Pramipexole

• Mirapex^®
• Mirapex^® ER

Pramipexole may cause serious side effects. See "Drug Precautions" section.

The most common side effects in people taking pramipexole for Restless Legs Syndrome are nausea and sleepiness.

The most common side effects in people taking pramipexole for Parkinson’s disease are nausea, dizziness, sleepiness, constipation, hallucinations, insomnia, muscle weakness, confusion, and abnormal movements.

Pramipexole may cause serious side effects, including:

• falling asleep during normal daily activities. Pramipexole may cause you to fall asleep while you are doing daily activities such as driving, talking with other people, or eating.
  • Some people taking the medicine in pramipexole have had car accidents because they fell asleep while driving.
  • Some patients did not feel sleepy before they fell asleep while driving. You could fall asleep without any warning.
    Tell your doctor right away if you fall asleep while you are doing activities such as talking, eating, driving, or if you feel sleepier than normal for you.
• low blood pressure when you sit or stand up quickly. You may have:
  • dizziness
  • nausea
  • fainting
  • sweating
    Sit and stand up slowly after you have been sitting or lying down.
• unusual urges. Some people who take certain medicines to treat Parkinson’s disease, including pramipexole, have reported problems, such as gambling, compulsive eating, compulsive buying, and increased sex drive.
  If you or your family members notice that you are developing unusual urges or behaviors, talk to your doctor.
• seeing visions, hearing sounds or feeling sensations that are not real (hallucinations). Your chance of having hallucinations is higher if you are elderly (age 65 or older).
  If you have hallucinations, talk with your doctor right away.
• uncontrolled sudden movements (dyskinesia). If you have new dyskinesia or your existing dyskinesia gets worse tell your doctor.
• skin cancer (melanoma). Some people with Parkinson’s disease may have a higher chance of having melanoma than people who do not have Parkinson’s disease. It is not known if the chance of having melanoma is higher because of the medicines to treat Parkinson’s disease, like pramipexole, or from the Parkinson’s disease. People who take pramipexole should have regular skin examinations to check for melanoma.

Do not drink alcohol while taking pramipexole. It can increase your chance of having serious side effects. 

Do not drive a car, operate a machine, or do other dangerous activities until you know how pramipexole affects you. Sleepiness caused by pramipexole can happen as late as 1 year after you start your treatment.

Tell your doctor if you are pregnant or plan to become pregnant.

The FDA categorizes medications based on safety for use during pregnancy. Five categories - A, B, C, D, and X, are used to classify the possible risks to an unborn baby when a medication is taken during pregnancy.

Pramipexole falls into category C. There are no well-controlled studies in pregnant women. Pramipexole should be used during pregnancy only if the possible benefit outweighs the possible risk to the unborn baby.

Follow all directions on your medicine label and package. Tell each of your healthcare providers about all your medical conditions, allergies, and all medicines you use.

You should not use pramipexole if you are allergic to it.

To make sure pramipexole is safe for you, tell your doctor if you have:

• low blood pressure;

• kidney disease; or

• problems controlling your muscle movements.

People with Parkinson's disease may have a higher risk of skin cancer (melanoma). Talk to your doctor about this risk and what skin symptoms to watch for.

It is not known whether pramipexole will harm an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant while using this medicine.

It is not known whether pramipexole passes into breast milk or if it could harm a nursing baby. You should not breast-feed while using this medicine.

Taking pramipexole with other drugs that make you sleepy can worsen this effect. Ask your doctor before taking a sleeping pill, narcotic medication, muscle relaxer, or medicine for anxiety, depression, or seizures.

Tell your doctor about all your current medicines and any you start or stop using, especially:

• cimetidine; or

• medicine to treat mental illness (such as chlorpromazine, droperidol, fluphenazine, haloperidol, perphenazine, prochlorperazine, thioridazine, and others).

This list is not complete. Other drugs may interact with pramipexole, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

It is very important that your doctor check your progress at regular visits. This is to allow for changes in your dose and to check for any unwanted effects.

