Clinical Use of New Antiepileptic Drugs: Lacosamide...

43
Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and Clobazam November 30, 2012 Edward Faught, MD Emory University School of Medicine Atlanta, Georgia American Epilepsy Society | Annual Meeting

Transcript of Clinical Use of New Antiepileptic Drugs: Lacosamide...

Page 1: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Clinical Use of New Antiepileptic

Drugs Lacosamide Ezogabine

Rufinamide and Clobazam November 30 2012

Edward Faught MD

Emory University School of Medicine

Atlanta Georgia

American Epilepsy Society | Annual Meeting

Disclosure

Eisai Data Monitoring Board Lundbeck Data Monitoring Board

SK LifeScience Data Monitoring Board Sunovion Consultant Supernus Consultant

UCB Pharma Consultant Research Support

Vertex Research Support

American Epilepsy Society | Annual Meeting 2012

Learning Objectives

1Know an indication by seizure type or syndrome for lacosamide ezogabine rufinamide

and clobazam

2 Select an appropriate drug for ldquodrop attacksrdquo in the Lennox-Gastaut syndrome

American Epilepsy Society | Annual Meeting 2012

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

6

Is it Worthwhile to Keep Trying New Medications in Refractory Epilepsy

1Schiller Y Najjar Y Neurology 200870(1)54-65 2Callaghan BC et al Ann Neurol 200762(4)382-389

Even after numerous

inefficient AEDs at least

265 of patients will

respond with a favorable

outcome to a new AED2

00

100

200

300

400

500

600

700

0 AEDs 1 past AED 2-5 past AEDs 6-7 past AEDs

Pe

rce

nt

res

po

nd

er

rate

Number of previously failed AEDs

N=94 N=88 N=119 N=9

Responder rates (50 seizure reductions) as a function of newly

administered AEDs failed due to lack of efficacy or adverse events gt

50

r

ed

uctio

n in s

eiz

ure

fre

qu

en

cy

2 Schiller Y Najjar Y et al Neurology 2008 70 54-

65

Schiller Y Najjar Y Quantifying the response to

antiepileptic drugs Neurology 2008 7054-65

ldquohellipno matter how many AED

therapies havefailed there is

always hope of a meaningful clinical

remission in this populationrdquo-1

Callaghan 2008

LACOSAMIDE

8

Lacosamide

Indication adjunctive therapy of partial-

onset seizures in patients 17 years of age or

older

Mechanism holds voltage-gated Na+

channels in their slow inactivated state

longer

L

10

Percent Reduction in Complex Partial Seizures with

Adjunctive Lacosamide- Pooled Studies

Isojarvi Faught et al presented at ANA annual meeting Baltimore Oct 2009

Metanalysis of RCTs

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf1

Lacosamide Dose-Related Adverse Effects

Placebo 200day 400day

Dizziness 7 10 25

Nausea 4 6 9

Diplopia 1 4 8

Rash somnolence cognitive effects low and equal to placebo

affected in clinical trials Product labeling 2012

Comment The dizziness tends to be subjective not true vertigo and

not usually associated with ataxia It may be worse when given with

other Na+ channel drugs eg CBZ (Faught opinion)

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf3

Lacosamide Clinical Use

bull Labeled dosing 50 bid week 1

Conservative dosing 50 hs week 1

bull Labeled titration 100 mgdayweek

Conservative titration 50 mgdayweek

bull Labeled target 400 mgday (200mg bid)

Conservative target 200 mgday initially increase slowly to 400 mg or max tolerability

Product labeling 2012

Opinion Faught

Lacosamide Pro and Con

Advantages

bull BID dosing

bull Renal excretion

bull No interactions

bull Low rate of somnolence rash cognitive effects

bull IV available

bull Adds well to LEV TPM PGN

Disadvantages

bull Modestly effective 20

greater reduction than

placebo at 400 mgday

bull Dizziness

bull Harder to add to PHT

CBZ OXCLTG ndash More

dizziness

bull Monotherapy unproven

bull Levels not established

Opinion Faught

EZOGABINE (US NAME)

RETIGABINE (EUROPEAN)

16

Ezogabine

bull Approved for adjunctive therapy of partial-

onset seizures in patients 18+ years of age

bull Facilitates and prolongs K+ channel

opening aiding repolarization of neurons

and inhibiting repetitive firing

bull Voltage-gate K+ channels are found in

brain heart and bladder but ezogabine

targets mostly the Kv72 and Kv73 channel

types not important for heart function Faught E Ezogabine A new angle on potassium currents

Epilepsy Currents 2011 July 11 1-15

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

Ezogabine

Adverse Effects somnolence dizziness

confusion other CNS effects dose related

Urinary retention can occur

17-29 withdrawal due to adverse effects in

double-blind trials vs 125 placebo

(This difference is about average in clinical

trials of AEDs)

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

(phase III RCT report)

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 2: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Disclosure

Eisai Data Monitoring Board Lundbeck Data Monitoring Board

SK LifeScience Data Monitoring Board Sunovion Consultant Supernus Consultant

UCB Pharma Consultant Research Support

Vertex Research Support

American Epilepsy Society | Annual Meeting 2012

Learning Objectives

1Know an indication by seizure type or syndrome for lacosamide ezogabine rufinamide

and clobazam

2 Select an appropriate drug for ldquodrop attacksrdquo in the Lennox-Gastaut syndrome

American Epilepsy Society | Annual Meeting 2012

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

6

Is it Worthwhile to Keep Trying New Medications in Refractory Epilepsy

1Schiller Y Najjar Y Neurology 200870(1)54-65 2Callaghan BC et al Ann Neurol 200762(4)382-389

