Felbatol (Page 3 of 7)

INDICATIONS AND USAGE

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.

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

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.

Table 1 Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

Indication

Placebo Patientswith EventsPer 1000 Patients

Drug Patients withEvents Per1000 Patients

Relative Risk:Incidence ofEvents in DrugPatients/Incidencein Placebo Patients

Risk Difference:Additional DrugPatients withEvents Per 1000Patients

Epilepsy

1.0

3.4

3.5

2.4

Psychiatric

5.7

8.5

1.5

2.9

Other

1.0

1.8

1.9

0.9

Total

2.4

4.3

1.8

1.9

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 (see DOSAGE AND ADMINISTRATION).

Information for Patients: 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.

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 (see Pregnancy section).

Drug Interactions: The drug interaction data described in this section were obtained from controlled clinical trials and studies involving otherwise healthy adults with epilepsy.

Use in Conjunction with Other Antiepileptic Drugs (see DOSAGE AND ADMINISTRATION ):

The addition of Felbatol® to antiepileptic drugs (AEDs) affects the steady-state plasma concentrations of AEDs. The net effect of these interactions is summarized in Table 2:

Table 2 Steady-State Plasma Concentrations of Felbatol When Coadministered With Other AEDs
*Not administered but an active metabolite of carbamazepine.
**No significant effect.

AEDCoadministered

AEDConcentration

Felbatol®Concentration

Phenytoin

Valproate

↔**

Carbamazepine (CBZ)*CBZ epoxide

↓↑

Phenobarbital

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: Felbatol® causes a decrease in the steady-state carbamazepine plasma concentrations and an increase in the steady-state carbamazepine epoxide plasma concentration. In nine otherwise healthy subjects with epilepsy ingesting carbamazepine, the steady-state trough (Cmin) carbamazepine concentration was 8±2 micrograms/mL. The carbamazepine steady-state Cmin decreased 31% to 5±1 micrograms/mL when felbamate (3000 mg/day, divided into three doses) was coadministered. Carbamazepine epoxide steady-state Cmin concentrations increased 57% from 1.0±0.3 to 1.6±0.4 micrograms/mL with the addition of felbamate.

In clinical trials, similar changes in carbamazepine and carbamazepine epoxide were seen.

Valproate: Felbatol® causes an increase in steady-state valproate concentrations. In four subjects with epilepsy ingesting valproate, the steady-state trough (Cmin) valproate plasma concentration was 63±16 micrograms/mL. The steady-state Cmin increased to 78±14 micrograms/mL when 1200 mg/day of felbamate was coadministered. Increasing the felbamate dose to 2400 mg/day increased the steady-state valproate Cmin to 96±25 micrograms/mL. Corresponding values for free valproate Cmin concentrations were 7±3, 9±4, and 11±6 micrograms/mL for 0, 1200, and 2400 mg/day Felbatol®, respectively. The ratios of the AUCs of unbound valproate to the AUCs of the total valproate were 11.1%, 13.0%, and 11.5%, with coadministration of 0, 1200, and 2400 mg/day of Felbatol®, respectively. This indicates that the protein binding of valproate did not change appreciably with increasing doses of Felbatol®.

Phenobarbital: Coadministration of felbamate with phenobarbital causes an increase in phenobarbital plasma concentrations. In 12 otherwise healthy male volunteers ingesting phenobarbital, the steady-state trough (Cmin) phenobarbital concentration was 14.2 micrograms/mL. The steady-state Cmin concentration increased to 17.8 micrograms/mL when 2400 mg/day of felbamate was coadministered for one week.

Effects of Other Antiepileptic Drugs on Felbatol®:
Phenytoin: Phenytoin causes an approximate doubling of the clearance of Felbatol® (felbamate) at steady-state and, therefore, the addition of phenytoin causes an approximate 45% decrease in the steady-state trough concentrations of Felbatol® as compared to the same dose of Felbatol® given as monotherapy.

