New Medicines Profile
February 2010
Issue No. 10/02
Eslicarbazepine
Concise evaluated information to support the managed entry of new medicines in the NHS
Introduction
Summary
• Eslicarbazepine acetate is a new antiepileptic drug (AED) which is licensed as
add-on therapy in adults with partial-onset seizures with or without secondary
generalisation.
• In three 12-week clinical trials eslicarbazepine has been shown to be more
effective than placebo at a dose of 800mg or 1,200mg once daily as add-on
treatment in patients receiving one or more AEDs in the management of simple
and complex partial seizures with or without secondary generalisation. There
are no active-comparator trials.
• Data from open-label extension studies of one year duration suggest that the
efficacy of eslicarbazepine is maintained.
• Eslicarbazepine has similar adverse effects to oxcarbazepine. The most
common adverse effects are dizziness, somnolence, headache, diplopia,
nausea and abnormal coordination. These are more frequent in patients treated
concurrently with carbamazepine.
• Data on eslicarbazepine are limited. Further trials are needed to ascertain if it
offers advantages over other AEDs in terms of efficacy, safety and quality of
life. For patients who have not responded well to other treatments it may be an
alternative although it is not clear which patients would benefit most.
• Currently there are no published economic analyses however, compared with
alternative AEDs eslicarbazepine is expensive.
Brand Name, (Manufacturer): Zebinix® (Eisai Limited)
BNF Therapeutic Class: 4.8.1
Licensed Indications: Adjunctive therapy in adults with partial-onset
seizures with or without secondary generalisation.
Dosage and Administration: Starting dose 400mg once daily
increased to 800mg once daily after one or two weeks. Based on
individual response, the dose may be increased to 1,200mg once daily.
Presentation: 800mg tablets. Pack of 30, £154.20
Marketed: October 2009
Cost Comparisons:
Cost for 28 days treatment (prices taken from Mims December 2009)
Carbamazepine
400mg bd
Oxcarbazepine
450mg bd
Lamotrigine
150mg bd
Eslicarbazepine
800mg od
£0
£50
£100
£150
£200
NB. Prices shown are for general comparison and do not imply
therapeutic equivalence.
Eslicarbazepine acetate (Zebinix®) is a
new antiepileptic drug (AED) licensed as
add-on therapy in adults with partialonset seizures with or without secondary
generalisation.1 It is a prodrug of
eslicarbazepine, the active component,
which acts by blocking voltage-gated
sodium channels. It is chemically related
to carbamazepine and oxcarbazepine.2
NICE guidance on newer AEDs (2004)
recommends monotherapy with an older
drug e.g. carbamazepine or sodium
valproate, as initial first-line treatment for
3
epilepsy. If monotherapy does not result
in seizure freedom then combination
therapy may be needed. Treatment is
often limited by adverse effects and drug
interactions. Despite the availability of a
range of AEDs only 52% of patients with
epilepsy achieve seizure-free status
(2004 data).4
Evidence
Data supporting the licence application
for eslicarbazepine come from three
pivotal studies all similar in design, and a
5,6,7,8
Further data from
pooled analysis.
one-year open-label extension studies
are available.9,10,11 Two trials have been
fully published to date;5,7 all other studies
are reported in conference abstracts.
The three pivotal studies5,6,7 were
multicentre, randomised, placebocontrolled, parallel-group trials which
included an 8 week baseline period
followed by a double-blind 2 week
titration, a 12 week maintenance period
and, in two studies, a 4 week tapering-off
period.5,7 Patients aged 18 years or older
with refractory partial-onset seizures
(simple or complex, with or without
secondary generalisation), with ≥ 4
partial-onset seizures per 4 weeks in the
baseline period whilst on treatment with
one to three concurrent AEDs (but not
oxcarbazepine or felbamate) were
included.
The primary outcome measure in all
three studies was seizure frequency for
the 12 week maintenance period
standardised to a ‘frequency per 4
weeks’ unit. Secondary endpoints
included proportion of responders
(patients with a ≥50% reduction in
seizure frequency in the maintenance
period) and relative reduction in seizure
frequency.