Even after numerous

inefficient AEDs at least

265 of patients will

respond with a favorable

outcome to a new AED2

00

100

200

300

400

500

600

700

0 AEDs 1 past AED 2-5 past AEDs 6-7 past AEDs

Pe

rce

nt

res

po

nd

er

rate

Number of previously failed AEDs

N=94 N=88 N=119 N=9

Responder rates (50 seizure reductions) as a function of newly

administered AEDs failed due to lack of efficacy or adverse events gt

50

r

ed

uctio

n in s

eiz

ure

fre

qu

en

cy

2 Schiller Y Najjar Y et al Neurology 2008 70 54-

65

Schiller Y Najjar Y Quantifying the response to

antiepileptic drugs Neurology 2008 7054-65

ldquohellipno matter how many AED

therapies havefailed there is

always hope of a meaningful clinical

remission in this populationrdquo-1

Callaghan 2008

LACOSAMIDE

8

Lacosamide

Indication adjunctive therapy of partial-

onset seizures in patients 17 years of age or

older

Mechanism holds voltage-gated Na+

channels in their slow inactivated state

longer

L

10

Percent Reduction in Complex Partial Seizures with

Adjunctive Lacosamide- Pooled Studies

Isojarvi Faught et al presented at ANA annual meeting Baltimore Oct 2009

Metanalysis of RCTs

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf1

Lacosamide Dose-Related Adverse Effects

Placebo 200day 400day

Dizziness 7 10 25

Nausea 4 6 9

Diplopia 1 4 8

Rash somnolence cognitive effects low and equal to placebo

affected in clinical trials Product labeling 2012

Comment The dizziness tends to be subjective not true vertigo and

not usually associated with ataxia It may be worse when given with

other Na+ channel drugs eg CBZ (Faught opinion)

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf3

Lacosamide Clinical Use

bull Labeled dosing 50 bid week 1

Conservative dosing 50 hs week 1

bull Labeled titration 100 mgdayweek

Conservative titration 50 mgdayweek

bull Labeled target 400 mgday (200mg bid)

Conservative target 200 mgday initially increase slowly to 400 mg or max tolerability

Product labeling 2012

Opinion Faught

Lacosamide Pro and Con

Advantages

bull BID dosing

bull Renal excretion

bull No interactions

bull Low rate of somnolence rash cognitive effects

bull IV available

bull Adds well to LEV TPM PGN

Disadvantages

bull Modestly effective 20

greater reduction than

placebo at 400 mgday

bull Dizziness

bull Harder to add to PHT

CBZ OXCLTG ndash More

dizziness

bull Monotherapy unproven

bull Levels not established

Opinion Faught

EZOGABINE (US NAME)

RETIGABINE (EUROPEAN)

16

Ezogabine

bull Approved for adjunctive therapy of partial-

onset seizures in patients 18+ years of age

bull Facilitates and prolongs K+ channel

opening aiding repolarization of neurons

and inhibiting repetitive firing

bull Voltage-gate K+ channels are found in

brain heart and bladder but ezogabine

targets mostly the Kv72 and Kv73 channel

types not important for heart function Faught E Ezogabine A new angle on potassium currents

Epilepsy Currents 2011 July 11 1-15

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

Ezogabine

Adverse Effects somnolence dizziness

confusion other CNS effects dose related

Urinary retention can occur

17-29 withdrawal due to adverse effects in

double-blind trials vs 125 placebo

(This difference is about average in clinical

trials of AEDs)

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

(phase III RCT report)

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 3: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Learning Objectives

1Know an indication by seizure type or syndrome for lacosamide ezogabine rufinamide

and clobazam

2 Select an appropriate drug for ldquodrop attacksrdquo in the Lennox-Gastaut syndrome

American Epilepsy Society | Annual Meeting 2012

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

6

Is it Worthwhile to Keep Trying New Medications in Refractory Epilepsy

1Schiller Y Najjar Y Neurology 200870(1)54-65 2Callaghan BC et al Ann Neurol 200762(4)382-389

Even after numerous

inefficient AEDs at least

265 of patients will

respond with a favorable

outcome to a new AED2

00

100

200

300

400

500

600

700

0 AEDs 1 past AED 2-5 past AEDs 6-7 past AEDs

Pe

rce

nt

res

po

nd

er

rate

Number of previously failed AEDs

N=94 N=88 N=119 N=9

Responder rates (50 seizure reductions) as a function of newly

administered AEDs failed due to lack of efficacy or adverse events gt

50

r

ed

uctio

n in s

eiz

ure

fre

qu

en

cy

2 Schiller Y Najjar Y et al Neurology 2008 70 54-

65

Schiller Y Najjar Y Quantifying the response to

antiepileptic drugs Neurology 2008 7054-65

ldquohellipno matter how many AED

therapies havefailed there is

always hope of a meaningful clinical

remission in this populationrdquo-1

Callaghan 2008

LACOSAMIDE

8

Lacosamide

Indication adjunctive therapy of partial-

onset seizures in patients 17 years of age or

older

Mechanism holds voltage-gated Na+

channels in their slow inactivated state

longer

L

10

Percent Reduction in Complex Partial Seizures with

Adjunctive Lacosamide- Pooled Studies

Isojarvi Faught et al presented at ANA annual meeting Baltimore Oct 2009

Metanalysis of RCTs

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf1

Lacosamide Dose-Related Adverse Effects

Placebo 200day 400day

Dizziness 7 10 25

Nausea 4 6 9

Diplopia 1 4 8

Rash somnolence cognitive effects low and equal to placebo

affected in clinical trials Product labeling 2012

Comment The dizziness tends to be subjective not true vertigo and

not usually associated with ataxia It may be worse when given with

other Na+ channel drugs eg CBZ (Faught opinion)

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf3

Lacosamide Clinical Use

bull Labeled dosing 50 bid week 1

Conservative dosing 50 hs week 1

bull Labeled titration 100 mgdayweek

Conservative titration 50 mgdayweek

bull Labeled target 400 mgday (200mg bid)

Conservative target 200 mgday initially increase slowly to 400 mg or max tolerability

Product labeling 2012

Opinion Faught

Lacosamide Pro and Con

Advantages

bull BID dosing

bull Renal excretion

bull No interactions

bull Low rate of somnolence rash cognitive effects

bull IV available

bull Adds well to LEV TPM PGN

Disadvantages

bull Modestly effective 20

greater reduction than

placebo at 400 mgday

bull Dizziness

bull Harder to add to PHT

CBZ OXCLTG ndash More

dizziness

bull Monotherapy unproven

bull Levels not established

Opinion Faught

EZOGABINE (US NAME)

RETIGABINE (EUROPEAN)

