VA Class:CN500

AHFS Class:

• Nonergot-derivative Dopamine Receptor Agonists 28:36.20.08

Generic Name(s):

• Pramipexole Dihydrochloride

• Pramipexole

Chemical Name:

• ( S )-4,5,6,7-Tetrahydro-N⁶-propyl,2,6-benzothiazolediamine

Molecular Formula:

• C₁₀H₁₇N₃S

Pramipexole dihydrochloride is a nonergot-derivative dopamine receptor agonist.1,2,3,6,7,8,9,15,16,17,18,19,25

Parkinsonian Syndrome

Pramipexole is used for the symptomatic management of parkinson disease.1,2,6,7,8,9,10,13,14,15,16,17,18,19,25,34,35,37

Dopamine receptor agonists (e.g., pramipexole, ropinirole, rotigotine) are used as initial monotherapy in patients with early parkinson disease or as an adjunct to levodopa in patients with advanced disease.101,115,123,157 Levodopa is currently the most effective drug for relieving motor symptoms of parkinson disease.115,123,157 However, the effectiveness of levodopa decreases over time as the disease progresses, and most patients develop motor complications (e.g., end-of-dose failure, “on-off” phenomenon, dyskinesias) with long-term use.101,115,157 Strategies for reducing the risk of motor complications include adjusting the dosage of levodopa or adding other antiparkinsonian agents such as a dopamine receptor agonist; alternatively, a levodopa-sparing strategy may be used in which other antiparkinsonian agents are initiated first to delay use of levodopa.101,115,116,123,157 This latter approach is often used in younger patients who have a higher risk of developing motor complications and a longer life expectancy.101,116,123,157 The appropriate treatment approach should be individualized based on the patient's age, symptoms, degree of disability, and adverse effects of therapy.101,120,122,123,124,125 (For additional information on treatment options in parkinson disease, see Uses: Parkinsonian Syndrome, in Levodopa/Carbidopa 28:36.16.)

Efficacy of conventional (immediate-release) pramipexole for the management of parkinson disease has been established in several placebo-controlled studies of up to 6 months' duration in patients with early parkinson disease not receiving levodopa,2,6,10,15,16 and in patients with advanced parkinson disease who were receiving concomitant levodopa therapy.1,7,8,11,13,15,16,25 Therapeutic response was assessed principally using the Unified Parkinson's Disease Rating Scale (UPDRS), a 4-part rating scale evaluating mentation, activities of daily living (ADL), motor performance, and complications of therapy.1,2,6,7,10,11,13 In these studies, pramipexole improved ADL and reduced motor manifestations of parkinson disease, such as tremor, rigidity, bradykinesia, and postural stability.2,6,8,10,11,13

In studies evaluating immediate-release pramipexole in patients with early parkinson disease, the drug was more effective than placebo in reducing the severity of symptoms.1,2,6,10 In one of these studies that was conducted in patients with a disease duration of less than 7 years, 10 weeks of therapy with pramipexole resulted in an average 20% improvement in total UPDRS scores compared with placebo.2

In studies evaluating immediate-release pramipexole in patients with advanced parkinson disease who were receiving concomitant levodopa therapy, pramipexole reduced the severity of symptoms and allowed for a reduction in levodopa dosage.1,7,8,11,13 In patients who were experiencing “on-off” phenomena (i.e., a deteriorating response to levodopa therapy), pramipexole was more effective than placebo in reducing “off” time (as measured by the ADL portion of the UPDRS).1,7,8,13 In one study, the duration of “off” time with pramipexole or placebo was reduced by an average of 31 or 7%, respectively, while the severity of “off” time was reduced by 17 or 5%, respectively.13

Efficacy of extended-release pramipexole has been established in 2 controlled studies of up to 33 weeks' duration in patients with early or advanced parkinson disease; in these studies, pramipexole was more effective than placebo and as effective as conventional tablets in improving ADL and motor manifestations of the disease (as assessed by the UPDRS); tolerability of the 2 pramipexole formulations was similar.25,34,35,37 In another study, patients who were receiving conventional pramipexole tablets given 3 times daily for the treatment of early parkinson disease were switched to the extended-release tablets given once daily at the same total daily dosa more than 80% of patients were successfully switched overnight to the extended-release formulation without the need for a dosage adjustment.36

Restless Legs Syndrome

Pramipexole is used for the symptomatic management of moderate-to-severe primary restless legs syndrome (RLS; also known as Willis-Ekbom disease).1,26,28,29,30,31,32,33 Experts state that treatment of RLS should be considered if symptoms substantially interfere with sleep or daytime function.40 Nonergot-derivative dopamine receptor agonists (e.g., pramipexole, ropinirole, rotigotine) are considered one of several drugs of choice for reducing symptoms of RLS; there is moderate to strong evidence supporting the use of any of the currently available drugs in this class.40 Treatment should be individualized based on the patient's symptoms, age, comorbidities, preference, and adverse effects of therapy (e.g., risk of augmentation).40

