Pramipexole dihydrochloride

1 INDICATIONS AND USAGE Pramipexole dihydrochloride extended- release tablet is a non-ergot dopamine agonist indicated for the treatment of Parkinson's disease (PD) ( 1 ) Pramipexole dihydrochloride extended- release tablets are indicated for the treatment of Parkinson's disease.

2 DOSAGE AND ADMINISTRATION Pramipexole dihydrochloride extended- release tablets are taken once daily, with or without food ( 2.1 ) Tablets must be swallowed whole and must not be chewed, crushed, or divided ( 2.1 ) Starting dose is 0.375 mg given once daily ( 2.2 ) Dose may be increased gradually, not more frequently than every 5 to 7 days, first to 0.75 mg per day and then by 0.75 mg increments up to a maximum recommended dose of 4.5 mg per day. Assess therapeutic response and tolerability at a minimal interval of 5 days or longer after each dose increment ( 2.2 ) Patients may be switched overnight from immediate-release pramipexole tablets to pramipexole dihydrochloride extended- release tablets at the same daily dose. Dose adjustment may be needed in some patients ( 2.3 ) Pramipexole dihydrochloride extended- release tablets should be discontinued gradually ( 2.2 ) 2.1 General Dosing Considerations Pramipexole dihydrochloride extended- release tablets are taken orally once daily, with or without food. Pramipexole dihydrochloride extended- release tablets must be swallowed whole and must not be chewed, crushed, or divided. If a significant interruption in therapy with pramipexole dihydrochloride extended- release tablets has occurred, re-titration of therapy may be warranted. 2.2 Recommended Dosage The starting dose is 0.375 mg given once per day. Based on efficacy and tolerability, dosages may be increased gradually, not more frequently than every 5 to 7 days, first to 0.75 mg per day and then by 0.75 mg increments up to a maximum recommended dose of 4.5 mg per day. In clinical trials, dosage was initiated at 0.375 mg/day and gradually titrated based on individual therapeutic response and tolerability. Doses greater than 4.5 mg/day have not been studied in clinical trials. Patients should be assessed for therapeutic response and tolerability at a minimal interval of 5 days or longer after each dose increment [ see Clinical Studies ( 14 ) ]. Due to the flexible dose design used in clinical trials, specific dose-response information could not be determined [ see Clinical Studies ( 14 ) ]. Pramipexole dihydrochloride extended- release 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 ( 5.10 , 5.11 ) ]. Recommended Dosage in Patients with Renal Impairment In patients with moderate renal impairment (creatinine clearance between 30 and 50 mL/min), pramipexole dihydrochloride extended- release tablets should initially be taken every other day. Caution should be exercised and careful assessment of therapeutic response and tolerability should be made before increasing to daily dosing after one week, and before any additional titration in 0.375 mg increments up to 2.25 mg per day. Dose adjustment should occur no more frequently than at weekly intervals. Pramipexole dihydrochloride extended- release tablets have not been studied in patients with severe renal impairment (creatinine clearance <30 mL/min) or patients on hemodialysis, and are not recommended in these patients. 2.3 Switching from Immediate-Release Pramipexole Tablets to Pramipexole Dihydrochloride Extended- Release Tablets Patients with Parkinson's disease may be switched overnight from immediate-release pramipexole tablets to pramipexole dihydrochloride extended-release tablets at the same daily dose. When switching between immediate-release pramipexole tablets and pramipexole dihydrochloride extended-release tablets, patients should be monitored to determine if dosage adjustment is necessary.

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 closely especially 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 extended- release tablets ( 5.5 ) Postural Deformity: Consider reducing the dose or discontinuing pramipexole dihydrochloride extended-release tablets if postural deformity occurs ( 5.6 ) 5.1 Falling Asleep During Activities of Daily Living and Somnolence Patients treated with pramipexole have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, which sometimes resulted in accidents. Although many of these patients reported somnolence while on pramipexole tablets, some perceived that they had no warning signs (sleep attack) such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some of these events had been reported as late as one year after the initiation of treatment. In placebo- controlled clinical trials in Parkinson's disease, the sudden onset of sleep or sleep attacks were reported in 8 of 387 (2%) patients treated with pramipexole dihydrochloride extended-release tablets compared to 2 of 281 (1%) patients on placebo. In early Parkinson's disease, somnolence was reported in 36% of 223 patients treated with pramipexole dihydrochloride extended-release tablets, median dose 3.0 mg/day, compared to 15% of 103 patients on placebo. In advanced Parkinson's disease, somnolence was reported in 15% of 164 patients treated with pramipexole dihydrochloride extended-release tablets, median dose 3 mg/day, compared to 16% of 178 patients on placebo. 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 extended-release tablets, advise patients of the potential to develop drowsiness, and specifically ask about factors that may increase the risk for somnolence 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 extended-release tablets should ordinarily be discontinued. If a decision is made to continue pramipexole dihydrochloride extended-release 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 …

4 CONTRAINDICATIONS None. None.

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 extended-release tablets.

