Felbatol Information
Felbatol () Warning
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.
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 ). 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.
Felbatol () Description
Felbatol () ® (felbamate) is an antiepileptic available as 400 mg and 600 mg tablets and as a 600 mg/5 mL suspension for oral administration. Its chemical name is 2-phenyl-1,3-propanediol dicarbamate.
Felbamate 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 C H N O ; its structural formula is:
The inactive ingredients for Felbatol () ® (felbamate) Tablets 400 mg and 600 mg are starch, microcrystalline cellulose, croscarmellose sodium, lactose, magnesium stearate, FD&C Yellow No. 6, D&C Yellow No. 10, and FD&C Red No. 40 (600 mg tablets only). The inactive ingredients for Felbatol () ® (felbamate) Oral Suspension 600 mg/5 mL are sorbitol, glycerin, microcrystalline cellulose, carboxymethylcellulose sodium, simethicone, polysorbate 80, methylparaben, saccharin sodium, propylparaben, FD&C Yellow No. 6, FD&C Red No. 40, flavorings, and purified water.
Felbatol () Clinical Pharmacology
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 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 .
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.
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 C felbamate was found in the urine. Absolute bioavailability (oral vs. parenteral) has not been measured. The tablet and suspension were each 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; the effect of food on absorption of the suspension has not been evaluated.
Following oral administration, felbamate is the predominant plasma species (about 90% of plasma radioactivity). About 40-50% 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 20-23 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 100-800 mg single doses and 1200-3600 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 4-12 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:
2. The only other change in vital signs was a mean decrease of approximately 1 respiration per minute in respiratory rate during adjunctive therapy in children. In adults, statistically significant mean reductions in body weight were observed during felbamate monotherapy and adjunctive therapy. In children, there were mean decreases in body weight during adjunctive therapy and monotherapy; however, these mean changes were not statistically significant. These mean reductions in adults and children were approximately 5% of the mean weights at baseline.
Felbatol () Clinical Studies
The results of controlled clinical trials established the efficacy of Felbatol () ® (felbamate) as monotherapy and adjunctive therapy in adults with partial-onset seizures with or without secondary generalization and in partial and generalized seizures associated with Lennox-Gastaut syndrome in children.
Felbatol () ® (3600 mg/day given QID) and low-dose valproate (15 mg/kg/day) were compared as monotherapy during a 112-day treatment period in a multicenter and a single-center double-blind efficacy trial. Both trials were conducted according to an identical study design. During a 56-day baseline period, all patients had at least four partial-onset seizures per 28 days and were receiving one antiepileptic drug at a therapeutic level, the most common being carbamazepine. In the multicenter trial, baseline seizure frequencies were 12.4 per 28 days in the Felbatol () ® group and 21.3 per 28 days in the low-dose valproate group. In the single-center trial, baseline seizure frequencies were 18.1 per 28 days in the Felbatol () ® group and 15.9 per 28 days in the low-dose valproate group. Patients were converted to monotherapy with Felbatol () ® or low-dose valproic acid during the first 28 days of the 112-day treatment period. Study endpoints were completion of 112 study days or fulfilling an escape criterion. Criteria for escape relative to baseline were: (1) twofold increase in monthly seizure frequency, (2) twofold increase in highest 2-day seizure frequency, (3) single generalized tonic-clonic seizure (GTC) if none occurred during baseline, or (4) significant prolongation of GTCs. The primary efficacy variable was the number of patients in each treatment group who met escape criteria.
In the multicenter trial, the percentage of patients who met escape criteria was 40% (18/45) in the Felbatol () ® group and 78% (39/50) in the low-dose valproate group. In the single-center trial, the percentage of patients who met escape criteria was 14% (3/21) in the Felbatol () ® group and 90% (19/21) in the low-dose valproate group. In both trials, the difference in the percentage of patients meeting escape criteria was statistically significant (P<.001 in favor of felbatol these two studies by design were intended to demonstrate the effectiveness monotherapy. not designed or comparative efficacy drugs. for example valproate was used at maximally effective dose.>
A double-blind, placebo-controlled crossover trial consisted of two 10-week outpatient treatment periods. Patients with refractory partial-onset seizures who were receiving phenytoin and carbamazepine at therapeutic levels were administered Felbatol () ® (felbamate) as add-on therapy at a starting dosage of 1400 mg/day in three divided doses, which was increased to 2600 mg/day in three divided doses. Among the 56 patients who completed the study, the baseline seizure frequency was 20 per month. Patients treated with Felbatol () ® had fewer seizures than patients treated with placebo for each treatment sequence. There was a 23% (P=.018) difference in percentage seizure frequency reduction in favor of Felbatol () ®.
