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© 2013 Direct One Communications, Inc. All rights reserved. 1 Optimal Use of the Newest Antiepileptic Drugs and Generics Peter Pressman, MD University of California, San Francisco, School of Medicine, San Francisco, California A REPORT FROM THE 66 th ANNUAL MEETING OF THE AMERICAN EPILEPSY SOCIETY
© 2013 Direct One Communications, Inc. All rights reserved. 2 Indications and Mechanisms of Action of the Newer AEDs
© 2013 Direct One Communications, Inc. All rights reserved. 3 Indications and Mechanisms of Action of the Newer AEDs: Stiripentol Approved in Europe for adjunctive treatment with clobazam and valproic acid of refractory generalized tonic-clonic seizures in infants with myoclonic epilepsy (Dravet syndrome) 1 Structurally unrelated to other antiepileptic drugs (AEDs) Mechanism of action unknown but is likely diverse Appears to increase the duration of opening of -aminobutyric acid type A (GABA A ) receptors (similar to the the action of barbiturates)
© 2013 Direct One Communications, Inc. All rights reserved. 4 Indications and Mechanisms of Action of the Newer AEDs: Stiripentol May interact with benzodiazepines May increase central GABA activity by interfering with uptake and metabolism 2 Inhibits various cytochrome P (CYP) 450 enzymes, decreasing metabolism of such AEDs as phenytoin, carbamazepine, and diazepam 2–4
© 2013 Direct One Communications, Inc. All rights reserved. 5 Indications and Mechanisms of Action of the Newer AEDs: Lacosamide FDA approved for adjunctive treatment of partial- onset seizures in patients > 17 years of age First AED to enhance the slow inactivation state of voltage-gated sodium channels 5,6 May regulate sodium-channel availability over the long term 7 Binds with collapsin response mediator protein, although effect on the antiepileptic activity of this drug is unclear 5
© 2013 Direct One Communications, Inc. All rights reserved. 6 Indications and Mechanisms of Action of the Newer AEDs: Rufinamide FDA approved for adjunctive treatment of seizures associated with Lennox-Gastaut syndrome in children 4 years of age and adults First drug approved in the US with a pediatric indication before adult use approved Possesses a novel triazole structure somewhat similar to that of lamotrigine Prolongs inactivated state of voltage-gated sodium channels 8 Activity against atonic seizures may involve additional mechanisms 6
© 2013 Direct One Communications, Inc. All rights reserved. 7 Indications and Mechanisms of Action of the Newer AEDs: Eslicarbazepine Acetate Approved in Europe for adjunctive treatment of partial seizures in adults 9 Being tested in the US in phase III trials in adults with partial-onset seizures and in phase II trials for possible use in bipolar disorder 10 Competitive antagonist of fast voltage-gated potassium channels, stabilizes the inactivated neuronal state, 9 and potentiates GABA currents May be given once daily 11 May enhance slow inactivation of voltage-dependent sodium channels (similar to lacosamide)
© 2013 Direct One Communications, Inc. All rights reserved. 8 Indications and Mechanisms of Action of the Newer AEDs: Vigabatrin FDA approved for adjunctive treatment of adults with refractory complex partial seizures and monotherapy for infantile spasm in patients 1 month to 2 years of age Benefits must outweigh the risks of potential vision loss (occurs in up to one third of treated patients) Irreversibly inhibits GABA transaminase 12 Inhibits vesicular GABA transporter and increases extracellular GABA concentrations in the CNS and tonic inhibition in extrasynaptic GABA receptors with prolonged activation 6
© 2013 Direct One Communications, Inc. All rights reserved. 9 Indications and Mechanisms of Action of the Newer AEDs: Ezogabine (Retigabine) FDA approved as adjunctive therapy for partial seizures and refractory partial epilepsy in patients 18 years of age First AED to target and open voltage-gated potassium channels Has a hyperpolarizing effect on neurons and reduces neuronal hyperexcitability 13 At supratherapeutic concentrations, enhances GABA A -activated currents 14 Use may cause urinary retention 15,16
