PRAMIPEXOLE DIHYDROCHLORIDE

Pramipexole dihydrochloride tablets contain pramipexole dihydrochloride. Pramipexole is a nonergot dopamine agonist. The chemical name of pramipexole dihydrochloride monohydrate is ( S )-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole dihydrochloride monohydrate. Its empirical formula is C 10 H 17 N 3 S·2HCl·H 2 O, and its molecular weight is 302.26. The structural formula is: Pramipexole dihydrochloride USP is a white or almost white, crystalline powder. Melting occurs above 280°C, with decomposition. Pramipexole dihydrochloride is more than 20% soluble in water, about 8% in methanol, about 0.5% in ethanol, and practically insoluble in dichloromethane. Pramipexole dihydrochloride tablets 0.125 mg: Each tablet contains 0.125 mg pramipexole dihydrochloride USP. Pramipexole dihydrochloride tablets 0.25 mg: Each tablet contains 0.25 mg pramipexole dihydrochloride USP. Pramipexole dihydrochloride tablets 0.5 mg: Each tablet contains 0.5 mg pramipexole dihydrochloride USP. Pramipexole dihydrochloride tablets 0.75 mg: Each tablet contains 0.75 mg pramipexole dihydrochloride USP. Pramipexole dihydrochloride tablets 1 mg: Each tablet contains 1 mg pramipexole dihydrochloride USP. Pramipexole dihydrochloride tablets 1.5 mg: Each tablet contains 1.5 mg pramipexole dihydrochloride USP. Inactive ingredients for all strengths of Pramipexole dihydrochloride tablets consist of silicified microcrystalline cellulose, croscarmellose sodium and magnesium stearate. Chemical Structure

Pramipexole dihydrochloride is a non-ergot dopamine agonist indicated for the treatment of: Parkinson's disease (PD) ( 1.1 ) Moderate-to-severe primary Restless Legs Syndrome (RLS) ( 1.2 ) 1.1 Parkinson's Disease Pramipexole dihydrochloride tablets are indicated for the treatment of Parkinson's disease. 1.2 Restless Legs Syndrome Pramipexole dihydrochloride tablets are indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS).

