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Pramipexole: Drug information

Pramipexole: Drug information
(For additional information see "Pramipexole: Patient drug information")

For abbreviations, symbols, and age group definitions used in Lexicomp (show table)
Special Alerts
Health Canada Dopamine Agonists Safety Alert June 2021

Health Canada's review of the available information has established a link between use of the dopamine agonists pramipexole, quinagolide, or ropinirole and the risk of dopamine agonist withdrawal syndrome (DAWS). DAWS may occur after reducing the dose of or discontinuing dopamine agonists, and includes symptoms such as apathy, anxiety, depression, fatigue, sweating, panic attacks, insomnia, irritability, and pain. The Canadian product information for pramipexole has been updated to include a warning on the risk of DAWS. Health Canada will work with the manufacturers of quinagolide and ropinirole to update the product information to include a warning on the risk of DAWS. At this time, there is not enough information to establish a link between other dopamine agonists that were assessed as part of this safety review (ie, apomorphine, bromocriptine, cabergoline, pergolide [no longer marketed], and rotigotine) and DAWS. As a precaution, Health Canada will work with the manufacturers of these dopamine agonists to include the potential risk of DAWS in the product information.

Further information is available at https://hpr-rps.hres.ca/reg-content/summary-safety-review-detail.php?lang=en&linkID=SSR00269.

Brand Names: US
  • Mirapex;
  • Mirapex ER
Brand Names: Canada
  • ACT Pramipexole;
  • APO-Pramipexole;
  • Auro-Pramipexole;
  • DOM-Pramipexole [DSC];
  • Mirapex;
  • PMS-Pramipexole [DSC];
  • RATIO-Pramipexole;
  • SANDOZ Pramipexole;
  • TEVA-Pramipexole [DSC]
Pharmacologic Category
  • Anti-Parkinson Agent, Dopamine Agonist
Dosing: Adult
Parkinson disease

Parkinson disease (monotherapy or adjunctive therapy):

Immediate release: Oral: Initial: 0.125 mg 3 times daily; increase gradually (eg, 0.125 mg/dose) every 5 to 7 days based on response and tolerability up to 4.5 mg/day. Usual dose: 1.5 to 4.5 mg/day in divided doses (Spindler 2021; manufacturer's labeling).

Extended release: Oral: Initial: 0.375 mg once daily; increase by 0.375 mg every 5 to 7 days based on response and tolerability. Usual dose: 1.5 to 4.5 mg once daily; maximum: 4.5 mg/day (Spindler 2020; manufacturer's labeling).

Converting from pramipexole immediate release to pramipexole extended release: May initiate extended release the morning after the last immediate release evening dose is taken. The total daily dose should remain the same.

Restless legs syndrome

Restless legs syndrome (alternative agent):

Immediate release: Oral: Initial: 0.125 mg once daily 2 to 3 hours before bedtime. Daily dose may be increased based on response and tolerability to 0.25 mg after 4 to 7 days. Daily dose may then be increased to 0.5 mg after 4 to 7 days. Alternatively, some experts recommend increasing by 0.125 mg every 2 to 3 days based on response and tolerability to lowest effective dose, up to a maximum of 0.75 mg/day (IRLSSG/EURLSSG/RLS-F [Garcia-Borreguero 2016]; Silber 2021).

Note: If augmentation occurs (worsening symptoms during dopaminergic therapy), dose earlier in the evening, divide into multiple evening doses, increase dose (keeping at or below 0.75 mg/day), or consider switching to alternative therapy (IRLSSG/EURLSSG/RLS-F [Garcia-Borreguero 2016]).

Discontinuation of therapy: Do not discontinue abruptly; the manufacturer of the IR and ER formulations recommends reducing dose by 0.75 mg/day until daily dose is 0.75 mg, then reducing by 0.375 mg/day thereafter.

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Kidney Impairment: Adult

Parkinson disease: Immediate release:

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

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

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

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

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

Parkinson disease: Extended release:

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

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

CrCl <30 mL/minute: Use not recommended.

ESRD requiring hemodialysis: Use not recommended.

Restless legs syndrome: Immediate release:

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

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

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

Dosing: Hepatic Impairment: Adult

There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); however, no adjustment expected since undergoes minimal hepatic metabolism.

Dosing: Older Adult

Refer to adult dosing.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral, as dihydrochloride monohydrate:

Mirapex: 0.125 mg [contains corn starch]

Mirapex: 0.25 mg [DSC], 0.5 mg [scored; contains corn starch]

Mirapex: 0.75 mg [contains corn starch]

Mirapex: 1 mg, 1.5 mg [DSC] [scored; contains corn starch]

Generic: 0.125 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 1.5 mg

Tablet Extended Release 24 Hour, Oral, as dihydrochloride monohydrate:

Mirapex ER: 0.375 mg, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg, 4.5 mg [contains corn starch]

Generic: 0.375 mg, 0.75 mg, 1.5 mg, 2.25 mg, 3 mg, 3.75 mg, 4.5 mg

Generic Equivalent Available: US

Yes

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral, as dihydrochloride monohydrate:

Mirapex: 0.125 mg, 0.25 mg, 0.5 mg [DSC], 1 mg [DSC], 1.5 mg [DSC]

Generic: 0.25 mg, 0.5 mg, 1 mg, 1.5 mg

Administration: Adult

Oral:

Administer with or without food; administer with food to decrease nausea. ER tablets should be swallowed whole and not chewed, crushed, or divided. For restless legs syndrome, administer 2 to 3 hours before bedtime; if augmentation occurs, dose earlier in the day, divide into multiple daily doses, or consider switching to alternative therapy (Garcia-Borreguero 2016).

