Pramipexole Dihydrochloride

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) ] . Rhabdomyolysis [ see Warnings and Precautions (5.7) ] . Retinal Pathology [ see Warnings and Precautions (5.8) ] . Events Reported with Dopaminergic Therapy [ see Warnings and Precautions (5.9) ] . 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). To report SUSPECTED ADVERSE REACTIONS, contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatc h 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 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 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. Although 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. 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. Similar types of reactions were grouped into a smaller number of standardized categories using the MedDRA terminology: cardiac failure, inappropriate antidiuretic hormone secretion (SIADH), skin reactions (including erythema, rash, pruritus, urticaria), syncope, vomiting, and weight increase.

4 CONTRAINDICATIONS None. None (4)

11 DESCRIPTION Pramipexole dihydrochloride tablets contain pramipexole, a nonergot dopamine agonist. The chemical name of pramipexole dihydrochloride 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 is a white to off-white powder substance. Melting occurs in the range of 296°C to 301°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, for oral administration, contain 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, or 1.5 mg of pramipexole dihydrochloride monohydrate USP. Inactive ingredients consist of betacyclodextrin (betadex), corn starch, colloidal silicon dioxide, povidone, magnesium stearate and microcrystalline cellulose. Structure

2 DOSAGE AND ADMINISTRATION 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 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 1.5 4 0.75 three times a day 2.25 5 1 three times a day 3 6 1.25 three times a day 3.75 7 1.5 three times a day 4.5 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 Warnings and Precautions (5.9)].

1 INDICATIONS AND USAGE Pramipexole dihydrochloride tablets are non-ergot dopamine agonist indicated for the treatment of: · Parkinson’s disease (PD) (1.1) 1.1 Parkinson's Disease Pramipexole dihydrochloride tablets are indicated for the treatment of Parkinson’s disease.

10 OVERDOSAGE There is no clinical experience with significant overdosage. One patient took 11 mg/day of pramipexole for 2 days in a clinical trial for an investigational use. Blood pressure remained stable although pulse rate increased to between 100 and 120 beats/minute. No other adverse reactions were reported related to the increased dose. There is no known antidote for overdosage of a dopamine agonist. If signs of central nervous system stimulation are present, a phenothiazine or other butyrophenone neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of overdosage has not been assessed. Management of overdose may require general supportive measures along with gastric lavage, intravenous fluids, and electrocardiogram monitoring.

