Simplified Strategies Slide Kit

1
Simplifying Strategies in the Management of AED
Therapy
2
Roundtable Faculty
Faculty James C. Cloyd III, PharmD University of
Minnesota Minneapolis, Minnesota Michael C.
Smith, MD Rush-Presbyterian-St. Luke's Medical
Center Chicago, Illinois Basim Uthman,
MD University of Florida Gainesville, Florida
B. J. Wilder, MD University of
Florida Gainesville, Florida
Meeting Chair John M. Pellock, MD Virginia
Commonwealth University Health Systems/Medical
College of Virginia Hospitals Richmond,
Virginia CME Coordinator Michael C. Smith,
MD Rush-Presbyterian-St. Luke's Medical
Center Chicago, Illinois
3
CME Learning Objectives

• After completion of this CME activity, the
  participant should be able to
• Identify the pharmacokinetic differences between
  immediate and delayed-release AED formulations
  and how these may impact efficacy and
  tolerability of therapy
• Describe the relationship between the frequency
  of AED administration and patient compliance and
  therapeutic efficacy
• Explain simplified AED selection strategies
  including methods for therapy initiation and
  optimization
• Identify key issues and treatment strategies in
  the management of special patient populations
  with epilepsy

4
Program Overview

• What are the advantages of extended-release AED
  formulations?
• What is the rationale for using broad-spectrum
  versus seizure-specific AEDs?
• What are the factors considered when initiating
  AED therapy with extended-release preparations?
• When and for whom should monotherapy or
  combination AED therapy be considered?
• What are the AED management issues associated
  with special patient populations?

5
Epilepsy

• Impact
• 2.3 million Americans of all ages
• Failure to achieve seizure freedom
• 1992 44 of patients
• 2000 47 of patients

Begley CE, et al. Epilepsia. 200041342-351. Matt
son RH, et al. N Engl J Med. 1992327765-771. Kwa
n P, et al. N Engl J Med. 2000342314-319.
6
Response to AED Therapy5-Year Follow-Up

• 525 newly diagnosed patients
• 470 AED-naïve
• 55 AED-experienced
• 63 seizure-free for 1 year
• AED-naïve 64
• 60 after first or second monotherapy trial
• AED-experienced 56
• Most withdrawals or change of treatment were due
  to intolerable side effects

AED-Naïve Patients
Response to AED ( patients)
47
13
3
1
First Second Third 2 drugs
Monotherapy Trial
Kwan P, et al. N Engl J Med. 2000342314-319.
7
Impact of Dosing Frequencyon Compliance

• In epilepsy patients
• Higher compliance rates are associated with
  once-daily dosing
• Noncompliance with AEDs is a major factor in
• Breakthrough seizures
• Recurrence of seizures

Epilepsy
87
81
77
Patients ()
39
QD BID TID QID
N24 patients followed for 2 to 37 weeks.
Cramer JA, et al. JAMA. 19892613273-3277.
8
Compliance and Seizure Control

• 661 patients taking AEDs
• National survey
• 71 of patients missed at least 1 dose
• Mean of 1.99 missed doses/month
• Odds of experiencing a seizure following a missed
  dose were highest among those taking
• A greater number of pills/day
• More frequent dosing qidgttidgtbidgtqd

Cramer JA, et al. Epilepsy Behav. 20023338-342.
9
Improving Seizure Control

• Simplify treatment regimen
• Minimize the number of daily doses
• Monotherapy if possible
• Decrease the number of pills taken daily
• Minimize trough levels
• Synchronize administration of therapies

10
Historical Perspective Increasing Options,
Simplifying Regimens
11
Immediate vs Extended-ReleaseAED
FormulationsPharmacokinetic Considerations
12
Simulated PharmacokineticsImmediate-Release
Day 1 Day 2
Concentration
0 8 16
24 32 40 48
Time (h)
Adapted from Cloyd JC, et al. Pharmacotherapy.
200020(8 Pt 2)139S-151S.
13
Simulated PharmacokineticsOnce-Daily,
Extended-Release
Day 1 Day 2
Zone of Seizure Control
Concentration
0 8 16
24 32 40 48
Time (h)
Adapted from Cloyd JC, et al. Pharmacotherapy.
200020(8 Pt 2)139S-151S.
14
Extended-Release, Once-DailyPotential for
Refinement of Dose
Day 1 Day 2
Extended-Release (Once-Daily)
Zone of Seizure Control
Concentration
0 8 16
24 32 40 48
Time (h)
Adapted from Cloyd JC, et al. Pharmacotherapy.
200020(8 Pt 2)139S-151S.
15
Extended-Release Options
16
Anticonvulsant ActivityPrimidone Plasma
Concentration
500 mg/day
1500 mg/day
Discrete discharges (No.) Mixed paroxysmal
activity (sec)
Primidone
135
92
Concentration (µg/mL)
Concentration (µg/mL)
Prolonged Clinical Seizures
Primidone
1200 1600 2000 2400 0400 0800

