AED Treatment Approaches. David Spencer, MD Director, OHSU Epilepsy Center Professor, Department of Neurology

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2 AED Treatment Approaches David Spencer, MD Director, OHSU Epilepsy Center Professor, Department of Neurology

3 Audience Response Keypads Please utilize the keypad at your table to answer questions throughout the program. You will have 10 seconds to answer the question. Please leave the keypad at your table at the end of the day.

4 A 61-year-old woman presents with focal seizures secondary to a left hemispheric stroke. She has atrial fibrillation on warfarin, osteoporosis and history of kidney stones. She was started on phenytoin by her primary care physician, which resulted in a rash. Which of the following is the most appropriate antiepileptic medication in this patient? A. Carbamazepine B. Levetiracetam C. Primidone D. Valproate E. Zonisamide

5 A 28-year-old man presents with several generalized tonicclonic seizure episodes. Some of his events may have started with focal shaking in the right arm, although this history is unclear and is unable to be corroborated. EEG reveals no epileptiform activity or asymmetry, and brain imaging is unremarkable. Of the following anticonvulsants, which would be most appropriate for this patient? A. Gabapentin B. Oxcarbazepine C. Pregabalin D. Phenobarbital E. Zonisamide

6 Learning Objectives Outline evidence-based antiepileptic treatment options with regard to efficacy, mechanism of action, pharmacokinetic profile, drug interactions, and risk of adverse effects

7 AEDs Marketed in the US 1912 Phenobarbital 1935 Mephobarbital 1938 Phenytoin 1947 Mephenytoin 1954 Primidone 1957 Methsuximide 1960 Ethosuximide 1968 Diazepam 1974 Carbamazepine 1975 Clonazepam 1978 Valproate 1981 Clorazepate 1993 Felbamate 1994 Lamotrigine 1996 Topiramate 1997 Tiagabine 2000 Zonisamide 2000 Levetiracetam 2000 Oxcarbazepine 2006 Pregabalin 2008 Lacosamide 2009 Vigabatrin 2009 Rufinamide 2012 Clobazam 2012 Ezogabine 2013 Eslicarbazepine 2013 Perampanel 2016 Brivaracetam 2018 Cannabidiol

8 How Do You Select an AED? A. Based on evidence in literature B. Based on experts experiences C. Based on my own experiences D. Based on what others taught me E. Based on insurance coverage F. All of the above

9 Factors to Consider When Choosing an AED Tolerability Potential Adverse Effects Previous Allergies Individual Circumstances Women of Childbearing Age Comorbidities Effectiveness for Epilepsy Syndrome MOA Pharmacokinetics Titration Rate Cost Drug Interactions

10 The Ideal AED Effective on multiple seizure types No exacerbation of other seizure types No side effects Predictable pharmacokinetics No interaction with other AEDs

11 Ideally. We obtain our data from population-based statistical analysis, but..

12 Issues with Trials Aim to demonstrate safety and efficacy rarely comparative studies Are predominantly in adult patients Are predominantly in patients with focal seizures Rarely obtain syndrome-specific efficacy, although this is the only variable that can be analyzed in an evidence-based manner Too brief

13 What to Compare and Consider? How well does the AED work? Tolerability & adverse events Mechanisms of action Drug-drug interactions Metabolism pathways Use in comorbidities Pregnancy safety FDA indications Formulations Cost

14 What to Compare and Consider? How well does the AED work? Tolerability & Adverse Events Mechanisms of Action Drug-drug Interactions

15 How Well Does an AED Work? Efficacy (effectiveness=efficacy and tolerability) Reduction in seizure rate Seizure freedom Responder rate: 50% reduction from baseline Actual seizure reduction compared to baseline Reduction in seizure severity Time to first (n th ) seizure Percent entering long-term remission Quality of Life Retention Ben-Menachem E, et al. Epilepsy Behav

16 Correct diagnosis Focal Generalized Unknown Specific syndrome Efficacy Incorrect diagnosis may lead to incorrect treatment Lack of efficacy or actual exacerbation

17 Kanner AM, et al. Neurology. 2018; Glauser TA, et al. Epilepsia

18 Evidence of Efficacy 64 RCT (7 class I and 2 class II) 11 meta-analysis Alarming lack of studies for patients with generalized epilepsy and children in general Glauser TA, et al. Epilepsia