7 DRUG INTERACTIONS 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.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pramipexole is a non-ergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D 2 subfamily of dopamine receptors, binding with higher affinity to D 3 than to D 2 or D 4 receptor subtypes. Parkinson’s Disease The precise mechanism of action of pramipexole as a treatment for Parkinson’s disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum. The relevance of D 3 receptor binding in Parkinson’s disease is unknown. 12.2 Pharmacodynamics The effect of pramipexole on the QT interval of the ECG was investigated in a clinical study in 60 healthy male and female volunteers. All subjects initiated treatment with 0.375 mg extended release pramipexole tablets administered once daily, and were up-titrated every 3 days to 2.25 mg and 4.5 mg daily, a faster rate of titration than recommended in the label. No dose- or exposure-related effect on mean QT intervals was observed; however, the study did not have a valid assessment of assay sensitivity. The effect of pramipexole on QTc intervals at higher exposures achieved either due to drug interactions (e.g., with cimetidine), renal impairment, or at higher doses has not been systematically evaluated. Although mean values remained within normal reference ranges throughout the study, supine systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate for subjects treated with pramipexole generally increased during the rapid up-titration phase, by 10 mmHg, 7 mmHg, and 10 bpm higher than placebo, respectively. Higher SBP, DBP, and pulse rates compared to placebo were maintained until the pramipexole doses were tapered; values on the last day of tapering were generally similar to baseline values. Such effects have not been observed in clinical studies with Parkinson’s disease patients, who were titrated according to labeled recommendations. 12.3 Pharmacokinetics Pramipexole displays linear pharmacokinetics over the clinical dosage range. Its terminal half-life is about 8 hours in young healthy volunteers and about 12 hours in elderly volunteers. Steady-state concentrations are achieved within 2 days of dosing. Absorption Pramipexole is rapidly absorbed, reaching peak concentrations in approximately 2 hours. The absolute bioavailability of pramipexole is greater than 90%, indicating that it is well absorbed and undergoes little presystemic metabolism. Food does not affect the extent of pramipexole absorption, although the time of maximum plasma concentration (T max ) is increased by about 1 hour when the drug is taken with a meal. Distribution Pramipexole is extensively distributed, having a volume of distribution of about 500 L (coefficient of variation [CV]=20%). It is about 15% bound to plasma proteins. Pramipexole distributes into red blood cells as indicated by an erythrocyte-to-plasma ratio of approximately 2. Metabolism Pramipexole is metabolized only to a negligible extent (<10%). No specific active metabolite has been identified in human plasma or urine. Elimination Urinary excretion is the major route of pramipexole elimination, with 90% of a pramipexole dose recovered in urine, almost all as unchanged drug. The renal clearance of pramipexole is approximately 400 mL/min (CV=25%), approximately three times higher than the glomerular filtration rate. Thus, pramipexole is secreted by the renal tubules, probably by the organic cation transport system. Pharmacokinetics in Specific Populations Because therapy with pramipexole dihydrochloride tablets is initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight, race, or age is not necessary. However, renal insufficiency, which can cause a large decrease in the ability to eliminate pramipexole, may necessitate dosage adjustment [ see Dosage and Administration (2.2) ]. Gender Pramipexole clearance is about 30% lower in women than in men, but this difference can be accounted for by differences in body weight. There is no difference in half-life between males and females. Age Pramipexole clearance decreases with age as the half-life and clearance are about 40% longer and 30% lower, respectively, in elderly (aged 65 years or older) compared with young healthy volunteers (aged less than 40 years). This difference is most likely due to the reduction in renal function with age, since pramipexole clearance is correlated with renal function, as measured by creatinine clearance. Race No racial differences in metabolism and elimination have been identified. Parkinson’s Disease Patients A cross-study comparison of data suggests that the clearance of pramipexole may be reduced by about 30% in Parkinson’s disease patients compared with healthy elderly volunteers. The reason for this difference appears to be reduced renal function in Parkinson’s disease patients, which may be related to their poorer general health. The pharmacokinetics of pramipexole were comparable between early and advanced Parkinson’s disease patients. Hepatic Impairment The influence of hepatic insufficiency on pramipexole pharmacokinetics has not been evaluated. Because approximately 90% of the recovered dose is excreted in the urine as unchanged drug, hepatic impairment would not be expected to have a significant effect on pramipexole elimination. Renal Impairment Clearance of pramipexole was about 75% lower in patients with severe renal impairment (creatinine clearance approximately 20 mL/min) and about 60% lower in patients with moderate impairment (creatinine clearance approximately 40 mL/min) compared with healthy volunteers [ see Warnings and Precautions (5.6) and Dosage and Administration (2.2) ]. In patients with varying degrees of renal impairment, pramipexole clearance correlates well with creatinine clearance. Therefore, creatinine clearance can be used as a predictor of the extent of decrease in pramipexole clearance. Drug Interactions Carbidopa/levodopa: Carbidopa/levodopa did not influence the pharmacokinetics of pramipexole in healthy volunteers (N=10). Pramipexole did not alter the extent of absorption (AUC) or the elimination of carbidopa/levodopa, although it caused an increase in levodopa C max by about 40% and a decrease in T max from 2.5 to 0.5 hours. Selegiline: In healthy volunteers (N=11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analyses suggest that amantadine may slightly decrease the oral clearance of pramipexole. Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N=12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transporter, did not noticeably influence pramipexole pharmacokinetics (N=12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. Other known organic cation transport substrates and/or inhibitors (e.g., cisplatin and procainamide) may also decrease the clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro . Pramipexole does not inhibit CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 μM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the clinical dose of 4.5 mg/day (1.5 mg TID).

12.1 Mechanism of Action Pramipexole is a non-ergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D 2 subfamily of dopamine receptors, binding with higher affinity to D 3 than to D 2 or D 4 receptor subtypes. Parkinson’s Disease The precise mechanism of action of pramipexole as a treatment for Parkinson’s disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum. The relevance of D 3 receptor binding in Parkinson’s disease is unknown.

12.2 Pharmacodynamics The effect of pramipexole on the QT interval of the ECG was investigated in a clinical study in 60 healthy male and female volunteers. All subjects initiated treatment with 0.375 mg extended release pramipexole tablets administered once daily, and were up-titrated every 3 days to 2.25 mg and 4.5 mg daily, a faster rate of titration than recommended in the label. No dose- or exposure-related effect on mean QT intervals was observed; however, the study did not have a valid assessment of assay sensitivity. The effect of pramipexole on QTc intervals at higher exposures achieved either due to drug interactions (e.g., with cimetidine), renal impairment, or at higher doses has not been systematically evaluated. Although mean values remained within normal reference ranges throughout the study, supine systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate for subjects treated with pramipexole generally increased during the rapid up-titration phase, by 10 mmHg, 7 mmHg, and 10 bpm higher than placebo, respectively. Higher SBP, DBP, and pulse rates compared to placebo were maintained until the pramipexole doses were tapered; values on the last day of tapering were generally similar to baseline values. Such effects have not been observed in clinical studies with Parkinson’s disease patients, who were titrated according to labeled recommendations.