1200 1600 2000 2400 0400 0800

Dose Dose Dose
Dose Dose Dose Dose
Clock Time
Clock Time
Rowan AJ, et al. Arch Neurol. 197532281-288.
17
Side Effects Associated With Oscillations in
Carbamazepine Concentrations

• 43 patients
• Carbamazepine dosed at 8 AM, 1230 PM, and 8 PM
• Average dose
• 18.9 4.68 mg/kg
• Carbamazepine
• Cmin 5.0 1.4 mg/L
• Cmax 10.0 1.6 mg/L
• Mean 7.5 1.4 mg/L
• Fluctuation 68.5 21.2

27-year-old patient
Drowsiness Ataxia
Threshold of Toxic Side Effects
Serum Concentration (mg/L)
0800 1000 1200 1400 1600 1800
Clock Time
Hoppener RJ, et al. Epilepsia. 198021341-350.
18
Carbamazepine IR to ER ConversionImpact on CNS
Toxicity

• 63 patients
• Age 19-76 years
• Partial-onset seizures
• Carbamazepine treatments
• IR for 1 year
• Then switch to ER for 1 year

CNS Toxicity
48
Patients ()
25
Plt0.001. CBZcarbamazepine IRimmediate-release
ERextended-release. Miller A, et al. Epilepsia.
200243(suppl 7)196. Abstract 2.197.
19
Divalproex to Divalproex ER Conversion Impact on
Tremors Gain

• 20 patients with epilepsy
• Age 5-75 years
• 6 generalized tonic-clonic
• 12 complex partial seizures
• 1 primary generalized
• 1 secondary partial seizures
• After switch to divalproex ER, twice daily
• Seizure control maintained or improved
• No increase in weight was observed
• Reduced lethargy, ataxia, and hair loss
• Improved compliance

Tremors
75
Patients ()
5
Standard ER
Divalproex
ERextended-release. Zielinski D, et al.
Epilepsia. 200142(suppl 7)92. Abstract 1.291.
20
Standard vs Extended-ReleaseDivalproex (Depakote
ER)
Standard Divalproex (three times daily)
Divalproex ER (once daily)
Valproic Acid (µg/mL)
0 2 4 6 8 10
12 14 16 18 20 22
24
Time (h)
Uthman B, et al. 5th European Epilepsy Congress.
Madrid, 2002. Abstract.
21
Divalproex ER Steady State Levels inChildren,
Adolescents, and Adults

• Phase 1, open-label study
• Epilepsy patients previously receiving standard
  divalproex
• 14 children (age 8-11 y)
• 12 adolescents (age 12-17 y)
• 14 adults (historical controls)
• Switched to divalproex ER
• Dose range 250 to 1750 mg
• Divalproex ER pharmacokinetics
• Similar among adolescents and historical adult
  controls
• Children had higher clearance per body weight (kg)

Valproic Acid (ng/mL)
Children Adolescents Adults
0 12
24
Time (hr)
per mg dose/kg body weight. ERextended-release.
Sallee FR, et al. 41st Annual Meeting Am Coll
Neuropsychopharmacology. San Juan. 2002. Abstract.
22
Immediate vs Extended-Release Carbamazepine
(Tegretol XR)

• Bioavailability study
• Open-label
• 22 patients with epilepsy
• Mean age 31 y (19-55 y)
• Carbamazepine 400-2000 mg/day
• IR four times daily
• ER twice daily
• Fasting plasma concentrations assessed after 21
  days

