Mirapex

Pramipexole is used alone or with other medications to treat the symptoms of Parkinson's disease (PD; a disorder of the nervous system that causes difficulties with movement, muscle control, and balance), including shaking of parts of the body, stiffness, slowed movements, and problems with balance. Pramipexole is also used to treat restless legs syndrome (RLS; a condition that causes discomfort in the legs and a strong urge to move the legs, especially at night and when sitting or lying down). Pramipexole is in a class of medications called dopamine agonists. It works by acting in place of dopamine, a natural substance in the brain that is needed to control movement.

Some variations between early Parkinson, advanced Parkinson, and restless legs syndrome

Incidence of some adverse drug reactions (eg, dizziness, accidental injury) >10% but comparable to placebo

>10%

Somnolence

Dyskinesia

Hallucinations

Insomnia

Dizziness

Postural hypotension

Nausea

Constipation

1-10% (partial list)

Abnormal dreams, thoughts, or vision

Amnesia

Confusion

Paranoia or delusion

Akathisia

Asthenia

Dry mouth

Urinary frequency

Postmarketing Reports

Neurologic: Abnormal behavior, abnormal dreams, compulsive shopping, fatigue, hallucinations (all kinds), headache, pathologic gambling

Cardiovascular: Hypotension (including syncope and postural hypotension)

Metabolic: Increased eating (including binge eating, compulsive eating, and hyperphagia), weight gain, SIADH

Dermatologic: Skin reactions, including rythema, rash, pruritus, urticaria

Gastrointestinal: Vomiting

Genitourinary: Libido disorders (including increased or decreased libido and hypersexuality)

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

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

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 and may not reflect the rates observed in clinical practice.

Parkinson's Disease

During the premarketing development of pramipexole, patients with either early or advanced Parkinson's disease were enrolled in clinical trials. Apart from the severity and duration of their disease, the two populations differed in their use of concomitant levodopa therapy. Patients with early disease did not receive concomitant levodopa therapy during treatment with pramipexole; those with advanced Parkinson's disease all received concomitant levodopa treatment. Because these two populations may have differential risks for various adverse reactions, this section will, in general, present adversereaction data for these two populations separately.

Because the controlled trials performed during premarketing development all used a titration design, with a resultant confounding of time and dose, it was impossible to adequately evaluate the effects of dose on the incidence of adverse reactions.

In the three double-blind, placebo-controlled trials of patients with early Parkinson's disease, the most common adverse reactions ( > 5%) that were numerically more frequent in the group treated with MIRAPEX tablets were nausea, dizziness, somnolence, insomnia, constipation, asthenia, and hallucinations.

Approximately 12% of 388 patients with early Parkinson's disease and treated with MIRAPEX tablets who participated in the double-blind, placebo-controlled trials discontinued treatment due to adverse reactions compared with 11% of 235 patients who received placebo. The adverse reactions most commonly causing discontinuation of treatment were related to the nervous system (hallucinations [3.1% on MIRAPEX tablets vs 0.4% on placebo]; dizziness [2.1% on MIRAPEX tablets vs 1% on placebo]; somnolence [1.6% on MIRAPEX tablets vs 0% on placebo]; headache and confusion [1.3% and 1.0%, respectively, on MIRAPEX tablets vs 0% on placebo]) and gastrointestinal system (nausea [2.1% on MIRAPEX tablets vs 0.4% on placebo]).

Adverse-reaction Incidence in Controlled Clinical Studies in Early Parkinson's Disease: Table 4 lists adverse reactions that occurred in the double-blind, placebo-controlled studies in early Parkinson's disease that were reported by ≥ 1% of patients treated with MIRAPEX tablets and were numerically more frequent than in the placebo group. In these studies, patients did not receive concomitant levodopa.