12.3 Pharmacokinetics Pramipexole displays linear pharmacokinetics over the clinical dosage range. Its terminal half-life is about 8 hours in young healthy volunteers and about 12 hours in elderly volunteers. Steady-state concentrations are achieved within 2 days of dosing. Absorption Pramipexole is rapidly absorbed, reaching peak concentrations in approximately 2 hours. The absolute bioavailability of pramipexole is greater than 90%, indicating that it is well absorbed and undergoes little presystemic metabolism. Food does not affect the extent of pramipexole absorption, although the time of maximum plasma concentration (T max ) is increased by about 1 hour when the drug is taken with a meal. Distribution Pramipexole is extensively distributed, having a volume of distribution of about 500 L (coefficient of variation [CV]=20%). It is about 15% bound to plasma proteins. Pramipexole distributes into red blood cells as indicated by an erythrocyte-to-plasma ratio of approximately 2. Metabolism Pramipexole is metabolized only to a negligible extent (<10%). No specific active metabolite has been identified in human plasma or urine. Elimination Urinary excretion is the major route of pramipexole elimination, with 90% of a pramipexole dose recovered in urine, almost all as unchanged drug. The renal clearance of pramipexole is approximately 400 mL/min (CV=25%), approximately three times higher than the glomerular filtration rate. Thus, pramipexole is secreted by the renal tubules, probably by the organic cation transport system. Pharmacokinetics in Specific Populations Because therapy with pramipexole dihydrochloride tablets is initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight, race, or age is not necessary. However, renal insufficiency, which can cause a large decrease in the ability to eliminate pramipexole, may necessitate dosage adjustment [ see Dosage and Administration (2.2) ]. Gender Pramipexole clearance is about 30% lower in women than in men, but this difference can be accounted for by differences in body weight. There is no difference in half-life between males and females. Age Pramipexole clearance decreases with age as the half-life and clearance are about 40% longer and 30% lower, respectively, in elderly (aged 65 years or older) compared with young healthy volunteers (aged less than 40 years). This difference is most likely due to the reduction in renal function with age, since pramipexole clearance is correlated with renal function, as measured by creatinine clearance. Race No racial differences in metabolism and elimination have been identified. Parkinson’s Disease Patients A cross-study comparison of data suggests that the clearance of pramipexole may be reduced by about 30% in Parkinson’s disease patients compared with healthy elderly volunteers. The reason for this difference appears to be reduced renal function in Parkinson’s disease patients, which may be related to their poorer general health. The pharmacokinetics of pramipexole were comparable between early and advanced Parkinson’s disease patients. Hepatic Impairment The influence of hepatic insufficiency on pramipexole pharmacokinetics has not been evaluated. Because approximately 90% of the recovered dose is excreted in the urine as unchanged drug, hepatic impairment would not be expected to have a significant effect on pramipexole elimination. Renal Impairment Clearance of pramipexole was about 75% lower in patients with severe renal impairment (creatinine clearance approximately 20 mL/min) and about 60% lower in patients with moderate impairment (creatinine clearance approximately 40 mL/min) compared with healthy volunteers [ see Warnings and Precautions (5.6) and Dosage and Administration (2.2) ]. In patients with varying degrees of renal impairment, pramipexole clearance correlates well with creatinine clearance. Therefore, creatinine clearance can be used as a predictor of the extent of decrease in pramipexole clearance. Drug Interactions Carbidopa/levodopa: Carbidopa/levodopa did not influence the pharmacokinetics of pramipexole in healthy volunteers (N=10). Pramipexole did not alter the extent of absorption (AUC) or the elimination of carbidopa/levodopa, although it caused an increase in levodopa C max by about 40% and a decrease in T max from 2.5 to 0.5 hours. Selegiline: In healthy volunteers (N=11), selegiline did not influence the pharmacokinetics of pramipexole. Amantadine: Population pharmacokinetic analyses suggest that amantadine may slightly decrease the oral clearance of pramipexole. Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N=12). Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transporter, did not noticeably influence pramipexole pharmacokinetics (N=12). Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. Other known organic cation transport substrates and/or inhibitors (e.g., cisplatin and procainamide) may also decrease the clearance of pramipexole. CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro . Pramipexole does not inhibit CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 μM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the clinical dose of 4.5 mg/day (1.5 mg TID).

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1

3 DOSAGE FORMS AND STRENGTHS 0.125 mg: White to off white, circular tablet debossed with “E” on one side and “33”on the other side. 0.25 mg: White to off white, oval shaped tablet with break line on both side and debossed with “E E” on one side and “34 34” on other side. 0.5 mg: White to off white, oval shaped tablet with break line on both side and debossed with “E E” on one side and “35 35” on other side. 1 mg: White to off white, circular tablet with break line on both side and debossed with “E E” on one side and “36 36” on other side. 1.5 mg: White to off white, circular tablet with break line on both side and debossed with “E E” on one side and “37 37” on other side. Tablets: 0.125 mg, 0.25 mg, 0.5 mg, 1 mg, and 1.5 mg (3).