16

Ezogabine

bull Approved for adjunctive therapy of partial-

onset seizures in patients 18+ years of age

bull Facilitates and prolongs K+ channel

opening aiding repolarization of neurons

and inhibiting repetitive firing

bull Voltage-gate K+ channels are found in

brain heart and bladder but ezogabine

targets mostly the Kv72 and Kv73 channel

types not important for heart function Faught E Ezogabine A new angle on potassium currents

Epilepsy Currents 2011 July 11 1-15

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

Ezogabine

Adverse Effects somnolence dizziness

confusion other CNS effects dose related

Urinary retention can occur

17-29 withdrawal due to adverse effects in

double-blind trials vs 125 placebo

(This difference is about average in clinical

trials of AEDs)

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

(phase III RCT report)

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 4: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

6

Is it Worthwhile to Keep Trying New Medications in Refractory Epilepsy

1Schiller Y Najjar Y Neurology 200870(1)54-65 2Callaghan BC et al Ann Neurol 200762(4)382-389

Even after numerous

inefficient AEDs at least

265 of patients will

respond with a favorable

outcome to a new AED2

00

100

200

300

400

500

600

700

0 AEDs 1 past AED 2-5 past AEDs 6-7 past AEDs

Pe

rce

nt

res

po

nd

er

rate

Number of previously failed AEDs

N=94 N=88 N=119 N=9

Responder rates (50 seizure reductions) as a function of newly

administered AEDs failed due to lack of efficacy or adverse events gt

50

r

ed

uctio

n in s

eiz

ure

fre

qu

en

cy

2 Schiller Y Najjar Y et al Neurology 2008 70 54-

65

Schiller Y Najjar Y Quantifying the response to

antiepileptic drugs Neurology 2008 7054-65

ldquohellipno matter how many AED

therapies havefailed there is

always hope of a meaningful clinical

remission in this populationrdquo-1

Callaghan 2008

LACOSAMIDE

8

Lacosamide

Indication adjunctive therapy of partial-

onset seizures in patients 17 years of age or

older

Mechanism holds voltage-gated Na+

channels in their slow inactivated state

longer

L

10

Percent Reduction in Complex Partial Seizures with

Adjunctive Lacosamide- Pooled Studies

Isojarvi Faught et al presented at ANA annual meeting Baltimore Oct 2009

Metanalysis of RCTs

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf1

Lacosamide Dose-Related Adverse Effects

Placebo 200day 400day

Dizziness 7 10 25

Nausea 4 6 9

Diplopia 1 4 8

Rash somnolence cognitive effects low and equal to placebo

affected in clinical trials Product labeling 2012

Comment The dizziness tends to be subjective not true vertigo and

not usually associated with ataxia It may be worse when given with

other Na+ channel drugs eg CBZ (Faught opinion)

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf3

Lacosamide Clinical Use

bull Labeled dosing 50 bid week 1

Conservative dosing 50 hs week 1

bull Labeled titration 100 mgdayweek

Conservative titration 50 mgdayweek

bull Labeled target 400 mgday (200mg bid)

Conservative target 200 mgday initially increase slowly to 400 mg or max tolerability

Product labeling 2012

Opinion Faught

Lacosamide Pro and Con

Advantages

bull BID dosing

bull Renal excretion

bull No interactions

bull Low rate of somnolence rash cognitive effects

bull IV available

bull Adds well to LEV TPM PGN

Disadvantages

bull Modestly effective 20

greater reduction than

placebo at 400 mgday

bull Dizziness

bull Harder to add to PHT

CBZ OXCLTG ndash More

dizziness

bull Monotherapy unproven

bull Levels not established

Opinion Faught

EZOGABINE (US NAME)

RETIGABINE (EUROPEAN)

16

Ezogabine

bull Approved for adjunctive therapy of partial-

onset seizures in patients 18+ years of age

bull Facilitates and prolongs K+ channel

opening aiding repolarization of neurons

and inhibiting repetitive firing

bull Voltage-gate K+ channels are found in

brain heart and bladder but ezogabine

targets mostly the Kv72 and Kv73 channel

types not important for heart function Faught E Ezogabine A new angle on potassium currents

Epilepsy Currents 2011 July 11 1-15

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

Ezogabine

Adverse Effects somnolence dizziness

confusion other CNS effects dose related

Urinary retention can occur

17-29 withdrawal due to adverse effects in

double-blind trials vs 125 placebo

(This difference is about average in clinical

trials of AEDs)

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

(phase III RCT report)

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 5: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

6

Is it Worthwhile to Keep Trying New Medications in Refractory Epilepsy

1Schiller Y Najjar Y Neurology 200870(1)54-65 2Callaghan BC et al Ann Neurol 200762(4)382-389

Even after numerous

inefficient AEDs at least

265 of patients will

respond with a favorable

outcome to a new AED2

00

100

200

300

400

500

600

700

0 AEDs 1 past AED 2-5 past AEDs 6-7 past AEDs

Pe

rce

nt

res

po

nd

er

rate

Number of previously failed AEDs

N=94 N=88 N=119 N=9

Responder rates (50 seizure reductions) as a function of newly

administered AEDs failed due to lack of efficacy or adverse events gt

50

r

ed

uctio

n in s

eiz

ure

fre

qu

en

cy

2 Schiller Y Najjar Y et al Neurology 2008 70 54-

65

Schiller Y Najjar Y Quantifying the response to

antiepileptic drugs Neurology 2008 7054-65

ldquohellipno matter how many AED

therapies havefailed there is

always hope of a meaningful clinical

remission in this populationrdquo-1

Callaghan 2008

LACOSAMIDE

8

Lacosamide

Indication adjunctive therapy of partial-

onset seizures in patients 17 years of age or

older

Mechanism holds voltage-gated Na+

channels in their slow inactivated state

longer

L

10

Percent Reduction in Complex Partial Seizures with

Adjunctive Lacosamide- Pooled Studies

Isojarvi Faught et al presented at ANA annual meeting Baltimore Oct 2009

Metanalysis of RCTs

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf1

Lacosamide Dose-Related Adverse Effects

Placebo 200day 400day

Dizziness 7 10 25

Nausea 4 6 9

Diplopia 1 4 8

Rash somnolence cognitive effects low and equal to placebo

affected in clinical trials Product labeling 2012

Comment The dizziness tends to be subjective not true vertigo and

not usually associated with ataxia It may be worse when given with

other Na+ channel drugs eg CBZ (Faught opinion)

