Mirapex ER

Dosage Forms And Strengths

• 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

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.

Unit of Use Bottles of 7 NDC 0597-0109-17
Unit of Use Bottles of 30 NDC 0597-0109-30

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.

Unit of Use Bottles of 7 NDC 0597-0285-17
Unit of Use Bottles of 30 NDC 0597-0285-30

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

Unit of Use Bottles of 7 NDC 0597-0113-17
Unit of Use Bottles of 30 NDC 0597-0113-30

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

Unit of Use Bottles of 30 NDC 0597-0286-30

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

Unit of Use Bottles of 30 NDC 0597-0115-30

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

Unit of Use Bottles of 30 NDC 0597-0287-30

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

Unit of Use Bottles of 30 NDC 0597-0116-30

Storage And Handling

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F). Protect from exposure to high humidity. Store in a safe place out of the reach of children.

Distributed by: Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, CT 06877 USA. Revised: January 2016

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

MIRAPEX ER® tablets are indicated for the treatment of Parkinson's disease.

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.

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.

Due to the flexible dose design used in clinical trials, specific dose-response information could not be determined.

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.

Dosing in Patients with Renal Impairment

In patients with moderate renal impairment (creatinine clearance between 30 and 50 mL/min), MIRAPEX ER 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.

MIRAPEX ER 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.

Switching From Immediate-Release Pramipexole Tablets To MIRAPEX ER

Patients 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.

None.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

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). 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.

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.

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 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 MIRAPEX ER. 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.

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%) SDWLHQWV. \HDUV RI DJH WDNLQJ 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 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, 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.

Dyskinesia

MIRAPEX ER tablets may potentiate the dopaminergic side effects of levodopa and may cause or exacerbate preexisting dyskinesia.

Renal Impairment

The elimination of pramipexole is dependent on renal function. 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.

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.

Retinal Pathology

Human Data

A two-year open-label, randomized, parallel-group safety study of retinal deterioration and vision compared immediate-release pramipexole tablets and immediate-release ropinirole. Two hundred thirty four Parkinson's disease patients (115 on pramipexole, mean dose 3.0 mg/day and 119 on ropinirole, mean dose 9.5 mg/day) were evaluated using a panel of clinical ophthalmological assessments. Of 234 patients who were evaluable, 196 had been treated for two years and 29 were judged to have developed clinical abnormalities that were considered meaningful (19 patients in each treatment arm had received treatment for less than two years). There was no statistical difference in retinal deterioration between the treatment arms; however, the study was only capable of detecting a very large difference between treatments. In addition, because the study did not include an untreated comparison group (placebo treated), it is unknown whether the findings reported in patients treated with either drug are greater than the background rate in an aging population.

Animal Data

Pathologic changes (degeneration and loss of photoreceptor cells) were observed in the retina of albino rats in a 2-year carcinogenicity study. While retinal degeneration was not diagnosed in pigmented rats treated for 2 years, a thinning in the outer nuclear layer of the retina was slightly greater in rats given drug compared with controls. Evaluation of the retinas of albino mice, monkeys, and minipigs did not reveal similar changes. The potential significance of this effect for humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (i.e., disk shedding) may be involved.

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.

Hyperpyrexia and Confusion

Although not reported with pramipexole in the clinical development program, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy. If possible, avoid sudden discontinuation or rapid dose reduction in patients taking MIRAPEX ER tablets. If the decision is made to discontinue MIRAPEX ER tablets, the dose should be tapered to reduce the risk of hyperpyrexia and confusion.

Fibrotic Complications

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.

Although these adverse events are believed to be related to the ergoline structure of these compounds, whether other, non-ergot derived dopamine agonists can cause them is unknown.

Cases of possible fibrotic complications, including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis have been reported in the postmarketing experience with immediate-release pramipexole tablets. While the evidence is not sufficient to establish a causal relationship between pramipexole and these fibrotic complications, a contribution of pramipexole cannot be completely ruled out.

Melanoma

Epidemiologic studies have shown that patients with Parkinson's disease have a higher risk (2-to approximately 6-fold higher) of developing melanoma than the general population. Whether the observed increased risk was due to Parkinson's disease or other factors, such as drugs used to treat Parkinson's disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using MIRAPEX ER tablets for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

Patient Counseling Information

Advise the patient to read the FDA-approved patient labeling (PATIENT INFORMATION).

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.

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).

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.

Hallucinations and Psychotic-like Behavior

Inform patients that hallucinations and other psychotic-like behavior can occur and that the elderly are at a higher risk than younger patients with Parkinson's disease.

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 .

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.

Nursing Mothers

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.

