Evidence-Based Management ofd2qrtshcpf0x30.cloudfront.net/nodes/58/Evidence... · Evidence-Based Management of AEDs in Adults David Spencer, MD Director, OHSU Epilepsy Center

Evidence-Based Management of AEDs in Adults

David Spencer, MDDirector, OHSU Epilepsy Center

Professor, Department of Neurology

• 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.

Audience Response Keypads

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


• 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


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


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


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!


• How well does an AED work?


• Mechanisms of Action


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


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


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


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


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 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.






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


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


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

Documents

Evidence-Based Management ofd2qrtshcpf0x30.cloudfront.net/nodes/58/Evidence... · Evidence-Based Management of AEDs in Adults David Spencer, MD Director, OHSU Epilepsy Center