol® conversion guidelines may result in a Felbatol® 3600 mg/day dose within 3 weeks, in some patients titration to a 3600 mg/day Felbatol® dose has been achieved in as little as 3 days with appropriate adjustment of other AEDs.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Felbamate in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Felbamate in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Children with Lennox-Gastaut Syndrome (Ages 2-14 years)
Adjunctive Therapy: Felbatol® 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 Felbatol® by 15 mg/kg/day increments at weekly intervals to 45 mg/kg/day. Most side effects seen during Felbatol® adjunctive therapy resolve as the dosage of concomitant AEDs is decreased.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Felbamate in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Felbamate in pediatric patients.
Contraindications
Felbatol® is contraindicated in patients with known hypersensitivity to Felbatol®, 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.
Warnings
WARNING 1. APLASTIC ANEMIA :
See full prescribing information for complete Boxed Warning.
WARNING 1. APLASTIC ANEMIA:
THE USE OF FELBATOL® (felbamate) IS ASSOCIATED WITH A MARKED INCREASE IN THE INCIDENCE OF APLASTIC ANEMIA. ACCORDINGLY, FELBATOL® SHOULD ONLY BE USED IN PATIENTS WHOSE EPILEPSY IS SO SEVERE THAT THE RISK OF APLASTIC ANEMIA IS DEEMED ACCEPTABLE IN LIGHT OF THE BENEFITS CONFERRED BY ITS USE (SEE INDICATIONS). ORDINARILY, A PATIENT SHOULD NOT BE PLACED ON AND/OR CONTINUED ON FELBATOL® WITHOUT CONSIDERATION OF APPROPRIATE EXPERT HEMATOLOGIC CONSULTATION.
AMONG FELBATOL® TREATED PATIENTS, APLASTIC ANEMIA (PANCYTOPENIA IN THE PRESENCE OF A BONE MARROW LARGELY DEPLETED OF HEMATOPOIETIC PRECURSORS) OCCURS AT AN INCIDENCE THAT MAY BE MORE THAN A 100 FOLD GREATER THAN THAT SEEN IN THE UNTREATED POPULATION (I.E., 2 TO 5 PER MILLION PERSONS PER YEAR). THE RISK OF DEATH IN PATIENTS WITH APLASTIC ANEMIA GENERALLY VARIES AS A FUNCTION OF ITS SEVERITY AND ETIOLOGY; CURRENT ESTIMATES OF THE OVERALL CASE FATALITY RATE ARE IN THE RANGE OF 20 TO 30%, BUT RATES AS HIGH AS 70% HAVE BEEN REPORTED IN THE PAST.
THERE ARE TOO FEW FELBATOL® ASSOCIATED CASES, AND TOO LITTLE KNOWN ABOUT THEM TO PROVIDE A RELIABLE ESTIMATE OF THE SYNDROME'S INCIDENCE OR ITS CASE FATALITY RATE OR TO IDENTIFY THE FACTORS, IF ANY, THAT MIGHT CONCEIVABLY BE USED TO PREDICT WHO IS AT GREATER OR LESSER RISK.
IN MANAGING PATIENTS ON FELBATOL®, IT SHOULD BE BORNE IN MIND THAT THE CLINICAL MANIFESTATION OF APLASTIC ANEMIA MAY NOT BE SEEN UNTIL AFTER A PATIENT HAS BEEN ON FELBATOL® FOR SEVERAL MONTHS (E.G., ONSET OF APLASTIC ANEMIA AMONG FELBATOL® EXPOSED PATIENTS FOR WHOM DATA ARE AVAILABLE HAS RANGED FROM 5 TO 30 WEEKS). HOWEVER, THE INJURY TO BONE MARROW STEM CELLS THAT IS HELD TO BE ULTIMATELY RESPONSIBLE FOR THE ANEMIA MAY OCCUR WEEKS TO MONTHS EARLIER. ACCORDINGLY, PATIENTS WHO ARE DISCONTINUED FROM FELBATOL® REMAIN AT RISK FOR DEVELOPING ANEMIA FOR A VARIABLE, AND UNKNOWN, PERIOD AFTERWARDS.
