Disclosures CHOOSING THE RIGHT I am President of the Epilepsy - PowerPoint PPT Presentation

2/15/2018 Disclosures CHOOSING THE RIGHT • I am President of the Epilepsy Study Consortium. All consulting is done on behalf of the consortium, and fees are paid to the consortium. The NYU Comprehensive Epilepsy Center receives salary support from the consortium; ANTIEPILEPTIC DRUG • I have acted as a consultant for Acadia, Acorda, Adamas, Alexza, Anavex, Axcella Health, Biogen, BioPharm Solutions, Cavion, Cerecor, Concert Pharmaceuticals, Covance, CuroNZ, Eisai, Empatica, Engage, Georgia Regents University, Glaxo Smith-Kline, GW Pharma, J&J Pharmaceuticals, Marinus, MonosolRx, Monteris, Nestle-Health Science, Neurelis, Novartis, Otsuka, Ovid, Pfizer, Pfizer-Neusentis, Sage Therapeutics, Shire, SK Life Sciences, Sunovion, Takeda, UCB Inc., Upsher Jacqueline A. French, M.D. Smith, Ultragenyx, Xenon Pharmaceuticals, Xeris, Zogenix and Zynerba • I have received grants from Acorda, Alexza, Eisai Medical Research, LCGH, Professor of Neurology Lundbeck, Pfizer, SK Life Sciences, Sunovion, Takeda, and UCB, Epilepsy Research Foundation, Epilepsy Study Consortium, Epilepsy Therapy Project, and NINDS New York University • I am on the editorial board of Lancet Neurology, Neurology Today and Epileptic disorders. What do we know about Suzie? Example :Drug selection • Suzie is single, but has a steady boyfriend • Sometime in the future, she wants to get married, and have • You need to select a drug for Suzie children • Suzie is a 21 year old college student • Suzie also suffers from mild depression-She currently takes who just presents with two GTCC. EEG citalopram which is working well. • Suzie is slightly overweight and is very worried about gaining shows generalized spike-wave. On more weight questioning, she reveals she has also • Suzie is premed, and needs to get the best grades to be had morning myoclonus competitive. 1

2/15/2018 Antiepileptic Drugs: 2018 Should Choices Be The Same For Everyone ? 1 st Generation 3rd Generation Phenytoin u Carbamazepine u Zonisamide u Sodium Valproate u Pregabalin u Phenobarbital u Lacosamide u Primidone u Rufinamide u 2 nd Generation Vigabatrin u Clobazam Felbamate u u Gabapentin Ezogabine u u Perampanel Lamotrigine u u Eslicarbazepine Topiramate/ u u Brivaracetam Tiagabine u u Oxcarbazepine u Levetiracetam Is there a drug of first choice? u How about using evidence-based Typical Randomized Controlled guidelines/RCT data to select? Trials vs Real Life  Evidence-based guidelines can provide some specific instructions for specific situations, but cannot select a specific drug for a specific patient  RCT’s are “idealized situations, and many of the unique characteristics of patients that would guide treatment choice would have excluded that patient from clinical trials! – (eg psychiatric disorders, desire for pregnancy, concomitant Restricted ages medical condition) No other medical Problems No psychiatric disease No pregnancy 2

2/15/2018 Using evidence-based guidelines/RCT data to select What we • The evidence is incomplete Know from RCT’s What we learn in other ways EXTRAPOLATION • FDA now accepts that • What is the class I evidence that drugs that work as add- any AED, old or new, is effective as on in a given syndrome will also work when monotherapy in Juvenile used as monotherapy Myoclonic Epilepsy? (and you should too!) 3

2/15/2018 Question # 1: What is the epilepsy Making choices syndrome? • Classification extremely important • Best to consider a number • Need to at least subdivide into: of questions, in order of – Generalized importance • Genetic (absence, myoclonic, GTCC) (formerly Idiopathic ) • Eventually, number of – Focal (formerly partial) appropriate drugs will be • Focal Aware (FA), focal with impaired awareness (FIA)(formerly simple partial and complex partial whittled down to one or seizures) 1 two • Focal seizures to bilateral tonic-clonic convulsion (formerly secondarily generalized TCC) 1 1. Operational Classification of Seizure Types by the International League Against Epilepsy Fisher et al, Epilepsia 2017 in press Question # 1: What is the epilepsy Generalized/Combined/Unknown onset syndrome? 1 • Different AED choices needed for pts with generalized/combined epilepsy or cannot – Combined Generalized and Focal Epilepsies be classified at time of diagnosis – Often, TCC, unclear if focal or generalized • Usually associated with epileptic encephalopathy. Both generalized seizures (tonic, atonic) and focal u Several AEDs may u Broad-spectrum seizures can occur. Formerly “Symptomatic exacerbate, or fail to treat agents a better generalized seizures: choice in these pts generalized” e.g. Lennox-Gastaut – Unknown Onset u Carbamazepine u Valproic acid • An important category-for example tonic-clonic u Oxcarbazepine u Topiramate seizures occurring in isolation with a normal EEG. u Lamotrigine u Tiagabine u Levetiracetam u Gabapentin/pregabalin 1. ILAE Classification of the Epilepsies:Position Paper of the ILAE Commission for u Zonisamide Classification and Terminology. Scheffer et al. Epilepsia 2017 in press u Perampanel 4

