Mirapex

Generic Name: Pramipexole Dihydrochloride
Class: Nonergot-derivative Dopamine Receptor Agonists
VA Class: CN500
Chemical Name: (S)-4,5,6,7-Tetrahydro-N6-propyl,2,6-benzothiazolediamine
Molecular Formula: C₁₀H₁₇N₃S
CAS Number: 104632-26-0

Introduction

Nonergot-derivative dopamine receptor agonist.^{1 2 3 6 7 8 9 15 16 17 18 19}

Uses for Mirapex

Parkinsonian Syndrome

Symptomatic management of idiopathic parkinsonian syndrome.^{1 2 6 7 8 9 10 13 14 15 16 17 18 19}

Used as an adjunct to levodopa for the symptomatic management of parkinsonian syndrome in patients with advanced disease.^{23 24}

Also used as monotherapy for the initial symptomatic management of parkinsonian syndrome.²³ Most clinicians would use levodopa for initial therapy in individuals >70 years of age (less likely than younger individuals to develop levodopa-related motor complications and because of concerns about cognitive dysfunction), in patients with cognitive impairment, and in those with severe disease.²³ A dopamine receptor agonist may be preferred for initial therapy in patients ≤70 years of age.²³

Mirapex Dosage and Administration

Administration

Oral Administration

Administer orally, usually in 3 equally divided doses daily.¹

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

Dosage

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

Adults

Parkinsonian Syndrome

Oral

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

Table 1. Usual Initial Dosage of Pramipexole Dihydrochloride for the Treatment of Parkinsonian Syndrome1

Week of Therapy	Daily Dosage Schedule	Total Daily Dose
1	0.125 mg 3 times daily	0.375 mg daily
2	0.25 mg 3 times daily	0.75 mg daily
3	0.5 mg 3 times daily	1.5 mg daily
4	0.75 mg 3 times daily	2.25 mg daily
5	1 mg 3 times daily	3 mg daily
6	1.25 mg 3 times daily	3.75 mg daily
7	1.5 mg 3 times daily	4.5 mg daily

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

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

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

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

Special Populations

Renal Impairment

Parkinsonian Syndrome

Oral

Modify dosage and/or frequency of administration in response to the degree of renal impairment.^{1 17}

Table 2. Recommended Dosage of Pramipexole Dihydrochloride for Patients with Renal Impairment115

Clcr	Initial Dosage	Maximum Dosage
≥60 mL/minute	0.125 mg 3 times daily	1.5 mg 3 times daily
35–59 mL/minute	0.125 mg twice daily	1.5 mg twice daily
15–34 mL/minute	0.125 mg once daily	1.5 mg once daily
<15 mL/minute	Not adequately studied; no specific recommendation
Hemodialysis	Not adequately studied; no specific recommendation

Geriatric Patients

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

Cautions for Mirapex

Contraindications

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  Known hypersensitivity to pramipexole dihydrochloride or to any ingredient in the formulation.¹

  
  

Warnings/Precautions

Warnings

Somnolence

Sudden, irresistible attacks of sleep that resemble narcolepsy have been reported in patients treated with pramipexole.^{1 20 21 22} Episodes of falling asleep while engaged in activities of daily living (e.g., business meetings, telephone calls, driving), which occasionally resulted in accidents, have been reported,^{1 20 21 22 23} in some cases as late as 1 year after initiation of pramipexole therapy.^{1 20 21 22} Some patients perceived no warning signs (e.g., excessive drowsiness) and believed that they were alert immediately prior to the event;^{1 20 21 22 23} many experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history.^{1 20 21 23}

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 experiencing sudden sleep onset.²⁰ Sleep attacks appear to occur more frequently at higher dosages but may occur at any dosage.²⁰ Somnolence is common at dosages >1.5 mg daily.^{1 20 21}

Patients should not drive or operate other machinery until effects on the individual are known.¹

