2.1 General Dosing Considerations

MIRAPEX ER tablets are taken orally once daily, with or without food.

MIRAPEX ER tablets must be swallowed whole and must not be chewed, crushed, or divided.

If a significant interruption in therapy with MIRAPEX ER tablets has occurred, re-titration of therapy may be warranted.

2.2 Dosing for Parkinson's Disease

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)].

MIRAPEX ER 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)].

2.3 Switching from Immediate-Release Pramipexole Tablets to MIRAPEX ER

Patients with Parkinson's disease may be switched overnight from immediate-release pramipexole tablets to MIRAPEX ER tablets at the same daily dose. When switching between immediate-release pramipexole tablets and MIRAPEX ER tablets, patients should be monitored to determine if dosage adjustment is necessary.

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 MIRAPEX ER 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 MIRAPEX ER, 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 MIRAPEX ER 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 MIRAPEX ER 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.), MIRAPEX ER tablets should ordinarily be discontinued. If a decision is made to continue MIRAPEX ER 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, Parkinson's disease patients being treated with dopaminergic agonists, including MIRAPEX ER, 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 MIRAPEX ER tablets compared to 3 of 281 (1%) patients on placebo. One patient of 387 on MIRAPEX ER tablets discontinued treatment due to hypotension.

5.3 Impulse 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 MIRAPEX ER, 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 MIRAPEX ER for Parkinson's disease. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking MIRAPEX ER.

A total of 1056 patients with Parkinson's disease who participated in two MIRAPEX ER 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 MIRAPEX ER 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.

5.4 Hallucinations 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 MIRAPEX ER tablets compared to 5 of 281 (2%) patients receiving placebo. Hallucinations led to discontinuation of treatment in 5 of 387 (1%) patients on MIRAPEX ER 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 MIRAPEX ER tablets compared to 10 of 225 (4%) patients <65 years of age taking MIRAPEX ER tablets.

Postmarketing reports with dopamine agonists, including MIRAPEX ER, 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 MIRAPEX ER or after starting or increasing the dose of MIRAPEX ER. 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, and delirium.

Patients with a major psychotic disorder should ordinarily not be treated with dopamine agonists, including MIRAPEX ER, because of the risk of exacerbating the psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson's disease and may decrease the effectiveness of MIRAPEX ER [see Drug Interactions (7.1)].

5.5 Dyskinesia

MIRAPEX ER tablets may cause or exacerbate preexisting dyskinesia.

5.6 Postural Deformity

Postural deformities, including antecollis, camptocormia (Bent Spine Syndrome), and pleurothotonus (Pisa Syndrome), have been reported in patients after starting or increasing the dose of MIRAPEX ER. Postural deformity may occur several months after starting treatment or increasing the dose. Reducing the dose or discontinuing MIRAPEX ER has been reported to improve postural deformity in some patients, and should be considered if postural deformity occurs.

5.7 Renal Impairment

The elimination of pramipexole is dependent on renal function [see Clinical Pharmacology (12.3)]. Patients with mild renal impairment (a creatinine clearance above 50 mL/min) require no reduction in daily dose. MIRAPEX ER tablets have not been studied in patients with moderate to severe renal impairment (creatinine clearance <50 mL/min) or on hemodialysis [see Dosage and Administration (2.2), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

5.8 Rhabdomyolysis

In the clinical development program for immediate-release pramipexole tablets, a single case of rhabdomyolysis occurred in a 49-year-old male with advanced Parkinson's disease. The patient was hospitalized with an elevated CPK (10,631 IU/L). The symptoms resolved with discontinuation of the medication.

Advise patients to contact a physician if they experience any unexplained muscle pain, tenderness, or weakness, as these may be symptoms of rhabdomyolysis.

5.9 Retinal Pathology

5.10 Events Reported with Dopaminergic Therapy

Although the events enumerated below may not have been reported with the use of pramipexole in its development program, they are associated with the use of other dopaminergic drugs. The expected incidence of these events, however, is so low that even if pramipexole caused these events at rates similar to those attributable to other dopaminergic therapies, it would be unlikely that even a single case would have occurred in a cohort of the size exposed to pramipexole in studies to date.

5.11 Withdrawal Symptoms

Symptoms including apathy, anxiety, depression, fatigue, insomnia, sweating, and pain have been reported during taper or after discontinuation of dopamine agonists, including MIRAPEX ER. These symptoms generally do not respond to levodopa.

Prior to discontinuation of MIRAPEX ER, patients should be informed about potential withdrawal symptoms, and monitored during and after discontinuation. In case of severe withdrawal symptoms, a trial re-administration of a dopamine agonist at the lowest effective dose may be considered.

