Pramipexole hydrochloride, tablets, 125 micrograms, 250 micrograms, 1mg, Sifrol®
Public Summary Document for Pramipexole hydrochloride, tablets, 125 micrograms, 250 micrograms, 1mg, Sifrol®
Page last updated: 30 October 2009
Public Summary Document
Product: Pramipexole hydrochloride, tablets, 125
micrograms, 250 micrograms, 1mg, Sifrol®
Sponsor: Boehringer Ingelheim Pty Limited
Date of PBAC Consideration: July 2009
1. Purpose of Application
The submission requested an extension to the current Restricted
benefit listing to include use as monotherapy for idiopathic
Parkinson disease in patients with motor disability and no evidence
of cognitive impairment.
2. Background
Pramipexole was listed on the PBS on 1 June 2008.
At the July 2008 meeting, the PBAC rejected a 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.
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 levodopa). 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.
Restricted Benefit:
Monotherapy for idiopathic Parkinson’s disease in a patient
with motor disability and no evidence of cognitive
impairment.
NOTE:
Patients with advanced age and cognitive impairment should commence
with levodopa.
For PBAC’s view, see Recommendation and Reasons.
5. Clinical Place for the Proposed Therapy
Parkinson disease is a progressively disabling neurodegenerative
disorder manifested clinically by bradykinesia, tremor, rigidity
and postural instability. 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 from early to advanced
disease.
6. Comparator
The submission nominated cabergoline as the appropriate
comparator.
The PBAC had previously accepted that cabergoline is a reasonable
comparator; however consistent with its consideration of
rotigotine, the PBAC also considered that levodopa with a
decarboxylase inhibitor is an appropriate additional comparator for
pramipexole in the treatment of patients with early Parkinson
disease. The PBAC noted advice from the Royal Australian College of
Physicians (RACP), supported by PBS drug utilisation data that
levodopa is currently and will continue to be used as first line
treatment of early Parkinson disease.
7. Clinical Trials
The submission presented no new trials. However, new analyses of
CALM-PD (trial of pramipexole versus levodopa) using individual
patient data were presented in the re-submission.
The re-submission did identify one meta-analysis, Stowe et al
(2008), comparing the efficacy and safety of dopamine agonists
versus levodopa or placebo. The study published at the time of
submission is as follows:
| Trial ID/First Author | Protocol title/ Publication title | Publication Citation |
| Meta-analysis | ||
| Stowe et al (2008) | Dopamine agonist therapy in early Parkinson’s disease (Review). | The Cochrane Library, 2008 Issue 2. |
Please see the July 2008 Public Summary Document for a list of
previously presented trials. Trial PKDS009 has been published by
Bracco (2004), Rinne (1997 and 1998).
8. Results of Trials
The following post-hoc analyses of the CALM-PD trial were conducted
using individual patient data (IPD): motor complications confirmed
at two consecutive visits, where motor events in CALM-PD were
redefined using similar confirmations to PKDS009. Events had to be
confirmed within at least 120 days or have led to intervention
(i.e. levodopa added);
proportion of patients with satisfactory clinical improvement in
motor disability (>30 % reduction in Unified Parkinson Disease
Rating Scale Scores (UPDRS) section III scores compared with
baseline) at 1 year, 3 years and 5 years analysed using redefined
IPD from CALM-PD and results of trial PKDS009.
With respect to motor complications, redefining the motor
complications for CALM-PD patients as confirmed within at least 120
days an event leading addition of levodopa, did not significantly
change the result of the indirect comparison between pramipexole
and cabergoline.
With respect to motor disability, the proportions of patients
experiencing satisfactory clinical improvement in motor disability
in the levodopa treatment arm of the CALM-PD trial were
consistently lower than the proportions of patients experiencing
satisfactory clinical improvement in motor disability with levodopa
treatment in the PKDS009 trial.
The re-submission also presented a comparison of mean change from
baseline in UPDRS motor scores for patients treated with
pramipexole and cabergoline.
