PRAMIPEXOLE DIHYDROCHLORIDE- pramipexole dihydrochloride_tablet

Pramipexole is a non-ergot dopamine agonist with high relative in vitro 2 3 2 4 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 Restless Legs Syndrome (RLS) The precise mechanism of action of pramipexole dihydrochloride tablets as a treatment for RLS is unknown. Although the pathophysiology of RLS is largely unknown, neuropharmacological evidence suggests primary dopaminergic system involvement. Positron Emission Tomographic (PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction may be involved in the pathogenesis of RLS. 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. , 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. 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 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. Restless Legs Syndrome Patients A cross-study comparison of data suggests that the pharmacokinetic profile of pramipexole administered once daily in RLS patients is similar to the pharmacokinetic profile of pramipexole in healthy volunteers. 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. 2 Drug Interactions Carbidopa/levodopa: max max Selegiline: Amantadine Cimetidine: Probenecid: Other drugs eliminated via renal secretion: CYP interactions in vivo in vitro.

Pramipexole dihydrochloride tablets are a non-ergot dopamine agonist indicated for the treatment of: 1. 2 Pramipexole dihydrochloride tablets are indicated for the treatment of Parkinson's disease. 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. 25 5 1 TID 3 6 1. 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. 5 TID 30 to 50 mL/min 0. 75 TID 15 to 30 mL/min 0. 5 QD < 15 mL/min and hemodialysis patients Data not available Restless Legs Syndrome* ( 2. 3 Titration Step Dose (mg) 2 to 3 hours before bedtime 1 0. 125 2 (if needed) 0. 25 3 (if needed) 0. 5 * Dosing interval is 4 to 7 days (14 days in patients with CrCl 20 to 60 mL/min) 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. 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. 25 three times a day 0. 5 three times a day 1. 75 three times a day 2. 25 5 1 three times a day 3 6 1. 25 three times a day 3. 5 three times a day 4. 50 Maintenance Treatment Pramipexole dihydrochloride tablets were effective and well tolerated over a dosage range of 1. 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. 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. Thereafter, the dose may be reduced by 0. 375 mg per day [see Warnings and Precautions ( 5. 11 The recommended starting dose of pramipexole dihydrochloride tablets is 0. 125 mg taken once daily 2 to 3 hours before bedtime. For patients requiring additional symptomatic relief, the dose may be increased every 4 to 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. Table 3 Ascending Dosage Schedule of Pramipexole Dihydrochloride Tablets for RLS Titration Step Duration Dose (mg) to be taken once daily, 2 to 3 hours before bedtime 1 4 to 7 days 0. 125 2* 4 to 7 days 0. 25 3* 4 to 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 to 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 treatment was suddenly withdrawn [ see Warnings and Precautions ( 5.