Parkinson's Disease-Normal Renal Function * (2.2) Week Dosage (mg) Total Daily Dose (mg) 1 0.125 TID 0.375 2 0.25 TID 0.75 3 0.5 TID 1.5 4 0.75 TID 2.25 5 1 TID 3 6 1.25 TID 3.75 7 1.5 TID 4.5 * Doses should not be increased more frequently than every 5 to 7 days. Titrate to effective dose. If used with levodopa, may need to reduce levodopa dose Parkinson's Disease-Impaired Renal Function (2.2) Creatinine Clearance Starting Dose (mg) Maximum Dose (mg) > 50 mL/min 0.125 TID 1.5 TID 30 to 50 mL/min 0.125 BID 0.75 TID 15 to 30 mL/min 0.125 QD 1.5 QD < 15 mL/min and hemodialysis patients Data not available Restless Legs Syndrome* (2.3) Titration Step Dose (mg) 2-3 hours before bedtime 1 0.125 2 (if needed) 0.25 3 (if needed) 0.5 * Dosing interval is 4-7 days (14 days in patients with CrCl 20-60 mL/min) 2.1 General Dosing Considerations Pramipexole dihydrochloride tablets are taken orally, with or without food. If a significant interruption in therapy with pramipexole dihydrochloride tablets has occurred, re-titration of therapy may be warranted. 2.2 Dosing for Parkinson's Disease In all clinical studies, dosage was initiated at a subtherapeutic level to avoid intolerable adverse effects and orthostatic hypotension. Pramipexole dihydrochloride tablets should be titrated gradually in all patients. The dose should be increased to achieve a maximum therapeutic effect, balanced against the principal side effects of dyskinesia, hallucinations, somnolence, and dry mouth. Dosing in Patients with Normal Renal Function Initial Treatment Doses should be increased gradually from a starting dose of 0.375 mg/day given in three divided doses and should not be increased more frequently than every 5 to 7 days. A suggested ascending dosage schedule that was used in clinical studies is shown in Table 1: Table 1. Ascending Dosage Schedule of Pramipexole Dihydrochloride Tablets for Parkinson's Disease Week Dosage (mg) Total Daily Dose (mg) 1 0.125 three times a day 0.375 2 0.25 three times a day 0.75 3 0.5 three times a day 1.50 4 0.75 three times a day 2.25 5 1 three times a day 3.0 6 1.25 three times a day 3.75 7 1.5 three times a day 4.50 Maintenance Treatment Pramipexole dihydrochloride tablets were effective and well tolerated over a dosage range of 1.5 to 4.5 mg/day administered in equally divided doses three times per day with or without concomitant levodopa (approximately 800 mg/day). In a fixed-dose study in early Parkinson's disease patients, doses of 3 mg, 4.5 mg, and 6 mg per day of pramipexole dihydrochloride tablets were not shown to provide any significant benefit beyond that achieved at a daily dose of 1.5 mg/day. However, in the same fixed-dose study, the following adverse events were dose related: postural hypotension, nausea, constipation, somnolence, and amnesia. The frequency of these events was generally 2-fold greater than placebo for pramipexole doses greater than 3 mg/day. The incidence of somnolence reported with pramipexole at a dose of 1.5 mg/day was comparable to placebo. When pramipexole dihydrochloride tablets are used in combination with levodopa, a reduction of the levodopa dosage should be considered. In a controlled study in advanced Parkinson's disease, the dosage of levodopa was reduced by an average of 27% from baseline. Dosing in Patients with Renal Impairment The recommended dosing of pramipexole dihydrochloride tablets in Parkinson's disease patients with renal impairment is provided in Table 2. Table 2. Dosing of Pramipexole Dihydrochloride Tablets in Parkinson's Disease Patients with Renal Impairment Renal Status Starting Dose (mg) Maximum Dose (mg) Normal to mild impairment (creatinine Cl > 50 mL/min) 0.125 three times a day 1.5 three times a day Moderate impairment (creatinine Cl = 30 to 50 mL/min) 0.125 twice a day 0.75 three times a day Severe impairment (creatinine Cl = 15 to < 30 mL/min) 0.125 once a day 1.5 once a day Very severe impairment (creatinine Cl < 15 mL/min and hemodialysis patients) The use of pramipexole dihydrochloride tablets has not been adequately studied in this group of patients. Discontinuation of Treatment Pramipexole dihydrochloride tablets may be tapered off at a rate of 0.75 mg per day until the daily dose has been reduced to 0.75 mg. Thereafter, the dose may be reduced by 0.375 mg per day [see 5.10 , 5.11 ]. 2.3 Dosing for Restless Legs Syndrome The recommended starting dose of Pramipexole dihydrochloride tablets is 0.125 mg taken once daily 2-3 hours before bedtime. For patients requiring additional symptomatic relief, the dose may be increased every 4-7 days (Table 3). Although the dose of Pramipexole dihydrochloride tablets was increased to 0.75 mg in some patients during long-term open-label treatment, there is no evidence that the 0.75 mg dose provides additional benefit beyond the 0.5 mg dose. Table 3 Ascending Dosage Schedule of Pramipexole dihydrochloride tablets for RLS Titration Step Duration Dose (mg) to be taken once daily, 2-3 hours before bedtime 1 4-7 days 0.125 2* 4-7 days 0.25 3* 4-7 days 0.5 * if needed Dosing in Patients with Renal Impairment The duration between titration steps should be increased to 14 days in RLS patients with moderate and severe renal impairment (creatinine clearance 20-60 ml/min) [see Clinical Pharmacology (12.3) ] . Discontinuation of Treatment In clinical trials of patients being treated for RLS with doses up to 0.75 mg once daily, Pramipexole dihydrochloride tablets were discontinued without a taper. In a 26 week placebo-controlled clinical trial, patients reported a worsening of RLS symptom severity as compared to their untreated baseline when Pramipexole dihydrochloride tablets treatment was suddenly withdrawn [see Warnings and Precautions (5.10) ].

None None.

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 Unichem Pharmaceuticals (USA), Inc., at 1-866-562-4616 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 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 events. 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 3 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 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 treatment-emergent events 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 † 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 0.25 mg (N=88) % Pramipexole Dihydrochloride 0.5 mg (N=80) % Pramipexole Dihydrochloride 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 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 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)

Dopamine antagonists: May diminish the effectiveness of pramipexole ( 7.1 ). 7.1 Dopamine Antagonists Since pramipexole is a dopamine agonist, it is possible that dopamine antagonists, such as the neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide, may diminish the effectiveness of pramipexole dihydrochloride tablets.