Pramipexole Dihydrochloride Pramipexole Dihydrochloride PRAMIPEXOLE DIHYDROCHLORIDE PRAMIPEXOLE BETADEX STARCH, CORN SILICON DIOXIDE POVIDONE K30 CELLULOSE, MICROCRYSTALLINE MAGNESIUM STEARATE White to off white Circular E;33 Pramipexole Dihydrochloride Pramipexole Dihydrochloride PRAMIPEXOLE DIHYDROCHLORIDE PRAMIPEXOLE BETADEX STARCH, CORN SILICON DIOXIDE POVIDONE K30 CELLULOSE, MICROCRYSTALLINE MAGNESIUM STEARATE White to off white E;E;34;34 Pramipexole Dihydrochloride Pramipexole Dihydrochloride PRAMIPEXOLE DIHYDROCHLORIDE PRAMIPEXOLE BETADEX STARCH, CORN SILICON DIOXIDE POVIDONE K30 CELLULOSE, MICROCRYSTALLINE MAGNESIUM STEARATE White to off white E;E;35;35 Pramipexole Dihydrochloride Pramipexole Dihydrochloride PRAMIPEXOLE DIHYDROCHLORIDE PRAMIPEXOLE BETADEX STARCH, CORN SILICON DIOXIDE POVIDONE K30 CELLULOSE, MICROCRYSTALLINE MAGNESIUM STEARATE White to off white Circular E;E;36;36 Pramipexole Dihydrochloride Pramipexole Dihydrochloride PRAMIPEXOLE DIHYDROCHLORIDE PRAMIPEXOLE BETADEX STARCH, CORN SILICON DIOXIDE POVIDONE K30 CELLULOSE, MICROCRYSTALLINE MAGNESIUM STEARATE White to off white Circular E;E;37;37

