Pramipexole (Sifrol): dopamine agonist for the treatment of Parkinson’s disease

From Australian Prescriber:


Sifrol (Boehringer Ingelheim)
125 microgram, 250 microgram and 1 mg tablets
Approved indications: Parkinson’s disease, restless legs syndrome
Australian Medicines Handbook section 16.2.1

In Parkinson’s disease, there is a reduced concentration of dopamine in the nigrostriatal system. Dopamine agonists, such as bromocriptine, therefore have a role in the treatment of Parkinson’s disease. Pramipexole is a non-ergoline dopamine agonist which acts on D2 and D3 receptors (see ‘Dopamine – clinical applications i. neurology’, Aust Prescr 1994;17:21-3).

Levodopa (combined with a decarboxylase inhibitor) remains the first-line drug treatment for Parkinson’s disease of moderate severity. In advanced disease, the effect of this therapy starts to wear off. Maintaining the stimulation of dopamine receptors may alleviate this disabling complication.

When pramipexole was added to levodopa treatment, in a double-blind trial of 291 patients with advanced disease, it was more effective than placebo. Pramipexole improved motor function and decreased ‘off’ time. The patients’ self-assessments also suggested that the severity of the ‘off’ time was reduced by pramipexole. Compared to placebo, the biggest changes were seen in rigidity, resting tremor, hand movements and finger tapping. At the end of the 32-week trial, the dose of levodopa required by the patients taking pramipexole had been significantly reduced.1

In the trial, the maximum dose was 4.5 mg a day. Usually pramipexole is given in divided doses, beginning with 125 microgram three times a day. The dose is increased every week if the patient is improving without adverse effects. While the dose is being titrated, the dose of levodopa can be reduced.

After a dose-ranging study in early Parkinson’s disease [2], pramipexole was compared with levodopa in a double-blind trial involving 301 patients. Those randomised to receive pramipexole took longer to develop problems with the effect wearing off, on-off fluctuations or dyskinesia.[3]

Pramipexole also has an indication for restless legs syndrome. It was compared with placebo in a 12-week trial involving 344 patients. On a 40-point symptom rating scale, there was a mean improvement of 9.3 points with placebo and a 12.8 point improvement in people taking pramipexole 250 microgram daily. While 75% of patients responded to this dose of pramipexole, the response in the placebo group was 51%.4

In Parkinson’s disease, lower doses of pramipexole are required if the patient has renal impairment as the drug is mainly excreted unchanged in the urine. The elimination half life is increased from 8 to 12 hours in elderly patients. Renal clearance is also reduced by cimetidine which is thought to inhibit secretion in the renal tubules. This mechanism also creates the potential for interactions between pramipexole and ranitidine, diltiazem, verapamil, digoxin, triamterene and trimethoprim.

Some of the adverse effects of pramipexole can be predicted because of its stimulation of dopamine receptors. For example, up to 17% of patients will develop hallucinations. Other common adverse effects include nausea, insomnia, somnolence and dyskinesia. A few patients have fallen asleep suddenly, including when driving, and others have become compulsive gamblers while taking pramipexole.

Pramipexole should be withdrawn gradually over several days. Sudden cessation of antiparkinson drugs can cause neuroleptic malignant syndrome.

There are few published comparative studies of the dopamine agonists. A study in which pramipexole compared favourably with bromocriptine did not have enough power to show a statistical difference.5 There is limited information about the long-term use of pramipexole. This is important because, for example, retinal degeneration has been seen in long-term studies of rats. Although fewer patients given pramipexole develop dopaminergic motor complications, patients given levodopa have a greater improvement in their early Parkinson’s disease. While both drugs cause an initial improvement, after two years the patients’ quality of life scores decline significantly less with levodopa.3

manufacturer provided additional useful information

Lieberman A, Ranhosky A, Korts D. Clinical evaluation of pramipexole in advanced Parkinson’s disease: results of a double-blind, placebo-controlled, parallel-group study. Neurology 1997;49:162-8.
Parkinson Study Group. Safety and efficacy of pramipexole in early Parkinson disease. JAMA 1997;278:125-30.
Parkinson Study Group. Pramipexole vs levodopa as initial treatment for Parkinson disease. A randomized controlled trial. JAMA 2000;284:1931-8.
Winkelman JW, Sethi KD, Kushida CA, Becker PM, Koester J, Cappola JJ, et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurology 2006;67:1034-9.
Guttman M; International Pramipexole-Bromocriptine Study Group. Double-blind comparison of pramipexole and bromocriptine treatment with placebo in advanced Parkinson’s disease. Neurology 1997;49:1060-5.

Source: Australian Prescriber. New drugs: pramipexole (Sifrol). Volume 31 Number 3 – June 2008.

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