Elitriptan Hydrobromide tablet, 40 mg (base) and 80 mg (base), Relpax® - March 2010
Public Summary Document for Elitriptan Hydrobromide tablet, 40 mg (base) and 80 mg (base), Relpax® - March 2010
Page last updated: 02 July 2010
Public Summary Document
Product: Elitriptan Hydrobromide tablet, 40 mg
(base) and 80 mg (base), Relpax®
Sponsor: Pfizer Australia Pty Ltd
Date of PBAC Consideration: March 2010
1. Purpose of Application
The submission sought an Authority required (Streamlined) listing
for the treatment of migraine attacks in patients who meet certain
criteria.
2. Background
This drug had not previously been considered by the PBAC.
3. Registration Status
Eletriptan hydrobromide 20 mg, 40 mg and 80 mg tablets were
registered with the Therapeutic Goods Administration (TGA) on 13
October 2000 for the acute treatment of migraine headache with or
without aura.
4. Listing Requested and PBAC’s View
Authority Required (Streamlined)
Migraine attacks in patients receiving, or who have failed a
reasonable trial of, prophylactic medication and where attacks in
the past have usually failed to respond to oral therapy with
ergotamine and other appropriate agents, or in whom these agents
are contraindicated.
The PBAC recommended the same restriction apply to eletriptan as
that recommended for rizatriptan benzoate and the other
Pharmaceutical Benefits Scheme (PBS) listed 5HT1 agonist
(triptans) at the November 2009 PBAC meeting. At the November 2009
PBAC meeting the PBAC considered that it was appropriate not to
include the necessity to trial ergotamine prior to the use of a
5HT1 agonist, and also that it not be a requirement to
fail a trial of prophylactic medication before using a
5HT1 agonist. The PBAC however considered that
5HT1 agonists should remain second line treatment of
migraine attack after failure of, or contraindication to,
analgesics.
5. Clinical Place for the Proposed Therapy
Eletriptan would provide an additional triptan for the treatment of
migraine attack. The submission claimed that the listing of
eletriptan would not change the current treatment algorithm but
would provide prescribers with a greater choice of triptans to
treat migraine attacks.
6. Comparator
The submission nominated sumatriptan as the comparator, as it is
the current market leader in terms of volume of PBS prescriptions
for the triptans. This was the appropriate comparator.
7. Clinical Trials
The submission presented 4 head-to-head randomised trials, and
meta-analyses of these trials, comparing eletriptan with
sumatriptan in patients with acute migraine attacks.
Three of the head-to-head randomised trials had been published at
the time of submission as follows:
| Trial ID / First author | Protocol title/ Publication title | Publication citation |
|---|---|---|
| Study 160-314 Goadsby PJ et al. (2000) Poole PH et al. (1998) |
A multicentre, double blind, double dummy, parallel group, placebo controlled, dose response study of oral UK-116,044 (eletriptan) and oral sumatriptan (100 mg) given for the acute treatment of migraine (with and without aura). | Neurology 2000, 54(1):156-63. Abstr P06.002. Neurology 1998, 50(4): A375-A6 |
| Study A160-1048 Mathew NT et al. (2003d) Mathew NT et al. (2003c) Mathew NT et al. (2003b) |
A multicentre, double-blind, randomised, placebo controlled parallel group comparative study of the efficacy and safety of oral eletriptan (40 mg) and sumatriptan (100 mg) given for the acute treatment of migraine. | Headache 2003,43(3): 214-22. Abstr F30. Headache 2003, 43(5):530-1. Abstr. P06.142. Neurology 2003, 60(5 Suppl 1): A494-A5. |
| Study 160-318 Sandrini G et al. (2002) Pryse-Phillips WEM (1999) Funk Orsini PA et al. (2001) |
A multicentre, double-blind, double-dummy, parallel group, placebo controlled, study of two dose levels of oral eletriptan and two dose levels of oral sumatriptan given for the acute treatment of migraine (with and without aura). | Neurology 2002, 59(8): 1210-7. Cephalalgia 1999, 19:355-6. Abstr P2-K62. Cephalalgia 2001, 21(4): 432. |
It was noted that sumatriptan tablets were encapsulated to ensure
blinding in all the key trials included in the submission. There
was evidence of a decreased absorption (27 % lower) in migraine
patients over the first two hours for the encapsulated sumatriptan
tablets compared with the standard tablets, based on area under
curve in the first two hours (AUC0-2), which is the more
relevant pharmacokinetic measure of bioequivalence in acute
migraine treatment. It was noted that the sumatriptan that is
marketed is not encapsulated. However, the PBAC noted that the
clinical outcomes did not appear to be affected. The PBAC also
noted that the TGA Clinical Evaluator had accepted bioequivalence
between the standard and encapsulated sumatriptan tablets.
8. Results of Trials
The main results are summarised below.
