Side Effects of Mirapex (pramipexole)

Mirapex (pramipexole) is a dopamine agonist used to treat Parkinson's disease (PD) and restless leg syndrome (RLS).

Mirapex stimulates dopamine receptors in the brain. The exact mechanism of action of Mirapex in Parkinson's disease is unknown. However, treatment benefits are thought to be related to the stimulation of dopamine receptors in the area of the brain known as the striatum.

Mirapex may improve movement performance and activities of daily living in patients usually within 2-3 weeks of starting treatment. The exact mechanism of action of Mirapex for the treatment of RLS is unknown. Benefits of treatment are thought to be associated with stimulating dopamine receptors in the brain.

Common side effects of Mirapex include

• nausea,
• dizziness,
• sleepiness,
• difficulty sleeping,
• constipation,
• weakness,
• dizziness on standing,
• movement disorder (extrapyramidal syndrome),
• dry mouth,
• amnesia (memory impairment), and
• urinary frequency.

Serious side effects of Mirapex include

• significant daytime sleepiness or falling asleep while engaged in activities of daily living, including the operation of motor vehicles which may result in accidents. 

Drug interactions of Mirapex include dopamine antagonists, which are drugs with the opposite pharmacological effects, from Mirapex, such as

• prochlorperazine,
• chlorpromazine,
• fluphenazine,
• haloperidol,
• thioxanthenes, and
• metoclopramide.

Mirapex has not been adequately evaluated in pregnant women. Due to the lack of conclusive safety data, Mirapex should be used in pregnancy only if the potential benefit justifies the potential risk to the fetus.

It is unknown if Mirapex is excreted in breast milk. Due to the lack of conclusive safety data, Mirapex should be used cautiously in females who are breastfeeding.

WARNING

Falling Asleep During Activities of Daily Living

• Patients treated with Mirapex (pramipexole dihydrochloride) tablets have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles which sometimes resulted in accidents.
• Although many of these patients reported somnolence while on Mirapex tablets, some perceived that they had no warning signs such as excessive drowsiness, and believed that they were alert immediately prior to the event.
• Some of these events had been reported as late as one year after the initiation of treatment.
• Before initiating treatment with Mirapex tablets, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with Mirapex tablets such as
  • concomitant sedating medications,
  • the presence of sleep disorders, and
  • concomitant medications that increase pramipexole plasma levels.
• If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), Mirapex tablets should ordinarily be discontinued.
• If a decision is made to continue Mirapex tablets, patients should be advised to not drive and to avoid other potentially dangerous activities.
• While dose reduction clearly reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

Common side effects

The most common side effects reported are:

• nausea,
• dizziness,
• somnolence (sleepiness),
• difficulty sleeping,
• constipation,
• weakness (asthenia),
• orthostatic hypotension (low blood pressure),
• movement disorder (extrapyramidal syndrome),
• dry mouth,
• amnesia (memory impairment), and
• urinary frequency.

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Falling Asleep During Activities of Daily Living and Somnolence.
• Symptomatic Orthostatic Hypotension.
• Impulse Control/Compulsive Behaviors.
• Hallucinations and Psychotic-like Behavior.
• Dyskinesia.
• Postural Deformity.
• Rhabdomyolysis.
• Retinal Pathology.
• Events Reported with Dopaminergic Therapy.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Parkinson's Disease

During the premarketing development of pramipexole, patients with either early or advanced Parkinson's disease were enrolled in clinical trials. Apart from the severity and duration of their disease, the two populations differed in their use of concomitant levodopa therapy.

Patients with early disease did not receive concomitant levodopa therapy during treatment with pramipexole; those with advanced Parkinson's disease all received concomitant levodopa treatment. Because these two populations may have differential risks for various adverse reactions, this section will, in general, present adverse-reaction data for these two populations separately.

Because the controlled trials performed during premarketing development all used a titration design, with a resultant confounding of time and dose, it was impossible to adequately evaluate the effects of dose on the incidence of adverse reactions.

Early Parkinson's Disease

In the three double-blind, placebo-controlled trials of patients with early Parkinson's disease, the most common adverse reactions (>5%) that were numerically more frequent in the group treated with Mirapex tablets were

• nausea,
• dizziness,
• somnolence,
• insomnia,
• constipation,
• asthenia, and
• hallucinations.

Approximately 12% of 388 patients with early Parkinson's disease and treated with Mirapex tablets who participated in the double-blind, placebo-controlled trials discontinued treatment due to adverse reactions compared with 11% of 235 patients who received placebo. The adverse reactions most commonly causing discontinuation of treatment were

• related to the nervous system (hallucinations [3.1% on Mirapex tablets vs 0.4% on placebo];
• dizziness [2.1% on Mirapex tablets vs 1% on placebo];
• somnolence [1.6% on Mirapex tablets vs 0% on placebo];
• headache and confusion [1.3% and 1.0%, respectively, on Mirapex tablets vs 0% on placebo]) and
• gastrointestinal system (nausea [2.1% on Mirapex tablets vs 0.4% on placebo]).

Adverse-reaction Incidence in Controlled Clinical Studies in Early Parkinson's Disease

Table 4 lists adverse reactions that occurred in the double-blind, placebo-controlled studies in early Parkinson's disease that were reported by ≥1% of patients treated with Mirapex tablets and were numerically more frequent than in the placebo group. In these studies, patients did not receive concomitant levodopa.

