Perampanel for focal epilepsy: insights from early clinical experience

E Trinka, B J Steinhoff, M Nikanorova, M J Brodie, E Trinka, B J Steinhoff, M Nikanorova, M J Brodie

Abstract

Perampanel is approved for adjunctive therapy of focal epilepsy with or without secondarily generalized seizures in patients aged >12 years. This narrative review uses real-world and clinical trial data to elucidate perampanel's role in the clinic. Audit data show good tolerability with perampanel and higher freedom-from-seizure rates in elderly vs younger patients. When using perampanel in elderly patients, special attention should be given to comorbidities and co-medication to avoid potential interactions or adverse events. Slower titration is generally recommended, and seizure control should be reassessed at a dose of 4 mg before further dose increases. Perampanel efficacy is similar in adolescents and adults; however, somnolence, nasopharyngitis, and aggression are more frequent in adolescents vs the overall population. Individualized and slow-dose titration can minimize adverse events. Low serum concentrations of perampanel may occur in patients also receiving some enzyme-inducing anti-epileptic drugs; a perampanel dose increase may be required. Adverse events of importance with perampanel include dizziness; anger, aggression, and hostile behavior (particularly in adolescents); and falls (particularly in patients >65 years). An individualized approach to dosing, including slower up-titration and bedtime dosing, reduces dizziness risk. Other drugs may cause or aggravate dizziness; reducing concomitant drugs may be necessary when up-titrating perampanel. It would seem clinically appropriate to give due consideration to avoiding use in patients with a history of anger or hostile/aggressive behavior. The possibility of such behaviors should be discussed with patients before starting perampanel, with monitoring during up-titration. Slower up-titration of perampanel in older patients helps reduce fall risk.

Keywords: clinical experience; focal epilepsy; perampanel; refractory; review.

© 2015 The Authors. Acta Neurologica Scandinavica Published by John Wiley & Sons Ltd.

