Pramipexole Dihydrochloride

5 WARNINGS AND PRECAUTIONS Falling Asleep During Activities of Daily Living: Sudden onset of sleep may occur without warning; advise patients to report symptoms ( 5.1 ) Symptomatic Orthostatic Hypotension: Monitor during dose escalation ( 5.2 ) Impulse Control/Compulsive Behaviors: Patients may experience compulsive behaviors and other intense urges ( 5.3 ) Hallucinations and Psychotic-like Behavior: May occur; risk increases with age. ( 5.4 ) Dyskinesia: May be caused or exacerbated by PRAMIPEXOLE DIHYDROCHLORIDE tablets ( 5.5 ) Postural Deformity: Consider reducing the dose or discontinuing PRAMIPEXOLE DIHYDROCHLORIDE tablets if postural deformity occurs ( 5.6 ) 5.1 Falling Asleep During Activities of Daily Living and Somnolence Patients treated with pramipexole 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 pramipexole tablets, some perceived that they had no warning signs (sleep attack) 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. Somnolence is a common occurrence in patients receiving pramipexole at doses above 1.5 mg/day (0.5 mg three times a day) for Parkinson’s disease. In controlled clinical trials in RLS, patients treated with pramipexole dihydrochloride tablets at doses of 0.25 to 0.75 mg once a day, the incidence of somnolence was 6% compared to an incidence of 3% for placebo-treated patients [ see Adverse Reactions ( 6.1 ) ]. It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should 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. Before initiating treatment with pramipexole dihydrochloride tablets, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with pramipexole dihydrochloride tablets such as the use of concomitant sedating medications or alcohol, the presence of sleep disorders, and concomitant medications that increase pramipexole plasma levels (e.g., cimetidine) [ see Clinical Pharmacology ( 12.3 ) ]. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), pramipexole dihydrochloride tablets should ordinarily be discontinued. If a decision is made to continue pramipexole dihydrochloride tablets, advise patients not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. While dose reduction 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. 5.2 Symptomatic Orthostatic Hypotension Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. Parkinson’s disease patients, in addition, appear to have an impaired capacity to respond to an orthostatic challenge. For these reasons, 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. In clinical trials of pramipexole, however, and despite clear orthostatic effects in normal volunteers, the reported incidence of clinically significant orthostatic hypotension was not greater among those assigned to pramipexole tablets than among those assigned to placebo. This result, especially with the higher doses used in Parkinson’s disease, is clearly unexpected in light of the previous experience with the risks of dopamine agonist therapy. While this finding could reflect a unique property of pramipexole, it might also be explained by the conditions of the study and the nature of the population enrolled in the clinical trials. Patients were very carefully titrated, and patients with active cardiovascular disease or significant orthostatic hypotension at baseline were excluded. Also, clinical trials in patients with RLS did not incorporate orthostatic challenges with intensive blood pressure monitoring done in close temporal proximity to dosing. 5.3 Impulse Control/Compulsive Behaviors Case reports and the results of a cross-sectional study suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, binge eating, and/or other intense urges and the inability to control these urges while taking one or more of the medications, including pramipexole dihydrochloride tablets, that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with pramipexole dihydrochloride tablets for Parkinson’s disease or RLS. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking pramipexole dihydrochloride tablets. 5.4 Hallucinations and Psychotic-like Behavior In the three double-blind, placebo-controlled trials in early Parkinson’s disease, hallucinations were observed in 9% (35 of 388) of patients receiving pramipexole dihydrochloride tablets, compared with 2.6% (6 of 235) of patients receiving placebo. In the four double-blind, placebo-controlled trials in advanced Parkinson’s disease, where patients received pramipexole dihydrochloride tablets and concomitant levodopa, hallucinations were observed in 16.5% (43 of 260) of patients receiving pramipexole dihydrochloride tablets compared with 3.8% (10 of 264) of patients receiving placebo. Hallucinations were of sufficient severity to cause discontinuation of treatment in 3.1% of the early Parkinson’s disease patients and 2.7% of the advanced Parkinson's disease patients compared with about 0.4% of placebo patients in both populations.In the three double-blind, placebo-controlled trials in early Parkinson’s disease, hallucinations were observed in 9% (35 of 388) of patients receiving pramipexole dihydrochloride tablets, compared with 2.6% (6 of 235) of patients receiving placebo. In the four double-blind, placebo-controlled trials in advanced Parkinson’s disease, where patients received pramipexole dihydrochloride tablets and concomitant levodopa, hallucinations were observed in 16.5% (43 of 260) of patients receiving pramipexole dihydrochloride tablets compared with 3.8% (10 of 264) of patients receiving placebo. Hallucinations were of sufficient severity to cause discontinuation of treatment in 3.1% of the early Parkinson’s disease patients and 2.7% of the advanced Parkinson's disease patients compared with about 0.4% of placebo patients in both populations. Age appears to increase the risk of hallucinations attributable to pramipexole. In the early Parkinson’s disease patients, the risk of hallucinations was 1.9 times greater than placebo in patients younger than 