Pramipexole hydrochloride, tablet, 125 micrograms, 250 micrograms and 1 mg, Sifrol®, July 2008
Public summary document for Pramipexole hydrochloride, tablet, 125 micrograms, 250 micrograms and 1 mg, Sifrol®, July 2008
Page last updated: 14 November 2008
Public Summary Documents
Product:Pramipexole hydrochloride, tablet, 125
micrograms, 250 micrograms and 1 mg, Sifrol®
Sponsor: Boehringer Ingelheim Pty Limited
Date of PBAC Consideration: July 2008
1. Purpose of Application
The submission sought to amend the Restricted benefit listing
(effective 1 June 2008) for Parkinson disease (PD) and requested
the removal of the requirement to be used with levodopa-
decarboxylase inhibitor combinations, which would allow use as
monotherapy (early disease) or in combination with levodopa
At the March 1999 meeting, the PBAC recommended an authority
required listing for 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 the basis of
cost-minimisation compared with bromocriptine.
At the December 1999 meeting, the PBAC recommended changing the authority required listing for pramipexole to a restricted benefit and to require that a caution note be included in the listing: CAUTION: Episodes of sudden onset of sleep without warning, during activity, have been reported with this drug.
Listing was effective from 1 June 2008.
3. Registration Status
Pramipexole was TGA registered on 20 April 1999 for:
- the treatment of signs and symptoms of idiopathic Parkinson
disease in advanced states of the disease (in combination with
An extension to the registration was granted on 14 June 2002 to
include the treatment of signs and symptoms of idiopathic Parkinson
disease as monotherapy or in combination with levodopa. Pramipexole
is also registered for the symptomatic treatment of primary
Restless Legs Syndrome.
4. Listing Requested and PBAC’s View
Caution: Episodes of sudden onset of sleep without
warning, during activity, have been reported with this drug.
See Recommendations and Reasons for the PBAC’s view.
5. Clinical Place for the Proposed Therapy
Parkinson disease is a progressively disabling neurodegenerative
disorder manifested clinically by bradykinesia (slow movement),
tremor, rigidity and postural instability caused by loss of
pigmented neurons in the brainstem. In addition to the progressive
motor disability, there are many disabling non-motor manifestations
including dementia, depression and autonomic instability.
Pramipexole is a non-ergot dopamine agonist therapy for the
treatment of Parkinson disease.
The submission nominated cabergoline as the main comparator.
Cabergoline is an ergot dopamine agonist that has a restricted
benefit listing for Parkinson disease. Carbergoline is the most
commonly used ergot dopamine agonist on the PBS.
The PBAC accepted that cabergoline is a reasonable comparator.
For PBAC’s view see Recommendations and Reasons.
7. Clinical Trials
The submission presented an indirect analysis of one trial
comparing pramipexole with carbidopa-levodopa (CALM-PD) and one
trial comparing cabergoline with carbidopa-levodopa (PKDS009) in
patients with early Parkinson disease. The common comparator was
The key trials (and associated reports) published at the time of submission are as follows:
|Protocol title/Publication title
|Randomised, double-blind trial comparing the safety and efficacy of pramipexole and carbidopa-levodopa in patients with early PD.
|BI Trial Report – Parallel Group, Double-Blind Comparison Study of Pramipexole and Carbidopa-Levodopa in the Treatment of Parkinson Disease.
|Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4–year randomized controlled trial.
|BI Trial Report – Parallel Group, double-blind comparison study of pramipexole and carbidopa-levodopa in the treatment of Parkinson disease. Archives of Neurology, 2004, Vol 61 p 1044-1053, 2004.
|Parkinson Study Group 2000
|Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group.
|Parkinson Study Group et al, JAMA, 2000, Vol 284 p 1931-1938, 2000.
|The long-acting dopamine receptor agonist cabergoline in early Parkinson disease: final results of a 5-year, double blind, levodopa-controlled study.
|Bracco et al,CNS Drugs, Vol 18 p 733-746, 2004.
|Early treatment of Parkinson disease with cabergoline delays the onset of motor complications. Results of a double-blind levodopa controlled trial.
|Drugs, Vol 55 Suppl 1 p 23-30, 1998.
|Cabergoline in the treatment of early Parkinson disease: results of the first year of treatment in a double-blind comparison of cabergoline and levodopa.
|Neurology, Vol 48 p 363-368, 1997.
|Cabergoline, Pramipexole and Ropinirole used as Monotherapy in Early Parkinson disease: An Evidence-based Comparison.
|Drugs & Aging, Vol 20 p 847-855, 2003.
Abbreviations: PD, Parkinson disease; RCT, randomised controlled
8. Results of Trials
The risk of developing motor complications, the primary outcome of
the CALM - PD trial, showed a statistically significant reduction
with pramipexole compared with carbidopa-levodopa. However there
was no significant difference between the two treatments in regards
to some of the secondary outcomes such as patients experiencing
“on-off” fluctuations and “off” period
dystonias. In addition, the risk of experiencing freezing, a
secondary outcome, was increased with pramipexole compared with
carbidopa-levodopa. Patients treated with carbidopa-levodopa
reported a statistically significant greater
improvement in disease symptoms than patients treated with
pramipexole (change in Unified Parkinson Disease Rating Scale
(UPDRS) scores from baseline, a secondary outcome).
