Felbamate


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Brian Hanrahan


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Updated:
6/7/2019 7:04:59 PM

Indications

Felbamate is an anti-epileptic drug (AED) that was approved by the Food and Drug Administration (FDA) in 1993 for the management of focal seizures and Lennox-Gastaut syndrome. Several small class III studies have suggested felbamate may be an effective treatment for absence seizures, juvenile myoclonic epilepsy, and infantile spasms.[1]

Felbamate's approval for focal seizures had its basis in trails which showed it was an effective monotherapy and add-on therapy to phenytoin and carbamazepine for patients with uncontrolled focal epilepsy[2][3]

A major multicenter trial in children with Lennox-Gastaut syndrome (LGS) led its approval for LGS.[4] This double-blinded, randomized control study found that treatment with felbamate led to an increased quality of life and a statistically significant reduction in the frequency of the various types of seizures associated with LGS. It seemed particularly effective in the treatment of atonic seizures. Being that atonic seizures are particularly debilitating in this patient population, the use of felbamate was anticipated to be commonplace in the management of LGS at the time of its FDA approval.

Roughly 4000 patients had exposure to felbamate prior to approval.[5] At its peak, over 100000 people had exposure to the medication. Unfortunately, post-approval use revealed a previously unknown risk of life-threatening adverse events (aplastic anemia, hepatic failure) not seen in pre-approval studies. This lead to a dramatic reduction in its use. Currently, it should be a consideration for patients with drug-resistant epilepsy where the benefit of seizure control outweighs the risk of severe idiosyncratic reactions.

Mechanism of Action

The mechanism of action of felbamate (2-phenyl-1,3-propanediol dicarbamate) is not well understood, but researchers believe there may be several. The primary antiepileptic activity is thought to be the modulation of the N-Methyl--aspartate (NMDA) receptor, reducing glutamatergic transmission.[5]  Other actions include weak inhibition GABA-receptor binding and inhibition of voltage-gated sodium channels as well as calcium channels.

Administration

Felbamate is available as conventional tablets and as an oral suspension. Available tablet formulations are in 400mg and 600mg doses. The oral suspension is available in a 600mg/5 ml suspension.

Felbamate has good bioavailability (greater than 90%) via the GI tract and reaches peak plasma concentration in 3 to 5 hours. It is minimally bound to serum protein (20 to 25%) and is primarily eliminated by renal excretion. The half-life of the drug is usually 14 to 23 hours, and serum concentrations are linearly related to the dose.[6] Interestingly, its clearance is 40 to 50% higher in children than adults.

If used as a monotherapy for partial seizures in adults, the recommendation is that felbamate is initiated at 1200mg/day in 3 to 4 divided doses. Dosing can be increased by 600 mg increments every two weeks up to 3600mg/day. If being added as an adjunctive therapy titration can be more aggressive; 1200 mg increments every week up to 3600mg/day.[7] Adolescents over 14 years of age receive the same dose as adults.

Lennox-Gastaut syndrome is the most common reason for using this medication in the pediatric population. Children (2 to 14 years of age) should initiate therapy at an initial dose of 15mg/kg/day in 3 to 4 divided doses. Titration should be 15mg/kg/day per week up to  45 mg/kg/day or 3600 mg/day, whichever is less.[7]

Felbamate should be used cautiously in patients with impaired renal function; with a 50% reduction in both initial and maintenance doses.

Felbamate has several drug interactions with commonly used AEDs. Enzyme-inducing AEDs, such as carbamazepine and phenytoin will increase the clearance of felbamate. Gabapentin and valproic acid will decrease felbamate clearance. Lastly, felbamate can increase levels of phenytoin, phenobarbital, and valproic acid and reduce levels of carbamazepine.[6]

Adverse Effects

Initial studies showed that felbamate carried relatively little systemic toxicity and less CNS depression when compared to the older generation AEDs. Common side effects include drowsiness, insomnia, anorexia, nausea, dizziness, and headache.[8] Anorexia and other side effects are more likely to occur with higher serum levels.[9]

A rapid titration schedule can increase the risk of neurologic side effects. Decreasing the titration rate may reduce this risk. Somnolence is more likely to occur in the first 4 weeks of treatment and decreases with continued therapy.

Contraindications

Felbamate should not be given to patients with a history of hepatic dysfunction or any form of blood dyscrasia. Patients with known hypersensitivity to felbamate or other carbamates should avoid felbamate.

Monitoring

The target serum concentrations for felbamate is between 30 to 60 mg/L[6]

Due to the increased risk of idiosyncratic reactions in the first 6 to 12 months after initiating therapy, clinical and laboratory monitoring is essential; this includes a comprehensive metabolic panel, blood counts and a hepatic function panel. Serum studies should be completed before, during and after completion of felbamate therapy. Blood work can be performed biweekly or less for the first 3 months of therapy and then every 6 to 12 months thereafter.

