The rise and fall of felbamate as a treatment for partial epilepsy – aplastic anemia and hepatic failure to blame?

Abstract

Felbamate has been approved for refractory partial seizures since the early nineties. Due to safety concerns regarding its use, namely, in aplastic anemia and hepatic failure, felbamate’s use has been restricted and a ‘Black Box’ warning has been inserted. Nonetheless, it is a useful drug in refractory cases of partial epilepsy. There are certain precautions which can prevent and minimize the serious idiosyncratic reactions associated with felbamate, thereby providing an option in refractory cases where no other drug works.

KEYWORDS:

• partial seizure
• Lennox-Gastaut syndrome
• glutathione
• N-acetyl cysteine

Epilepsy

Epilepsy is a chronic central nervous system disorder affecting approximately 50 million people worldwide, of which around 80% are from developing countries.[1] Out of all the cases of epilepsy, as many as 30–40% can be refractory to conventional therapy.[2–6] Cases of epilepsy, especially refractory epilepsy, lead to significant adverse physical, psychological, social and economic implications.[1,7,8]

History of felbamate

Felbamate was first synthesized in the 1950s but its anti-epileptic activity was discovered in the 1980s. It was approved by the US FDA in 1993 for partial seizures (with or without secondary generalization) in adults and for Lennox-Gastaut syndrome.[4,9] But its withdrawal was recommended in August 1994 due to cases of aplastic anemia. Restricted use of felbamate, only in refractory cases, was advised and the drug came with a ‘Black Box’ warning of aplastic anemia and Hepatic failure.[10,11] The first generic version of felbamate was approved in the USA in the year 2011.[12] With the possibility of more pharmaceutical companies introducing generic felbamate, it is worthwhile to have a look at the utility of this drug.

Felbamate is a broad spectrum anti-epileptic drug (AED) particularly effective in refractory partial seizures (with or without generalization). Years of clinical experience and research have brought to light many facts about the safety profile of felbamate not know earlier.

Felbamate—label information [13]:

Felbamate is available as 400 and 600 mg tablets and as a 600 mg/5 ml suspension for oral administration. The recommended dose is:

Adults (for seizures): starting dose 1200 mg/day divided every 6–8 h,. followed by increments of 600 mg every 2 weeks to the maximum of 3600 mg/ day.

Pediatric

For Lennox-Gastaut as adjunctive therapy: 2–14 years – initial dose is 15 mg/kg/day per oral divided every 6–8 h. May be increased by 15 mg/kg/day every week, to the maximum of 45 mg/kg/day.

For seizures: it is not approved for use below the age of 14 years due to lack of supporting data. Above the age of 14 years the dose is same as adults.

Pharmacokinetics

Felbamate is well-absorbed orally. There is no effect of food on its absorption form the tablet form. It has about 22–25% albumin binding. It has a terminal half-life of 20–23 h, which is unaltered after multiple doses. About 90% of felbamate is excreted by the kidneys. Therefore, the individuals with impaired renal function have a 40–50% reduction in total body clearance and 9–15 h prolongation of half-life.

Pharmacodymanics

Its exact mechanism of action is unknown. Felbamate has shown weak inhibitory effects on GABA-receptor binding and benzodiazepine receptor binding. It is also an antagonist at the strychnine-insensitive glycine recognition site of the NMDA receptor–ionophore complex.

Drug interactions

Felbamate has significant interactions with other anti-epileptic drugs. Appropriate dose modifications are necessary during concomitant use. For example, it is recommended to decrease dose of carbamazepine, phenytoin, phenobarbital or valproic acid by 20% when initiating felbamate. It is advisable to refer to the felbamate labeling information and tools like ‘Medscape interaction checker’ for detailed interaction profile prior to starting treatment.

Safety profile of felbamate

The most common adverse effects of felbamate are anorexia, headache, insomnia, nausea, dizziness and gait disturbance; these are reversible after discontinuation or dose reduction.[2,3] Two rare but serious idiosyncratic adverse effects of felbamate observed during post-marketing trials are aplastic anemia and hepatic toxicity. Idiosyncratic drug reactions (IDR) are a specific type of drug toxicity characterized by their delayed onset, low incidence and reactive metabolite formation with little, if any, correlation between pharmacokinetics or pharmacodynamics and the toxicological outcome.[4]

Aplastic anemia can be caused by a variety of factors like drugs, chemicals, viral infections etc. In the general population, this condition affects 2–5 people per million.[14] However, the incidence of bone marrow aplasia among patients taking felbamate was estimated to be many times greater than the expected rate.[15] Nonetheless, studies have revealed that a significant proportion of aplastic anemia cases may be prevented by proper screening, as most patients with felbamate induced bone marrow failure had either pre-existing blood dyscrasias or pre-existing immune disorders.[16] Studies have shown that out of all the patients who developed aplastic anemia while on felbamate, 42% had a past history of cytopenia, 52% had a history of allergy or significant toxicity to another AED and 33% had evidence of an underlying autoimmune disease.[2] Therefore, before staring felbamate prior screening for the above conditions is mandatory.

The risk of fatal hepatotoxicity from felbamate is estimated to a range 1:7000–1:22,000.[3] This is similar to older anti-epileptic drugs and it does not significantly differ from that of a commonly used anti-epileptic drug – valproate.[16]

A study has shown that felbamate undergoes bioactivation to a highly reactive electrophilic metabolite that is capable of forming covalent protein adducts in vivo.[4] Research has shown that 2-phenylpropenal, a reactive metabolite of felbamate, is a very potent immunogen and is possibly responsible for the felbamate-induced hepatotoxicity and aplastic anemia.[14] Glutathione should act as a protecting mechanism by binding the reactive compound before it can cause damage. Most felbamate patients will maintain sufficient levels of glutathione to detoxify the reactive metabolite of felbamate.[4] As a corollary, it would be prudent to test a prospective patient’s blood for adequate glutathione levels before starting treatment with felbamate. Such patients could also be given glutathione or low doses of oral N-acetylcysteine (NAC) while on treatment with felbamate.[17–20]

The signs of aplastic anemia and liver failure are normally seen in the first 6–12 months of therapy. Thus, frequent monitoring, perhaps, on a weekly basis for the first 6 months and then bi-weekly for 6 months and so on, is required during this period. Thus, monitoring during felbamate therapy would resemble that during clozapine therapy.[21]

Given its usefulness in refractory cases of partial seizures, felbamate is a very important member of the armamentarium of AEDs. Safety concerns do exist, but they can be avoided/ minimized with requisite measures and precautions as discussed above.[2]

Summary and recommendations

• Evaluation of the risk-benefit ratio and proper patient selection are ‘sine qua non’ before staring felbamate therapy.

• A comprehensive history and medical evaluation including liver function tests, blood cell counts and tests to screen for auto-immune diseases should be part of the pre-treatment evaluation.

• After initiation of treatment, monitoring through clinical examination for signs of toxicity, evaluation of seizure reduction and frequent laboratory visits are necessary.

• Testing patients for adequate blood glutathione levels and/or supplementation with glutathione or NAC should also be explored.

Rajen Shah

Raptim Research, Mahape, Navi Mumbai 400703, India

Sailendra Goswami

Medical writing department, Raptim Research, Mahape, Navi Mumbai 400703, India

Hiren Chudasama

Clinical department, Raptim Research, Mahape, Navi Mumbai, 400703, India

Jay Rane

Raptim Research, Mahape, Navi Mumbai 400703, India

Gauri Billa

NMMC, Navi Mumbai, India

Financial & competing interests disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Acknowledgements

We thank the Department of Medical Writing and Clinical trials of Raptim Research for their support.