Felbamate toxicity

Leone, A.M. et al. (2007) Evaluation of felbamate and other antiepileptic drug toxicity potential based on hepatic protein covalent binding and gene expression. Chemical Research in Toxicology, 20 (4), 600-608. 

Felbamate (Felbatol) was introduced with the expectation that it would become a major drug in the treatment of epilepsy. Felbamate exhibited few manifestations of serious toxicity in early clinical trials. Soon after its introduction, however, it became apparent that its use was associated with a high incidence of aplastic anemia. Consequently, felbamate is indicated only for patients whose epilepsy is so severe that the risk of aplastic anemia is considered acceptable. 

Phenobarbital Enhances phasic GABAa receptor responses reduces excitatory synaptic responses Nearly complete absorption not significantly bound to plasma proteins peak concentrations in Vi to 4 h no active metabolites tjy2 varies from 75 to 125 h Generalized tonic-clonic seizures, partial seizures, myoclonic seizures, generalized seizures, neonatal seizures, status epilepticus Toxicity Sedation, cognitive issues, ataxia, hyperactivity Interactions Valproate, carbamazepine, felbamate, phenytoin, cyclosporine, felodipine, lamotrigine, nifedipine, nimodipine, steroids, theophylline, verapamil, others... 

Phenobarbital Phenytoin Primidone Felbamate Lamotrigine Tiagabide Topiramate Valproate Zonisamide Clobazam Clonazepam Diazepam usually compensated by the effect of the added drug risk of toxicity when interfering drug is discontinued drug... 

Felbamate Clonazepam Diazepam Phenobarbital Phenytoin Valproate High risk of toxicity with phenytoin, phenobarbital, and valproate Inhibition of metabolism of the affected drug... 

Felbamate Carbamazepine Risk of toxicity due to concomitant rise in carbamazepine epoxide concentration and pharmacodynamic interaction Induction of carbamazepine metabolism, possible inhibition of epoxide hydrolase and pharmacodynamic interaction... 

Of 34 cases of aplastic anemia (mean age 41 years, mean time of felbamate exposure 154 days), 20 occurred in combination with other compounds implicated as a possible cause of aplastic anemia and 5 occurred concurrently with viral infections (7). Although 5 patients were taking felbamate monotherapy, 13 of the 34 suffered from autoimmune disease, and 1 was receiving cytostatic therapy. Past allergic or toxic reactions to other anticonvulsants were reported by 65% of the patients and blood dyscrasias by 45%, while 32% had serological evidence of a previous immune disorder. Eight of nine patients tested had experienced at least one episode of aplastic anemia associated with HLA antigens. 

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. 

Because felbamate-induced aplastic anemia might be linked to the formation of atropaldehyde, a urine screening test has been developed that indirectly assesses the formation of this toxic metabolite (8). The risk of serious toxicity may also be related to HLA status, and HLA typing is being performed in patients entered in the manufacturer s felbamate registry. The potential value of these tests in reducing the risk of toxicity remains to be established. 

Of 23 reported cases of hepatic failure, only 10 (includ-ing 5 who died) were considered to be probably related to the drug (7,14). There have also been 20 cases of hepatitis in which no deaths occurred in five of these a relation to felbamate was unlikely. Overall the incidence of fatal liver toxicity is estimated at 1 per 26 000-34 000. A careful history of past hepatic toxicity with other drugs should be taken and liver function tests are recommended before starting felbamate. Patients should have hepatic function monitored regularly and should be alerted to the signs and symptoms of hepato-toxicity. 

Pellock J. Progress in felbamate research toxic metabolite test and HLA typing. Epilepsia 1999 40(Suppl 2) 251. 

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. 

Table IV-1 -3 summarizes the mechanisms, indications for use, and potential toxic effects of some i newer anticonvulsants. Those listed are felbamate, gabapentin, lamotrigine, tiagabine, topiramate, and j...

Despite this, felbamate continues to be used in many patients, although not as a first-line treatment. These toxicity effects may be attributed to the formation of toxic metabolites (66). Although felbamate use is now uncommon, it is used for severe refractory seizures, either partial, myoclonic, or atonic, or in Lennox-Gastaut syndrome. 

Any changes in the pharmacokinetics of oxcarbazepine brought about by other antiepileptics seem to be of minimal clinical relevance. However, the clinical relevance of the increase in the active metabolite monohydroxyoxcarbazepine with lamotrigine requires further study. In addition, there is the theoretical risk that monohydroxyoxcarbazepine levels might rise to toxic levels if carbamazepine or phenytoin were withdrawn. For mention that there may be an increase in adverse effects if oxcarbazepine is used with felbamate, see Oxcarbazepine +Felbamate , p.545. 

Felbamate causes a moderate increase in plasma phenobarbital levels (including those derived from primidone), which has resulted in phenobarbital toxicity. 

Felbamate can raise valproate serum levels causing toxicity. Valproate may slightly decrease the clearance of felbamate. 

The average steady-state valproate serum levels in 7 epileptics were raised by 28%, from 66.9 to 85.4 micrograms/mL, by felbamate 1.2 g daily, and by 54%, from 66.9 to 103 micrograms/mL by felbamate 2.4 g daily. The AUC of valproate was raised by 28% and 54% by felbamate 1.2 and 2.4 g, respectively. Valproate clearance was correspondingly reduced by felbamate. Similar effects were seen in another study.It was suggested that in children the interaction may be more marked. Many of the patients experienced nausea. Other toxic effects included lethargy, drowsiness, headaches, cognitive disturbances and low platelet counts. ... 

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