Pramipexole Dihydrochloride (Page 3 of 8)

6 ADVERSE REACTIONS

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

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%, 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 (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 (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

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. No gender-related differences were observed in Parkinson’s disease 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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