Felbamate

Benefit to harm balance

The Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society [ ] has reviewed efficacy and safety data to establish recommendations for felbamate use in the light of the risk of aplastic anemia and liver toxicity [ , ]. Felbamate was considered to have a favorable benefit to harm balance in patients with Lennox–Gastaut syndrome aged over 4 years who were unresponsive to primary anticonvulsants, in patients over 18 years of age with intractable partial seizures that have not responded to standard antiepileptic drugs in therapeutic concentrations, and in patients who are already taking felbamate and benefit from it for more than 18 months. There are conditions in which the benefit to harm balance is unclear, but for which use may be appropriate under certain circumstances, depending on the nature and severity of the seizure disorder; these include children with intractable partial epilepsy, patients with other generalized epilepsies unresponsive to primary agents, patients who have unacceptable sedative or cognitive effects with traditional antiepileptic drugs, and patients under 4 years with Lennox–Gastaut syndrome unresponsive to other antiepileptic drugs.

Assessment of its benefit to harm balance does not support the use of felbamate in new-onset epilepsy in children and adults, in patients who have significant prior hematological adverse events, in patients in whom follow-up and compliance will not allow careful monitoring, and in patients who are unable to discuss benefits and harms and for whom no parent or legal guardian is available to provide consent.

In patients taking felbamate, the benefit to harm balance should be constantly assessed. Patients should be educated about early signs of liver and bone-marrow toxicity, and about the manufacturers’ recommendations. Laboratory monitoring has not been proven efficacious, but the manufacturer and the FDA suggest liver function and hematology testing at baseline and every 1–2 weeks for the first year. After that, the risk of aplastic anemia falls and the need for regular testing is less clear. A registry has been set up by the manufacturers to collect further safety data in patients started on the drug.

An open trial with 3-year follow up has been conducted in 36 patients with catastrophic childhood onset epilepsy [ ]. The overall responder rate (more than a 50% reduction in seizure frequency) fell with time: 69% at 3 months, 66% at 6 months, 47% at 1 year, and 41% at the end of the study. The most frequent adverse reactions were anorexia, weight loss, urinary retention, somnolence, nervousness, and insomnia. Other reported adverse reactions include skin reactions (including Stevens–Johnson syndrome), various blood dyscrasias, hepatotoxicity, and systemic lupus erythematosus [ ].

Nervous system

Central nervous system adverse reactions are common with felbamate, and consist mainly of insomnia, headache, impaired concentration, ataxia, dizziness, somnolence, behavioral disturbances, and mood changes. Movement disorders, psychosis, increased seizures, status epilepticus, and withdrawal seizures are less common [ , ]. The incidence of these effects is increased in the elderly, possibly owing to reduced drug clearance [ ], whereas patients with mental retardation may be more prone to behavioral disorders [ ].

Hematologic

Aplastic anemia affects 1 in 5000, or even 1 in 2000 patients [ ], although a more recent estimate is 27–209 per million, compared with 2–2.5 per million in the general population [ ]. The underlying mechanism is unknown, although a deficiency in free radical scavenging activity may play a role [ ], and a reactive metabolite, 2-phenylpropenal, has been implicated [ ].

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 [ ]. Although five patients were taking felbamate monotherapy, 13 of the 34 suffered from autoimmune disease, and one 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 benefit to harm 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 [ ]. 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.