IT IS NOT KNOWN WHETHER OR NOT THE RISK OF DEVELOPING APLASTIC ANEMIA CHANGES WITH DURATION OF EXPOSURE. CONSEQUENTLY, IT IS NOT SAFE TO ASSUME THAT A PATIENT WHO HAS BEEN ON FELBATOL® WITHOUT SIGNS OF HEMATOLOGIC ABNORMALITY FOR LONG PERIODS OF TIME IS WITHOUT RISK.
IT IS NOT KNOWN WHETHER OR NOT THE DOSE OF FELBATOL® AFFECTS THE INCIDENCE OF APLASTIC ANEMIA.
IT IS NOT KNOWN WHETHER OR NOT CONCOMITANT USE OF ANTIEPILEPTIC DRUGS AND/OR OTHER DRUGS AFFECTS THE INCIDENCE OF APLASTIC ANEMIA.
APLASTIC ANEMIA TYPICALLY DEVELOPS WITHOUT PREMONITORY CLINICAL OR LABORATORY SIGNS, THE FULL BLOWN SYNDROME PRESENTING WITH SIGNS OF INFECTION, BLEEDING, OR ANEMIA. ACCORDINGLY, ROUTINE BLOOD TESTING CANNOT BE RELIABLY USED TO REDUCE THE INCIDENCE OF APLASTIC ANEMIA, BUT, IT WILL, IN SOME CASES, ALLOW THE DETECTION OF THE HEMATOLOGIC CHANGES BEFORE THE SYNDROME DECLARES ITSELF CLINICALLY. FELBATOL® SHOULD BE DISCONTINUED IF ANY EVIDENCE OF BONE MARROW DEPRESSION OCCURS.
2. HEPATIC FAILURE :
EVALUATION OF POSTMARKETING EXPERIENCE SUGGESTS THAT ACUTE LIVER FAILURE IS ASSOCIATED WITH THE USE OF FELBATOL®. THE REPORTED RATE IN THE U.S. HAS BEEN ABOUT 6 CASES OF LIVER FAILURE LEADING TO DEATH OR TRANSPLANT PER 75,000 PATIENT YEARS OF USE. THIS RATE IS AN UNDERESTIMATE BECAUSE OF UNDER REPORTING, AND THE TRUE RATE COULD BE CONSIDERABLY GREATER THAN THIS. FOR EXAMPLE, IF THE REPORTING RATE IS 10%, THE TRUE RATE WOULD BE ONE CASE PER 1,250 PATIENT YEARS OF USE.
OF THE CASES REPORTED, ABOUT 67% RESULTED IN DEATH OR LIVER TRANSPLANTATION, USUALLY WITHIN 5 WEEKS OF THE ONSET OF SIGNS AND SYMPTOMS OF LIVER FAILURE. THE EARLIEST ONSET OF SEVERE HEPATIC DYSFUNCTION FOLLOWED SUBSEQUENTLY BY LIVER FAILURE WAS 3 WEEKS AFTER INITIATION OF FELBATOL®. ALTHOUGH SOME REPORTS DESCRIBED DARK URINE AND NONSPECIFIC PRODROMAL SYMPTOMS (E.G., ANOREXIA, MALAISE, AND GASTROINTESTINAL SYMPTOMS), IN OTHER REPORTS IT WAS NOT CLEAR IF ANY PRODROMAL SYMPTOMS PRECEDED THE ONSET OF JAUNDICE.
IT IS NOT KNOWN WHETHER OR NOT THE RISK OF DEVELOPING HEPATIC FAILURE CHANGES WITH DURATION OF EXPOSURE.
IT IS NOT KNOWN WHETHER OR NOT THE DOSAGE OF FELBATOL® AFFECTS THE INCIDENCE OF HEPATIC FAILURE.
IT IS NOT KNOWN WHETHER CONCOMITANT USE OF OTHER ANTIEPILEPTIC DRUGS AND/OR OTHER DRUGS AFFECT THE INCIDENCE OF HEPATIC FAILURE.
FELBATOL® SHOULD NOT BE PRESCRIBED FOR ANYONE WITH A HISTORY OF HEPATIC DYSFUNCTION.
