Levetiracetam, tablet 250 mg, 500 mg and 1000 mg, oral solution 100 mg per mL, Keppra®, November 2008
Public summary document for Levetiracetam, tablets 250 mg, 500 mg, 1000 mg and 100 mg per mL, Keppra®, November 2008
Page last updated: 24 March 2009
Public Summary Document
Product: Levetiracetam, tablet 250 mg, 500 mg and
1000 mg, oral solution 100 mg per mL, Keppra®
Sponsor:UCB Australia Pty Ltd
Date of PBAC Consideration:November 2008
1. Purpose of Application
The submission sought to extend the current PBS listing to include
treatment of primary generalised tonic clonic seizures (PGTCS) and
generalised myoclonic seizures [also called juvenile myoclonic
epilepsy (JME)].
2. Background
At the June 2001 meeting, the PBAC recommended an authority
required listing for levetiracetam tablets for treatment of partial
epileptic seizures which are not controlled satisfactorily by other
anti-epileptic drugs on a cost-minimisation basis compared with
lamotrigine, with 2 g levetiracetam being similar in effectiveness
and safety to 300 mg lamotrigine (drug costs only). Listing was
effective from 1 August 2003.
Levetiracetam was listed as a Special Pharmaceutical Benefit from 1
August 2005, with the Special Patient Contribution applying to the
restriction “Treatment of partial epileptic seizures which
are not controlled satisfactorily by other anti-epileptic
drugs” because the company did not agree to a price reduction
under the 12.5% pricing policy.
At the November 2007 meeting, the PBAC recommended listing
levetiracetam oral solution for the treatment of partial epileptic
seizures which are not controlled satisfactorily by other
anti-epileptic drugs in patients who have difficulty swallowing
tablets.
3. Registration Status
Levetiracetam was first TGA registered on 22 February 2001 for:
- Use in epileptic patients aged 4 years and older, initially as add-on therapy, in the treatment of partial onset seizures with or without secondary generalisation.
In May 2008, the approved indications were extended to include:
- Monotherapy in the treatment of partial onset seizures, with or without secondary generalisation, in patients from 16 years of age with newly diagnosed epilepsy.
- Add-on therapy in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy (JME).
- Add-on therapy in the treatment of PGTC seizures in adults and children from 4 years of age with idiopathic generalised epilepsy (IGE).
4. Listing Requested and PBAC’s View
Authority required
Treatment of primary generalised tonic clonic seizures initially as
add-on therapy and treatment of generalised myoclonic seizures
initially as add-on therapy.
Alternative wording for the indication proposed by the sponsor
was:
Idiopathic generalised epilepsy where the predominant seizure type
is tonic clonic or myoclonic.
For PBAC’s view, see Recommendation and
Reasons.
5. Clinical Place for the Proposed Therapy
In all patients with epilepsy, around 57% have partial seizures,
23% tonic clonic seizures, 6% absence seizures and 3% myoclonic
seizures. The last three seizures comprise the majority of
generalised seizures, with the tonic clonic variety being by far
the biggest of these types, comprising around 88%.
Levetiracetam will provide an option as add-on therapy for the
treatment of primary generalised tonic clonic (PGTC) seizures and
myoclonic seizures
6. Comparator
The submission nominated lamotrigine and topiramate for the PGTCS
indication.
The PBAC considered that the proper comparison for the PGTCS
indication was with lamotrigine. No comparator was presented for
the myoclonic seizures of idiopathic generalised epilepsy (IGE)
indication.
7. Clinical Trials
The submission presented a single placebo-controlled randomised trial for each of
levetiracetam, topiramate and lamotrigine for the primary generalised tonic clonic
indication and a single placebo-controlled randomised trial of levetiracetam for the
myoclonic indication.