© 2013 Direct One Communications, Inc. All rights reserved. 10 Indications and Mechanisms of Action of the Newer AEDs: Clobazam FDA approved for adjunctive therapy of Lennox- Gastaut syndrome in children 2 years of age and adults. Can lead up to a 70% reduction in drop seizures 17 First approved in Australia in 1970 and used for years in Europe Potentiates GABAergic neurotransmission Less lipophilic and acidic, better tolerated, and less sedating than 1,4-benzodiazepines Tolerance to clobazam develops more slowly than with other AEDs 18
© 2013 Direct One Communications, Inc. All rights reserved. 11 Indications and Mechanisms of Action of the Newer AEDs: Perampanel FDA approved for adjunctive therapy of partial-onset seizures, with or without secondarily generalized seizures, in patients 12 years of age First inotropic -amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) glutamate receptor antagonist Reduces fast excitatory signaling in the brain 6,19
© 2013 Direct One Communications, Inc. All rights reserved. 12 Indications and Mechanisms of Action of the Newer AEDs: Summary
© 2013 Direct One Communications, Inc. All rights reserved. 13 Drug Interactions of the Newer AEDs
© 2013 Direct One Communications, Inc. All rights reserved. 14 Drug Interactions of the Newer AEDs: Interactions with Other Drug Classes Use of oral contraceptives may lead to CYP3A4- mediated induction by carbamazepine, felbamate, oxcarbazepine, topiramate, rufinamide, eslicarbazepine acetate, and perampanel 20 and UDP- glucuronosyltransferase (UGT)-mediated induction of lamotrigine and valproic acid In older patients, CYP2C9-mediated induction of warfarin by carbamazepine and eslicarbazepine acetate may occur, as well as inhibition by felbamate and stiripentol 21
© 2013 Direct One Communications, Inc. All rights reserved. 15 Drug Interactions of the Newer AEDs: Interactions with Other Drug Classes
© 2013 Direct One Communications, Inc. All rights reserved. 16 Pharmacokinetics of the Newer AEDs
© 2013 Direct One Communications, Inc. All rights reserved. 17 Pharmacokinetics of the Newer AEDs: Lacosamide Well absorbed; maximum concentration in the blood (T max ) reached within 0.5–4 hours Serum concentrations increase greatly during the first 3 hours after dosing 22 Dosing three times daily may reduce fluctuations and improve tolerability Available in both oral and intravenous forms Predominantly excreted renally 23
© 2013 Direct One Communications, Inc. All rights reserved. 18 Pharmacokinetics of the Newer AEDs: Rufinamide Dose-dependent absorption; less absorbed in absence of food Not highly protein-bound (26%–35%) Metabolized via non–CYP-dependent hydrolysis Short half-life Valproic acid increases serum levels up to 50% 24 Serum levels ~19% lower in children compared with adults 25 Therapeutic drug monitoring recommended
© 2013 Direct One Communications, Inc. All rights reserved. 19 Pharmacokinetics of the Newer AEDs: Eslicarbazepine Acetate Prodrug: 100% of dose converted into active metabolite (eslicarbazepine) T max is 2–3 hours Protein binding is about 40%; volume of distribution (V d ) is 2.7 L/kg Induces other CYP isoenzymes, leading to a 12%– 16% increase in clearance of carbamazepine, lamotrigine, and topiramate Reduced excretion in patients with renal or hepatic impairment 6,7,26,27
© 2013 Direct One Communications, Inc. All rights reserved. 20 Pharmacokinetics of the Newer AEDs: Vigabatrin Low potential for pharmacokinetic interactions 100% bioavailable, with no protein binding and a T max of 1 hour Has caused irreversible peripheral vision loss in many patients 28 Half-life of biological activity exceeds serum half- life 29 Half-life of biologic activity likely depends most on the regeneration of GABA transaminase, which may take up to 6 days after administration 30
© 2013 Direct One Communications, Inc. All rights reserved. 21 Pharmacokinetics of the Newer AEDs: Ezogabine Higher V d (6.2 L/kg) than that of other AEDs Metabolized by UGT and N-acetylation With lamotrigine, can cause a 20% increase in clearance 31,32