65 years and 6.8 times greater than placebo in patients older than 65 years. In the advanced Parkinson's disease patients, the risk of hallucinations was 3.5 times greater than placebo in patients younger than 65 years and 5.2 times greater than placebo in patients older than 65 years.Age appears to increase the risk of hallucinations attributable to pramipexole. In the early Parkinson’s disease patients, the risk of hallucinations was 1.9 times greater than placebo in patients younger than 65 years and 6.8 times greater than placebo in patients older than 65 years. In the advanced Parkinson's disease patients, the risk of hallucinations was 3.5 times greater than placebo in patients younger than 65 years and 5.2 times greater than placebo in patients older than 65 years. Postmarketing reports with medications used to treat Parkinson’s disease or RLS, including pramipexole, indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with pramipexole or after starting or increasing the dose of pramipexole. Other drugs prescribed to improve the symptoms of Parkinson’s disease or RLS can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, symptoms of mania (e.g., insomnia, psychomotor agitation), disorientation, aggressive behavior, agitation, and delirium. Patients with a major psychotic disorder should ordinarily not be treated with dopamine agonists, including pramipexole, because of the risk of exacerbating the psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of pramipexole [ ]. Patients with a major psychotic disorder should ordinarily not be treated with dopamine agonists, including pramipexole, because of the risk of exacerbating the psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of pramipexole [ see Drug Interactions ( 7.1 ) ]. In the RLS clinical trials, one pramipexole-treated patient (of 889) reported hallucinations; this patient discontinued treatment and the symptoms resolved. In the RLS clinical trials, one pramipexole-treated patient (of 889) reported hallucinations; this patient discontinued treatment and the symptoms resolved. 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. Postural deformity may occur several months after starting treatment or increasing the dose. Reducing the dose or discontinuing pramipexole 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 postmarketing 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 ) ] Most common adverse reactions (incidence >5% and greater than placebo): Early PD without levodopa: nausea, dizziness, somnolence, insomnia, constipation, asthenia, and hallucinations ( 6.1 ) Advanced PD with levodopa: 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 ( 6.1 ) RLS: nausea, somnolence, fatigue, and headache ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact ScieGen Pharmaceuticals, Inc. at 1-855-724-3436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 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 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 tablets 0.125 - 0.75 mg/day tablets (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-RelatedAdverse 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 tablets 0.25 mg (N=88) % Pramipexole dihydrochloride tablets 0.5 mg (N=80) % Pramipexole dihydrochloride tablets 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 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. 6.2 Postmarketing Experience In addition to the adverse events reported during clinical trials, the following adverse reactions have been identified during post-approval use of pramipexole dihydrochloride 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 General Disorders and Administration Site Conditions: withdrawal symptoms [ see Warnings and Precautions ( 5.11 ) ] Metabolism and Nutrition Disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH), weight increase Musculoskeletal and Connective Tissue Disorders: postural deformity [ see Warnings and Precautions ( 5.6 ) ] Nervous System Disorders: syncope Reproductive System and Breast Disorders: priapism Skin and Subcutaneous Tissue Disorders: skin reactions (including erythema, rash, pruritus, urticaria)

<table><caption>Table 4: Adverse-Reactions in Pooled Double-Blind, Placebo-Controlled Trials with Pramipexole Dihydrochloride Tablets in Early Parkinson&#x2019;s Disease</caption><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Body System/Adverse Reaction </content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Pramipexole dihydrochloride</content> <content styleCode="bold">tablets</content></paragraph><paragraph><content styleCode="bold">(N=388)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(N=235)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous System</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dizziness</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>25</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>24</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Somnolence</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>22</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Insomnia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>17</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hallucinations</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Confusion</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Amnesia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Hypesthesia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dystonia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Akathisia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Thinking abnormalities</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Decreased libido</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Myoclonus</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Digestive System</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>28</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>18</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Anorexia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dysphagia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Body