Eslicarbazepine
In studies BIA-2093-3015 and 3026,
patients were randomised to treatment
with placebo, eslicarbazepine 400mg,
800mg, or 1,200mg once daily in
addition to their usual AEDs. In study
5
301 the ITT population included 397
patients and 330 completed the study. In
study 3026, 393 were included in the ITT
population. The number of patients
completing the study was not stated. In
7
study 303 , 252 patients were
randomised to treatment with placebo,
eslicarbazepine 800mg or 1,200mg once
daily.7 The ITT population included 245
patients and 194 completed the study.
Across the three studies, discontinuation
rates due to adverse effects were 4.5%,
11.6%, and 19.3% in the placebo,
eslicarbazepine 800mg and 1,200mg
groups, respectively.2
In all three studies there was a
statistically significant improvement in
the primary outcome for the
eslicarbazepine 800mg and 1,200mg
groups compared to placebo, but not for
the eslicarbazepine 400mg group. The
CHMP raised concerns about study 303
due to a high percentage of major
protocol violations (34%) and considered
some results implausible.2 See Table 1
for results.
Data from these studies were integrated
in a pooled analysis.8 The mean
standardised seizure frequency at
baseline was approximately 13 seizures
per 4 weeks in all treatment groups.
There was a statistically significant
decrease to 9.8 (± 14.79) and 9.0 (±
13.10) in the eslicarbazepine 800mg and
1,200mg groups, respectively, compared
with 11.7 (± 17.85) in the placebo group.
The proportion of responders was 22%,
36%, and 44% in the placebo,
eslicarbazepine 800mg and 1,200mg
groups, respectively.
All three studies included an optional
open-label extension period of one year.
Patients received eslicarbazepine
(median dose 800mg once daily, n=830).
29% of patients included received
9,10,11
placebo in the initial studies.
Compared to the baseline period of the
RCTs seizure frequency was decreased
by 41%, 39% and 58% in weeks 41 to 52
of extension studies 301, 302, and 303,
respectively (see Table 2 for results).
Treatment-related adverse effects were
reported by 51% to 83% of patients.9,10,11
This led to treatment discontinuation in
4% to 11% of patients.9,10
There were limitations to these studies.
The CHMP requested further analyses due
to inconsistencies in the data. However,
overall results from these additional
analyses were consistent with the original
results.2
and Thai origin should be screened for
allele HLA-B*1502 before starting
treatment as this is a risk factor for
1
SJS.
The most frequent concomitant AEDs at the
end of the baseline period were
carbamazepine (56%), sodium valproate
(24%) and lamotrigine (21%). In the pooled
analysis approximately 70% of patients
were on two concomitant AEDs. Only 3%
2
were on three AEDs.
Approximately 456,000 people in the
UK have epilepsy (2003 data) with an
annual incidence of 46 per 100,000.4
An average GP will care for 15 people
with epilepsy and see one to two new
13
cases per year.
The percentage of patients with ≥25%
increase in seizure frequency was slightly
higher in the eslicarbazepine 1,200mg
group vs. the 800mg group in some
studies. However, following further analysis
the CHMP concluded that there is no
indication of potential exacerbation of
2
seizures.
In one extension study quality of life (QOL),
as assessed by QOL in Epilepsy Inventory31, and depressed mood, as assessed by
Montgomery-Asberg Depression Rating
Scale showed clinical and statistical
12
improvement from baseline.
Safety
Eslicarbazepine has a similar adverseeffect profile to oxcarbazepine. The most
common adverse effects are dizziness,
somnolence, headache, diplopia, nausea
and abnormal coordination and occur
mainly during the first six weeks of
treatment.1 These are more frequent in
patients treated concurrently with
carbamazepine than those who are not
(dizziness 30% vs. 11.5%, diplopia 11.4%
vs. 2.4%, abnormal coordination 6.7% vs.
2
2.7%).
