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Pramipexole

Pronunciation

Pronunciation

(pra mi PEKS ole)

Index Terms

  • Pramipexole Dihydrochloride Monohydrate

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral, as dihydrochloride monohydrate:

Mirapex: 0.125 mg [contains corn starch]

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

Mirapex: 0.75 mg [contains corn starch]

Mirapex: 1 mg, 1.5 mg [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

Brand Names: U.S.

  • Mirapex
  • Mirapex ER

Pharmacologic Category

  • Anti-Parkinson Agent, Dopamine Agonist

Pharmacology

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.

Absorption

Rapid

Distribution

Vd: 500 L

Metabolism

Negligible (<10%)

Excretion

Urine (90% as unchanged drug)

Time to Peak

Serum: Immediate release: ~2 hours; Extended release: 6 hours

Half-Life Elimination

8.5 hours; Elderly: 12 hours

Protein Binding

~15%

Special Populations: 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).

Special Populations: Elderly

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.

Special Populations: Gender

Clearance is approximately 30% lower in women.

Use: Labeled Indications

Parkinson disease: Treatment of Parkinson disease.

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

Use: Unlabeled

Treatment of depression in bipolar disorder; treatment of fibromyalgia

Contraindications

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

Dosing: Adult

Note: Retitration of dose should be considered for any significant interruption in therapy.

Parkinson disease: Oral:

Immediate release: Initial: 0.125 mg 3 times daily, increase gradually every 5 to 7 days; maintenance (usual): 0.5 to 1.5 mg 3 times daily

Discontinuation of therapy: Reduce dose by 0.75 mg per day until daily dose is equivalent to 0.75 mg once daily, then reduce by 0.375 mg per day thereafter

Extended release: Initial: 0.375 mg once daily; increase gradually not more frequently than every 5 to 7 days to 0.75 mg once daily and then (if necessary) by 0.75 mg per dose; maximum: 4.5 mg once daily.

Discontinuation of therapy: Reduce dose by 0.75 mg per day until daily dose is equivalent to 0.75 mg once daily, then reduce by 0.375 mg per day thereafter.

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

Restless legs syndrome: Oral: Immediate release: Initial: 0.125 mg once daily 2 to 3 hours before bedtime. Dose may be doubled every 4 to 7 days up to 0.5 mg once daily. Note: If augmentation occurs, dose earlier in the day.

Discontinuation of therapy: No gradual dose reduction recommended in manufacturer's labeling; however, worsening of symptoms may occur with abrupt discontinuation.

Bipolar depression (off-label use): Oral: Immediate release: Initial: 0.125 mg given 2 to 3 times daily; increase gradually by 0.125 to 0.25 mg daily every 3 to 7 days to a target range of 1 to 3 mg/day given in 2 to 3 divided doses. In clinical trials, the average dose was 1.7 mg/day and maximum dose allowed was 4.5 to 5 mg/day. Used in combination with mood stabilizers (Goldberg 2004; Zarate 2004).

Fibromyalgia (off-label use): Oral: Immediate release: Initial: 0.25 mg once daily at bedtime; may be increased weekly by 0.25 mg/day increments up to 4.5 mg daily as a single bedtime dose. Note: Study evaluated use in patients receiving concomitant medications (Holman 2005).

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

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

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

Administration

Doses should be titrated gradually to avoid the onset of intolerable side effects. The dosage should be increased to achieve a maximum therapeutic effect, balanced against the side effects of dyskinesia, hallucinations, somnolence, and dry mouth. Administer with or without food; administer with food to decrease nausea. Extended-release tablets should be swallowed whole and not chewed, crushed, or divided. For RLS, administer 2 to 3 hours before bedtime; if augmentation occurs, dose earlier in the day.

Dietary Considerations

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

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F). Protect from light and high humidity.

Drug Interactions

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

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

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Amisulpride: Anti-Parkinson Agents (Dopamine Agonist) may diminish the therapeutic effect of Amisulpride. Amisulpride may diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). 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 and monitor for decreased effects of both agents when these combinations cannot be avoided. Atypical antipsychotics such as clozapine and quetiapine may be less likely to reduce the effects of anti-Parkinson agents. Consider therapy modification

Antipsychotic Agents (Second Generation [Atypical]): May diminish the therapeutic effect of Anti-Parkinson Agents (Dopamine Agonist). Management: Consider using an alternative antipsychotic agent when possible in patients with Parkinson disease. If an atypical antipsychotic is necessary, consider using clozapine or quetiapine, which may convey the lowest interaction risk. Consider therapy modification

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

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

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

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

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

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

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

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

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

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

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

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

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

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

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

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

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

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. 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. Consider therapy modification

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

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

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

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

Sulpiride: May diminish the therapeutic effect of Pramipexole. Pramipexole may diminish the therapeutic effect of Sulpiride. Avoid combination

Adverse Reactions

Actual frequency may be dependent on dose and/or formulation. All adverse reactions are as reported for Parkinson disease unless otherwise noted.

