Immediate-release pramipexole (Sifrol) and extended-release pramipexole (Sifrol ER) for Parkinson's disease

Published in NPS RADAR

Date published: About this date

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This article has been updated since its original release. [Details]

PBS listing | Reason for PBS listing | Place in therapy | Safety issues | Dosing issues Information for patients | References

Key points

  • Pramipexole is a non-ergot dopamine agonist for treating the symptoms of Parkinson's disease.
  • Using pramipexole instead of levodopa as initial therapy for early Parkinson's disease delays the development of motor complications (wearing off, dyskinesias or on–off fluctuations).
  • Pramipexole is less effective than levodopa at treating the symptoms of early Parkinson's disease.
  • There have been no head-to-head trials comparing pramipexole with any other dopamine agonist in early Parkinson's disease.
  • Somnolence and oedema are more common in people treated initially with pramipexole than levodopa.
  • Sleep attacks and compulsive behaviour have been reported with pramipexole and other dopamine agonists.

PBS listing

Restricted benefit

Parkinson's disease

Previously, the use of pramipexole was restricted to adjunctive therapy in people being treated with levodopa–decarboxylase inhibitor combinations. This listing allows pramipexole to be used as monotherapy in early stages of Parkinson's disease.

The listing also notes that:

  • episodes of sudden-onset of sleep without warning, during activity, have been reported
  • care should be taken when using dopamine agonists in older people with significant cognitive impairment.

Reason for PBS listing

The Pharmaceutical Benefits Advisory Committee (PBAC) recommended pramipexole for listing on a cost-minimisation basis — that is, similar efficacy and cost — compared with cabergoline for the treatment of Parkinson's disease.1 This decision was based on an indirect comparison in which a randomised trial of pramipexole and a randomised trial of cabergoline were compared using levodopa as the common comparator.1

An extended-release formulation of the drug was later recommended for listing to treat Parkinson's disease.2 

Place in therapy

Pramipexole is a non-ergot dopamine agonist used for symptomatic treatment of Parkinson's disease and restless legs syndrome.

Selection of either a dopamine agonist (including pramipexole) or levodopa as treatment for early Parkinson's disease must be individualised for each person as it is not possible to identify a universal first-choice drug therapy.3,4

Using pramipexole instead of levodopa in early Parkinson's disease delays the development of motor complications (wearing off, dyskinesias or on–off fluctuations).5 However, pramipexole is less effective than levodopa at treating the symptoms of Parkinson's disease and is associated with increased rates of somnolence, hallucinations and oedema.5,6

When choosing initial therapy, consider levodopa for people whose major concern is control of existing motor symptoms and pramipexole for those more concerned about the development of motor complications because of longer levodopa use (e.g. younger people). Other factors to consider include:

  • age — pramipexole may cause more adverse effects, such as hallucinations and confusion, in older people (over 65).4,7,8
  • cognitive impairment — pramipexole may cause more adverse effects, such as hallucinations and confusion, in people with cognitive impairment.4,7,8
  • the impact of somnolence on daily activities, as pramipexole causes more somnolence than levodopa.5

No trials have directly compared pramipexole with other dopamine agonists as monotherapy in early Parkinson's disease.

For further information on pramipexole in restless legs syndrome read the NPS RADAR review: Pramipexole (Sifrol) for severe primary restless legs syndrome.

Pramipexole delays motor complications but is less effective than levodopa at controlling Parkinson's symptoms

Randomised trials have compared pramipexole with placebo and levodopa in early Parkinson's disease. Against placebo, pramipexole produced modest, but statistically significant, mean improvements in motor scores and activities of daily living scores on the Unified Parkinson's Disease Rating Scale (UPDRS) in people with early disease.9–11

A single trial (n = 301) compared the efficacy of pramipexole and levodopa in people with early disease.5 After 10 weeks of monotherapy, people in both groups could be given additional open-label levodopa to treat ongoing or emerging disability.5

After 2 years, motor complications (defined as the first instance of wearing off, dyskinesias or on–off fluctuations) were significantly less common in people treated with pramipexole than levodopa (28% vs 51%: hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.30 to 0.66). However, people treated with levodopa experienced modest but significantly better symptomatic control over the 2 years of the trial.