Bariatric surgery: Tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. IR tablet formulation is available. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery.

Use: Labeled Indications

Parkinson disease: Treatment of Parkinson disease.

Restless legs syndrome (immediate release only): Treatment of moderate to severe primary restless legs syndrome.

Medication Safety Issues
Sound-alike/look-alike issues:

Mirapex may be confused with Hiprex, Mifeprex, MiraLax

Adverse Reactions (Significant): Considerations
Augmentation

Augmentation, a worsening of symptoms beyond the level of severity that was experienced when the medication was initiated, has been reported with dopamine agonists such as pramipexole, in patients with restless leg syndrome (RLS) (Ref). In addition to severity, the symptoms occur at an earlier time of day compared to pretreatment timing of symptoms (Ref). A pooled meta-analysis reported an overall augmentation rate of 5.6% in RLS with treatment (not specifically with pramipexole) (Ref). Historically, treatment with levodopa has been associated with the highest rate followed by dopamine agonists, such as pramipexole (Ref).

Mechanism: Dose- and duration-related; not clearly established. Proposed mechanisms include increased dopamine concentrations in the CNS and overstimulation of the dopamine D1 receptors compared to dopamine D2 receptors in the spinal cord (Ref). Iron deficiency may also reduce the function of the dopamine transporter, increasing dopamine concentrations (Ref). In addition, augmentation may also result from dopamine receptor down-regulation, which lowers tolerance to dopaminergic effects in a circadian manner (Ref).

Onset: Delayed; usually after months of treatment (mean duration 8.8 months) (Ref).

Risk factors:

• Higher doses (Ref)

• Longer duration of therapy (Ref)

• More severe RLS prior to treatment (may be related to higher dose use) (Ref)

• Iron deficiency (Ref)

• Older patients (Ref)

• Use of IR formulations (Ref)

Heart failure

Studies have identified a possible link between heart failure and pramipexole use (Ref). In these studies, the incidence of heart failure was higher in patients taking pramipexole compared to other dopamine agonists used for Parkinson disease or restless leg syndrome (RLS). This suggests that this adverse effect is most likely not a class effect (Ref).

Mechanism: Non–dose-related. In addition to high affinity for the dopamine D2, D3, and D4 receptors, pramipexole is also an alpha-2 adrenergic receptor agonist. It has been proposed by directly activating alpha-2 adrenergic receptors, this agent may reduce adrenergic tone and myocardial contractility (Ref).

Onset: Not clearly established. One study demonstrated the highest risk within the first 3 months after initiation (Ref) while two studies suggested otherwise (Ref).

Risk factors:

• Longer duration of use (Ref)

• History of cardiac disease (Ref)

• Older patients (Ref)

Impulse control disorders

Pramipexole has been associated with impulse control disorders, manifesting as pathological gambling, increased libido (hypersexuality), compulsive or binge buying/eating, and/or other intense urges (Ref). The prevalence of impulsive control was reported to range from 2.6% to 34.8% in Parkinson disease (PD). A lower prevalence was reported in patients taking dopamine agonists, such as pramipexole, for restless leg syndrome (RLS) (Ref). Rates of clearly pathological behaviors (ie, behaviors affecting social or occupational functioning) as high as 13% have been reported with therapeutic doses of pramipexole (defined as >2 mg/day) (Ref). Literature suggests that a clear temporal relationship exists between initiation and symptom onset and rapid resolution of symptoms usually occur after discontinuation (Ref).

Mechanism: Possibly dose-related; May be due to activation of dopamine receptors (mostly D3) involved in both the nigrostriatal and the reward pathways (Ref).

Onset: Difficult to determine. Most case reports discussed this presentation within months of therapy (Ref).

Risk factors:

• Higher doses (Ref)

• Higher affinity for D3 receptors (Ref)

• Males (for PD) (Ref)

• Younger age (Ref)

• Family or personal history of psychiatric symptoms (eg, anxiety and depression) (Ref)

• Earlier onset of PD (Ref)

• Longer duration of PD (Ref)

Nausea and vomiting

Nausea and vomiting are known side effects of dopamine agonists, such as pramipexole. Studies have shown no apparent difference between immediate-release and extended-release treatment (Ref).

Mechanism: Dose-related; may be related to direct D2 receptor agonism within the chemoreceptor trigger zone (Ref).