8.1 Pregnancy Risk Summary There are no adequate data on the developmental risk associated with the use of pramipexole dihydrochloride extended-release 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 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 Most common adverse reactions (incidence ≥5% and greater than placebo): Early PD without levodopa: somnolence, nausea, constipation, dizziness, fatigue, hallucinations, dry mouth, muscle spasms, and peripheral edema ( 6.1 ) Advanced PD with levodopa: dyskinesia, nausea, constipation, hallucinations, headache, and anorexia ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Ingenus Pharmaceuticals, LLC Toll-Free at 1-877-748-1970 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . The following adverse reactions are discussed in greater detail in other sections of the labeling: Falling Asleep During Activities of Daily Living and Somnolence [ see Warnings and Precautions ( 5.1 ) ] Symptomatic Orthostatic Hypotension [ see Warnings and Precautions ( 5.2 ) ] Impulse Control/Compulsive Behaviors [ see Warnings and Precautions ( 5.3 ) ] Hallucinations and Psychotic-like Behavior [ see Warnings and Precautions ( 5.4 ) ] Dyskinesia [ see Warnings and Precautions ( 5.5 ) ] Postural Deformity [ see Warnings and Precautions ( 5.6 ) ] Rhabdomyolysis [ see Warnings and Precautions ( 5.8 ) ] Retinal Pathology [ see Warnings and Precautions ( 5.9 ) ] Events Reported with Dopaminergic Therapy [ see Warnings and Precautions ( 5.10 ) ] Withdrawal Symptoms [ see Warnings and Precautions ( 5.11 ) ] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug (or of another development program of a different formulation of the same drug) and may not reflect the rates observed in practice. During the premarketing development of pramipexole dihydrochloride extended-release tablets, patients with early Parkinson's disease were treated with pramipexole dihydrochloride extended-release tablets, placebo, or immediate-release pramipexole tablets. In addition, a randomized, double-blind, parallel group trial was conducted in 156 early Parkinson's disease patients (Hoehn & Yahr Stages I-III) to assess overnight switching of immediate-release pramipexole tablets to pramipexole dihydrochloride extended-release tablets. In this latter study, concomitant treatment with stable doses of levodopa, monoamine oxidase B inhibitor (MAOB-I) drugs, anticholinergics, or amantadine, individually or in combination, was allowed. In a third trial, advanced Parkinson's disease patients received pramipexole dihydrochloride extended-release tablets, placebo, or immediate-release pramipexole tablets as adjunctive therapy to levodopa. Early Parkinson's Disease The most common adverse reactions (≥5% and more frequent than placebo) after 33 weeks of treatment with pramipexole dihydrochloride extended-release tablets in the trial of early Parkinson's disease patients were somnolence, nausea, constipation, dizziness, fatigue, hallucinations, dry mouth, muscle spasms, and peripheral edema. Twenty four of 223 (11%) patients treated with pramipexole dihydrochloride extended-release tablets for 33 weeks discontinued treatment due to adverse reactions compared to 4 of 103 (4%) patients who received placebo and approximately 20 of 213 (9%) patients who received immediate-release pramipexole tablets. The adverse reaction most commonly causing discontinuation of treatment with pramipexole dihydrochloride extended-release tablets was nausea (2%). Table 1 lists adverse reactions that occurred with a frequency of at least 2% with pramipexole dihydrochloride extended-release tablets and were more frequent than with placebo during 33 weeks of treatment in a double-blind, placebo-controlled study in early Parkinson's disease. In this study, patients did not receive concomitant levodopa; however, levodopa was permitted as rescue medication. Table 1 Adverse-Reactions in a 33-Week Double-Blind, Placebo-Controlled Trial with P ramipexole D ihydrochloride E xtended- R elease T ablets in Early Parkins…