Factors Associated with Poor Antiepileptic Drugs Adherence ...
Clinical Use of New Antiepileptic Drugs: Lacosamide...
Transcript of Clinical Use of New Antiepileptic Drugs: Lacosamide...
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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