OVERVIEW

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NO.	MOLECULAR FORMULA	STRUCTURE
Perampanel	380917-97-5	C23-H15-N3-O

ANNOTATED BIBLIOGRAPHY

References updated: 04 May 2016

• 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 before the availability of perampanel).
• Pirmohamed M, Leeder SJ. Anticonvulsant agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013: pp 423-42.

  (Review of anticonvulsant induced liver injury; perampanel is not discussed).
• 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. 583-607.

  (Textbook of pharmacology and therapeutics).
• Krauss GL, Bar M, Biton V, Klapper JA, Rektor I, Vaiciene-Magistris N, Squillacote D, et al. Tolerability and safety of perampanel: two randomized dose-escalation studies. Acta Neurol Scand 2012; 125: 8-15. [PubMed: 21883097]

  (Among 201 adults with refractory partial onset seizures enrolled in two studies of different doses of perampanel vs placebo for 6 to 7 weeks, there were no serious liver related adverse events and “no clinically significant differences” in laboratory values between placebo and perampanel treated subjects).
• Rektor I, Krauss GL, Bar M, Biton V, Klapper JA, Vaiciene-Magistris N, Kuba R, et al. Perampanel Study 207: long-term open-label evaluation in patients with epilepsy. Acta Neurol Scand 2012; 126: 263-9. [PubMed: 22913800]

  (Among 130 patients with refractory partial onset seizures who continued on perampanel after participation in controlled trials, 57 had at least 3 years and 18 had 4 years exposure; no new adverse events were uncovered, although one patient developed an ALT elevation above 5 times ULN at 2 years, but no details given).
• French JA, Krauss GL, Biton V, Squillacote D, Yang H, Laurenza A, Kumar D, et al. Adjunctive perampanel for refractory partial-onset seizures: randomized phase III study 304. Neurology 2012; 79: 589-96. [PMC free article: PMC3413761] [PubMed: 22843280]

  (Among 388 patients with refractory partial onset seizures treated with adjunctive perampanel [8 or 12 mg daily] or placebo for 19 weeks, serious adverse events occurred in 6.0 and 6.7% of perampanel vs 5.0% of placebo recipients, and there were no “clinically important mean changes in laboratory values”).
• Hsu WW, Sing CW, He Y, Worsley AJ, Wong IC, Chan EW. Systematic review and meta-analysis of the efficacy and safety of perampanel in the treatment of partial-onset epilepsy. CNS Drugs 2013; 27: 817-27. [PMC free article: PMC3784051] [PubMed: 23918722]

  (Systematic review of efficacy and safety of perampanel concludes that it resulted in a statistically significant decrease in seizure frequency and common side effects are dizziness and somnolence; no mention of ALT elevations or hepatotoxicity).
• Steinhoff BJ, Ben-Menachem E, Ryvlin P, Shorvon S, Kramer L, Satlin A, Squillacote D, et al. Efficacy and safety of adjunctive perampanel for the treatment of refractory partial seizures: a pooled analysis of three phase III studies. Epilepsia 2013; 54: 1481-9. [PubMed: 23663001]

  (Pooled analysis of results of three controlled trials of perampanel in patients with refractory partial onset seizures, mentions that there were no deaths and that serious adverse events occurred in 5.0% of placebo and 5.5% of perampanel recipients, none of which were liver related and that there were “no clinically important mean changes in laboratory values”).
• French JA, Krauss GL, Steinhoff BJ, Squillacote D, Yang H, Kumar D, Laurenza A. Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: results of randomized global phase III study 305. Epilepsia 2013; 54: 117-25. [PubMed: 22905857]

  (Among 386 patients with refractory partial onset seizures treated with perampanel [8 or 12 mg] or placebo for 19 weeks, the most common side effects were dizziness, somnolence, fatigue and headache, and there were no liver related serious adverse events and “no clinically important changes from baseline in mean laboratory values”).
• Drugs for epilepsy. Treat Guidel Med Lett 2013; 11: 9-18. [PubMed: 23348233]