Continually reassess patients for drowsiness or sleepiness.^{1 20 21 22} Patients may not acknowledge drowsiness or sleepiness until directly questioned about such adverse effects during specific activities.^{1 20 21} Ask patients about any factors that may increase the risk of somnolence (e.g., concomitant sedating drugs, the presence of sleep disorders, concomitant drugs that increase plasma pramipexole concentrations).^{1 20 21}

Pramipexole generally should be discontinued if a patient develops clinically important daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating).^{1 20 21} If the drug is continued, the patient should be advised not to drive and to avoid other potentially dangerous activities.^{1 20 21} Insufficient information to establish that dosage reduction will eliminate episodes of falling asleep while engaged in activities of daily living.^{1 20 21}

Hallucinations

Potential for hallucinations, particularly in geriatric patients.¹

Symptomatic Hypotension

Dopamine agonists appear to impair systemic regulation of BP in patients with parkinsonian syndrome; patients with parkinsonian syndrome appear to have an impaired capacity to respond to an orthostatic challenge.¹

Use of dopamine agonists in patients with parkinsonian syndrome ordinarily requires careful monitoring for manifestations of orthostatic hypotension, especially during dosage escalation.¹ Unexpectedly, the reported incidence of clinically important orthostatic hypotension with pramipexole did not differ from that with placebo in clinical trials;¹ however, a dose-dependent increase in the incidence of postural hypotension occurs over a pramipexole dihydrochloride dosage range of 1.5–6 mg daily.¹

Caution patients about 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

General Precautions

Rhabdomyolysis

Rhabdomyolysis reported in at least 1 patient with advanced parkinsonian syndrome treated with pramipexole.¹

Nervous System and Muscular Effects

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

If pramipexole therapy is discontinued, gradual dosage reduction over a period of 1 week is recommended; in some studies, however, abrupt discontinuance was uneventful.¹

Dyskinesia

May potentiate adverse dopaminergic effects of levodopa and may cause or exacerbate preexisting dyskinesias.^{1 7 8 11 13} Reduction of levodopa dosage may ameliorate dyskinesia.¹

Fibrotic Effects

Retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, and thickening of pleura reported in patients receiving ergot-derivative dopamine receptor agonists (e.g., bromocriptine, pergolide);¹ presumably related to the ergoline structure of these agents.¹ Not known whether non-ergot-derived drugs that increase dopaminergic activity (e.g., pramipexole) may induce similar changes.¹

Ocular Effects

Retinal degeneration reported in albino rats receiving pramipexole for 2 years; similar changes not observed in albino mice, monkeys, or minipigs.¹ Clinical importance in humans not established.¹

Specific Populations

Pregnancy

Category C.¹

Lactation

Appears to be distributed into milk in rats.¹ Not known whether pramipexole is distributed into human milk.¹ Pramipexole inhibits prolactin secretion.¹ Discontinue nursing or the drug.¹

Pediatric Use

Safety and efficacy not established in children.^{1 20}

Geriatric Use

Geriatric patients are at increased risk for hallucinations.¹ No other apparent differences in efficacy or safety between geriatric patients and younger adults.¹

Renal Impairment

Use with caution.¹ Clearance is decreased.¹ Dosage adjustment recommended.^{1 15} (See Renal Impairment under Dosage and Administration.)

Safety and efficacy not evaluated systematically in patients with Cl_cr <15 mL/minute or in those undergoing hemodialysis.¹

Common Adverse Effects

Patients with early parkinsonian syndrome (without levodopa): Nausea, dizziness, somnolence, insomnia, asthenia, constipation, hallucinations, general edema, peripheral edema.¹

Patients with advanced parkinsonian syndrome (with concomitant levodopa): Postural hypotension, dyskinesia, extrapyramidal syndrome, insomnia, dizziness, hallucinations, accidental injury, dream abnormalities, confusion, asthenia, constipation, somnolence, dystonia, dry mouth, gait abnormalities, hypertonia, amnesia, urinary frequency.¹

Interactions for Mirapex

Does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2E1, 3A4, or 2D6 at usual plasma concentrations; is not appreciably metabolized by CYP isoenzymes.¹