© 2013 Direct One Communications, Inc. All rights reserved. 22 Pharmacokinetics of the Newer AEDs: Clobazam Close to 100% bioavailability Protein binding is 85%; Vd is 1 L/kg. Metabolized by CYP3A4 and CYP2C19 Adverse effects akin to benzodiazepine toxicity may occur with slow CYP metabolism Lower doses needed for patients with renal or hepatic impairment 28,33
© 2013 Direct One Communications, Inc. All rights reserved. 23 Pharmacokinetics of the Newer AEDs: Perampanel Food may delay absorption by 2 hours 96% protein-bound Possible displacement interactions with other highly bound AEDs High V d at 77 L/kg Long half-life, reaching steady-state serum levels after 14 days Clearance doubled or tripled with carbamazepine, oxcarbazepine, or phenytoin Limited experience so far in clinical practice 14,34
© 2013 Direct One Communications, Inc. All rights reserved. 24 Efficacy and Safety of the Newer AEDs
© 2013 Direct One Communications, Inc. All rights reserved. 25 Efficacy and Safety of the Newer AEDs At least 27% of patients respond favorably to treatment with a newer AED 35,36 Meaningful benefit may be achieved in the majority of patients with refractory epilepsy However, < 20% of patients attain freedom from seizures after trying a third or fourth drug
© 2013 Direct One Communications, Inc. All rights reserved. 26 Efficacy and Safety of the Newer AEDs: Lacosamide Dose-response plateaus at 400 mg/d 37 Linear relationship between dose and side effects Dizziness seen in almost 25% of patients and worsened with concomitant use of another sodium- channel blocker Vertigo, ataxia, balance disorders, coordination abnormalities, and diplopia are also common Relatively low frequency of somnolence, rash, and cognitive side effects
© 2013 Direct One Communications, Inc. All rights reserved. 27 Efficacy and Safety of the Newer AEDs: Lacosamide Recommended dose is 50 mg twice daily for the first week. Increased in weekly intervals by 100 mg/d in two divided doses, as tolerated, until a goal of 200–400 mg/d in two divided doses is reached Doses may be halved Upward titration may be prolonged May be better tolerated if taken three times daily No proven benefit of using lacosamide as a single agent
© 2013 Direct One Communications, Inc. All rights reserved. 28 Efficacy and Safety of the Newer AEDs: Ezogabine Modest efficacy Recommended starting dose is 100 mg three times a day; then titrate upward to 600–1,200 mg/d in three divided doses. Dose-related side effects include somnolence, dizziness, confusion Causes potentially severe urinary retention, an unusual side effect for an AED Use caution in patients with an enlarged prostate gland or other problems with urinary voiding Low rate of rash and cognitive complaints
© 2013 Direct One Communications, Inc. All rights reserved. 29 Efficacy and Safety of the Newer AEDs: Rufinamide Particularly successful for atonic seizures or “drop attacks” Dosing for children starts at 10 mg/kg/d given in two divided doses (target dose, 45 mg/kg/d). In adults, the starting dose is 200 mg twice daily (maximum dose, 3,200 mg/d). Prone to interact with other AEDs
© 2013 Direct One Communications, Inc. All rights reserved. 30 Efficacy and Safety of the Newer AEDs: Clobazam In patients weighing > 30 kg, dosing ranges from 10 to 40 mg/d given in two divided doses A conservative starting dose would be 5 mg/d given for 1 week, followed by 5-mg/d increases at weekly intervals to reach a goal of 20 mg/d Often added to valproic acid, felbamate, lamotrigine, or topiramate
© 2013 Direct One Communications, Inc. All rights reserved. 31 Emerging Uses of the Newer AEDs
© 2013 Direct One Communications, Inc. All rights reserved. 32 Emerging Uses of the Newer AEDs: Lacosamide Evidence of a > 50% decrease in the frequency of epileptic episodes in 18 of 24 patients with generalized tonic-clonic seizure 38 In children, lacosamide is capable of reducing seizure frequency by 30%–50%, although patients frequently stopped taking the medication because of side effects. 39–42 Results of using lacosamide for status epilepticus are conflicting.
