Felbamate (Page 3 of 6)

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 felbamate 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 felbamate therapy (see PATIENT/PHYSICIAN ACKNOWLEDGMENT FORM section).

Patients should be instructed to read the Medication Guide supplied as required by law when felbamate tablets are 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 felbamate 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 felbamate.

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 felbamate 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 felbamate.

Patients should be advised to follow their physician’s directives for liver function testing both before starting felbamate and at frequent intervals while taking felbamate.

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 felbamate therapy, frequently during therapy, and for a significant period of time after discontinuation of felbamate therapy. While it might appear prudent to perform frequent CBCs in patients continuing on felbamate 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. Felbamate 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 felbamate treatment, felbamate 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 felbamate, 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 felbamate to antiepileptic drugs (AEDs) affects the steady-state plasma concentrations of AEDs. The net effect of these interactions is summarized in Table 2:

*Not administered but an active metabolite of carbamazepine. **No significant effect.

Table 2 Steady-State Plasma Concentrations of Felbamate When Coadministered With Other AEDs

AED Coadministered

AED Concentration

Felbamate Concentration

Phenytoin

Valproate

↔**

Carbamazepine (CBZ) *CBZ epoxide

↓↑

Phenobarbital

Specific Effects of Felbamate on Other Antiepileptic Drugs:
Phenytoin: Felbamate causes an increase in steady-state phenytoin plasma concentrations. In 10 otherwise healthy subjects with epilepsy ingesting phenytoin, the steady-state trough (Cmin ) phenytoin plasma concentration was 17±5 micrograms/mL. The steady-state Cmin increased to 21±5 micrograms/mL when 1200 mg/day of felbamate was coadministered. Increasing the felbamate dose to 1800 mg/day in six of these subjects increased the steady-state phenytoin Cmin to 25±7 micrograms/mL. In order to maintain phenytoin levels, limit adverse experiences, and achieve the felbamate dose of 3600 mg/day, a phenytoin dose reduction of approximately 40% was necessary for eight of these 10 subjects.

In a controlled clinical trial, a 20% reduction of the phenytoin dose at the initiation of felbamate therapy resulted in phenytoin levels comparable to those prior to felbamate administration.

Carbamazepine: Felbamate 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: Felbamate 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 felbamate, 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 felbamate, respectively. This indicates that the protein binding of valproate did not change appreciably with increasing doses of felbamate.

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 Felbamate:
Phenytoin: Phenytoin causes an approximate doubling of the clearance of felbamate at steady-state and, therefore, the addition of phenytoin causes an approximate 45% decrease in the steady-state trough concentrations of felbamate as compared to the same dose of felbamate given as monotherapy.

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

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

The rate and extent of absorption of a 2400 mg dose of felbamate as monotherapy given as tablets was not affected when coadministered with antacids.

Effects of Erythromycin on Felbamate:

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 Felbamate 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.

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