Lacosamide, tablets, 50 mg, 100 mg, 150 mg and 200 mg, oral solution, 15 mg per mL, Vimpat®, November 2009
Public Summary Document for Lacosamide, tablets, 50 mg, 100 mg, 150 mg and 200 mg, oral solution, 15 mg per mL, Vimpat®, November 2009
Page last updated: 05 March 2010
Public Summary Document
Product: Lacosamide, tablets, 50 mg, 100 mg, 150
mg and 200 mg, oral solution, 15 mg per mL,
Vimpat®
Sponsor: UCB Australia Pty Ltd
Date of PBAC Consideration: November 2009
1. Purpose of Application
To request an Authority Required listing for treatment of partial
epileptic seizures which are not controlled satisfactorily by other
anti-epileptic drugs (AEDs) in patients who meet certain
criteria.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Lacosamide tablets and oral solution were TGA registered on 20 July
2009 for use as add-on therapy, in the treatment of partial
seizures with or without secondary generalisation in patients with
epilepsy aged 16 years and older.
4. Listing Requested and PBAC’s View
Authority Required
Treatment of partial epileptic seizures which are not controlled
satisfactorily by other anti-epileptic drugs, and where:
(a) at least three anti-epileptic drugs have been unsuccessfully
trialled, including at least two of the following adjunctive
anti-epileptic drugs: lamotrigine, levetiracetam, topiramate,
oxcarbazepine, tiagabine, and gabapentin; AND
(b) current treatment consists of at least 2 AEDs, including at
least one adjunctive anti-epileptic drug.
For PBAC’s view see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
Epilepsy is a common neurological condition, characterised by
recurrent, unprovoked seizures, and produces significant morbidity
in the general community. For many patients, existing antiepileptic
drugs are either ineffective or produce unacceptable side-effects.
Published reviews of the treatment of partial onset epilepsies
define treatment refractory patients as having tried 3 or more
anti-epileptic drugs without achieving seizure control.
Lacosamide would provide an additional therapeutic option in the
management of refractory epilepsy.
6. Comparator
The submission nominated placebo plus standard care as the main
comparator, which the PBAC considered appropriate. Standard care
could include numerous combinations of first and second-line
agents.
7. Clinical Trials
The submission presented three randomised trials, SP667, SP754 and
SP755, comparing lacosamide (200 mg/day, 400 mg/day and 600 mg/day)
with placebo in patients with partial onset epilepsy that is
refractory to current treatment.
The below table provides the publication detail of the trials
presented in the submission :
| Trial ID / First author | Protocol title / Publication title | Publication citation |
| Direct randomised trials | ||
| Ben-Menachem E, et al. (2007) (SP667) | Efficacy and safety of oral lacosamide as adjunctive therapy in adults with partial-onset seizures. | Epilepsia; 48(7): 1308-17. |
| Halasz P, et al (2009) (SP755) | Adjunctive lacosamide for partial-onset seizures: Efficacy and safety results from a randomized controlled trial. | Epilepsia, 50 (3):443-453 |
8. Results of Trials
The primary outcomes of the trials were:
- 50% responder rate to treatment based on the percent change in seizure frequency (all types) per 4 week period in the baseline and maintenance phases, and
- Percent Reduction of Seizure Frequency over Placebo at Maintenance Endpoint.
For the first outcome listed above, there were statistically
significant differences in favour of the lacosamide 400 mg/day
treatment group compared to placebo in all three trials. Trials
SP667 and SP755 also included a lacosamide 200 mg/day treatment
group and although these groups had a higher proportion of
responders than placebo, the difference in each trial was not
statistically significant. The combined meta-analysis showed that a
significantly larger proportion of patients treated with lacosamide
(either 200 mg or 400 mg/day) experienced a 50% reduction in
seizure frequency per 28 days from baseline to the maintenance
phase compared to patients treated with placebo.
The results of the second primary outcome from the trials of
percentage reduction of seizure frequency over placebo at the
maintenance endpoint showed a statistically significant reduction
in seizure frequency over placebo for the 400 mg/day lacosamide
treatment group in all three trials. SP667 and SP755 included a 200
mg/day treatment group and both trials showed a reduction in
seizure frequency with 200 mg/day, but only in trial SP755 did this
reach statistical significance.
The submission presented meta-analyses of the randomised trials for
a number of safety parameters.
Meta-analysis estimates of risk difference and relative
risk for a number of safety parameters
| Parameter | RD (LCM-PBO) (95%CI) | RR (LCM/PBO) (95%CI) |
| Total withdrawals LCM 200 or 400 mg/day vs placebo | 0.08 (0.04, 0.13) | 1.63 (1.20, 2.20) |
| Withdrawals due to adverse events LCM 200 or 400 mg/day vs placebo | 0.09 (0.05, 0.14) | 2.68 (1.67, 4.31) |
| Dizziness LCM 200 or 400 mg/day vs placebo | 0.18 (0.04, 0.32) | 3.04 (2.10, 4.39) |
| Headache LCM 200 or 400 mg/day vs placebo | 0.03 (0.00, 0.07) | 1.38 (0.95, 2.02) |
| Nausea LCM 200 or 400 mg/day vs placebo | 0.06 (0.03, 0.08) | 2.20 (1.05, 4.60) |
| Diplopia LCM 200 or 400 mg/day vs placebo | 0.07 (0.05, 0.09) | 4.43 (2.05, 9.57) |
LCM: lacosamide; PBO: placebo; RD: risk difference; RR:
relative risk; CI: confidence interval.