19 Evidence of Efficacy by Syndrome

20 Ethosuximide, Valproate, and Lamotrigine in Childhood Absence Seizures Freedom-from-failure rates (%) 70% 60% 50% 40% 30% 20% 10% Attentional dysfunction was more common with valproic acid than with ethosuximide (in 49% of the children vs 33%) * 53% * 58% 29% *P<.001 vs. lamotrigine 0% Ethosuximide Valproic acid Lamotrigine Glauser, et al. N Engl J Med

21 Cumulative % with spasms Days from Randomization Vigabatrin Hormone Number at risk of relapse Hormone Vigabatrin Proportion with no spasms at Days 13 and 14: Hormonal 73% Vigabatrin 54% P=.043 Adverse Events: Hormonal 55% Vigabatrin 54% Lux AL, et al. Lancet. 2004; Lux AL, et al. Lancet Neurol

22 Lennox-Gastaut Syndrome Cochrane review 2013: The optimum treatment for Lennox-Gastaut syndrome remains uncertain and no study to date has shown any one drug to be highly efficacious Best evidence/fda indication*: Topiramate, felbamate, clonazepam, lamotrigine, rufinamide, valproate, clobazam Some evidence of efficacy: zonisamide, levetiracetam *All adjunctive except clonazepam Hancock EC, Cross JH. Cochrane Database Syst Rev. 2013; Azar NJ, et al. Semin Neurol

23 Dravet Syndrome Randomized, placebo-controlled trial Placebo (N=20) Stiripentol (N=21) Responders 5% 71% <.0001 Change in frequency +7% -69% <.0001 Seizure free 0% 43%.0013 P Chiron C, et al. Lancet

24 Median % Reduction Cannabidiol and Dravet and LGS Dravet Syndrome Lennox-Gastaut Syndrome Percent Change from Baseline in Drop and Total Seizure Frequency (28-day Change) 60% 50% 40% 30% 20% 10% 0% Drop Seizures P= % 49% Treatment Period P= % 20% Maintenance Period P= % 45% Treatment Period Total Seizures P= % 15% Maintenance Period CBD (n=86) Placebo (n=85) Significantly greater reductions for CBD than for placebo; this difference was established during the first 4 weeks of maintenance. Reduction in non-drop seizures was statistically different for subgroup of pts who had non-drop seizures: CBD (n=77; 49%) vs placebo (n=79, 23%) (P=.0044) Devinsky O, et al. N Engl J Med. 2017; Adapted from Thiele EA, et al. AES Abstract

25 Median Percent Reduction in Seizure Frequency Cannabidiol and Dravet and LGS Lennox-Gastaut Syndrome Estimated median difference, 21.6 percentage points 95% CI, ) P=0.005 Estimated median difference, 19.2 percentage points 95% CI, ) P=0.002 Estimated median difference, 18.8 percentage points 95% CI, ) P=0.009 Estimated median difference, 19.5 percentage points 95% CI, ) P=0.002 Estimated median difference, 22.4 percentage points 95% CI, ) Estimated median difference, 28.3 percentage points 95% CI, ) Devinsky O, et al. NEJM

26 Do CBZ and PHT Exacerbate Juvenile Myoclonic Epilepsy? (%) Worse Better Unchanged CBZ, N=28 PHT, N=16 Genton P, et al. Neurology

27 Do Certain AEDs Exacerbate Absence Epilepsy? Scattered reports: CBZ, OXC, PB, PHT, TGB, VGB may aggravate absence seizures (Juvenile and Childhood) Somerville ER. Epilepsia. 2009; Guerrini R, et al. Epilepsia

28 Evidence of Efficacy by Broad Syndrome Categories: Focal Seizures

29 Percent Continuing Efficacy of Classic AEDs in Patients With Focal Seizures Phenytoin Carbamazepine Primidone Phenobarbital Months Mattson RH, et al. N Engl J Med

30 Patients Remaining in Trial (%) 1.0 Percentage of Patients Remaining in the Trial Over Time (52 weeks) Carbamazepine Gabapentin Lamotrigine LTG and GBP were better tolerated than CBZ-IR Weeks Rowan AJ, et al. Neurology

