Pramipexole hydrochloride, tablet, 125 micrograms and 250 micrograms, Sifrol®, November 2008
Public summary document for Hydrochloride, tablet, 125 micrograms and 250 micrograms, Sifrol® November 2008
Page last updated: 24 March 2009
Public Summary Document
Product: Pramipexole hydrochloride, tablet, 125
micrograms and 250 micrograms, Sifrol®
Sponsor: Boehringer Ingelheim Pty Ltd
Date of PBAC Consideration: November 2008
1. Purpose of Application
The submission requested an extension of the current Restricted
Benefit listing to include the treatment of severe idiopathic
Restless Legs Syndrome (RLS).
2. Background
At its March 1999 meeting the PBAC recommended the listing of
pramipexole hydrochloride tablets 125 micrograms, 250 micrograms
and 1 mg for the treatment of Parkinson Disease as adjunctive
therapy in combination with levodopa-decarboxylase inhibitor
combinations on a cost-minimisation compared with bromocriptine.
Listing took place on 1 June 2008.
At the November 2006 meeting, the PBAC rejected an application for
pramipexole for use in moderate to very severe, idiopathic RLS in
patients who meet certain criteria because of uncertain clinical
benefit and uncertain cost-effectiveness. The PBAC agreed that the
selection of cabergoline as the comparator in preference to
levodopa was not fully justified in the submission. The PBAC
considered this to be a major impediment to the cost-minimisation
approach taken by the sponsor for the submission and provided no
basis to establish the cost-effectiveness of pramipexole. (See also
Public Summary Document in November 2006).
At the July 2007 meeting, the PBAC again rejected an application
for pramipexole for treatment of severe, idiopathic RLS in patients
who meet certain criteria because of high and uncertain
cost-effectiveness. The PBAC noted the requested listing was for
severe RLS with an International Restless Legs Syndrome Rating
Scale (IRLSRS) score of greater than or equal to 21, compared with
greater than or equal to 15 in the previous submission. The
nominated comparators were levodopa/benserazide and placebo, which
were considered appropriate. Overall, the PBAC considered that the
primary evidence supported the conclusion that pramipexole is no
worse than levodopa/benserazide in terms of clinical effectiveness
and toxicity, but did not justify the claim of overall superiority.
(See also Public Summary Document at July 07).
3. Registration Status
Pramipexole was first registered by the TGA on 20 April 1999 for
the treatment of the signs and symptoms of Parkinson Disease. An
application to extend the registered indications to include the
symptomatic treatment of primary restless legs syndrome was
approved on 10 August 2006.
4. Listing Requested and PBAC’s View
CAUTION
Episodes of sudden onset of sleep without warning, during activity, have been reported
with this drug.
Restricted Benefit
Treatment of severe idiopathic Restless Legs Syndrome (RLS) in a patient who manifests
all four diagnostic criteria below and who has a baseline International Restless Legs
Syndrome Rating Scale (IRLSRS) score of greater than or equal to 21 points.
a. An urge to move the legs usually accompanied or caused by unpleasant sensations in the legs; and
b. The urge to move or unpleasant sensations begins or worsens during periods of rest of inactivity such as lying or sitting; and
c. The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues; and
d. The urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur during the evening or night.
NOTE:
Pramipexole is not PBS subsidised for Restless Legs Syndrome secondary to other causes.
For PBAC’s view see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
RLS is a neurological disorder characterised by unpleasant
sensations in the legs and an irresistible urge to move the legs to
relieve the discomfort. Symptoms worsen during the evening and
during periods of inactivity or relaxation.
Dopamine agonists are considered first-line medications for RLS but
are not currently listed on the PBS for this indication.
Pramipexole is a non-ergot dopamine agonist and may provide an
alternative treatment option for RLS.
6. Comparator
The submission nominated levodopa with benserazide as the main
comparator. This is as previously agreed by the PBAC.
7. Clinical Trials
The basis of the submission was a double-blind, randomised,
cross-over trial comparing pramipexole versus levodopa with
benserazide (Trial 518). This trial was not published at the time
of the submission.
No changes had been made to the trial data presented in the
previous submission.
