Pramipexole Dihydrochloride

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

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) <15 mL/min and hemodialysis patients Data not available >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 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) 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 hemod…

5 WARNINGS AND PRECAUTIONS Falling Asleep During Activities of Daily Living: Sudden onset of sleep may occur without warning; advise patients to report symptoms (5.1) Symptomatic Orthostatic Hypotension: Monitor during dose escalation (5.2) Impulse Control/Compulsive Behaviors: Patients may experience compulsive behaviors and other intense urges (5.3) Hallucinations and Psychotic-like Behavior: May occur; risk increases with age (5.4) Dyskinesia: May be caused or exacerbated by pramipexole dihydrochloride (5.5) Postural Deformity: Consider reducing the dose or discontinuing pramipexole dihydrochloride if postural deformity occurs (5.6) 5.1 Falling Asleep During Activities of Daily Living and Somnolence Patients treated with pramipexole have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles which sometimes resulted in accidents. Although many of these patients reported somnolence while on pramipexole tablets, some perceived that they had no warning signs (sleep attack) such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events had been reported as late as one year after the initiation of treatment. Somnolence is a common occurrence in patients receiving pramipexole at doses above 1.5 mg/day (0.5 mg three times a day) for Parkinson's disease. In controlled clinical trials in RLS, patients treated with pramipexole dihydrochloride tablets at doses of 0.25 to 0.75 mg once a day, the incidence of somnolence was 6% compared to an incidence of 3% for placebo-treated patients [ see Adverse Reactions (6.1) ]. It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Before initiating treatment with pramipexole dihydrochloride tablets, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with pramipexole dihydrochloride tablets such as the use of concomitant sedating medications or alcohol, the presence of sleep disorders, and concomitant medications that increase pramipexole plasma levels (e.g., cimetidine) [ see Clinical Pharmacology (12.3) ]. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), pramipexole dihydrochloride tablets should ordinarily be discontinued. If a decision is made to continue pramipexole dihydrochloride tablets, advise patients not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. While dose reduction reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living. 5.2 Symptomatic Orthostatic Hypotension Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. Parkinson's disease patients, in addition, appear to have an impaired capacity to respond to an orthostatic challenge. For these reasons, both Parkinson's disease patients and RLS patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk. In clinical trials of pramipexole, however, and despite clear orthostati…

4 CONTRAINDICATIONS None. None (4)

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.

8.1 Pregnancy 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.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 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 4.5 mg/day. 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 (0.1, 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.

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Falling Asleep During Activities of Daily Living and Somnolence [ see Warnings and Precautions (5.1) ] Symptomatic Orthostatic Hypotension [ see Warnings and Precautions (5.2) ] Impulse Control/Compulsive Behaviors [ see Warnings and Precautions (5.3) ] Hallucinations and Psychotic-like Behavior [ see Warnings and Precautions (5.4) ] Dyskinesia [ see Warnings and Precautions (5.5) ] Postural Deformity [ see Warnings and Precautions (5.6 ) ] Rhabdomyolysis [ see Warnings and Precautions (5.8) ] Retinal Pathology [ see Warnings and Precautions (5.9) ] Events Reported with Dopaminergic Therapy [ see Warnings and Precautions (5.10) ] Withdrawal Symptoms [ see Warnings and Precautions (5.11) ] Most common adverse reactions (incidence >5% and greater than placebo): Early PD without levodopa: nausea, dizziness, somnolence, insomnia, constipation, asthenia, and hallucinations (6.1) Advanced PD with levodopa: postural (orthostatic) hypotension, dyskinesia, extrapyramidal syndrome, insomnia, dizziness, hallucinations, accidental injury, dream abnormalities, confusion, constipation, asthenia, somnolence, dystonia, gait abnormality, hypertonia, dry mouth, amnesia, and urinary frequency (6.1) RLS: nausea, somnolence, fatigue, and headache ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Rising Health, LLC at 1-833-395-6928 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Parkinson's Disease During the premarketing development of pramipexole, patients with either early or advanced Parkinson's disease were enrolled in clinical trials. Apart from the severity and duration of their disease, the two populations differed in their use of concomitant levodopa therapy. Patients with early disease did not receive concomitant levodopa therapy during treatment with pramipexole; those with advanced Parkinson's disease all received concomitant levodopa treatment. Because these two populations may have differential risks for various adverse reactions, this section will, in general, present adverse-reaction data for these two populations separately. Because the controlled trials performed during premarketing development all used a titration design, with a resultant confounding of time and dose, it was impossible to adequately evaluate the effects of dose on the incidence of adverse reactions. Early Parkinson's Disease In the three double-blind, placebo-controlled trials of patients with early Parkinson's disease, the most common adverse reactions (>5%) that were numerically more frequent in the group treated with pramipexole dihydrochloride tablets were nausea, dizziness, somnolence, insomnia, constipation, asthenia, and hallucinations. Approximately 12% of 388 patients with early Parkinson's disease and treated with pramipexole dihydrochloride tablets who participated in the double-blind, placebo-controlled trials discontinued treatment due to adverse reactions compared with 11% of 235 patients who received placebo. The adverse reactions most commonly causing discontinuation of treatment were related to the nervous system (hallucinations [3.1% on pramipexole dihydrochloride tablets vs 0.4% on placebo]; dizziness [2.1% on pramipexole dihydrochloride tablets vs 1% on placebo]; somnolence [1.6% on pramipexole dihydrochloride tablets vs 0% on placebo]; headache and confusion [1.3% and 1.0%, respectively, on pramipexole dihydrochloride tablets vs 0% on placebo]) and gastrointestinal system (nausea [2.1% on pramipexole dihydrochloride tablets vs 0.4% on placebo]). Adverse-reaction Incidence in Controlled Clinical Studies in Early Parkinso…