References

    1. Rheims S, Ryvlin P. Profile of perampanel and its potential in the treatment of partial onset seizures. Neuropsychiatr Dis Treat 2013;9:629–37.
    1. Kwan P, Schachter SC, Brodie MJ. Drug‐resistant epilepsy. N Engl J Med 2011;365:919–26.
    1. Stephen LJ, Brodie MJ. Antiepileptic drug monotherapy versus polytherapy: pursuing seizure freedom and tolerability in adults. Curr Opin Neurol 2012;25:164–72.
    1. Trinka E. Ideal characteristics of an antiepileptic drug: how do these impact treatment decisions for individual patients? Acta Neurol Scand Suppl 2012;194:10–8.
    1. Faught E. Antiepileptic drug trials: the view from the clinic. Epileptic Disord 2012;14:114–23.
    1. Marson AG, Williamson PR. Interpreting regulatory trials in epilepsy. Curr Opin Neurol 2009;22:167–73.
    1. Brodie MJ. Meta‐analyses of antiepileptic drugs for refractory partial (focal) epilepsy: an observation. Br J Clin Pharmacol 2013;76:630–1.
    1. Brodie MJ, Kelly K, Stephen LJ. Prospective audits with newer antiepileptic drugs in focal epilepsy: insights into population responses? Epilepsy Behav 2014;31:73–6.
    1. Berger ML, Dreyer N, Anderson F et al. Prospective observational studies to assess comparative effectiveness: the ISPOR good research practices task force report. Value Health 2012;15:217–30.
    1. Krauss GL, Serratosa JM, Villanueva V et al. Randomized phase III study 306: adjunctive perampanel for refractory partial‐onset seizures. Neurology 2012;78:1408–15.
    1. French JA, Krauss GL, Biton V et al. Adjunctive perampanel for refractory partial‐onset seizures: randomized phase III study 304. Neurology 2012;79:589–96.
    1. French JA, Krauss GL, Steinhoff BJ et al. Evaluation of adjunctive perampanel in patients with refractory partial‐onset seizures: results of randomized global phase III study 305. Epilepsia 2013;54:117–25.
    1. Krauss GL, Perucca E, Ben‐Menachem E 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.
    1. Steinhoff BJ, Ben‐Menachem E, Ryvlin P 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.
    1. Ettinger A, Lopresti A, Yang H, et al. Psychiatric and behavioural adverse events in randomized clinical studies of the noncompetitive AMPA receptor antagonist perampanel. Epilepsia 2015;56:1252–63.
    1. Steinhoff BJ, Bacher M, Bast T et al. First clinical experiences with perampanel–the Kork experience in 74 patients. Epilepsia 2014;55(Suppl 1):16–8.
    1. Steinhoff BJ, Hamer H, Trinka E et al. A multicenter survey of clinical experiences with perampanel in real life in Germany and Austria. Epilepsy Res 2014;108:986–8.
    1. Juhl S, Rubboli G. Perampanel as add‐on treatment in patients with drug‐resistant focal epilepsy: the clinical experience of the Danish epilepsy center. Epilepsia 2014;55:348.
    1. Kelly K, Stephen LJ, Parker P et al. Adjunctive perampanel in highly drug‐resistant localization‐related epilepsy – a prospective audit. Epilepsia 2014;55:119.
    1. Pilay N, Hwang P, McLachlan R. Canadian experience with extended use of over 3 years of perampanel in partial‐onset seizures in patients aged 12 and above. 30th International Epilepsy Congress; 23–27 June; Montreal, Canada, 2013.
    1. Sieradzan K, Hodgson H. Efficacy and tolerability of perampanel in patients with refractory partial epilepsy in a tertiary epilepsy centre. Epilepsia 2014;55:137.
    1. Parrett MP, McLean BN, Shankar R et al. A service evaluation of perampanel in Cornwall, UK. Epilepsia 2014;55:334.
    1. Goulding P, Wright E, Geldard J et al. A service evaluation of perampanel (Fycompa) at Leeds General Infirmary. Epilepsia 2014;55:335.
    1. Keogh S, Greenhill L, O'Donnell M et al. The efficacy and tolerability of perampanel (Fycompa) in everyday clinical practice using a retrospective multicentre audit. Epilepsia 2014;55:358.
    1. Coyle H, Hmohanraj R. Clinical experience with perampanel in a regional epilepsy clinic. Epilepsia 2014;55:563.
    1. Lawthom C, Powell R, Hillman E et al. Perampanel in south Wales: a multi‐centre clinical evaluation. Epilepsia 2014;55:138.
    1. Flynn C, Delanty N. Seizure response to perampanel in a severe refractory group of epilepsy patients. Epilepsia 2014;55:343.
    1. Trinka E. Epilepsy: comorbidity in the elderly. Acta Neurol Scand Suppl 2003;180:33–6.
    1. Brodie MJ, Elder AT, Kwan P. Epilepsy in later life. Lancet Neurol 2009;8:1019–30.
    1. Brodie MJ, Overstall PW, Giorgi L. Multicentre, double‐blind, randomised comparison between lamotrigine and carbamazepine in elderly patients with newly diagnosed epilepsy. The UK Lamotrigine Elderly Study Group. Epilepsy Res 1999;37:81–7.
    1. Rowan AJ, Ramsay RE, Collins JF et al. New onset geriatric epilepsy: a randomized study of gabapentin, lamotrigine, and carbamazepine. Neurology 2005;64:1868–73.
    1. Saetre E, Perucca E, Isojarvi J et al. An international multicenter randomized double‐blind controlled trial of lamotrigine and sustained‐release carbamazepine in the treatment of newly diagnosed epilepsy in the elderly. Epilepsia 2007;48:1292–302.
    1. Werhahn KJ, Trinka E, Dobesberger J et al. A randomized, double‐blind comparison of antiepileptic drug treatment in the elderly with new‐onset focal epilepsy. Epilepsia 2015;56:450–9.
    1. Giorgi L, Gomez G, O'Neill F et al. The tolerability of lamotrigine in elderly patients with epilepsy. Drugs Aging 2001;18:621–30.
    1. Kutluay E, McCague K, D'Souza J et al. Safety and tolerability of oxcarbazepine in elderly patients with epilepsy. Epilepsy Behav 2003;4:175–80.
    1. Werhahn KJ, Klimpe S, Balkaya S et al. The safety and efficacy of add‐on levetiracetam in elderly patients with focal epilepsy: a one‐year observational study. Seizure 2011;20:305–11.
    1. Trinka E, Giorgi L, Patten A et al. Safety and tolerability of zonisamide in elderly patients with epilepsy. Acta Neurol Scand 2013;128:422–8.