Table 4 : Adverse-Reactions in Pooled Double-Blind, Placebo-Controlled Trials with MIRAPEX in Early Parkinson's Disease

In a fixed-dose study in early Parkinson's disease, occurrence of the following reactions increased in frequency as the dose increased over the range from 1.5 mg/day to 6 mg/day: postural hypotension, nausea, constipation, somnolence, and amnesia. The frequency of these reactions was generally 2-fold greater than placebo for pramipexole doses greater than 3 mg/day. The incidence of somnolence with pramipexole at a dose of 1.5 mg/day was comparable to that reported for placebo.

In the four double-blind, placebo-controlled trials of patients with advanced Parkinson's disease, the most common adverse reactions ( > 5%) that were numerically more frequent in the group treated with MIRAPEX tablets and concomitant levodopa were postural (orthostatic) hypotension, dyskinesia, extrapyramidal syndrome, insomnia, dizziness, hallucinations, accidental injury, dream abnormalities, confusion, constipation, asthenia, somnolence, dystonia, gait abnormality, hypertonia, dry mouth, amnesia, and urinary frequency.

Approximately 12% of 260 patients with advanced Parkinson's disease who received MIRAPEX tablets and concomitant levodopa in the double-blind, placebo-controlled trials discontinued treatment due to adverse reactions compared with 16% of 264 patients who received placebo and concomitant levodopa. The reactions most commonly causing discontinuation of treatment were related to the nervous system (hallucinations [2.7% on MIRAPEX tablets vs 0.4% on placebo]; dyskinesia [1.9% on MIRAPEX tablets vs 0.8% on placebo]) and cardiovascular system (postural [orthostatic] hypotension [2.3% on MIRAPEX tablets vs 1.1% on placebo]).

Adverse-reaction Incidence in Controlled Clinical Studies in Advanced Parkinson's Disease: Table 5 lists adverse reactions that occurred in the double-blind, placebo-controlled studies in advanced Parkinson's disease that were reported by ≥ 1% of patients treated with MIRAPEX tablets and were numerically more frequent than in the placebo group. In these studies, MIRAPEX tablets or placebo was administered to patients who were also receiving concomitant levodopa.

Table 5 : Adverse-Reactions in Pooled Double-Blind, Placebo-Controlled Trials with MIRAPEX in Advanced Parkinson's Disease

Restless Legs Syndrome

MIRAPEX tablets for treatment of RLS have been evaluated for safety in 889 patients, including 427 treated for over six months and 75 for over one year.

The overall safety assessment focuses on the results of three double-blind, placebo-controlled trials, in which 575 patients with RLS were treated with MIRAPEX tablets for up to 12 weeks. The most common adverse reactions with MIRAPEX tablets in the treatment of RLS (observed in > 5% of pramipexoletreated patients and at a rate at least twice that observed in placebo-treated patients) were nausea and somnolence. Occurrences of nausea and somnolence in clinical trials were generally mild and transient.

Approximately 7% of 575 patients treated with MIRAPEX tablets during the double-blind periods of three placebo-controlled trials discontinued treatment due to adverse reactions compared to 5% of 223 patients who received placebo. The adverse reaction most commonly causing discontinuation of treatment was nausea (1%).

Table 6 lists reactions that occurred in three double-blind, placebo-controlled studies in RLS patients that were reported by ≥ 2% of patients treated with MIRAPEX tablets and were numerically more frequent than in the placebo group.

Table 6 Adverse-Reactions in Pooled Double-Blind, Placebo-Controlled Trials with MIRAPEX in Restless Legs Syndrome

Table 7 summarizes data for adverse reactions that appeared to be dose related in the 12-week fixed dose study.

Table 7 : Dose-Related Adverse Reactions in a 12-Week Double-Blind, Placebo-Controlled Fixed Dose Study in Restless Legs Syndrome (Occurring in ≥ 5% of all Patients in the Treatment Phase)

Among the adverse reactions in patients treated with MIRAPEX tablets, hallucination appeared to exhibit a positive relationship to age in patients with Parkinson's disease. Although no gender-related differences were observed in Parkinson's disease patients, nausea and fatigue, both generally transient, were more frequently reported by female than male RLS patients. Less than 4% of patients enrolled were non-Caucasian: therefore, an evaluation of adverse reactions related to race is not possible.

