Pramipexole Dihydrochloride (Page 3 of 9)

5.5 Dyskinesia

Pramipexole dihydrochloride tablets may cause or exacerbate preexisting dyskinesia.

5.6 Postural Deformity

Postural deformities, including antecollis, camptocormia (Bent Spine Syndrome), and pleurothotonus (Pisa Syndrome), have been reported in patients after starting or increasing the dose of pramipexole dihydrochloride. Postural deformity may occur several months after starting treatment or increasing the dose. Reducing the dose or discontinuing pramipexole dihydrochloride has been reported to improve postural deformity in some patients, and should be considered if postural deformity occurs.

5.7 Renal Impairment

Since pramipexole is eliminated through the kidneys, caution should be exercised when prescribing pramipexole dihydrochloride tablets to patients with renal impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

5.8 Rhabdomyolysis

A single case of rhabdomyolysis occurred in a 49-year-old male with advanced Parkinson’s disease treated with pramipexole dihydrochloride tablets. The patient was hospitalized with an elevated CPK (10,631 IU/L). The symptoms resolved with discontinuation of the medication.

Advise patients to contact a physician if they experience any unexplained muscle pain, tenderness, or weakness, as these may be symptoms of rhabdomyolysis.

5.9 Retinal Pathology

Human Data

A two-year open-label, randomized, parallel-group safety study of retinal deterioration and vision compared pramipexole dihydrochloride tablets and immediate-release ropinirole. Two hundred thirty four Parkinson’s disease patients (115 on pramipexole, mean dose 3.0 mg/day and 119 on ropinirole, mean dose 9.5 mg/day) were evaluated using a panel of clinical ophthalmological assessments. Of 234 patients who were evaluable, 196 had been treated for two years and 29 were judged to have developed clinical abnormalities that were considered meaningful (19 patients in each treatment arm had received treatment for less than two years). There was no statistical difference in retinal deterioration between the treatment arms; however, the study was only capable of detecting a very large difference between treatments. In addition, because the study did not include an untreated comparison group (placebo treated), it is unknown whether the findings reported in patients treated with either drug are greater than the background rate in an aging population.

Animal Data

Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2-year carcinogenicity study. While retinal degeneration was not diagnosed in pigmented rats treated for 2 years, a thinning in the outer nuclear layer of the retina was slightly greater in rats given drug compared with controls. Evaluation of the retinas of albino mice, monkeys, and minipigs did not reveal similar changes. 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 [see Nonclinical Toxicology (13.2) ].

5.10 Events Reported with Dopaminergic Therapy

Although the events enumerated below may not have been reported in association with the use of pramipexole in its development program, they are associated with the use of other dopaminergic drugs. The expected incidence of these events, however, is so low that even if pramipexole caused these events at rates similar to those attributable to other dopaminergic therapies, it would be unlikely that even a single case would have occurred in a cohort of the size exposed to pramipexole in studies to date.

Hyperpyrexia and Confusion

Although not reported with pramipexole in the clinical development program, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy. If possible, avoid sudden discontinuation or rapid dose reduction in patients taking pramipexole dihydrochloride tablets. If the decision is made to discontinue pramipexole dihydrochloride tablets, the dose should be tapered to reduce the risk of hyperpyrexia and confusion [see Dosage and Administration (2.2)].

Fibrotic Complications

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.

Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, nonergot-derived dopamine agonists can cause them is unknown.

Cases of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis have been reported in the post marketing experience with pramipexole dihydrochloride tablets. While the evidence is not sufficient to establish a causal relationship between pramipexole dihydrochloride tablets and these fibrotic complications, a contribution of pramipexole dihydrochloride tablets cannot be completely ruled out.

Rebound and Augmentation in RLS

Reports in the literature indicate treatment of RLS with dopaminergic medications can result in rebound: a worsening of symptoms following treatment cessation with greater intensity than described before starting treatment. In a 26 week placebo controlled clinical trial in patients with RLS, a worsening of symptoms scores (IRLS) beyond their untreated baseline levels was reported more frequently by patients suddenly withdrawn from pramipexole dihydrochloride tablets (up to 0.75 mg once daily) compared to the group assigned to placebo (10% vs. 2%, respectively). The worsening of RLS symptoms was considered generally mild.