IR carbamazepine qid (n22) ER carbamazepine bid
(n22)
CBZ
Plasma Concentration (µg/mL)
CBZE
0 6 12 18
24
Time (h)
CBZcarbamazepine CBZECBZ epoxide IRimmediate-
release ERextended-release. Thakker KM, et al.
Biopharm Drug Dispos. 199213559-569.
23
Immediate vs Extended-Release Carbamazepine
(Carbatrol)

• Bioavailability study
• Double-blind
• 24 patients with epilepsy
• Mean age 36 y (21-54 y)
• Carbamazepine 800-1600 mg/day
• IR four times daily
• ER twice daily
• Fasting plasma concentrations assessed after 14
  days

IR carbamazepine qid (n24) ER carbamazepine bid
(n24)
CBZ
Plasma Concentration (µg/mL)
CBZE
0 6 12 18
24
Time (h)
CBZcarbamazepine CBZECBZ epoxide IRimmediate-
release ERextended-release. Garnett WR, et al.
Epilepsia. 199839274-279.
24
Extended-Release FormulationsImpact on
Therapeutic Use

• Extended-release AED formulations
• Provide for once or twice-daily dosing
• Minimize peak/trough fluctuations
• Enhance tolerability/minimize troublesome side
  effects
• May improve compliance and facilitate treatment
  synchronization
• Once-daily, extended-release formulations may
  provide the greatest benefit in
• Minimizing peak/trough levels
• Improving compliance and facilitating treatment
  synchronization

25
Initiating AED Therapy
26
Treatment Goals

• Prevent occurrence of seizures
• Prevent or reduce
• Side effects
• Drug interactions
• Worsening current medical problems or
  specific seizure types
• Improve quality of life, patient satisfaction
• Provide simple, cost-effective care

27
Proper Selection of AED Dependson Multiple
Clinical Variables

• Experience of treating physician with diagnosis
  and treatment of epilepsy
• Certainty of diagnosis
• Seizure type
• Epilepsy syndrome
• Extent of work-up
• History/physical examination, neuroimaging,
  routine EEG, closed circuit TV-EEG
• Urgency/severity of clinical situation

28
Proper Selection of AED Experience of Treating
Physician

• Majority of patients with new-onset seizure are
  treated by emergency room or primary care
  physicians
• Treatment often started with inadequate
  diagnostic information
• Routine CT scan without contrast
• Broad-spectrum agent is preferred
• Treats all seizure types

29
Broad-Spectrum AEDsClinical Implications
Adapted from Pellock J. Epilepsia. 199435(suppl
4)S11-S18.
30
Possible Aggravation ofSeizures or Epilepsy
Syndromes
CBZcarbamazepine PHTphenytoin
LTGlamotrigine GBPgabapentin VGBvigabatrin
TGBtiagabine BDZbenzodiazepine. Bourgeois BF.
Epilepsy Res. 20025253-60.
31
Proper Selection of AED Examples of Diagnostic
Dilemmas
Bourgeois BF. Epilepsy Res. 20025253-60.
32
Considerations for Broad-Spectrum

• While seizure-specific treatment approach is
  ideal, it is often not possible
• Emergency room
• Primary care
• Managed care
• When there is diagnostic uncertainty about
  seizure type or epilepsy syndrome
• Broad-spectrum is preferred
• Simplifying therapy extended-release options
• Divalproex broad-spectrum
• Carbamazepine seizure-specific

Bourgeois BF. Epilepsy Res. 20025253-60. Levy
RH, et al. eds. Antiepileptic Drugs. Fifth
Edition. Lippincott Wilkins Williams 2002.
33
Rational Choice andSequencing of AEDs

• Efficacy appropriate for broad spectrum of
  patients
• Mechanisms of action
• No evidence of therapeutic tolerance
• Favorable safety profile
• Well-tolerated with dose-management techniques
• Simplified, monotherapy whenever possible

34
Clinical Characteristics of Extended-Release
Options
Levy RH, et al. eds. Antiepileptic Drugs. Fifth
Edition. Lippincott Wilkins Williams
2002. Sirven JI, et al. Mayo Clin Proc.
2002771367-1375.
35
Dosing of Extended-Release Options(gt12 Years of
Age)
Full prescribing information for Depakote ER,
Tegretol XR, and Carbatrol.
36
Divalproex to Divalproex Extended-Release Dose
Conversion
Full prescribing information for Depakote ER.
37
AED Drug-Interactions andExtended-Release Options
Levy RH, et al. eds. Antiepileptic Drugs. Fifth
Edition. Lippincott Wilkins Williams 2002.
38
Special Patient Populations
39
Principles of AED Treatmentin Pediatric
Populations

