Pramipexole dihydrochloride tablets are non-ergot dopamine agonist indicated for the treatment of: · Parkinson’s disease (PD) (1.1)
1.1Parkinson's Disease
Pramipexole dihydrochloride tablets are indicated for the treatment of Parkinson’s disease.
Contraindications
None. None (4)
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 Pschyotic-like Behaviour: May occur; risk increases with age. (5.4) · Dyskinesia: May be caused or exacerbated by pramipexole dihydrochloride tablets (5.5) · Events reported with dopaminergic therapy: Include hyperpyrexia and confusion, fibrotic complications, and melanoma (5.9)
5.1Falling 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. It has been reported that falling asleep while engaged in activities of daily living usually occurs in a setting of pre-existing somnolence, although patients may not give such a history.
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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 asked 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.
5.2Symptomatic 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, Parkinson’s disease 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.
5.3Impulse 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 and that are generally used for the treatment of Parkinson’s disease.
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.
Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking pramipexole dihydrochloride tablets.
5.4 Hallucinations and Psychotic-like Behavior In the three double-blind, placebo-controlled trials in early Parkinson’s disease, hallucinations were observed in 9% (35 of 388) of patients receiving pramipexole dihydrochloride tablets, compared with 2.6% (6 of 235) of patients receiving placebo. In the four double-blind, placebo-controlled trials in advanced Parkinson’s disease, where patients received pramipexole dihydrochloride tablets and concomitant levodopa, hallucinations were observed in 16.5% (43 of 260) of patients receiving pramipexole dihydrochloride tablets compared with 3.8% (10 of 264) of patients receiving placebo.
Hallucinations were of sufficient severity to cause discontinuation of treatment in 3.1% of the early Parkinson’s disease patients and 2.7% of the advanced Parkinson’s disease patients compared with about 0.4% of placebo patients in both populations. Age appears to increase the risk of hallucinations attributable to pramipexole. In the early Parkinson’s disease patients, the risk of hallucinations was 1.9 times greater than placebo in patients younger than 65 years and 6.8 times greater than placebo in patients older than 65 years.
In the advanced Parkinson’s disease patients, the risk of hallucinations was 3.5 times greater than placebo in patients younger than 65 years and 5.2 times greater than placebo in patients older than 65 years. Postmarketing reports with medication used to treat Parkinson’s disease, including pramipexole dihydrochloride tablets, indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with pramipexole dihydrochloride tablets or after starting or increasing the dose of pramipexole dihydrochloride tablets.
Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. Patients with a major psychotic disorder should ordinarily not be treated with dopamine agonists, including pramipexole dihydrochloride tablets, because of the risk of exacerbating the psychosis.
In addition, certain medications used to treat psychosis may exacerb
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Interactions
Dopamine antagonists: May diminish the effectiveness of pramipexole (7.1).
7.1Dopamine 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.
Pregnancy and breastfeeding
8.1Pregnancy 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.
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
6.1Clinical 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 U
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
PRAMIPEXOLE DIHYDROCHLORIDE 0.5MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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