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In 1993, felbamate, a 2-phenyl-1,3-propanediol dicarbamate, became the first AED since 1978 to be approved by the FDA with the brand name Felbatol. Unlike its dicarbamate analog meprobamate, it has minimal anxiolytic and sedative-hypnotic effects in therapeutic doses.
UK-SmPC: not licensed.
FDA-PI: alone or as an adjunct in the treatment of focal seizures in adults and as an adjunct in focal and generalised seizures of Lennox–Gastaut syndrome in children.
Warnings apply: felbamate should only be used in patients who respond inadequately to alternative treatments and whose epilepsy is so severe that a substantial risk of aplastic anaemia and/ or liver failure is deemed acceptable in light of the benefits conferred by its use.
The clinical use of felbamate as an AED practically ended 1 year after its FDA approval, when it became apparent that felbamate is associated with a high incidence of aplastic anaemia and hepatic failure, and also with some fatalities. 2-5 In addition, felbamate is difficult to use because of its narrow therapeutic range and significant drug– drug interactions. Currently, the use of felbamate as an AED is cautiously limited to severe cases of Lennox–Gastaut syndrome, mainly with atonic/astatic seizures, and with bi-monthly follow-up of transaminases and blood cell counts. Possibly, the risk of using felbamate in Lennox–Gastaut syndrome outweighs any benefits, which, even if they occur, are short lived.
However, an expert panel concluded in 2006 that “although felbamate is not indicated as first-line AED, its utility in treating seizures that are refractory to other AEDs is undisputed, as shown by the number of patients who continue to use it. New exposures to felbamate number approximately 3200–4200 patients annually, and it is estimated that over the past 10 years, approximately 35,000 new starts have occurred.”1
The stated numbers in the above quotation cannot be used as evidence of effectiveness because they are influenced by factors other than efficacy (Panayitopoulos, communication).
Adults (14 years of age and older): start felbamate at 1200 mg/day in three or four divided doses while reducing present AEDs by 20% in order to control plasma levels of concurrent phenytoin, valproate, phenobarbital, and carbamazepine and its metabolites. Further reductions of the concomitant AEDs dosage may be necessary to minimise side effects due to drug interactions. Titrate in increments of 1200 mg /day at weekly intervals to a maintenance dose of 3600 mg/day. Higher doses of 5000–6000 mg/day may be used. If the patient is not taking enzyme-inducing AED, then a slower titration is recommended.
Children with Lennox-Gastaut Syndrome (2–14 years of age): start felbamate at 15 mg/kg/day in three or four divided doses while reducing present AEDs by 20% in order to control plasma levels of concurrent phenytoin, valproic acid, phenobarbital, and carbamazepine and its metabolites. Further reductions of the concomitant AEDs dosage may be necessary to minimise side effects due to drug interactions. Titrate in increments of 15 mg/kg/day at weekly intervals to a maintenance dose of 45 mg/kg/day.
Dosing: Three to four-times daily.
TDM: It is mandatory because of its many interactions with other AEDs.
Reference range: 50–110 mg/l (300- 750 μmol/l)
It is because of serious ADRs that felbamate has been downgraded in its license indications and clinical practice.
Frequent and/or important: insomnia, anorexia, nausea, dizziness, headache, vomiting, weight loss, irritability, hyperactivity and behavioural disturbances.
Serious: Aplastic anaemia and hepatic failure which are usually seen during the first 6–12 months of felbamate therapy.
Aplastic anaemia: Aplastic anaemia (pancytopenia in the presence of a bone marrow largely depleted of hematopoietic precursors) occurs with felbamate at an incidence that may be more than a 100 fold greater than that seen in the untreated population (i.e., 2 to 5 per million persons per year). The risk of death in patients with aplastic anaemia generally varies as a function of its severity and aetiology; current estimates of the overall case fatality rate are in the range of 20–30%, but rates as high as 70% have been reported in the past. There are too few felbamate-associated cases, and too little known about them, to provide a reliable estimate of the syndrome’s incidence or its case fatality rate or to identify the factors, if any, that might conceivably be used to predict who is at greater or lesser risk. Most of the cases of aplastic anaemia with felbamate occurred in women over the age of 17 years with a history of idiosyncratic reactions to other AEDs or a history of cytopenia, allergy and underlying autoimmune disease previous to felbamate use.1 It was not reported in children younger than 13 years.