Laboratory Tests

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

Post Marketing Experience

In addition to the adverse events reported during clinical trials, the following adverse reactions have been identified during post-approval use of MIRAPEX 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.

Included as part of the PRECAUTIONS section.

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

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

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

Tell your doctor if you are breastfeeding or plan to breastfeed. It is not known if Mirapex is excreted in human breast milk or if it will harm your nursing baby.

Administration

Oral Administration

Parkinsonian syndrome: Usually administered in 3 equally divided doses daily.1

Restless legs syndrome: Administer once daily 2–3 hours before bedtime.1

May be administered without regard to meals;20 however, taking the drug with food may reduce the occurrence of nausea.1

Parkinsonian syndrome: Administer once daily.25

Swallow tablet whole; do not chew, crush, or divide.25

May be administered without regard to meals; however, taking the drug with food may reduce the occurrence of nausea.25

Dosage

Pending revision, the material in this section should be considered in light of more recently available information in the MedWatch notification at the beginning of this monograph.

Available as pramipexole dihydrochloride; dosage expressed in terms of the monohydrated form of this salt.1 25

Initiate at low dosage and titrate slowly based on response and tolerability.1 25 Increases in BP and heart rate observed in healthy individuals when dosage titrated up to 4.5 mg daily more quickly (i.e., every 3 days) than is recommended.1 25

Adults

Initiate at a low dosage and increase slowly (at intervals of at least 5–7 days) until the maximum therapeutic response is achieved.1

Continually reevaluate and adjust the dosage according to the needs of the patient in an effort to find a dosage schedule that provides maximum relief of symptoms with minimum adverse effects.1 17

In a fixed-dose study in patients with early parkinsonian syndrome, dosages >1.5 mg daily (i.e., 3, 4.5, or 6 mg daily) were not associated with additional therapeutic benefit.1 As the dosage increased over the range from 1.5 mg to 6 mg daily, the incidence of postural hypotension, nausea, constipation, somnolence, and amnesia increased.1

When pramipexole is used as an adjunct to levodopa, consider reducing the levodopa dosage.1

Discontinue pramipexole therapy gradually over a period of 1 week.1 (See Nervous System and Muscular Effects under Cautions.)

Initiate at a low dosage and increase slowly (at intervals of at least 5–7 days) based on response and tolerability assessed after ≥5 days at each dosage level.25

Initially, 0.375 mg once daily; if needed, may increase to 0.75 mg once daily and then increase in 0.75-mg increments up to maximum of 4.5 mg once daily.25

If therapy is interrupted for a substantial period of time, retitration of dosage may be warranted.25

Discontinue pramipexole therapy gradually over a period of 1 week.25 (See Nervous System and Muscular Effects under Cautions.)

Switch patient overnight from conventional tablets to extended-release tablets at the same total daily dosage.25 Because some patients may require dosage adjustment,25 36 monitor patient to determine if dosage adjustment is necessary.25

Initially, 0.125 mg (as conventional tablets) once daily.1 If relief is inadequate, may increase dosage at intervals of 4–7 days to 0.25 mg daily and then to 0.5 mg daily.1

Was discontinued without gradual reduction in dosage in clinical trials evaluating dosages up to 0.75 mg daily; however, in a 26-week trial, abrupt discontinuance resulted in rebound in symptoms.1 (See Rebound and Augmentation in Restless Legs Syndrome under Cautions.)