Efficacy of pramipexole for this indication has been established in 4 randomized, double-blind, placebo-controlled studies in a total of approximately 1000 patients with primary moderate-to-severe RLS (defined in most of the studies as a score exceeding 15 on the International Restless Legs Syndrome [IRLS] scale and a history of RLS symptoms at least 2 or 3 days per week for at least the past 3 months).1,30,31,32,33 Patients were excluded from these studies if they had RLS associated with other conditions, such as renal failure, anemia, or pregnancy.1 Pramipexole dihydrochloride was administered in dosages of 0.125, 0.25, 0.5, or 0.75 mg daily 2-3 hours before bedtime as the immediate-release formulation, and response was assessed using the IRLS scale (designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, activities of daily living, and mood) and the Clinical Global Impression-Improvement (CGI-I) scale.1,30,31,32,33 Two studies evaluated fixed dosages of the drug, one study evaluated flexible dosages, and one study evaluated time to treatment failure following discontinuance of the drug (randomized withdrawal study).1,30,31,32,33

In the fixed-dose studies, pramipexole dosages of 0.25, 0.5, and 0.75 mg daily were substantially more effective than placebo for the IRLS end point at 12 weeks; in addition, 74.7, 67.9, or 72.9% of patients receiving the drug at dosages of 0.25, 0.5, or 0.75 mg once daily, respectively, were described as responders (defined as being much improved or very much improved) on the CGI-I scale, compared with 51.2% of those receiving placebo.1,30 There was no clear evidence of a dose-response relationship; although a dosage of 0.5 mg daily was generally superior to a dosage of 0.25 mg daily, the 0.75-mg dosage did not appear to provide any additional benefit over the 0.5-mg dosage, and a dosage of 0.125 mg daily was not more effective than placebo.1,30

In the flexible-dose study, patients receiving pramipexole dihydrochloride (median dosage of 0.35 mg daily; range: 0.125-0.75 mg daily) experienced substantially greater improvement in IRLS score than those receiving placebo; in addition, 62.9% of patients receiving pramipexole compared with 32.5% of those receiving placebo were described as responders on the CGI-I scale.1,33

In the randomized withdrawal study, patients who achieved a sustained response after 6 months of open-label pramipexole therapy were randomized to receive continued pramipexole or placebo.1,32 Following 12 weeks of follow-up, substantially more patients who switched to placebo experienced treatment failure compared with those who continued receiving pramipexole (approximately 85 versus 21%).1,32 Most of the treatment failures occurred within 10 days of randomization.1,32

Administration

Pramipexole dihydrochloride is administered orally as conventional (immediate-release) tablets or extended-release tablets; the extended-release tablets are FDA-labeled for use only in the treatment of parkinson disease.1,25 For the management of parkinson disease, pramipexole is administered as immediate-release tablets in 3 equally divided doses daily or as extended-release tablets given once daily.1,25 When used for the management of restless legs syndrome (RLS), pramipexole is administered as immediate-release tablets once daily 2-3 hours before bedtime.1

Pramipexole extended-release tablets should be swallowed whole and should not be chewed, crushed, or divided.25

Administration of the immediate-release tablets with food decreases the rate, but not the extent, of absorption; time to peak concentration is delayed by about 1 hour.1,12 Administration of the extended-release tablets with food increases peak plasma concentrations by approximately 20% and delays time to peak concentration by approximately 2 hours, but does not affect the extent of exposure.25 Therefore, both the immediate-release and extended-release tablets may be administered without regard to meals; however, taking the drug with food may reduce the occurrence of nausea.1,20,25

Dosage

Dosage of pramipexole dihydrochloride is expressed in terms of the monohydrated form of the salt.1,25

Pramipexole therapy is initiated at a low dosage and titrated slowly based on response and tolerability.1,25 Increases in blood pressure and heart rate have been observed in healthy individuals when dosage was titrated more quickly (i.e., every 3 days) than recommended.1,25

If pramipexole therapy is interrupted for a substantial period of time, retitration may be warranted.1,25

Parkinsonian Syndrome

For the management of parkinson disease, dosage of pramipexole dihydrochloride should be increased slowly at intervals of no less than 5-7 days until the maximum therapeutic response is achieved.1,25

For the management of parkinson disease, the recommended initial dosage of pramipexole dihydrochloride as immediate-release tablets is 0.125 mg 3 times daily; dosage may be increased weekly based on response and tolerability.1 The manufacturer recommends the following dosage titration schedule that was used in clinical studies (see Table 1).1 In clinical studies, pramipexole dihydrochloride dosages of 1.5-4.5 mg daily administered in 3 divided doses as immediate-release tablets were effective and well tolerated when administered with or without concomitant levodopa therapy.1

If the extended-release tablets are used, an initial dosage of 0.375 mg once daily is recommended; if needed, dosage may be increased slowly (at intervals of not less than 5-7 days) based on response and tolerability to 0.75 mg once daily and then in increments of 0.75 mg daily, up to a maximum recommended dosage of 4.5 mg once daily.25 Dosages exceeding 4.5 mg daily have not been evaluated in clinical trials.25