Do not stop taking pramipexole without first checking with your doctor. Your doctor may want you to gradually reduce the amount you are taking before stopping it completely.

People taking pramipexole have reported falling asleep without warning during activities of daily living, including driving, which sometimes resulted in accidents. This may happen as late as one year after taking the medicine. Make sure you know how you react to pramipexole before you drive, use machines, or do anything else that could be dangerous if you are not alert, well-coordinated, or able to think or see well.

pramipexole will add to the effects of alcohol and other CNS depressants (medicines that make you drowsy or less alert). Some examples of CNS depressants are antihistamines or medicine for hay fever or colds, sedatives, tranquilizers, or sleeping medicine, prescription pain medicine or narcotics, barbiturates or medicine for seizures, muscle relaxants, or anesthetics, including some dental anesthetics. Check with your doctor before taking any of the above while you are taking pramipexole.

Dizziness, lightheadedness, or fainting may occur, especially when you get up suddenly from a lying or sitting position. These symptoms are more likely to occur when you begin taking pramipexole, or when the dose is increased. Getting up slowly may help. If you have this problem, talk to your doctor.

Hallucinations (seeing, hearing, or feeling things that are not there) may occur in some patients. This is more common with elderly patients. If you have hallucinations, check with your doctor.

Check with your doctor right away if you have dark-colored urine, fever, muscle cramps or spasms, muscle pain or stiffness, or unusual tiredness or weakness. These may be symptoms of a condition called rhabdomyolysis.

Some people who have used pramipexole had unusual changes in their behavior, such as having problems with gambling, increased sex drive, or compulsive eating. Talk with your doctor if this is a concern for you.

Do not take other medicines unless they have been discussed with your doctor. This includes prescription or nonprescription (over-the-counter [OTC]) medicines and herbal or vitamin supplements.

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.

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. For this reason, prescribers should reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.

Before initiating treatment with Pramipexole dihydrochloride tablets, advise patients of the potential to develop drowsiness and specifically ask about factors that may increase the risk for somnolence with Pramipexole dihydrochloride tablets such as the use of concomitant sedating medications or alcohol, the presence of sleep disorders, and concomitant medications that increase Pramipexole plasma levels (e.g., cimetidine) [see Clinical Pharmacology (12.3)]. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating, etc.), Pramipexole dihydrochloride tablets should ordinarily be discontinued. If a decision is made to continue Pramipexole dihydrochloride tablets, advise patients not to drive and to avoid other potentially dangerous activities that might result in harm if the patients become somnolent. While dose reduction reduces the degree of somnolence, there is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

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 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.

Impulse Control/Compulsive Behaviors

Case reports and the results of a cross-sectional study suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money uncontrollably, binge eating, and/or other intense urges and the inability to control these urges while taking one or more of the medications, including Pramipexole dihydrochloride, 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. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Pramipexole dihydrochloride.

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, 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 or after starting or increasing the dose of Pramipexole dihydrochloride. 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, 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 Pramipexole dihydrochloride [see Drug Interactions (7.1)].

Dyskinesia

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

Renal Impairment

Since Pramipexole is eliminated through the kidneys, caution should be exercised when prescribing Pramipexole dihydrochloride tablets to patients with renal impairment [see Dosage and Administration (2.3), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

Rhabdomyolysis

A single case of rhabdomyolysis occurred in a 49 year old male with advanced Parkinson's disease treated with Pramipexole dihydrochloride tablets. The patient was hospitalized with an elevated CPK (10,631 IU/L). The symptoms resolved with discontinuation of the medication.

Retinal Pathology

Human Data

A two-year open-label, randomized, parallel-group safety study of retinal deterioration and vision compared Pramipexole dihydrochloride tablets and immediate-release ropinirole. Two hundred thirty four Parkinson's disease patients (115 on Pramipexole, mean dose 3 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 the 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 in 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 [see Nonclinical Toxicology (13.2)].