Prescribing Limits

Adults

Maximum 4.5 mg once daily.25 Dosages >4.5 mg daily not evaluated in clinical trials.25

No evidence that 0.75 mg daily provides additional benefit compared with 0.5 mg daily.1

Special Populations

Renal Impairment

Modify dose and/or frequency of administration in response to the degree of renal impairment.1 17

Clcr >50 mL/minute: Dosage adjustment not required.25

Clcr 30–50 mL/minute: Initiate therapy with every-other-day dosing schedule; carefully assess response and tolerability before increasing to daily dosing after 1 week and before any further dosage titration.25 Increase dosage in 0.375-mg increments at intervals of at least 1 week, up to maximum dosage of 2.25 mg once daily.25

Clcr <30 mL/minute or hemodialysis: Extended-release tablets not studied and not recommended.25

Clcr 20–60 mL/minute: Increase interval between dosage adjustments to 14 days.1

Geriatric Patients

No dosage adjustments necessary, since therapy is initiated at a low dosage and titrated according to clinical response.1 25

Absorption

Bioavailability

Peak plasma concentration attained in approximately 2 hours (conventional tablets) or 6 hours (extended-release tablets).1 25 Absolute bioavailability is >90%.1 25

Bioavailability of extended-release tablets relative to conventional tablets is about 100%.25 Equivalent daily dosages of conventional tablets (given 3 times daily) and extended-release tablets (given once daily) result in comparable peak and trough plasma concentrations and systemic exposure over 24 hours.25

Food

Conventional tablets: Food decreases rate but not extent of absorption; time to peak concentration is delayed by about 1 hour.1 12

Extended-release tablets: Food increases peak plasma concentrations by approximately 20% and delays time to peak concentration by approximately 2 hours, but does not affect extent of exposure.25

Distribution

Extent

Widely distributed throughout the body.1 25

Plasma Protein Binding

15%.1 25

Elimination

Metabolism

No metabolites have been identified in plasma or urine.1 25

Elimination Route

Eliminated in urine (90%), almost entirely as unchanged drug.1 25 Renal clearance of pramipexole is approximately 3 times higher than GFR.1 25 Pramipexole is secreted by the renal tubules, probably by the organic cationic transport system.1 25

Half-life

Terminal half-life is about 8 hours in young healthy individuals.1

Special Populations

In individuals >65 years of age, clearance of pramipexole is reduced by approximately 30% and the terminal half-life is about 12 hours.1 25

Pharmacokinetics not evaluated to date in patients with hepatic impairment; however, hepatic impairment would not be expected to have a significant effect on pramipexole elimination, since approximately 90% of a dose is excreted in urine as unchanged drug.1 25

In patients with renal impairment, clearance of pramipexole is about 75% lower in patients with Clcr of approximately 20 mL/minute and about 60% lower in patients with Clcr of approximately 40 mL/minute compared with healthy individuals.1 25

Pramipexole is used to treat Parkinson disease. It may be used alone or in combination with other medicines (eg, levodopa). Pramipexole is a dopamine agonist that works on the nervous system to help treat the symptoms of Parkinson disease.

Pramipexole is also used to treat Restless Legs Syndrome (RLS). RLS is a neurologic disorder that affects sensation and movement in the legs and causes the legs to feel uncomfortable. This results in an irresistible feeling of wanting to move your legs to make them comfortable. .

This medicine is available only with your doctor's prescription.

• Tell all of your health care providers that you take this medicine. This includes your doctors, nurses, pharmacists, and dentists.
• Avoid driving and doing other tasks or actions that call for you to be alert until you see how Mirapex affects you.
• To lower the chance of feeling dizzy or passing out, rise slowly if you have been sitting or lying down. Be careful going up and down stairs.
• Have your blood pressure checked often. Talk with your doctor.
• Do not stop taking this medicine all of a sudden without calling your doctor. You may have a greater risk of side effects. If you need to stop Mirapex, you will want to slowly stop it as ordered by your doctor.
• Avoid drinking alcohol while taking this medicine.
• Talk with your doctor before you use other drugs and natural products that slow your actions.
• The chance of a type of skin cancer called melanoma may be raised in people with Parkinson's disease. It is not known if Mirapex may also raise the chance. Have skin exams while you take this medicine. Talk with your doctor.
• If you are 65 or older, use Mirapex with care. You could have more side effects.
• Tell your doctor if you are pregnant or plan on getting pregnant. You will need to talk about the benefits and risks of using this medicine while you are pregnant.
• Tell your doctor if you are breast-feeding. You will need to talk about any risks to your baby.