Patients may be switched overnight from the immediate-release to extended-release tablets at the same total daily dosage.25 Following conversion, dosage should be adjusted if necessary based on patient response and tolerability.25,36

Dosage of pramipexole dihydrochloride must be continually reevaluated and adjusted according to the needs of the patient in a constant effort to find a dosage that provides maximum relief of symptoms with minimum adverse effects.1,17 In a fixed-dose study in patients with early parkinson disease, pramipexole dihydrochloride dosages exceeding 1.5 mg daily (i.e., 3, 4.5, or 6 mg daily as conventional tablets) were not associated with additional therapeutic benefit.1 However, as the dosage increased over the range from 1.5 to 6 mg daily, the incidence of postural hypotension, nausea, constipation, somnolence, and amnesia also increased.1 For pramipexole dihydrochloride dosages exceeding 3 mg daily, the frequency of these events generally was twofold greater than with placebo.1 Specific relationships between dose and either therapeutic response or frequency of adverse effects have not been established for the extended-release formulation.25

Sudden discontinuance of pramipexole therapy or rapid dosage reductions should be avoided.1,25 When discontinuing pramipexole therapy, dosage should gradually reduced; the manufacturer states that the dosage may be tapered at a rate of 0.75 mg per day until the daily dosage has been reduced to 0.75 mg, and then the dosage may be further reduced by 0.375 mg per day.1,25

Since concomitant therapy with pramipexole and levodopa may result in additive dopaminergic effects (e.g., dyskinesia),1,7,8,11,13 a reduction in levodopa dosage should be considered when pramipexole is added to levodopa therapy.1 In a controlled study in patients with advanced parkinson disease, dosage of levodopa was reduced by an average of 27% from baseline with concomitant pramipexole therapy.1,13

Restless Legs Syndrome

The usual initial dosage of pramipexole dihydrochloride (as immediate-release tablets) for the management of RLS in adults is 0.125 mg given once daily 2-3 hours before bedtime.1 If symptomatic relief is inadequate, dosage may be increased at intervals of 4-7 days to 0.25 mg daily and then to 0.5 mg daily.1 Although some patients received a dosage of 0.75 mg daily in clinical studies, there was no evidence of additional benefit over a dosage of 0.5 mg daily.1

Pramipexole dihydrochloride (administered at dosages up to 0.75 mg once daily) was discontinued without a taper in clinical trials in RLS patients.1 However, patients receiving the drug were more likely than placebo recipients to report a rebound in symptoms when treatment was discontinued abruptly.1 (See Augmentation and Rebound in Restless Legs Syndrome under Cautions.)

Special Populations

In patients with renal impairment, dosage and/or frequency of administration of pramipexole must be modified based on the degree of impairment.1,17,25

Renal Impairment in Patients with Parkinson Disease

No dosage adjustment is necessary in patients with mild renal impairment (creatinine clearance exceeding 50 mL/minute).1

In patients with moderate renal impairment (creatinine clearance of 30-50 mL/minute) receiving immediate-release pramipexole dihydrochloride tablets, an initial dosage of 0.125 mg twice daily (up to a maximum dosage of 0.75 mg 3 times daily) is recommended; patients with severe renal impairment (creatinine clearance of 15 to less than 30 mL/minute) should receive a dosage of 0.125 mg once daily (up to a maximum dosage of 1.5 mg once daily).1 Patients with creatinine clearance less than 15 mL/minute or those undergoing hemodialysis have not been adequately evaluated.1

In patients with moderate renal impairment (creatinine clearance of 30-50 mL/minute) receiving the extended-release tablets, therapy should be initiated with an every-other-day dosing schedule; response and tolerability should be carefully assessed before increasing to daily dosing after one week and before any further dosage titration.25 Dosage may be titrated no more frequently than once weekly in increments of 0.375 mg, up to a maximum dosage of 2.25 mg once daily.25 Patients with creatinine clearance less than 30 mL/minute or those undergoing hemodialysis have not been adequately evaluated; the manufacturer states that the drug is not recommended for use in these patients.25

Renal Impairment in Patients with Restless Legs Syndrome

If conventional pramipexole dihydrochloride tablets are used for the management of RLS in patients with moderate to severe renal impairment (i.e., creatinine clearance of 20-60 mL/minute), the interval between dosage adjustments should be increased to 14 days.1

Dosage Adjustment in Geriatric Patients

Because dosage of pramipexole is titrated to clinical response, routine dosage adjustment based solely on age is not necessary in geriatric patients.1,25

Contraindications

There are no contraindications to the use of pramipexole.1,25

Warnings/Precautions

Falling Asleep During Activities of Daily Living and Somnolence

Falling asleep while engaged in activities of daily living, including operating a motor vehicle, has been reported in patients receiving pramipexole; such events have sometimes resulted in accidents.1,20,21,22,25 Some of the cases were reported as late as 1 year after initiation of pramipexole therapy.1 Although many patients reported somnolence while receiving the drug, some patients did not perceive warning signs, such as excessive drowsiness, and believed they were alert prior to sudden sleep onset.1,20,21,22,101,25 Falling asleep while engaged in activities of daily living usually occurs in a setting of preexisting somnolence, although patients may not give such a history.1