Events Reported with Dopaminergic Therapy

Although the events enumerated below may not have been reported in association 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 Pramipexole dihydrochloride tablets. If the decision is made to discontinue Pramipexole dihydrochloride tablets, the dose should be tapered to reduce the risk of hyperpyrexia and confusion [see Dosage and Administration (2.2)].

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, nonergot-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 post marketing experience with Pramipexole dihydrochloride tablets. While the evidence is not sufficient to establish a causal relationship between Pramipexole dihydrochloride tablets and these fibrotic complications, a contribution of Pramipexole dihydrochloride tablets cannot be completely ruled out.

Melanoma

Epidemiological 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 Pramipexole dihydrochloride tablets for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

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.

Parkinson's Disease

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.

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 extended release Pramipexole 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.

Pharmacokinetics

Pramipexole displays linear pharmacokinetics over the clinical dosage range. Its terminal half-life is about 8 hours in young healthy volunteers and about 12 hours in elderly volunteers. Steady-state concentrations are achieved within 2 days of dosing.

Absorption

Pramipexole is rapidly absorbed, reaching peak concentrations in approximately 2 hours. The absolute bioavailability of Pramipexole is greater than 90%, indicating that it is well absorbed and undergoes little presystemic metabolism. Food does not affect the extent of Pramipexole absorption, although the time of maximum plasma concentration (Tmax) is increased by about 1 hour when the drug is taken with a meal.

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.

Pharmacokinetics in Specific Populations

Because therapy with Pramipexole dihydrochloride tablets is initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight, race, or age is not necessary. However, renal insufficiency, which can cause a large decrease in the ability to eliminate Pramipexole, may necessitate dosage adjustment [see Dosage and Administration (2.2)] .

Gender

Pramipexole clearance is about 30% lower in women than in men, but this difference can be accounted for by differences in body weight. There is no difference in half-life between males and females.

Age

Pramipexole clearance decreases with age as the half-life and clearance are about 40% longer and 30% lower, respectively, in elderly (aged 65 years or older) compared with young healthy volunteers (aged less than 40 years). This difference is most likely due to the reduction in renal function with age, since Pramipexole clearance is correlated with renal function, as measured by creatinine clearance.

Race

No racial differences in metabolism and elimination have been identified.

Parkinson's Disease Patients

A cross-study comparison of data suggests that the clearance of Pramipexole may be reduced by about 30% in Parkinson's disease patients compared with healthy elderly volunteers. The reason for this difference appears to be reduced renal function in Parkinson's disease patients, which may be related to their poorer general health. The pharmacokinetics of Pramipexole were comparable between early and advanced Parkinson's disease patients.

Hepatic Impairment

The influence of hepatic insufficiency on Pramipexole pharmacokinetics has not been evaluated. Because approximately 90% of the recovered dose is excreted in the urine as unchanged drug, hepatic impairment would not be expected to have a significant effect on Pramipexole elimination.

Renal Impairment

Clearance of Pramipexole was about 75% lower in patients with severe renal impairment (creatinine clearance approximately 20 mL/min) and about 60% lower in patients with moderate impairment (creatinine clearance approximately 40 mL/min) compared with healthy volunteers [see Warnings and Precautions (5.6) and Dosage and Administration (2.2)]. In patients with varying degrees of renal impairment, Pramipexole clearance correlates well with creatinine clearance. Therefore, creatinine clearance can be used as a predictor of the extent of decrease in Pramipexole clearance.

Drug Interactions 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 (1.5 mg TID).

Parkinson’s Disease

The effectiveness of Pramipexole dihydrochloride tablets in the treatment of Parkinson's disease was evaluated in a multinational drug development program consisting of seven randomized, controlled trials. Three were conducted in patients with early Parkinson's disease who were not receiving concomitant levodopa, and four were conducted in patients with advanced Parkinson's disease who were receiving concomitant levodopa. Among these seven studies, three studies provide the most persuasive evidence of Pramipexole's effectiveness in the management of patients with Parkinson's disease who were and were not receiving concomitant levodopa. Two of these three trials enrolled patients with early Parkinson's disease (not receiving levodopa), and one enrolled patients with advanced Parkinson's disease who were receiving maximally tolerated doses of levodopa.