Summary of headache response* at 1 and 2 hours across the
published key direct randomised trials (risk difference)
| Trial ID | E40 vs S50 | E80 vs S50 | E40 vs E80 |
|---|---|---|---|
| Risk difference (95% CI) | |||
| Headache response 1 hour post-dose | |||
| Headache response 2 hour post-dose | |||
| 160-314 | -0.03 (-0.15, 0.09) | ||
| 160-318 | 0.06 (-0.03, 0.15) | 0.13 (0.03, 0.22) | -0.07 (-0.17, 0.03) |
| Pooled analysis | 0.00 (-0.11, 0.11) P=0.98 |
0.10 (0.03, 0.17) P=0.004 |
-0.08 (-0.15, -0.02) P=0.007 |
| NNT | NA | 10 (6, 33) | NNH = 13 (7, 50) |
| N† | 348/354 | 331/354 | 472/459 |
| 160-314 | -0.12 (-0.24, -0.01) | ||
| 160-318 | 0.14 (0.04, 0.24) |
0.17 (0.06, 0.27) |
-0.03 (-0.13, 0.07) |
| Pooled analysis | 0.10 (0.03, 0.18) P=0.008 |
0.15 (0.08, 0.23) P<0.0001 |
-0.07 (-0.13, -0.01) P=0.02 |
| NNT | 10 (6, 33) | 7 (4, 13) | NNH = 14 (8, 100) |
| N† | 344/351 | 330/351 | 461/448 |
CI = confidence internal; E40 = eletriptan 40 mg; S50 = sumatriptan
50 mg; E80 = eletriptan 80 mg.
* Headache response was defined as a reduction of headache severity
from moderate/severe (Grade 2/3) pain at baseline to no/mild (Grade
0/1) pain (measured on a 4-grade scale: 0 = no headache, 1 = mild
headache, 2 = moderate headache, 3 = severe headache) post dose.
This is reported for the first dose of the treatment drugs for all
the studies and is for the first attack only in the two multiple
attack studies (an unpublished study and 160-318).
† Total number of patients per treatment
group
Summary of pain-free response* at 2 hours across the
published key direct randomised trials
| Trial ID | E40 vs. S50 | E80 vs. S50 | E40 vs. E80 |
|---|---|---|---|
| Risk difference (95% CI) | |||
| Relative risk (95% CI) | |||
| 160-314 | -0.08 (-0.20, 0.04) | ||
| 160-318 | 0.12 (0.03, 0.21) | 0.18 (0.09, 0.28) | -0.06 (-0.16, 0.04) |
| Pooled analysis | 0.07 (-0.03, 0.17) P=0.19 | 0.13 (0.04, 0.22) P=0.005 |
-0.07 (-0.13, -0.01) P=0.02 |
| N† | 344/351 | 330/351 | 461/448 |
| 160-314 | 0.78 (0.54, 1.13) | ||
| 160-318 | 1.64 (0.12, 2.40) | 1.97 (1.36, 2.84) | 0.83 (0.62, 1.13) |
| Pooled analysis | 1.36 (0.92, 2.40) P=0.17 |
1.74 (1.32, 2.28) P<0.0001 |
0.79 (0.65, 0.97) P=0.02 |
| N† | 344/351 | 330/351 | 461/448 |
CI = confidence internal; E40 = eletriptan 40mg; S50 = sumatriptan
50mg; E80 = eletriptan 80mg.
* Pain-free response was defined as grade 0 headache (measured on a
4-grade scale: 0 = no headache, 1 = mild headache, 2 = moderate
headache, 3 = severe headache) at two hours post dose. This is
reported for the first dose of the treatment drugs for all the
studies and is for the first attack only in the two multiple attack
studies (an unpublished study and 160-318).
† Total number of patients per treatment group
The PBAC noted that for the primary outcomes of headache response
at one hour and the secondary outcome of pain free response at two
hours there was no statistically significant difference between
eletriptan 40 mg and sumatriptan 50 mg. The PBAC also noted that
the results for the primary and secondary outcomes favoured
eletriptan 80 mg compared to sumatriptan 50 mg.
The PBAC noted that the safety profile of eletriptan appeared
similar to sumatriptan, with no differences in the proportion of
patients discontinuing due to adverse events, however that
treatment-emergent adverse event rates were, in general,
significantly higher for eletriptan. Similarly, the PBAC noted that
treatment-emergent adverse event rates were significantly higher
for eletriptan 80 mg compared with eletriptan 40 mg.
Overall, there were no differences in the proportion of patients
discontinuing due to adverse events for any eletriptan versus
sumatriptan comparison, nor for eletriptan 40 mg versus 80
mg.
It was noted that in the comparison of eletriptan 40 mg and
sumatriptan 50 mg, the only adverse event for which there was a
significantly increased risk was somnolence (RD = 0.04, number
needed to harm = 25), and in the comparison of eletriptan 80 mg
against sumatriptan 50 mg the only significant differences were for
somnolence (RD = 0.053, number needed to harm = 19) and nausea (RD
= 0.046, number needed to harm = 22).
Periodic safety data beyond the trials revealed that a series of
safety-related revisions were made to the relevant product
information documents, but no other action taken by either health
authorities or the sponsor.