In managing patients on felbamate, it should be borne in mind that the clinical manifestation of aplastic anaemia may not be seen until after a patient has been on this drug from 5–30 weeks. However, the injury to bone marrow stem cells that is held to be ultimately responsible for the anaemia may occur weeks to months earlier. It is not known whether or not the risk of developing aplastic anaemia changes with duration of exposure. Consequently, it is not safe to assume that a patient who has been on felbamate without signs of haematologic abnormality for long periods of time is without risk.
It is not known whether or not the dose of felbamate or concomitant use of AEDs and/or other drugs affects the incidence of aplastic anaemia.
Aplastic anaemia typically develops without premonitory clinical or laboratory signs, the full blown syndrome presenting with signs of infection, bleeding, or anaemia. Accordingly, routine blood testing cannot be reliably used to reduce the incidence of aplastic anaemia, but it will, in some cases, allow the detection of the haematologic changes before the syndrome declares itself clinically.
Hepatic failure: this has mainly occurred in young children. The reported rate of hepatic failure with felbamate in the US has been about 6 cases leading to death or transplant per 75,000 patient years of use. This rate may be an underestimate because of underreporting. Of the cases reported, about 67% resulted in death or liver transplantation, usually within 5 weeks of the onset of signs and symptoms of liver failure. The earliest onset of severe hepatic dysfunction followed subsequently by liver failure was 3 weeks after initiation of felbamate. Some reports described dark urine and nonspecific prodromal symptoms (e.g., anorexia, malaise, and gastrointestinal symptoms) but in other reports it was not clear if any prodromal symptoms preceded the onset of jaundice. It is not known whether or not the risk of developing hepatic failure changes with duration of exposure. It is also not known whether or not the dosage of felbamate or concomitant use of other drugs affects the incidence of hepatic failure.
It has not been proved that periodic serum transaminase testing will prevent serious hepatic injury but it is generally believed that early detection of drug-induced hepatic injury along with immediate withdrawal of the suspect drug enhances the likelihood for recovery. There is no information available that documents how rapidly patients can progress from normal liver function to liver failure, but other drugs known to be hepatotoxins can cause liver failure rapidly (e.g., from normal enzymes to liver failure in 2-4 weeks). Accordingly, monitoring of serum transaminase levels is recommended at baseline and periodically thereafter. Felbamate should be discontinued if either serum alanine or aspartate transaminase levels become increased ≥ 2 times the upper limit of normal, or if clinical signs and symptoms suggest liver failure.
FDA warning: All patients who are currently taking or starting on felbamate for any indication should be monitored for notable changes in behaviour that could indicate the emergence or worsening of suicidal thoughts or behaviour or depression.
Pregnancy: category C. Breastfeeding: unknown but excreted in human breast milk. Interactions with hormonal contraception: Significant reduction of the efficacy of hormonal contraception.
These are unknown and but are likely to be multiple. The most probable mechanisms are (a) potentiation of GABA responses via its interaction with a site on the GABAA receptor that is distinct from the benzodiazepine recognition site and (b) inhibition of N-methyl-D-aspartate (NMDA) receptors via a channel-blocking action and also possibly by distinct effects on channel gating.
Felbamate has weak inhibitory effects on GABA receptor binding and benzodiazepine receptor binding and is devoid of activity at the MK-801 receptor binding site of the NMDA receptor-ionophore complex. However, felbamate does interact as an antagonist at the strychnine-insensitive glycine recognition site of the NMDA receptor-ionophore complex.
Oral bioavailability: 90% Protein binding: 22% to 25% Metabolism: Felbamate is metabolised by the hepatic CYP3A4 system and it is an enzyme inhibitor. Following oral administration, about 40–50% of absorbed dose appears unchanged in urine, and an additional 40% is present as unidentified metabolites and conjugates. About 15% is present as parahydroxyfelbamate, 2-hydroxyfelbamate, and felbamate monocarbamate, none of which have significant antiepileptic activity. Elimination half life: 20 hours (without enzymeinducing drugs).
These are numerous. Felbamate significantly increases the plasma levels of phenytoin, valproate, carbamazepine epoxide (but decreases carbamazepine) and phenobarbital. Conversely, phenytoin, carbamazepine and phenobarbital approximately double the clearance of felbamate and, therefore, their addition causes a significant decrease in the plasma levels of felbamate. Valproate probably does not affect felbamate. Felbamate’s interaction with newer AEDs is not well studied, but the elimination of felbamate is strikingly reduced in co-medication with gabapentin.6
Probably more disadvantages than advantages.
