NEW WEAPONS IN AN OLD BATTLE SIDDHARTH KAPOOR, MD FAHS DIRECTOR, UK EPILEPSY NETWORK DIRECTOR, HEADACHE MEDICINE PROGRAM DIRECTOR, FELLOWSHIP, HEADACHE MEDICINE ASST. PROF. DEPT. OF NEUROLOGY UNIV. OF KENTUCKY COLLEGE OF MEDICINE, LEXINGTON, KY

Disclosures PI & SUBI FOR MULTIPLE DRUG TRIALS ON AED AT UK WITH NO DIRECT BENEFIT SPEAKERS BUREAU FOR ALLERGAN: NO AED 2 MEALS IN THE LAST 12 MONTHS DURING INDUSTRY SPONSORED EVENTS(UCB) WILL DISCUSS EVIDENCE BASED, BUT OFF LABEL, USE OF EMERGING THERAPIES

1.Review changes in the definition of epilepsy 2.Review the clinical use of recently approved anti- epileptic drugs 3.Review the recent approval of responsive neurostimulation for the treatment of epilepsy OBJECTIVES

Defining the battle Epilepsia, 55(4):475–482, 2014 CONCEPTUAL DEFINITON: disorder of the brain characterized by an enduring predisposition to generate epileptic seizures. PRACTICAL DEFINITION :two unprovoked seizures >24 h apart. (1)At least two unprovoked (or reflex) seizures occurring >24 h apart (2) one unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after two unprovoked seizures, occurring over the next 10 years; (3) diagnosis of an epilepsy syndrome. RESOLUTION: for individuals past the applicable age who had an age- dependent epilepsy syndrome who have remained seizure-free for the last 10 years and off antiseizure medicines for at least the last 5 years.

RECOMMENDED CHANGES WHAT’S IN  DISEASE  ENDURING PREDISPOSITION  RESOLVED  DISEASE  ENDURING PREDISPOSITION  RESOLVED WHAT’S OUT  DISORDER  UNPROVOKED / PROVOKED  REMISSION

Medical & Device Advances Vagus Nerve Stimulator Deep Brain Stimulator (SANTE) NOT FDA APPROVED Responsive Neuro-Stimulation ( Neuropace; FDA Approved)

 lacosamide  Rufinamide  vigabatrin  ezogabine/ retigabine in Europe  clobazam  perampanel  eslicarbazepine In the last 5 years

 Formulation:  Oral  Tablet & Solution (10mg/ml),  IV (10 mg/ml)  1:1 conversion between formulations  MOA: Voltage gated Na + channels in SLOW inactivated state  Metabolism: Biotransformation & renal excretion  Interactions: NONE  Dosing: 50 mg bid x 1 week then increase 100 mg/week to goal 200 mg – 400 mg/day LACOSAMIDE

 SE: Dizziness (30%), Headache (14%), Nausea (11%), Diplopia (10%)  BLACK BOX WARNING: Suicidality & Depression (AAN QI)  CARDIAC: PR interval prolongation, Atrial arrhythmias.  Recommended: Baseline EKG  Women with childbearing potential:  Interaction with OCPs: NONE  Pregnancy: Category C  DEA SCHEDULE V  FDA APPROVAL FOR ADJUNCTIVE USE WITH POS LACOSAMIDE

Lacosamide Responder Rate for Adjunctive Therapy in Adults with Partial‐Onset Seizures Epilepsia Volume 48, Issue 7, pages , 16 JUL 2007 DOI: /j x Volume 48, Issue 7,

Lacosamide Median seizure reduction as Adjunctive Therapy in Adults with Partial‐Onset Seizures Epilepsia Volume 48, Issue 7, pages , 16 JUL 2007 DOI: /j x Volume 48, Issue 7,

 STATUS EPILEPTICUS: CLASS IV EVIDENCE  136 episodes of refractory SE (50% NCSE, 31% focal SE, and 19% convulsive SE) ; Success rate was 56% Hofler, J. and E. Trinka (2013). Epilepsia 54(3):  126 patients IV lacosamide for SE /seizure clusters overall success rate of 67%. ( Retrospective, open label, uncontrolled, no protocol, publication bias, off label use) [Trinka, E. (2011), Epilepsia, 52: 35–38] LACOSAMIDE

 Pediatric:  Awaiting further studies in POS,  Safe and effective in open label study (Yorns et al J Child Neurol :23-27),  safe and effective in infants and young children (Grosso, S. et al, European Journal of Paediatric Neurology, 2014)  Generalized epilepsy: Case reports, Trial completed, Results not known, Open label study (SP0962) suggested no worsening  Monotherapy: Trial completed, results not known  LGS: might be effective (Grosso, S.Acta Neurol Scand 2014) LACOSAMIDE: CLINICAL USE