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf3

Lacosamide Clinical Use

bull Labeled dosing 50 bid week 1

Conservative dosing 50 hs week 1

bull Labeled titration 100 mgdayweek

Conservative titration 50 mgdayweek

bull Labeled target 400 mgday (200mg bid)

Conservative target 200 mgday initially increase slowly to 400 mg or max tolerability

Product labeling 2012

Opinion Faught

Lacosamide Pro and Con

Advantages

bull BID dosing

bull Renal excretion

bull No interactions

bull Low rate of somnolence rash cognitive effects

bull IV available

bull Adds well to LEV TPM PGN

Disadvantages

bull Modestly effective 20

greater reduction than

placebo at 400 mgday

bull Dizziness

bull Harder to add to PHT

CBZ OXCLTG ndash More

dizziness

bull Monotherapy unproven

bull Levels not established

Opinion Faught

EZOGABINE (US NAME)

RETIGABINE (EUROPEAN)

16

Ezogabine

bull Approved for adjunctive therapy of partial-

onset seizures in patients 18+ years of age

bull Facilitates and prolongs K+ channel

opening aiding repolarization of neurons

and inhibiting repetitive firing

bull Voltage-gate K+ channels are found in

brain heart and bladder but ezogabine

targets mostly the Kv72 and Kv73 channel

types not important for heart function Faught E Ezogabine A new angle on potassium currents

Epilepsy Currents 2011 July 11 1-15

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

Ezogabine

Adverse Effects somnolence dizziness

confusion other CNS effects dose related

Urinary retention can occur

17-29 withdrawal due to adverse effects in

double-blind trials vs 125 placebo

(This difference is about average in clinical

trials of AEDs)

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

(phase III RCT report)

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 6: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Schiller Y Najjar Y Quantifying the response to

antiepileptic drugs Neurology 2008 7054-65

ldquohellipno matter how many AED

therapies havefailed there is

always hope of a meaningful clinical

remission in this populationrdquo-1

Callaghan 2008

LACOSAMIDE

8

Lacosamide

Indication adjunctive therapy of partial-

onset seizures in patients 17 years of age or

older

Mechanism holds voltage-gated Na+

channels in their slow inactivated state

longer

L

10

Percent Reduction in Complex Partial Seizures with

Adjunctive Lacosamide- Pooled Studies

Isojarvi Faught et al presented at ANA annual meeting Baltimore Oct 2009

Metanalysis of RCTs

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf1

Lacosamide Dose-Related Adverse Effects

Placebo 200day 400day

Dizziness 7 10 25

Nausea 4 6 9

Diplopia 1 4 8

Rash somnolence cognitive effects low and equal to placebo

affected in clinical trials Product labeling 2012

Comment The dizziness tends to be subjective not true vertigo and

not usually associated with ataxia It may be worse when given with

other Na+ channel drugs eg CBZ (Faught opinion)

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf3

Lacosamide Clinical Use

bull Labeled dosing 50 bid week 1

Conservative dosing 50 hs week 1

bull Labeled titration 100 mgdayweek

Conservative titration 50 mgdayweek

bull Labeled target 400 mgday (200mg bid)

Conservative target 200 mgday initially increase slowly to 400 mg or max tolerability

Product labeling 2012

Opinion Faught

Lacosamide Pro and Con

Advantages

bull BID dosing

bull Renal excretion

bull No interactions

bull Low rate of somnolence rash cognitive effects

bull IV available

bull Adds well to LEV TPM PGN

Disadvantages

bull Modestly effective 20

greater reduction than

placebo at 400 mgday

bull Dizziness

bull Harder to add to PHT

CBZ OXCLTG ndash More

dizziness

bull Monotherapy unproven

bull Levels not established

Opinion Faught

EZOGABINE (US NAME)

RETIGABINE (EUROPEAN)

16

Ezogabine

bull Approved for adjunctive therapy of partial-

onset seizures in patients 18+ years of age

bull Facilitates and prolongs K+ channel

opening aiding repolarization of neurons

and inhibiting repetitive firing

bull Voltage-gate K+ channels are found in

brain heart and bladder but ezogabine

targets mostly the Kv72 and Kv73 channel

types not important for heart function Faught E Ezogabine A new angle on potassium currents

Epilepsy Currents 2011 July 11 1-15

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

Ezogabine

Adverse Effects somnolence dizziness

confusion other CNS effects dose related

Urinary retention can occur

17-29 withdrawal due to adverse effects in

double-blind trials vs 125 placebo

(This difference is about average in clinical

trials of AEDs)

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

(phase III RCT report)

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 7: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

LACOSAMIDE

8

Lacosamide

Indication adjunctive therapy of partial-

onset seizures in patients 17 years of age or

older

Mechanism holds voltage-gated Na+

channels in their slow inactivated state

longer

L

10

Percent Reduction in Complex Partial Seizures with

Adjunctive Lacosamide- Pooled Studies

Isojarvi Faught et al presented at ANA annual meeting Baltimore Oct 2009

Metanalysis of RCTs

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf1

Lacosamide Dose-Related Adverse Effects

Placebo 200day 400day

Dizziness 7 10 25

Nausea 4 6 9

Diplopia 1 4 8

Rash somnolence cognitive effects low and equal to placebo

affected in clinical trials Product labeling 2012

Comment The dizziness tends to be subjective not true vertigo and

not usually associated with ataxia It may be worse when given with

other Na+ channel drugs eg CBZ (Faught opinion)

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf3

Lacosamide Clinical Use

bull Labeled dosing 50 bid week 1

Conservative dosing 50 hs week 1

bull Labeled titration 100 mgdayweek

Conservative titration 50 mgdayweek

bull Labeled target 400 mgday (200mg bid)

Conservative target 200 mgday initially increase slowly to 400 mg or max tolerability

