Felbamate

FELBAMATE- felbamate tablet
ANI Pharmaceuticals, Inc.

WARNING
1. APLASTIC ANEMIA

THE USE OF FELBAMATE IS ASSOCIATED WITH A MARKED INCREASE IN THE INCIDENCE OF APLASTIC ANEMIA. ACCORDINGLY, FELBAMATE 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 FELBAMATE WITHOUT CONSIDERATION OF APPROPRIATE EXPERT HEMATOLOGIC CONSULTATION.

AMONG FELBAMATE 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 FELBAMATE 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 FELBAMATE, IT SHOULD BE BORNE IN MIND THAT THE CLINICAL MANIFESTATION OF APLASTIC ANEMIA MAY NOT BE SEEN UNTIL AFTER A PATIENT HAS BEEN ON FELBAMATE FOR SEVERAL MONTHS (E.G., ONSET OF APLASTIC ANEMIA AMONG FELBAMATE 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 FELBAMATE 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 FELBAMATE WITHOUT SIGNS OF HEMATOLOGIC ABNORMALITY FOR LONG PERIODS OF TIME IS WITHOUT RISK.

IT IS NOT KNOWN WHETHER OR NOT THE DOSE OF FELBAMATE 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. FELBAMATE 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 FELBAMATE. 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 FELBAMATE. 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 FELBAMATE 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.

FELBAMATE SHOULD NOT BE PRESCRIBED FOR ANYONE WITH A HISTORY OF HEPATIC DYSFUNCTION.

TREATMENT WITH FELBAMATE 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 TO 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.

FELBAMATE 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 FELBAMATE AND ARE WITHDRAWN FROM THE DRUG FOR ANY REASON SHOULD BE PRESUMED TO BE AT INCREASED RISK FOR LIVER INJURY IF FELBAMATE IS REINTRODUCED. ACCORDINGLY, SUCH PATIENTS SHOULD NOT BE CONSIDERED FOR RE-TREATMENT.

DESCRIPTION

Felbamate USP is an antiepileptic available as 400 mg and 600 mg tablets for oral administration. Its chemical name is 2-phenyl-1,3-propanediol dicarbamate.

Felbamate USP is a white to off-white crystalline powder with a characteristic odor. It is very slightly soluble in water, slightly soluble in ethanol, sparingly soluble in methanol, and freely soluble in dimethyl sulfoxide. The molecular weight is 238.24; felbamate’s molecular formula is C11 H14 N2 O4 ; its structural formula is:

structural formula

The inactive ingredients for Felbamate Tablets USP, 400 mg and 600 mg are: croscarmellose sodium, lactose monohydrate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and iron oxide yellow.

CLINICAL PHARMACOLOGY

Mechanism of Action:

The mechanism by which felbamate exerts its anticonvulsant activity is unknown, but in animal test systems designed to detect anticonvulsant activity, felbamate has properties in common with other marketed anticonvulsants. Felbamate is effective in mice and rats in the maximal electroshock test, the subcutaneous pentylenetetrazol seizure test, and the subcutaneous picrotoxin seizure test. Felbamate also exhibits anticonvulsant activity against seizures induced by intracerebroventricular administration of glutamate in rats and N-methyl-D,L-aspartic acid in mice. Protection against maximal electroshock-induced seizures suggests that felbamate may reduce seizure spread, an effect possibly predictive of efficacy in generalized tonic-clonic or partial seizures. Protection against pentylenetetrazol-induced seizures suggests that felbamate may increase seizure threshold, an effect considered to be predictive of potential efficacy in absence seizures.

Receptor-binding studies in vitro indicate that felbamate has weak inhibitory effects on GABA-receptor binding, benzodiazepine receptor binding, and is devoid of activity at the MK-801 receptor binding site of the NMDA receptor-ionophore complex. However, felbamate does interact as an antagonist at the strychnine-insensitive glycine recognition site of the NMDA receptor-ionophore complex. Felbamate is not effective in protecting chick embryo retina tissue against the neurotoxic effects of the excitatory amino acid agonists NMDA, kainate, or quisqualate in vitro.

The monocarbamate, p-hydroxy, and 2-hydroxy metabolites were inactive in the maximal electroshock-induced seizure test in mice. The monocarbamate and p-hydroxy metabolites had only weak (0.2 to 0.6) activity compared with felbamate in the subcutaneous pentylenetetrazol seizure test. These metabolites did not contribute significantly to the anticonvulsant action of felbamate.

Pharmacokinetics:

The numbers in the pharmacokinetic section are mean ± standard deviation.

Felbamate is well-absorbed after oral administration. Over 90% of the radioactivity after a dose of 1000 mg 14 C felbamate was found in the urine. Absolute bioavailability (oral vs. parenteral) has not been measured. The tablet was shown to be bioequivalent to the capsule used in clinical trials, and pharmacokinetic parameters of the tablet and suspension are similar. There was no effect of food on absorption of the tablet.

Following oral administration, felbamate is the predominant plasma species (about 90% of plasma radioactivity). About 40 to 50% of absorbed dose appears unchanged in urine, and an additional 40% is present as unidentified metabolites and conjugates. About 15% is present as parahydroxyfelbamate, 2-hydroxyfelbamate, and felbamate monocarbamate, none of which have significant anticonvulsant activity.

Binding of felbamate to human plasma protein was independent of felbamate concentrations between 10 and 310 micrograms/mL. Binding ranged from 22% to 25%, mostly to albumin, and was dependent on the albumin concentration.

Felbamate is excreted with a terminal half-life of 20 to 23 hours, which is unaltered after multiple doses. Clearance after a single 1200 mg dose is 26±3 mL/hr/kg, and after multiple daily doses of 3600 mg is 30±8 mL/hr/kg. The apparent volume of distribution was 756±82 mL/kg after a 1200 mg dose. Felbamate Cmax and AUC are proportionate to dose after single and multiple doses over a range of 100 to 800 mg single doses and 1200 to 3600 mg daily doses. Cmin (trough) blood levels are also dose proportional. Multiple daily doses of 1200, 2400, and 3600 mg gave Cmin values of 30±5, 55±8, and 83±21 micrograms/mL (N=10 patients). Linear and dose proportional pharmacokinetics were also observed at doses above 3600 mg/day up to the maximum dose studied of 6000 mg/day. Felbamate gave dose proportional steady-state peak plasma concentrations in children age 4 to 12 over a range of 15, 30, and 45 mg/kg/day with peak concentrations of 17, 32, and 49 micrograms/mL.

The effects of race and gender on felbamate pharmacokinetics have not been systematically evaluated, but plasma concentrations in males (N=5) and females (N=4) given felbamate have been similar. The effects of felbamate kinetics on hepatic functional impairment have not been evaluated.

Renal Impairment:

Felbamate’s single dose monotherapy pharmacokinetic parameters were evaluated in 12 otherwise healthy individuals with renal impairment. There was a 40 to 50% reduction in total body clearance and 9 to 15 hours prolongation of half-life in renally impaired subjects compared to that in subjects with normal renal function. Reduced felbamate clearance and a longer half-life were associated with diminishing renal function.

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