Carbamazepine: Carbamazepine causes an approximate 50% increase in the clearance of Felbatol® at steady-state and, therefore, the addition of carbamazepine results in an approximate 40% decrease in the steady-state trough concentrations of Felbatol® as compared to the same dose of Felbatol® given as monotherapy.

Valproate: Available data suggest that there is no significant effect of valproate on the clearance of Felbatol® at steady-state. Therefore, the addition of valproate is not expected to cause a clinically important effect on Felbatol® (felbamate) plasma concentrations.

Phenobarbital: It appears that phenobarbital may reduce plasma felbamate concentrations. Steady-state plasma felbamate concentrations were found to be 29% lower than the mean concentrations of a group of newly diagnosed subjects with epilepsy also receiving 2400 mg of felbamate a day.

Effects of Antacids on Felbatol®:
The rate and extent of absorption of a 2400 mg dose of Felbatol® as monotherapy given as tablets was not affected when coadministered with antacids.

Effects of Erythromycin on Felbatol®:
The coadministration of erythromycin (1000 mg/day) for 10 days did not alter the pharmacokinetic parameters of Cmax, Cmin, AUC, Cl/kg or tmax at felbamate daily doses of 3000 or 3600 mg/day in 10 otherwise healthy subjects with epilepsy.

Effects of Felbatol® on Low-Dose Combination Oral Contraceptives:
A group of 24 nonsmoking, healthy white female volunteers established on an oral contraceptive regimen containing 30 µg ethinyl estradiol and 75 µg gestodene for at least 3 months received 2400 mg/day of felbamate from midcycle (day 15) to midcycle (day 14) of two consecutive oral contraceptive cycles. Felbamate treatment resulted in a 42% decrease in the gestodene AUC 0-24, but no clinically relevant effect was observed on the pharmacokinetic parameters of ethinyl estradiol. No volunteer showed hormonal evidence of ovulation, but one volunteer reported intermenstrual bleeding during felbamate treatment.

Drug/Laboratory Test Interactions: There are no known interactions of Felbatol® with commonly used laboratory tests.

Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies were conducted in mice and rats. Mice received felbamate as a feed admixture for 92 weeks at doses of 300, 600, and 1200 mg/kg and rats were also dosed by feed admixture for 104 weeks at doses of 30, 100, and 300 (males) or 10, 30, and 100 (females) mg/kg. The maximum doses in these studies produced steady-state plasma concentrations that were equal to or less than the steady-state plasma concentrations in epileptic patients receiving 3600 mg/day. There was a statistically significant increase in hepatic cell adenomas in high-dose male and female mice and in high-dose female rats. Hepatic hypertrophy was significantly increased in a dose-related manner in mice, primarily males, but also in females. Hepatic hypertrophy was not found in female rats. The relationship between the occurrence of benign hepatocellular adenomas and the finding of liver hypertrophy resulting from liver enzyme induction has not been examined. There was a statistically significant increase in benign interstitial cell tumors of the testes in high-dose male rats receiving felbamate. The relevance of these findings to humans is unknown.

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/m2 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 Salmonella /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/m2 basis.

Pregnancy: The incidence of malformations was not increased compared to control in offspring of rats or rabbits given doses up to 13.9 times (rat) and 4.2 times (rabbit) the human daily dose on a mg/kg basis, or 3 times (rat) and less than 2 times (rabbit) the human daily dose on a mg/m 2 basis. However, in rats, there was a decrease in pup weight and an increase in pup deaths during lactation. The cause for these deaths is not known. The no effect dose for rat pup mortality was 6.9 times the human dose on a mg/kg basis or 1.5 times the human dose on a mg/m 2 basis.

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: The effect of felbamate on labor and delivery in humans is unknown.

Nursing Mothers: Felbamate has been detected in human milk. The effect on the nursing infant is unknown (see Pregnancy section).

Pediatric Use: The safety and effectiveness of Felbatol® in children other than those with Lennox-Gastaut syndrome has not been established.

Geriatric Use: No systematic studies in geriatric patients have been conducted. Clinical studies of Felbatol® did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dosage selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

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