Product labeling 2012

Opinion Faught

Lacosamide Pro and Con

Advantages

bull BID dosing

bull Renal excretion

bull No interactions

bull Low rate of somnolence rash cognitive effects

bull IV available

bull Adds well to LEV TPM PGN

Disadvantages

bull Modestly effective 20

greater reduction than

placebo at 400 mgday

bull Dizziness

bull Harder to add to PHT

CBZ OXCLTG ndash More

dizziness

bull Monotherapy unproven

bull Levels not established

Opinion Faught

EZOGABINE (US NAME)

RETIGABINE (EUROPEAN)

16

Ezogabine

bull Approved for adjunctive therapy of partial-

onset seizures in patients 18+ years of age

bull Facilitates and prolongs K+ channel

opening aiding repolarization of neurons

and inhibiting repetitive firing

bull Voltage-gate K+ channels are found in

brain heart and bladder but ezogabine

targets mostly the Kv72 and Kv73 channel

types not important for heart function Faught E Ezogabine A new angle on potassium currents

Epilepsy Currents 2011 July 11 1-15

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

Ezogabine

Adverse Effects somnolence dizziness

confusion other CNS effects dose related

Urinary retention can occur

17-29 withdrawal due to adverse effects in

double-blind trials vs 125 placebo

(This difference is about average in clinical

trials of AEDs)

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

(phase III RCT report)

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 8: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Lacosamide

Indication adjunctive therapy of partial-

onset seizures in patients 17 years of age or

older

Mechanism holds voltage-gated Na+

channels in their slow inactivated state

longer

L

10

Percent Reduction in Complex Partial Seizures with

Adjunctive Lacosamide- Pooled Studies

Isojarvi Faught et al presented at ANA annual meeting Baltimore Oct 2009

Metanalysis of RCTs

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf1

Lacosamide Dose-Related Adverse Effects

Placebo 200day 400day

Dizziness 7 10 25

Nausea 4 6 9

Diplopia 1 4 8

Rash somnolence cognitive effects low and equal to placebo

affected in clinical trials Product labeling 2012

Comment The dizziness tends to be subjective not true vertigo and

not usually associated with ataxia It may be worse when given with

other Na+ channel drugs eg CBZ (Faught opinion)

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf3

Lacosamide Clinical Use

bull Labeled dosing 50 bid week 1

Conservative dosing 50 hs week 1

bull Labeled titration 100 mgdayweek

Conservative titration 50 mgdayweek

bull Labeled target 400 mgday (200mg bid)

Conservative target 200 mgday initially increase slowly to 400 mg or max tolerability

Product labeling 2012

Opinion Faught

Lacosamide Pro and Con

Advantages

bull BID dosing

bull Renal excretion

bull No interactions

bull Low rate of somnolence rash cognitive effects

bull IV available

bull Adds well to LEV TPM PGN

Disadvantages

bull Modestly effective 20

greater reduction than

placebo at 400 mgday

bull Dizziness

bull Harder to add to PHT

CBZ OXCLTG ndash More

dizziness

bull Monotherapy unproven

bull Levels not established

Opinion Faught

EZOGABINE (US NAME)

RETIGABINE (EUROPEAN)

16

Ezogabine

bull Approved for adjunctive therapy of partial-

onset seizures in patients 18+ years of age

bull Facilitates and prolongs K+ channel

opening aiding repolarization of neurons

and inhibiting repetitive firing

bull Voltage-gate K+ channels are found in

brain heart and bladder but ezogabine

targets mostly the Kv72 and Kv73 channel

types not important for heart function Faught E Ezogabine A new angle on potassium currents

Epilepsy Currents 2011 July 11 1-15

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

Ezogabine

Adverse Effects somnolence dizziness

confusion other CNS effects dose related

Urinary retention can occur

17-29 withdrawal due to adverse effects in

double-blind trials vs 125 placebo

(This difference is about average in clinical

trials of AEDs)

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

(phase III RCT report)

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 9: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

L

10

Percent Reduction in Complex Partial Seizures with

Adjunctive Lacosamide- Pooled Studies

Isojarvi Faught et al presented at ANA annual meeting Baltimore Oct 2009

Metanalysis of RCTs

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf1

Lacosamide Dose-Related Adverse Effects

Placebo 200day 400day

Dizziness 7 10 25

Nausea 4 6 9

Diplopia 1 4 8

Rash somnolence cognitive effects low and equal to placebo

affected in clinical trials Product labeling 2012

Comment The dizziness tends to be subjective not true vertigo and

not usually associated with ataxia It may be worse when given with

other Na+ channel drugs eg CBZ (Faught opinion)

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf3

Lacosamide Clinical Use

bull Labeled dosing 50 bid week 1

Conservative dosing 50 hs week 1

bull Labeled titration 100 mgdayweek

Conservative titration 50 mgdayweek

bull Labeled target 400 mgday (200mg bid)

Conservative target 200 mgday initially increase slowly to 400 mg or max tolerability

Product labeling 2012

Opinion Faught

Lacosamide Pro and Con

Advantages

bull BID dosing

bull Renal excretion

bull No interactions

bull Low rate of somnolence rash cognitive effects

bull IV available

bull Adds well to LEV TPM PGN

Disadvantages

bull Modestly effective 20

greater reduction than

placebo at 400 mgday

bull Dizziness

bull Harder to add to PHT

CBZ OXCLTG ndash More

dizziness

bull Monotherapy unproven

bull Levels not established

Opinion Faught

EZOGABINE (US NAME)

RETIGABINE (EUROPEAN)

16

Ezogabine

bull Approved for adjunctive therapy of partial-

onset seizures in patients 18+ years of age

bull Facilitates and prolongs K+ channel

opening aiding repolarization of neurons

and inhibiting repetitive firing

bull Voltage-gate K+ channels are found in

brain heart and bladder but ezogabine

targets mostly the Kv72 and Kv73 channel

types not important for heart function Faught E Ezogabine A new angle on potassium currents

Epilepsy Currents 2011 July 11 1-15

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

Ezogabine

Adverse Effects somnolence dizziness

confusion other CNS effects dose related

Urinary retention can occur

17-29 withdrawal due to adverse effects in

double-blind trials vs 125 placebo

(This difference is about average in clinical

trials of AEDs)

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

(phase III RCT report)

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 10: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf1