Eslicarbazepine is a weak inducer of
CYP3A4 and an inhibitor of CYP2C19
hepatic enzymes. Dose adjustments may
be needed if eslicarbazepine is given
concurrently with medicines metabolised by
1
these enzymes (see SPC for details).
In clinical trials ECG changes were
recorded in patients treated with
eslicarbazepine. Therefore Zebinix® is
contraindicated in patients with second and
third degree atrioventricular block and
should be used with caution in patients with
medical conditions or on concurrent
medication associated with PR
prolongation.1
Rash occurred in 1.1% of patients in clinical
trials.1 There were no reports of severe skin
reactions such as Stevens-Johnson
syndrome (SJS), but there have been
reports with oxcarbazepine. The SPC for
Zebinix® states that people of Han Chinese
NHS Impact
In clinical trials eslicarbazepine was
more effective than placebo at a dose
of 800mg or 1,200mg once daily as
add-on treatment in patients receiving
one or more AEDs in the management
of simple and complex partial-onset
seizures with or without secondary
generalisation. There are no activecomparator trials.
Eslicarbazepine is an addition to the
available AEDs for patients with
refractory epilepsy. It is given once
daily which may improve compliance.
A high percentage of patients in trials
experienced adverse effects. Most
adverse effects are mild and occur
within the first few weeks.
Further trials are needed to ascertain
if eslicarbazepine offers any
advantages over other AEDs in terms
of efficacy, safety and QOL. It may be
an alternative for patients who have
not responded well to other treatments
although it is not clear which patients
would benefit most.
The Scottish Medicines Consortium
has rejected eslicarbazepine for use
within NHS Scotland for the licensed
indication.14
Currently there are no published
economic analyses however,
compared with alternative AEDs
eslicarbazepine is expensive.
An update to NICE guidance on
epilepsy is expected in November
2010.
Appendix I
Table 1: Clinical trials of
eslicarbazepine vs. placebo
Table 2: Data from oneyear extension studies
Risk Management Issues:
Patients on warfarin: monitor INR
carefully in the first weeks after
starting concurrent treatment with
eslicarbazepine.
Produced for the UK Medicines Information Service
By Lindsay Banks
North West Medicines Information Centre, 70 Pembroke Place, Liverpool L69 3GF
The information contained in this document will be superseded in due course.
Not to be used for commercial purposes. May be copied for use within the NHS.
Eslicarbazepine
References
1.
Summary of Product Characteristics: Zebinix. Eisai
Limited. April 2009. Accessed at
www.emc.medicines.org.uk 27/11/2009.
2.
Zebinix.European Public Assessment Report (EPAR).
Scientific discussion. February 2009. Accessed at
http://www.emea.europa.eu/humandocs/PDFs/EPAR
/zebinix/H-988-en6.pdf 27/11/2009.
3.
National Institute for Health and Clinical Excellence.
NICE TA76; Newer drugs for epilepsy in adults.
March 2004. Accessed at www.nice.org.uk
27/11/2009.
4.
Joint Epilepsy Council. Epilepsy prevalence, incidence
and other statistics. August 2005.
5.
Elger C, Halasz P, Maia J et al. Efficacy and
safety of eslicarbazepine acetate as adjunctive
treatment in adults with refractory partialonset seizures: A randomised, double-blind,
placebo-controlled, parallel-group phase III
study. Epilepsia 2009; 50 (3): 454-463.
6.
Hufnagel A, Ben-Menachem E, Gabbai AA et al.
Efficacy and safety of eslicarbazepine acetate
as add-on treatment in adults with refractory
partial-onset seizures: BIA-2093-302 study.
Epilepsia 2008; 49 (Suppl 7): 424-425.
7.
Gil-Nagel A, Lopes-Lima J, Almeida L et al.
Efficacy and safety of 800 and 1200 mg
eslicarbazepine acetate as adjunctive
treatment in adults with refractory partialonset seizures. Acta Neurol Scand 2009: 120:
281-287.
8.
Elger C, French J, Halasz P et al. Evaluation of
eslicarbazepine acetate as add-on treatment in
patients with partial-onset seizures: Pooled
analysis of three double-blind phase III clinical
studies. Epilepsia 2008; 49 (Suppl 7): 433-434.