The reported adverse events of dizziness, nausea and diplopia were
statistically significantly more frequently in patients treated
with lacosamide compared to those treated with placebo, with the
exception of ‘headache’. There was no significant
difference from placebo for the 200 mg/day group in total
withdrawals (RD: 0.05, 95%CI: -0.01, 0.12), but the difference was
significant at 400 mg/day (RD: 0.10, 95%CI: 0.05, 0.15). This was
the same for withdrawals due to adverse events, which was not
significantly different from placebo for the 200 mg/day treatment
group (RD: 0.05, 95%CI: -0.04, 0.14) but were significantly
different at 400 mg/day (RD: 0.12, 95%CI: 0.08, 0.16).
The extended assessment of comparative harms confirmed the safety
conclusions of the direct randomised trials.
9. Clinical Claim
The submission described lacosamide as superior in terms of
comparative effectiveness and inferior in terms of comparative
safety over placebo. The PBAC accepted this claim.
10. Economic Analysis
The submission presented a trial-based cost-per-responder analysis,
which was based on direct randomised trials and using the primary
outcome, 50% responder rate for the subgroup of the trial patient
population who were representative of those for whom PBS listing is
intended. The inputs into this estimation were the incremental cost
of treatment with lacosamide (from the proposed PBS price and the
mean dose of lacosamide) and the incremental increase in the
proportion of responders to lacosamide in the post-hoc target
subgroup (defined as patients with at least 50% reduction in
seizure frequency).
The incremental cost per extra responder over 12 weeks for the
subgroup population and the total population was calculated to be
less than $15,000.
The economic evaluation was only for 12 weeks duration and this
made the assessment of the cost-effectiveness of lacosamide
difficult, as lacosamide is intended as a long-term maintenance
therapy. A sensitivity analysis was conducted independently during
the evaluation to determine a cost per additional seizure-free
patient. This was calculated to be between $15,000 - $45,000. The
PBAC considered that there should be a continuation rule
incorporated in the listing
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year was estimated to be less
than 10,000 in year 5. This estimate was considered
uncertain.
The financial cost per year to the PBS was estimated to be less
than $10 million in Year 5. The submission’s estimate was
considered uncertain, as it was based upon a number of uncertain
assumptions, including the proportion of patients who would fulfil
the requirements for lacosamide treatment, the potential uptake
rate and compliance rate, the point of withdrawal due to adverse
events and lack of effect as well as the breakdown of the strengths
of lacosamide dispensed dependent upon the maximum tolerated
dose.
For PBAC’s view see Recommendation and
Reasons.
12. Recommendation and Reasons
The PBAC recommended the listing of lacosamide on a cost-effectiveness basis compared
with placebo plus standard background therapy as an authority required benefit for
intractable epilepsy as add-on treatment initiated by a neurologist in a patient who
has failed previous therapy. A streamlined authority was not considered suitable for
use in this last-line setting.
Despite concerns about usage outside the intended population into 2nd line use, the PBAC recognised that there is a high clinical need for an effective
treatment for intractable epilepsy, as highlighted in the hearing. Although other
adjunctive anti-epileptic drugs have been listed on the basis of evidence from placebo-controlled,
add-on studies, on a cost-minimisation basis compared with lamotrigine, lacosamide
appears to be effective in heavily treated patients as more than 60% of patients in
the trials had received seven prior treatments.
The PBAC noted that the economic analysis calculated an incremental cost/extra responder
over 12 weeks (subgroup population) of less than $15,000 based on a 50% reduction
in seizures (the primary outcome in the trials). The outcome of 50% responder rate
is dependent on a patient’s baseline seizure frequency and in a less severe population
is of doubtful clinical relevance. However, although an outcome in epilepsy trials
that is potentially more patient-relevant is the proportion of patients achieving
a particular threshold such as, proportion of seizure-free patients), the PBAC recognised
that in patients with intractable epilepsy, a 50% reduction in seizures was likely
to be clinically important. Further, it would be unlikely for such patients to be
seizure-free. Although an incremental cost-effectiveness ratio expressed in terms
of QALYs gained was not provided in the submission, the PBAC considered that if the
ICER per 50% responder were to be quality-adjusted, the resulting cost per QALY would
most likely be within an acceptable range.
Recommendation:
LACOSAMIDE, tablets, 50 mg, 100 mg, 150 mg and 200 mg, 14 tablet packs of 100 mg and
150 mg tablets, and oral solution 15 mg per mL, 465 mL
Restriction:
Authority Required
Treatment, initiated by a neurologist, in combination with two or more anti-epileptic
drugs which includes one second-line adjunctive agent, of partial epileptic seizures
which are not controlled satisfactorily by other anti-epileptic drugs in a patient
aged 16 years or older with intractable epilepsy.
A patient must have trialled and failed to achieve satisfactory seizure control with:
(i) at least one first-line anti-epileptic agent; and
(ii) at least two second-line adjunctive anti-epileptic agents.
Continuing treatment, in combination with two or more anti-epileptic drugs which includes one second-line adjunctive agent, of partial epileptic seizures in a patient aged 16 years or older, who has previously been treated with PBS-subsidised lacosamide.
NOTE:
No applications for increased maximum quantities will be authorised for the 56 tablet packs of the 150 mg and 200 mg strengths.
Maximum quantity:
14 (50 mg)
‡1 (100 mg (14) and 150 mg (14))
56 (100 mg, 150 mg and 200 mg)
1 (15 mg per mL)
Repeats:
1 (50 mg, 100 mg (14) and 150 mg (14))
5 (100 mg, 150 mg, 200 mg and 15 mg per mL)
13. Context for Decision
The PBAC helps decide whether and, if so, how medicines should be
subsidised in Australia. It considers submissions in this context.
A PBAC decision not to recommend listing or not to recommend
changing a listing does not represent a final PBAC view about the
merits of the medicine. A company can resubmit to the PBAC or seek
independent review of the PBAC decision.
14. Sponsor’s Comment
The Sponsor has no comment.