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 MIRAPEX ER tablets, patients with early Parkinson's disease were treated with MIRAPEX ER 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 MIRAPEX ER 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 MIRAPEX ER tablets, placebo, or immediate-release pramipexole tablets as adjunctive therapy to levodopa.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of MIRAPEX immediate-release or MIRAPEX ER tablets, primarily in Parkinson's disease patients. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to pramipexole tablets.

Cardiac Disorders: cardiac failure

Gastrointestinal Disorders: vomiting

General Disorders and Administration Site Conditions: withdrawal symptoms [see Warnings and Precautions (5.11)]

Metabolism and Nutrition Disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH), weight increase

Musculoskeletal and Connective Tissue Disorders: postural deformity [see Warnings and Precautions (5.6)]

Nervous System Disorders: syncope

Skin and Subcutaneous Tissue Disorders: skin reactions (including erythema, rash, pruritus, urticaria)

There are postmarketing reports of patients noticing tablet residue in their stool that resembles a swollen MIRAPEX ER whole tablet or swollen pieces of the tablet. Some patients have reported worsening of their Parkinson's disease symptoms when tablet residue was observed. If a patient reports tablet residue with worsening of their Parkinson's symptoms, prescribers may need to re-evaluate their medications.

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 MIRAPEX ER tablets.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness of MIRAPEX ER tablets in pediatric patients have not been evaluated.

8.5 Geriatric Use

Pramipexole total oral clearance is approximately 30% lower in subjects older than 65 years compared with younger subjects, because of a decline in pramipexole renal clearance due to an age-related reduction in renal function. This resulted in an increase in elimination half-life from approximately 8.5 hours to 12 hours. In a placebo-controlled clinical trial of MIRAPEX ER tablets in early Parkinson's disease, 47% of the 259 patients were ≥65 years of age. Among patients receiving MIRAPEX ER tablets, hallucinations were more common in the elderly, occurring in 13% of the patients ≥65 years of age compared to 2% of the patients <65 years of age.

8.6 Renal Impairment

The elimination of pramipexole is dependent upon renal function. Pramipexole clearance is extremely low in dialysis patients, as a negligible amount of pramipexole is removed by dialysis [see Dosage and Administration (2.2), Warnings and Precautions (5.7), and Clinical Pharmacology (12.3)].

12.1 Mechanism of Action

Pramipexole is a non-ergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes.

The precise mechanism of action of pramipexole as a treatment for Parkinson's disease is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum. This conclusion is supported by electrophysiologic studies in animals that have demonstrated that pramipexole influences striatal neuronal firing rates via activation of dopamine receptors in the striatum and the substantia nigra, the site of neurons that send projections to the striatum. The relevance of D3 receptor binding in Parkinson's disease is unknown.

12.2 Pharmacodynamics

The effect of pramipexole on the QT interval of the ECG was investigated in a clinical study in 60 healthy male and female volunteers. All subjects initiated treatment with 0.375 mg MIRAPEX ER tablets administered once daily, and were up-titrated every 3 days to 2.25 mg and 4.5 mg daily, a faster rate of titration than recommended in the label. No dose- or exposure-related effect on mean QT intervals was observed; however, the study did not have a valid assessment of assay sensitivity. The effect of pramipexole on QTc intervals at higher exposures achieved either due to drug interactions (e.g., with cimetidine), renal impairment, or at higher doses has not been systematically evaluated.

Although mean values remained within normal reference ranges throughout the study, supine systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse rate for subjects treated with pramipexole generally increased during the rapid up-titration phase, by 10 mmHg, 7 mmHg, and 10 bpm higher than placebo, respectively. Higher SBP, DBP, and pulse rates compared to placebo were maintained until the pramipexole doses were tapered; values on the last day of tapering were generally similar to baseline values. Such effects have not been observed in clinical studies with Parkinson's disease patients, who were titrated according to labeled recommendations.

12.3 Pharmacokinetics

MIRAPEX ER tablets, like immediate-release pramipexole tablets, display linear pharmacokinetics over the entire clinical dosage range. Slow release of pramipexole from MIRAPEX ER tablets with once-daily administration results in the same daily maximum and minimum pramipexole plasma concentrations (Cmax, Cmin) as three times daily administration of immediate-release pramipexole tablets.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Two-year carcinogenicity studies with pramipexole have been conducted in mice and rats. Pramipexole was administered in the diet to mice at doses up to 10 mg/kg/day [or approximately 10 times the maximum recommended human dose (MRHD) of 1.5 mg TID on a mg/m2 basis]. Pramipexole was administered in the diet to rats at doses up to 8 mg/kg/day. These doses were associated with plasma AUCs up to approximately 12 times that in humans at the MRHD. No significant increases in tumors occurred in either species.