Felbatol () ® 3600 mg/day given QID and placebo were compared in a 28-day double-blind add-on trial in patients who had their standard antiepileptic drugs reduced while undergoing evaluations for surgery of intractable epilepsy. All patients had confirmed partial-onset seizures with or without generalization, seizure frequency during surgical evaluation not exceeding an average of four partial seizures per day or more than one generalized seizure per day, and a minimum average of one partial or generalized tonic-clonic seizure per day for the last 3 days of the surgical evaluation. The primary efficacy variable was time to fourth seizure after randomization to treatment with Felbatol () ® or placebo. Thirteen (46%) of 28 patients in the Felbatol () ® group versus 29 (88%) of 33 patients in the placebo group experienced a fourth seizure. The median times to fourth seizure were greater than 28 days in the Felbatol () ® group and 5 days in the placebo group. The difference between Felbatol () ® and placebo in time to fourth seizure was statistically significant (P=.002) in favor of Felbatol () ®.
In a 70-day double-blind, placebo-controlled add-on trial in the Lennox-Gastaut syndrome, Felbatol () ® 45 mg/kg/day given QID was superior to placebo in controlling the multiple seizure types associated with this condition. Patients had at least 90 atonic and/or atypical absence seizures per month while receiving therapeutic dosages of one or two other antiepileptic drugs. Patients had a past history of using an average of eight antiepileptic drugs. The most commonly used antiepileptic drug during the baseline period was valproic acid. The frequency of all types of seizures during the baseline period was 1617 per month in the Felbatol () ® group and 716 per month in the placebo group. Statistically significant differences in the effect on seizure frequency favored Felbatol () ® over placebo for total seizures (26% reduction vs. 5% increase, P<.001 atonic seizures reduction vs. p=".002)," and generalized tonic-clonic increase parent global evaluations based on impressions of quality life with respect to alertness verbal responsiveness general well-being seizure control significantly favored felbatol over placebo.>
When efficacy was analyzed by gender in four well-controlled trials of felbamate as adjunctive and monotherapy for partial-onset seizures and Lennox-Gastaut syndrome, a similar response was seen in 122 males and 142 females.
Felbatol () Indications And Usage
Felbatol () ® is not indicated as a first line antiepileptic treatment (see ). 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.
Felbatol () 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.
Felbatol () Warnings
See regarding aplastic anemia and hepatic failure. Antiepileptic drugs should not be suddenly discontinued because of the possibility of increasing seizure frequency.
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.
Felbatol () Precautions
Dosage Adjustment in the Renally Impaired:
Information for Patients:
The physician should obtain written acknowledgement prior to initiation of Felbatol () ® therapy (see 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
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
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.
See 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 ).
Suicidal Thinking and Behavior:
Pregnancy:
Drug Interactions:
Use in Conjunction with Other Antiepileptic Drugs (see ):
The addition of Felbatol () ® to antiepileptic drugs (AEDs) affects the steady-state plasma concentrations of AEDs.
In a controlled clinical trial, a 20% reduction of the phenytoin dose at the initiation of Felbatol () ® therapy resulted in phenytoin levels comparable to those prior to Felbatol () ® administration.
Carbamazepine:
In clinical trials, similar changes in carbamazepine and carbamazepine epoxide were seen.
Valproate:
Phenobarbital:
Carbamazepine:
Valproate:
Phenobarbital:
Effects of Antacids on Felbatol () ®:
Effects of Erythromycin on Felbatol () ®:
Effects of Felbatol () ® on Low-Dose Combination Oral Contraceptives:
Drug/Laboratory Test Interactions:
Carcinogenesis, Mutagenesis, Impairment of Fertility:
As a result of the synthesis process, felbamate could contain small amounts of two known animal carcinogens, the genotoxic compound ethyl carbamate (urethane) and the nongenotoxic compound methyl carbamate. It is theoretically possible that a 50 kg patient receiving 3600 mg of felbamate could be exposed to up to 0.72 micrograms of urethane and 1800 micrograms of methyl carbamate. These daily doses are approximately 1/35,000 (urethane) and 1/5,500 (methyl carbamate) on a mg/kg basis, and 1/10,000 (urethane) and 1/1,600 (methyl carbamate) on a mg/m basis, of the dose levels shown to be carcinogenic in rodents. Any presence of these two compounds in felbamate used in the lifetime carcinogenicity studies was inadequate to cause tumors.