Onset: Commonly seen in early phase of treatment (Ref). It is important to note that reports of nausea and vomiting in studies may be subject to recall bias; so, it is unclear whether the onset of symptoms occurred with the first doses or required weeks of therapy prior to onset (Ref).

Risk factors (possible):

• Higher dose (Ref)

• Rapid up-titration (Ref)

• Administration on an empty stomach (Ref)

Orthostatic hypotension

Pramipexole may cause orthostatic hypotension (Ref). Patients with Parkinson disease (PD) may have an impaired capacity to respond to a postural change due to neurodegenerative processes in the brain stem. Orthostatic hypotension may be asymptomatic or symptomatic, leading to dizziness and falling (Ref). In one systematic review, the risk of hypotension was approximately four times lower with pramipexole than ropinirole when each drug was individually compared with placebo (Ref).

Mechanism: Primarily by venous and arterial dilation through inhibition of the sympathetic nervous system (Ref). Agents with lower affinity for D2 receptors may be associated with lower risk of orthostatic hypotension (Ref).

Onset: Varied; may occur at any point during treatment (Ref).

Risk factors:

• Initiation of therapy or dose escalation

• Autonomic dysfunction (as with PD) (Ref)

• Concurrent medications that may cause orthostatic hypotension (eg, antihypertensive or antiarrhythmic medications, diuretics, levodopa, monoamine oxidase inhibitors, tricyclic antidepressants) (Ref)

• Cardiovascular disease (eg, heart failure) (Ref)

• Hypovolemia (Ref)

• Younger patients with asthenic features (Ref)

Psychotic-like effects

Pramipexole may cause or exacerbate behavioral changes, including psychotic symptoms (eg, paranoid ideation, hallucinations, delusions, confusion, mania, disorientation, aggressive behavior, agitation, delirium) (Ref). Data have suggested a higher incidence with pramipexole versus ropinirole when compared to placebo (Ref).

Mechanism: Dose- and duration-related; Pramipexole is a non-ergot full agonist at D2 receptors, with some activity at D3 and D4 receptors as well (Ref). Psychosis is thought to result from D2 receptor stimulation (Ref).

Onset: Varied; one case report identified effects (eg, visual hallucinations) within approximately 2 to 4 weeks of dose up-titration (Ref).

Risk factors:

• Higher doses (Ref)

• Longer duration of therapy (Ref)

• Comorbid cognitive impairment or dementia (Ref)

• Older patients (hallucinations)

• Number of comorbidities and concurrent medications (Ref)

Somnolence and sleep attacks

Somnolence (drowsiness) is an adverse reaction of dopamine agonists, including pramipexole (Ref). Patients taking pramipexole may experience sleep attacks (sudden onset of sleep), defined as sudden, irresistible, overwhelming sleepiness without awareness of falling sleep (Ref). Sleep attacks may also occur in patients with Parkinson disease (PD) in the absence of dopaminergic medications (Ref).

Mechanism: Likely multifactorial; related to modulation of dopamine receptors, specifically D3 agonist activity. May also be the result of increased dopamine, leading to down regulation of dopaminergic input to the reticular activating system. Genetic polymorphisms in dopamine receptors may play a role (Ref).

Onset: Delayed; some cases have occurred more than a year after initiation.

Risk factors:

• Longer treatment duration (Ref)

• Patients with PD (Ref)

• Depression in patients with PD (Ref)

• Disease duration <7 years (Ref)

• Age <70 years (Ref)

• History of sleep disorders (other than RLS)

• Concurrent alcohol or medications that may cause sedation or increase pramipexole plasma levels

Withdrawal syndrome

Dopamine agonist withdrawal syndrome (DAWS) has been defined as a stereotyped cluster of physical and psychological symptoms that may be mild, moderate, or severe. Psychiatric symptoms may include anxiety, panic attacks, depression, irritability, agitation, dysphoria, agoraphobia, insomnia, drug cravings, and pain. Physical symptoms may include diaphoresis, flushing, nausea, fatigue, orthostatic hypotension, and vomiting. Psychiatric symptoms are the most common and prominent symptoms (Ref). DAWS has been reported mainly in Parkinson disease (PD), where it affects about 15% to 19% of patients who taper or discontinue a dopamine agonist (Ref). Some recent case reports have identified this syndrome in patients with restless leg syndrome (RLS) as well (Ref). Symptoms may be self-limited or protracted, lasting for months to years (Ref).

Mechanism: Exact mechanism unknown; may be dose-and duration-related. May be due to sudden changes in dopaminergic stimulation (Ref).

Onset: Varied; may occur at any time during taper or after discontinuation (Ref).

Risk factors:

• Higher daily doses (≥1.5 mg/day) (Ref)

• Cumulative exposure to dopamine agonists (Ref)

• Presence of impulse control disorder (Ref)

• History of deep brain stimulation (Ref)

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling as reported with the immediate-release (IR) and extended-release (ER) formulations. IR data are inclusive of trials in early Parkinson disease (PD) without levodopa and restless legs syndrome (RLS). Extended-release (ER) data are from trials in early PD without levodopa.