13.2 Animal Toxicology and/or Pharmacology Retinal Pathology in Rats Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2-year carcinogenicity study with pramipexole. These findings were first observed during week 76 and were dose-dependent in animals receiving 2 or 8 mg/kg/day (plasma AUCs equal to 2.5 and 12.5 times that in humans at the MRHD). In a similar study of pigmented rats with 2 years exposure to pramipexole at 2 or 8 mg/kg/day, retinal degeneration was not observed. Animals given drug had thinning in the outer nuclear layer of the retina that was only slightly greater (by morphometric analysis) than that seen in control rats. Investigative studies demonstrated that pramipexole reduced the rate of disk shedding from the photoreceptor rod cells of the retina in albino rats, which was associated with enhanced sensitivity to the damaging effects of light. In a comparative study, degeneration and loss of photoreceptor cells occurred in albino rats after 13 weeks of treatment with 25 mg/kg/day of pramipexole (54 times the MRHD on a mg/m 2 basis) and constant light (100 lux) but not in pigmented rats exposed to the same dose and higher light intensities (500 lux). Thus, the retina of albino rats is considered to be uniquely sensitive to the damaging effects of pramipexole and light. Similar changes in the retina did not occur in a 2-year carcinogenicity study in albino mice treated with 0.3, 2, or 10 mg/kg/day (0.3, 2.2 and 11 times the MRHD on a mg/m 2 basis). Evaluation of the retinas of monkeys given 0.1, 0.5, or 2 mg/kg/day of pramipexole (0.4, 2.2, and 8.6 times the MRHD on a mg/m 2 basis) for 12 months and minipigs given 0.3, 1, or 5 mg/kg/day of pramipexole for 13 weeks also detected no 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. Fibro-osseous Proliferative Lesions in Mice An increased incidence of fibro-osseous proliferative lesions occurred in the femurs of female mice treated for 2 years with 0.3, 2, or 10 mg/kg/day (0.3, 2.2, and 11 times the MRHD on a mg/m 2 basis). Similar lesions were not observed in male mice or rats and monkeys of either sex that were treated chronically with pramipexole. The significance of this lesion to humans is not known.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies with pramipexole have been conducted in mice and rats. Pramipexole was administered in the diet to mice at doses up to 10 mg/kg/day (or approximately 10 times the maximum recommended human dose (MRHD) for Parkinson’s disease of 4.5 mg/day on a mg/m 2 basis). Pramipexole wasadministered in the diet to rats at doses up to 8 mg/kg/day. These doses were associated with plasma AUCs up to approximately 12 times that in humans at the MRHD. No significant increases in tumors occurred in either species. Pramipexole was not mutagenic or clastogenic in a battery of in vitro (bacterial reverse mutation, V79/HGPRT gene mutation, chromosomal aberration in CHO cells) and in vivo (mouse micronucleus) assays. In rat fertility studies, pramipexole at a dose of 2.5 mg/kg/day (5 times the MRHD on a mg/m 2 basis) prolonged estrus cycles and inhibited implantation. These effects were associated with reductions in serum levels of prolactin, a hormone necessary for implantation and maintenance of early pregnancy in rats.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Two-year carcinogenicity studies with pramipexole have been conducted in mice and rats. Pramipexole was administered in the diet to mice at doses up to 10 mg/kg/day (or approximately 10 times the maximum recommended human dose (MRHD) for Parkinson’s disease of 4.5 mg/day on a mg/m 2 basis). Pramipexole wasadministered in the diet to rats at doses up to 8 mg/kg/day. These doses were associated with plasma AUCs up to approximately 12 times that in humans at the MRHD. No significant increases in tumors occurred in either species. Pramipexole was not mutagenic or clastogenic in a battery of in vitro (bacterial reverse mutation, V79/HGPRT gene mutation, chromosomal aberration in CHO cells) and in vivo (mouse micronucleus) assays. In rat fertility studies, pramipexole at a dose of 2.5 mg/kg/day (5 times the MRHD on a mg/m 2 basis) prolonged estrus cycles and inhibited implantation. These effects were associated with reductions in serum levels of prolactin, a hormone necessary for implantation and maintenance of early pregnancy in rats. 13.2 Animal Toxicology and/or Pharmacology Retinal Pathology in Rats Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in the 2-year carcinogenicity study with pramipexole. These findings were first observed during week 76 and were dose-dependent in animals receiving 2 or 8 mg/kg/day (plasma AUCs equal to 2.5 and 12.5 times that in humans at the MRHD). In a similar study of pigmented rats with 2 years exposure to pramipexole at 2 or 8 mg/kg/day, retinal degeneration was not observed. Animals given drug had thinning in the outer nuclear layer of the retina that was only slightly greater (by morphometric analysis) than that seen in control rats. Investigative studies demonstrated that pramipexole reduced the rate of disk shedding from the photoreceptor rod cells of the retina in albino rats, which was associated with enhanced sensitivity to the damaging effects of light. In a comparative study, degeneration and loss of photoreceptor cells occurred in albino rats after 13 weeks of treatment with 25 mg/kg/day of pramipexole (54 times the MRHD on a mg/m 2 basis) and constant light (100 lux) but not in pigmented rats exposed to the same dose and higher light intensities (500 lux). Thus, the retina of albino rats is considered to be uniquely sensitive to the damaging effects of pramipexole and light. Similar changes in the retina did not occur in a 2-year carcinogenicity study in albino mice treated with 0.3, 2, or 10 mg/kg/day (0.3, 2.2 and 11 times the MRHD on a mg/m 2 basis). Evaluation of the retinas of monkeys given 0.1, 0.5, or 2 mg/kg/day of pramipexole (0.4, 2.2, and 8.6 times the MRHD on a mg/m 2 basis) for 12 months and minipigs given 0.3, 1, or 5 mg/kg/day of pramipexole for 13 weeks also detected no 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. Fibro-osseous Proliferative Lesions in Mice An increased incidence of fibro-osseous proliferative lesions occurred in the femurs of female mice treated for 2 years with 0.3, 2, or 10 mg/kg/day (0.3, 2.2, and 11 times the MRHD on a mg/m 2 basis). Similar lesions were not observed in male mice or rats and monkeys of either sex that were treated chronically with pramipexole. The significance of this lesion to humans is not known.

ANDA078894

Pramipexole Dihydrochloride

Pramipexole Dihydrochloride

46708-003

HUMAN PRESCRIPTION DRUG

ORAL

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - 0.125 mg Pramipexole Dihydrochloride Tablets 0.125 mg (90 Tablets in 1 Bottle) Each uncoated tablet contains : Pramipexole dihydrochloride monohydrate USP 0.125 mg 46708-003-90 90's bottle pack