The following adverse reactions are discussed in greater detail in other sections of the labeling: see Warnings and Precautions ( 5. 1 see Warnings and Precautions ( 5. 2 see Warnings and Precautions ( 5. 3 see Warnings and Precautions ( 5. 4 see Warnings and Precautions ( 5. 5 see Warnings and Precautions ( 5. 6 see Warnings and Precautions ( 5. 8 see Warnings and Precautions ( 5. 9 see Warnings and Precautions ( Error! Hyperlink reference not valid. ) see Warnings and Precautions ( 5. 11 Most common adverse reactions (incidence >5% and greater than placebo): 6. 1 To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc. , USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www. gov/medwatch. 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. 4% on placebo]). Adverse-reaction Incidence in Controlled Clinical Studies in Early Parkinson's Disease: Table 4 Adverse-Reactions in Pooled Double-Blind, Placebo-Controlled Trials with Pramipexole Dihydrochloride in Early Parkinson’s Disease Body System/Adverse Reaction Pramipexole Dihydrochloride (N=388) % Placebo (N=235) % Nervous System 25 24 22 9 17 12 9 3 4 1 4 2 3 1 2 1 2 0 2 0 1 0 1 0 Digestive System 28 18 14 6 4 2 2 0 Body as a Whole 14 12 5 3 2 1 2 1 1 0 Metabolic & Nutritional System 5 4 2 0 Special Senses 3 0 Urogenital System 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 Adverse-Reactions in Pooled Double-Blind, Placebo-Controlled Trials with Pramipexole Dihydrochloride in Advanced Parkinson’s Disease Body System/Adverse Reaction Pramipexole Dihydrochloride (N=260) % Placebo (N=264) % Nervous System 47 31 28 26 27 22 26 25 17 4 11 10 10 7 9 6 8 7 7 5 7 6 6 4 3 2 3 2 2 0 1 0 1 0 Cardiovascular System 53 48 Body as a Whole 17 15 10 8 4 3 3 2 3 2 Digestive System 10 9 7 3 Urogenital System 6 3 4 3 2 1 Respiratory System 4 3 3 1 2 0 Special Senses 4 2 3 1 1 0 Musculoskeletal System 3 1 2 0 2 0 1 0 Metabolic & Nutritional System 2 1 1 0 Skin & Appendages 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 in Restless Legs Syndrome Body System/Adverse Reaction Pramipexole Dihydrochloride 0. 75 mg/day (N=575) % Placebo (N=223) % Gastrointestinal disorders 16 5 4 1 3 1 3 1 Nervous system disorders 16 15 6 3 General disorders and administration site conditions 9 7 Infections and infestations 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 11 19 27 5 3 1 7 0 3 1 4 7 Psychiatric disorders 9 9 13 9 2 1 8 2 General disorders and administration site conditions 3 5 7 5 Musculoskeletal and connective tissue disorders 3 3 7 1 Infections and infestations 1 4 7 1 Respiratory, thoracic and mediastinal disorders 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. 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: Gastrointestinal Disorders: General Disorders and Administration Site Conditions Warnings and Precautions ( 5. 11 Metabolism and Nutrition Disorders: Musculoskeletal and Connective Tissue Disorders: see Warnings and Precautions ( 5. 6 Nervous System Disorders: Skin and Subcutaneous Tissue Disorders:.

Pregnancy: Based on animal data, may cause fetal harm ( 8. 1 Risk Summary There are no adequate data on the developmental risk associated with the use of pramipexole dihydrochloride 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. 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. 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 in 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. There were no adverse effects on embryo-fetal development following oral administration of pramipexole (0. 1, 1, or 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. 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. 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 and any potential adverse effects on the breastfed infant from pramipexole dihydrochloride 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. Safety and effectiveness of pramipexole dihydrochloride in pediatric patients has not been established. 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. In clinical studies with RLS patients, 22% of patients were at least 65 years old. There were no apparent differences in efficacy or safety between older and younger patients. 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.

Dopamine antagonists: May diminish the effectiveness of pramipexole ( 7. 1 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.

