Mirapex (pramipexole dihydrochloride) - 2 Indications

Scroll down for more information on each indication:

• for the treatment of Parkinson’s Disease; approved June 1997
• for the treatment of restless legs syndrome; approved November 2006

General Information

Mirapex (pramipexole) is a non-ergot D3 dopamine agonist.

Mirapex is specifically indicated:

• for the treatment of Parkinson's disease
• for the treatment of moderate-to-severe primary Restless Legs Syndrome

Mirapex is supplied as tablets are taken orally, with or without food. Scroll own for recommended dosing/administration for each indication.

Mechanism of Action

Pramipexole is a non-ergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes.

Parkinson’s Disease: The precise mechanism of action of pramipexole as a treatment for Parkinson's disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum.

Restless Legs Syndrome (RLS): The precise mechanism of action of MIRAPEX tablets as a treatment for RLS is unknown. Although the pathophysiology of RLS is largely unknown, neuropharmacological evidence suggests primary dopaminergic system involvement. Positron Emission Tomographic (PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction may be involved in the pathogenesis of RLS.

Side Effects

Adverse effects associated with the use of Mirapex may include, but are not limited to, the following:

• nausea
• dizziness
• somnolence
• insomnia
• constipation
• asthenia
• hallucination
• fatigue
• headache

Indication 1 - for the treatment of Parkinson’s Disease

approved June 1997

Dosing/Administration

In all clinical studies, dosage was initiated at a subtherapeutic level to avoid intolerable adverse effects and orthostatic hypotension. Mirapex tablets should be titrated gradually in all patients. The dose should be increased to achieve a maximum therapeutic effect, balanced against the principal side effects of dyskinesia, hallucinations, somnolence, and dry mouth.

Dosing in Patients with Normal Renal Function:

Initial Treatment: Doses should be increased gradually from a starting dose of 0.375 mg/day given in three divided doses and should not be increased more frequently than every 5 to 7 days. 

Maintenance Treatment: Mirapex tablets were effective and well tolerated over a dosage range of 1.5 to 4.5 mg/day administered in equally divided doses three times per day with or without concomitant levodopa (approximately 800 mg/day).

Discontinuation of Treatment: Mirapex tablets may be tapered off at a rate of 0.75 mg per day until the daily dose has been reduced to 0.75 mg. Thereafter, the dose may be reduced by 0.375 mg per day. 

Clinical Trial Results

Efficacy was demonstrated in patients with early Parkinson’s disease who were not receiving concomitant levodopa therapy as well as in patients with advanced disease on concomitant levodopa. In a pivotal study in advanced Parkinson’s patients receiving levodopa, pramipexole reduced off hours from six hours per day to four hours per day. After a six-month maintenance period, symptom scores, as assessed by the Unified Parkinson’s Disease Rating Scale for daily living decreased by 2.7 points on a scale from zero to 52 in the pramipexole group, compared to 0.5 for the placebo.

Indication 2 - for the treatment of restless legs syndrome

approved November 2006

Dosing/Administration

The recommended starting dose of Mirapex tablets is 0.125 mg taken once daily 2-3 hours before bedtime. For patients requiring additional symptomatic relief, the dose may be increased every 4-7 days

Clinical Trial Results

The efficacy of Mirapex tablets in the treatment of RLS was evaluated in a multinational drug development program consisting of 4 randomized, double-blind, placebo-controlled trials. This program included approximately 1000 patients with moderate to severe RLS; patients with RLS secondary to other conditions (e.g., pregnancy, renal failure, and anemia) were excluded. All patients were administered MIRAPEX tablets (0.125 mg, 0.25 mg, 0.5 mg, or 0.75 mg) or placebo once daily 2-3 hours before going to bed. Across the 4 studies, the mean duration of RLS was 4.6 years (range of 0 to 56 years), mean age was approximately 55 years (range of 18 to 81 years), and approximately 66.6% were women. 

In Study 1, fixed doses of Mirapex tablets were compared to placebo in a study of 12 weeks duration. A total of 344 patients were randomized equally to the 4 treatment groups. Patients treated with Mirapex tablets (n=254) had a starting dose of 0.125 mg/day and were titrated to one of the three randomized doses (0.25, 0.5, 0.75 mg/day) in the first three weeks of the study. The mean improvement from baseline on the IRLS Scale total score and the percentage of CGI-I responders for each of the Mirapex tablets treatment groups compared to placebo were the endpoints. All treatment groups reached statistically significant superiority compared to placebo for both endpoints. 

Study 2 was a randomized-withdrawal study, designed to demonstrate the sustained efficacy of pramipexole for treatment of RLS after a period of six months. RLS patients who responded to Mirapex tablets treatment in a preceding 6-month open-label treatment phase (defined as having a CGI-I rating of “very much improved” or “much improved” compared to baseline and an IRLS score of 15 or below) were randomized to receive either continued active treatment (n=78) or placebo (n=69) for 12 weeks. The primary endpoint of this study was time to treatment failure, defined as any worsening on the CGI-I score along with an IRLS Scale total score above 15. In patients who had responded to 6-month open label treatment with MIRAPEX tablets, the administration of placebo led to a rapid decline in their overall conditions and return of their RLS symptoms. At the end of the 12-week observation period, 85% of patients treated with placebo had failed treatment, compared to 21% treated with blinded pramipexole, a difference that was highly statistically significant. The majority of treatment failures occurred within 10 days of randomization. For the patients randomized, the distribution of doses was: 7 on 0.125 mg, 44 on 0.25 mg, 47 on 0.5 mg, and 49 on 0.75 mg.

Study 3 was a 6-week study, comparing a flexible dose of MIRAPEX tablets to placebo. In this study, 345 patients were randomized in a 2:1 ratio to Mirapex tablets or placebo. The mean improvement from baseline on the IRLS Scale total score was -12 for Mirapex-treated patients and -6 for placebo-treated patients. The percentage of CGI-I responders was 63% for Mirapex-treated patients and 32% for placebo-treated patients. The between-group differences were statistically significant for both outcome measures. For the patients randomized to Mirapex tablets, the distribution of achieved doses was: 35 on 0.125 mg, 51 on 0.25 mg, 65 on 0.5 mg, and 69 on 0.75 mg.

Study 4 was a 3-week study, comparing 4 fixed doses of Mirapex tablets, 0.125 mg, 0.25 mg, 0.5 mg, and 0.75 mg, to placebo. Approximately 20 patients were randomized to each of the 5 dose groups. The mean Page 23 of 25 improvement from baseline on the IRLS Scale total score and the percentage of CGI-I responders for each of the Mirapex tablets treatment groups compared to placebo are summarized in Table 9. In this study, the 0.125 mg dose group was not significantly different from placebo. On average, the 0.5 mg dose group performed better than the 0.25 mg dose group, but there was no difference between the 0.5 mg and 0.75 mg dose groups.