Patients with a history of sleep disorders (e.g., somnolence) or those taking multiple drugs known to cause sedation may be at increased risk of sudden sleep onset.20 Sleep attacks appear to occur more frequently at higher dosages, but may occur at any dosage.20

Somnolence commonly occurs in patients receiving pramipexole and is more frequent in patients with parkinson disease than in patients with restless legs syndrome (RLS).1,20,21 However, patients may not acknowledge drowsiness or sleepiness until directly questioned about such adverse effects during specific activities.1

Before initiating pramipexole therapy, patients should be advised of the potential to develop drowsiness and specifically asked about any factors that may increase the risk of somnolence (e.g., concomitant use of sedating drugs or drugs that can increase plasma concentrations of pramipexole, presence of sleep disorders).1,20,21,25 Patients should be continually reassessed for drowsiness or sleepiness during therapy, especially since some of these episodes occur well after starting treatment.1,20,21,22,25 If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating), pramipexole generally should be discontinued.1,20,21,25 If a decision is made to continue therapy, the patient should be advised not to drive and to avoid other potentially dangerous activities.1,25 There is insufficient information to establish whether dosage reduction will eliminate this adverse event.1,20,21,25

Orthostatic Hypotension

Dopaminergic agents appear to impair systemic regulation of blood pressure, which can cause orthostatic hypotension, particularly during dosage escalation.1,123 Orthostatic hypotension can also be a manifestation of parkinson disease.1,123

In clinical trials, symptomatic orthostatic hypotension occurred in 3% of patients with parkinson disease receiving extended-release pramipexole compared with 1% of those receiving placebo.25 However, unexpectedly, the reported incidence of clinically important orthostatic hypotension with the immediate-release tablet formulation did not differ from the incidence with placebo in clinical trials.1

Patients receiving pramipexole should be monitored for signs and symptoms of orthostatic hypotension, particularly during dosage escalation.1

Impulse Control/Compulsive Behaviors

Intense urges and compulsive behaviors (e.g., urge to gamble, increased sexual urges, binge eating, uncontrolled spending, other intense urges) and the inability to control these urges have been reported in some patients receiving dopaminergic agents.1,25 These urges stopped in some cases when dosage was reduced or the drug was discontinued.1,25 If a patient develops any such behaviors while receiving pramipexole, consideration should be given to reducing the dosage or discontinuing therapy.1,25

Hallucinations/Psychotic-like Behavior

An increased risk of hallucinations has been reported in patients with parkinson disease receiving pramipexole.1,25 In clinical studies, hallucinations were reported in 9% of patients with early parkinson disease and 16.5% of patients with advanced parkinson disease receiving pramipexole (compared with 2.6 and 3.8%, respectively, of those receiving placebo).1 The risk of hallucinations was increased in geriatric patients.1

Other new or worsening mental status and behavioral changes, which can be severe and include psychotic-like behavior, have been reported during pramipexole therapy or after initiating therapy or increasing dosage of the drug in the postmarketing setting.1,25 Such abnormal thinking and behavior may consist of one or more of the following manifestations: paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.1 Other antiparkinsonian agents can produce similar effects on thinking and behavior.1

Because of the risk of exacerbating psychosis, pramipexole should generally not be used in patients with a major psychotic disorder.1,25 In addition, concomitant use of pramipexole with antipsychotic agents may exacerbate parkinsonian symptoms and result in decreased efficacy of pramipexole.1,25

Dyskinesia

Pramipexole may cause or exacerbate preexisting dyskinesia.1,7,8,11,13,25

Postural Deformity

Postural deformities, including antecollis, camptocormia (bent spine syndrome), and pleurothotonus (pisa syndrome), have been reported after starting or increasing the dosage of pramipexole.1,25 A delayed onset (after several months) has been observed in some patients.1,25

If postural deformity occurs, consideration should be given to reducing the dosage of pramipexole or discontinuing therapy.1,25

Rhabdomyolysis

Rhabdomyolysis has been reported in at least one patient with advanced parkinson disease receiving pramipexole; symptoms resolved upon discontinuance of therapy.1,25 Patients should be advised to contact a clinician if they experience any symptoms of rhabdomyolysis (e.g., unexplained muscle pain, tenderness, weakness).1,25

Ocular Effects

In animal studies, retinal degeneration was observed in albino rats and thinning of the outer nuclear layer of the retina was observed in pigmented rats treated with pramipexole for 2 years; similar changes were not observed in other animal species.1,25 The clinical importance of these animal findings has not been established.1,25

Results of a 2-year open-label study in patients with early parkinson disease did not reveal any clinically important ophthalmologic changes between patients receiving pramipexole and those receiving ropinirole.1,38

Hyperpyrexia and Confusion

Although not reported in clinical trials of pramipexole, a symptom complex resembling neuroleptic malignant syndrome (NMS; characterized by elevated temperature, muscular rigidity, altered consciousness, autonomic instability) has been reported in association with rapid dosage reduction of, withdrawal of, or changes in dopaminergic therapy.1,25