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.
NONCLINICAL TOXICOLOGY
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 Pramipexole was not mutagenic or clastogenic in a battery of in vitro in vivo In rat fertility studies, pramipexole at a dose of 2. 5 mg/kg/day (5 times the MRHD on a mg/m 2 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 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. I 2 2 2 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. , 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. 2, and 11 times the MRHD on a mg/m 2.
CLINICAL STUDIES
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. , 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. 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. 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. 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. The efficacy of pramipexole dihydrochloride tablets in the treatment of RLS was evaluated in a multinational drug development program consisting of 4 randomized, double-blind, placebo-controlled trials. This program included approximately 1000 patients with moderate to severe RLS; patients with RLS secondary to other conditions (e. , pregnancy, renal failure, and anemia) were excluded. All patients were administered pramipexole dihydrochloride tablets (0. 75 mg) or placebo once daily 2 to 3 hours before going to bed. Across the 4 studies, the mean duration of RLS was 4. 6 years (range of 0 to 56 years), mean age was approximately 55 years (range of 18 to 81 years), and approximately 66. 6% were women. Key diagnostic criteria for RLS are: an urge to move the legs usually accompanied or caused by uncomfortable and unpleasant leg sensations; symptoms begin or worsen during periods of rest or inactivity such as lying or sitting; symptoms are partially or totally relieved by movement such as walking or stretching at least as long as the activity continues; and symptoms are worse or occur only in the evening or night. Difficulty falling asleep may frequently be associated with symptoms of RLS. The two outcome measures used to assess the effect of treatment were the International RLS Rating Scale (IRLS Scale) and a Clinical Global Impression-Improvement (CGI-I) assessment. The IRLS Scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. The CGI-I is designed to assess clinical progress (global improvement) on a 7-point scale. In Study 1, fixed doses of pramipexole dihydrochloride tablets were compared to placebo in a study of 12 weeks duration. A total of 344 patients were randomized equally to the 4 treatment groups. Patients treated with pramipexole dihydrochloride tablets (n=254) had a starting dose of 0. 125 mg/day and were titrated to one of the three randomized doses (0. 75 mg/day) in the first three weeks of the study. The mean improvement from baseline on the IRLS Scale total score and the percentage of CGI-I responders for each of the pramipexole dihydrochloride tablets treatment groups compared to placebo are summarized in Table 8. All treatment groups reached statistically significant superiority compared to placebo for both endpoints. There was no clear evidence of a dose-response across the 3 randomized dose groups. Table 8 Mean Changes from Baseline to Week 12 in IRLS Score and CGI-I (Study 1) Pramipexole Dihydrochloride 0. 25 mg Pramipexole Dihydrochloride 0. 5 mg Pramipexole Dihydrochloride 0. 75 mg Pramipexole Dihydrochloride Total Placebo No. Patients 88 79 87 254 85 IRLS score -13. 4 CGI-I responders* 74. 2% *CGI-I responders = “much improved” and “very much improved” Study 2 was a randomized-withdrawal study, designed to demonstrate the sustained efficacy of pramipexole for treatment of RLS after a period of six months. RLS patients who responded to pramipexole dihydrochloride tablets treatment in a preceding 6-month open-label treatment phase (defined as having a CGI-I rating of “very much improved” or “much improved” compared to baseline and an IRLS score of 15 or below) were randomized to receive either continued active treatment (n=78) or placebo (n=69) for 12 weeks. The primary endpoint of this study was time to treatment failure, defined as any worsening on the CGI-I score along with an IRLS Scale total score above 15. In patients who had responded to 6-month open label treatment with pramipexole dihydrochloride tablets, the administration of placebo led to a rapid decline in their overall conditions and return of their RLS symptoms. At the end of the 12-week observation period, 85% of patients treated with placebo had failed treatment, compared to 21% treated with blinded pramipexole, a difference that was highly statistically significant. The majority of treatment failures occurred within 10 days of randomization. For the patients randomized, the distribution of doses was: 7 on 0. 125 mg, 44 on 0. 25 mg, 47 on 0. 