Nonclinical Toxicology

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.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. MIRAPEX ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

When pramipexole was given to female rats throughout pregnancy, implantation was inhibited at a dose of 2.5 mg/kg/day [5 times the maximum recommended human dose (MRHD) on a mg/m² basis]. Administration of 1.5 mg/kg/day of pramipexole to pregnant rats during the period of organogenesis (gestation days 7 through 16) resulted in a high incidence of total resorption of embryos. The plasma AUC in rats at this dose was 4 times the AUC in humans at the MRHD. These findings are thought to be due to the prolactin-lowering effect of pramipexole, since 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 these studies, the teratogenic potential of pramipexole could not be adequately evaluated. There was no evidence of adverse effects on embryo-fetal development following administration of up to 10 mg/kg/day to pregnant rabbits during organogenesis (plasma AUC was 70 times that in humans at the MRHD). Postnatal growth was inhibited in the offspring of rats treated with 0.5 mg/kg/day (approximately equivalent to the MRHD on a mg/m² basis) or greater during the latter part of pregnancy and throughout lactation.

Nursing Mothers

A single-dose, radio-labeled study showed that drug-related material was present in rat milk at concentrations three to six times higher than in plasma at equivalent time points.

Studies have shown that pramipexole treatment resulted in an inhibition of prolactin secretion in humans and rats.

It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from pramipexole, a decision should be made as to whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

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

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 ZHUH. \HDUV RI DJH Among patients receiving MIRAPEX ER tablets, hallucinations were more common in the elderly, occurring in 13 RI WKH SDWLHQWV. \HDUV RI DJH FRPSDUHG WR RI WKH SDWLHQWV \HDUV RI DJH

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.

No specific pharmacokinetic drug interaction trials were conducted with MIRAPEX ER tablets since the potential for drug interactions mainly depends on the active drug substance pramipexole and not the formulation. The following interaction data were obtained using immediate-release pramipexole tablets.

Carbidopa/levodopa: Carbidopa/levodopa did not influence the pharmacokinetics of pramipexole in healthy volunteers (N=10). Pramipexole did not alter the extent of absorption (AUC) or the elimination of carbidopa/levodopa, although it caused an increase in levodopa Cmax by about 40% and a decrease in Tmax from 2.5 to 0.5 hours.

Selegiline: In healthy volunteers (N=11), selegiline did not influence the pharmacokinetics of pramipexole.

Amantadine: Population pharmacokinetic analyses suggest that amantadine may slightly decrease the oral clearance of pramipexole.

Cimetidine: Cimetidine, a known inhibitor of renal tubular secretion of organic bases via the cationic transport system, caused a 50% increase in pramipexole AUC and a 40% increase in half-life (N=12).

Probenecid: Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transporter, did not noticeably influence pramipexole pharmacokinetics (N=12).

Other drugs eliminated via renal secretion: Population pharmacokinetic analysis suggests that coadministration of drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, and quinine) decreases the oral clearance of pramipexole by about 20%, while those secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, and chlorpropamide) are likely to have little effect on the oral clearance of pramipexole. Other known organic cation transport substrates and/or inhibitors (e.g., cisplatin and procainamide) may also decrease the clearance of pramipexole.

CYP interactions: Inhibitors of cytochrome P450 enzymes would not be expected to affect pramipexole elimination because pramipexole is not appreciably metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4. Inhibition of CYP2D6 was observed with an apparent Ki of 30 μM, indicating that pramipexole will not inhibit CYP enzymes at plasma concentrations observed following the clinical dose of 4.5 mg/day.

Drugs affecting gastrointestinal motility or gastric pH: Population pharmacokinetic analysis suggests that co-administration of antacids (N=6) decreased the oral clearance of pramipexole by about 25%, while H2-blockers (N=5), anticholinergics (N=27), propulsive (N=7), and proton pump inhibitors (N=16) are likely to have little effect on the oral clearance of pramipexole.

Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. MIRAPEX ER should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

When pramipexole was given to female rats throughout pregnancy, implantation was inhibited at a dose of 2.5 mg/kg/day [5 times the maximum recommended human dose (MRHD) on a mg/m² basis]. Administration of 1.5 mg/kg/day of pramipexole to pregnant rats during the period of organogenesis (gestation days 7 through 16) resulted in a high incidence of total resorption of embryos. The plasma AUC in rats at this dose was 4 times the AUC in humans at the MRHD. These findings are thought to be due to the prolactin-lowering effect of pramipexole, since 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 these studies, the teratogenic potential of pramipexole could not be adequately evaluated. There was no evidence of adverse effects on embryo-fetal development following administration of up to 10 mg/kg/day to pregnant rabbits during organogenesis (plasma AUC was 70 times that in humans at the MRHD). Postnatal growth was inhibited in the offspring of rats treated with 0.5 mg/kg/day (approximately equivalent to the MRHD on a mg/m² basis) or greater during the latter part of pregnancy and throughout lactation.

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Falling Asleep During Activities of Daily Living and Somnolence
• Symptomatic Orthostatic Hypotension
• Impulse Control/Compulsive Behaviors
• Hallucinations and Psychotic-like Behavior
• Dyskinesia
• Rhabdomyolysis
• Retinal Pathology
• Events Reported with Dopaminergic Therapy

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.

Early Parkinson's Disease

The most common adverse reactions ( ≥ 5% and more frequent than placebo) after 33 weeks of treatment with MIRAPEX ER 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 MIRAPEX ER 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 MIRAPEX ER tablets was nausea (2%).