9.
Guekht A, Elger C, Halasz P et al. Long-term
treatment of partial epilepsy with eslicarbazepine
acetate: results of a 1 year open-label extension
study. Epilepsia 2009; 50 (Suppl 4): 126.
Key papers are highlighted in bold
10. Gabbai AA, Ben-Menachem E, Maia J et al. Longterm treatment of partial epilepsy with
eslicarbazepine acetate (ESL): Results of a one-year
open-label extension of study BIA-2093-302.
Epilepsia 2008; 49 (Suppl 7): 432-433.
11. Lopes-Lima J, Gil-Nagel A, Maia J et al. Long-term
treatment of partial epilepsy with eslicarbazepine
acetate (ESL): Results of a one-year open-label
extension of study BIA-2093-303. Epilepsia 2008; 49
(Suppl 7): 441-442.
12. Cramer J, Elger C, Halasz P et al. Improvement in
quality-of-life and depressive symptoms during longterm treatment with eslicarbazepine acetate: BIA2093-301 study. Epilepsia 2008; 49 (Suppl 7): 426427.
13. National Institute for Health and Clinical Excellence.
NICE CG20; Epilepsy in adults and children. October
2004. Accessed at
www.guidance.nice.org.uk/CG20/Guidance/pdf/Engli
sh 27/11/2009.
14. Scottish Medicines Consortium. Eslicarbazepine
acetate 800mg tablets (Zebinix®) No.(592/09).
Januray 2010. Accessed at
www.scottishmedicines.org.uk/files/eslicarbazepine%
20acetate%20(Zebinix)%20FINAL%20December%2
02009.doc%20for%20website.pdf 11/02/2010.
Eslicarbazepine
Appendix I
Table 1: Clinical trials of eslicarbazepine vs. placebo in adults with refractory partial-onset epilepsy.
Reference
Inclusion/Exclusion
Criteria
Population
data
Study
5
BIA-2093-301
Inclusion criteria
Œ ≥18 years of age
Πdiagnosis of simple or
complex partial seizures with or
without secondary
generalisation for at least 12
months prior to screening.
Œ ≥ 4 partial-onset seizures in
each 4 week period during 8
weeks prior to screening and no
seizure-free interval exceeding
21 consecutive days.
Πtreatment with 1 or 2 AEDs*
(not oxcarbazepine or
felbamate) in a stable dosage
regimen for at least 2 months
prior to screening.
Πnot pregnant/breastfeeding
and using acceptable
contraception
Exclusion criteria
Πsimple partial seizures
without motor symptoms.
Πprimarily generalised
epilepsy.
Πknown rapid progressive
neurological disorder.
Πhistory of status epilepticus
or cluster seizures within 3
months prior to screening.
Πhistory of schizophrenia or
attempted suicide.
Πseizures of psycogenic
origin within the last 2 years
Πsecond or third-degree
atrioventricular not corrected
with a pacemaker
Πrelevant clinical laboratory
abnormalities
Πexposure to oxcarbazepine
or felbamate within one month
of screening.