In all studies, the Unified Parkinson's Disease Rating Scale (UPDRS), or one or more of its subparts, served as the primary outcome assessment measure. The UPDRS is a four-part multi-item rating scale intended to evaluate mentation (part I), Activities of Daily Living (ADL) (part II), motor performance (part III), and complications of therapy (part IV).

Part II of the UPDRS contains 13 questions relating to ADL, which are scored from 0 (normal) to 4 (maximal severity) for a maximum (worst) score of 52. Part III of the UPDRS contains 27 questions (for 14 items) and is scored as described for part II. It is designed to assess the severity of the cardinal motor findings in patients with Parkinson's disease (e.g., tremor, rigidity, bradykinesia, postural instability, etc.), scored for different body regions, and has a maximum (worst) score of 108.

Studies in Patients with Early Parkinson's Disease

Patients (N=599) in the two studies of early Parkinson's disease had a mean disease duration of 2 years, limited or no prior exposure to levodopa (generally none in the preceding 6 months), and were not experiencing the "on-off" phenomenon and dyskinesia characteristic of later stages of the disease.

One of the two early Parkinson's disease studies (N=335) was a double-blind, placebo-controlled, parallel trial consisting of a 7 week dose-escalation period and a 6 month maintenance period. Patients could be on selegiline, anticholinergics, or both, but could not be on levodopa products or amantadine. Patients were randomized to Pramipexole dihydrochloride tablets or placebo. Patients treated with Pramipexole dihydrochloride tablets had a starting daily dose of 0.375 mg and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At the end of the 6 month maintenance period, the mean improvement from baseline on the UPDRS part II (ADL) total score was 1.9 in the group receiving Pramipexole dihydrochloride tablets and -0.4 in the placebo group, a difference that was statistically significant. The mean improvement from baseline on the UPDRS part III total score was 5 in the group receiving Pramipexole dihydrochloride tablets and -0.8 in the placebo group, a difference that was also statistically significant. A statistically significant difference between groups in favor of Pramipexole dihydrochloride tablets was seen beginning at week 2 of the UPDRS part II (maximum dose 0.75 mg/day) and at week 3 of the UPDRS part III (maximum dose 1.5 mg/day).

The second early Parkinson's disease study (N=264) was a double-blind, placebo-controlled, parallel trial consisting of a 6 week dose-escalation period and a 4 week maintenance period. Patients could be on selegiline, anticholinergics, amantadine, or any combination of these, but could not be on levodopa products. Patients were randomized to 1 of 4 fixed doses of Pramipexole dihydrochloride tablets (1.5 mg, 3 mg, 4.5 mg, or 6 mg per day) or placebo. At the end of the 4 week maintenance period, the mean improvement from baseline on the UPDRS part II total score was 1.8 in the patients treated with Pramipexole dihydrochloride tablets, regardless of assigned dose group, and 0.3 in placebo-treated patients. The mean improvement from baseline on the UPDRS part III total score was 4.2 in patients treated with Pramipexole dihydrochloride tablets and 0.6 in placebo-treated patients. No dose-response relationship was demonstrated. The between-treatment differences on both parts of the UPDRS were statistically significant in favor of Pramipexole dihydrochloride tablets for all doses.

No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race. Patients receiving selegiline or anticholinergics had responses similar to patients not receiving these drugs.

Studies in Patients with Advanced Parkinson's Disease

In the advanced Parkinson's disease study, the primary assessments were the UPDRS and daily diaries that quantified amounts of "on" and "off" time.

Patients in the advanced Parkinson's disease study (N=360) had a mean disease duration of 9 years, had been exposed to levodopa for long periods of time (mean 8 years), used concomitant levodopa during the trial, and had "on-off" periods.