8. Results of Trials
The primary outcome measure for Trial 518 was change from baseline
in Periodic Limb Movement Index (PLMI). There were no statistically
significant differences between pramipexole and levodopa with
benserazide treatment in PLMI in both the intention-to-treat (ITT)
and per-protocol (PP) populations. The submission did not present
results for the severe sub-population for the primary outcome. The
PBAC had previously noted that there were no statistically
significant differences between pramipexole and levodopa with
benserazide in any of the secondary outcomes. (Refer to the July
2007 Pramipexole PSD).
The PBAC agreed with the submission’s claim that pramipexole
was non-inferior in terms of comparative effectiveness with
levodopa/benserazide in patients with moderate to severe RLS.
No new toxicity data were presented in the re-submission. The PBAC
agreed with the submission’s claim that pramipexole was
non-inferior in terms of comparative safety over
levodopa/benserazide in patients with moderate to severe RLS.
9. Clinical Claim
The submission described pramipexole as non-inferior in terms of
comparative effectiveness and non-inferior in terms of comparative
safety over levodopa/benserazide. The re-submission did not present
evidence whether this claim also applied to the sub-group of
patients with severe RLS. Based on the supporting data, the PBAC
accepted that pramipexole was non-inferior for patients with
moderate to severe RLS.
10. Economic Analysis
The submission presented a cost minimisation analysis. The PBAC
accepted pramipexole
490 microgram and levodopa with benserazide 192 mg/48 mg to be
equi-effective for the purposes of this listing.
11. Estimated PBS Usage and Financial Implications
The likely number of patients per year (accounting for market
share) was estimated by the submission to be in the range of 10,000
– 50,000, while the financial cost per year to the PBS
(excluding co-payments) minus any savings in use of other drugs was
estimated by the submission to be < $10 million in Year 5. The
PBAC considered this to be uncertain.
12. Recommendation and Reasons
The PBAC recommended the listing of pramipexole on the Pharmaceutical Benefits Scheme
as a Section 85 Restricted Benefit item for the treatment of severe idiopathic (primary)
restless legs syndrome on a cost-minimisation basis with levodopa with benserazide.
The equi-effective doses for the purposes of this listing were pramipexole 490 micrograms
and levodopa with benserazide 192/48 mg. The restriction appropriately limited treatment
to patients who met the all diagnostic criteria and whose pre-treatment score on the
International Restless Legs Rating Scale (IRLRS) was equal to or greater than 21.
The PBAC agreed with the submission’s claim that pramipexole was non-inferior in terms
of comparative effectiveness and non-inferior in terms of comparative safety over
levodopa/ benserazide in patients with moderate to severe RLS.
The Committee, although agreeing with the ESC and the DUSC that utilisation in this
indication was highly uncertain as there was likely to be usage beyond the restriction,
noted that the pre-PBAC response reiterated the sponsor’s conviction that the submission’s
estimates were reasonable.
The PBAC noted Boehringer Ingelheim’s commitment to promoting the quality use of pramipexole
in this indication through its planned educational activities and also requested that
the National Prescribing Service consider providing independent educational material
on idiopathic restless legs, its diagnosis and severity ratings as well as on the
use of pramipexole as a treatment option.
Recommendation
PRAMIPEXOLE, tablet 125 micrograms, 250 micrograms, Sifrol®
Restriction:
CAUTION:
Episodes of sudden onset of sleep without warning, during activity, have been reported
with this drug.
Restricted Benefit:
Treatment of severe primary Restless Legs Syndrome in a patient who manifests all
four diagnostic criteria below and whose baseline International Restless Legs Syndrome
Rating Scale (IRLSRS) score is greater than or equal to 21 points prior to initiation
of pramipexole.The date and IRLSRS score must be documented in the patient’s medical
records at the time pramipexole treatment is initiated.
The diagnostic criteria for Restless Legs Syndrome are:
a. An urge to move the legs usually accompanied or caused by unpleasant sensations in the legs; and
b. The urge to move or unpleasant sensations begins or worsens during periods of rest of inactivity such as lying or sitting; and
c. The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues; and
d. The urge to move or unpleasant sensations are worse in the evening or night than during the day or only occur during the evening or night.
Pramipexole is not PBS subsidised for Restless Legs Syndrome secondary to other causes.
NOTE:
No applications for increased maximum quantities and/or repeats will be authorised.Maximum
quantity: 30 (125 micrograms); 100 (250 micrograms)
Number of repeats: 2 (both strengths)
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
Boehringer Ingelheim welcomes the PBAC decision to approve
pramipexole for patients with severe primary RLS satisfying the
above criteria.