More than half of the people using pramipexole required supplemental levodopa within 2 years, compared with 39% of those in the levodopa group (HR 1.54, 95% CI 1.09 to 2.17).

Within 4 years, significantly more people discontinued pramipexole than levodopa (44% vs 33%).6 After 4 years, freezing was more common in the pramipexole group than the levodopa group (37% vs 25%: HR 1.70, 95% CI 1.11 to 2.59).6 However, quality-of-life scores were similar in both groups.

Extended-release pramipexole has similar efficacy to that of immediate-release pramipexole

In unpublished trials, extended-release pramipexole was more effective than placebo and had similar efficacy to that of immediate-release pramipexole in patients with early (n = 539) and advanced Parkinson's disease (n = 507).12–14

No head-to-head trials of pramipexole and the other dopamine agonists in early Parkinson's disease

There are no head-to-head comparisons of pramipexole with any of the other dopamine agonists in early Parkinson's disease. An indirect comparison was presented in the PBAC submission, comparing a trial of pramipexole against a trial of cabergoline, using levodopa as the common comparator.

Suggest non-drug measures for everyone with Parkinson's disease

Physiotherapy, occupational therapy, and speech and language therapy are recommended for people with Parkinson's disease.3

A general therapeutic exercise program for individuals or groups includes exercises for the trunk and upper limbs, speech and breathing exercises, gait training, balance training, transfer training and relaxation.15

Safety issues

Common adverse effects among people with early Parkinson's disease treated with pramipexole include nausea, somnolence, constipation, hallucinations, confusion, dizziness and oedema.12 Sleep attacks and compulsive behaviour have been reported with pramipexole and other dopamine agonists.12,16

The ergot-derived dopamine agonists cabergoline and pergolide increase the risk of valvular heart disease, but this has not been shown with pramipexole.17,18 Whether non-ergot dopamine agonists, such as pramipexole, can cause such events is unknown.12

In clinical studies and postmarketing experience cardiac failure has been reported in patients with pramipexole. In a pharmacoepidemiological study pramipexole use was associated with an increased risk of cardiac failure compared with non-use of pramipexole.12,22 

The adverse event profiles for the immediate- and the extended-release tablets are similar.12–14,19

Report suspected adverse reactions to the Therapeutic Goods Administration (TGA) online or by using the 'Blue Card' distributed three times a year with Australian Prescriber. For information about reporting adverse reactions, see the TGA website.

More adverse effects with pramipexole than levodopa

Pramipexole causes more somnolence, oedema and hallucinations in people with early Parkinson's disease than levodopa (Table 1).5

Table 1.
Comparison of the adverse effects of pramipexole and levodopa*5

Adverse effectPramipexole (%)Levodopa (%)

Somnolence

32

17

Oedema

18

8

Peripheral oedema

15

4

Hallucination

9

3


* All differences are statistically significant

† Includes peripheral, generalised, localised, facial, tongue or periorbital oedema or lymphodema

A retrospective analysis of data collected during the trial suggests the risk of developing oedema while using pramipexole appears to be greater in people with a history of cardiac disease. Hallucinations were associated with older age (≥ 65 years) and lower Mini-Mental State Examination scores.8

Pramipexole may cause somnolence and sleep attacks

Somnolence was a common drug-related adverse effect in trials of pramipexole.5,6,10–12

Sudden onset of sleep during daily activities — in some cases without awareness or warning signs ('sleep attack') — has been reported in people with Parkinson's disease receiving pramipexole.16 Sleep attacks have been reported with all dopamine agonists and levodopa; it is not yet clear whether they are caused by the disease itself or if they are more frequent with some dopamine agonists.3,7

Advise patients not to drive, use tools or operate machinery until the effects of pramipexole are known.