• Store at room temperature.
• Protect from light.
• Store in a dry place. Do not store in a bathroom.
• Keep all drugs in a safe place. Keep all drugs out of the reach of children and pets.
• Check with your pharmacist about how to throw out unused drugs.

• If your symptoms or health problems do not get better or if they become worse, call your doctor.
• Do not share your drugs with others and do not take anyone else's drugs.
• Keep a list of all your drugs (prescription, natural products, vitamins, OTC) with you. Give this list to your doctor.
• Talk with the doctor before starting any new drug, including prescription or OTC, natural products, or vitamins.
• Some drugs may have another patient information leaflet. Check with your pharmacist. If you have any questions about Mirapex, please talk with your doctor, nurse, pharmacist, or other health care provider.
• If you think there has been an overdose, call your poison control center or get medical care right away. Be ready to tell or show what was taken, how much, and when it happened.

This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about Mirapex. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using Mirapex.

Review Date: October 4, 2017

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.

Restless Legs Syndrome (RLS)
The precise mechanism of action of Mirapex tablets as a treatment for RLS is unknown. Although the pathophysiology of RLS is largely unknown, neuropharmacological evidence suggests primary dopaminergic system involvement. Positron Emission Tomographic (PET) studies suggest that a mild striatal presynaptic dopaminergic dysfunction may be involved in the pathogenesis of RLS.

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 Mirapex 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.

Restless Legs Syndrome Patients
A cross-study comparison of data suggests that the pharmacokinetic profile of pramipexole administered once daily in RLS patients is similar to the pharmacokinetic profile of pramipexole in healthy volunteers.

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 Mirapex 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 Mirapex tablets or placebo. Patients treated with Mirapex 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 Mirapex 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 5.0 in the group receiving Mirapex tablets and -0.8 in the placebo group, a difference that was also statistically significant. A statistically significant difference between groups in favor of Mirapex 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 Mirapex tablets (1.5 mg, 3.0 mg, 4.5 mg, or 6.0 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 Mirapex 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 Mirapex 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 Mirapex 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 Mirapex 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 Mirapex 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 Mirapex tablets and 2.8 in the placebo group, a difference that was statistically significant. A statistically significant difference between groups in favor of Mirapex 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 Mirapex 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 Mirapex 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.

Restless Legs Syndrome

The efficacy of Mirapex tablets in the treatment of RLS was evaluated in a multinational drug development program consisting of 4 randomized, double-blind, placebo-controlled trials. This program included approximately 1000 patients with moderate to severe RLS; patients with RLS secondary to other conditions (e.g., pregnancy, renal failure, and anemia) were excluded. All patients were administered Mirapex tablets (0.125 mg, 0.25 mg, 0.5 mg, or 0.75 mg) or placebo once daily 2-3 hours before going to bed. Across the 4 studies, the mean duration of RLS was 4.6 years (range of 0 to 56 years), mean age was approximately 55 years (range of 18 to 81 years), and approximately 66.6% were women.

Key diagnostic criteria for RLS are: an urge to move the legs usually accompanied or caused by uncomfortable and unpleasant leg sensations; symptoms begin or worsen during periods of rest or inactivity such as lying or sitting; symptoms are partially or totally relieved by movement such as walking or stretching at least as long as the activity continues; and symptoms are worse or occur only in the evening or night. Difficulty falling asleep may frequently be associated with symptoms of RLS.