Table B(i).2.3: Trials and associated reports presented in the submission
| Trial ID/ First Author | Protocol title/ Publication title | Publication citation |
| Primary generalised tonic clonic seizures | ||
| Levetiracetam versus placebo | ||
| N01057 |
On behalf of Levetiracetam N01057 Study Group. Placebo-controlled study of levetiracetam in idiopathic generalized epilepsy. Efficacy and safety o f levetiracetam as adjunctive treatment in adult and paediatric patients suffering from idiopathic generalised epilepsy with primary generalised tonic–clonic seizures |
Berkovic SF, et al. Neurology. 2007; 69 (18): 1751-60 Morrow J. Epilepsia 2006; 47 (Suppl3) p180. |
| Topiramate | ||
| Biton 1999 | A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. | Biton V, et al. Neurology 1999; 52: 1330-1337 |
| Ben-Menachem 1997 | A Double-Blind Trial of Topiramate in Patients with Generalised Tonic-Clonic Seizures of Non-Focal Origin. | Ben-Menachem E, et al. Epilepsia, 1997; 38 (Suppl 3): 60 |
| Biton 2005 | Topiramate in Patients with Juvenile Myoclonic Epilepsy, | Biton V, et al. Arch Neurol 2005; 62: 1705-1708 |
| Lamotrigine | ||
| Biton 2005 | Double-blind, placebo-controlled study of lamotrigine in primary generalized tonic-clonic seizures. | Biton V, et al. Neurology 2005; 65: 1737-1743 |
| Lamotrigine adjunctive therapy among children and adolescents with primary generalized tonic clonic seizures. | Trevathan E, et al. Pediatrics, 118 (2): e371-8. | |
| Myoclonic seizures | ||
| Levetiracetam | ||
| Study N166 | Levetiracetam for the treatment of idiopathic generalized epilepsy with myoclonic seizures. | Noachtar, et al. Neurology 2008;70: 607–616 |
| Efficacy and Safety of Levetiracetam 3000 mg/d as Adjunctive Treatment in Adolescents and Adults Suffering from Idiopathic Generalised Epilepsy with Myoclonic Seizures | Verdru P, et al. Eplilepsia 2005; 46 (Suppl6): 56-7 | |
| Seizure Control with Levetiracetam in Juvenile Myoclonic Epilepsies | Andermann E, et al. Epilepsia 2005 46 (Suppl8) 205 | |
8. Results of Trials
Key results of the randomised trials are presented below.
Primary Generalised Tonic Clonic Seizures
Median % reduction (double blind treatment period compared
with baseline) rate of primary generalised tonic clonic seizures
– primary outcome in all trials
| N01057 | Biton 1999 | Biton 2005 | ||||
| Placebo (n=84) | LEV (n=78) | Placebo (n=40) | TOP (n=39) | Placebo (n=59) | LAM (n=58) | |
| Median % reduction PGTC | 44.57 | 77.58 | 9.0 | 56.7 | 34.2 | 66.5 |
| Median difference (95% CI) p-value | 27.99 (11.96, 39.72) <0.001 | 0.019 | 0.06 | |||
Abbreviations: LEV = levetiracetam; TOP = topiramate; LAM =
lamotrigine
These results indicate that patients treated with levetiracetam and
topiramate have a statistically significantly reduced mean
reduction rate of PGTCS compared with those treated with placebo.
No statistically significant differences were observed between
patients treated with lamotrigine or placebo as reported in Biton
(2005).
The following tables present the proportion of patients in the
levetiracetam and topiramate trials, and the levetiracetam and
lamotrigine trials, who achieved at least a 50 % reduction, and a
100% reduction in PGTCS rate. Indirect comparisons are also
presented.
