MIRAPEX SIDE EFFECTS
- Generic Name: pramipexole
- Brand Name: Mirapex
SIDE EFFECTS
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 [see
- 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 1 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 1Adverse-Reactions in Pooled Double-Blind, Placebo-Controlled Trials with MIRAPEX in Early Parkinson’s Disease
| Body System/Adverse Reaction | MIRAPEX (N=388) % |
Placebo (N=235) % |
| Nervous System | ||
| Dizziness | 25 | 24 |
| Somnolence | 22 | 9 |
| Insomnia | 17 | 12 |
| Hallucinations | 9 | 3 |
| Confusion | 4 | 1 |
| Amnesia | 4 | 2 |
| Hypesthesia | 3 | 1 |
| Dystonia | 2 | 1 |
| Akathisia | 2 | 0 |
| Thinking abnormalities | 2 | 0 |
| Decreased libido | 1 | 0 |
| Myoclonus | 1 | 0 |
| Digestive System | ||
| Nausea | 28 | 18 |
| Constipation | 14 | 6 |
| Anorexia | 4 | 2 |
| Dysphagia | 2 | 0 |
| Body as a Whole | ||
| Asthenia | 14 | 12 |
| General edema | 5 | 3 |
| Malaise | 2 | 1 |
| Reaction unevaluable | 2 | 1 |
| Fever | 1 | 0 |
| Metabolic & Nutritional System | ||
| Peripheral edema | 5 | 4 |
| Decreased weight | 2 | 0 |
| Special Senses | ||
| Vision abnormalities | 3 | 0 |
| Urogenital System | ||
| Impotence | 2 | 1 |
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 2 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 2 Adverse-Reactions in Pooled Double-Blind, Placebo-Controlled Trials with MIRAPEX in Advanced Parkinson’s Disease
| Body System/Adverse Reaction | MIRAPEX (N=260) % |
Placebo (N=264) % |
| Nervous System | ||
| Dyskinesia | 47 | 31 |
| Extrapyramidal syndrome | 28 | 26 |
| Insomnia | 27 | 22 |
| Dizziness | 26 | 25 |
| Hallucinations | 17 | 4 |
| Dream abnormalities | 11 | 10 |
| Confusion | 10 | 7 |
| Somnolence | 9 | 6 |
| Dystonia | 8 | 7 |
| Gait abnormalities | 7 | 5 |
| Hypertonia | 7 | 6 |
| Amnesia | 6 | 4 |
| Akathisia | 3 | 2 |
| Thinking abnormalities | 3 | 2 |
| Paranoid reaction | 2 | 0 |
| Delusions | 1 | 0 |
| Sleep disorders | 1 | 0 |
| Cardiovascular System | ||
| Postural hypotension | 53 | 48 |
| Body as a Whole | ||
| Accidental injury | 17 | 15 |
| Asthenia | 10 | 8 |
| General edema | 4 | 3 |
| Chest pain | 3 | 2 |
| Malaise | 3 | 2 |
| Digestive System | ||
| Constipation | 10 | 9 |
| Dry mouth | 7 | 3 |
| Urogenital System | ||
| Urinary frequency | 6 | 3 |
| Urinary tract infection | 4 | 3 |
| Urinary incontinence | 2 | 1 |
| Respiratory System | ||
| Dyspnea | 4 | 3 |
| Rhinitis | 3 | 1 |
| Pneumonia | 2 | 0 |
| Special Senses | ||
| Accommodation abnormalities | 4 | 2 |
| Vision abnormalities | 3 | 1 |
| Diplopia | 1 | 0 |
| Musculoskeletal System | ||
| Arthritis | 3 | 1 |
| Twitching | 2 | 0 |
| Bursitis | 2 | 0 |
| Myasthenia | 1 | 0 |
| Metabolic & Nutritional System | ||
| Peripheral edema | 2 | 1 |
| Increased creatine PK | 1 | 0 |
| Skin & Appendages | ||
| Skin disorders | 2 | 1 |
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 3 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 3Adverse-Reactions in Pooled Double-Blind, Placebo-Controlled Trials with MIRAPEX in Restless Legs Syndrome
| Body System/Adverse Reaction | MIRAPEX 0.125 – 0.75 mg/day (N=575) % |
Placebo (N=223) % |
| Gastrointestinal disorders | ||
| Nausea | 16 | 5 |
| Constipation | 4 | 1 |
| Diarrhea | 3 | 1 |
| Dry mouth | 3 | 1 |
| Nervous system disorders | ||
| Headache | 16 | 15 |
| Somnolence | 6 | 3 |
| General disorders and administration site conditions | ||
| Fatigue | 9 | 7 |
| Infections and infestations | ||
| Influenza | 3 | 1 |
Table 4 summarizes data for adverse reactions that appeared to be dose related in the 12-week fixed dose study.
Table 4 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)
| Body System/Adverse Reaction | MIRAPEX 0.25 mg (N=88) % |
MIRAPEX 0.5 mg (N=80) % |
MIRAPEX 0.75 mg (N=90) % |
Placebo (N=86) % |
| Gastrointestinal disorders | ||||
| Nausea | 11 | 19 | 27 | 5 |
| Diarrhea | 3 | 1 | 7 | 0 |
| Dyspepsia | 3 | 1 | 4 | 7 |
| Psychiatric disorders | ||||
| Insomnia | 9 | 9 | 13 | 9 |
| Abnormal dreams | 2 | 1 | 8 | 2 |
| General disorders and administration site conditions | ||||
| Fatigue | 3 | 5 | 7 | 5 |
| Musculoskeletal and connective tissue disorders | ||||
| Pain in extremity | 3 | 3 | 7 | 1 |
| Infections and infestations | ||||
| Influenza | 1 | 4 | 7 | 1 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Nasal congestion | 0 | 3 | 6 | 1 |
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)
SRC: NLM .