Augmentation has also been described during therapy for RLS. 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 26 week placebo controlled clinical trial in patients with RLS, augmentation was reported with greater frequency by patients treated with pramipexole dihydrochloride tablets (up to 0.75 mg once daily) compared to patients who received placebo (12% vs. 9%, respectively). The incidence of augmentation increased with increasing duration of exposure to pramipexole dihydrochloride tablets and to placebo.

The frequency and severity of augmentation and/or rebound after longer-term use of pramipexole dihydrochloride tablets and the appropriate management of these events have not been adequately evaluated in controlled clinical trials.

5.11 Withdrawal Symptoms

Symptoms including apathy, anxiety, depression, fatigue, insomnia, sweating, and pain have been reported during taper or after discontinuation of dopamine agonists, including Pramipexole dihydrochloride tablets. These symptoms generally do not respond to levodopa.

Prior to discontinuation of Pramipexole dihydrochloride tablets, patients should be informed about potential withdrawal symptoms, and monitored during and after discontinuation. In case of severe withdrawal symptoms, a trial re-administration of a dopamine agonist at the lowest effective dose may be considered.

6 ADVERSE REACTIONS

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

  • Falling Asleep During Activities of Daily Living and Somnolence [see Warnings and Precautions (5.1) ]
  • Symptomatic Orthostatic Hypotension [see Warnings and Precautions (5.2) ]
  • Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.3) ]
  • Hallucinations and Psychotic-like Behavior [see Warnings and Precautions (5.4)]
  • Dyskinesia [see Warnings and Precautions (5.5)]
  • Postural Deformity [see Warnings and Precautions (5.6)]
  • Rhabdomyolysis [see Warnings and Precautions (5.8)]
  • Retinal Pathology [see Warnings and Precautions (5.9)]
  • Events Reported with Dopaminergic Therapy [see Warnings and Precautions (5.10)]
  • Withdrawal Symptoms [see Warnings and Precautions (5.11) ]

6.1 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 pramipexole dihydrochloride tablets were nausea, dizziness, somnolence, insomnia, constipation, asthenia, and hallucinations.

Approximately 12% of 388 patients with early Parkinson’s disease and treated with pramipexole dihydrochloride 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 pramipexole dihydrochloride tablets vs 0.4% on placebo]; dizziness [2.1% on pramipexole dihydrochloride tablets vs 1% on placebo]; somnolence [1.6% on pramipexole dihydrochloride tablets vs 0% on placebo]; headache and confusion [1.3% and 1.0%, respectively, on pramipexole dihydrochloride tablets vs 0% on placebo]) and gastrointestinal system (nausea [2.1% on pramipexole dihydrochloride 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 pramipexole dihydrochloride 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 Pramipexole dihydrochloride tablets in Early Parkinson’s Disease
Body System/Adverse Reaction Pramipexole dihydrochloride tablets (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 pramipexole dihydrochloride 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 pramipexole dihydrochloride 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 pramipexole dihydrochloride tablets vs 0.4% on placebo]; dyskinesia [1.9% on pramipexole dihydrochloride tablets vs 0.8% on placebo]; and cardiovascular system (postural [orthostatic] hypotension [2.3% on pramipexole dihydrochloride 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 pramipexole dihydrochloride tablets and were numerically more frequent than in the placebo group. In these studies, pramipexole dihydrochloride 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 Pramipexole dihydrochloride tablets in Advanced Parkinson’s Disease
Body System/Adverse Reaction Pramipexole dihydrochloride tablets (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
Accomodation 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

Pramipexole dihydrochloride 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 pramipexole dihydrochloride tablets for up to 12 weeks. The most common adverse reactions with pramipexole dihydrochloride 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 pramipexole dihydrochloride 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 pramipexole dihydrochloride tablets and were numerically more frequent than in the placebo group.

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

Body System/Adverse Reaction Pramipexole dihydrochloride tablet 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 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)
Body System/Adverse Reaction Pramipexole dihydrochloride tablet 0.25mg (N=88) % Pramipexole dihydrochloride tablet 0.5mg (N=80) % Pramipexole dihydrochloride tablet 0.75mg (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 pramipexole dihydrochloride 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 pramipexole dihydrochloride tablets, no systematic abnormalities on routine laboratory testing were noted.

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