The two outcome measures used to assess the effect of treatment were the International RLS Rating Scale (IRLS Scale) and a Clinical Global Impression - Improvement (CGI-I) assessment. The IRLS Scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. The CGI-I is designed to assess clinical progress (global improvement) on a 7-point scale.

In Study 1, fixed doses of Mirapex tablets were compared to placebo in a study of 12 weeks duration. A total of 344 patients were randomized equally to the 4 treatment groups. Patients treated with Mirapex tablets (n=254) had a starting dose of 0.125 mg/day and were titrated to one of the three randomized doses (0.25, 0.5, 0.75 mg/day) in the first three weeks of the study. The mean improvement from baseline on the IRLS Scale total score and the percentage of CGI-I responders for each of the Mirapex tablets treatment groups compared to placebo are summarized in Table 8. All treatment groups reached statistically significant superiority compared to placebo for both endpoints. There was no clear evidence of a dose-response across the 3 randomized dose groups.

Study 2 was a randomized-withdrawal study, designed to demonstrate the sustained efficacy of pramipexole for treatment of RLS after a period of six months. RLS patients who responded to Mirapex tablets treatment in a preceding 6-month open-label treatment phase (defined as having a CGI-I rating of “very much improved” or “much improved” compared to baseline and an IRLS score of 15 or below) were randomized to receive either continued active treatment (n=78) or placebo (n=69) for 12 weeks. The primary endpoint of this study was time to treatment failure, defined as any worsening on the CGI-I score along with an IRLS Scale total score above 15.

In patients who had responded to 6-month open label treatment with Mirapex tablets, the administration of placebo led to a rapid decline in their overall conditions and return of their RLS symptoms. At the end of the 12-week observation period, 85% of patients treated with placebo had failed treatment, compared to 21% treated with blinded pramipexole, a difference that was highly statistically significant. The majority of treatment failures occurred within 10 days of randomization. For the patients randomized, the distribution of doses was: 7 on 0.125 mg, 44 on 0.25 mg, 47 on 0.5 mg, and 49 on 0.75 mg.

Study 3 was a 6-week study, comparing a flexible dose of Mirapex tablets to placebo. In this study, 345 patients were randomized in a 2:1 ratio to Mirapex tablets or placebo. The mean improvement from baseline on the IRLS Scale total score was -12 for Mirapex-treated patients and -6 for placebo-treated patients. The percentage of CGI-I responders was 63% for Mirapex-treated patients and 32% for placebo-treated patients. The between-group differences were statistically significant for both outcome measures. For the patients randomized to Mirapex tablets, the distribution of achieved doses was: 35 on 0.125 mg, 51 on 0.25 mg, 65 on 0.5 mg, and 69 on 0.75 mg.

Study 4 was a 3-week study, comparing 4 fixed doses of Mirapex tablets, 0.125 mg, 0.25 mg, 0.5 mg, and 0.75 mg, to placebo. Approximately 20 patients were randomized to each of the 5 dose groups. The mean improvement from baseline on the IRLS Scale total score and the percentage of CGI-I responders for each of the Mirapex tablets treatment groups compared to placebo are summarized in Table 9. In this study, the 0.125 mg dose group was not significantly different from placebo. On average, the 0.5 mg dose group performed better than the 0.25 mg dose group, but there was no difference between the 0.5 mg and 0.75 mg dose groups.

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

Mirapex (pramipexole) has some of the same effects as a chemical called dopamine, which occurs naturally in your body. Low levels of dopamine in the brain are associated with Parkinson's disease.

Mirapex is used to treat symptoms of Parkinson's disease, such as stiffness, tremors, muscle spasms, and poor muscle control. Mirapex is also used to treat restless legs syndrome (RLS).

Immediate-release tablet (Mirapex) is approved to treat either Parkinson symptoms or RLS. The extended-release tablet (Mirapex ER) is only approved to treat Parkinson symptoms.