5 mg, and 49 on 0. Study 3 was a 6-week study, comparing a flexible dose of pramipexole dihydrochloride tablets to placebo. In this study, 345 patients were randomized in a 2:1 ratio to pramipexole dihydrochloride tablets or placebo. The mean improvement from baseline on the IRLS Scale total score was -12 for pramipexole dihydrochloride-treated patients and -6 for placebo-treated patients. The percentage of CGI-I responders was 63% for pramipexole dihydrochloride-treated patients and 32% for placebo-treated patients. The between-group differences were statistically significant for both outcome measures. For the patients randomized to pramipexole dihydrochloride tablets, the distribution of achieved doses was: 35 on 0. 125 mg, 51 on 0. 25 mg, 65 on 0. 5 mg, and 69 on 0. Study 4 was a 3-week study, comparing 4 fixed doses of pramipexole dihydrochloride tablets, 0. 5 mg, and 0. 75 mg, to placebo. Approximately 20 patients were randomized to each of the 5 dose groups. The mean improvement from baseline on the IRLS Scale total score and the percentage of CGI-I responders for each of the pramipexole dihydrochloride tablets treatment groups compared to placebo are summarized in Table 9. In this study, the 0. 125 mg dose group was not significantly different from placebo. On average, the 0. 5 mg dose group performed better than the 0. 25 mg dose group, but there was no difference between the 0. 75 mg dose groups. Table 9 Mean Changes from Baseline to Week 3 in IRLS Score and CGI-I (Study 4) Pramipexole Dihydrochloride 0. 125 mg Pramipexole Dihydrochloride 0. Patients 21 22 22 21 86 21 IRLS score -11. 2 CGI-I responders* 61. 9% *CGI-I responders = “much improved” and “very much improved” No differences in effectiveness based on age or gender were detected.
PATIENT INFORMATION
Pramipexole Dihydrochloride (PRAM-i-PEX-ole dye-HYE-droe-KLOR-ide) Tablets Read this Patient Information before you start taking pramipexole dihydrochloride tablets and each time you get a refill. There may be new information. This information does not take the place of talking with your doctor about your medical condition or your treatment. What are pramipexole dihydrochloride tablets? Pramipexole dihydrochloride tablets are a prescription medicine used to treat: It is not known if pramipexole dihydrochloride tablets are safe and effective in children. What should I tell my doctor before taking pramipexole dihydrochloride tablets? Before taking pramipexole dihydrochloride tablets, tell your doctor if you: Tell your doctor about all the medicines you take, including The combination of pramipexole dihydrochloride tablets and other medicines may affect each other and may cause side effects. Pramipexole dihydrochloride tablets may affect the way other medicines work, and other medicines may affect how pramipexole dihydrochloride tablets works. Especially tell your doctor if you take: Ask your doctor for a list of these medicines if you are not sure. Know the medicines you take. Keep a list of them and show it to your doctor and pharmacist when you get a new medicine. How should I take pramipexole dihydrochloride tablets? do not double your next dose Do not What are the possible side effects of ? What should I avoid while taking pramipexole dihydrochloride tablets? What are the possible side effects of pramipexole dihydrochloride tablets? Pramipexole dihydrochloride tablets may cause serious side effects, including: falling asleep during normal daily activities. o o low blood pressure when you sit or stand up quickly. o o o o unusual urges hallucinations and other psychotic-like behavior uncontrolled sudden movements posture changes withdrawal symptoms After you have stopped taking pramipexole dihydrochloride tablets, your doctor may need to restart you at a low dose of pramipexole dihydrochloride tablets if you get severe withdrawal symptoms. The most common side effects in people taking pramipexole dihydrochloride tablets for Restless Legs Syndrome are nausea and headache. The most common side effects in people taking pramipexole dihydrochloride tablets for Parkinson’s disease are: These are not all the possible side effects of pramipexole dihydrochloride tablets. Tell your doctor if you have any side effect that bothers you. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should I store pramipexole dihydrochloride tablets? General Information about the safe and effective use of pramipexole dihydrochloride tablets. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use pramipexole dihydrochloride tablets for a condition for which it was not prescribed. Do not give pramipexole dihydrochloride tablets to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about pramipexole dihydrochloride tablets. If you would like more information, talk with your doctor. You can ask your pharmacist or doctor for information about pramipexole dihydrochloride tablets that is written for healthcare professionals. For more information, call Glenmark Pharmaceuticals Inc. , USA at 1 (888) 721-7115. What are the ingredients in pramipexole dihydrochloride tablets? Active Ingredient Inactive Ingredients This Patient Information has been approved by the U. Food and Drug Administration. *Trademarks are the property of their respective owners. Manufactured by: Glenmark Pharmaceuticals Limited Manufactured for: Glenmark Pharmaceuticals Inc. , USA Questions? 1 (888) 721-7115 August 2021 logo.

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