31 SANAD Trial Time to Treatment Failure AFTER 2001 LTG 12 and 8% less treatment failure at 1 and 2 years as compared to CBZ, but similar to OXC Marson AG, et al. Lancet

32 SANAD Time to 12 Month Remission CBZ and LTG had the shortest time to 12 month remission CBZ > LTG/TPX/OXC non-significant CBZ > GBP (significant) Marson AG, et al. Lancet

33 SANAD Trial Treatment failure due to side effects was least for lamotrigine and gabapentin Treatment failure for inadequate seizure control was most for gabapentin OXC and CBZ had similar treatment failure rates OXC was more likely to fail because seizure control and less likely to fail because of side effects Marson AG, et al. Lancet

34 Median % Seizure Reduction* in Regulatory Studies (Adjunct for Focal Epilepsy) Ezogabine (900 mg) 40% Gabapentin (1800 mg) 26% Lacosamide (400 mg) 41% Levetiracetam (3000 mg) 39% Lamotrigine (500 mg) 36% Oxcarbazepine (1200 mg) 40% Pregabalin (600 mg) 48% Tiagabine (56 mg) 36% Topiramate (800 mg) 43% Zonisamide (400 mg) 40% *Studies used varied widely in populations and methodology FDA Prescribing Information.

35 AAN/AES Guidelines New Onset (2004; Level A/B) GBP LMT TPM OXC New Onset (2018) LMT (B) Should LEV (C) May ZNS(C) Adjunctive (2004; Level A/B) GBP/LMT/LEV/OXC/TGB/TPM/ ZNS Adjunctive (2018) PER/PGB (A) Established VGB (not 1 st line -AE) RUF (not 1 st line efficacy) LAC/ESL/TPM-XR (B) CLB (C) OXC-XR (C) Kanner AM, et al. Neurology

36 Evidence of Efficacy by Broad Syndrome Categories: Generalized Seizures

37 Probability of Remaining on Drug SANAD Trial, Generalized or Unclassified 1.0 Time to Treatment Failure Valproate Lamotrigine Topiramate Log-rank test statistic =10.117, df=2, P= Time from Randomisation (years) Marson, et al. Lancet

38 Efficacy of AEDs in Patients With Generalized Onset Seizures CBZ and PHT may aggravate generalized onset seizures Lamotrigine may aggravate myoclonic seizures Guerrini R, et al. Epilepsia

39 Proposed Algorithm Generalized Epilepsy Syndrome Diagnosis of Epilepsy Data on Relative Efficacy Data on Relative Tolerability Classify Epilepsy Type Co-morbidities Drug-drug Interactions Cost Pharmacokinetics Not Sure Clinical (unclassified) Judgment! Focal Epilepsy Syndrome Absence: Ethosuximide Tonic/Atonic: Rufinamide/clobazam IS: ACTH, Broad prednisolone, Spectrum vigabatrin AED NOS: Valproate, topiramate, lamotrigine, zonisamide, levetiracetam, rufinamide, felbamate, clobazam, perampanel Phenytoin, carbamazepine, oxcarbazepine, gabapentin, pregabalin, Narrow lacosamide, Spectrum AED tiagabine, vigabatrin, eslicarbazepine, brivaracetam or broad spectrum drug

40 What to Compare and Consider? How well does an AED work? Tolerability & Adverse Events Mechanisms of Action Drug-drug Interactions

41 Adverse Effects Acute dose-related: Non-differentiating Common, benign, predictable Sedation, dizziness Idiosyncratic Rare, serious, unpredictable Skin, liver, bone marrow Unique to particular drugs Vary by drug Reversibility varies

42 Adverse Events: Unique or Differentiating PHT: Gingival hyperplasia, hirsutism, cerebellar atrophy CBZ: Hyponatremia, agranulocytosis EZG: Urinary retention VPA: Weight gain, hair loss GBP: Weight gain, pedal edema LTG: Rash, insomnia TPM: Weight loss, kidney stones OXC: Hyponatremia PGB: Weight gain, pedal edema LEV: Behavior or psychiatric changes ZNS: Weight loss, kidney stones VGB: Visual field changes, white matter changes FDA Prescribing Information.