Dosage of pramipexole should be gradually tapered when discontinuing therapy.1,25

Fibrotic Effects

Retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, thickening of pleura, pericarditis, and cardiac valvulopathy have been reported in patients receiving ergot-derivative dopamine agonists, presumably related to the ergoline structure of these agents.1,25 It is not known whether nonergot-derived dopamine agonists may induce similar changes.1,25

Possible fibrotic complications (e.g., peritoneal, pleural, or pulmonary fibrosis) have been reported during postmarketing experience with pramipexole.1,25 A causal relationship has not been established; however, the possibility that pramipexole may have a contributory role cannot be excluded.1,25

Augmentation and Rebound in Restless Legs Syndrome

Long-term use of dopaminergic agents in patients with RLS has been associated with augmentation (a worsening of symptoms during treatment); augmentation can manifest as an increase in overall symptom severity or earlier time of symptom onset each day.1 In a 26-week clinical trial in patients with RLS, augmentation was reported more frequently in patients receiving pramipexole compared with those receiving placebo (12 versus 9%), and the incidence of augmentation increased with increasing duration of treatment.1 Patients receiving pramipexole also were more likely than placebo recipients to report a rebound in symptoms when treatment was discontinued abruptly; such symptoms were generally mild.1 The incidence, severity, and appropriate management of augmentation and/or rebound in patients receiving long-term therapy with pramipexole have not been adequately evaluated in controlled studies to date.1

Specific Populations

Pregnancy

There are no adequate data on the developmental risks associated with the use of pramipexole in pregnant women; the teratogenic potential of the drug has not been completely established in animal studies.1,25 No adverse developmental effects were observed in studies conducted in rabbits; although increased embryolethality was observed in rat studies, this was thought to result from a species-specific effect of pramipexole on prolactin.1,25 In rats, inhibition of postnatal growth was observed at pramipexole dose exposures similar to those in humans.1,25

Lactation

It is not known whether pramipexole is distributed into human milk; the drug is distributed into milk in rats.1,25 The effects of pramipexole on the breast-fed infant or on milk production are not known.1,25 The known benefits of breast-feeding should be considered along with the mother's clinical need for pramipexole and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1,25

Because pramipexole inhibits prolactin secretion, the drug is expected to inhibit lactation.1,25

Pediatric Use

Safety and efficacy of pramipexole in pediatric patients have not been established.1,20,25

Geriatric Use

Due to age-related changes in renal function, clearance of pramipexole is reduced (by about 30%) and elimination half-life is increased (from approximately 8.5 to 12 hours) in geriatric patients older than 65 years of age compared with younger adults.1,25

Geriatric patients with parkinson disease may be at increased risk of hallucinations; no other apparent differences in safety or efficacy have been observed between geriatric patients and younger adults.1,25

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of pramipexole has not been evaluated to date.1,25 Because pramipexole is eliminated mainly (90%) as unchanged drug in the urine, hepatic impairment would not be expected to substantially affect pramipexole elimination.1,25

Renal Impairment

Pramipexole is eliminated renally; caution is advised if pramipexole is used in patients with renal impairment and dosage reductions may be necessary.1,15,25

Pramipexole is removed only to a negligible extent by dialysis.1,25

Common Adverse Effects

Common adverse effects in patients with early parkinson disease (who are not receiving concomitant levodopa) include nausea,1,25 dizziness,1,25 somnolence,1,25 insomnia,1 asthenia,1 fatigue,25 muscle spasms,25 dry mouth,25 constipation,1,25 hallucinations,1,25 general edema,1 and peripheral edema.1,25

Common adverse effects in patients with advanced parkinson disease (who are receiving concomitant levodopa) include postural hypotension,1 dyskinesia,1,25 extrapyramidal syndrome,1 insomnia,1 dizziness,1 hallucinations,1,25 accidental injury,1 headache,25 dream abnormalities,1 confusion,1 asthenia,1 nausea,25 anorexia,25 constipation,1,25 somnolence,1 dystonia,1 dry mouth,1 gait abnormalities,1 hypertonia,1 amnesia,1 and urinary frequency.1

Common adverse effects in patients with RLS include nausea,1 headache,1 fatigue,1 insomnia,1 somnolence,1 abnormal dreams,1 diarrhea,1 nasal congestion,1 influenza,1 and pain in extremity.1

Drugs Metabolized or Affected by Hepatic Microsomal Enzymes

Pramipexole is not appreciably metabolized by cytochrome P-450 (CYP) isoenzymes and does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2E1, 3A4, or 2D6 at clinically relevant concentrations.1,25

Drugs that inhibit CYP isoenzymes are not expected to affect pramipexole concentrations.1,25

Drugs Eliminated by Renal Secretion

Drugs that are secreted by the cationic transport system (e.g., cimetidine, ranitidine, diltiazem, triamterene, verapamil, quinidine, quinine) may decrease oral clearance of pramipexole by about 20%; drugs secreted by the anionic transport system (e.g., cephalosporins, penicillins, indomethacin, hydrochlorothiazide, chlorpropamide) are likely to have little effect on the oral clearance of pramipexole.1,25