TREATMENT WITH FELBATOL® SHOULD BE INITIATED ONLY IN INDIVIDUALS WITHOUT ACTIVE LIVER DISEASE AND WITH NORMAL BASELINE SERUM TRANSAMINASES. IT HAS NOT BEEN PROVED THAT PERIODIC SERUM TRANSAMINASE TESTING WILL PREVENT SERIOUS INJURY BUT IT IS GENERALLY BELIEVED THAT EARLY DETECTION OF DRUG-INDUCED HEPATIC INJURY ALONG WITH IMMEDIATE WITHDRAWAL OF THE SUSPECT DRUG ENHANCES THE LIKELIHOOD FOR RECOVERY. THERE IS NO INFORMATION AVAILABLE THAT DOCUMENTS HOW RAPIDLY PATIENTS CAN PROGRESS FROM NORMAL LIVER FUNCTION TO LIVER FAILURE, BUT OTHER DRUGS KNOWN TO BE HEPATOTOXINS CAN CAUSE LIVER FAILURE RAPIDLY (E.G., FROM NORMAL ENZYMES TO LIVER FAILURE IN 2-4 WEEKS). ACCORDINGLY, MONITORING OF SERUM TRANSAMINASE LEVELS (AST AND ALT) IS RECOMMENDED AT BASELINE AND PERIODICALLY THEREAFTER. WHILE THE MORE FREQUENT THE MONITORING THE GREATER THE CHANCES OF EARLY DETECTION, THE PRECISE SCHEDULE FOR MONITORING IS A MATTER OF CLINICAL JUDGEMENT.
FELBATOL® SHOULD BE DISCONTINUED IF EITHER SERUM AST OR SERUM ALT LEVELS BECOME INCREASED ≥ 2 TIMES THE UPPER LIMIT OF NORMAL, OR IF CLINICAL SIGNS AND SYMPTOMS SUGGEST LIVER FAILURE (SEE PRECAUTIONS). PATIENTS WHO DEVELOP EVIDENCE OF HEPATOCELLULAR INJURY WHILE ON FELBATOL® AND ARE WITHDRAWN FROM THE DRUG FOR ANY REASON SHOULD BE PRESUMED TO BE AT INCREASED RISK FOR LIVER INJURY IF FELBATOL® IS REINTRODUCED. ACCORDINGLY, SUCH PATIENTS SHOULD NOT BE CONSIDERED FOR RE-TREATMENT.
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 Felbatol ®, 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 (5-100 years) in the clinical trials analyzed.
Table 1 shows absolute and relative risk by indication for all evaluated AEDs.
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 Felbatol 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.
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
Laboratory Tests: Full hematologic evaluations should be performed before Felbatol® therapy, frequently during therapy, and for a significant period of time after discontinuation of Felbatol® therapy. While it might appear prudent to perform frequent CBCs in patients continuing on Felbatol®, 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. Felbatol® 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 Felbatol® treatment, Felbatol® 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 Felbatol®, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of 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.
Pregnancy: Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Clinical Trial Experience of Felbamate in the drug label.
Body as a Whole
Cardiovascular
Digestive
Endocrine
Hematologic and Lymphatic
Metabolic and Nutritional
Musculoskeletal
Neurologic
Respiratory
Skin and Hypersensitivy Reactions
Special Senses
Urogenital
Miscellaneous
Postmarketing Experience
There is limited information regarding Postmarketing Experience of Felbamate in the drug label.
Patients should be informed that the use of Felbatol® is associated with aplastic anemia and hepatic failure, potentially fatal conditions acutely or over a long term.
The physician should obtain written acknowledgement prior to initiation of Felbatol® therapy (see PATIENT/PHYSICIAN ACKNOWLEDGMENT FORM section).
Patients should be instructed to read the Medication Guide supplied as required by law when Felbatol® 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 Felbatol® 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 Felbatol®.
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 Felbatol® 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 Felbatol®.
Patients should be advised to follow their physician's directives for liver function testing both before starting Felbatol® (felbamate) and at frequent intervals while taking Felbatol®.
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.
Precautions with Alcohol
Alcohol-Felbamate interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