>10%:

Gastrointestinal: Constipation (IR: PD: 12% to 14%, RLS: 4%; ER: 14%), nausea (IR: PD: 24% to 28%, RLS: 11% to 19%; ER: 22%) (table 1)

Pramipexole: Adverse Reaction: Nausea

Drug (Pramipexole)

Placebo

Dose

Dosage Form

Indication

Number of Patients (Pramipexole)

Number of Patients (Placebo)

28%

18%

N/A

Immediate-release tablets

Early Parkinson disease

388

235

24%

9%

N/A

Immediate-release tablets

Early Parkinson disease

213

103

22%

9%

N/A

Extended-release tablets

Early Parkinson disease

223

103

19%

5%

0.5 mg

Immediate-release tablets

Restless legs syndrome

80

86

16%

5%

0.125 to 0.75 mg/day

Immediate-release tablets

Restless legs syndrome

575

223

11%

5%

0.25 mg

Immediate-release tablets

Restless legs syndrome

88

86

Nervous system: Dizziness (IR: PD: 12% to 25%; ER: 12%) (table 2), drowsiness (IR: PD: 22% to 33%, RLS: 6%; ER: 36%) (table 3), headache (IR: RLS: 16%), insomnia (IR: PD: 4% to 17%; ER: 4%)

Pramipexole: Adverse Reaction: Dizziness

Drug (Pramipexole)

Placebo

Dose

Dosage Form

Indication

Number of Patients (Pramipexole)

Number of Patients (Placebo)

25%

24%

N/A

Immediate-release tablets

Early Parkinson disease

388

235

12%

7%

N/A

Immediate-release tablets

Early Parkinson disease

213

103

12%

7%

N/A

Extended-release tablets

Early Parkinson disease

223

103

Pramipexole: Adverse Reaction: Drowsiness

Drug (Pramipexole)

Placebo

Dose

Dosage Form

Indication

Number of Patients (Pramipexole)

Number of Patients (Placebo)

36%

15%

N/A

Extended-release tablets

Early Parkinson disease

223

103

33%

15%

N/A

Immediate-release tablets

Early Parkinson disease

213

103

22%

9%

N/A

Immediate-release tablets

Early Parkinson disease

388

235

6%

3%

0.125 to 0.75 mg/day

Immediate-release tablets

Restless legs syndrome

575

223

Neuromuscular & skeletal: Asthenia (IR: PD:14%; ER: 3%)

1% to 10%:

Cardiovascular: Edema (IR: PD: 5%), orthostatic hypotension (ER: 3%) (table 4), peripheral edema (IR: PD: 5% to 8%; ER: 5%)

Pramipexole: Adverse Reaction: Orthostatic Hypotension

Drug (Pramipexole)

Placebo

Dose

Dosage Form

Indication

Number of Patients (Pramipexole)

Number of Patients (Placebo)

3%

1%

N/A

Extended-release tablets

Early Parkinson disease

223

103

0%

1%

N/A

Immediate-release tablets

Early Parkinson disease

213

103

Endocrine & metabolic: Decreased libido (IR: PD: 1%), weight loss (IR: PD: 2%)

Gastrointestinal: Abdominal distress (IR: PD: 1%; ER: 2%), anorexia (IR: PD: 4%), diarrhea (IR: RLS: 1% to 3%), dyspepsia (IR: PD: 3%; ER: 3%), dysphagia (IR: PD: 2%), increased appetite (IR: PD: 2%; ER: 3%), upper abdominal pain (IR: PD: 4%; ER: 3%), vomiting (IR: PD: 4%; ER: 4%) (table 5), xerostomia (IR: PD: 4%, RLS: 3%; ER: 5%)

Pramipexole: Adverse Reaction: Vomiting

Drug (Pramipexole)

Placebo

Dose

Dosage Form

Indication

Number of Patients (Pramipexole)

Number of Patients (Placebo)

4%

0%

N/A

Immediate-release tablets

Early Parkinson disease

213

103

4%

0%

N/A

Extended-release tablets

Early Parkinson disease

223

103

Genitourinary: Impotence (IR: PD: 2%)

Infection: Influenza (IR: RLS: 3% to 4%)

Nervous system: Abnormality in thinking (IR: PD: 2%), akathisia (IR: PD: 2%), amnesia (IR: PD: 4%), balance impairment (ER: 2%), confusion (IR: PD: 4%) (table 6), depression (ER: 2%), dystonia (IR: PD: 2%), falling (IR: PD: 4%; ER: 4%) (table 7), fatigue (IR: PD: 6%, RLS: 9%; ER: 6%), hallucination (IR: PD: 6% to 9%, RLS: <1%; ER: 5%; includes auditory hallucination, visual hallucination, and mixed hallucinations) (table 8), hypoesthesia (IR: PD: 3%), malaise (IR: PD: 2%), myoclonus (IR: PD: 1%), sleep disorder (IR: PD: 3%; ER: 2%), sudden onset of sleep (IR: PD: 6%; ER: 3%) (table 9), vertigo (IR: PD: 2%; ER: 4%)