Lacosamide Dose-Related Adverse Effects

Placebo 200day 400day

Dizziness 7 10 25

Nausea 4 6 9

Diplopia 1 4 8

Rash somnolence cognitive effects low and equal to placebo

affected in clinical trials Product labeling 2012

Comment The dizziness tends to be subjective not true vertigo and

not usually associated with ataxia It may be worse when given with

other Na+ channel drugs eg CBZ (Faught opinion)

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf3

Lacosamide Clinical Use

bull Labeled dosing 50 bid week 1

Conservative dosing 50 hs week 1

bull Labeled titration 100 mgdayweek

Conservative titration 50 mgdayweek

bull Labeled target 400 mgday (200mg bid)

Conservative target 200 mgday initially increase slowly to 400 mg or max tolerability

Product labeling 2012

Opinion Faught

Lacosamide Pro and Con

Advantages

bull BID dosing

bull Renal excretion

bull No interactions

bull Low rate of somnolence rash cognitive effects

bull IV available

bull Adds well to LEV TPM PGN

Disadvantages

bull Modestly effective 20

greater reduction than

placebo at 400 mgday

bull Dizziness

bull Harder to add to PHT

CBZ OXCLTG ndash More

dizziness

bull Monotherapy unproven

bull Levels not established

Opinion Faught

EZOGABINE (US NAME)

RETIGABINE (EUROPEAN)

16

Ezogabine

bull Approved for adjunctive therapy of partial-

onset seizures in patients 18+ years of age

bull Facilitates and prolongs K+ channel

opening aiding repolarization of neurons

and inhibiting repetitive firing

bull Voltage-gate K+ channels are found in

brain heart and bladder but ezogabine

targets mostly the Kv72 and Kv73 channel

types not important for heart function Faught E Ezogabine A new angle on potassium currents

Epilepsy Currents 2011 July 11 1-15

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

Ezogabine

Adverse Effects somnolence dizziness

confusion other CNS effects dose related

Urinary retention can occur

17-29 withdrawal due to adverse effects in

double-blind trials vs 125 placebo

(This difference is about average in clinical

trials of AEDs)

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

(phase III RCT report)

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 11: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Lacosamide Dose-Related Adverse Effects

Placebo 200day 400day

Dizziness 7 10 25

Nausea 4 6 9

Diplopia 1 4 8

Rash somnolence cognitive effects low and equal to placebo

affected in clinical trials Product labeling 2012

Comment The dizziness tends to be subjective not true vertigo and

not usually associated with ataxia It may be worse when given with

other Na+ channel drugs eg CBZ (Faught opinion)

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf3

Lacosamide Clinical Use

bull Labeled dosing 50 bid week 1

Conservative dosing 50 hs week 1

bull Labeled titration 100 mgdayweek

Conservative titration 50 mgdayweek

bull Labeled target 400 mgday (200mg bid)

Conservative target 200 mgday initially increase slowly to 400 mg or max tolerability

Product labeling 2012

Opinion Faught

Lacosamide Pro and Con

Advantages

bull BID dosing

bull Renal excretion

bull No interactions

bull Low rate of somnolence rash cognitive effects

bull IV available

bull Adds well to LEV TPM PGN

Disadvantages

bull Modestly effective 20

greater reduction than

placebo at 400 mgday

bull Dizziness

bull Harder to add to PHT

CBZ OXCLTG ndash More

dizziness

bull Monotherapy unproven

bull Levels not established

Opinion Faught

EZOGABINE (US NAME)

RETIGABINE (EUROPEAN)

16

Ezogabine

bull Approved for adjunctive therapy of partial-

onset seizures in patients 18+ years of age

bull Facilitates and prolongs K+ channel

opening aiding repolarization of neurons

and inhibiting repetitive firing

bull Voltage-gate K+ channels are found in

brain heart and bladder but ezogabine

targets mostly the Kv72 and Kv73 channel

types not important for heart function Faught E Ezogabine A new angle on potassium currents

Epilepsy Currents 2011 July 11 1-15

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

Ezogabine

Adverse Effects somnolence dizziness

confusion other CNS effects dose related

Urinary retention can occur

17-29 withdrawal due to adverse effects in

double-blind trials vs 125 placebo

(This difference is about average in clinical

trials of AEDs)

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

(phase III RCT report)

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 12: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

The adverse event profile of lacosamide A systematic review and meta‐analysis of randomized controlled trials

Epilepsia pages no-no 10 JUL 2012 DOI 101111j1528-1167201203589x Zaccara G et al EPUB ahead of printhttponlinelibrarywileycomdoi101111j1528-

1167201203589xfullf3

Lacosamide Clinical Use

bull Labeled dosing 50 bid week 1

Conservative dosing 50 hs week 1

bull Labeled titration 100 mgdayweek

Conservative titration 50 mgdayweek

bull Labeled target 400 mgday (200mg bid)

Conservative target 200 mgday initially increase slowly to 400 mg or max tolerability

Product labeling 2012

Opinion Faught

Lacosamide Pro and Con

Advantages

bull BID dosing

bull Renal excretion

bull No interactions

bull Low rate of somnolence rash cognitive effects

bull IV available

bull Adds well to LEV TPM PGN

Disadvantages

bull Modestly effective 20

greater reduction than

placebo at 400 mgday

bull Dizziness

bull Harder to add to PHT

CBZ OXCLTG ndash More

dizziness

bull Monotherapy unproven

bull Levels not established

Opinion Faught

EZOGABINE (US NAME)

RETIGABINE (EUROPEAN)

16

Ezogabine

bull Approved for adjunctive therapy of partial-

onset seizures in patients 18+ years of age

bull Facilitates and prolongs K+ channel

opening aiding repolarization of neurons

and inhibiting repetitive firing

bull Voltage-gate K+ channels are found in

brain heart and bladder but ezogabine

targets mostly the Kv72 and Kv73 channel

types not important for heart function Faught E Ezogabine A new angle on potassium currents

Epilepsy Currents 2011 July 11 1-15

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

Ezogabine

Adverse Effects somnolence dizziness

confusion other CNS effects dose related

Urinary retention can occur

17-29 withdrawal due to adverse effects in

double-blind trials vs 125 placebo

(This difference is about average in clinical

trials of AEDs)

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

(phase III RCT report)

