OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Felbamate	25451-15-4	C11-H14-N2-O4

ANNOTATED BIBLIOGRAPHY

References updated: 29 January 2018

• Zimmerman HJ. Anticonvulsants. In, Zimmerman, HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999: pp. 498-516.

  (Expert review of anticonvulsants and liver injury published in 1999, mentions that there have been at least 14 cases of fulminant hepatic failure linked to felbamate as well as cases of aplastic anemia).
• Pirmohamed M, Leeder SJ. Anticonvulsant agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013: pp 423-41.

  (Review of anticonvulsant induced liver injury published in 2007, mentions that felbamate has been associated with hepatic failure estimated to occur in one per 26,000-34,000 exposures; among 7 cases described, 2 were in children, 6 in women and time to onset ranged from 25 to 181 days).
• McNamara JO. Pharmacology of the epilepsies. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 583-608.

  (Textbook of pharmacology and therapeutics).
• Nightingale SL. From the FDA. Recommendation to immediately withdraw patients from treatment with felbamate. JAMA 1994; 272: 995.

  (FDA recommendation to immediately withdraw patients from felbamate based upon 20 reports of aplastic anemia [3 fatal]; in follow up, 34 cases of aplastic anemia [13 deaths] and 23 of acute liver failure [5 deaths] were reported: ages of 2 to 28 years, onset after 14 to 257 days).
• Brodie MJ, Pellock JM. Taming the brain storms: felbamate updated. Lancet 1995; 346(8980): 918-9. [PubMed: 7564721]

  (Editorial summarizing the history of the release, marketing, rapid wide scale initial use, and eventual withdrawal and restriction of felbamate; mentions 32 cases of aplastic anemia and 19 cases of liver injury, 5 of which were fatal).
• Wallace SJ. A comparative review of the adverse effects of anticonvulsants in children with epilepsy. Drug Saf 1996; 15: 378-93. [PubMed: 8968693]

  (Systematic review; ALT elevations occur in 4% of children on phenytoin, 6% on valproate, and 1% on carbamazepine, but not with gabapentin or phenobarbital; skin rashes, Stevens- Johnson syndrome and hepatic failure reported with felbamate).
• O'Neil MG, Perdun CS, Wilson MB, McGown ST, Patel S. Felbamate-associated fatal acute hepatic necrosis. Neurology 1996; 46: 1457-9. [PubMed: 8628501]

  (61 year old woman developed nausea and then jaundice 3-4 weeks after starting felbamate [bilirubin 2.8 rising to 18.7 mg/dL, AST 601 U/L, GGT 987 U/L, eosinophils 12%], with subsequent liver failure leading to death; autopsy showed massive collapse. Meanwhile 36 cases reported to FDA, including 5 deaths).
• Li LM, Nashef L, Moriarty J, Duncan JS, Sander JW. Felbamate as add-on therapy. Eur Neurol 1996; 36: 146-8. [PubMed: 8738944]

  (Among 111 patients who had felbamate added to stable anticonvulsant regimen, nausea, headache, drowsiness and dizziness were common; no case of liver injury).
• Pellock JM, Brodie MJ. Felbamate: 1997 update. Epilepsia. 1997; 38: 1261-4. [PubMed: 9578519]

  (Commentary about felbamate and its association with aplastic anemia and hepatotoxicity; recommended limitation in its use).
• Pellock JM. Felbamate in epilepsy therapy: evaluating the risks. Drug Saf 1999; 21: 225-39. [PubMed: 10487399]

  (Review of toxicity and uses of felbamate which is “too valuable an anticonvulsant to be relegated to the therapeutic scrap heap.” Seven cases of hepatic failure that were considered “likely”, including 6 women, with latency of 1-6 months, usually with other agents; an epoxide metabolite is potentially responsible for hepatotoxicity; most felbamate is excreted unmetabolized).
• Dieckhaus CM, Thompson CD, Roller SG, Macdonald TL. Mechanisms of idiosyncratic drug reactions: the case of felbamate. Chem Biol Interact 2002; 142: 99-117. [PubMed: 12399158]

  (Detailed analysis of metabolism of felbamate and studies in vitro and in vivo suggesting an idiosyncratic metabolic pathway and bioactivation of felbamate to a highly reactive electrophilic metabolite, possibly atropaldehyde is responsible for its idiosyncratic toxicity).
• Björnsson E. Hepatotoxicity associated with antiepileptic drugs. Acta Neurol Scan 2008; 118: 281-90. [PubMed: 18341684]

  (Review of all anticonvulsants; indicates that felbamate has been associated with hepatotoxicity and cases of aplastic anemia, such that it is now rarely used).
• Toledano R, Gil-Nagel A. Adverse effects of antiepileptic drugs. Semin Neurol 2008; 28: 317-27. [PubMed: 18777478]

  (Review of adverse reactions to anticonvulsants, including hepatotoxicity; highlights felbamate).
• Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]

  (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury including 11 due to anticonvulsants [phenytoin 8, valproate 2, carbamazepine 3], but none were attributed to felbamate).
• Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol 2010; 105: 2396-404. [PubMed: 20648003]

  (313 cases of drug induced liver injury were seen over a 12 year period at a large hospital in Bangalore, India; 11% were attributed to anticonvulsants, but none were attributed to felbamate).
• Heyman E, Levin N, Lahat E, Epstein O, Gandelman-Marton R. Efficacy and safety of felbamate in children with refractory epilepsy. Eur J Paediatr Neurol 2014; 18: 658-62. [PubMed: 24906615]

  (Among 50 children with refractory epilepsy treated with felbamate for an average of one year, seizure frequency decreased by half in 26 [58%] and, while 2 patients developed abnormal liver tests, none developed hepatic failure).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 40 [4.5%] were due to anticonvulsants, but none were attributed to felbamate).
• Shah YD, Singh K, Friedman D, Devinsky O, Kothare SV. Evaluating the safety and efficacy of felbamate in the context of a black box warning: A single center experience. Epilepsy Behav 2016; 56:50-3. [PubMed: 26828692]

  (Among 103 patients with refractory epilepsy treated with felbamate for 1 month to 20 years, adverse events included insomnia, nausea, anorexia, weight loss, diarrhea and liver enzyme elevations above 3 times ULN in one patient, but no patient developed aplastic anemia or hepatic failure).
• Vidaurre J, Gedela S, Yarosz S. Antiepileptic Drugs and Liver Disease. Pediatr Neurol 2017; 77: 23-36. [PubMed: 29097018]

  (Review of hepatotoxicity of anticonvulsants and their use in patients with liver disease; felbamate is listed as an agent "of last resort" because of its potential for adverse side effects including liver toxicity).