>10%:

Cardiovascular: Orthostatic hypotension (3% to 53%; dose related)

Central nervous system: Drowsiness (Parkinson disease: 9% to 36%; dose related; restless leg syndrome: 6%), extrapyramidal reaction (28%), insomnia (Parkinson disease: 4% to 27%; restless leg syndrome: 13%), dizziness (2% to 26%), hallucination (5% to 17%), headache (restless leg syndrome: 16%; Parkinson disease: 4% to 7%), worsening of restless leg syndrome (augmentation; 12%), abnormal dreams (Parkinson disease: 11%; restless leg syndrome: 8%)

Gastrointestinal: Nausea (Parkinson disease: 11% to 28%; dose related; restless leg syndrome: 11% to 27%), constipation (Parkinson disease: 6% to 14%; dose related; restless leg syndrome: 4%)

Neuromuscular & skeletal: Dyskinesia (17% to 47%), weakness (3% to 14%)

Miscellaneous: Accidental injury (17%)

1% to 10%:

Cardiovascular: Peripheral edema (2% to 8%), edema (4% to 5%), chest pain (3%)

Central nervous system: Worsening of restless leg syndrome (rebound; 10%), confusion (4% to 10%), fatigue (restless leg syndrome: 7% to 9%; Parkinson disease: 6%), dystonia (2% to 8%), abnormal gait (7%), hypertonia (7%), amnesia (4% to 6%; dose related), narcolepsy (2% to 6%), falling (4%), impulse control disorder (3% to 4%; eg, binge eating, hypersexuality, pathological gambling, shopping), vertigo (2% to 4%), hypoesthesia (3%), abnormality in thinking (2% to 3%), akathisia (2% to 3%), malaise (2% to 3%), sleep disorder (1% to 3%), equilibrium disturbance (2%), paranoia (2%), depression (2%), delusions (1%), myasthenia (1%), myoclonus (1%)

Dermatologic: Dermatological disease (2%)

Endocrine & metabolic: Weight loss (2%), decreased libido (1%)

Gastrointestinal: Xerostomia (Parkinson disease: 4% to 7%; restless leg syndrome: 3%), diarrhea (restless leg syndrome: 1% to 7%; Parkinson disease: 2%), anorexia (4% to 5%), vomiting (4%), upper abdominal pain (3% to 4%), dyspepsia (3%), increased appetite (2% to 3%), dysphagia (2%), sialorrhea (2%), abdominal distress (1% to 2%)

Genitourinary: Urinary frequency (6%), urinary tract infection (4%), impotence (2%), urinary incontinence (2%)

Infection: Influenza (restless leg syndrome: 3% to 7%)

Neuromuscular & skeletal: Limb pain (restless leg syndrome: 3% to 7%), muscle spasm (5%), arthritis (3%), tremor (3%), back pain (2% to 3%), bursitis (2%), muscle twitching (2%), elevated creatinine phosphokinase (1%)

Ophthalmic: Accommodation disturbance (4%), visual disturbance (3%), diplopia (1%)

Respiratory: Nasal congestion (restless leg syndrome: 3% to 6%), dyspnea (4%), cough (3%), rhinitis (3%), pneumonia (2%)

Miscellaneous: Fever (1%)

<1% (Limited to important or life-threatening): Aggressive behavior, agitation, altered mental status, behavioral changes, cardiac failure, delirium, delusions, disorientation, fibrothorax, increased libido, paranoia, peritoneal fibrosis, psychotic symptoms, pulmonary fibrosis, rhabdomyolysis, SIADH, syncope

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.

• Melanoma: Risk for melanoma development is increased in Parkinson disease patients; drug causation or factors contributing to risk have not been established. Patients should be monitored closely and periodic skin examinations should be performed.

• 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 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, 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.

• 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 (HF): A pooled analysis of randomized, placebo-controlled phase 2 and 3 clinical trials demonstrated a more frequent incidence of newly diagnosed HF (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 HF. 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 HF 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 HF 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 HF 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 HF. 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. Extended-release tablets are not recommended for use in patients with CrCl <30 mL/minute or ESRD requiring hemodialysis.

• Restless legs syndrome (RLS): Augmentation (earlier onset of symptoms in the evening/afternoon, increase and/or spread of symptoms to other extremities) or rebound (worsening of symptoms following treatment cessation with greater intensity than before treatment initiation) may occur in some RLS patients.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: May be prone to an increased risk of adverse drug reactions.

Dosage form specific issues:

• Extended-release tablet: Tablet residue resembling a swollen whole or partial tablet may be visible in the stool after taking the extended-release 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.

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.

Pregnancy Considerations

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

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience headache, nausea, constipation, insomnia, dry mouth, loss of strength and energy, nightmares, diarrhea, muscle spasms, or weight loss. Have patient report immediately to prescriber uncontrollable urges, confusion, skin growths, mole changes, polyuria, severe dizziness, passing out, sweating a lot, shortness of breath, excessive weight gain, swelling of arms or legs, vision changes, abnormal movements, difficulty moving, hallucinations, memory impairment, muscle pain, muscle weakness, behavioral changes, mood changes, narcolepsy, severe fatigue, or signs of restless leg syndrome (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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