Pramipexole: Adverse Reaction: Confusion

Drug (Pramipexole)

Placebo

Dose

Dosage Form

Indication

Number of Patients (Pramipexole)

Number of Patients (Placebo)

4%

1%

N/A

Immediate-release tablets

Early Parkinson disease

388

235

Pramipexole: Adverse Reaction: Falling

Drug (Pramipexole)

Placebo

Dose

Dosage Form

Indication

Number of Patients (Pramipexole)

Number of Patients (Placebo)

4%

1%

N/A

Extended-release tablets

Early Parkinson disease

223

103

4%

1%

N/A

Immediate-release tablets

Early Parkinson disease

213

103

Pramipexole: Adverse Reaction: Hallucination

Drug (Pramipexole)

Placebo

Dose

Dosage Form

Indication

Number of Patients (Pramipexole)

Number of Patients (Placebo)

9%

3%

N/A

Immediate-release tablets

Early Parkinson disease

388

235

6%

1%

N/A

Immediate-release tablets

Early Parkinson disease

213

103

5%

1%

N/A

Extended-release tablets

Early Parkinson disease

223

103

0.1%

N/A

N/A

Immediate-release tablets

Restless legs syndrome

889

N/A

Pramipexole: Adverse Reaction: Sudden Onset of Sleep

Drug (Pramipexole)

Placebo

Dose

Dosage Form

Indication

Number of Patients (Pramipexole)

Number of Patients (Placebo)

6%

1%

N/A

Immediate-release tablets

Early Parkinson disease

213

103

3%

1%

N/A

Extended-release tablets

Early Parkinson disease

223

103

Neuromuscular & skeletal: Limb pain (IR: RLS: 3%), muscle spasm (ER: 5%), tremor (IR: PD: 3%; ER: 3%)

Ophthalmic: Visual disturbance (IR: PD: 3%)

Respiratory: Cough (IR: PD: 3%; ER: 3%), nasal congestion (IR: RLS: 3%)

Miscellaneous: Fever (IR: PD: 1%)

Frequency not defined: Nervous system: Restless leg syndrome (IR: augmentation, rebound, or worsening of RLS)

Postmarketing (all indications and formulations):

Cardiovascular: Heart failure (Mokhles 2012), syncope

Dermatologic: Erythema of skin, pruritus, skin rash (Tashkent 2018), urticaria

Endocrine & metabolic: SIADH (Tomita 2005), weight gain

Gastrointestinal: Abnormal stools (tablet residue; may be associated with worsening of PD symptoms)

Genitourinary: Retroperitoneal fibrosis (Antonini 2007)

Nervous system: Aggressive behavior, agitation, altered mental status, behavioral changes, delirium, delusion, disorientation, impulse control disorder (including binge eating, compulsive shopping, increased libido, mania, pathological gambling) (Kolla 2010), paranoid ideation, psychotic symptoms (Li 2008), withdrawal syndrome (including anxiety, diaphoresis, and pain) (Yu 2017)

Neuromuscular & skeletal: Abnormal posture (postural deformities including antercollis, camptocormia [bent spine syndrome] [Kim 2012], and pleurothotonus [Pisa syndrome] [Galati 2014]), rhabdomyolysis

Respiratory: Pleuropulmonary fibrosis (Andersohn 2009)

Contraindications

There are no contraindications listed in the manufacturer's labeling.

Canadian labeling: Hypersensitivity to pramipexole or any component of the formulation.

Warnings/Precautions

Concerns related to adverse effects:

• Dyskinesias: May cause or exacerbate dyskinesias. Use with caution in patients with preexisting dyskinesias.

• Impulse control disorders: Has been associated with compulsive behaviors and/or loss of impulse control, which has manifested as pathological gambling, compulsive buying, libido increases (hypersexuality), binge eating, and/or other intense urges. Dose reduction or discontinuation of therapy has been reported to reverse these behaviors in some, but not all cases.

• Neuroleptic malignant syndrome: Dopaminergic therapy has been reported to cause symptoms resembling neuroleptic malignant syndrome (altered consciousness, autonomic instability, elevated temperature, and muscular rigidity) associated with rapid dose reduction, discontinuation, or changes in therapy; taper dose to decrease risk of hyperpyrexia and confusion.

• Orthostatic hypotension: May cause orthostatic hypotension; Parkinson disease patients appear to have an impaired capacity to respond to a postural challenge. Use with caution in patients at risk of hypotension (such as those receiving antihypertensive drugs) or where transient hypotensive episodes would be poorly tolerated (cardiovascular disease or cerebrovascular disease). Parkinson disease and restless leg syndrome (RLS) patients being treated with dopaminergic agonists ordinarily require careful monitoring for signs and symptoms of postural hypotension, especially during dose escalation, and should be informed of this risk.