During the first 2 years of the trial comparing levodopa and pramipexole, three people reported falling asleep while driving; two were using pramipexole and one was using levodopa. Another two people using pramipexole reported sudden drowsiness unrelated to driving.5

People who have a sleep attack should refrain from driving and other dangerous activities until they receive medical advice (see Information for patients). Consider dose reduction or discontinue pramipexole in these cases.12

Dopamine agonists may cause compulsive behaviours

Inform patients and carers that there is a small risk of compulsive behaviours (e.g. pathological gambling, hypersexuality) but that the consequences can be serious, and to seek medical advice promptly if there are early signs of a developing problem.12

Dosing issues

For Parkinson's disease, immediate-release pramipexole is taken 3 times daily in equally divided doses. Extended-release pramipexole is taken once daily. The starting dose for both immediate-release and extended-release pramipexole is 375 micrograms. Titrate the dose as required every 5–7 days to a maximum of 4.5 mg daily (Table 2).12

Table 2.
Initial dose titration for Parkinson's disease



Dose
Immediate-releaseExtended-release
Week 1125 micrograms 3 times a day375 micrograms once a day
Week 2250 micrograms 3 times a day750 micrograms once a day
Week 3500 micrograms 3 times a day1.5 mg once a day
Week 4 onwardsIf necessary, increase dose every 5–7 days by adding an additional 750 micrograms per day (maximum dose 4.5 mg daily)

 ‡ Early or advanced Parkinson's disease. Reduce the dose of levodopa when introducing pramipexole as adjunctive therapy in advanced disease.12 A smaller dose is used to treat restless legs syndrome (see the Product Information)

Extended-release tablets should not be broken or crushed.

Initial daily doses should be reduced if creatinine clearance is < 50 mL/min.12

Centrally active dopamine antagonists (i.e. antipsychotics or metoclopramide) diminish the effect of pramipexole. These drugs should not be used with pramipexole.12

Cimetidine, and possibly amantadine, may reduce renal excretion of pramipexole.7,20

Switching from immediate-release to extended-release pramipexole

A single unpublished study investigated the efficacy and safety of an overnight switch from immediate-release to extended-release pramipexole in people with early Parkinson's disease.12,21 A successful switch was defined as less than a 15% worsening in the motor score and activities of daily living score on the Unified Parkinson's Disease Rating Scale (UPDRS) 9 weeks after switching. Most patients — 87 out of 103 patients randomised to the extended-release tablets — were successfully switched. A dose adjustment was not usually required but in some of these 87 patients the dose was increased (n = 12) or decreased (n = 3).12

Use the same daily dose if switching from the immediate-release to the extended-release product. Monitor patients after switching to ensure that their symptoms remain under control: some patients may need to have their dose adjusted.

Information for patients

Advise patients:

  • that pramipexole may cause sudden attacks of sleep in some people
  • if they have a sleep attack at any time to refrain from driving and contact a doctor
  • not to drive or perform dangerous tasks requiring constant attention until accustomed to the side effects
  • that pramipexole may make them more susceptible to compulsive behaviours (e.g. compulsive gambling)
  • that nausea, oedema and drowsiness are common side effects and that they may experience hallucinations
  • that sedatives or alcohol may worsen any drowsiness
  • not to chew, crush or break the extended-release tablets.

Discuss the Sifrol or the Sifrol ER (pramipexole) consumer medicine information (CMI) leaflet with the patient.

State and Territory Parkinson's organisations offer information and support for people with Parkinson's disease and their carers. Contact details for each can be found though Parkinson's Australia (www.parkinsons.org.au).

Medicine Update The Medicine Update logo

An NPS Medicine Update leaflet on pramipexole is available for consumers. Medicine Update helps consumers to ask the right questions about new medicines, and helps them compare the potential benefits and harms of a new medicine with other medicines.

