Felbamate (Page 4 of 9)

Valproate

Felbamate causes an increase in steady-state valproate concentrations. In four subjects with epilepsy ingesting valproate, the steady-state trough (C min ) valproate plasma concentration was 63±16 micrograms/mL. The steady-state C min increased to 78±14 micrograms/mL when 1,200 mg/day of felbamate was coadministered. Increasing the felbamate dose to 2,400 mg/day increased the steady-state valproate C min to 96±25 micrograms/mL. Corresponding values for free valproate C min concentrations were 7±3, 9±4, and 11±6 micrograms/mL for 0; 1,200 and 2,400 mg/day felbamate, respectively. The ratios of the AUCs of unbound valproate to the AUCs of the total valproate were 11.1%, 13%, and 11.5%, with coadministration of 0; 1,200 and 2,400 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 (C min ) phenobarbital concentration was 14.2 micrograms/mL. The steady-state C min concentration increased to 17.8 micrograms/mL when 2,400 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 2,400 mg of felbamate a day.

Effects of Antacids on Felbamate

The rate and extent of absorption of a 2,400 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 (1,000 mg/day) for 10 days did not alter the pharmacokinetic parameters of C max , C min , AUC, Cl/kg or T max at felbamate daily doses of 3,000 or 3,600 mg/day in 10 otherwise healthy subjects with epilepsy.

Effects of Felbamate 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 2,400 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 felbamate 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 1,200 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 3,600 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 3,600 mg of felbamate could be exposed to up to 0.72 micrograms of urethane and 1,800 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 2 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 3,600 mg on a mg/kg basis, or up to 3 times the human total daily dose on a mg/m 2 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 felbamate, physicians are advised to recommend that pregnant patients taking felbamate 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 Pregnancysection).

Pediatric Use

The safety and effectiveness of felbamate 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 felbamate 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.

ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact Taro at 1-866-923-4914 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

The most common adverse reactions seen in association with felbamate in adults during monotherapy are anorexia, vomiting, insomnia, nausea, and headache.

The most common adverse reactions seen in association with felbamate in adults during adjunctive therapy are anorexia, vomiting, insomnia, nausea, dizziness, somnolence, and headache.

The most common adverse reactions seen in association with felbamate 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%). 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%).

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