Drugs Eliminated via Renal Secretion

Drugs that are secreted by the cationic transport system may decrease the oral clearance of pramipexole by about 20%; those secreted by the anionic transport system are likely to have little effect on the oral clearance of pramipexole.¹

Dopamine Antagonists

Possible pharmacodynamic interaction, resulting in diminished effectiveness of pramipexole.¹

Specific Drugs

Drug	Interaction	Comments
Amantadine	Alteration of oral clearance of pramipexole is unlikely1
Antipsychotic agents (e.g., phenothiazines, butyrophenones, thioxanthenes)	Dopamine antagonist activity of the antipsychotic agent may diminish effectiveness of pramipexole1
Cephalosporins	Effect on oral clearance of pramipexole is unlikely1
Chlorpropamide	Effect on oral clearance of pramipexole is unlikely1
Cimetidine	Cimetidine-induced inhibition of renal tubular secretion of organic bases via the cationic transport system increases the AUC and prolongs the half-life of pramipexole1
CNS depressants (e.g., alcohol, antidepressants, antipsychotics, benzodiazepines)	Possible additive sedative effects1 20 21
Diltiazem	Diltiazem is secreted by the cationic transport system and may decrease oral clearance of pramipexole1
Hydrochlorothiazide	Effect on oral clearance of pramipexole is unlikely1
Indomethacin	Effect on oral clearance of pramipexole is unlikely1
Levodopa	Additive therapeutic and/or adverse (e.g., dyskinesia) effects; peak plasma levodopa concentration may be higher and occur sooner after administration, but extent of levodopa absorption is not altered1	Consider a reduction in levodopa dosage when pramipexole is added to levodopa therapy1
Metoclopramide	Dopamine antagonist activity of metoclopramide may diminish effectiveness of pramipexole1
Penicillins	Effect on oral clearance of pramipexole is unlikely1
Probenecid	No appreciable alteration of pramipexole pharmacokinetics1
Quinidine and Quinine	Quinidine and quinine are secreted by the cationic transport system and may decrease oral clearance of pramipexole1
Ranitidine	Ranitidine is secreted by the cationic transport system and may decrease oral clearance of pramipexole1
Selegiline	Alteration of oral clearance of pramipexole is unlikely1
Triamterene	Triamterene is secreted by the cationic transport system and may decrease oral clearance of pramipexole1
Verapamil	Verapamil is secreted by the cationic transport system and may decrease oral clearance of pramipexole1

Mirapex Pharmacokinetics

Absorption

Bioavailability

Rapidly absorbed after oral administration, with peak plasma concentration attained in approximately 2 hours.¹ Absolute bioavailability is >90%.¹

Food

Food decreases the rate but not the extent of absorption; time to peak concentration is delayed by about 1 hour.^{1 12}

Distribution

Extent

Widely distributed throughout the body.¹

Plasma Protein Binding

15%.¹

Elimination

Metabolism

No metabolites have been identified in plasma or urine.¹

Elimination Route

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

Half-life

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

Special Populations

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

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

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

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).¹ Protect from light.¹

ActionsActions

• 
  

  Exhibits high binding specificity for and intrinsic activity at dopamine D₂ receptors in vitro compared with other dopamine receptor agonists (e.g., bromocriptine, pergolide);^{3 6 7 8 9 18 19} has a higher affinity for the D₃ subtype¹³ than for the D₂ or D₄ subtypes.^{1 2 9 15 16 19}

  
  


• 
  

  Appears to act by directly stimulating postsynaptic dopamine receptors in the corpus striatum.^{1 6 9 15 16}

  
  

Advice to Patients

• 
  

  Risk of somnolence;¹ possibility of falling asleep while engaged in activities of daily living.^{1 20 21 22 23} Avoid driving or operating machinery until effects on the individual are known.¹

  
  


• 
  

  Potential for orthostatic hypotension (e.g., dizziness, nausea, syncope, sweating), especially during dosage escalation.¹ 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

  
  


• 
  

  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

  
  


• 
  

  Risk of hallucinations, particularly in geriatric patients.¹

  
  


• 
  

  Pramipexole may be taken with or without food; however, taking the drug with food may reduce the occurrence of nausea.¹