Other known organic cation transport substrates and/or inhibitors (e.g., cisplatin, procainamide) may decrease clearance of pramipexole.1,25

Drugs Affecting GI Motility or Gastric pH

Population pharmacokinetic analysis suggests that antacids may decrease oral clearance of pramipexole by about 25%; however, histamine H₂-receptor blockers, anticholinergic agents, prokinetic (propulsive) agents, and proton-pump inhibitors are likely to have little effect on pramipexole clearance.25

Amantadine

Population pharmacokinetic analysis suggests that amantadine may slightly decrease oral clearance of pramipexole.1,25

Antipsychotic Agents

Certain antipsychotic agents may exacerbate symptoms of parkinson disease and diminish the effectiveness of pramipexole.1,25

CNS Depressants

When pramipexole is used concomitantly with CNS depressants (e.g., alcohol, antidepressants, antipsychotic agents, benzodiazepines), possible additive sedative effects may occur.1,20,21,25

Dopamine Antagonists

Dopamine antagonists (e.g., phenothiazines, butyrophenones, thioxanthenes, metoclopramide) may diminish the effectiveness of pramipexole.1,25

Levodopa/Carbidopa

Peak plasma concentrations of levodopa may be higher and occur sooner after administration in patients receiving pramipexole, but the extent of levodopa absorption does not appear to be altered.1,25

Levodopa/carbidopa did not affect the pharmacokinetics of pramipexole in healthy individuals.1,25

Concomitant use of levodopa and pramipexole may increase the risk of dyskinesia in patients with parkinson disease.1,25

Probenecid

Probenecid, a known inhibitor of renal tubular secretion of organic acids via the anionic transporter, does not appear to appreciably alter the pharmacokinetics of pramipexole.1,25

Selegiline

In healthy volunteers, selegiline did not affect the pharmacokinetics of pramipexole when the drugs were used concomitantly.1,25

Description

Pramipexole dihydrochloride, a synthetic benzothiazolamine derivative,1,2,6,13,15,16,25 is a nonergot-derivative dopamine receptor agonist.1,2,3,6,7,8,9,15,16,17,18,19,25 Pramipexole demonstrates high binding specificity for and intrinsic activity at dopamine D₂ receptors compared with other dopamine receptor agonists (e.g., bromocriptine, pergolide),3,6,7,8,9,18,19,25 having a higher affinity for the D₃ receptor subtype13,25 than for the D₂ or D₄ subtypes.1,2,9,15,16,19,25 Pramipexole binds with moderate affinity to α₂-adrenergic receptors but has little or no affinity for α₁- or β-adrenergic, acetylcholine, dopamine D₁, or serotonin (5-hydroxytryptamine [5-HT]) receptors.19

The exact mechanism of action of pramipexole in the management of parkinson disease has not been fully elucidated.1,25 There is considerable evidence that manifestations of parkinsonian syndrome, regardless of the cause of the syndrome, are related to depletion of dopamine in the corpus striatum.6,9 While levodopa is believed to act principally by increasing dopamine concentration in the brain, pramipexole appears to act by directly stimulating postsynaptic dopamine receptors in the corpus striatum.1,6,9,15,16,25

The exact mechanism of action of pramipexole in the management of restless legs syndrome remains to be determined, but is thought to involve the dopaminergic system.1

Advice to Patients

Importance of reading the manufacturer's patient information.1,25

Importance of taking pramipexole as prescribed.1,25 Pramipexole may be taken with or without food; however, taking the drug with food may reduce the occurrence of nausea.1,25 If a dose of the immediate-release tablets is missed, advise patient not to double the next dose.1 If a dose of the extended-release tablets is missed, advise patient to take the dose as soon as possible, but no later than 12 hours after the regularly scheduled time; after 12 hours, the missed dose should be skipped and the next dose should be taken on the following day at the regularly scheduled time.25

Importance of swallowing the extended-release tablets whole; do not chew, crush, or divide.25 Importance of advising patients who are taking the extended-release tablets that a residue resembling swollen pieces of the original tablet may be found in the stool.25 Instruct patients to contact their clinician if this occurs since some patients have reported a worsening of their parkinsonian symptoms when such residue was observed.25

Importance of not taking both immediate-release and extended-release tablets of pramipexole concurrently.25

Importance of advising patients of the potential for sedating effects, including somnolence and the possibility of falling asleep while engaged in activities of daily living.1,25 Patients should avoid driving, operating machinery, or participating in other potentially dangerous activities until effects on the individual are known.1,25

Potential for orthostatic hypotension (e.g., dizziness, nausea, syncope, sweating), especially during dosage escalation.1,25 Patients should avoid rising rapidly after sitting or lying down, especially if they have been in a seated or recumbent position for prolonged periods and/or if they are just beginning pramipexole therapy.1,25

Risk of hallucinations and psychotic-like behavior, particularly in geriatric patients.1,25

Importance of asking patients whether they have developed any new or increased urges or compulsive behaviors (e.g., gambling urges, sexual urges, uncontrolled spending, binge eating) while receiving pramipexole and of advising them of the importance of reporting such urges.1,25

Importance of informing clinician of existing or contemplated concomitant therapy, including prescription and OTC drugs (especially CNS depressants or alcohol), as well as any concomitant illnesses.1,25

Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.1,25

Importance of informing patients of other important precautionary information.1,25 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. Boehringer Ingelheim. Mirapex^® (pramipexole dihydrochloride) tablets prescribing information. Ridgefield, CT; 2018 May.