• Be aware of age-related differences
• Consider seizure type and expected severity
• Avoid AEDs that may worsen current medical
  problems
• Be aware of drug interactions
• Start with low doses, titrate slowly
• Some products allow once or twice-daily dosing

Pellock JM. Pediatrics. 19991041106-1111. Brodie
MJ, et al. Lancet. 2000356323-329.
40
Pediatric EpilepsySpecial Considerations

• Clearance rates
• Vary as a function of age group, individual
  maturity, comorbidities, specific AED
• Initial and periodic blood level monitoring
  may help
• Adverse effects
• Idiosyncratic
• Hematologic, dermatologic, hepatic
• Behavioral
• Aggression, mania, concentration, memory
  difficulties

Pellock JM. In Engel J Jr, Pedley TA. eds.
Epilepsy A Comprehensive Textbook.
19971205-1210.
41
AED Delivery Systems for ChildrenOptions to
Simplify Therapy

• Extended-release
• Suspension
• Syrup
• Sprinkle capsules
• Chewable tablets

• Dispersible tablets
• Sublingual
• IV/IM
• Rectal

42
AED SelectionWomen

• Oral contraceptives
• Pregnancy
• Seizure risk is greater in pregnancy
• AEDs may affect pregnancy outcomes
• Teratogenicity concerns
• Menopause

Levy RH, et al. eds. Antiepileptic Drugs. Fifth
Edition. Lippincott Wilkins Williams 2002.
43
AEDs and Oral Contraceptives
Levy RH, et al. eds. Antiepileptic Drugs. Fifth
Edition. Lippincott Wilkins Williams 2002.
44
Menopause and WomenWith Epilepsy

• Variable effect on seizure pattern
• Seizures may remit if
• Onset is late in life
• Easily controlled
• AEDs may affect bone metabolism

Abbasi F, et al. Epilepsia. 199940205-210. Gough
H, et al. Q J Med. 198659569-577.
45
Seizures in the ElderlyDemographics of the 60
Age Group

• Fastest growing segment of the population
• gt75 years of age
• Highest incidence
• gt65 years of age
• 50 of new epilepsy cases are complex partial
  seizures
• Elderly incidence is double that of people aged
  40-59 y
• More likely to have concurrent medical disorders

Epilepsy Incidence (per 100,00 person-y)
55-59 65-69 75-79 85
Age Group
Hauser WA, et al. Epilepsia. 199334453-468
Berg AT, et al. Neurology. 199141965-972
Leppik IE. In Wyllie E, ed. The Treatment of
Epilepsy Principles and Practice. 2001787-794.
46
Managing Seizure Disordersin Older Patients

• Seizure presentation may be different
• Start low, titrate slowly
• Most sensitive to fluctuations in AED blood
  levels
• Extended-release AEDs may be preferred
• Anticipate disruption of therapy
• Drug interactions and side effects
• Noncompliance
• Educate patient, family, and healthcare providers
• Consider pharmacoeconomics

Hauser WA, et al. Epilepsia. 199233(suppl
4)S6-S14.
47
Seizures in the ElderlyAdverse Effects of AEDs

• AEs frequently lead to stopping medications
• Dose-dependent AEs are common
• Dizziness, lethargy, unsteady gait, visual
  disturbance
• Drug-specific AEs are common
• Hyponatremia, tremor, cardiotoxicity, ataxia,
  encephalopathies, neuropathies, weight change,
  cognitive dysfunction
• AEs occur at lower blood levels
• Multiple medications may predispose to AEs

Ramsay RE, et al. Neurology. 200055(5 suppl
1)S9-S14.
48
Epilepsy Treatment Summary

• Based on seizure type/epilepsy syndrome
• Balance likely efficacy versus adverse effects
• Maximize desired side effects to best affect
  comorbidity
• Monotherapy with first drug
• Best alternative if unsuccessful
• Successful long-term treatment requires patient
  compliance and clinical observation
• Decisions concerning initial and chronic therapy
  depend on age, gender, epilepsy, and comorbid
  issues
• Extended-release formulations may improve care
  associated with many issues raised with these
  factors