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TRANSCRIPT
Evidence-Based Management of AEDs in Adults
David Spencer, MDDirector, OHSU Epilepsy Center
Professor, Department of Neurology
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Learning Objectives
• Outline evidence-based antiepileptic treatment options with regard to
• Efficacy
• Mechanism of action
• Pharmacokinetic profile & drug interactions
• Risk of adverse effects
• Updates on new AEDs
brivaracetam
cannabidiol
stiripentol
AEDs Marketed in the US
Is AED Therapy Needed?
Individualize Decision!
For Treatment of First Seizure
⬧ Estimate risk of recurrence• Overall, 16-62% will recur within 5 years• ~30% recurrence if normal evaluation
⬧ Risk factors for relapse• Abnormal imaging• Abnormal neurological exam• Abnormal EEG• Family history of epilepsy
⬧ Individual determination• Driving?• Working? • Consequences of 2nd seizure?
Effectiveness for Epilepsy Syndrome
TolerabilityPotential Adverse Effects
Previous Allergies
PharmacokineticsTitration Rate
Cost Drug Interactions
Individual CircumstancesWomen of Childbearing Age
Comorbidities
MOA
Factors to Consider When Choosing an AED
The Ideal AED
• Effective on multiple seizure types
• No exacerbation of other seizure types
• No side effects
• Predictable pharmacokinetics
• No interaction with other AEDs
Ideally….
We obtain our data from population-based statistical analysis, but …..
Issues with Trials and Guidelines
• Aim to demonstrate safety and efficacy – rarely comparative studies
• Are predominantly in adult patients
• Don’t reflect “real life”• Are predominantly in patients with refractory focal seizures
• Rigid inclusion/exclusion criteria
• Fixed titrations
• Too brief
• Rarely obtain syndrome-specific efficacy
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
What to Compare and Consider?
• How well does the AED work?
• Tolerability & Adverse Events
•Mechanisms of Action
• Drug-drug Interactions
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 (nth) seizure
• Percent entering long-term remission
• Quality of Life
• RetentionBen-Menachem E, et al. Epilepsy Behav. 2010.
Kanner AM, et al. Neurology. 2018; Glauser TA, et al. Epilepsia. 2013.
Comparative Efficacy by Broad Syndrome Categories:
Focal Seizures
Efficacy of Classic AEDs in Patients With Focal Seizures
100
Pe
rce
nt
Co
nti
nu
ing
80
60
40
20
0
0 3 6 9 12 15 18 21 24 27 30 33 36
Months
Phenobarbital
Phenytoin
Primidone
Carbamazepine
Mattson RH, et al. N Engl J Med. 1985.
Focal Seizures:Alternative AEDs (Newer)
• Lamotrigine (Lamictal)1,2,3
• Topiramate (Topamax)1,2,3
• Oxcarbazepine (Trileptal)1,2,3
• Gabapentin (Neurontin)2,3
• Tiagabine (Gabatril)3
• Zonisamide (Zonegran)2,3
• Levetiracetam (Keppra)2,3
• Pregabalin (Lyrica)2,3
1 = FDA indication monotherapy 2 = AAN/ILAE evidence review 3 = FDA indication add-on
• Lacosamide (Vimpat)1,3
• Vigabatrin (Sabril)3
• Ezogabine (Potiga)3
• Perampanel (Fycompa)1,2,3
• Eslicarbazepine (Aptiom)1,3
• Brivaracetam (Briviact)1,3
• Cannabidiol (Epidiolex)3
FDA Prescribing Information; Glauser TA, et al. Epilepsia. 2013.
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 1st line -AE)
• RUF (not 1st line – efficacy)
• LAC/ESL/TPM-XR (B)
• CLB (C)
• OXC-XR (C)
Kanner AM, et al. Neurology. 2018.
SANAD Trial
Time to Treatment Failure
Marson AG, et al. Lancet. 2007.