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information). Dosing Instructions Instruct patients to take pramipexole dihydrochloride tablets only as prescribed. If a dose is missed, advise patients not to double their next dose. Pramipexole dihydrochloride tablets can be taken with or without food. If patients develop nausea, advise that taking pramipexole dihydrochloride tablets with food may reduce the occurrence of nausea. Pramipexole is the active ingredient that is in both pramipexole dihydrochloride tablets and extended-release pramipexole tablets. Ensure that patients do not take both extended-release pramipexole and pramipexole dihydrochloride tablets. Sedating Effects Alert patients to the potential sedating effects associated with pramipexole dihydrochloride tablets, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse reaction with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with pramipexole dihydrochloride tablets to gauge whether or not it affects their mental and/or motor performance adversely. Advise patients that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., conversations or eating) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Because of possible additive effects, advise caution when patients are taking other sedating medications or alcohol in combination with pramipexole dihydrochloride tablets and when taking concomitant medications that increase plasma levels of pramipexole (e.g., cimetidine) [ see Warnings and Precautions (5.1) ]. Impulse Control Symptoms Including Compulsive Behaviors Alert patients and their caregivers to the possibility that they may experience intense urges to spend money uncontrollably, intense urges to gamble, increased sexual urges, binge eating and/or other intense urges and the inability to control these urges while taking pramipexole dihydrochloride tablets [ see Warnings and Precautions (5.3) ]. Hallucinations and Psychotic-like Behavior Inform patients that hallucinations and other psychotic-like behavior can occur and that the elderly are at a higher risk than younger patients with Parkinson’s disease [ see Warnings and Precautions (5.4) ]. Postural (Orthostatic) Hypotension Advise patients that they may develop postural (orthostatic) hypotension, with or without symptoms such as dizziness, nausea, fainting or blackouts, and sometimes, sweating. Hypotension may occur more frequently during initial therapy. Accordingly, caution patients against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with pramipexole dihydrochloride tablets [ see Warnings and Precautions (5.2) ]. Pregnancy Because the teratogenic potential of pramipexole has not been completely established in laboratory animals, and because experience in humans is limited, advise women to notify their physicians if they become pregnant or intend to become pregnant during therapy [ see Use in Specific Populations (8.1) ]. Lactation Because of the possibility that pramipexole may be excreted in breast milk, advise women to notify their physicians if they intend to breast-feed or are breast-feeding an infant [ see Use in Specific Populations (8.2) ]. Manufactured by: Alembic Pharmaceuticals Limited (Formulation Division), Village Panelav, P. O. Tajpura, Near Baska, Taluka-Halol, Panchmahal, Gujarat, India. Revised: 07/2017

14 CLINICAL STUDIES 14.1 Parkinson's Disease The effectiveness of pramipexole dihydrochloride tablets in the treatment of Parkinson’s disease was evaluated in a multinational drug development program consisting of seven randomized, controlled trials. Three were conducted in patients with early Parkinson’s disease who were not receiving concomitant levodopa, and four were conducted in patients with advanced Parkinson’s disease who were receiving concomitant levodopa. Among these seven studies, three studies provide the most persuasive evidence of pramipexole's effectiveness in the management of patients with Parkinson’s disease who were and were not receiving concomitant levodopa. Two of these three trials enrolled patients with early Parkinson’s disease (not receiving levodopa), and one enrolled patients with advanced Parkinson’s disease who were receiving maximally tolerated doses of levodopa. In all studies, the Unified Parkinson’s Disease Rating Scale (UPDRS), or one or more of its subparts, served as the primary outcome assessment measure. The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (part I), Activities of Daily Living (ADL) (part II), motor performance (part III), and complications of therapy (part IV). Part II of the UPDRS contains 13 questions relating to ADL, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52. Part III of the UPDRS contains 27 questions (for 14 items) and is scored as described for part II. It is designed to assess the severity of the cardinal motor findings in patients with Parkinson’s disease (e.g., tremor, rigidity, bradykinesia, postural instability, etc.), scored for different body regions, and has a maximum (worst) score of 108. Studies in Patients with Early Parkinson's Disease Patients (N=599) in the two studies of early Parkinson’s disease had a mean disease duration of 2 years, limited or no prior exposure to levodopa (generally none in the preceding 6 months), and were not experiencing the "on-off" phenomenon and dyskinesia characteristic of later stages of the disease. One of the two early Parkinson’s disease studies (N=335) was a double-blind, placebo-controlled, parallel trial consisting of a 7-week dose-escalation period and a 6-month maintenance period. Patients could be on selegiline, anticholinergics, or both, but could not be on levodopa products or amantadine. Patients were randomized to pramipexole dihydrochloride tablets or placebo. Patients treated with pramipexole dihydrochloride tablets had a starting daily dose of 0.375 mg and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At the end of the 6-month maintenance period, the mean improvement from baseline on the UPDRS part II (ADL) total score was 1.9 in the group receiving pramipexole dihydrochloride tablets and -0.4 in the placebo group, a difference that was statistically significant. The mean improvement from baseline on the UPDRS part III total score was 5 in the group receiving pramipexole dihydrochloride tablets and -0.8 in the placebo group, a difference that was also statistically significant. A statistically significant difference between groups in favor of pramipexole dihydrochloride tablets was seen beginning at week 2 of the UPDRS part II (maximum dose 0.75 mg/day) and at week 3 of the UPDRS part III (maximum dose 1.5 mg/day). The second early Parkinson’s disease study (N=264) was a double-blind, placebo-controlled, parallel trial consisting of a 6-week dose-escalation period and a 4-week maintenance period. Patients could be on selegiline, anticholinergics, amantadine, or any combination of these, but could not be on levodopa products. Patients were randomized to 1 of 4 fixed doses of pramipexole dihydrochloride tablets (1.5 mg, 3 mg, 4.5 mg, or 6 mg per day) or placebo. At the end of the 4-week maintenance period, the mean improvement from baseline on the UPDRS part II total score was 1.8 in the patients treated with pramipexole dihydrochloride tablets, regardless of assigned dose group, and 0.3 in placebo-treated patients. The mean improvement from baseline on the UPDRS part III total score was 4.2 in patients treated with pramipexole dihydrochloride tablets and 0.6 in placebo-treated patients. No dose-response relationship was demonstrated. The between-treatment differences on both parts of the UPDRS were statistically significant in favor of pramipexole dihydrochloride tablets for all doses. No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race. Patients receiving selegiline or anticholinergics had responses similar to patients not receiving these drugs. Studies in Patients with Advanced Parkinson's Disease In the advanced Parkinson’s disease study, the primary assessments were the UPDRS and daily diaries that quantified amounts of “on” and “off” time. Patients in the advanced Parkinson’s disease study (N=360) had a mean disease duration of 9 years, had been exposed to levodopa for long periods of time (mean 8 years), used concomitant levodopa during the trial, and had “on-off” periods. The advanced Parkinson’s disease study was a double-blind, placebo-controlled, parallel trial consisting of a 7-week dose-escalation period and a 6-month maintenance period. Patients were all treated with concomitant levodopa products and could additionally be on concomitant selegiline, anticholinergics, amantadine, or any combination. Patients treated with pramipexole dihydrochloride tablets had a starting dose of 0.375 mg/day and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At selected times during the 6-month maintenance period, patients were asked to record the amount of “off,” “on, “or” on with dyskinesia” time per day for several sequential days. At the end of the 6-month maintenance period, the mean improvement from baseline on the UPDRS part II total score was 2.7 in the group treated with pramipexole dihydrochloride tablets and 0.5 in the placebo group, a difference that was statistically significant. The mean improvement from baseline on the UPDRS part III total score was 5.6 in the group treated with pramipexole dihydrochloride tablets and 2.8 in the placebo group, a difference that was statistically significant. A statistically significant difference between groups in favor of pramipexole dihydrochloride tablets was seen at week 3 of the UPDRS part II (maximum dose 1.5 mg/day) and at week 2 of the UPDRS part III (maximum dose 0.75 mg/day). Dosage reduction of levodopa was allowed during this study if dyskinesia (or hallucinations) developed; levodopa dosage reduction occurred in 76% of patients treated with pramipexole dihydrochloride tablets versus 54% of placebo patients. On average, the levodopa dose was reduced 27%. The mean number of "off" hours per day during baseline was 6 hours for both treatment groups. Throughout the trial, patients treated with pramipexole dihydrochloride tablets had a mean of 4 "off" hours per day, while placebo-treated patients continued to experience 6 "off" hours per day. No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race.

