Pramipexole: uses, appearance and warnings

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).

Tablets: 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, and 1.5 mg ( 3 ) • 0.125 mg: White to off white, round, flat, bevel edged, uncoated tablets, debossed with “91” on one side and plain on other side. Each tablet contains 0.125 mg pramipexole dihydrochloride USP (in monohydrate form) equivalent to 0.118 mg pramipexole dihydrochloride (in anhydrous basis). • 0.25 mg: Peach colored, round, flat, bevel edged, uncoated tablets with “9/2” debossed on one side and breakline on other side. Each tablet contains 0.25 mg pramipexole dihydrochloride USP (in monohydrate form) equivalent to 0.235 mg pramipexole dihydrochloride (in anhydrous basis). • 0.5 mg: Reddish brown colored, round, biconvex, uncoated tablets with “9/3” debossed on one side and breakline on other side. Each tablet contains 0.5 mg pramipexole dihydrochloride USP (in monohydrate form) equivalent to 0.47 mg pramipexole dihydrochloride (in anhydrous basis). • 0.75 mg: Yellow colored, round, flat, bevel edged, uncoated tablets with “84” debossed on one side and plain on other side. Each tablet contains 0.75 mg pramipexole dihydrochloride USP (in monohydrate form) equivalent to 0.705 mg pramipexole dihydrochloride (in anhydrous basis). • 1 mg: Light pink colored, round, flat, bevel edged, uncoated tablets with “9/4” debossed on one side and breakline on other side. Each tablet contains 1 mg pramipexole dihydrochloride USP (in monohydrate form) equivalent to 0.94 mg pramipexole dihydrochloride (in anhydrous basis). …

16.1 How Supplied Pramipexole Dihydrochloride Tablets are available as follows: Pramipexole Dihydrochloride Tablets 0.125 mg are white to off white, round, flat, bevel edged, uncoated tablets with "91" debossed on one side and plain on other side. Bottles of 30 NDC 13668-091-30 Bottles of 90 NDC 13668-091-90 Bottles of 500 NDC 13668-091-05 Bottles of 6,000 NDC 13668-091-42 Pramipexole Dihydrochloride Tablets 0.25 mg are peach colored, round, flat, bevel edged, uncoated tablets with "9/2" debossed on one side and breakline on other side. Bottles of 30 NDC 13668-092-30 Bottles of 90 NDC 13668-092-90 Bottles of 500 NDC 13668-092-05 Bottles of 5,500 NDC 13668-092-41 Pramipexole Dihydrochloride Tablets 0.5 mg are reddish brown colored, round, biconvex, uncoated tablets with "9/3" debossed on one side and breakline on other side. Bottles of 30 NDC 13668-093-30 Bottles of 90 NDC 13668-093-90 Bottles of 500 NDC 13668-093-05 Bottles of 4,000 NDC 13668-093-40 Pramipexole Dihydrochloride Tablets 0.75 mg are yellow colored, round, flat, bevel edged, uncoated tablets with "84" debossed on one side and plain on other side. Bottles of 30 NDC 13668-184-30 Bottles of 90 NDC 13668-184-90 Bottles of 500 NDC 13668-184-05 Bottles of 2,500 NDC 13668-184-31 Pramipexole Dihydrochloride Tablets 1 mg are light pink colored, round, flat, bevel edged, uncoated tablets with "9/4" debossed on one side and breakline on other side. Bottles of 30 NDC 13668-094-30 Bottles of 90 NDC 13668-094-90 Bottles of 500 NDC 13668-094-05 Bottles of 2,500 NDC 13668-094-31 Pramipexole Dihydrochloride Tablets 1.5 mg are white to off white, round, flat, bevel edged, uncoated tablets with "9/5" debossed on one side and breakline on other side. Bottles of 30 NDC 13668-095-30 Bottles of 90 NDC 13668-095-90 Bottles of 500 NDC 13668-095-05 Bottles of 1,500 NDC 13668-095-15 16.2 Storage and Handling Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Protect from light. Store in a safe place out of the reach of children. 16.1 How Supplied Pramipexole Dihydrochloride Tablets are available as follows: Pramipexole Dihydrochloride Tablets 0.125 mg are white to off white, round, flat, bevel edged, uncoated tablets with "91" debossed on one side and plain on other side. …

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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 tablets ( 5.5 ) Postural Deformity: Consider reducing the dose or discontinuing pramipexole dihydrochloride 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 dihydrochloride 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 orthostatic effects in normal volunteers, the reported incidence of clinically significant orthostatic hypotension was not greater among those assigned to pramipexole tablets than among those assigned to placebo. This result, especially with the higher doses used in Parkinson's disease, is clearly unexpected in light of the previous experience with the risks of dopamine agonist therapy. While this finding could reflect a unique property of pramipexole, it might also be explained by the conditions of the study and the nature of the population enrolled in the clinical trials. Patients were very carefully titrated, and patients with active cardiovascular disease or significant orthostatic hypotension at baseline were excluded. Also, clinical trials in patients with RLS did not incorporate orthostatic challenges with intensive blood pressure monitoring done in close temporal proximity to dosing. 5.3 Impulse Control/Compulsive Behaviors Case reports and the results of a cross-sectional study suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, binge eating, and/or other intense urges and the inability to control these urges while taking one or more of the medications, including pramipexole dihydrochloride tablets, that increase central dopaminergic tone. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending or other urges while being treated with pramipexole dihydrochloride tablets for Parkinson's disease or RLS. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking pramipexole dihydrochloride tablets. …

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 Torrent Pharma Inc. at 1-800-912-9561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatc h. 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 )] . …

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.