as a Whole</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Asthenia</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>12</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>General edema</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Malaise</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Reaction unevaluable</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Fever</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolic &amp; Nutritional System</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Peripheral edema</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Decreased weight</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Special Senses</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vision abnormalities</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Urogenital System</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Impotence</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>2</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td></tr></tbody></table>

<table cellspacing="0" cellpadding="0" border="0" width="70%"><caption>Table 5: Adverse-Reactions in Pooled Double-Blind, Placebo-Controlled Trials with Pramipexole Dihydrochloride Tablets in Advanced Parkinson&#x2019;s Disease</caption><thead><tr><th styleCode="Lrule Rrule Toprule">Body System/Adverse Reaction </th><th styleCode="Lrule Rrule Toprule">Pramipexole dihydrochloride tablets (N=260) % </th><th styleCode="Lrule Rrule Toprule">Placebo (N=264) % </th></tr></thead><tbody><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Nervous System</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Dyskinesia </td><td align="center" styleCode="Rrule" valign="top">47 </td><td align="center" styleCode="Rrule" valign="top">31 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Extrapyramidal syndrome </td><td align="center" styleCode="Rrule" valign="top">28 </td><td align="center" styleCode="Rrule" valign="top">26 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Insomnia </td><td align="center" styleCode="Rrule" valign="top">27 </td><td align="center" styleCode="Rrule" valign="top">22 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Dizziness </td><td align="center" styleCode="Rrule" valign="top">26 </td><td align="center" styleCode="Rrule" valign="top">25 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Hallucinations </td><td align="center" styleCode="Rrule" valign="top">17 </td><td align="center" styleCode="Rrule" valign="top">4 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Dream abnormalities </td><td align="center" styleCode="Rrule" valign="top">11 </td><td align="center" styleCode="Rrule" valign="top">10 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Confusion </td><td align="center" styleCode="Rrule" valign="top">10 </td><td align="center" styleCode="Rrule" valign="top">7 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Somnolence </td><td align="center" styleCode="Rrule" valign="top">9 </td><td align="center" styleCode="Rrule" valign="top">6 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Dystonia </td><td align="center" styleCode="Rrule" valign="top">8 </td><td align="center" styleCode="Rrule" valign="top">7 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Gait abnormalities </td><td align="center" styleCode="Rrule" valign="top">7 </td><td align="center" styleCode="Rrule" valign="top">5 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Hypertonia </td><td align="center" styleCode="Rrule" valign="top">7 </td><td align="center" styleCode="Rrule" valign="top">6 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Amnesia </td><td align="center" styleCode="Rrule" valign="top">6 </td><td align="center" styleCode="Rrule" valign="top">4 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Akathisia </td><td align="center" styleCode="Rrule" valign="top">3 </td><td align="center" styleCode="Rrule" valign="top">2 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Thinking abnormalities </td><td align="center" styleCode="Rrule" valign="top">3 </td><td align="center" styleCode="Rrule" valign="top">2 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Paranoid reaction </td><td align="center" styleCode="Rrule" valign="top">2 </td><td align="center" styleCode="Rrule" valign="top">0 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Delusions </td><td align="center" styleCode="Rrule" valign="top">1 </td><td align="center" styleCode="Rrule" valign="top">0 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Sleep disorders </td><td align="center" styleCode="Rrule" valign="top">1 </td><td align="center" styleCode="Rrule" valign="top">0 </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Cardiovascular System</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Postural hypotension </td><td align="center" styleCode="Rrule" valign="top">53 </td><td align="center" styleCode="Rrule" valign="top">48 </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Body as a Whole</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Accidental injury </td><td align="center" styleCode="Rrule" valign="top">17 </td><td align="center" styleCode="Rrule" valign="top">15 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Asthenia </td><td align="center" styleCode="Rrule" valign="top">10 </td><td align="center" styleCode="Rrule" valign="top">8 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> General edema </td><td align="center" styleCode="Rrule" valign="top">4 </td><td align="center" styleCode="Rrule" valign="top">3 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Chest pain </td><td align="center" styleCode="Rrule" valign="top">3 </td><td align="center" styleCode="Rrule" valign="top">2 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Malaise </td><td align="center" styleCode="Rrule" valign="top">3 </td><td