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 13: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Lacosamide Clinical Use

bull Labeled dosing 50 bid week 1

Conservative dosing 50 hs week 1

bull Labeled titration 100 mgdayweek

Conservative titration 50 mgdayweek

bull Labeled target 400 mgday (200mg bid)

Conservative target 200 mgday initially increase slowly to 400 mg or max tolerability

Product labeling 2012

Opinion Faught

Lacosamide Pro and Con

Advantages

bull BID dosing

bull Renal excretion

bull No interactions

bull Low rate of somnolence rash cognitive effects

bull IV available

bull Adds well to LEV TPM PGN

Disadvantages

bull Modestly effective 20

greater reduction than

placebo at 400 mgday

bull Dizziness

bull Harder to add to PHT

CBZ OXCLTG ndash More

dizziness

bull Monotherapy unproven

bull Levels not established

Opinion Faught

EZOGABINE (US NAME)

RETIGABINE (EUROPEAN)

16

Ezogabine

bull Approved for adjunctive therapy of partial-

onset seizures in patients 18+ years of age

bull Facilitates and prolongs K+ channel

opening aiding repolarization of neurons

and inhibiting repetitive firing

bull Voltage-gate K+ channels are found in

brain heart and bladder but ezogabine

targets mostly the Kv72 and Kv73 channel

types not important for heart function Faught E Ezogabine A new angle on potassium currents

Epilepsy Currents 2011 July 11 1-15

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

Ezogabine

Adverse Effects somnolence dizziness

confusion other CNS effects dose related

Urinary retention can occur

17-29 withdrawal due to adverse effects in

double-blind trials vs 125 placebo

(This difference is about average in clinical

trials of AEDs)

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

(phase III RCT report)

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 14: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Lacosamide Pro and Con

Advantages

bull BID dosing

bull Renal excretion

bull No interactions

bull Low rate of somnolence rash cognitive effects

bull IV available

bull Adds well to LEV TPM PGN

Disadvantages

bull Modestly effective 20

greater reduction than

placebo at 400 mgday

bull Dizziness

bull Harder to add to PHT

CBZ OXCLTG ndash More

dizziness

bull Monotherapy unproven

bull Levels not established

Opinion Faught

EZOGABINE (US NAME)

RETIGABINE (EUROPEAN)

16

Ezogabine

bull Approved for adjunctive therapy of partial-

onset seizures in patients 18+ years of age

bull Facilitates and prolongs K+ channel

opening aiding repolarization of neurons

and inhibiting repetitive firing

bull Voltage-gate K+ channels are found in

brain heart and bladder but ezogabine

targets mostly the Kv72 and Kv73 channel

types not important for heart function Faught E Ezogabine A new angle on potassium currents

Epilepsy Currents 2011 July 11 1-15

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

Ezogabine

Adverse Effects somnolence dizziness

confusion other CNS effects dose related

Urinary retention can occur

17-29 withdrawal due to adverse effects in

double-blind trials vs 125 placebo

(This difference is about average in clinical

trials of AEDs)

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

(phase III RCT report)

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 15: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

EZOGABINE (US NAME)

RETIGABINE (EUROPEAN)

16

Ezogabine

bull Approved for adjunctive therapy of partial-

onset seizures in patients 18+ years of age

bull Facilitates and prolongs K+ channel

opening aiding repolarization of neurons

and inhibiting repetitive firing

bull Voltage-gate K+ channels are found in

brain heart and bladder but ezogabine

targets mostly the Kv72 and Kv73 channel

types not important for heart function Faught E Ezogabine A new angle on potassium currents

Epilepsy Currents 2011 July 11 1-15

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

Ezogabine

Adverse Effects somnolence dizziness

confusion other CNS effects dose related

Urinary retention can occur

17-29 withdrawal due to adverse effects in

double-blind trials vs 125 placebo

(This difference is about average in clinical

trials of AEDs)

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

(phase III RCT report)

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 16: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Ezogabine

bull Approved for adjunctive therapy of partial-

onset seizures in patients 18+ years of age

bull Facilitates and prolongs K+ channel

opening aiding repolarization of neurons

and inhibiting repetitive firing

bull Voltage-gate K+ channels are found in

brain heart and bladder but ezogabine

targets mostly the Kv72 and Kv73 channel

types not important for heart function Faught E Ezogabine A new angle on potassium currents

Epilepsy Currents 2011 July 11 1-15

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

Ezogabine

Adverse Effects somnolence dizziness

confusion other CNS effects dose related

Urinary retention can occur

17-29 withdrawal due to adverse effects in

double-blind trials vs 125 placebo

(This difference is about average in clinical

trials of AEDs)

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

(phase III RCT report)

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 17: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

Ezogabine

Adverse Effects somnolence dizziness

confusion other CNS effects dose related

Urinary retention can occur

17-29 withdrawal due to adverse effects in

double-blind trials vs 125 placebo

(This difference is about average in clinical

trials of AEDs)

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

(phase III RCT report)

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 18: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Ezogabine

Adverse Effects somnolence dizziness

confusion other CNS effects dose related

Urinary retention can occur

17-29 withdrawal due to adverse effects in

double-blind trials vs 125 placebo

(This difference is about average in clinical

trials of AEDs)

Porter RJ Partiot A Sachdeo R et al Neurology 2007 681197-1204

(phase III RCT report)

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 19: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Cardiac considerations

bull Extensive ECGs during development

program showed no effect on heart

bull No ECG screening required

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 20: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Bladder considerations

bull Kv72 and Kv73 channels are present in

bladder innervation

bull 2 urinary retention in clinical trials of

ezogabine 8 some complaint of voiding

difficulty

bull Consider another drug in patients with

prostatism or other voiding problems

Product labeling 2012

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 21: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

FDA has determined that a Risk Evaluation and Mitigation

Strategy (REMS) will be necessary for ezogabine with the

goal of informing healthcare professionals of the risk of urinary

retention and the symptoms of acute urinary retention

Ezogabine caused urinary retention in clinical trials Urinary

retention was reported as an adverse event in 29 out of 1365

(approximately 2) patients treated with ezogabine In all

studies of patients with partial-onset seizures including open-

label studies five patients required catheterization (four on

ezogabine and one on placebo)

