Pramipexole dihydrochloride extended-release tablets are indicated for the treatment of Parkinson's disease. Pramipexole dihydrochloride extended-release tablet is a non-ergot dopamine agonist indicated for the treatment of Parkinson’s disease (PD) (1)
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 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. (5.5) Postural Deformity: Consider reducing the dose or discontinuing pramipexole dihydrochloride extended-release tablets if postural deformity occurs. ( 5.6 )
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. 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, median dose 3 mg/day, compared to 15% of 103 patients on placebo.
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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.
5.2Symptomatic 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, including pramipexole dihydrochloride extended-release, ordinarily require careful monitoring for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of this risk.
In placebo-controlled clinical trials in Parkinson’s disease, symptomatic orthostatic hypotension was reported in 10 of 387 (3%) patients treated with pramipexole dihydrochloride extended-release tablets compared to 3 of 281 (1%) patients on placebo. One patient of 387 on pramipexole dihydrochloride extended-release tablets discontinued treatment due to hypotension.
5.3Impulse Control/Compulsive Behaviors
Case reports and the results of cross-sectional studies suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, 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 extended-release, 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 extended-release for Parkinson’s disease. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking pramipexole dihydrochloride extended-release.
A total of 1056 patients with Parkinson’s disease who participated in two pramipexole dihydrochloride extended-release placebo-controlled studies of up to 33 weeks duration were specifically asked at each visit about the occurrence of these symptoms. A total of 14 of 387 (4%) treated with pramipexole dihydrochloride extended-release tablets, 12 of 388 (3%) treated with immediate-release pramipexole tablets, and 4 of 281 (1%) treated with placebo reported compulsive behaviors, including pathological gambling, hypersexuality, and/or compulsive buying.
5.4Hallucinations and Psychotic-like Behavior
In placebo-controlled clinical trials in Parkinson's disease, hallucinations (visual or auditory or mixed) were reported in 25 of 387 (6%) patients treated with pramipexole dihydrochloride extended-release tablets compared to 5 of 281 (2%) patients receiving placebo. Hallucinations led to discontinuation of treatment in 5 of 387 (1%) patients on pramipexole dihydrochloride extended-release tablets. Age appears to increase the risk of hallucinations attributable to pramipexole.
In placebo-controlled clinical trials in Parkinson’s disease, hallucinations were reported in 15 of 162 (9%)patients ≥ 65 years of age taking pramipexole dihydrochloride extended-release tablets compared to 10 of 225 (4%)patients <65 years of age taking pramipexole dihydrochloride extended-release tablets. Postmarketing reports with dopamine agonists, including pramipexole dihydrochloride extended-release, indicate that patients with Parkinson’s disease may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with pramipexole dihydrochloride extended-release or after starting or increasing the dose of pramipexole dihydrochloride extended-release.
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, symptoms of mania (e.g., insomnia, psychomotor agitation), disorientation, aggressive behavior, agitation, a
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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 extended-release tablets.
Pregnancy and breastfeeding
8.1Pregnancy Risk Summary
There are no adequate data on the developmental risk associated with the use of pramipexole dihydrochloride extended-release 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.
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: 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 Dr.
Reddy’s Laboratories, Inc. at 1-888-375-3784 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
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 (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 extended-release pramipexole 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 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 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 Pramipexole Dihydrochloride Extended-Release in Early Parkinson’s Disease Body System / Adverse Reaction Placebo Extended-Release Pramipexole Immediate Release Pramipexole (n=103) (n=223) (n=213) % % % Nervous system disorders Somnolence 15 36 33 Dizziness 7 12 12 Tremor 1 3 3 Balance disorder 1 2 0 Gastrointestinal disorders Nausea 9 22 24 Constipation 2 14 12 Dry mouth 1 5 4 Vomiting 0 4 4 Upper abdominal pain 1 3 4 Dyspepsia 2 3 3 Abdominal discomfort 0 2 1 Psychiatric disorders Hallucinations, including visual, auditory and mixed 1 5 6 Insomnia 3 4 4 Sleep attacks or sudden onset of sleep 1 3 6 Sleep disorder 1 2 3 Depression 0 2 0 General disorders and administration site conditions Fatigue 4 6 6 Peripheral edema 4 5 8 Asthenia 2 3 1 Musculoskeletal and connective tissue disorders Muscle spasms 3 5 3 Injury, poisoning and procedural complications Fall 1 4 4 Ear and labyrinth disorders Vertigo 1 4 2 Respiratory, thoracic and mediastinal disorders Cough 1 3 3 Metabolism and nutrition disorders Increased appetite 1 3 2 Vascular disorders Orthostatic hypotension 1 3 0 Because this study used a flexible dose titration design, it was not possible to assess the effects of dose on the incidence of adverse reactions.
Adverse reactions can initially occur in either the titration or maintenance phase. Some adverse reactions developed in pramipexole dihydrochloride extended-release-treated patients during the titration phase and persisted (≥7 days) into the maintenance phase (i.e., pramipexole dihydrochloride extended-release % - placebo % = treatment difference ≥2%); persistent adverse reactions were somnolence, nausea, constipation, fatigue, and dry mouth.
A double-blind, randomized, parallel group trial evaluated the tolerability of an overnight switch from immediate-release pramipexole tablets to extended-release pramipexole tablets at the same daily dose in 156 early Parkinson’s disease patients with or without levodopa. One of 104 patients switched from immediate-release pramipexole tablets to extended-release pramipexole tablets discontinued due to adverse reactions (vertigo and nausea).
Advanced Parkinson's Disease The most common adverse reactions (≥5% and greater frequency than in placebo) during 18 weeks of treatment with pramipexole dihydrochloride extended-release tablets in the trial of advanced Parkinson’s disease patients with concomitant levodopa were dyskinesia, nausea, constipation, hallucinations, headache, and anorexia. Eight of 164 (5%) patients treated with pramipexole dihydrochloride extended-release tablets for 18 weeks discontinued treatment due to adverse reactions compared to 7 of 178 (4%) patients who received placebo and 8 of 175 (5%) patients who received immediate-release pramipexole tablets.
The most common adverse reactions leading to discontinuation of treatment with pramipexole dihydrochloride extended-release tablets were nausea (1%) and hallucination (1%). Table 2 lists adverse reactions that occurred with a frequency of at least 2% with pramipexole dihydrochloride extended-release and were more frequent than with placebo during 18 weeks of treatment in patients with advanced Parkinson’s disease treated with pramipexole dihydrochloride extended-release tablets.
In this study, pramipexole dihydrochloride extended-release tablets, immediate-release pramipexole tablets, or placebo was administered to patients who were also receiving concomitant levodopa. Table 2 Adverse-Reactions in an 18-Week Double-Blind, Placebo-Controlled Trial with Pramipexole Dihydrochloride Extended-Release in Advanced Parkinson’s Disease Body System/Adverse Reaction Placebo Extended-Release Pramipexole Immediate-Release Pramipexole n = 178 n = 164 n = 175 % % % Nervous system disorders Dyskinesia 8 17 18 Headache 3 7 4 Dizziness (postural) 1 2 3 Gastrointestinal disorders Nausea 10 11 11 Constipation 5 7 6 Salivary hypersecretion 0 2 0 Diarrhea 1 2 1 Psychiatric disorders Hallucinations, including visual, auditory and mixed 2 9 7 Insomnia 2 4 4 Metabolism and nutrition disorders Anorexia 2 5 1 Musculoskeletal and connective tissue disorders Back pain 1 2 3 Because this flex
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 1.5MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
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