Table 4 Adverse-Reactions in Pooled Double-Blind, Placebo-Controlled Trials with Mirapex in Early Parkinson's Disease

In a fixed-dose study in early Parkinson's disease, occurrence of the following reactions increased in frequency as the dose increased over the range from 1.5 mg/day to 6 mg/day:

• postural hypotension,
• nausea,
• constipation,
• somnolence, and
• amnesia.

The frequency of these reactions was generally 2-fold greater than placebo for pramipexole doses greater than 3 mg/day. The incidence of somnolence with pramipexole at a dose of 1.5 mg/day was comparable to that reported for placebo.

Advanced Parkinson's Disease

In the four double-blind, placebo-controlled trials of patients with advanced Parkinson's disease, the most common adverse reactions (>5%) that were numerically more frequent in the group treated with Mirapex tablets and concomitant levodopa were

• postural (orthostatic) hypotension,
• dyskinesia, extrapyramidal syndrome,
• insomnia,
• dizziness,
• hallucinations,
• accidental injury,
• dream abnormalities,
• confusion,
• constipation,
• asthenia,
• somnolence,
• dystonia,
• gait abnormality,
• hypertonia,
• dry mouth,
• amnesia, and
• urinary frequency.

Approximately 12% of 260 patients with advanced Parkinson's disease who received Mirapex tablets and concomitant levodopa in the double-blind, placebo-controlled trials discontinued treatment due to adverse reactions compared with 16% of 264 patients who received placebo and concomitant levodopa.

The reactions most commonly causing discontinuation of treatment were

• related to the nervous system (hallucinations [2.7% on Mirapex tablets vs 0.4% on placebo];
• dyskinesia [1.9% on Mirapex tablets vs 0.8% on placebo]) and
• cardiovascular system (postural [orthostatic] hypotension [2.3% on Mirapex tablets vs 1.1% on placebo]).

Adverse-reaction Incidence in Controlled Clinical Studies in Advanced Parkinson's Disease

Table 5 lists adverse reactions that occurred in the double-blind, placebo-controlled studies in advanced Parkinson's disease that were reported by ≥1% of patients treated with Mirapex tablets and were numerically more frequent than in the placebo group. In these studies, Mirapex tablets or placebo was administered to patients who were also receiving concomitant levodopa.

Table 5 Adverse-Reactions in Pooled Double-Blind, Placebo-Controlled Trials with Mirapex in Advanced Parkinson's Disease

Restless Legs Syndrome

Mirapex tablets for treatment of RLS have been evaluated for safety in 889 patients, including 427 treated for over six months and 75 for over one year.

The overall safety assessment focuses on the results of three double-blind, placebo-controlled trials, in which 575 patients with RLS were treated with Mirapex tablets for up to 12 weeks.

The most common adverse reactions with Mirapex tablets in the treatment of RLS (observed in >5% of pramipexole-treated patients and at a rate at least twice that observed in placebo-treated patients) were nausea and somnolence. Occurrences of nausea and somnolence in clinical trials were generally mild and transient.

Approximately 7% of 575 patients treated with Mirapex tablets during the double-blind periods of three placebo-controlled trials discontinued treatment due to adverse reactions compared to 5% of 223 patients who received placebo. The adverse reaction most commonly causing discontinuation of treatment was nausea (1%).

Table 6 lists reactions that occurred in three double-blind, placebo-controlled studies in RLS patients that were reported by ≥2% of patients treated with Mirapex tablets and were numerically more frequent than in the placebo group.

Table 6 Adverse-Reactions in Pooled Double-Blind, Placebo-Controlled Trials with Mirapex in Restless Legs Syndrome

Table 7 summarizes data for adverse reactions that appeared to be dose related in the 12-week fixed dose study.

Table 7 Dose-Related Adverse Reactions in a 12-Week Double-Blind, Placebo-Controlled Fixed Dose Study in Restless Legs Syndrome (Occurring in ≥5% of all Patients in the Treatment Phase)

Adverse Reactions

Relationship to Age, Gender, and Race

Among the adverse reactions in patients treated with Mirapex tablets, hallucination appeared to exhibit a positive relationship to age in patients with Parkinson’s disease. Although no gender-related differences were observed in Parkinson’s disease patients, nausea and fatigue, both generally transient, were more frequently reported by female than male RLS patients. Less than 4% of patients enrolled were non-Caucasian: therefore, an evaluation of adverse reactions related to race is not possible.

Laboratory Tests

During the development of Mirapex tablets, no systematic abnormalities on routine laboratory testing were noted.

Post Marketing Experience

In addition to the adverse events reported during clinical trials, the following adverse reactions have been identified during post-approval use of Mirapex tablets, primarily in Parkinson’s disease patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors:

• (1) seriousness of the reaction,
• (2) frequency of reporting, or
• (3) strength of causal connection to pramipexole tablets.

Cardiac Disorders: cardiac failure

Gastrointestinal Disorders: vomiting

Metabolism and Nutrition Disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH), weight increase

Musculoskeletal and Connective Tissue Disorders: postural deformity

Nervous System Disorders: syncope

Skin and Subcutaneous Tissue Disorders: skin reactions (including erythema, rash, pruritus, urticaria)

Dopamine Antagonists

Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of Mirapex tablets.