 FORMULATION: Tablet (200/400 mg) or suspension (40 mg/ml)  MOA: Broad spectrum Na + channel blocker  Metabolism: Hydrolysis to acid & renal excretion  Interactions:  RUF clearance decreased by VPA  P450 inducers (PHT, PB, CBZ) can decrease RUF levels  Dosing:  Adults: mg/qd, increase mg every od to max 3200 mg/day Children: 10mg/kg/day. Increase 10mg/kg every od. Target 45/mg/kg/day. RUFINAMIDE

 SE: Adults: HA, Dizziness, Fatigue, Nausea  Children: Somnolence, Vomiting and HA  CARDIAC: QT Shortening  SYSTEMIC: DRESS and SJS  Women with childbearing potential:  Interaction with OCPs: Possible. Use non-hormonal contraception.  Pregnancy: Category C  DEA SCHEDULE  FDA APPROVAL FOR ADJUNCTIVE TREATMENT IN LGS > 4 YR RUFINAMIDE

Median percentage reduction in total seizure frequency and tonic–atonic seizure frequency Glauser T et al. Neurology 2008;70: © 2013 American Academy of Neurology

Responder rate Glauser T et al. Neurology 2008;70: © 2013 American Academy of Neurology

Rufinamide for the adjunctive treatment of partial seizures in adults and adolescents: A randomized placebo‐controlled trial ( NOT FDA APPROVED) Epilepsia Volume 50, Issue 8, pages , 1 JUN 2009 DOI: /j x Volume 50, Issue 8,

 Formulation: Tablets (50, 200, 300, 400 mg)  MOA: K + channel opener  Metabolism: Hepatic  Interactions: PHT & CBZ can lower EZG  Dosing: 100 mg tid x 1 week, max titration 150 mg/day. Goal 200 mg tid to 400 mg tid EZOGABINE

 NOTABLE SE:  Urinary Retention due to bladder smooth muscle relaxation (KCN)  Skin Discoloration (“Blue Person syndrome”)  Retinal Pigment changes, 6 MONTHLY OPTHALMOLOGY CHECK RECOMMENDED BY FDA  Neuro-Psychiatric  QT prolongation  FDA recommends to discontinue medication if there is no benefit due to these side effects as they appear to be related to chronic long term use  SE: Dizziness, Confusion, Fatigue, Somnolence  Women with childbearing potential:  Interaction with OCPs: NONE  Pregnancy: Category C  FDA APPROVAL for adjunct use with POS  DEA: SCHEDULE V EZOGABINE

FDA website

Median change in monthly total partial seizure frequency in the intent-to-treat population Porter R J et al. Neurology 2007;68: © 2013 American Academy of Neurology

RESPONDER RATES Porter R J et al. Neurology 2007;68: © 2013 American Academy of Neurology

EZOGABINE  Pediatric  Ring Chromosome 20: case report [Walleigh, DJ et al Pediatric Neurology, November 2013]  NO large population data  NO EVIDENCE TO SUPPORT OFF LABEL USE IN GENERALIZED EPILEPSY, MONOTHERAPY USE, STATUS EPILEPTICUS

 Formulation: Tablet (10, 20 mg) and Oral Suspension (2.5 mg/mL  MOA: GABA A receptors ( BZD)  Metabolism: Hepatic (CYP3A4) & renal excretion  Interactions: CYP2C19 Inhibitors (some OCP)  Dosing: Children <30 kg, start 5 mg/qd up to 20 mg/qd. Adults 10 mg/qd up to 40 mg/qd CLOBAZAM

 SE: Sedation  NOTABLE SE: Stevens Johnson Syndrome  Women of childbearing potential:  Interaction with OCPs: Possible. Use non-hormonal contraception  Pregnancy: Category C  FDA APPROVAL : Adjunctive therapy in LGS > 2 yrs  DEA SCHEDULE IV CLOBAZAM

Mean percentage decreases in weekly rate of seizures Ng Y et al. Neurology 2011;77: © 2013 American Academy of Neurology

Responder rates Ng Y et al. Neurology 2011;77: © 2013 American Academy of Neurology

 Case series in refractory SE: [ Corman, C. et al us, Seizure, June 1998]  CANADA:  1,300 refractory epileptic patients  adults had more complex partial seizures, whereas children had more atypical absence and myoclonic types  Duration of CLB therapy ranged from a few days to > 4 years, with 40% being treated > 1 year  4 years after starting, 40–50% of patients continued CLB. 40% of patients with single seizure type had at least a 50% reduction in seizure frequency (improved).  At least 60% of patients with multiple seizure type had improvement in one or more seizure types, and nearly 40% of the patients had all their seizure types improved.  “Tolerance,” leading to discontinuation of CLB, was reported for 9% [(1991), Clobazam in Treatment of Refractory Epilepsy: The Canadian Experience. A Retrospecti. Epilepsia, 32: 407–416] CLOBAZAM: CLINICAL USE

