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.
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