The advanced Parkinson's disease study was a double-blind, placebo-controlled, parallel trial consisting of a 7 week dose-escalation period and a 6 month maintenance period. Patients were all treated with concomitant levodopa products and could additionally be on concomitant selegiline, anticholinergics, amantadine, or any combination. Patients treated with Pramipexole dihydrochloride tablets had a starting dose of 0.375 mg/day and were titrated to a maximally tolerated dose, but no higher than 4.5 mg/day in three divided doses. At selected times during the 6 month maintenance period, patients were asked to record the amount of "off," "on," or "on with dyskinesia" time per day for several sequential days. At the end of the 6 month maintenance period, the mean improvement from baseline on the UPDRS part II total score was 2.7 in the group treated with Pramipexole dihydrochloride tablets and 0.5 in the placebo group, a difference that was statistically significant. The mean improvement from baseline on the UPDRS part III total score was 5.6 in the group treated with Pramipexole dihydrochloride tablets and 2.8 in the placebo group, a difference that was statistically significant. A statistically significant difference between groups in favor of Pramipexole dihydrochloride tablets was seen at week 3 of the UPDRS part II (maximum dose 1.5 mg/day) and at week 2 of the UPDRS part III (maximum dose 0.75 mg/day). Dosage reduction of levodopa was allowed during this study if dyskinesia (or hallucinations) developed; levodopa dosage reduction occurred in 76% of patients treated with Pramipexole dihydrochloride tablets versus 54% of placebo patients. On average, the levodopa dose was reduced 27%.

The mean number of "off" hours per day during baseline was 6 hours for both treatment groups. Throughout the trial, patients treated with Pramipexole dihydrochloride tablets had a mean of 4 "off" hours per day, while placebo-treated patients continued to experience 6 "off" hours per day.

No differences in effectiveness based on age or gender were detected. There were too few non-Caucasian patients to evaluate the effect of race.

How Supplied

Pramipexole Dihydrochloride Tablets, 0.125 mg are pink color, capsule-shaped, flat, beveled-edged, uncoated tablets debossed with 'P1'on one side and plain on other side and are supplied are as follows:

NDC 68382-196-16 in bottle of 90 tablets

NDC 68382-196-05 in bottle of 500 tablets

NDC 68382-196-10 in bottle of 1000 tablets

Pramipexole Dihydrochloride Tablets, 0.25 mg are pale blue color, round, flat, beveled-edged, uncoated tablets debossed with 'P2'on one side and break line on other side and are supplied as follows:

NDC 68382-197-16 in bottle of 90 tablets

NDC 68382-197-05 in bottle of 500 tablets

NDC 68382-197-10 in bottle of 1000 tablets

Pramipexole Dihydrochloride Tablets, 0.5 mg are lavender, capsule-shaped, flat, beveled-edged, uncoated tablets debossed with 'P' breakline '3' on one side and plain on other side and are supplied as follows:

NDC 68382-198-16 in bottle of 90 tablets

NDC 68382-198-05 in bottle of 500 tablets

NDC 68382-198-10 in bottle of 1000 tablets

Pramipexole Dihydrochloride Tablets, 1 mg are light peach to peach, round, flat, beveled-edged, uncoated tablets debossed with 'P4'on one side and break line on other side and are supplied as follows:

NDC 68382-199-16 in bottle of 90 tablets

NDC 68382-199-05 in bottle of 500 tablets

NDC 68382-199-10 in bottle of 1000 tablets

Pramipexole Dihydrochloride Tablets, 1.5 mg are yellow color, round, flat, beveled- edged, uncoated tablets debossed with 'P5'on one side and break line on other side and are supplied as follows:

NDC 68382-200-16 in bottle of 90 tablets

NDC 68382-200-05 in bottle of 500 tablets

NDC 68382-200-10 in bottle of 1000 tablets

Storage and Handling

Storage:                     

Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light.

Dispense in a tight, light-resistant container.

Store in a safe place out of the reach of children.

• Mirapex
• Mirapex ER

Clearance is 75% lower with severe impairment (CrCl ~20 mL/min) and approximately 60% lower with moderate impairment (CrCl ~40 mL/min).