AFTER 2001
LTG 12 and 8% less treatment failure at 1 and 2 years as compared to CBZ, but similar to OXC
SANAD
Marson AG, et al. Lancet. 2007.
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)
Drugs for Focal-Onset Seizures are NOT all the Same
• Treatment failure due to side effects was least for lamotrigineand gabapentin
• Oxcarbazepine had fewer side effects than carbamazepine but both had relatively high rash rates (6-7%)
• Treatment failure for inadequate seizure control was most for gabapentin
• OXC and CBZ had similar efficacy and relatively high rash rates (6-7%)
• Topiramate showed greatest risk of psychiatric symptoms
Marson AG, et al. Lancet. 2007.
SANAD and AED choice in Focal Epilepsy: Not all the Same
• There are some important differences between drugs, and tolerability is important
• Consider efficacy, but especially tolerability and comorbidities in AED choice
Median % Seizure Reduction* in Regulatory Studies
FDA Prescribing Information.
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%
(Adjunct for Focal Epilepsy)
*Studies used varied widely in populations and methodology
Evidence of Efficacy by Broad Syndrome Categories:
Generalized Seizures
SANAD Trial, Generalized or Unclassified
Time to Treatment Failure
Marson AG, et al. Lancet. 2007.
Pro
bab
ility
of
Re
mai
nin
g o
n D
rug
Time from Randomisation (years)
1.0
0.8
0.6
0.4
0.2
00 1 2 3 4 5 6
ValproateLamotrigineTopiramate Log-rank test statistic
=10.117, df=2, P=.006
Efficacy of AEDs in Patients With Generalized Onset Seizures
• Carbamazepine, Oxcarbazepine/Eslicarbazepine, Vigabatrin, Phenobarbital, and Ethosuximide may aggravate Generalized onset seizures
• Carbamazepine, Phenytoin, Oxcarbazepine/Eslicarbazepine, Vigabatrin, Tiagabine, Lamotrigine, and Pregabalin may aggravate myoclonic seizures
Chaves J, et al. Epilepsia. 2005.
Narrow Spectrum AEDBroad Spectrum AED
Proposed Algorithm
Diagnosis of Epilepsy
Classify Epilepsy Type
Generalized Epilepsy Syndrome
Not Sure (unclassified)
Focal Epilepsy Syndrome
Phenytoin, carbamazepine, oxcarbazepine, gabapentin,
pregabalin, lacosamide, tiagabine, vigabatrin, eslicarbazepine,
brivaracetam or broad spectrum drug
Absence: EthosuximideTonic/Atonic: Rufinamide/clobazamIS: ACTH, prednisolone, vigabatrin
NOS: Valproate, topiramate, lamotrigine, zonisamide, levetiracetam, rufinamide,
felbamate, clobazam, perampanel
Data on Relative EfficacyData on Relative Tolerability
Co-morbiditiesDrug-drug Interactions
CostPharmacokineticsClinical Judgment!
What to Compare and Consider?
• How well does an AED work?
• Tolerability & Adverse Events
• Mechanisms of Action
• Drug-drug Interactions
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
Acute, Dose-Related Adverse Effects of AEDs
Neurologic/Psychiatric – most common
• Sedation, fatigue
• Unsteadiness, incoordination, dizziness
• Tremor
• Paresthesia
• Diplopia, blurred vision
• Mental/motor slowing or impairment
• Mood or behavioral changes
• Changes in libido or sexual function
Bromfield EB, et al. American Epilepsy Society. 2006.
Acute, Dose-Related Adverse Effects of AEDs (cont.)
• Gastrointestinal (nausea, heartburn)
• Mild to moderate laboratory changes
• Hyponatremia (may be asymptomatic)
• Increases in ALT or AST
• Leukopenia
• Thrombocytopenia
• Elevations of alkaline phosphatase
• Weight gain or loss
Bromfield EB, et al. American Epilepsy Society. 2006.