© 2013 Direct One Communications, Inc. All rights reserved. 33 Emerging Uses of the Newer AEDs: Rufinamide Drug has been evaluated for adjunctive treatment of focal seizures in children and adults, malignant migrating partial epilepsy, epilepsy with myoclonic absence seizures, Dravet syndrome, myoclonic astatic epilepsy, West syndrome, multifocal encephalopathy with bifrontal spike-wave discharges, and other unspecified symptomatic or cryptogenic generalized seizures. 43–50 In almost all cases, responses varied, and no clear picture emerged from the data.
© 2013 Direct One Communications, Inc. All rights reserved. 34 Emerging Uses of the Newer AEDs: Clobazam Additional indications being investigated include: » Treatment of other electroclinical syndromes » Monotherapy for focal or generalized seizure in adults » Adjunctive therapy for focal or generalized seizure in adults and children Possible future indications include status epilepticus and febrile seizures
© 2013 Direct One Communications, Inc. All rights reserved. 35 Generic AEDs: Fact and Fiction
© 2013 Direct One Communications, Inc. All rights reserved. 36 Definitions of Equivalence Bioequivalence—pharmacokinetic parameters of the area under the curve (AUC) and maximum serum concentration (C max ) fall within a certain range Therapeutic equivalence—two products have an equal clinical benefit for a patient Switchability—no change in therapeutic effect noted when one drug is exchanged for another
© 2013 Direct One Communications, Inc. All rights reserved. 37 The Crux of the Problem Neurologists argue that the FDA standards of bioequivalence do not reliably predict actual therapeutic equivalence or switchability. Use of generic AEDs may increase the need for emergency services. 51 A model using data from five generic carbamazepine products demonstrated AUC variations of up to 21% and variations in C max reaching 40%. 52 No rigorous assessment of seizure frequency or blood levels of AEDs has been done. Studies of adherence to medication, stress, and sleep deprivation have been uncontrolled.
© 2013 Direct One Communications, Inc. All rights reserved. 38 Improving Equivalence Research Results of the Equivalence Among Antiepileptic Drug Generic and Brand Products in People with Epilepsy (EQUIGEN) and BEEP studies are expected early in 2013. Research focuses on bioequivalence rather than therapeutic equivalence
© 2013 Direct One Communications, Inc. All rights reserved. 39 Improving Equivalence Research Physicians should: » Investigate cost differences » Recognize that patients who are pregnant, have a history of status epilepticus, or are seizure-free and driving a vehicle are at higher risk than others Patients should be counseled about: » Unauthorized formulation substitution » Calling a physician if pills in a newly refilled prescription look different from those used previously » Medication adherence » Avoiding triggers like alcohol and sleep deprivation
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© 2013 Direct One Communications, Inc. All rights reserved. 41 References 13.Brodie MJ, Lerche H, Gil-Nagel A, et al. Efficacy and safety of adjunctive ezogabine (retigabine) in refractory partial epilepsy. Neurology. 2010;75:1817–1824. 14.Stephen LJ, Brodie MJ. Pharmacotherapy of epilepsy: newly approved and developmental agents. CNS Drugs. 2011;25:89–107. 15.Gil-Nagel A, Brodie MJ, Leroy R, et al. Safety and efficacy of ezogabine (retigabine) in adults with refractory partial-onset seizures: interim results from two ongoing open-label studies. Epilepsy Res. 2012;102:117–121. 16.Porter RJ, Burdette DE, Gil-Nagel A, et al. Retigabine as adjunctive therapy in adults with partial-onset seizures: integrated analysis of three pivotal controlled trials. Epilepsy Res. 2012;101:103–112. 17.Ng YT, Conry JA, Drummond R, Stolle J, Weinberg MA. Randomized, phase III study results of clobazam in Lennox-Gastaut syndrome. Neurology. 2011;77:1473–1481. 18.Buck ML. Clobazam: a new option for children with refractory seizures. Pediatric Pharmacotherapy. December 2011. Available at: http://www.medicine.virginia.edu/clinical/departments/pediatrics/ education/pharm-news/current/201112.pdf. Accessed January 8, 2013. 19.Krauss GL, Serratosa JM, Villanueva V, et al. Randomized phase III study 306: adjunctive perampanel for refractory partial-onset seizures. Neurology. 2012;78:1408–1415. 20.Dutton C, Foldvary-Schaefer N. Contraception in women with epilepsy: pharmacokinetic interactions, contraceptive options, and management. Int Rev Neurobiol. 2008;83:113–134. 21.Chaudhry AS, Urban TJ, Lamba JK, et al. CYP2C9*1B promoter polymorphisms, in linkage with CYP2C19*2, affect phenytoin autoinduction of clearance and maintenance dose. J Pharmacol Exp Ther. 2010;332:599–611. 22.Sattler A, Schaefer M, May TW, Rambeck B, Brandt C. Fluctuation of lacosamide serum concentrations during the day and occurrence of adverse drug reactions—first clinical experience. Epilepsy Res. 2011;95:207–212.