The indirectly estimated difference of mean changes from baseline
in UPDRS motor score at 1 year between total trial population of
CALM-PD and only patients not taking added levodopa in PKDS009 was
not statistically significant.
No new toxicity data were presented in the re-submission, however
the re-submission conducted indirect comparisons of the safety
outcomes from the trials. An indirect estimate of effect showed
that compared with cabergoline, a statistically significantly
higher proportion of pramipexole treated patients experience
somnolence.
9. Clinical Claim
The submission described pramipexole as non-inferior in terms of
comparative effectiveness and comparative safety over cabergoline,
based on the two trials presented in the submission.
For PBAC's views see Recommendations and Reasons.
10. Economic Analysis
The submission presented a cost minimisation analysis. The
equi-effective doses were estimated as pramipexole 2.77 mg and
cabergoline 2.90 mg
For PBAC’s views see Recommendation and Reasons.
11. Estimated PBS Usage and Financial Implications
The submission estimated the likely number of packs dispensed/year
(accounting for market share as necessary) to be in the range
50,000 – 100,000 per year and the financial savings/year to
the PBS (excluding co-payments) minus any savings in use of other
drugs was estimated to be less than $1 million in Year 5.
12. Recommendation and Reasons
The PBAC recommended the listing of pramipexole on the PBS on a
cost minimisation basis compared with cabergoline. The PBAC
accepted that pramipexole has similar effectiveness, with a
different safety profile to cabergoline and the equi-effective
doses are 2.77 mg pramipexole is equivalent to 2.90 mg cabergoline.
Despite the advice in the RACP clinical impact statement stating
that it is clinically inappropriate to restrict PBS subsidised
access to monotherapy with pramipexole for patients with cognitive
impairment, the Committee was of the view that it was important to
alert prescribers of this concern. The PBAC recommended this be
managed by means of a NOTE stating that care should be taken when
treating patients with advanced age and significant cognitive
impairment with dopamine agonists.
The PBAC noted that the majority of patients with Parkinson disease
are commenced with a levodopa-decarboxylase inhibitor, based on
Medicare data. The PBAC accepted that cabergoline is the
appropriate comparator for the small number of new patients with
Parkinson disease not commencing on levodopa therapy and noted that
cabergoline is often the preferred option for younger
patients.
The submission claimed that in the majority of patients levodopa is
preferred over dopamine agonists and the listing of pramipexole is
unlikely to alter that decision and the substitution will be
between cabergoline and pramipexole. However, the PBAC was
concerned that pramipexole could substitute for levodopa
combinations in new patients with early Parkinson disease in whom
cabergoline might have been preferred over levodopa, but not
prescribed because of concerns about valvulopathy. The PBAC
therefore recommended that any risk-share arrangement should
mitigate these concerns.
The PBAC noted the outcome considered of most relevance, change in
UPDRS motor disability scale from baseline, was not able to be
adequately assessed in the indirect analysis as a comparison
between similar populations was not possible. However, the PBAC
agreed that the data regarding the comparison between cabergoline
and pramipexole are acceptable in the context of a cost
minimisation consideration.
Recommendation
PRAMIPEXOLE HYDROCHLORIDE, tablets, 125 micrograms, 250 micrograms,
1 mg
Amend the restriction relating to Parkinson disease as
follows:
Restriction:
CAUTION:
Episodes of sudden onset of sleep without warning, during activity,
have been reported with this drug.
NOTE:
Care should be taken when treating patients with advanced age and
significant cognitive impairment with dopamine agonists.
Restricted Benefit:
Parkinson disease
Max qty: 30 (125 micrograms) Repeats: Nil (125 micrograms)
Max qty: 100 (250 micrograms and 1 mg) Repeats: 5 (250 micrograms
and 1 mg)
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 delighted that pramipexole, a non-ergot dopamine agonist, is available to patients with early Parkinson disease.