Pramipexole was not mutagenic or clastogenic in a battery of in vitro (bacterial reverse mutation, V79/HGPRT gene mutation, chromosomal aberration in CHO cells) and in vivo (mouse micronucleus) assays.

In rat fertility studies, pramipexole at a dose of 2.5 mg/kg/day (5 times the MRHD on a mg/m2 basis) prolonged estrus cycles and inhibited implantation. These effects were associated with reductions in serum levels of prolactin, a hormone necessary for implantation and maintenance of early pregnancy in rats.

13.2 Animal Toxicology and/or Pharmacology

Early Parkinson's Disease

The effectiveness of MIRAPEX ER tablets in early Parkinson's disease patients (Hoehn & Yahr Stages I-III) who were not on levodopa therapy was established in a randomized, double-blind, placebo-controlled, 3-parallel-group clinical study. Patients were treated with MIRAPEX ER tablets, immediate-release pramipexole tablets, or placebo; those treated with MIRAPEX ER tablets or immediate-release pramipexole tablets had a starting dose of 0.375 mg/day followed by a flexible up-titration, based on efficacy and tolerability, up to 4.5 mg/day. Levodopa was permitted during the study as rescue medication. Stable doses of concomitant MAO-B inhibitors, anticholinergics, or amantadine, individually or in combination, were allowed. The primary efficacy endpoint was the mean change from baseline in the UPDRS Parts II+III score for MIRAPEX ER tablets versus placebo following 18 weeks of treatment.

At 18 weeks of treatment, the mean change from baseline UPDRS Parts II+III score was −8.1 points in patients receiving MIRAPEX ER tablets (n=102) and −5.1 points in patients receiving placebo (n=50), a difference that was statistically significant (p<0.03). Seven patients treated with placebo (14%) and 3 patients treated with MIRAPEX ER tablets (3%) received levodopa rescue medication. At 18 weeks, the mean dose of MIRAPEX ER was 3 mg/day.

At 33-weeks, the adjusted mean improvement from baseline UPDRS Parts II+III score was −8.6 points in patients receiving MIRAPEX ER tablets (n=213), compared to −3.8 points in patients receiving placebo (n=103).

At 18 and 33 weeks, the mean dose of MIRAPEX ER tablets was approximately 3 mg/day. Twenty-two patients treated with placebo (21%) and 15 patients treated with MIRAPEX ER tablets (7%) received levodopa rescue medication before the final assessment.

No differences in effectiveness based on age or gender were detected. Patients receiving MAOB-I, anticholinergics, or amantadine had responses similar to patients not receiving these drugs.

Advanced Parkinson's Disease

The effectiveness of MIRAPEX ER tablets in advanced Parkinson's disease patients (Hoehn & Yahr Stages II-IV at "on" time) who were on concomitant levodopa therapy (at an optimized dose) and who had motor fluctuations (at least 2 cumulative hours of "off" time per day) was established in a randomized, double-blind, placebo-controlled, 3-parallel-group clinical study. Patients were treated with MIRAPEX ER tablets, immediate-release pramipexole tablets, or placebo; those treated with MIRAPEX ER tablets or immediate-release pramipexole tablets had a starting dose of 0.375 mg/day followed by a flexible up-titration over 7 weeks, based on efficacy and tolerability, up to 4.5 mg/day, followed by a 26 week maintenance period. Levodopa dosage reduction was permitted only in the case of dopaminergic adverse events. The primary efficacy endpoint was the adjusted mean change from baseline in the UPDRS Parts II+III score for MIRAPEX ER tablets versus placebo following 18 weeks of treatment.

At 18 weeks of treatment, the adjusted mean improvement from baseline UPDRS Parts II+III score was −11.0 points in patients receiving MIRAPEX ER tablets (n=161) and −6.1 points in patients receiving placebo (n=174), (p=0.0001). At week 18, the adjusted mean improvement from baseline in "off" time was −2.1 hours for MIRAPEX ER and −1.4 hours for placebo (p=0.0199).

At 33-weeks the adjusted mean improvement from baseline UPDRS Parts II+III score was −11.1 points in patients receiving MIRAPEX ER tablets (n=117) and −6.8 points in patients receiving placebo (n=136) (p=0.0135).

At both 18 and 33 weeks the mean daily dose of MIRAPEX ER was 2.6 mg/day. At week 18, 4 patients (3%) in the placebo group and 14 patients (11%) in the MIRAPEX ER group had decreased their levodopa daily dose compared to baseline due to dopaminergic adverse events. No clinically relevant difference in effectiveness was observed in the sub-group analyses based on gender, age, race (White vs Asian), or concomitant use of antiparkinsonian treatment (MAOB-I, amantadine or anticholinergics).