• Pleural/Retroperitoneal fibrosis: Ergot-derived dopamine agonists have been associated with fibrotic complications (eg, retroperitoneal fibrosis, pleural effusion, pleural thickening, pulmonary infiltrates, pericarditis, cardiac valvulopathy). Although pramipexole is not an ergot, there have been postmarketing reports of possible fibrotic complications (peritoneal, pleural, pulmonary) with pramipexole; monitor closely for signs and symptoms of fibrosis. Discontinuation of therapy may resolve complications, but not in all cases.

• Postural deformity: Postural deformities, including antecollis, camptocormia (Bent Spine Syndrome) and pleurothotonus (Pisa Syndrome) have been reported following initiation, several months into treatment, or after increasing the dose. Consider dose reduction or treatment discontinuation in patients who develop postural deformity (complications may improve).

• Psychotic effects: May cause or exacerbate mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment or after starting or increasing the dose; manifestations may include paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium. Avoid use in patients with a major psychotic disorder. Older adults may be at a higher risk for hallucinations.

• Retinal changes: Pathologic degenerative changes were observed in the retinas of albino rats during studies with this agent, but were not observed in the retinas of albino mice or in other species. The significance of these data for humans remains uncertain.

• Somnolence: Patients have reported falling asleep while engaging in activities of daily living; this has been reported to occur without significant warning signs; some of these events had been reported one year after the initiation of therapy. Before initiating treatment, advise patients of the potential to develop drowsiness, and inquire about factors that may increase the risk (eg, concomitant sedating medications and/or alcohol, presence of sleep disorders, concomitant medications that increase pramipexole plasma levels). Patients must be cautioned about performing tasks which require mental alertness (eg, operating machinery or driving). Monitor for daytime somnolence or preexisting sleep disorder; discontinue if significant daytime sleepiness or episodes of falling asleep occur; if a decision is made to continue therapy, advise patients not to drive and to avoid other potentially dangerous activities. Pramipexole has been associated with somnolence.

Disease-related concerns:

• Heart failure: A pooled analysis of randomized, placebo-controlled phase 2 and 3 clinical trials demonstrated a more frequent incidence of newly diagnosed heart failure (not statistically significant) in patients receiving pramipexole compared with patients receiving placebo (0.28% [12/4,157] vs 0.14% [4/2,820], respectively) (FDA Drug Safety Communication 2012). Two epidemiologic studies have also suggested an increased incidence of heart failure. The first epidemiologic study, a case-control study in a United Kingdom cohort of patients receiving anti-Parkinson agents (eg, dopamine agonists), revealed a statistically significant increased risk for heart failure in patients exposed to any dopamine agonist compared with no exposure (RR: 1.58; 95% CI: 1.26 to 1.96) with pramipexole being associated with a statistically significant increased risk of heart failure versus no exposure (RR: 1.86; 95% CI: 1.21 to 2.85) (Renoux 2012). In the second epidemiologic study, a case-control study in a cohort of Parkinson disease patients newly initiated on a dopamine agonist or levodopa, found that among the individual non-ergot dopamine agonists studied, only current use of pramipexole was associated with an increased risk of heart failure compared with levodopa use (OR: 1.61; 95% CI: 1.09 to 2.38). This increased risk occurred in the first 3 months of treatment (OR: 3.06; 95% CI: 1.74 to 5.39) and in patients ≥80 years of age (OR: 3.30; 95% CI: 1.62 to 7.13). Of note, the increased risk was not significant with pramipexole use >3 months (Mokhles 2012). The FDA has not concluded that pramipexole increases the risk of heart failure. Due to study limitations and the potential for confounders, the FDA is continuing its review. Monitor for signs and symptoms of heart failure. In a scientific statement from the American Heart Association, pramipexole has been determined to be an agent that may cause direct myocardial toxicity (magnitude: major) (AHA [Page 2016]).

• Renal impairment: Use with caution in patients with renal impairment; dose adjustment may be necessary. ER tablets are not recommended for use in patients with CrCl <30 mL/minute or end-stage renal disease requiring hemodialysis.

• Restless legs syndrome: Augmentation (earlier onset of symptoms in the evening/afternoon, increase and/or spread of symptoms to other extremities) may occur in some RLS patients. Risk factors for dopaminergic-induced augmentation include higher doses of dopaminergic agents, use of shorter-acting dopamine agonists (ie, pramipexole, ropinirole) or levodopa, low iron stores, and increased severity of symptoms prior to treatment initiation. To minimize risk of augmentation, treatment should only be initiated when symptoms significantly impact quality of life; intermittent treatment should also be considered. If dopaminergic agents are used as initial treatment, use the lowest effective dose and avoid exceeding recommended doses. If augmentation occurs, dose earlier in the day, divide into multiple daily doses, or consider switching to alternative therapy. End-of-dose rebound (reappearance of symptoms in the early morning hours that are worse than baseline) may also occur (Garcia-Borreguero 2016). Consider dosage adjustment or discontinuation of treatment if rebound symptoms occur.