2. Parkinson Study Group. Safety and efficacy of pramipexole in early Parkinson disease. JAMA . 1997; 278:125-130. [PubMed 9214527]

3. Schilling JC, Adamus WS, Palluk R. Neuroendocrine and side effect profile of pramipexole, a new dopamine receptor agonist, in humans. Clin Pharmacol Ther . 1992; 51:541-8. [PubMed 1350237]

4. Eli Lilly and Company. Permax^® (pergolide mesylate) prescribing information (dated 1995 Feb 15). In: Physicians' desk reference. 51st ed. Montvale, NJ: Medical Economics Company Inc; 1997:571-3.

5. Sandoz. Parlodel^® SnapTabs^® (bromocriptine mesylate) prescribing information (dated 1996 Feb). In: Physicians' desk reference. 51st ed. Montvale, NJ: Medical Economics Company Inc; 1997:2411-3.

6. Hubble JP, Koller WC, Cutler NR et al. Pramipexole in patients with early Parkinson's disease. Clin Neuropharmacol . 1995; 18:338-47. [PubMed 8665547]

7. Molho ES, Factor SA, Weiner WJ et al. The use of pramipexole, a novel dopamine (DA) agonist, in advanced Parkinson's disease. J Neural Transm . 1995; 45(Suppl):225-30.

8. Rabey JM. Second generation of dopamine agonists: pros and cons. J Neural Transm . 1995; 45(Suppl):213-24.

9. Goetz CG. New strategies with dopaminergic drugs: modified formulations of levodopa and novel agonists. Exp Neurol . 1997; 144:17-20. [PubMed 9126145]

10. Shannon KM for the Pramipexole Study Group. Pramipexole monotherapy in early Parkinson's disease: long-term follow-up and interim analysis. Paper presented at XIIth International Symposium on Parkinson's Disease. London: World Health Organization; 1997 Mar.

11. Oertel WH, Pogarell O. Long-term follow-up of patients with advanced Parkinson's disease. Paper presented at XIIth International Symposium on Parkinson's Disease. London: 1997 Mar.

12. Wright CE, Sisson L, Ichhpurani AK et al. Influence of food on the bioavailability of pramipexole. J Neurol . 1997; 244(Suppl 3):S52.

13. Lieberman A, Ranhosky A, Korts D. Clinical evaluation of pramipexole in advanced Parkinson's disease: results of a double-blind, placebo-controlled, parallel-group study. Neurology . 1997; 49:162-8. [PubMed 9222185]

14. Wright CE, Sisson TL, Ichhpurani AK et al. Pramipexole and levodopa pharmacokinetics following concomitant administration. Neurology . 1997; 48:A185.

15. Wright CE, Sisson L, Ichhpurani AK et al. Influence of renal impairment and hemodialysis on pramipexole pharmacokinetics. Movement Disorders . 1997; 12(Suppl 1):66. [PubMed 8990056]

16. Wright CE, Sisson L, Ichhpurani AK et al. Pramipexole steady-state pharmacokinetics in healthy male and female volunteers. Movement Disorders . 1997; 12(Suppl 1):65.

17. Wright CE, Lasher Sisson T, Ichhpurani AK et al. Influence of age and gender on pramipexole pharmacokinetics. Clin Pharmacol Ther . 1996; 59:184.

18. Albani C, Popescu R, Lacher R et al. Single dose response to pramipexole in patients with Parkinson's disease. Movement Disorders . 1992; 7(Suppl 1):98.

19. Piercey MF, Hoffmann WE, Smith MW et al. Inhibition of dopamine neuron firing by pramipexole, a dopamine D₃ receptor-preferring agonist: comparison to other dopamine receptor agonists. Eur J Pharmacol . 1996; 312:35-44. [PubMed 8891576]

20. Pharmacia & Upjohn, Kalamazoo, MI: Personal communication.

21. Gallen CC. Dear healthcare professional letter regarding pramipexole and reports of sudden sleep onset during daily activities. Kalamazoo, MI: Pharmacia & Upjohn; 1999 Aug.

22. Frucht S, Rogers JD, Greene PE et al. Falling asleep at the wheel: motor vehicle mishaps in persons taking pramipexole and ropinirole. Neurology . 1999; 52:1908-10. [PubMed 10371546]

25. Boehringer Ingelheim. Mirapex ER^® (pramipexole dihydrochloride) extended-release tablets prescribing information. Ridgefield, CT; 2018 May.