8.5 Geriatric Use Pramipexole total oral clearance is approximately 30% lower in subjects older than 65 years compared with younger subjects, because of a decline in pramipexole renal clearance due to an age-related reduction in renal function. This resulted in an increase in elimination half-life from approximately 8.5 hours to 12 hours. In clinical studies with Parkinson’s disease patients, 38.7% of patients were older than 65 years. There were no apparent differences in efficacy or safety between older and younger patients, except that the relative risk of hallucination associated with the use of pramipexole dihydrochloride tablets was increased in the elderly.

8.2 Lactation Risk Summary There are no data on the presence of pramipexole in human milk, the effects of pramipexole on the breastfed infant, or the effects of pramipexole on milk production. However, inhibition of lactation is expected because pramipexole inhibits secretion of prolactin in humans. Pramipexole or metabolites, or both, are present in rat milk [see Data] . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for pramipexole dihydrochloride tablets and any potential adverse effects on the breastfed infant from pramipexole dihydrochloride tablets or from the underlying maternal condition. Data In a study of radio-labeled pramipexole, pramipexole or metabolites, or both, were present in rat milk at concentrations three to six times higher than those in maternal plasma.

8.4 Pediatric Use Safety and effectiveness of pramipexole dihydrochloride tablets in pediatric patients has not been established.

8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate data on the developmental risk associated with the use of pramipexole dihydrochloride tablets in pregnant women. No adverse developmental effects were observed in animal studies in which pramipexole was administered to rabbits during pregnancy. Effects on embryofetal development could not be adequately assessed in pregnant rats; however, postnatal growth was inhibited at clinically relevant exposures [see Data]. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Oral administration of pramipexole (0.1, 0.5, or 1.5 mg/kg/day) to pregnant rats during the period of organogenesis resulted in a high incidence of total resorption of embryos at the highest dose tested. This increase in embryolethality is thought to result from the prolactin-lowering effect of pramipexole; prolactin is necessary for implantation and maintenance of early pregnancy in rats but not rabbits or humans. Because of pregnancy disruption and early embryonic loss in this study, the teratogenic potential of pramipexole could not be adequately assessed in rats. The highest no-effect dose for embryolethality in rats was associated with maternal plasma drug exposures (AUC) approximately equal to those in humans receiving the maximum recommended human dose (MRHD) of 4.5 mg/day. There were no adverse effects on embryo-fetal development following oral administration of pramipexole (0.1, 1, and 10 mg/kg/day) to pregnant rabbits during organogenesis (plasma AUC up to approximately 70 times that in humans at the MRHD). Postnatal growth was inhibited in the offspring of rats treated with pramipexole (0.1, 0.5, or 1.5 mg/kg/day) during the latter part of pregnancy and throughout lactation. The no-effect dose for adverse effects on offspring growth (0.1 mg/kg/day) was associated with maternal plasma drug exposures lower than that in humans at the MRHD.