Parkinson disease: Immediate release:

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl 30 to 50 mL/minute: Initial: 0.125 mg twice daily (maximum: 0.75 mg 3 times daily)

CrCl 15 to 29 mL/minute: Initial: 0.125 mg once daily (maximum: 1.5 mg once daily)

CrCl <15 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

ESRD requiring hemodialysis: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Parkinson disease: Extended release:

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl 30 to 50 mL/minute: Initial: 0.375 mg every other day; may increase to 0.375 mg once daily no sooner than 1 week after initiation. If necessary, may increase by 0.375 mg per dose not more frequently than every 7 days; maximum recommended dose: 2.25 mg once daily

CrCl <30 mL/minute: Use not recommended.

ESRD requiring hemodialysis: Use not recommended.

Restless legs syndrome: Immediate release:

CrCl >60 mL/minute: No dosage adjustment necessary.

CrCl 20 to 60 mL/minute: No dosage adjustment necessary; however, duration between titration should be increased to 14 days.

CrCl <20 mL/minute: There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).

Adverse events were observed in animal reproduction studies. Information related to the use of pramipexole for the treatment of Parkinson’s disease (Benbir, 2013; Mucchiut 2004) or restless legs syndrome (RLS) (Dostal, 2013) in pregnant women is limited. Current guidelines note that the available information is insufficient to make a recommendation for the treatment of RLS in pregnant women (Aurora, 2012).

Immediate-release:
Initial dose: 0.125 mg orally once a day 2 to 3 hours before bedtime
Titration: If needed, dose may be titrated upwards by increments of 0.125 mg every 4 to 7 days.
Maximum dose: 0.5 mg orally once a day

Comments:
-Extended-release tablets are not indicated for Restless Legs Syndrome.
-Doses of 0.75 mg once a day were used in clinical trials, but were not found to provide additional benefit as compared to the 0.5 mg dose.

Use: For the treatment of moderate to severe primary Restless Legs Syndrome.

Parkinson's Disease:
Immediate-release:
-Very severe renal impairment (CrCl less than 15 mL/min): Not recommended
-Severe renal impairment (CrCl 15 to less than 30 mL/min): Initial dose: 0.125 mg orally once a day; titrate gradually at intervals of no more frequently than every 5 to 7 days to a maximum dose of 1.5 mg once a day; Maximum dose: 1.5 mg once per day
-Moderate renal impairment (CrCl 30 to 50 mL/min): Initial dose: 0.125 mg orally twice a day; titrate gradually at intervals of no more frequently than every 5 to 7 days to a maximum dose of 0.75 mg 3 times a day; Maximum dose: 2.25 mg per day
-Normal to mild renal impairment (CrCl greater than 50 mL/min): No adjustment recommended

Extended-release:
Severe renal impairment: Not recommended
Moderate renal impairment (CrCl 30 to 50 mL/min): Initial dose: 0.375 mg orally every other day; after 1 week, may increase to once a day dosing based on therapeutic response and tolerability; subsequent dose titrations should be in increments of 0.375 mg no more frequently every 7 days; Maximum dose: 2.25 mg per day
Mild renal impairment (CrCl greater than 50 mL/min): No adjustment recommended

Restless Legs Syndrome:
Immediate-release:
Moderate to severe renal impairment (CrCl 20 to 60 mL/min): Initial dose: 0.125 mg orally once a day 2 to 3 hours before bedtime
Titration: If needed, dose may be titrated upwards by increments of 0.125 mg every 14 days; Maximum dose: 0.5 mg orally once a day

• Pramipexole binds to dopamine receptors and mimics the actions of dopamine, a naturally occurring neurotransmitter.
• Dopamine is known to be reduced or absent in the brains of people with Parkinson's disease (PD), and this lack of dopamine is thought to cause many of the symptoms associated with PD. By stimulating the same receptor sites as dopamine, pramipexole helps to restore dopamine activity in the brain, reducing the symptoms of PD.
• Experts aren't sure exactly how pramipexole works in the treatment of restless legs syndrome (RLS).