 Formulation: Tablets (2, 4, 6, 8, 10, 12mg)  MOA: Selective, Non-competitive AMPA receptor antagonist  Half life of 105 hours  Extensive plasma protein binding (95%)  Metabolism: Hepatic (CYP3A4)  Interactions: CYP inducers will induce metabolism (PHT, CBZ or OXC), perampanel does not inhibit or induce  Dosing:  Without inducers: 2mg qhs, Incr weekly by 2mg qhs to max 8 mg qhs  With inducers: 4 mg qhs, Incr weekly by 2mg qhs to max 12 mg qhs PERAMPANEL

 Adverse Effects: Dizziness, Fatigue, Headache, weakness  UNIQUE SE: Gait Disturbance & Falls and violent thoughts, irritability  Women with childbearing potential:  Interaction with OCPs: Possible. Use non-hormonal contraception  Pregnancy: Category C  FDA APPROVAL FOR ADJUNCTIVE THERAPY IN POS  DEA CLASS III PERAMPANEL

Perampanel for adjunctive treatment of partial‐onset seizures: A pooled dose–response analysis of phase III studies Epilepsia Volume 55, Issue 3, pages , 7 MAR 2014 DOI: /epi Volume 55, Issue 3,

 a missed dose is unlikely to cause as much fluctuation in plasma concentration as would be expected for a drug with a short half-life. Importantly, simulations suggest that supplementing a missed dose 6-12h later, followed by continuation of the regular schedule, may not result in any significant "spikes" in perampanel plasma concentrations. (Gidal, Majid et al. 2014)  Increasing perampanel dose from 8 to 12 mg can produce additional benefits in seizure control in at least some patients who tolerate the higher dose. (Kramer, Satlin et al. 2014) PERAMPANEL: DOSING

 Pediatric: Approved for > 12 years for POS  Generalized epilepsy: Trial completed, NO RESULTS  Status Epilepticus: NO DATA  Monotherapy: NO DATA PERAMPANEL: CLINICAL USE

 Formulation: Tablets (200, 400, 600, 800 mg), can be crushed and administered with food  MOA: Na+ channel blocker  Indications: Adjunctive treatment of partial onset seizures  Metabolism: Hepatic & Renal excretion  Interactions: EI-AEDs may need dose adjustments for both agents  Dosing: 400 mg/once daily x 1 wk then increase to 800 mg/once daily ; Max 1200 mg/qd. ESLICARBAZEPINE

 Common SE: Dizziness, somnolence, nausea, headache, diplopia, vomiting, fatigue, vertigo, ataxia, blurred vision, and tremor  Women of childbearing potential:  Interaction with OCPs: Possible. Use non-hormonal contraception  Pregnancy: Category C  FDA APPROVED FOR ADJUNCTIVE THERAPY IN POS > 18?  DEA SCHEDULE: NONE ESLICARBAZEPINE

 Pediatric: Awaiting studies in POS  Generalized epilepsy: NO DATA  Status Epilepticus: NO DATA  Monotherapy: NO DATA ESLICARBAZEPINE: CLINICAL USE

 Extended release formulation of oxcarbazepine (Oxtellar XR)  Extended release formulation of topiramate  Trokendi XR  Qudexy XR NEW XR PREPARATIONS

RNS: Background  Animal and human data suggest that:  Electrographic seizures can be stopped with applied cortical stimulation.  Cortical stimulation can be done safely. Slides courtesy of J. Edwards, MUSC

RNS Slides courtesy of J. Edwards, MUSC

RNS Slides courtesy of J. Edwards, MUSC

RNS Slides courtesy of J. Edwards, MUSC

RNS Slides courtesy of J. Edwards, MUSC

RNS Slides courtesy of J. Edwards, MUSC

RNS Slides courtesy of J. Edwards, MUSC

Figure 2 Mean disabling seizures by month, observed data N represents the number of subjects with seizure data during that interval. Morrell M J Neurology 2011;77: © 2013 American Academy of Neurology

RNS Epilepsia Volume 55, Issue 3, pages , 22 FEB 2014 DOI: /epi , Issue 3,

2 year FU of RNS Epilepsia Volume 55, Issue 3, pages , 22 FEB 2014 DOI: /epi Volume 55, Issue 3, Epilepsia Volume 55, Issue 3, pages , 22 FEB 2014 DOI: /epi Volume 55, Issue 3,

 New definition of epilepsy  Novel mechanisms of action of recently approved drugs  No significant difference in clinical outcome  New era of closed loop neurostimulation  Continued need for future research SUMMARY

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