16.1 How Supplied

MIRAPEX ER tablets are available as follows:

0.375 mg: white to off-white, round, bevel-edged, extended-release tablets debossed with "ER" on one side and "0.375" on the other side.

0.75 mg: white to off-white, round, bevel-edged, extended-release tablets debossed with "ER" on one side and "0.75" on the other side.

1.5 mg: white to off-white, oval, extended-release tablets debossed with "ER" on one side and "1.5" on the other side.

2.25 mg: white to off-white, oval, extended-release tablets debossed with "ER" on one side and "2.25" on the other side.

3 mg: white to off-white, oval, extended-release tablets debossed with "ER" on one side and "3.0" on the other side.

3.75 mg: white to off-white, oval, extended-release tablets debossed with "ER" on one side and "3.75" on the other side.

4.5 mg: white to off-white, oval, extended-release tablets debossed with "ER" on one side and "4.5" on the other side.

16.2 Storage and Handling

Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]. Protect from exposure to high humidity. Store in a safe place out of the reach of children.

Dosing Instructions

Instruct patients to take MIRAPEX ER tablets only as prescribed. If a dose is missed, MIRAPEX ER tablets should be taken as soon as possible, but no later than 12 hours after the regularly scheduled time. After 12 hours, the missed dose should be skipped and the next dose should be taken on the following day at the regularly scheduled time.

MIRAPEX ER tablets can be taken with or without food. If patients develop nausea, advise that taking MIRAPEX ER tablets with food may reduce the occurrence of nausea.

MIRAPEX ER tablets should be swallowed whole. They should not be chewed, crushed, or divided [see Dosage and Administration (2.1)].

Inform patients that residue in stool which may resemble a swollen original MIRAPEX ER tablet or swollen pieces of the original tablet have been reported [see Adverse Reactions (6.2)]. Instruct patients to contact their physician if this occurs.

Pramipexole is the active ingredient that is in both MIRAPEX ER tablets and immediate-release pramipexole tablets. Ensure that patients do not take both immediate-release pramipexole and MIRAPEX ER.

Sedating Effects

Alert patients to the potential sedating effects of MIRAPEX ER tablets, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse reaction with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with MIRAPEX ER tablets to gauge whether or not it affects their mental and/or motor performance adversely. Advise patients that if increased somnolence or new episodes of falling asleep during activities of daily living (e.g., conversations or eating) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Because of possible additive effects, advise caution when patients are taking other sedating medications or alcohol in combination with MIRAPEX ER and when taking concomitant medications that increase plasma levels of pramipexole (e.g., cimetidine) [see Warnings and Precautions (5.1)].

Postural (Orthostatic) Hypotension

Advise patients that they may develop postural (orthostatic) hypotension, with or without symptoms such as dizziness, nausea, fainting, or blackouts, and sometimes, sweating. Hypotension may occur more frequently during initial therapy. Accordingly, caution patients against rising rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with MIRAPEX ER [see Warnings and Precautions (5.2)].

Impulse Control Symptoms Including Compulsive Behaviors

Alert patients and their caregivers to the possibility that they may experience intense urges to spend money, intense urges to gamble, increased sexual urges, binge eating and/or other intense urges and the inability to control these urges while taking MIRAPEX ER [see Warnings and Precautions (5.3)].

Hallucinations and Psychotic-like Behavior

Inform patients that hallucinations and other psychotic-like behavior can occur. In patients with Parkinson's disease, the elderly are at a higher risk than younger patients [see Warnings and Precautions (5.4)].

Withdrawal-Emergent Hyperpyrexia and Confusion

Advise patients who have been prescribed a lower dose or who have been withdrawn from the drug to notify their healthcare provider if they have symptoms such as fever, muscular rigidity, or altered consciousness [see Warnings and Precautions (5.10)].

Withdrawal Symptoms

Advise patients that withdrawal symptoms may occur during or after discontinuation or dose reduction of MIRAPEX ER. Advise patients who have been prescribed a lower dose or who have been withdrawn from the drug to notify their healthcare provider if they have withdrawal symptoms such as apathy, anxiety, depression, fatigue, insomnia, sweating, or pain. Notify patients that in case of severe withdrawal symptoms, a trial re-administration of a dopamine agonist at the lowest effective dose may be considered [see Warnings and Precautions (5.11)].

Pregnancy

Because the teratogenic potential of pramipexole has not been completely established in laboratory animals, and because experience in humans is limited, advise women to notify their physicians if they become pregnant or intend to become pregnant during therapy [see Use in Specific Populations (8.1)].

Lactation

Because of the possibility that pramipexole may be excreted in breast milk, advise women to notify their physicians if they intend to breast-feed or are breast-feeding an infant [see Use in Specific Populations (8.2)].