Parkinson's and RLS are two separate disorders. Having one of these conditions will not cause you to have the other condition.

Applies to pramipexole: oral tablet, oral tablet extended release

General

The most common adverse reactions occurring in early Parkinson's disease when used without levodopa were somnolence, insomnia, nausea, constipation, dizziness, fatigue, asthenia, hallucinations, dry mouth, muscle spasms, and peripheral edema. In advanced Parkinson's disease when used with levodopa, the more common adverse reactions included postural hypotension, dyskinesia, extrapyramidal syndrome, insomnia, abnormal dreams, confusion, asthenia, dystonia, somnolence, hypertonia, dry mouth, amnesia, urinary frequency, dizziness, nausea, constipation, hallucinations, headache, and anorexia.

The most common adverse reactions occurring in patients receiving treatment for Restless Legs Syndrome were nausea, somnolence, fatigue, and headache.[Ref]

Nervous system

Early Parkinson's disease:
Very common (10% or more): Somnolence (up to 36%), dizziness (up to 25%), dyskinesia (17%)
Common (1% to 10%): Headache, hypesthesia, dystonia, myoclonus, akathisia, tremor, balance disorder, amnesia, abnormal thinking
Frequency not reported: Restlessness

Advanced Parkinson's disease:
Very common (10% or more): Dyskinesia (up to 47%), extrapyramidal syndrome (28%), dizziness (up to 26%),
Common (1% to 10%): Somnolence, dystonia, gait abnormalities, hypertonia, headache

Restless Legs Syndrome:
Very common (10% or more): Augmentation (12%), headache (17%)
Common (1% to 10%): Worsening of Restless Legs Syndrome, somnolence
Uncommon (0.1% to 1%): Dyskinesia
Postmarketing reports: Amnesia, hyperkinesia[Ref]

In a 26-week clinical trial, worsening of Restless Legs Syndrome (RLS) occurred in 10% of patients suddenly withdrawn from pramipexole 0.75 mg once a day compared to 2% of placebo patients; the RLS symptoms were generally considered mild. Augmentation was reported in 12% and 9% of patients receiving pramipexole 0.75 mg once a day and placebo, respectively. The incidence of augmentation increased with increasing duration of exposure.[Ref]

Psychiatric

Parkinson's disease:
Very common (10% or more): Hallucinations (17%), insomnia (27%), dream abnormalities (11%), confusion (10%)
Common (1% to 10%): Paranoid reaction, delusions, confusion, sleep attacks, sleep disorder, depression
Uncommon (0.1% to 1%): Hypersexuality, pathological gambling, delirium
Rare (less than 0.1%): Mania
Frequency not reported: Impulse control/compulsive behaviors
Postmarketing reports: New or worsening mental status and behavioral changes, binge eating, compulsive shopping

Restless Legs Syndrome:
Very common (10% or more): Insomnia (up to 13%)
Common (1% to 10%): Abnormal dreams
Uncommon (0.1% to 1%): Hypersexuality, pathological gambling, delirium
Rare (less than 0.1%): Mania
Frequency not reported: Impulse control/compulsive behaviors
Postmarketing reports: New or worsening mental status and behavioral changes, binge eating, compulsive shopping[Ref]

Gastrointestinal

Very common (10% or more): Nausea (28%), constipation (14%)
Common (1% to 10%): Dysphagia, dry mouth, diarrhea, dyspepsia, vomiting, upper abdominal pain, abdominal discomfort, salivary hypersecretion
Uncommon (0.1% to 1%): Hiccup
Frequency not reported: Hyperphagia
Postmarketing reports: Peritoneal fibrosis[Ref]

Nausea and vomiting were commonly reported early in therapy and resolved with continued therapy. While there have been postmarketing reports of fibrotic complications including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis, the evidence is not sufficient to establish a causal relationship with use of this drug; however a contribution of treatment cannot be completely ruled out.[Ref]