The results of the indirect comparison of pramipexole with cabergoline showed only weak evidence in support of the non-inferiority claim made in the submission.
There was no significant difference in the number of total adverse events or the number of serious adverse events for either pramipexole or cabergoline compared with carbidopa-levodopa. However, the submission highlighted the risk of fibrotic complications, including cardiac valvulopathy, pericarditis and retroperitoneal or pleural fibrosis associated with carbergoline in the extended assessment of comparative harms.
For PBAC’s comments on these results, see Recommendations and Reasons.
9. Clinical Claim
The submission described pramipexole as non-inferior in terms of
comparative effectiveness and superior in terms of comparative
safety over cabergoline.
For PBAC’s view, see Recommendations and Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis, based on the
currently approved prices for pramipexole and cabergoline, and the
average daily doses used in the trials.
The submission presented a supportive cost-analysis for monitoring patients receiving treatment with cabergoline. The submission estimated that the substitution of cabergoline with pramipexole would represent an annual cost saving per patient.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of patients/year to be
less than 10,000 patients in Year 5 at a financial cost/year to the
PBS of less than $10 million in Year 5.
12. Recommendation and Reasons
The PBAC noted the submission nominated cabergoline, an ergot
dopamine agonist, as the main comparator. The PBAC accepted that
cabergoline is a reasonable comparator, however consistent with its
recent consideration of rotigotine, the Committee also considered
that levodopa with a decarboxylase inhibitor is an appropriate
additional comparator for pramipexole in the treatment of patients
with early Parkinson disease. This reflects the current situation
where some neurologists favour using dopamine agonists early in
Parkinson disease, whereas other neurologists prefer to begin
therapy with a levodopa product and taking into account that a
proportion of this latter group may be persuaded to switch to a
non-ergot dopamine agonist such as pramipexole.
The Committee noted the submission presented an indirect analysis of one trial comparing pramipexole with carbidopa-levodopa (CALM-PD) and one trial comparing cabergoline with carbidopa-levodopa (PKDS009) in patients with early Parkinson disease.
The PBAC agreed that the evidence to support the claim that pramipexole was non-inferior to cabergoline was weak. First, the claim is based on an indirect comparison and suffers from all the inherent uncertainty around such comparisons. Second, the submission did not specify a non-inferiority margin, as is standard for a head-to-head non-inferiority trial. Third, the outcome considered of most relevance by PBAC, change in UPDRS motor disability scale from baseline, could not be assessed in the indirect analysis. Additionally the outcome, risk of motor complications over time, was not able to be evaluated because the definition and confirmation of motor complications differed between the trials.
The PBAC agreed that the CALM-PD study provided a good basis upon which to compare pramipexole with carbidopa-levodopa, notwithstanding that the Committee had some concern that the patients recruited into this trial did not meet the definition of early Parkinson disease, with some patients having had the disease for 7 years at study entry (mean 1.4 years). The Committee was more concerned however, that, on the outcome of most interest, the UPDRS, which is a measure of the success of treatment, patients treated with carbidopa-levodopa reported a statistically significant greater improvement in disease symptoms than patients treated with pramipexole (change in UPDRS scores from baseline).
Although, the submission described pramipexole as superior to cabergoline in terms of safety, the PBAC concluded that the safety evidence presented was insufficient to determine the superiority or equivalence between the two dopamine agonists. Pramipexole and cabergoline appear to have different safety profiles, however no significant difference was demonstrated in the number of total adverse events or the number of serious adverse events for either pramipexole or cabergoline compared with carbidopa-levodopa. Data was outlined in the submission on the risk of fibrotic (including cardiac valvulopathy) and serosal inflammatory conditions associated with cabergoline treatment, however the relative importance of episodes of somnolence associated with pramipexole treatment was not addressed.
The PBAC noted that although the submission presented a cost minimisation analysis against cabergoline, no economic analysis against levodopa-carbidopa was presented. Given the concerns the PBAC had with the indirect comparison of the two trials, there was also uncertainty regarding the equi-effective doses presented.
In summary, the PBAC rejected the request to extend the PBS-subsidy of pramipexole to include early Parkinson disease because of insufficient evidence to substantiate the claim that pramipexole is non-inferior to cabergoline or levodopa-carbidopa.
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 is disappointed that pramipexole was rejected
for use in patients with early Parkinson’s disease and
intends to work with the PBAC to facilitate listing. The sponsor
has submitted a minor submission to the PBAC to seek clarity on the
appropriate comparator for a resubmission. The sponsor is concerned
that the only dopamine agonists currently listed to treat patients
with early Parkinson’s disease are the ergot dopamine
agonists. These drugs are associated with significant fibrotic
complications and ongoing monitoring costs.