© 2013 Direct One Communications, Inc. All rights reserved. 42 References 23.Ben-Menachem E, Biton V, Jatuzis D, Abou-Khalil B, Doty P, Rudd GD. Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. Epilepsia. 2007;48:1308–1317. 24.Perucca E, Cloyd J, Critchley D, Fuseau E. Rufinamide: clinical pharmacokinetics and concentration- response relationships in patients with epilepsy. Epilepsia. 2008;49:1123–1141. 25.May TW, Boor R, Rambeck B, Jurgens U, Korn-Merker E, Brandt C. Serum concentrations of rufinamide in children and adults with epilepsy: the influence of dose, age, and comedication. Ther Drug Monit. 2011;33:214–221. 26.Falcao A, Fuseau E, Nunes T, Almeida L, Soares-da-Silva P. Pharmacokinetics, drug interactions and exposure-response relationship of eslicarbazepine acetate in adult patients with partial-onset seizures: population pharmacokinetic and pharmacokinetic/pharmacodynamic analyses. CNS Drugs. 2012;26:79–91. 27.Fontes-Ribeiro C, Nunes T, Falcao A, et al. Eslicarbazepine acetate (BIA 2-093): relative bioavailability and bioequivalence of 50 mg/mL oral suspension and 200mg and 800mg tablet formulations. Drugs RD. 2005;6:253–260. 28.Johannessen Landmark C, Patsalos PN. Drug interactions involving the new second- and third-generation antiepileptic drugs. Expert Rev Neurother. 2010;10:119–140. 29.Lindberger M, Luhr O, Johannessen SI, Larsson S, Tomson T. Serum concentrations and effects of gabapentin and vigabatrin: observations from a dose titration study. Ther Drug Monit. 2003;25:457–462. 30.Sheean G, Schramm T, Anderson DS, Eadie MJ. Vigabatrin—plasma enantiomer concentrations and clinical effects. Clin Exp Neurol. 1992;29:107–116. 31.Hermann R, Knebel NG, Niebch G, Richards L, Borlak J, Locher M. Pharmacokinetic interaction between retigabine and lamotrigine in healthy subjects. Eur J Clin Pharmacol. 2003;58:795–802. 32.Yamada M, Welty TE. Ezogabine: an evaluation of its efficacy and safety as adjunctive therapy for partial- onset seizures in adults. Ann Pharmacother. 2012;46:1358–1367.