Levetiracetam vs Topiramate: Indirect Comparison of PGTC
50% and 100% Responder Rates
| Trial of LEV (N01057) | Trial of TOP (Biton 1999) | Indirect estimate of effect Indirect RR(95% CI) | ||||
| Treatment effect RR (95% CI) | LEV n/N (%) | PBO n/N (%) | PBO n/N (%) | TOP n/N (%) | Treatment effect RR (95% CI) | |
| PGTC 50% Responder Rate | ||||||
| 1.595 (1.215, 2.094) | 57/79 (72.2) | 38/84 (45.2) | 8/4 0 ( 20 ) | 22/39 (56.4) | 2.8 2 (1.4 3, 5. 56 ) | 0.566 (0.272, 1.175) |
| PGTC 100% Responder Rate | ||||||
| 3.367 (1.418, 7.996) | 19/79 (24.1%) | 6/84 (7.1%) | 2/4 0 (5.0%) | 5/39 (12.8%) | 2. 56 (0.5 3 , 12. 44 ) | 1. 3 16 (0.204, 8.498) |
Levetiracetam versus Lamotrigine: Indirect comparison of PGTC 50% and 100% responder rates
| Trial of LEV (N01057) | Trial of LTG (Biton 2005) | Indirect estimate of effect Indirect RR(95% CI) | ||||
| Treatment effect RR (95% CI) | LEV n/N (%) | PBO n/N (%) | PBO n/N (%) | TOP n/N (%) | Treatment effect RR (95% CI) | |
| PGTC 50% Responder Rate | ||||||
| 1.595 (1.215, 2.094) | 57/79 (72.2%) | 38/84 (45.2%) | 23/59 (39.0%) | 37/58 (63.8%) | 1.636 (1.126, 2.377) | 0.975 (0.614, 1.547) |
| PGTC 100% Responder Rate | ||||||
| 3.367 (1.418, 7.996) | 19/79 (24.1%) | 6/84 (7.1%) | 10/59 (16.9%) | 12/58 (20.7%) | 1.221 (0.573, 2.602) | 2.758 (0.874, 8.706) |
All three studies demonstrated a statistically significant benefit
over placebo in achieving a 50 % reduction in PGTC seizure rate.
The proportion achieving PGTC seizure freedom rate (100%
responders) was greater in the treatment groups compared with the
placebo groups in all trials, however the difference reached
statistical significance only in Trial N01057. The indirect
comparisons of levetiracetam versus topiramate and lamotrigine
indicate there are no statistically significant differences between
the treatments in the proportion of patients achieving a 50% or
100% responder rate.
Generalised Myoclonic Seizures
50% Responder rate in myoclonic seizure days per week over
the treatment period – mITT population (primary
outcome)
| LEV N=60 n/N (%) | PBO N=60 n/N | Odds ratio (95% CI) | (p-value) |
| 35 (58%) | 14 (23%) | 4.77 (2.12, 10.77) | (0.0002) |
Responders were defined as patients with at least 50% reduction of
seizures. The odds of achieving a 50% response were statistically
significantly greater in the treatment group than in placebo.
An indirect comparison of adverse events reported in the
levetiracetam, topiramate and lamotrigine trials indicated there
are no statistically significant differences between the
treatments. An extended assessment revealed no other safety
concerns beyond those reported in the randomised trials.
9. Clinical Claim
The submission claimed equivalency in terms of comparative
effectiveness and equivalency in terms of comparative safety with
topiramate and lamotrigine in primary generalised tonic clonic
seizures.
The Committee considered that the proper comparison for the PGTCS
indication was with lamotrigine and that the presented data
generally support the claim of non-inferiority in this indication
as there was no statistical difference in any of the outcomes, but
the confidence intervals were wide due to small sample numbers and
additionally, no non-inferiority limits had been given.
The submission did not make a therapeutic claim regarding the
comparative effectiveness and safety of levetiracetam over
topiramate and lamotrigine in myoclonic seizures.
For PBAC’s view, see Recommendation and
Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis. The submission argued that
the current therapeutic relativities of levetiracetam, topiramate and lamotrigine
for partial seizures are maintained for primary generalised tonic clonic seizures
(dosage data available) and although not explicitly stated, that the relativities
are maintained for the myoclonic seizures (for which no dosage or comparative dosage
data is provided). The table below summarises the current therapeutic relativities
for the partial seizure indication and the maintenance doses reported for the primary
generalised tonic clonic seizures.