Table 1 lists adverse reactions that occurred with a frequency of at least 2% with MIRAPEX ER 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 MIRAPEX ER in Early Parkinson's Disease

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 MIRAPEX ER-treated patients during the titration phase and SHUVLVWHG .7 days) into the maintenance phase (i.e., MIRAPEX ER % -SODFHER WUHDWPHQW GLIIHUHQFH. SHUVLVWHQW DGYHUVH 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 MIRAPEX ER 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 MIRAPEX ER tablets discontinued due to adverse reactions (vertigo and nausea).

Advanced Parkinson's Disease

The most common adverse reactions. DQG JUHDWHU IUHTXHQF\ WKDQ LQ SODFHER GXULQJ ZHHNV RI WUHDWPHQW with MIRAPEX ER 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 MIRAPEX ER 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 MIRAPEX ER tablets were nausea (1%) and hallucination (1%).

Table 2 lists adverse reactions that occurred with a frequency of at least 2% with MIRAPEX ER and were more frequent than with placebo during 18 weeks of treatment in patients with advanced Parkinson's disease treated with MIRAPEX ER tablets. In this study, MIRAPEX ER 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 MIRAPEX ER in Advanced Parkinson's Disease

Because this flexible dose study used a 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 MIRAPEX ER-treated patients during the titration phase and pHUVLVWHG . GD\V LQWR WKH maintenance phase (i.e., MIRAPEX ER % -SODFHER WUHDWPHQW GLIIHUHQFH. SHUVLVWHQW DGYHUVH reactions were dyskinesia and insomnia.

Laboratory Tests

During the development of MIRAPEX ER tablets, no systematic abnormalities on routine laboratory testing were noted.

Other adverse reactions observed during clinical trials of MIRAPEX immediate-release or MIRAPEX ER in early and advanced Parkinson's disease

Other adverse reactions in clinical studies involving MIRAPEX immediate-release or MIRAPEX ER tablets include abnormal dreams, akathisia, amnesia, decreased libido, decreased weight, dyspnea, pneumonia, and vision abnormalities.

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. Similar types of reactions were grouped into a smaller number of standardized categories using the MedDRA terminology: cardiac failure, inappropriate antidiuretic hormone secretion (SIADH), skin reactions (including erythema, rash, pruritus, urticaria), syncope, vomiting, and weight increase.

There is no clinical experience with significant overdosage. One patient took 11 mg/day of pramipexole for 2 days in a clinical trial for an investigational use. Blood pressure remained stable, although pulse rate increased to between 100 and 120 beats/minute. No other adverse reactions were reported related to the increased dose.

There is no known antidote for overdosage of a dopamine agonist. If signs of central nervous system stimulation are present, a phenothiazine or other butyrophenone neuroleptic agent may be indicated; the efficacy of such drugs in reversing the effects of overdosage has not been assessed. Management of overdose may require general supportive measures along with gastric lavage, intravenous fluids, and electrocardiogram monitoring.

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.

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.

Absorption

The absolute bioavailability of pramipexole is greater than 90%, indicating that it is well absorbed and undergoes little presystemic metabolism.

Increase in systemic exposure of pramipexole following oral administration of 0.375 mg to 4.5 mg of MIRAPEX ER tablets was dose-proportional. For MIRAPEX ER tablets, steady state of exposure is reached within 5 days of continuous dosing.

Relative bioavailability of MIRAPEX ER tablets compared with immediate-release tablets was approximately 100%. In a repeat-dose study in healthy, normal volunteers, MIRAPEX ER tablets 4.5 mg administered once daily was bioequivalent with regard to Cmax and AUC over 24 hours to immediate-release pramipexole tablets 1.5 mg administered three times daily. The average time-to-peak concentration for MIRAPEX ER tablets is 6 hours. Administration of MIRAPEX ER tablets with food (i.e., high-fat meal) did not affect AUC but increased Cmax by approximately 20% and delayed Tmax by approximately 2 hours compared with dosing under fasted conditions; these differences are not considered to be clinically relevant.

Distribution

Pramipexole is extensively distributed, having a volume of distribution of about 500 L (coefficient of variation [CV] = 20%). It is about 15% bound to plasma proteins. Pramipexole distributes into red blood cells as indicated by an erythrocyte-to-plasma ratio of approximately 2.

Metabolism

Pramipexole is metabolized only to a negligible extent ( < 10%). No specific active metabolite has been identified in human plasma or urine.

Elimination

Urinary excretion is the major route of pramipexole elimination, with 90% of a pramipexole dose recovered in urine, almost all as unchanged drug. The renal clearance of pramipexole is approximately 400 mL/min (CV=25%), approximately three times higher than the glomerular filtration rate. Thus, pramipexole is secreted by the renal tubules, probably by the organic cation transport system.

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain

• R52.1 – Chronic intractable pain
• R52.2 – Other chronic pain
• R52.9 – Unspecified pain