8 USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data, may cause fetal harm (8.1). 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate data on the developmental risk associated with the use of pramipexole dihydrochloride tablets in pregnant women. No adverse developmental effects were observed in animal studies in which pramipexole was administered to rabbits during pregnancy. Effects on embryofetal development could not be adequately assessed in pregnant rats; however, postnatal growth was inhibited at clinically relevant exposures [see Data]. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Data Animal Data Oral administration of pramipexole (0.1, 0.5, or 1.5 mg/kg/day) to pregnant rats during the period of organogenesis resulted in a high incidence of total resorption of embryos at the highest dose tested. This increase in embryolethality is thought to result from the prolactin-lowering effect of pramipexole; prolactin is necessary for implantation and maintenance of early pregnancy in rats but not rabbits or humans. Because of pregnancy disruption and early embryonic loss in this study, the teratogenic potential of pramipexole could not be adequately assessed in rats. The highest no-effect dose for embryolethality in rats was associated with maternal plasma drug exposures (AUC) approximately equal to those in humans receiving the maximum recommended human dose (MRHD) of 4.5 mg/day. There were no adverse effects on embryo-fetal development following oral administration of pramipexole (0.1, 1, and 10 mg/kg/day) to pregnant rabbits during organogenesis (plasma AUC up to approximately 70 times that in humans at the MRHD). Postnatal growth was inhibited in the offspring of rats treated with pramipexole (0.1, 0.5, or 1.5 mg/kg/day) during the latter part of pregnancy and throughout lactation. The no-effect dose for adverse effects on offspring growth (0.1 mg/kg/day) was associated with maternal plasma drug exposures lower than that in humans at the MRHD. 8.2 Lactation Risk Summary There are no data on the presence of pramipexole in human milk, the effects of pramipexole on the breastfed infant, or the effects of pramipexole on milk production. However, inhibition of lactation is expected because pramipexole inhibits secretion of prolactin in humans. Pramipexole or metabolites, or both, are present in rat milk [see Data] . The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for pramipexole dihydrochloride tablets and any potential adverse effects on the breastfed infant from pramipexole dihydrochloride tablets or from the underlying maternal condition. Data In a study of radio-labeled pramipexole, pramipexole or metabolites, or both, were present in rat milk at concentrations three to six times higher than those in maternal plasma. 8.4 Pediatric Use Safety and effectiveness of pramipexole dihydrochloride tablets in pediatric patients has not been established. 8.5 Geriatric Use Pramipexole total oral clearance is approximately 30% lower in subjects older than 65 years compared with younger subjects, because of a decline in pramipexole renal clearance due to an age-related reduction in renal function. This resulted in an increase in elimination half-life from approximately 8.5 hours to 12 hours. In clinical studies with Parkinson’s disease patients, 38.7% of patients were older than 65 years. There were no apparent differences in efficacy or safety between older and younger patients, except that the relative risk of hallucination associated with the use of pramipexole dihydrochloride tablets was increased in the elderly. 8.6 Renal Impairment The elimination of pramipexole is dependent on renal function. Pramipexole clearance is extremely low in dialysis patients, as a negligible amount of pramipexole is removed by dialysis. Caution should be exercised when administering pramipexole dihydrochloride tablets to patients with renal disease [ see Dosage and Administration (2.2), Warnings and Precautions (5.6), and Clinical Pharmacology (12.3) ].

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Pramipexole dihydrochloride tablets are available as follows: 0.125 mg: White to off white, circular tablet debossed with “E” on one side and “33” on the other side. Bottles of 90 NDC 46708-003-90 0.25 mg: White to off white, oval shaped tablet with break line on both side and debossed with “E E” on one side and “34 34” on other side. Bottles of 90 NDC 46708-004-90 0.5 mg: White to off white, oval shaped tablet with break line on both side and debossed with “E E” on one side and “35 35” on other side. Bottles of 90 NDC 46708-005-90 1 mg: White to off white, circular tablet with break line on both side and debossed with “E E” on one side and “36 36” on other side. Bottles of 90 NDC 46708-006-90 1.5 mg: White to off white, circular tablet with break line on both side and debossed with “E E” on one side and “37 37” on other side. Bottles of 90 NDC 46708-007-90 16.2 Storage and Handling Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP Controlled Room Temperature]. Protect from light. Store in a safe place out of the reach of children.