Cardiovascular

Very common (10% or more): Postural hypotension (up to 53%)
Common (1% to 10%): Chest pain, general edema
Postmarketing reports: Cardia failure, syncope[Ref]

Cardiovascular side effects have included orthostatic hypotension, with or without symptoms, although the overall incidence was not significantly different from that in placebo-treated patients. In advanced Parkinson's disease trials, postural hypotension was reported in 53% (n=260) of patients receiving immediate-release pramipexole compared with 48% (n=264) of patients receiving placebo. In fixed-dose trials in early Parkinson's disease, orthostatic hypotension was shown to be dose related with a frequency 2-fold greater than placebo for doses greater than 1.5 mg/day. Among patients with advanced Parkinson's disease treated concomitantly with levodopa, orthostatic hypotension was reported much more frequently than in those with early disease and not receiving levodopa.

In a pharmacoepidemiology study, pramipexole use was associated with an increased risk of cardiac failure compared with non-use (observed risk ratio: 1.86; 95% confidence interval, 1.21 to 2.85).[Ref]

Genitourinary

Common (1% to 10%): Urinary frequency, urinary tract infection, urinary incontinence, impotence[Ref]

Musculoskeletal

One case of rhabdomyolysis occurred in a 49- year old male patient with advanced Parkinson's disease receiving pramipexole (the active ingredient contained in Mirapex) His creatinine phosphokinase level was elevated to 10,631 IU/L. His symptoms resolved with discontinuation of the medication.[Ref]

Common (1% to 10%): Arthritis, twitching, bursitis, myasthenia, extremity pain, back pain, muscle spasms, increased creatine phosphokinase
Very rare (less than 0.01%): Rhabdomyolysis[Ref]

Ocular

Common (1% to 10%): Vision abnormalities, accommodation abnormalities, diplopia,
Frequency not reported: Blurred vision[Ref]

Dermatologic

Common (1% to 10%): Skin disorders
Frequency not reported: Pruritus[Ref]

Respiratory

Common (1% to 10%): Dyspnea, rhinitis, pneumonia, nasal congestion, cough
Uncommon (0.1% to 1%): Pneumonia
Postmarketing reports: Pleural fibrosis, pulmonary fibrosis[Ref]

There have been postmarketing reports of fibrotic complications including peritoneal fibrosis, pleural fibrosis, and pulmonary fibrosis, the evidence is not sufficient to establish a causal relationship with use of this drug; however a contribution of treatment cannot be completely ruled out.[Ref]

Metabolic

Common (1% to 10%): Decreased weight, increased appetite, anorexia
Postmarketing reports: Increased weight[Ref]

Other

Very common (10% or more): Asthenia (up to 14%)
Common (1% to 10%): Malaise, fever, vertigo[Ref]

Endocrine

Frequency not reported: Libido disorders
Postmarketing reports: Inappropriate antidiuretic hormone secretion (SIADH)[Ref]

Hypersensitivity

Frequency not reported: Rash and other hypersensitivity reactions[Ref]

Immunologic

Common (1% to 10%): Influenza[Ref]

Some side effects of Mirapex may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.

Breastfeeding is not recommended during use of this drug. Excreted into human milk: Unknown Excreted into animal milk: Yes Comments: This drug inhibits prolactin secretion and could potentially inhibit lactation.

A single-dose, radio-labeled study in rats showed this drug is present in rat milk at concentrations 3 to 6 times higher than plasma. There is no information on use in human nursing mothers. As this drug suppresses serum prolactin, it may interfere with breastfeeding. Use of this drug is not recommended while breastfeeding and a decision should be made to discontinue breastfeeding or discontinue this drug, taking into account the importance of the drug to the mother.

Substance Name

Pramipexole

CAS Registry Number

104632-26-0

Drug Class

Antiparkinson Agents

Dopamine Agonists