Microbial and mammalian cell assays revealed no evidence of mutagenesis in the Ames /microsome plate test, CHO/HGPRT mammalian cell forward gene mutation assay, sister chromatid exchange assay in CHO cells, and bone marrow cytogenetics assay.
Reproduction and fertility studies in rats showed no effects on male or female fertility at oral doses of up to 13.9 times the human total daily dose of 3600 mg on a mg/kg basis, or up to 3 times the human total daily dose on a mg/m basis.
Pregnancy: Pregnancy Category C.
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 Felbatol () ®, physicians are advised to recommend that pregnant patients taking Felbatol () 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/.
Labor and Delivery:
Nursing Mothers:
Pediatric Use:
Geriatric Use:
Felbatol () Adverse Reactions
The most common adverse reactions seen in association with Felbatol () ® (felbamate) in adults during monotherapy are anorexia, vomiting, insomnia, nausea, and headache. The most common adverse reactions seen in association with Felbatol () ® in adults during adjunctive therapy are anorexia, vomiting, insomnia, nausea, dizziness, somnolence, and headache.
The most common adverse reactions seen in association with Felbatol () ® 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%).
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 monotherapy, or with adjustment of the dosage of other antiepileptic drugs.
Events are classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100-1/1000 patients; and rare events are those occurring in fewer than 1/1000 patients.
Event frequencies are calculated as the number of patients reporting an event divided by the total number of patients (N=1334) exposed to Felbatol () ®.
Felbatol () Drug Abuse And Dependence
Abuse:
Dependence:
Felbatol () Overdosage
Four subjects inadvertently received Felbatol () ® (felbamate) as adjunctive therapy in dosages ranging from 5400 to 7200 mg/day for durations between 6 and 51 days. One subject who received 5400 mg/day as monotherapy for 1 week reported no adverse experiences. Another subject attempted suicide by ingesting 12,000 mg of Felbatol () ® in a 12-hour period. The only adverse experiences reported were mild gastric distress and a resting heart rate of 100 bpm. No serious adverse reactions have been reported. General supportive measures should be employed if overdosage occurs. It is not known if felbamate is dialyzable.
Felbatol () Dosage And Administration
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 subsection).
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.
Felbatol () How Supplied
Felbatol () ® (felbamate) Tablets, 400 mg, are yellow, scored, capsule-shaped tablets, debossed 0430 on one side and Felbatol () 400 on the other; available in bottles of 100 (NDC 0037-0430-01). Felbatol () ® (felbamate) Tablets, 600 mg, are peach-colored, scored, capsule-shaped tablets, debossed 0431 on one side and Felbatol () 600 on the other; available in bottles of 100 (NDC 0037-0431-01). Felbatol () ® (felbamate) Oral Suspension, 600 mg/5 mL, is peach-colored; available in 8 oz bottles (NDC 0037-0442-67) and 32 oz bottles (NDC 0037-0442-17).
Shake suspension well before using. Store at controlled room temperature 20°-25°C (68°-77°F). Dispense in tight container.
MEDA Pharmaceuticals® MEDA Pharmaceuticals Inc. Somerset, NJ 08873 IN-00431-18 Rev. 7/11
Felbatol () Patient/physician Acknowledgment Form
Felbatol () ® (felbamate) SHOULD NOT BE USED BY PATIENTS UNTIL THERE HAS BEEN A COMPLETE DISCUSSION OF THE RISKS. All patients treated with Felbatol () should acknowledge that they understand the risks and other information about Felbatol () discussed below, and physicians should acknowledge this discussion.
IMPORTANT INFORMATION AND WARNING: Felbatol () ®, taken by itself or with other prescription and/or non-prescription drugs, can result in a severe, potentially fatal blood abnormality ("aplastic anemia") and/or severe, potentially fatal liver damage.