References

  1. Pharmaceutical Benefits Advisory Committee. Positive Recommendations made by the PBAC — July 2009. Canberra: Australian Government Department of Health and Ageing, 2009. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbacrec-jul09-positive (accessed 23 Sept 2009).
  2. Pharmaceutical Benefits Advisory Committee. Positive Recommendations made by the PBAC — March 2010. Canberra: Australian Government Department of Health and Ageing, 2009. http://www.health.gov.au/internet/main/publishing.nsf/Content/pbacrec-mar10-positive (accessed 18 May 2010).
  3. National Institute for Health and Clinical Excellence. Parkinson's disease: diagnosis and management in primary and secondary care. NICE clinical guideline 35. 2006. http://www.nice.org.uk/Guidance/CG35 (accessed 4 Aug 2009).
  4. Neurology Writing Group. Therapeutic Guidelines: Neurology. Version 3. Melbourne: Therapeutic Guidelines Ltd, 2007.
  5. Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: A randomized controlled trial. Parkinson Study Group. JAMA 2000;284:1931–8. [PubMed]
  6. Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease: a 4-year randomized controlled trial. Arch Neurol 2004;61:1044–53. [PubMed]
  7. Rossi S (ed). Australian Medicines Handbook 2009. Adelaide: Australian Medicines Handbook Pty Ltd, 2009.
  8. Biglan KM, Holloway RG Jr, McDermott MP, et al. Risk factors for somnolence, edema, and hallucinations in early Parkinson disease. Neurology 2007;69:187–95. [PubMed]
  9. Hubble JP, Koller WC, Cutler NR, et al. Pramipexole in patients with early Parkinson's disease. Clin Neuropharmacol 1995;18:338–47. [PubMed]
  10. Parkinson Study Group. Safety and efficacy of pramipexole in early Parkinson disease. A randomized dose-ranging study. Parkinson Study Group. JAMA 1997;278:125–30. [PubMed]
  11. Shannon KM, Bennett JP Jr, Friedman JH. Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson's disease. The Pramipexole Study Group.[Erratum appears in Neurology 1998 Mar;50(3):838]. Neurology 1997;49:724–8. [PubMed]
  12. Boehringer Ingelheim Pty Limited. Australia. Sifrol and Sifrol ER product information. 16 March 2010.
  13. Boehringer Ingelheim Pty Limited. A double-blind, double-dummy, placebo-controlled, randomized, three parallel groups study comparing the efficacy, safety and tolerability of pramipexole ER versus placebo and versus pramipexole IR administered orally over a 26-week maintenance phase in patients with early Parkinson's disease (PD). 2009; 8. http://trials.boehringer-ingelheim.com/res/trial/data/pdf/248.524_U09-1232.pdf (accessed 15 June 2010).
  14. Boehringer Ingelheim Pty Limited. A double-blind, double-dummy, placebo-controlled, randomized, three parallel groups study comparing the efficacy, safety and tolerability of pramipexole ER versus placebo and versus pramipexole IR administered orally over a 26-week maintenance phase in l-Dopa treated patients with advanced Parkinson's disease (PD). 2009; 10. http://trials.boehringer-ingelheim.com/res/trial/data/pdf/248.525_U09-1270.pdf (accessed 15 June 2010).
  15. Plant R, Walton G, Ashburn A, et al. Guidelines for physiotherapy practice in Parkinson's disease. Newcastle, UK: University of Northumbria, Institute of Rehabilitation: 2001. http://hces.unn.ac.uk/guidelines (accessed 4 Aug 2009).
  16. Homann CN, Wenzel K, Suppan K, et al. Sleep attacks in patients taking dopamine agonists: review. BMJ 2002;324:1483–7. [PubMed]
  17. Schade R, Andersohn F, Suissa S, et al. Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med 2007;356:29–38. [PubMed]
  18. Zanettini R, Antonini A, Gatto G, et al. Valvular heart disease and the use of dopamine agonists for Parkinson's disease. N Engl J Med 2007;356:39–46. [PubMed]
  19. European Medicines Agency. Assessment report for Sifrol. London: EMEA, 2009. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000133/WC500049957.pdf (accessed 17 June 2010)
  20. Baxter K, ed. Stockley's Drug Interactions. 8th edn. London: Pharmaceutical Press, 2008.
  21. Boehringer Ingelheim Pty Limited. A double-blind, randomized, parallel groups study to assess the efficacy, safety and tolerability of switching patients with early Parkinson's disease (PD) from pramipexole IR to pramipexole ER or pramipexole IR. 2008; 9. http://trials.boehringer-ingelheim.com/res/trial/data/pdf/248.636_U08-1964.pdf (accessed 15 June 2010).
  22. U.S. Food and Drug Administration. Mirapex (pramipexole): Drug Safety Communication - Ongoing Safety Review, Possible Risk of Heart Failure. 2012. http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm320054.htm (accessed 27 September 2012).

Revision history

Updated September 2012: statement added regarding association with increased risk of cardiac failure.
Updated August 2010: addition of extended-release pramipexole.
First published: December 2009.