FDA Statement on Ezogabine and Urinary

Retention (2011)

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 22: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Ezogabine Dosing

bull Effective dose range 600-1200 mgday in

THREE divided doses

bull Recommended starting dose is 100 mg

TID (Conservative start 50 mg TID)

Product label 2012 Opinion Faught

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 23: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Ezogabine Pros

bull Novel mechanism

bull No significant interactions

bull Renally excreted

bull Low rash rate

bull Low cognitive complaint rate

bull No apparent serious skin blood liver effects

so far

Opinion

Faught

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 24: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Ezogabine Cons

bull Modestly effective 231 greater

reduction than placebo at 1200

mgday

bull Short elimination half life TID dosing

bull Urinary retention may limit use in

some patients especially older men

Opinion Faught

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 25: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

RUFINAMIDE

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 26: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

RUFINAMIDE

bull Indication Adjunctive therapy of seizures

associated with the Lennox-Gastaut

syndrome in patients 4 years of age or

older

bull Mechanism of action Na+ channel

blockade (and possibly other mechanisms

since traditional sodium channel blockers

are not very effective vs atonic seizures) bull Product labeling

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 27: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Lennox-Gastaut Syndrome

Drop Attacks

-10

0

10

20

30

40

50

Felbamate Lamotrigine Topiramate

Study drug

Placebo

S

eiz

ure

red

ucti

on

P=002

P=02

P=04

Felbamate Study Group N Engl J Med 199332829-33

Motte J N Engl J Med 19973371807-1812

Sachdeo RC et al Neurology 1999521982-1987

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 28: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

copy2008 American Academy of Neurology Published by LWW_American Academy of Neurology 7

Figure 2

Rufinamide for generalized seizures associated with Lennox-Gastaut syndrome SYMBOL Glauser T Kluger G Sachdeo R Krauss G Perdomo C Arroyo S MD PhD Neurology 70(21)1950-1958 May 20 2008 DOI 10121201wnl0000303813958000d

Figure 2 Median percentage reduction in total seizure frequency and tonic-atonic seizure frequency (per 28 days during the double-blind phase relative to baseline)

Rufinamide- Reduction in generalized seizures associated with

LGS

Glauser T et al Neurology 2008 701950-8

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 29: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Rufinamide Drug Interactions

RUF Reduced BY

bull PHT

bull PB

bull CBZ

RUF Increased By

bull VPA

RUF Induces

Metabolism of 3A4

metabolized

drugs reduces

serum levels by 7-

21 eg

PHT CBZ PB

Product Labeling 2012

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 30: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Rufinamide Clinical Use

bull CHILDREN 10 mgkgday (divide into two

doses)

bull Target 45 mgkgday or max 3200

mgday

bull ADULTS 400 mg (200 mg bid)

MAX 3200 mgday

Product Labeling 2012

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 31: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

CLOBAZAM

32

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 32: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

From Seif-Edeinne H Ng YT Clobazam for patients with Lennox-Gastaut

syndrome and epilepsy Expert Rev Neurother 2012 Apr12(4)385-93

Seif-Eddeine H Ng YT

Diazepam

Clobazam

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 33: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Clobazam

bull Benzodiazepine 5-substituted rather than

3-substituted (different affinity for various

GABA receptor configurations)

bull Designed to produce less somnolence and

tolerance than other benzodiazepines

bull Approved 2011 in US for adjunctive therapy

of seizures associated with LGS age 2+

(Approved Australia 1970)

34

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 34: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Clobazam dosing

bull Dose range children lt30kg start 5

mgday titrate up to 20 mgday as

needed

bull Dose range adults 10-40 mgday as 2

divided doses available as 51020 mg

Conservative start 5 mg hs x 1 week

increase by 5 mgweek to target 20mgday

35

Opinion Faught Product labeling 2012

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 35: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Clobazam reduction in weekly ldquodroprdquo seizures in

Lennox-Gastaut syndrome n = 239

0 50 100

bull 10 mgkg = -68

bull 05 mgkg = -49

bull 025 mgkg = -41

bull Placebo = - 12

Ng YT et al Neurology 2011 77(15) 1473-81 36

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 36: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Four New Drugs Two for a Seizure Type

Two for a Syndrome

bull Lacosamide- An add-on Na+-channel choice for partial-onset seizures no interactions good profile for cognition and behavior dizziness is frequent

bull Ezogabine- another add-on choice for partial-onset seizures but with a twist a K+ channel operer Good AE profile note bladder issue

bull Rufinamide and Clobazam- Drugs for seizures associated with the Lennox-Gastaut syndrome (Often added to VPA and other options include FBM LTG and TPM)

Faught opinion

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 37: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 38: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Considerations bull A sodium channel blocker might

complement levetiracetamrsquos mechanism

but lamotrigine and oxcarbazepine carry

higher rash risk with previous ring-

compound allergy Lacosamide has a low

rash rate

bull Valproate can cause weight gain and is

teratogenic she is premenopausal

bull A K+ channel facilitator ezogabine might

complement levetiracetam

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 39: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Three things we really need in AED

pharmacology

bull An antiepileptogenic agent

bull Delivery systems that minimizes patient

adherence as a variable

bull Other choices for generalized-onset

seizures

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 40: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Case

bull A 38-yo woman has 2 complex partial

seizuresmonth despite levetiracetam 3000

mgday She has had an allergic rash to

phenytoin and carbamazepine and had

cognitive difficulty with topiramate 100 mgday

Zonisamide at 400 mgday and pregabalin 600

mgday did not improve seizure control when

added to levetiracetam

bull Seizure monitoring revealed bilateral

independent temporal onsets

bull Choose a treatment for her

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome

Page 41: Clinical Use of New Antiepileptic Drugs: Lacosamide ...az9194.vo.msecnd.net/pdfs/121201/102.03.pdf · Clinical Use of New Antiepileptic Drugs: Lacosamide, Ezogabine, Rufinamide, and

Impact on Clinical Care and Practice

bull Two new options for adjunctive therapy

of partial-onset seizures

bull Two new drug mechanisms of action

which may be useful

bullTwo new options for adjunctive therapy

of seizures associated with the Lennox-

Gastaut syndrome