PATIENT ACKNOWLEDGMENT:
My [My son, daughter, ward treatment with Felbatol () ® has been personally explained to me by Dr. The following points of information, among others, have been specifically discussed and made clear and I have had the opportunity to ask any questions concerning this information:
1. I, (Patient's Name), understand that Felbatol () ® is used to treat certain types of seizures and my physician has told me that I have this type(s) of seizures;INITIALS:
2. I understand that Felbatol () ® is being used because my seizures have not been satisfactorily treated with other antiepileptic drugs;INITIALS:
3. I understand that there is a serious risk that I could develop aplastic anemia and/or liver failure, both of which are potentially fatal, by using Felbatol () ®;INITIALS:
4. I understand that there are no laboratory tests which will predict if I am at an increased risk for one of the potentially fatal conditions;INITIALS:
5. I understand that I should have the recommended blood work before my treatment with Felbatol () ® is begun (baseline) and periodically thereafter as clinical judgement warrants. I understand that although this blood work may help detect if I develop one of these conditions, it may do so only after significant, irreversible and potentially fatal damage has already occurred;INITIALS:
6. If I am currently taking other antiepileptic drugs, I understand that the manufacturer of Felbatol () ® recommends that the dosage of these other drugs be decreased by a certain amount when Felbatol () ® is started; if my physician determines that this should not be done in my case, he/she has explained the reason(s) for this decision;INITIALS:
7. I understand that I must immediately report any unusual symptoms to Dr. and be especially aware of any rashes, easy bruising, bleeding, sore throats, fever, and/or dark urine; INITIALS:
8. I understand that antiepileptic drugs such as Felbatol () ® may increase the risk of suicidal thoughts and behavior. I understand that I must immediately report any unusual changes in mood or behavior, symptoms of depression or thoughts about self-harm to Dr. INITIALS:
Revised: 7/11
MEDA Pharmaceuticals® MEDA Pharmaceuticals Inc.Somerset, New Jersey 08873-4120
Felbatol () Medication Guide
IS-00431-01 Rev. 7/11
Read this Medication Guide before you start taking Felbatol () and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.
Felbatol () can cause serious side effects, including:
Call your healthcare provider between visits as needed, especially if you are worried about symptoms.
Stopping Felbatol () suddenly can cause serious problems. You should talk to your health care provider before stopping. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures.
Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.
Felbatol () is a prescription medicine used when other treatments have failed in:
Taking Felbatol () with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.
Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist when you get a new medicine.
The most common side effects of Felbatol () include:
These are not all the possible side effects of Felbatol () . For more information, ask your healthcare provider or pharmacist.
Tell your healthcare provider if you have any side effect that bothers you or that does not go away.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Felbatol () for a condition for which it was not prescribed. Do not give Felbatol () to other people, even if they have the same symptoms that you have. It may harm them.
This Medication Guide summarizes the most important information about Felbatol () . If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Felbatol () that is written for health professionals.
For more information, go to www. Felbatol () .com or call 1-800-526-3840.
This Medication Guide has been approved by the U.S. Food and Drug Administration.
MEDA Pharmaceuticals Issued 7/11
MEDA Pharmaceuticals Inc., Somerset, NJ 08873-4120
Felbatol () is a registered trademark of Meda Pharmaceuticals Inc.
IS-00431-01 Rev. 7/11
Felbatol () Package Label - Principal Display Panel – -count Bottle, Mg Tablet
NDC 0037-0430-01 (felbamate) 400 mg Tablets LB-024G5-09 Rev. 12/10 For full prescribing information, see accompanying package insert. Store at controlled room temperature 20°-25°C (68°-77°F). Dispense in a tight container. Meda Pharmaceuticals Inc. Somerset, New Jersey 08873-4120
Felbatol () Package Label - Principal Display Panel – -count Bottle, Mg Tablet
NDC 0037-0431-01 (felbamate) 600 mg Tablets LB-024H5-09 Rev. 12/10 For full prescribing information, see accompanying package insert. Store at controlled room temperature 20°-25°C (68°-77°F). Dispense in a tight container. Meda Pharmaceuticals Inc. Somerset, New Jersey 08873-4120
Felbatol () Package Label - Principal Display Panel – Fl Oz ( Ml) Bottle, Mg Suspension
NDC 0037-0442-67 (felbamate) Oral Suspension Each 5 mL contains 600 mg felbamate LB-024F5-10 Rev. 12/10 For full prescribing information, see accompanying package insert. Store at controlled room temperature 20°-25°C (68°-77°F). Dispense in a tight container. Meda Pharmaceuticals Inc. Somerset, New Jersey 08873-4120