  
  


• 
  

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

  
  


• 
  

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

  
  

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Pramipexole Dihydrochloride

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	0.125 mg	Mirapex (with povidone)	Pfizer
		0.25 mg	Mirapex (with povidone; scored)	Pfizer
		0.5 mg	Mirapex (with povidone; scored)	Pfizer
		1 mg	Mirapex (with povidone; scored)	Pfizer
		1.5 mg	Mirapex (with povidone; scored)	Pfizer

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 03/2011. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Mirapex 0.125MG Tablets (BOEHRINGER INGELHEIM): 30/$130.99 or 90/$360.95

Mirapex 0.25MG Tablets (BOEHRINGER INGELHEIM): 90/$349 or 270/$1020.97

Mirapex 0.5MG Tablets (BOEHRINGER INGELHEIM): 90/$336 or 270/$985.96

Mirapex 1MG Tablets (BOEHRINGER INGELHEIM): 90/$336 or 270/$985.96

Mirapex 1.5MG Tablets (BOEHRINGER INGELHEIM): 90/$341 or 270/$974.93

Pramipexole Dihydrochloride 0.125MG Tablets (TEVA PHARMACEUTICALS USA): 30/$85.99 or 90/$239.99

Pramipexole Dihydrochloride 0.25MG Tablets (TEVA PHARMACEUTICALS USA): 90/$239.99 or 270/$679.98

Pramipexole Dihydrochloride 0.5MG Tablets (TEVA PHARMACEUTICALS USA): 90/$239.99 or 270/$679.98

Pramipexole Dihydrochloride 1MG Tablets (TEVA PHARMACEUTICALS USA): 90/$239.99 or 270/$679.98

Pramipexole Dihydrochloride 1.5MG Tablets (TEVA PHARMACEUTICALS USA): 90/$239.99 or 270/$679.98

Disclaimer

This report on medications is for your information only, and is not considered individual patient advice. Because of the changing nature of drug information, please consult your physician or pharmacist about specific clinical use.

The American Society of Health-System Pharmacists, Inc. and Drugs.com represent that the information provided hereunder was formulated with a reasonable standard of care, and in conformity with professional standards in the field. The American Society of Health-System Pharmacists, Inc. and Drugs.com make no representations or warranties, express or implied, including, but not limited to, any implied warranty of merchantability and/or fitness for a particular purpose, with respect to such information and specifically disclaims all such warranties. Users are advised that decisions regarding drug therapy are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and the information is provided for informational purposes only. The entire monograph for a drug should be reviewed for a thorough understanding of the drug's actions, uses and side effects. The American Society of Health-System Pharmacists, Inc. and Drugs.com do not endorse or recommend the use of any drug. The information is not a substitute for medical care.

AHFS Drug Information. © Copyright, 1959-2011, Selected Revisions October 2007. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

References

1. Pfizer. Mirapex (pramipexole dihydrochloride) tablets prescribing information. Kalamazoo, MI; 2003 Jun.

2. Parkinson Study Group. Safety and efficacy of pramipexole in early Parkinson disease. JAMA. 1997; 278:125-130. [IDIS 388331] [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. [IDIS 297374] [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. [IDIS 388119] [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. [IDIS 430280] [PubMed 10371546]

23. 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.

24. Anon. Initial treatment of Parkinson’ disease: wait just a minute. Med Lett Drugs Ther. 2001; 43:59-60. [PubMed 11445778]

More Mirapex resources

• Mirapex Side Effects (in more detail)
• Mirapex Dosage
• Mirapex Use in Pregnancy & Breastfeeding
• Drug Images
• Mirapex Drug Interactions
• Mirapex Support Group
• 39 Reviews for Mirapex - Add your own review/rating

• Mirapex Prescribing Information (FDA)


• Mirapex Consumer Overview


• Mirapex Advanced Consumer (Micromedex) - Includes Dosage Information


• Mirapex MedFacts Consumer Leaflet (Wolters Kluwer)


• Pramipexole Prescribing Information (FDA)


• Mirapex ER Prescribing Information (FDA)


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