    1. Rohracher A, Hofler J, Leitinger M et al. One‐year real‐world experience of perampanel in elderly patients with refractory focal epilepsy. 68th Annual Meeting of the American Epilepsy Society; 5–9 Dec 2014; Seattle, WA, USA, 2014.
    1. Rosenfeld W, Rozentals G, Yang H et al. Efficacy and safety of adjunctive perampanel in the subgroup of adolescent patients with refractory, partial onset seizures included in the 3 double‐blind, placebo‐controlled phase III clinical trials. 41st Annual Meeting of the Child Neurology Society; 31 Oct–3 Nov 2012; Huntington Beach, CA, USA, 2012.
    1. Conry J, Lagae L, Yang H et al. Interim analysis of efficacy and safety of adjunctive perampanel in the adolescent population in the open‐label extension phase of the double‐blind, placebo‐controlled, parallel‐group studies in patients with refractory partial onset seizures. Child Neurology Society 41st Annual Meeting; Huntington Beach, CA, USA, 2012.
    1. Renfroe B, Yang H, Williams B. Interim efficacy and safety analysis of adjunctive perampanel in the adolescent population from the extension phase of 3 double‐blind, placebo‐controlled phase 3 (core) studies in patients with refractory partial‐onset seizures. 42nd Annual Meeting of the Child Neurology Society; 30 Oct–2 Nov 2013; Austin, TX, USA, 2013.
    1. Rosenfeld W, Conry J, Lagae L 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.
    1. Laurenza A, Ferry J, Hussein Z. Population pharmacokinetics and pharmacodynamics of perampanel: a pooled analysis of three phase III trials. Epilepsy Curr 2012;12(Suppl 1):216–7.
    1. Gidal BE, Ferry J, Majid O et al. Concentration‐effect relationships with perampanel in patients with pharmacoresistant partial‐onset seizures. Epilepsia 2013;54:1490–7.
    1. Kwan P, Brodie MJ, Squillacote D et al. Impact of concomitant sodium channel blocker antiepileptic drugs (AEDs) on the efficacy of adjunctive perampanel for partial‐onset seizures: an analysis of pooled phase III data (Abstract P530). Epilepsia 2013;54:167.
    1. Patsalos PN. The clinical pharmacology profile of the new antiepileptic drug perampanel: a novel noncompetitive AMPA receptor antagonist. Epilepsia 2015;56:12–27.
    1. Unabridged DC. dizziness (n.d.): 2015; (cited 17 April 2015).
    1. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000;356:1255–9.
    1. Perucca P, Gilliam FG. Adverse effects of antiepileptic drugs. Lancet Neurol 2012;11:792–802.
    1. Mattson RH, Cramer JA, Collins JF et al. Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic‐clonic seizures. N Engl J Med 1985;313:145–51.
    1. Sirven JI, Fife TD, Wingerchuk DM et al. Second‐generation antiepileptic drugs’ impact on balance: a meta‐analysis. Mayo Clin Proc 2007;82:40–7.
    1. Hsu WW, Sing CW, He Y et al. 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.
    1. Steinhoff BJ, Laurenza A, Yang H et al. Safety profile of perampanel as an adjunctive treatment for partial‐onset seizures. J Symptoms Signs 2014;3:64–70.
    1. Lin JJ, Mula M, Hermann BP. Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan. Lancet 2012;380:1180–92.
    1. Comai S, Tau M, Gobbi G. The psychopharmacology of aggressive behavior: a translational approach: part 1: neurobiology. J Clin Psychopharmacol 2012;32:83–94.
    1. Cramer JA, de Rue K, Devinsky O et al. A systematic review of the behavioral effects of levetiracetam in adults with epilepsy, cognitive disorders, or an anxiety disorder during clinical trials. Epilepsy Behav 2003;4:124–32.
    1. Dinkelacker V, Dietl T, Widman G et al. Aggressive behavior of epilepsy patients in the course of levetiracetam add‐on therapy: report of 33 mild to severe cases. Epilepsy Behav 2003;4:537–47.
    1. Mula M, Trimble MR, Yuen A et al. Psychiatric adverse events during levetiracetam therapy. Neurology 2003;61:704–6.
    1. Mula M, Trimble MR, Sander JW. Psychiatric adverse events in patients with epilepsy and learning disabilities taking levetiracetam. Seizure 2004;13:55–7.
    1. Mohanraj R, Parker PG, Stephen LJ et al. Levetiracetam in refractory epilepsy: a prospective observational study. Seizure 2005;14:23–7.
    1. Levisohn PM, Mintz M, Hunter SJ et al. Neurocognitive effects of adjunctive levetiracetam in children with partial‐onset seizures: a randomized, double‐blind, placebo‐controlled, noninferiority trial. Epilepsia 2009;50:2377–89.
    1. Stephen LJ, Kelly K, Parker P et al. Levetiracetam monotherapy–outcomes from an epilepsy clinic. Seizure 2011;20:554–7.
    1. Schiemann‐Delgado J, Yang H, Loge CDEL et al. A long‐term open‐label extension study assessing cognition and behavior, tolerability, safety, and efficacy of adjunctive levetiracetam in children aged 4 to 16 years with partial‐onset seizures. J Child Neurol 2012;27:80–9.
    1. Mula M, Trimble MR, Lhatoo SD et al. Topiramate and psychiatric adverse events in patients with epilepsy. Epilepsia 2003;44:659–63.
    1. White JR, Walczak TS, Leppik IE et al. Discontinuation of levetiracetam because of behavioral side effects: a case‐control study. Neurology 2003;61:1218–21.
    1. Eisai Ltd . Fycompa Summary of Product Characteristics: Electronic Medicines Compendium. 2014; (cited 16 April 2015).
    1. Lagae L, Velkey I, Bagul M. Impact of adjunctive perampanel on behaviour in adolescents with refractory partial‐onset seizures. 11th European Congress on Epileptology; 29 June–3 July 2015; Stockholm, Sweden, 2014.
    1. Wieshmann UC, Baker GA. Self‐reported feelings of anger and aggression towards others in patients on levetiracetam: data from the UK antiepileptic drug register. BMJ Open 2013;3:pii:e002564. DOI:.
    1. Ettinger A, Lo Presti A, Yang H, et al. Review of psychiatric and behavioural events in perampanel clinical studies. American Epilepsy Society; 8–10 December 2013; Washington, DC, 2013.
    1. Krauss GL, Bar M, Biton V et al. Tolerability and safety of perampanel: two randomized dose‐escalation studies. Acta Neurol Scand 2012;125:8–15.

Source: PubMed

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