Idiosyncratic Adverse Effects of AEDs
• Rash, Exfoliation
• Signs of potential Stevens-Johnson syndrome
• Skin changes- maculopapular rash
• Fever and mucous membrane involvement
• Laboratory monitoring probably not helpful in early
detection
• Patient education
Bromfield EB, et al. American Epilepsy Society. 2006; Zaccara G, et al. Epilepsia. 2007.
AED-Related Rash in Adults
Arif H, et al. Neurology. 2007.
▲▲= 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)
Idiosyncratic Adverse Effects of AEDs
• Hematologic damage
(aplastic anemia, agranulocytosis)
• Early symptoms: abnormal bleeding, acute onset of
fever, symptoms of anemia
• Laboratory monitoring probably not helpful in early
detection
• Patient education
• Hepatic failure
• Concentric visual field loss
Bromfield EB, et al. American Epilepsy Society. 2006; Zaccara G, et al. Epilepsia. 2007.
Long-Term Adverse Effects of AEDs
• Neurologic:
• Neuropathy
• Cerebellar syndrome
• Endocrine/Metabolic Effects• Vitamin D – Osteomalacia, osteoporosis
• Folate – Anemia, teratogenesis
• Altered connective tissue metabolism or growth• Facial coarsening
• Hirsutism
• Gingival hyperplasia
Bromfield EB, et al. American Epilepsy Society. 2006.
Adverse Events: Unique or Differentiating
PHT: Gingival hyperplasia, hirsutism, cerebellar atrophy
CBZ: Hyponatremia, agranulocytosis
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.
Safety of AEDsAED Black Box Warning
Phenytoin Stevens-Johnson syndromeCardiovascular risk with rapid infusion
Carbamazepine Serious dermatologic reactions (HLA-B 1502 allele), aplastic anemia, and agranulocytosis
Valproate Hepatotoxicity, teratogenicity, pancreatitis
Lamotrigine Serious skin rashes, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and/or rash-related death
Felbamate Aplastic anemia and hepatic failure
Vigabatrin Vision loss
Perampanel Serious behavioral and psychiatric reactions
Clobazam Sedation when used with opiates or other benzodiazepines
FDA Prescribing Information.
Discontinuing AEDs
• Seizure freedom for 2 years implies overall >60% chance of successful withdrawal in some epilepsy syndromes
• Favorable factors• Control achieved easily on one drug at low dose
• No previous unsuccessful attempts at withdrawal
• Normal neurologic exam and EEG
• Genetic Generalized Epilepsy(except JME)
• “Benign” syndrome
• Consider relative risks/benefits (e.g., driving, pregnancy)
Schmidt D, Sillanpaa M. Seizure. 2017.
What to Compare and Consider?
• How well does an AED work?
• Tolerability & Adverse Events
• Mechanisms of Action
• Drug-drug Interactions
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
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. 2000.
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. 2010.
What to Compare and Consider?
• How well does an AED work?
• Tolerability & Adverse Events
• Mechanisms of Action
• Drug-drug Interactions
Antiepileptic Drug Interactions
• Pharmacokinetic• Displacement from plasma proteins
• Metabolic drug interactions• Cytochrome P450 isoenzymes
• Glucuronidation
• Renal excretion
• Pharmacodynamic
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
Potential for Drug-Drug Interactions with AEDs
Cytochrome P450
Negligible or no effect
GabapentinLacosamideLamotrigine
LevetiracetamPregabalinTiagabineVigabatrin
Zonisamide
Asconape, et al. Neurol Clin. 2010.FDA Prescribing Information.