  (Concise review of indications and side effects of anticonvulsants; perampanel is approved only as adjunctive treatment for partial onset seizures in patients 12 years old or older; no mention of adverse effects on the liver).
• Gaitatzis A, Sander JW. The long-term safety of antiepileptic drugs. CNS Drugs 2013; 27 (6): 435-55. [PubMed: 23673774]

  (Review of the adverse effects with long term anticonvulsant therapy including liver failure, nonalcoholic fatty liver, osteoporosis, skin and hair changes, reproductive health, cancer, heart, renal, lung, pancreas, gastrointestinal and psychiatric conditions; perampanel is mentioned, but not discussed).
• Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]

  (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, but none of the 96 were attributed to perampanel).
• Faulkner MA. Perampanel: a new agent for adjunctive treatment of partial seizures. Am J Health Syst Pharm 2014; 71: 191-8. [PubMed: 24429011]

  (Review of the mechanism of action, pharmacology, clinical efficacy and safety of perampanel does not mention any liver related serious adverse events and states that ALT and AST elevations above 3 times ULN occurred in fewer than 1% of recipients).
• Krauss GL, Perucca E, Ben-Menachem E, Kwan P, Shih JJ, Clément JF, Wang X, et al. Long-term safety of perampanel and seizure outcomes in refractory partial-onset seizures and secondarily generalized seizures: results from phase III extension study 307. Epilepsia 2014; 55: 1058-68. [PMC free article: PMC4283992] [PubMed: 24867391]

  (Summary of continued follow up on 1216 patients with refractory seizures who were enrolled in open label long term extension studies of perampanel including more than 300 followed for at least 2 years, ALT elevations above 3 times ULN occurred in less than 1% of patients; no specific mention of liver related serious adverse events).
• Rugg-Gunn F. Adverse effects and safety profile of perampanel: a review of pooled data. Epilepsia. 2014 Jan; 55 Suppl 1: 13-5. [PubMed: 24400692]

  (Review of adverse events reported in three controlled trials of perampanel mentions that there were “no clinically important changes” in biochemical parameters).
• Perampanel (Fycompa) for epilepsy. Med Lett Drugs Ther 2014; 56 (1435): 9-10. [PubMed: 24662975]

  (Concise review of the mechanism of action, clinical efficacy, adverse events, drug interactions, dosage and cost of perampanel shortly after its approval for use in epilepsy in the US does not mention hepatotoxicity or ALT elevations).
• 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. [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 attributed to anticonvulsants, but none to perampanel).
• Laurenza A, Yang H, Williams B, Zhou S, Ferry J. Absence of liver toxicity in perampanel-treated subjects: pooled results from partial seizure phase III perampanel clinical studies. Epilepsy Res 2015; 113: 76-85. [PubMed: 25986193]

  (Among 1038 patients with refractory partial onset seizures treated with perampanel in 3 controlled trials, de novo ALT elevations occurred in 2.6% of placebo and 1.7% of perampanel treated subjects, and hepatobiliary adverse events occurred in only 4 perampanel and no placebo treated subjects which were cholelithiasis in 3 and transiently elevated liver tests without jaundice in 1 [<0.2%]).
• Rosenfeld W, Conry J, Lagae L, Rozentals G, Yang H, Fain R, Williams B, et al. Efficacy and safety of perampanel in adolescent patients with drug-resistant partial seizures in three double-blind, placebo-controlled, phase III randomized clinical studies and a combined extension study. Eur J Paediatr Neurol 2015; 19: 435-45. [PubMed: 25823975]

  (Summary of 3 controlled trials and an extension study of perampanel in 143 adolescents [ages 12-17] with refractory partial onset seizures, serious adverse events were rare, and none were liver related; there were “no clinically significant changes from baseline in clinical laboratory values”).
• French JA, Krauss GL, Wechsler RT, Wang XF, DiVentura B, Brandt C, Trinka E, et al. Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy: A randomized trial. Neurology 2015; 85: 950-7. [PMC free article: PMC4567458] [PubMed: 26296511]

  (Among 164 patients with refractory tonic-clonic seizures treated with adjunctive perampanel or placebo for 17 weeks, there were no liver related serious adverse events and “no significant laboratory abnormalities”).