© 2013 Direct One Communications, Inc. All rights reserved. 43 References 33.Johannessen Landmark C, Johannessen SI, Tomson T. Host factors affecting antiepileptic drug delivery- pharmacokinetic variability. Adv Drug Deliv Rev. 2012;64:896–910. 34.Hibi S, Ueno K, Nagato S, et al. Discovery of 2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin- 3-yl)benzonitrile (perampanel): a novel, noncompetitive alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropanoic acid (AMPA) receptor antagonist. J Med Chem. 2012;55:10584–10600. 35.Schiller Y, Najjar Y. Quantifying the response to antiepileptic drugs: effect of past treatment history. Neurology. 2008;70:54–65. 36.Callaghan BC, Anand K, Hesdorffer D, Hauser WA, French JA. Likelihood of seizure remission in an adult population with refractory epilepsy. Ann Neurol. 2007;62:382–389. 37.Zaccara G, Perucca P, Loiacono G, Giovannelli F, Verrotti A. The adverse event profile of lacosamide: a systematic review and meta-analysis of randomized controlled trials. Epilepsia. 2013;54:66–74. 38.Harden CL, Cohn A, Lowe M, Serrano E. Initial post marketing experience with lacosamide in adult patients with epilepsy. Epilepsy Res. 2012;98:260–263. 39.Gavatha M, Ioannou I, Papavasiliou AS. Efficacy and tolerability of oral lacosamide as adjunctive therapy in pediatric patients with pharmacoresistant focal epilepsy. Epilepsy Behav. 2011;20:691–693. 40.Guilhoto LM, Loddenkemper T, Gooty VD, et al. Experience with lacosamide in a series of children with drug-resistant focal epilepsy. Pediatr Neurol. 2011;44:414–419. 41.Heyman E, Lahat E, Levin N, Berkovitch M, Gandelman-Marton R. Preliminary efficacy and safety of lacosamide in children with refractory epilepsy. Eur J Paediatr Neurol. 2012;16:15–19. 42.Rastogi RG, Ng YT. Lacosamide in refractory mixed pediatric epilepsy: a prospective add-on study. J Child Neurol. 2012;27:492–495. 43.Vendrame M, Poduri A, Loddenkemper T, Kluger G, Coppola G, Kothare SV. Treatment of malignant migrating partial epilepsy of infancy with rufinamide: report of five cases. Epileptic Disord. 2011;13:18–21.
© 2013 Direct One Communications, Inc. All rights reserved. 44 References 44.Hausler M, Kluger G, Nikanorova M. Epilepsy with myoclonic absences—favourable response to add-on rufinamide treatment in 3 cases. Neuropediatrics. 2011;42:28–29. 45.Coppola G. Update on rufinamide in childhood epilepsy. Neuropsychiatr Dis Treat. 2011;7:399–407. 46.Joseph JR, Schultz RJ, Wilfong AA. Rufinamide for refractory epilepsy in a pediatric and young adult population. Epilepsy Res. 2011;93:87–89. 47.Kluger G, Kurlemann G, Haberlandt E, et al. Effectiveness and tolerability of rufinamide in children and adults with refractory epilepsy: first European experience. Epilepsy Behav. 2009;14:491–495. 48.Mueller A, Boor R, Coppola G, et al. Low long-term efficacy and tolerability of add-on rufinamide in patients with Dravet syndrome. Epilepsy Behav. 2011;21:282–284. 49.Olson HE, Loddenkemper T, Vendrame M, et al. Rufinamide for the treatment of epileptic spasms. Epilepsy Behav. 2011;20:344–348. 50.von Stulpnagel C, Coppola G, Striano P, Muller A, Staudt M, Kluger G. First long-term experience with the orphan drug rufinamide in children with myoclonic-astatic epilepsy (Doose syndrome). Eur J Paediatr Neurol. 2012;16:459–463. 51.Zachry WM, 3rd, Doan QD, Clewell JD, Smith BJ. Case-control analysis of ambulance, emergency room, or inpatient hospital events for epilepsy and antiepileptic drug formulation changes. Epilepsia. 2009;50:493– 500. 52.Krauss GL, Caffo B, Chang YT, Hendrix CW, Chuang K. Assessing bioequivalence of generic antiepilepsy drugs. Ann Neurol. 2011;70:221–228.
© 2015 Direct One Communications, Inc. All rights reserved. 1 The New Antiepileptic Drugs: Where Do They Belong in Our Armamentarium? Madhu Jasti, MD University.
© 2016 Direct One Communications, Inc. All rights reserved. 1 Recent Research Expands Our Understanding of Perampanel Christian M. Cabrera Kang, MD Emory.
© 2014 Direct One Communications, Inc. All rights reserved. 1 Treating the New-Onset Epilepsy Patient Ching Y. Tsao, MD Emory University Hospital, Atlanta,
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Chapter 24 Drugs for Epilepsy.
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An Overview of Eslicarbazepine Acetate (ESL) as Adjunctive Therapy for Partial-Onset Seizures Mark Versavel MD, PhD, MBA Vice President, Clinical Research.
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