Mild inducers (3A4) or inhibitors (2C19)
Oxcarbazepine, Topiramate, Brivaracetam
Inhibitors(2C9, UGT, EH)
ValproateFelbamate
Inducers(1A2, 2C, 3A4, UGT)
PhenytoinCarbamazepinePhenobarbital
Primidone
Treatment Recommendations: The Elderly
• Choose AEDs according to adverse effect profile and interactions with coexisting medical conditions
• AEDs with no drug-drug interactions are desirable
• Begin at low dosage and titrate to clinical effect
• Monitoring of serum AED levels may be useful
LTG and GBP were better tolerated
than CBZ-IR
Rowan AJ, et al. Neurology. 2005.
Pat
ien
ts R
em
ain
ing
in T
rial
(%
)
Weeks
1.0
0.8
0.6
0.4
0.2
0
0 6 12 18 24 30 36 42 48 54
CarbamazepineGabapentinLamotrigine
Percentage of Patients Remaining in the Trial Over Time (52 weeks)
Pharmacokinetic Factors in the Elderly
• Absorption — little change
• Distribution
• decrease in lean body mass important for highly lipid-
soluble drugs
• fall in albumin leading to higher free fraction
• Metabolism — decreased hepatic enzyme content and blood flow
• Excretion — decreased renal clearance
Bromfield EB, et al. American Epilepsy Society. 2006.
New AEDs:What You Need to Know
New AEDs
Indication Treatment of seizures associated with Lennox-Gastaut syndrome or Dravet syndrome ≥2yo
Dosing Start 5 mg/kg/day (BID)Advance to 10 mg/kg/dayMax 20 mg/kg/day
Common AEs SomnolenceGIMonitor LFTs
Mechanism Uncertain, probably not via cannabinoid receptors
Other Metabolized by CYP3A4 and CYP2C19(Increases clobazam metabolites)
Indication Treatment of seizures associated with Dravetsyndrome ≥2yo taking clobazam
Dosing 50 mg/kg/day in 2-3 divideddosesCapsules or powder for oral suspension
CommonAEs
Somnolence (considerdecreased clobazam)Decreased appetite/weight, neutropenia/thrombocytopenia
Mechanism Uncertain. GABAA and via clobazam inhibition
Other Inhibits CYP3A4 and CYP2C19 (increases clobazam and metabolites)
Cannabidiol Stiripentol
FDA Prescribing Information.
Arriving Soon…
• Rescue Medications• Rectal diazepam gel
• IM autoinjector formulations studied
• Inhaled alprazolam studies underway
• Intranasal midazolam recently approved May 2019• Treatment of acute repetitive seizures
• Age 12 and older
• 5mg spray in one nostril
• May repeat after 10 minutes in other nostril
FDA Prescribing Information; www.clinicaltrials.gov.
Intranasal Midazolam
• Primary Outcome = “Treatment Success”• Seizures stopped within
10 minutes and no recurrences in 6 hours
• Intranasal midazolam: 53.7% success
• Placebo: 34.4% success
Detyniecki K, et al. Epilepsia. 2019.N=292 (262 randomized, 201 treated)
Arriving Soon: Cenobamate
0
10
20
30
40
50
60
% seizure reduction 50% responder rate
YKP3089C013
Placebo 200 mg
0
10
20
30
40
50
60
70
% seizure reduction 50% responder rate
YKP3089C017
Placebo 100 mg 200 mg 400 mg
Kamin M, Ferrari L. Neurology. 2019.
N=222 N=437
Arriving Soon: Cenobamate
• Most common adverse events• Somnolence, dizziness, nausea, fatigue
• Study 2 (YKP3018C017) with initial rapid titration schedule• 1 non-serious rash
• 1 moderate rash with increased AST/ALT
• 1 case of DRESS
• Phase 3 long-term safety/tolerability• N=1339
• No cases of DRESS
Marc Kamin, Louis Ferrari. Neurology. 2019; Sperling M, et al. Neurology. 2019.
Summary
Selection of appropriate therapy should consider the current level of evidence available in conjunction with
patient factors and AED characteristics
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
• For combination therapy: The best combination is one that produces best efficacy with fewest adverse effects
• Always involve patient/family in decision making