2/15/2018 Question # 2: How well does the Monotherapy 2018 drug work • In the past, few AEDs FDA approved for use as monotherapy, because monotherapy trials (very difficult)were required to obtain approval • Fall 2017: Change in FDA perspective, trials no longer • Efficacy in newly diagnosed patients necessary (efficacy can be extrapolated). Once add-on studies are completed, PK and safety studies in monotherapy are sufficient for monotherapy approval. • Relative efficacy in treatment resistant • This means monotherapy approval will be available quickly for new AEDs • Eslicarbazepine (Aptiom TM ) Lacosamide (Vimpat TM ), patients perampanel (Fycompa TM ), Brivaracetam (Briviact TM ) already approved for monotherapy • Seizure free rate in treatment resistance • Notably Levetiracetam (Keppra TM ) still not approved as monotherapy ACTIVE-CONTROL COMPARISON Equivalence To A “Standard” STUDY STILL REQUIRED IN (Carbamazepine, Lamotrigine) EUROPE FOR MONOTHERAPY Demonstrated In Newly Diagnosed Patients (gtcc or focal seizures) • YES TREATMENT B – Oxcarbazepine • NO (NOT EQUIVALENT) – Lamotrigine – Pregabalin (? Inferior) TREATMENT A – Gabapentin – Vigabatrin (? Inferior) – Topiramate BASELINE TITRA- • TREATMENT NO (NOT DONE) TION – Levetiracetam – Tiagabine – Ezogabine – Zonisamide – Perampanel – Eslicarbazepine 1 – Brivaracetam – Lacosamide 1. Published in abstract form only 5

2/15/2018 Seizure Freedom In Randomized Question # 3: What Are The Controlled Add-on Trials* Adverse Reactions Associated Dose Sz Free AED Gabapentin 600-1800 mg up to 1.1% With The Drug? Lamotrigine 300-500 mg .8% It is important to consider side effects when selecting an Topiramate 200-1000 mg 5% (pooled) Oxcarbazepine 600-2400 mg 2.2% AED, and avoid potential issues in advance Levetiracetam 1000-3000 mg up to 6.4%  Dose-related Zonisamide 500 mg 1.7%  Idiosyncratic-minor Pregabalin 50-600 mg up to 1.1%  Idiosyncratic-Major Lacosamide 600mg 3.0 % Eslicarbazepine 2400 mg 2.0 %  Exacerbation of co-morbidities Perampanel 12 mg 1.9 %  Teratogenicity *Based on completer ITT, Gazzola et al Epilepsia 2007 Jul;48(7):1303-7 Chung et al CNS Drugs. 2010;24(12):1041-54,Kramer et al, Epilepsia. 2014 ;55(3):423-31, personal communication Sunovion Specific Adverse Reactions More Common Adverse Events Should Drive AED Choice: • Dose-Related – May occur at any dose, but likelihood goes up • Risk of Hyponatremia (on diuretics, elderly): avoid as dose goes up carbamazepine, oxcarbazepine, eslicarbazepine – May happen during titration, then abate • Psychiatric/Behavioral • Risk/Hx of Renal calculi: Avoid topiramate, zonisamide • Body changes • Hx eating disorder: Avoid drugs that impact weight – Hormonal changes, bone changes • Increase in cardiovascular risk factors (High cholesterol, • Laboratory – Change in laboratory values other risk factors present): Avoid carbamazepine, phenytoin 6

2/15/2018 Drugs That Are More Likely To Impact WEIGHT Psychiatric Function* May Worsen May Improve • Levetiracetam • Some antiepileptic • Carbamazepine • Topiramate drugs increase or • Valproate • Zonisamide decrease weight • Lamotrigine • Tiagabine • Only happens to a • Pregabalin (anxiety) • Phenobarbital portion of those • Perampanel taking drug, not all. *This is only the most common-sometimes each can do the opposite! All AEDs may be associated with suicidality ANTIEPILEPTIC DRUGS THAT ANTIEPILEPTIC DRUGS THAT AFFECT WEIGHT AFFECT WEIGHT INCREASE Valproate (Depakote TM ) DECREASE Gabapentin (Neurontin TM ) Topiramate Carbamazepine (Tegretol TM , Carbatrol Zonisamide TM ) Felbamate Pregabalin (Lyrica TM ) Ezogabine (Potiga TM ) Perampanel (Fycompa TM ) 7