9. Clinical Claim
The submission described eletriptan 40 mg tablets as non-inferior,
and eletriptan 80 mg tablets as superior to 50 mg sumatriptan in
terms of comparative effectiveness. The submission also described
eletriptan 40 mg and eletriptan 80 mg tablets as similar to
sumatriptan 50 mg in terms of comparative safety.
The PBAC considered the results of the four head to head randomised
trials comparing eletriptan with sumatriptan and meta-analyses of
these trials presented in the submission supported the claim of
non-inferior efficacy of eletriptan to sumatriptan.
10. Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses were estimated as eletriptan 40 mg and
sumatriptan 50 mg. A flat price was proposed for eletriptan 40 mg
and 80 mg.
Based on the evidence overall the PBAC accepted the flat pricing
structure proposed in the submission with eletriptan 40 mg and 80
mg to be priced the same as sumatriptan 50 mg.
11. Estimated PBS Usage and Financial Implications
The likely number of packs/year dispensed was estimated to be in
the range of 50,000 – 100,000 packs in Year 5.
The financial cost/year to the PBS was estimated to be less than
$10 million in Year 5. The submission’s estimate of less than
$10 million net financial impact for the PBS/RPBS was reliant on
the assumptions of a constant ratio of PBS-subsidised to private
prescriptions of triptan use and a moderate uptake rate of
eletriptan.
The PBAC considered the utilisation of eletriptan is uncertain,
noting that two of the PBS listed triptans, naratriptan and
zolmitriptan, are listed as Authority required items with a Special
Patient Contribution, and that the listing of eletriptan as an
Authority required (Streamlined) benefit may be a more appealing
option to prescribers and patients.
12. Recommendation and Reasons
The PBAC recommended the listing of eletriptan hydrobromide on the
PBS as an Authority required (streamlined) listing for the
treatment of migraine attack in patients where attacks in the past
have usually failed to respond to analgesics on a cost minimisation
basis with sumatriptan. The equi-effective doses are eletriptan 40
mg and sumatriptan 50 mg.
The PBAC considered the results of the four head to head randomised
trials comparing eletriptan with sumatriptan and meta-analyses of
these trials presented in the submission supported the claim of
non-inferior efficacy of eletriptan to sumatriptan. The PBAC noted
that for the primary outcomes of headache response at one hour and
the secondary outcome of pain free response at two hours there was
no statistically significant difference between eletriptan 40 mg
and sumatriptan 50 mg. The PBAC also noted that the results for the
primary and secondary outcomes favoured eletriptan 80 mg compared
to sumatriptan 50 mg.
The PBAC noted that sumatriptan tablets were encapsulated to ensure
blinding in all the key trials included in the submission. The PBAC
noted that encapsulation delayed the absorption of sumatriptan
however that the clinical outcomes did not appear to be affected.
The PBAC also noted that the TGA Clinical Evaluator had accepted
bioequivalence between the standard and encapsulated sumatriptan
tablets.
The PBAC noted that the safety profile of eletriptan appeared
similar to sumatriptan, with no differences in the proportion of
patients discontinuing due to adverse events, however that
treatment-emergent adverse event rates were, in general,
significantly higher for eletriptan. Similarly, the PBAC noted that
treatment-emergent adverse event rates were significantly higher
for eletriptan 80 mg compared with eletriptan 40 mg.
Based on the evidence overall the PBAC accepted the flat pricing
structure proposed in the submission with eletriptan 40 mg and 80
mg to be priced the same as sumatriptan 50 mg.
The PBAC recommended the same restriction apply to eletriptan as
that recommended for rizatriptan benzoate and the other PBS listed
5HT1 agonist (triptans) at the November 2009 PBAC
meeting. At the November 2009 PBAC meeting the PBAC considered that
it was appropriate not to include the necessity to trial ergotamine
prior to the use of a 5HT1 agonist, and also that it not
be a requirement to fail a trial of prophylactic medication before
using a 5HT1 agonist. The PBAC however considered that
5HT1 agonists should remain second line treatment of
migraine attack after failure of, or contraindication to,
analgesics.
The PBAC considered the utilisation of eletriptan is uncertain,
noting that two of the PBS listed triptans, naratriptan and
zolmitriptan, are listed as authority required items with a Special
Patient Contribution, and that the listing of eletriptan as an
authority required (streamlined) benefit may be a more appealing
option to prescribers and patients. The PBAC also noted however
that rizatriptan was also recently listed on the PBS as an
Authority required (Streamlined) item.
Recommendation:
ELETRIPTAN HYDROBROMIDE, tablets, 40 mg and 80 mg (base)
Restriction: CAUTION:
Eletriptan is contraindicated in patients with known or suspected coronary artery disease. The drug should not be used within 24 hours of ergotamine or dihydroergotamine use.
Authority Required (STREAMLINED)
Migraine attack in a patient where attacks in the past have usually failed to respond to analgesics.
NOTE
: No applications for increased maximum quantities and/or repeats will be authorised.
Maximum quantity: 4
Repeats: 5
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.