Toxicity

Felbamate use is limited by severe, life-threatening, and idiosyncratic reactions (aplastic anemia and hepatic failure). Both reactions can carry a mortality rate above 30%. These reactions are usually seen during the first 6 to 12 months of therapy but can occur later. Aplastic anemia can lead to symptoms of bleeding, bruising, and pale skin color. The first symptoms of hepatic dysfunction include lethargy, nausea, and vomiting. If hepatic enzymes (AST, ALT) increase to two or more times the upper limit of normal felbamate should be discontinued.

Aplastic anemia: There were 34 reported cases of felbamate-related aplastic anemia in the first six years of FDA approval.[5] None of these cases occurred in children below the age of 13. Patients who developed aplastic anemia tended to be older (above 17 years of age) and have a history of AED allergies/toxicity, cytopenia and/or immune disease.[5] Researchers estimated that patients on felbamate were at a more than 100 fold greater risk for developing aplastic anemia (27 to 207/million) than the general population (2 to 2.5/million).[10] There is no known way to reduce the risk of occurrence. Early signs of aplastic anemia include declining reticulocyte counts and thrombocytopenia. Patients with any symptoms of easy bruising, bleeding and/or lethargy should seek immediate medical care.

Hepatic Failure: In the first six years after FDA approval, there were 18 cases of hepatic failure in patients taking felbamate[5] The risk for developing hepatotoxicity and liver failure is higher than the general population, approximately 1 in 30000, but less than the risk of aplastic anemia. Cases have occurred in children as young as 5 years old. The mean time of hepatic failure after the initiation of therapy ranged between 25 to 939 days.[5] Patients with symptoms of jaundice, fatigue and/or GI complaints should seek immediate medical care.

Enhancing Healthcare Team Outcomes

The monitoring for idiosyncratic reactions from felbamate falls upon the responsibilities of neurologists and primary care physicians. The pharmacist should thoroughly educate the patient and caregiver about medication compliance, and the need for regular follow up. Because the drug has correlations with severe adverse reactions, close monitoring is vital; this requires interprofessional communication between the two specialties to ensure no issues arise. As noted above, clinical and laboratory monitoring is essential following drug initiation, though may be spaced out after the first 3 months of therapy.  If there is a concern for aplastic anemia or hepatic dysfunction in any patients on felbamate they should be evaluated in an emergency care setting.


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Felbamate - Questions

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Which of the following antiseizure medications is most likely to cause aplastic anemia?



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A 3-year-old boy with developmental delay and multiple seizure types, including absence, generalized tonic-clonic, tonic, and atonic seizures presents to the clinic. Prior EEGs have demonstrated 2 Hz spike-and-slow wave discharges as well as clinical seizures accompanied by generalized paroxysmal fast activity. He continues to have multiple seizures daily. He has continued seizures despite treatment with clobazam, rufinamide, and cannabidiol. What additional medication approved for this indication may be considered next?



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Felbamate - References

References

French J,Smith M,Faught E,Brown L, Practice advisory: The use of felbamate in the treatment of patients with intractable epilepsy: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology. 1999 May 12;     [PubMed]
Efficacy of felbamate in childhood epileptic encephalopathy (Lennox-Gastaut syndrome). The New England journal of medicine. 1993 Jan 7;     [PubMed]
Harden CL,Trifiletti R,Kutt H, Felbamate levels in patients with epilepsy. Epilepsia. 1996 Mar;     [PubMed]
Heyman E,Levin N,Lahat E,Epstein O,Gandelman-Marton R, Efficacy and safety of felbamate in children with refractory epilepsy. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2014 Nov;     [PubMed]
Johannessen SI,Battino D,Berry DJ,Bialer M,Krämer G,Tomson T,Patsalos PN, Therapeutic drug monitoring of the newer antiepileptic drugs. Therapeutic drug monitoring. 2003 Jun;     [PubMed]
Leppik IE,Dreifuss FE,Pledger GW,Graves NM,Santilli N,Drury I,Tsay JY,Jacobs MP,Bertram E,Cereghino JJ, Felbamate for partial seizures: results of a controlled clinical trial. Neurology. 1991 Nov;     [PubMed]
Pellock JM, Felbamate. Epilepsia. 1999;     [PubMed]
Pellock JM,Brodie MJ, Felbamate: 1997 update. Epilepsia. 1997 Dec;     [PubMed]
Shi LL,Dong J,Ni H,Geng J,Wu T, Felbamate as an add-on therapy for refractory partial epilepsy. The Cochrane database of systematic reviews. 2017 Jul 18;     [PubMed]
Thakkar K,Billa G,Rane J,Chudasama H,Goswami S,Shah R, The rise and fall of felbamate as a treatment for partial epilepsy--aplastic anemia and hepatic failure to blame? Expert review of neurotherapeutics. 2015;     [PubMed]

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