align="center" styleCode="Rrule" valign="top">2 </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Digestive System</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Constipation </td><td align="center" styleCode="Rrule" valign="top">10 </td><td align="center" styleCode="Rrule" valign="top">9 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Dry mouth </td><td align="center" styleCode="Rrule" valign="top">7 </td><td align="center" styleCode="Rrule" valign="top">3 </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Urogenital System</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Urinary frequency </td><td align="center" styleCode="Rrule" valign="top">6 </td><td align="center" styleCode="Rrule" valign="top">3 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Urinary tract infection </td><td align="center" styleCode="Rrule" valign="top">4 </td><td align="center" styleCode="Rrule" valign="top">3 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Urinary incontinence </td><td align="center" styleCode="Rrule" valign="top">2 </td><td align="center" styleCode="Rrule" valign="top">1 </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Respiratory System</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Dyspnea </td><td align="center" styleCode="Rrule" valign="top">4 </td><td align="center" styleCode="Rrule" valign="top">3 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Rhinitis </td><td align="center" styleCode="Rrule" valign="top">3 </td><td align="center" styleCode="Rrule" valign="top">1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Pneumonia </td><td align="center" styleCode="Rrule" valign="top">2 </td><td align="center" styleCode="Rrule" valign="top">0 </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Special Senses</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Accommodation abnormalities </td><td align="center" styleCode="Rrule" valign="top">4 </td><td align="center" styleCode="Rrule" valign="top">2 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Vision abnormalities </td><td align="center" styleCode="Rrule" valign="top">3 </td><td align="center" styleCode="Rrule" valign="top">1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Diplopia </td><td align="center" styleCode="Rrule" valign="top">1 </td><td align="center" styleCode="Rrule" valign="top">0 </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Musculoskeletal System</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Arthritis </td><td align="center" styleCode="Rrule" valign="top">3 </td><td align="center" styleCode="Rrule" valign="top">1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Twitching </td><td align="center" styleCode="Rrule" valign="top">2 </td><td align="center" styleCode="Rrule" valign="top">0 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Bursitis </td><td align="center" styleCode="Rrule" valign="top">2 </td><td align="center" styleCode="Rrule" valign="top">0 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Myasthenia </td><td align="center" styleCode="Rrule" valign="top">1 </td><td align="center" styleCode="Rrule" valign="top">0 </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Metabolic &amp; Nutritional System</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Peripheral edema </td><td align="center" styleCode="Rrule" valign="top">2 </td><td align="center" styleCode="Rrule" valign="top">1 </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Increased creatine PK </td><td align="center" styleCode="Rrule" valign="top">1 </td><td align="center" styleCode="Rrule" valign="top">0 </td></tr><tr styleCode="Botrule"><td colspan="3" styleCode="Lrule Rrule" valign="top"><content styleCode="bold">Skin &amp; Appendages</content> </td></tr><tr styleCode="Botrule"><td styleCode="Lrule Rrule" valign="top"> Skin disorders </td><td align="center" styleCode="Rrule" valign="top">2 </td><td align="center" styleCode="Rrule" valign="top">1 </td></tr></tbody></table>

<table><caption>Table 6 Adverse-Reactions in Pooled Double-Blind, Placebo-Controlled Trials with Pramipexole dihydrochloride tablets in Restless Legs Syndrome</caption><tbody><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Body System/Adverse Reaction </content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Pramipexole dihydrochloride tablets 0.125 - 0.75 mg/day </content><content styleCode="bold">tablets</content></paragraph><paragraph><content styleCode="bold">(N=575)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph><content styleCode="bold">Placebo</content></paragraph><paragraph><content styleCode="bold">(N=223)</content></paragraph><paragraph><content styleCode="bold">%</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal disorders</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>5</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Constipation</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dry mouth</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Nervous system disorders</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Headache</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>16</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>15</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Somnolence</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General disorders and administration site conditions</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Fatigue</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>9</paragraph></td><td align="center" styleCode="Rrule Lrule Toprule Botrule " valign="top"><paragraph>7</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Infections and infestations</content></paragraph></td><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/><td styleCode="Rrule Lrule Toprule Botrule " valign="top"/></tr><tr><td styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>Influenza</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule Toprule " valign="top"><paragraph>1</paragraph></td></tr></tbody></table>