Mean maintenance dose
| levetiracetam | topiramate | lamotrigine | |
| Indirect comparison in submission | 2549 a | 359 | 315.96 |
| Indirect comparison – steady state only | 2887.2 b | 359 | 296.61 |
| Current therapeutic relativity | 2000 c | 300mg | 300mg |
| Ratio current trial dose to comparison trial dose | 1.44 | 1.2 | 0.99 |
a treatment period (up-titration plus evaluation)
b evaluation dose, trial N01057
c partial seizures
The PBAC agreed with the ESC regarding the appropriate means of determining the equi-effective
doses in these indications, considering that the therapeutic relativities of levetiracetam
and lamotrigine for partial seizures cannot be maintained because the dose relativity
of the drugs change in this indication compared to the data on partial seizures presented
in earlier submissions and that because epilepsy requires chronic treatment, the dose
relativity should be determined at steady state.
Listing was recommended on a cost-minimisation basis with lamotrigine with the equi-effective
doses for these indications being levetiracetam 2887 mg and lamotrigine 296 mg.
11. Estimated PBS Usage and Financial Implications
The submission estimated the financial cost per year to the PBS to
be less than $10 million (SPC inclusive) in Year 5.
The submission estimated the likely number of patients per year to
be less than 10,000 in Year 5.
12. Recommendation and Reasons
The PBAC recommended extending the authority required listing of
levetiracetam on the Pharmaceutical Benefits Scheme to include the
treatment of primary generalised tonic clonic seizures (PGTCS) and
generalised myoclonic seizures. Listing was recommended on a
cost-minimisation basis with lamotrigine with the equi-effective
doses for these indications being levetiracetam 2887 mg and
lamotrigine 296 mg.
In making this recommendation, the Committee considered that the
proper comparison for the PGTCS indication was with lamotrigine and
that the presented data generally support the claim of
non-inferiority in this indication as there was no statistical
difference in any of the outcomes, but the confidence intervals are
wide due to small sample numbers and additionally, no
non-inferiority limits have been given.
The Committee accepted that although a true cost-minimisation or
cost-effectiveness analysis had not been conducted for the
myoclonic seizure listing, the cross study comparison between
myoclonic seizures and PGTCS indicates that the increase in the
percentage of 50 % responders is similar in both cases. Furthermore
the comparison between the placebo controlled trials for
levetiracetam in both seizure types provided by the sponsor
suggests similar improvements in the both types of epilepsy and the
dose is also similar in both types. Noting that myoclonic seizures
account for around 3 % of all epilepsy and taking into account the
totally of the data set and the ESC advice, the Committee concluded
that it is probable that the benefits of levetiracetam are similar
between the two types of epilepsy and thus the data set can be used
for the cost-minimisation analysis as proposed.
The PBAC however agreed with the ESC regarding the appropriate
means of determining the equi-effective doses in these indications,
considering that the therapeutic relativities of levetiracetam and
lamotrigine for partial seizures cannot be maintained because the
dose relativity of the drugs change in this indication compared to
the data on partial seizures presented in earlier submissions and
that because epilepsy requires chronic treatment, the dose
relativity should be determined at steady state.
Finally, the Committee noted the submission’s request to
maintain the current Special Patient Contribution for levetiracetam
for the new indications, but noted that this is a matter for policy
consideration which falls outside the remit of PBAC.
Recommendation
LEVETIRACETAM, tablet, 250 mg, 500 mg, 1000 mg, oral solution 100
mg per mL
Restriction:
Authority Required
Treatment of partial epileptic seizures which are not controlled
satisfactorily by other anti-epileptic drugs.
Treatment, as add-on therapy, of primary generalised tonic clonic
seizures.
Treatment, as add-on therapy, of generalised myoclonic
seizures.
Maximum quantity: 60 (tablets – all strengths); 1 (oral
solution)
Number of repeats: 5 (all forms)
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 disagrees with the PBAC's statement that lamotrigine is
the comparator thus ignoring topiramate, especially given that
there is no clinical difference at a population level between using
topiramate as the comparator instead of lamotrigine. Given the
disparity in view points (PBAC and sponsor) in reference to the
comparator issue, the sponsor is re-evaluating its options.