Dosage form specific issues:

• ER tablet: Tablet residue resembling a swollen whole or partial tablet may be visible in the stool after taking the ER formulation. Some patients reported a worsening of their Parkinson disease symptoms when tablet residue was observed.

Other warnings/precautions:

• Discontinuation of therapy: Taper gradually when discontinuing therapy in patients with Parkinson disease; dopaminergic agents have been associated with a syndrome resembling neuroleptic malignant syndrome on abrupt withdrawal or significant dosage reduction after long-term use. Apathy, anxiety, depression, fatigue, insomnia, pain, and sweating have occurred during taper or after discontinuation of therapy and may not respond well to levodopa. Educate patient on potential of withdrawal symptoms; consider readministration of a dopamine agonist at the lowest effective dose in patients experiencing symptoms.

Metabolism/Transport Effects

None known.

Drug Interactions

Alcohol (Ethyl): May enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Alizapride: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk X: Avoid combination

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification

Amisulpride (Injection): May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk X: Avoid combination

Amisulpride (Oral): Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Amisulpride (Oral). Amisulpride (Oral) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk X: Avoid combination

Antipsychotic Agents (First Generation [Typical]): Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Antipsychotic Agents (First Generation [Typical]). Antipsychotic Agents (First Generation [Typical]) may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Avoid concomitant therapy if possible. If antipsychotic use is necessary, consider using atypical antipsychotics such as clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin). Risk D: Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Consider avoiding atypical antipsychotic use in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine, quetiapine, or ziprasidone at lower initial doses, or a non-dopamine antagonist (eg, pimavanserin). Risk D: Consider therapy modification

Blood Pressure Lowering Agents: May enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Brivudine [INT]: May enhance the adverse/toxic effect of Anti-Parkinson Agents (Dopamine Agonist). Specifically, the risk of chorea may be increased. Risk C: Monitor therapy

Bromopride: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk C: Monitor therapy

Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination

BuPROPion: Anti-Parkinson Agents (Dopamine Agonist) may enhance the adverse/toxic effect of BuPROPion. Risk C: Monitor therapy

Cimetidine: May increase the serum concentration of Pramipexole. Risk C: Monitor therapy

CNS Depressants: May enhance the sedative effect of Pramipexole. Risk C: Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

DilTIAZem: May enhance the hypotensive effect of Pramipexole. DilTIAZem may increase the serum concentration of Pramipexole. Risk C: Monitor therapy

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy

Fexinidazole: May increase the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of fexinidazole with MATE1/2-K substrates when possible. If combined, monitor for increased MATE1/2-K substrate toxicities. Risk D: Consider therapy modification

Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of Anti-Parkinson Agents (Dopamine Agonist). Kava Kava may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk C: Monitor therapy

Levodopa-Containing Products: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Containing Products. Risk C: Monitor therapy

Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Methotrimeprazine: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Methotrimeprazine. Risk X: Avoid combination

Methylphenidate: May enhance the adverse/toxic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk C: Monitor therapy

Metoclopramide: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk X: Avoid combination

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy

Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy

Risdiplam: May increase the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of risdiplam with MATE substrates if possible. If the combination cannot be avoided, monitor closely for adverse effects. Consider a reduced dose of the MATE substrate according to that substrate's labeling if appropriate. Risk D: Consider therapy modification

Solriamfetol: May enhance the adverse/toxic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk C: Monitor therapy

Sulpiride: May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Risk X: Avoid combination

Tafenoquine: May increase the serum concentration of MATE1/2-K Substrates (Clinically Relevant with Inhibitors). Management: Avoid use of MATE substrates with tafenoquine, and if the combination cannot be avoided, monitor closely for evidence of toxicity of the MATE substrate and consider a reduced dose of the MATE substrate according to that substrate's labeling. Risk D: Consider therapy modification

Triamterene: May enhance the hypotensive effect of Pramipexole. Triamterene may increase the serum concentration of Pramipexole. Risk C: Monitor therapy

Verapamil: May enhance the hypotensive effect of Pramipexole. Verapamil may increase the serum concentration of Pramipexole. Risk C: Monitor therapy

Food Interactions

Food intake does not affect the extent of drug absorption although the time to maximal plasma concentration is delayed when taken with a meal. Management: Administer without regard to meals.

Pregnancy Considerations

Information related to the use of pramipexole for the treatment of Parkinson disease (Benbir 2014; Lamichhane 2014; Mucchiut 2004; Tüfekçioglu 2018) or restless legs syndrome (RLS) (Dostal 2013) in pregnant women is limited. Current guidelines note that the available information is insufficient to make a recommendation for the treatment of RLS in pregnant women (Aurora 2012).

Breastfeeding Considerations

It is not known if pramipexole is present in breast milk.

Pramipexole inhibits prolactin secretion in humans and may potentially inhibit lactation. According to the manufacturer, the decision to continue or discontinue breastfeeding during therapy should take into account the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother.

