1. © 2015 Direct One Communications, Inc. All rights reserved. 1 The New Antiepileptic Drugs: Where Do They Belong in Our Armamentarium? Madhu Jasti, MD University of Alabama at Birmingham School of Medicine, Birmingham, Alabama A REPORT FROM THE 68 th ANNUAL MEETING OF THE AMERICAN EPILEPSY SOCIETY

2. © 2015 Direct One Communications, Inc. All rights reserved. 2 Overview Selection of an antiepileptic drug (AED) is based primarily on efficacy for specific seizure types and epileptic syndromes. Because different AEDs may be similarly effective, the choice of one AED over another often rests on other properties, such as their side-effect profile and tolerability, potential for drug interactions, pharmacokinetic properties, and cost. Over the past decade, many new drugs have been added to the therapeutic armamentarium for epilepsy; many more are clinically useful even though their mode of action may not have been completely elucidated.

3. © 2015 Direct One Communications, Inc. All rights reserved. 3 Ezogabine Broad-spectrum AED First-in-class KCNQ agonist Daily dose: 600–1,200 mg PO in 3 divided doses May cause skin discoloration and/or retinal pigmentation (FDA black-box warning) Overall assessment: Third/fourth-line AED reserved for patients ≥ 18 years of age with focal seizures refractory to other drugs Wuttke TV et al. Mol Pharmacol. 2005;67:1009; Stephen LJ, Brodie MJ. CNS Drugs. 2011;25:89; French JA et al. Neurology. 2011;76:1555; Brodie MJ et al. Neurology. 2010;75:1817

4. © 2015 Direct One Communications, Inc. All rights reserved. 4 Eslicarbazepine Acetate Narrow-spectrum AED Structurally related to carbamazepine and oxcarbazepine and equally efficacious Daily dose: 800–1,200 mg PO in a single dose Tends to be well tolerated Overall assessment: Useful first-line AED for adults ≥ 18 years of age with focal seizures; similar to carbamazepine and oxcarbazepine but offering simpler dosage titration and once-daily dosing Singh RP, Asconap é JJ. J Cent Nerv Syst Dis. 2011;3:179; Almeida L, Soares-da-Silva P. Neurotherapeutics. 2007;4:88; Bonif á cio MJ et al. Epilepsia. 2001;42:600; Hebeisen S et al. Epilepsia. 2011;52(suppl 6):257; Almeida L et al. J Clin Pharmacol. 2005;45:1062; Falcão A et al. CNS Drugs. 2012;26:79; Keating GM. CNS Drugs. 2014;28:583; Chung S et al. AAN 2014, Poster 3.329; Benbadis S et al. AAN 2014, Poster 3.237; Gil-Nagel A et al. Acta Neurol Scand. 2009;120:281

5. © 2015 Direct One Communications, Inc. All rights reserved. 5 Stiripentol Not FDA approved; orphan drug status in the US GABA receptor modulator Daily dose: 50–100 mg/kg (maximum, 4 g) PO in 2–3 divided doses Overall assessment: Niche drug for use with clobazam and valproate as adjunctive therapy of refractory generalized tonic-clonic seizures in patients with severe myoclonic epilepsy in infancy (Dravet syndrome) whose seizures are not adequately controlled Poisson M et al. Arzneimittelforschung. 1984;34:199; Fisher JL. Eur J Pharmacol. 2011;654:160; Tran A et al. Clin Pharmacol Ther. 1997;62:490; Chiron C et al. Lancet. 2000;356:1638; Levy RH et al. Clin Pharmacol Ther. 1984;36:661; Kassa ï B et al. Epilepsia. 2008;49:343; Wirrell EC et al. Epilepsia. 2013;54:1595; Peign é S et al. Epilepsy Res. 2014;108:909

6. © 2015 Direct One Communications, Inc. All rights reserved. 6 Vigabatrin Broad-spectrum AED GABA transaminase inhibitor Daily dose: for infantile spasms, up to 150 mg/kg PO in 2 divided doses; for refractory complex partial seizures, 1,000 mg PO twice daily for patients 10–16 years old and 1,500 mg PO twice daily for those > 16 years of age or weighing > 60 kg May cause permanent vision loss (FDA black-box warning) Overall assessment: Drug of choice for patients with epileptic spasms and tuberous sclerosis Ben-Menachem E. Acta Neurol Scand Suppl. 2011;192:5; Appleton RE et al. Epilepsia. 1999;40:1627; Ben- Menachem E, Sander JW. Acta Neurol Scand Suppl. 2011;192:16; Wild JM et al. CNS Drugs. 2009;23:965

7. © 2015 Direct One Communications, Inc. All rights reserved. 7 Perampanel Broad-spectrum AED First-in-class AMPA glutamate receptor antagonist Daily dose: 4–12 mg PO in a single dose Use with caution in patients with hepatic or renal failure May cause aggression and hostility (FDA black-box warning) Overall assessment: Useful adjunctive therapy for patients ≥ 12 years of age with partial-onset seizures, with or without generalized seizures, particularly for those who are refractory to other AEDs Faulkner MA. Am J Health Syst Pharm. 2014;71:191; Steinhoff BJ et al. Epilepsia. 2013;54:1481; Michael A. Epilepsy Curr. 2011;11:56

8. © 2015 Direct One Communications, Inc. All rights reserved. 8 Lacosamide Narrow-spectrum AED Enhances slow inactivation of sodium channels Daily dose: 150–200 mg PO twice daily Overall assessment: Useful as monotherapy or adjunctive therapy for patients ≥ 17 years of age with partial-onset seizures, with or without secondary generalization; IV formulation is useful in inpatient/emergency department settings; possible role in status epilepticus Chung S et al. Epilepsia. 2010;51:958; Hoy SM. CNS Drugs. 2013;27:1125; Italiano D, Perucca E. Clin Pharmacokinet. 2013;52:627; Cawello W et al. Epilepsia. 2013;54:530; Grosso S et al. Acta Neurol Scand. 2014;129:420; H ö fler J, Trinka E. Epilepsia. 2013;54:393; Stephen LJ et al. Epilepsy Behav. 2011;22:499; Sake JK et al. CNS Drugs. 2010;24:1055

9. © 2015 Direct One Communications, Inc. All rights reserved. 9 Rufinamide Broad-spectrum AED Prolongs inactive state of sodium channels Daily dose: 45 mg/kg (maximum, 3,200 mg) PO in 2 divided doses Overall assessment: Indicated for adjunctive treatment of Lennox-Gastaut syndrome in patients ≥ 4 years of age; possibly useful as a third-line AED for treating focal epilepsy Grosso S et al. Eur J Paediatr Neurol. 2014;18:641; Thome-Souza S et al. Epilepsia. 2014;55:1235; Cusmai R et al. Epilepsy Res. 2014;108:542

10. © 2015 Direct One Communications, Inc. All rights reserved. 10 Clobazam Broad-spectrum AED Potentiation of GABAergic neurotransmission Daily dose: for patients weighing ≤ 30 kg, 5–20 mg PO in 2 divided doses; for those weighing > 30 kg, 10–40 mg PO in 2 divided doses Overall assessment: Currently approved only for treatment of Lennox-Gastaut syndrome in patients ≥ 2 years of age but also may be useful as adjunctive therapy of Dravet syndrome and as second- or third- line therapy of focal epilepsy Conry JA et al. Epilepsia. 2014;55:558; Ogungbenro K, Aarons L. Pharm Res. 2015;32:144; Tolbert D et al. Epilepsy Behav. 2014;37:11