43 AED Phenytoin Safety of AEDs Black Box Warning Stevens-Johnson syndrome Cardiovascular risk with rapid infusion Carbamazepine Serious dermatologic reactions (HLA-B 1502 allele), aplastic anemia, and agranulocytosis Valproate Lamotrigine Felbamate Vigabatrin Perampanel Clobazam Hepatotoxicity, teratogenicity, pancreatitis Serious skin rashes, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and/or rashrelated death Aplastic anemia and hepatic failure Vision loss Serious behavioral and psychiatric reactions Sedation when used with opiates FDA Prescribing Information.

44 AED-Related Rash in Adults = rash rate significantly greater than average of all other AEDs (P<.003) = rash rate significantly lower than average of all other AEDs (P<.003) = trend towards significantly higher than average rash rate of all other AEDs (.003<P<.05) = trend towards significantly lower than average rash rate of all other AEDs (.003<P<.05) Arif, et al. Neurology

45 Summary of Old vs. New Studies New = Old AEDs for efficacy New Old AEDs for tolerability Posner EB, et al. Seizure. 2005; Muller M, et al. Cochrane Database Syst Rev

46 What to Compare and Consider? How well does an AED work? Tolerability & Adverse Events Mechanisms of Action Drug-drug Interactions

47 What About MOA? We don t understand some MOAs Many drugs may have multiple relevant mechanisms We are assuming what we see in mice and rats studies applies to humans Does this help when we attempt rational polytherapy? Synergy between medications

48 Can Different Mechanisms Be Used to the Patient s Advantage? Reinforcement on a single pharmacological pathway is less effective than a combined effect on two distinct pathways. Examples: Lacosamide, eslicarbazepine: Na + channels Perampanel: AMPA receptor antagonist Most successful in lab studies appears to be a drug with a single mechanism of action combined with another that has multiple mechanisms Side effects more likely if combining two with similar mechanism of action and occasionally has less efficacy Deckers CL, et al. Epilepsia

49 Can Different Mechanisms Be Used to the Patient s Advantage? Anecdotal reports: Phenobarbital and phenytoin: GTC Ethosuximide and valproic acid: Absence seizures Carbamazepine and valproic acid: Focal seizures Lamotrigine and topiramate: Different types Clinical trials: Valproic acid and lamotrigine Lacosamide and Na + channel blockers Pisani F, et al. Epilepsia. 1999; Sake JK, et al. CNS Drugs

50 What to Compare and Consider? How well does an AED work? Tolerability & Adverse Events Mechanisms of Action Drug-drug Interactions

51 Antiepileptic Drug Interactions Pharmacokinetic Displacement from plasma proteins Metabolic drug interactions Cytochrome P450 isoenzymes Glucuronidation Renal excretion Pharmacodynamic

52 Displacement from Plasma Proteins Clinically important only for drugs >90% protein bound Phenytoin, valproic acid, diazepam, tiagabine, perampanel Only the free fraction of drug is active Small proportion of total drug displaced (may be substantial increase in free drug) Therapeutic effects seen at lower total drug level

53 Potential for Drug-Drug Interactions with AEDs Inducers (1A2, 2C, 3A4, UGT) Phenytoin Carbamazepine Phenobarbital Primidone Inhibitors (2C9, UGT, EH) Valproate Felbamate Cytochrome P450 Negligible or no effect Gabapentin Lacosamide Lamotrigine Levetiracetam Pregabalin Tiagabine Vigabatrin Zonisamide Mild inducers (3A4) or inhibitors (2C19) Oxcarbazepine, Topiramate, Brivaracetam Asconape, et al. Neurol Clin FDA Prescribing Information.

54 Summary Selection of appropriate monotherapy should consider the current level of evidence available in conjunction with patient factors and AED characteristics

55 Summary Diagnose the seizure type and syndrome in order to select the most appropriate AED Select the most appropriate initial treatment and individualize therapy: aim for seizure freedom and adverse effect freedom. BUT also consider factors such as titration regimen, simplicity of use (once daily) and impact on overall patient outcomes, comorbidities Always involve patient/family in decision making

56 Summary For combination therapy: The perceived best combination is one that produces best efficacy with fewest adverse effects