Dietary Considerations

May be taken with or without food. May be taken with food to decrease nausea.

Monitoring Parameters

Blood pressure, heart rate (especially during dose escalation); body weight changes; CNS depression, fall risk, behavior changes (eg, compulsive behaviors); periodic skin examinations.

Mechanism of Action

Pramipexole is a nonergot dopamine agonist with specificity for the D2 subfamily dopamine receptor, and has also been shown to bind to D3 and D4 receptors. By binding to these receptors, it is thought that pramipexole can stimulate dopamine activity on the nerves of the striatum and substantia nigra.

Pharmacokinetics

Absorption: Rapid

Distribution: Vd: 500 L

Protein binding: ~15%

Metabolism: Negligible (<10%)

Bioavailability: Immediate release: >90%; Extended release (as compared to immediate release): 100%

Half-life elimination: 8.5 hours; Elderly: 12 hours

Time to peak, serum: Immediate release: ~2 hours; Extended release: 6 hours

Excretion: Urine (90% as unchanged drug)

Pharmacokinetics: Additional Considerations

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

Geriatric: The half-life increases approximately 40% and clearance decreases approximately 30% in patients 65 years and older mostly because of reduced renal function with age.

Gender: Clearance is approximately 30% lower in women.

Pricing: US

Tablet, 24-hour (Mirapex ER Oral)

0.375 mg (per each): $27.42

0.75 mg (per each): $27.42

1.5 mg (per each): $27.42

2.25 mg (per each): $27.42

3 mg (per each): $27.42

3.75 mg (per each): $27.42

4.5 mg (per each): $27.42

Tablet, 24-hour (Pramipexole Dihydrochloride ER Oral)

0.375 mg (per each): $6.11 - $16.14

0.75 mg (per each): $6.11 - $16.14

1.5 mg (per each): $16.14

2.25 mg (per each): $16.14

3 mg (per each): $16.14

3.75 mg (per each): $17.74

4.5 mg (per each): $16.14

Tablets (Pramipexole Dihydrochloride Oral)

0.125 mg (per each): $2.95 - $3.34

0.25 mg (per each): $2.94 - $3.34

0.5 mg (per each): $2.95 - $3.34

0.75 mg (per each): $2.95 - $3.34

1 mg (per each): $2.95 - $3.34

1.5 mg (per each): $2.95 - $3.34

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Brand Names: International
  • BI-Sifrol (JP);
  • Biopsol (CL);
  • Calmolan (AT, CZ, HU);
  • Derinik (SE);
  • Doparoxen (EG);
  • Ezaprev (IT, LV);
  • Frodix (GR);
  • Glepark (CZ, NL);
  • Hitoff (PL);
  • Labrixile (CR, DO, GT, HN, NI, PA, SV);
  • Mariprax (GR);
  • Medopexal (LV);
  • Medopexol (CZ);
  • Mepimer (CR, DO, GT, HN, MX, NI, PA, SV);
  • Miramel (IE);
  • Miraper (IT);
  • Mirapex (BB, HK, JP, KR, TW, UA, VE);
  • Mirapexin (BE, BG, CH, CZ, ES, FI, FR, GB, GR, HR, HU, IE, IT, LU, LV, MT, NL, PL, PT, RO, RU, SE, SI);
  • Miraxol (UA);
  • Nixol (AR);
  • Nulipar (AR);
  • Oprimeta (RU);
  • Oprymea (AT, DE, DK, ES, FI, FR, GB, GR, HR, HU, IE, NO);
  • Oxpola (ZA);
  • Pacto (TR);
  • Parkpax (MX);
  • Parmital (CL, VE);
  • Pazoram (ZA);
  • Pexa (TR);
  • Pexola (CO, UY, ZA);
  • Pexolasab (EG);
  • Pipexus (GB, IE);
  • Pisa (BR);
  • Pramex (ZA);
  • Pramexol (TH);
  • Pramifer (GR);
  • Praminex (ID);
  • Pramipex (UA);
  • Pramiprex (LK);
  • Prapexin (IE);
  • Ramipex (NZ, PH, TR);
  • Redipex (VE);
  • Sifrol (AE, AR, AT, AU, BE, BG, BH, BR, CH, CL, CN, CY, CZ, DE, DK, EG, FI, FR, GB, GR, HR, ID, IE, IL, IQ, IR, IS, IT, JO, KW, LB, LK, LT, LY, MT, MX, MY, NL, NO, OM, PE, PH, PL, PT, PY, QA, RO, RU, SA, SE, SG, SK, SY, TH, TR, VN, YE);
  • Sifrol ER (CR, CU, DO, GT, HN, KW, LB, NI, PA, QA, SV);
  • Sifstad (VN);
  • Simipex (AU);
  • Simpral (AU);
  • Stabil (BR);
  • Treatson (ID);
  • Xolepral (LK, ZW)


For country abbreviations used in Lexicomp (show table)

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