26. Gamaldo CE, Earley CJ. Restless legs syndrome: a clinical update. Chest . 2006; 130:1596-604. [PubMed 17099042]

27. Trenkwalder C, Garcia-Borreguero D, Montagna P et al. Ropinirole in the treatment of restless legs syndrome: results from the TREAT RLS 1 study, a 12 week, randomised, placebo controlled study in 10 European countries. J Neurol Neurosurg Psychiatry . 2004; 75:92-7. [PubMedCentral][PubMed 14707315]

28. Earley CJ. Restless legs syndrome. N Engl J Med . 2003; 348:2103-9. [PubMed 12761367]

29. Littner MR, Kushida C, Anderson WM et al. Practice parameters for the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder-An American Academy of Sleep Medicine Report. Sleep . 2004; 27:557-9. [PubMed 15164914]

30. Winkelman JW, Sethi KD, Kushida CA et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurology . 2006; 67:1034-9. [PubMed 16931507]

31. Partinen M, Hirvonen K, Jama L et al. Efficacy and safety of pramipexole in idiopathic restless legs syndrome: a polysomnographic dose-finding study--the PRELUDE study. Sleep Med . 2006; 7:407-17. [PubMed 16815748]

32. Trenkwalder C, Stiasny-Kolster K, Kupsch A et al. Controlled withdrawal of pramipexole after 6 months of open-label treatment in patients with restless legs syndrome. Mov Disord . 2006; 21:1404-10. [PubMed 16755554]

33. Oertel WH, Stiasny-Kolster K, Bergtholdt B et al. Efficacy of pramipexole in restless legs syndrome: a six-week, multicenter, randomized, double-blind study (effect-RLS study). Mov Disord . 2007; 22:213-9. [PubMed 17133582]

34. Poewe W, Rascol O, Barone P et al. Extended-release pramipexole in early Parkinson disease: a 33-week randomized controlled trial. Neurology . 2011; 77:759-66. [PubMed 21832218]

35. Schapira AH, Barone P, Hauser RA et al. Extended-release pramipexole in advanced Parkinson disease: a randomized controlled trial. Neurology . 2011; 77:767-74. [PubMed 21832216]

36. Rascol O, Barone P, Hauser RA et al. Efficacy, safety, and tolerability of overnight switching from immediate- to once daily extended-release pramipexole in early Parkinson's disease. Mov Disord . 2010; 25:2326-32. [PubMed 20669265]

37. Hauser RA, Schapira AH, Rascol O et al. Randomized, double-blind, multicenter evaluation of pramipexole extended release once daily in early Parkinson's disease. Mov Disord . 2010; 25:2542-9. [PubMed 20669317]

38. Seiple W, Jennings D, Rosen RB et al. Ophthalmologic Baseline Characteristics and 2-Year Ophthalmologic Safety Profile of Pramipexole IR Compared with Ropinirole IR in Patients with Early Parkinson's Disease. Parkinsons Dis . 2016; 2016:8298503. [PubMed 28078162]

40. Winkelman JW, Armstrong MJ, Allen RP et al. Practice guideline summary: Treatment of restless legs syndrome in adults: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology . 2016; 87:2585-2593. [PubMed 27856776]

101. Olanow CW, Watts RL, Koller WC. An algorithm (decision tree) for the management of Parkinson's disease (2001): treatment guidelines. Neurology . 2001; 56:S1-S88.

115. Lewitt PA. Levodopa for the treatment of Parkinson's disease. N Engl J Med . 2008; 359:2468-76. [PubMed 19052127]

116. PD Med Collaborative Group, Gray R, Ives N et al. Long-term effectiveness of dopamine agonists and monoamine oxidase B inhibitors compared with levodopa as initial treatment for Parkinson's disease (PD MED): a large, open-label, pragmatic randomised trial. Lancet . 2014; 384:1196-205. [PubMed 24928805]

120. Fahn S, Oakes D, Shoulson I et al. Levodopa and the progression of Parkinson's disease. N Engl J Med . 2004; 351:2498-508. [PubMed 15590952]

121. Verschuur CVM, Suwijn SR, Boel JA et al. Randomized Delayed-Start Trial of Levodopa in Parkinson's Disease. N Engl J Med . 2019; 380:315-324. [PubMed 30673543]

122. Bressman S, Saunders-Pullman R. When to Start Levodopa Therapy for Parkinson's Disease. N Engl J Med . 2019; 380:389-390. [PubMed 30673551]

123. Connolly BS, Lang AE. Pharmacological treatment of Parkinson disease: a review. JAMA . 2014 Apr 23-30; 311:1670-83. [PubMed 24756517]

124. Williams DR, Litvan I. Parkinsonian syndromes. Continuum (Minneap Minn) . 2013; 19:1189-212. [PubMed 24092286]

125. Patel T, Chang F, Parkinson Society Canada. Parkinson's disease guidelines for pharmacists. Can Pharm J (Ott) . 2014; 147:161-70. [PubMed 24847369]

157. . Drugs for Parkinson's disease. Med Lett Drugs Ther . 2017; 59:187-194. [PubMed 29136401]