n=397
Study
6
BIA-2093-302
Study
7
BIA-2092-303
Pooled
8
analysis
Efficacy outcome
Mean ± SD baseline seizure
frequency per 4 weeks
Results: ITT population
Placebo
Eslicarbazepine
400mg daily
Eslicarbazepine
800mg daily
Eslicarbazepine
1,200mg daily
12.4 ± 17.94
11.4 ± 9.74
11.2 ± 11.21
11.6 ± 15.92
5.7
(4.92 to 6.45)
p<0.01
5.4
(4.63 to 6.12)
p<0.001
Primary outcome
LS Mean (95% CI) seizure
frequency per 4 weeks
(maintenance period)
7.6
(6.78 to 8.58)
6.7
(5.93 to 7.60)
p=ns
Secondary outcomes
Responder rate in 12 week
maintenance period
Median relative reduction in seizure
frequency (maintenance period)
20%
23%
34%
43%
16%
26%
36%
45%
7.1
(6.2 to 8.2)
p<0.01
7.0
(6.0 to 8.1)
p<0.001
n=393
Primary outcome
LS Mean (95% CI) seizure
frequency per 4 weeks
(maintenance period)
9.8
(8.7 to 11.1)
8.7
(7.7 to 9.9)
p=ns
Secondary outcome
Responder rate in 12 week
maintenance period
n=245
Mean ± SD baseline seizure
frequency per 4 weeks
18.%
19.8%
32%
35.1%
11.3 ± 18.48
N/A
11.6 ± 22.12
11.3 ± 10.27
5.7
(4.9 to 6.7)
p=0.048
5.5
(4.6 to 6.5)
p=0.021
Primary outcome
LS Mean (95% CI) seizure
frequency per 4 weeks
(maintenance period)
7.3
(6.3 to 8.5)
N/A
Secondary outcome
Responder rate in 12 week
maintenance period
n=1,035
*1 to 3 AEDs in study 302, p values stated = comparison to placebo
Mean ± SD baseline seizure
2
frequency per 4 weeks
Mean ± SD seizure frequency per 4
2
week period (maintenance period)
Responder rate in 12 week
maintenance period (n=986)
Median relative reduction in seizure
frequency (maintenance period)
(n=983)
LS=Least square
22.6%
N/A
34.5%
37.7%
12.9 ± 16.82
13.0 ± 15.08
13.4 ± 15.31
13.1 ± 15.26
11.7 ± 17.85
10.6 ± 13.11
9.8 ± 14.79
9.0 ± 13.10
21.5%
22.9%
36.3%
43.5%
14.6%
23.4%
35.4%
38.8%
Responder rate = patients with a ≥50% reduction in seizure frequency in the maintenance period.
Eslicarbazepine
Appendix I
Table 2: Data from one-year extension studies of eslicarbazepine in adults with refractory partial-onset epilepsy
Reference
Extension
9
study 301
Extension
10
study 302
Extension
11
study 303
Inclusion/Exclusion
Criteria
Population
data
Inclusion criteria
Œ ≥18 years of age
Πdiagnosis of simple or complex
partial seizures with or without
secondary generalisation for at least 12
months prior to screening.
Œ ≥ 4 partial-onset seizures in each 4
week period during 8 weeks prior to
screening and no seizure-free interval
exceeding 21 consecutive days.
Πtreatment with 1 or 2 AEDs* (not
oxcarbazepine or felbamate) in a stable
dosage regimen for at least 2 months
prior to screening.
Πnot pregnant/breastfeeding and using
acceptable contraception
Exclusion criteria
Πsimple partial seizures without motor
symptoms.
Πprimarily generalised epilepsy.
Πknown rapid progressive neurological
disorder.
Πhistory of status epilepticus or cluster
seizures within 3 months prior to
screening.
Πhistory of schizophrenia or attempted
suicide.
Πseizures of psycogenic origin within
the last 2 years
Πsecond or third-degree
atrioventricular blockade not corrected
with a pacemaker
Πrelevant clinical laboratory
abnormalities
Πexposure to oxcarbazepine or
felbamate within one month of
screening.
n=314
80 (25.5%)
patients from
placebo group
n=325
94 (28.9%)
patients from
placebo group
n=191
65 (33.5%)
patients from
placebo group
Efficacy outcome
Results: ITT population
Eslicarbazepine median 800mg daily
Weeks 1 to 4
Weeks 5 to 16
Weeks 41 to 52
Reduction in seizure frequency
compared with baseline period in
initial RCT
32%
38%
41%
Responder rate
41%
Reduction in seizure frequency
compared with baseline period in
initial RCT
32%
Responder rate
37%
Reduction in seizure frequency
compared with baseline period in
initial RCT
48%
Responder rate
46%
*1 to 3 AEDs in study 302, Responder rate = patients with a ≥50% reduction in seizure frequency in the maintenance period
48 to 53% per 12 week interval
38%
39%
38 to 42% per 12 week interval
54%
58%
52 to 56% per 12 week interval