Safety and Tolerability

Adverse Events

Most patients who take MIRAPEX for moderate-to-severe primary RLS tolerate it well. MIRAPEX has been evaluated for safety in 889 patients, including 427 treated for over 6 months and 75 for over 1 year.⁹

The main safety appraisal centers on the results of 3 double-blind, placebo-controlled clinical trials involving 575 patients receiving MIRAPEX for RLS for up to 12 weeks.

Treatment-Emergent Adverse Events for MIRAPEX and Placebo in 3 Double-Blind, Placebo-Controlled Trials*

*Occurring in ≥2% of patients taking MIRAPEX and occurring numerically more frequently than in the placebo group.

Hallucinations and postural (orthostatic) hypotension may occur. In clinical trials for RLS, the most commonly reported side effects of MIRAPEX that were more frequent than with placebo are nausea (16% vs. 5%), headache (16% vs. 15%), fatigue (9% vs. 7%) and somnolence (6% vs. 3%).

It should be noted that these results cannot be used to predict the incidence of adverse events during the course of usual medical practice where a variety of factors differ from those in the clinical trials.

Warnings

• Patients treated with MIRAPEX tablets have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles which sometimes resulted in accidents. Prescribers should continually reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities
• Dopamine agonists, in clinical trials and clinical experience, may be associated with impairment of the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. Both Parkinson's disease patients and RLS patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk
• Sometimes hallucinations have been reported in patients taking MIRAPEX. In clinical trials, patients with RLS treated with pramipexole rarely reported hallucinations, the risk being greater in patients who are taking MIRAPEX for Parkinson's disease

Precautions

Renal

• Since pramipexole is eliminated through the kidneys, caution should be exercised when prescribing MIRAPEX to patients with renal insufficiency

Retinal Pathology in Albino Rats

• Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2-year carcinogenicity study. The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved

Fibrotic Complications

• Although not reported with pramipexole in the clinical development program, cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and pleural thickening, pericarditis, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur
• A small number of reports have been received of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis in the post-marketing experience for MIRAPEX. While the evidence is not sufficient to establish a causal relationship between MIRAPEX and these fibrotic complications, a contribution of MIRAPEX cannot be completely ruled out in rare cases

Melanoma

• Although MIRAPEX has not been associated with an increased risk of melanoma specifically, its potential role as a risk factor has not been systematically studied. Patients using MIRAPEX for any indication should be made aware of these results and should undergo periodic dermatologic screening

Impulse Control/Compulsive Behaviors

• Cases of pathological gambling, hypersexuality, and compulsive eating (including binge eating) have been reported in patients treated with dopamine agonist therapy, including pramipexole therapy. As described in the literature, such behaviors are generally reversible upon dose reduction or treatment discontinuation

Augmentation and Rebound

Reports in the literature indicate that the treatment of restless legs syndrome (RLS) with dopaminergic agents may result in 2 separate phenomena known as augmentation and rebound.

• Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities. In a controlled trial of MIRAPEX for RLS, approximately 20% of both the MIRAPEX- and the placebo-treated patients reported at least a 2-hour earlier onset of symptoms during the day by the end of 3 months of treatment
• Reports in the literature indicate treatment of RLS with dopaminergic medications can result in a shifting of symptoms to the early morning hours, referred to as rebound. Rebound was not reported in the clinical trials of MIRAPEX but the trials were generally not of sufficient duration to capture this phenomenon
• The frequency and severity of augmentation and/or rebound after longer-term use of MIRAPEX and the appropriate management of these events have not been adequately evaluated in controlled clinical trials

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