Felbamate dosing

A pilot study in 4 patients noted that felbamate increased plasma phenytoin levels. Therefore, in a further study the phenytoin dose was automatically reduced by 20% when felbamate was given. Of 5 patients, one needed a slight increase in phenytoin dosage, whereas 2 others needed a further reduction in their phenytoin dosage. In a later full report of this study, it was noted that phenytoin dosage decreases of 10 to 30% were required to maintain stable levels. Another study in epileptic patients found that felbamate 1.2 or 1.8 g daily increased the maximum plasma phenytoin levels by 31% and 69%, respectively. Higher felbamate doses necessitated phenytoin dose reductions of 20 to 40%. ... 

Felbamate is currently reserved for patients who are refractory to other drugs after careful consideration of the benefitrharm balance. In some countries the indication has been restricted to refractory Lennox-Gastaut syndrome. It is wise to avoid felbamate in patients with previous blood dyscrasias or autoimmune disorders, especially lupus erythematosus. Before they start to take it, patients should be informed about the potential risks and early symptoms of bone-marrow toxicity, such as bruisability, petechiae, fever of unknown origin, weakness, and fatigue. Hematology tests should be performed at baseline and during treatment, and dose escalation should be slow. 

Richens A, Banfield CR, Salfi M, Nomeir A, Lin CC, Jensen P, Affrime MB, Glue P. Single and multiple dose pharmacokinetics of felbamate in the elderly. Br J Qin Pharmacol 1997 44(2) 129-34. 

Sachdeo R, Wagner ML, Sachdeo S, Shumaker RC, Lyness WH, Rosenberg A, Ward D, Perhach JL. Coadministration of phenytoin and felbamate evidence of additional phenytoin dose-reduction requirements based on pharmacokinetics and tolerabihty with increasing doses of felbamate. Epilepsia 1999 40(8) 1122-8. 

Felbamate. Felbamate is an adjuvant anticonvulsant, containing the warning that its use is associated with a marked increase in the incidence of aplastic anemia and that patients being started on the drug should have liver function tests performed before therapy is initiated. Animal studies have revealed a statistically significant increase in hepatic cell adenomas in high dose studies (18). It is postulated that this cancer was induced by toxic by-products urethane and methyl carbamate. Felbamate is not recommended as first-line therapy and is indicated for those patients who respond inadequately to alternative treatments and whose epilepsy is so severe that a substantial risk of aplastic anemia or liver failure is deemed acceptable in light of the benefits provided by its use. 

Pharmacokinetics. Felbamate is rapidly and well absorbed. The absorption is unaffected by food or antacids. About 40% to 50% of a dose of felbamate is metabolized by hydroxylation and conjngation pathways in the liver, with the remainder being excreted imchanged in the mine. Felbamate displays linear pharmacokinetics. ... 

Drug Interactions. Felbamate inhibits the clearance and increases the serum concentration of phenytoin, valproic acid, and phenobar-bital. The concentration of carbamazepine decreases in patients on concmrent therapy with felbamate secondary to enzyme induction however, the concentration of the 10,11 -epoxide metabolite increases. It is recommended that the dose of phenytoin, carbamazepine, and valproic acid be decreased by about 30% when felbamate is added. Felbamate does not appear to interact with either gabapentin or 1am-otrigine. Phenytoin and carbamazepine are enzyme inducers and have been shown to increase the clearance of felbamate. Interactions with warfarin also have been reported. ... 

Dosing and Administration. A therapeutic range for felbamate has not been established. The drug is dosed to clinical response. If felbamate is used as monotherapy, the dose is initiated at 1200 mg/day (15 mg/kg in children) and then is increased by 600 mg every 2 weeks up to a maximum dose of 3600 mg (45 mg/kg in children). 

Drug Interactions. Phenobarbital is a potent enzyme inducer and may increase the elimination of any drug metabolized by CYP450-or UGT-mediated metabolism. Valproic acid, phenytoin, felbamate, cimetidine, and chloramphenicol inhibit phenobarbital metabolism, necessitating a decrease in dose. Ethanol increases the metabolism of phenobarbital. ... 

Myoclonic syndromes Myoclonic seizure syndromes are usually treated with valproic acid. Clonazepam can be effective, but the high doses required cause drowsiness. Lamotrigine is also reported to be effective in myoclonic syndromes in children. Felbamate has been used adjunctively with the primary drugs but has hematotoxic and hepatotoxic potential. 

This interaction is established, but its clinical importance is uncertain because the modest fall in serum carbamazepine levels would seem to be offset by the rise in levels of its metabolite, carbamazepine-10,11-epoxide, which also has anticonvulsant activity. However, monitor carbamazepine levels carefully, reducing the dose as necessary, and be alert for any changes in the anticonvulsant control. The importance of the increased felbamate clearance is uncertain. More study is needed. 

The activity of mesuximide is thought to be due to its active metabolite, A-desmethylmesuximide. Therefore, it has been suggested that levels of this metabolite should also be monitored. Anticipate the need to reduce the dose of mesuximide if felbamate is added. Other antiepileptics such as phenobarbital and phenytoin may also increase levels of A-desmethylm-esuximide. ... 

An established interaction. If felbamate is added to established treatment with phenobarbital or primidone, particularly in patients already taking substmtial doses, monitor well for any evidence of increased adverse effects (drowsiness, lethargy, anorexia, ataxia) and reduce the dosages of the phenobarbital or primidone if necessary. 

Studies in children and adults have found that phenytoin increased the clearance of felbamate by about 40%, - and decreased maximum fel-bamate levels by 56 to 60%, when compared with patients receiving felbamate alone/ Another report suggested that this effect was dose-dependent/... 

Delgado MR. Changes in valproic acid concentrations and dose/level ratios by felbamate coadministration in children. Ann Neurol (1994) 36,538. 

Saano V, Glue P, Banfield CR, Reidenberg P, Colucci RD, Meehan JW, Haring P, Radwanski E, Nomeir A, Lin C-C, Jensen PK, Affrime MB. Effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive. Clin Pharmacol Ther 99S) 58, 523-31. 

Urinary tract Four pediatric patients were reported to have urolithiasis, which was attributed to felbamate use. All patients were taking doses greater than 65 mg/d. Further examination of the stones showed that three of the four stones were radiolucent on X-ray and were pure felbamate stones the fourth stone had mixed composition containing felbamate and calcium phosphate. Three of the four patients went on to develop recurrent stones [66 ]. 

Ghousheh Al, Groth TW, Fryjoff KM, Wille DF, Mandel NS, Roddy JT, et al. Urolithiasis in patients on high dose felbamate. J Urol May 2013 189(5) 1865-9. 

---