Brand names: Mirapex, Mirapex ER
Drug class: Nonergot-derivative Dopamine Receptor Agonists
- Antiparkinsonian Agents
VA class: CN500
Chemical name: (S)-4,5,6,7-Tetrahydro-N6-propyl,2,6-benzothiazolediamine
Molecular formula: C₁₀H₁₇N₃S
CAS number: 104632-26-0

Medically reviewed by Drugs.com on Mar 21, 2024. Written by ASHP.

Introduction

Nonergot-derivative dopamine receptor agonist.

Uses for Pramipexole

Parkinson Disease

Symptomatic management of parkinson disease.

Used as monotherapy in patients with early disease or as an adjunct to levodopa in patients with advanced disease.

Levodopa is currently the most effective drug for relieving motor symptoms of parkinson disease. However, effectiveness of levodopa decreases over time and most patients develop motor complications (e.g., wearing-off symptoms, dyskinesias) with long-term use. Strategies to reduce these complications include adjusting dosage of levodopa, adding other antiparkinsonian agents (e.g., dopamine receptor agonists), or initiating other agents first to delay use of levodopa.

Restless Legs Syndrome

Symptomatic management of moderate-to-severe primary restless legs syndrome (RLS; Willis-Ekbom disease).

Nonergot-derivative dopamine receptor agonists (e.g., pramipexole, ropinirole, rotigotine) are considered one of several drugs of choice for reducing symptoms of RLS.

Pramipexole Dosage and Administration

Administration

Oral Administration

Administer orally as conventional (immediate-release) tablets or extended-release tablets. Extended-release tablets are FDA-labeled for use only in the treatment of parkinson disease.

Immediate-release Tablets

Usually administered in 3 equally divided doses daily in patients with parkinson disease.

Administer once daily 2–3 hours before bedtime in patients with RLS.

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

Extended-release Tablets

Administer once daily.

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

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

Dosage

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

Initiate with low dosage and titrate slowly based on response and tolerability. Increases in BP and heart rate observed in healthy individuals when dosage titrated more quickly (i.e., every 3 days) than recommended.

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

Adults

Parkinsonian Syndrome

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

Immediate-release Tablets

Oral

Initiate with a dosage of 0.375 mg daily (given in 3 divided doses) and increase slowly (no more frequently than every 5–7 days) based on efficacy and tolerability until maximum therapeutic response is achieved. The manufacturer suggests the following dosage titration schedule used in clinical studies (see Table 1).

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

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

When discontinuing therapy, may taper dosage at a rate of 0.75 mg per day until the daily dosage has been reduced to 0.75 mg; thereafter, reduce dosage by 0.375 mg per day.

Extended-release Tablets

Oral

Initiate with a dosage of 0.375 mg once daily and increase gradually (no more frequently than every 5–7 days) based on response and tolerability; manufacturer recommends first increase to 0.75 mg once daily and then subsequent increases by 0.75-mg daily increments up to maximum of 4.5 mg once daily.

When discontinuing therapy, may taper dosage at a rate of 0.75 mg per day until the daily dosage has been reduced to 0.75 mg; thereafter, reduce dosage by 0.375 mg per day.

Switching from Immediate-release to Extended-release Tablets

Oral

Switch patient overnight from immediate-release to extended-release tablets at the same total daily dosage. Following conversion, adjust dosage if necessary based on patient response and tolerability.

Restless Legs Syndrome

Oral

Initially, 0.125 mg (as immediate-release tablets) once daily 2–3 hours before bedtime. If relief is inadequate, may increase dosage at intervals of 4–7 days to 0.25 mg daily and then to 0.5 mg daily.

In clinical studies, dosage of 0.75 mg daily did not provide additional benefit over dosage of 0.5 mg daily.

Pramipexole was discontinued without gradual reduction in dosage in clinical trials evaluating dosages up to 0.75 mg daily; however, abrupt discontinuance resulted in rebound symptoms.

Prescribing Limits

Adults

Parkinsonian Syndrome

Immediate-release Tablets

Oral

Maximum dosage used in clinical studies was 4.5 mg daily.

Extended-release Tablets

Oral

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

Special Populations

Renal Impairment

Modify dose and/or frequency of administration based on degree of renal impairment.

Parkinsonian Syndrome

Immediate-release Tablets

Oral

Extended-release Tablets

Oral

Cl_cr >50 mL/minute: Dosage adjustment not required.

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

Cl_cr <30 mL/minute or hemodialysis: Not studied and not recommended.

Restless Legs Syndrome

Oral

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

Geriatric Patients

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

Cautions for Pramipexole

Contraindications

• None.

Warnings/Precautions

Falling Asleep During Activities of Daily Living and Somnolence

Episodes of falling asleep while engaged in activities of daily living (e.g., driving) reported; sometimes resulted in accidents. Reported as late as 1 year after initiation of pramipexole therapy.

Some patients perceived no warning signs (e.g., excessive drowsiness) and believed they were alert immediately prior to the event. Falling asleep while engaged in activities of daily living usually occurs in a setting of preexisting somnolence, although patients may not give such a history.

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

Somnolence commonly occurs with pramipexole and is more frequent in patients with parkinson disease than in those with RLS.

Continually reassess patients for drowsiness or sleepiness. Patients may not acknowledge drowsiness or sleepiness until directly questioned about such adverse effects during specific activities. 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).

In general, discontinue therapy if a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating). If the drug is continued, advise patient not to drive and to avoid other potentially dangerous activities. Insufficient information to establish whether dosage reduction will eliminate this adverse event.

Orthostatic Hypotension

Dopamine agonists appear to impair systemic regulation of BP, which can result in orthostatic hypotension, especially during dosage escalation. Orthostatic hypotension can also be a manifestation of parkinson disease.

Carefully monitor patients for signs and symptoms of orthostatic hypotension, particularly during dosage escalation.

Impulse Control/Compulsive Behaviors

Intense urges and compulsive behaviors (e.g., urge to gamble, increased sexual urges, binge eating, uncontrolled spending, other intense urges) and inability to control these urges reported in some patients receiving dopaminergic agents. In some cases, urges stopped when dosage was reduced or drug was discontinued.

Consider reducing dosage or discontinuing pramipexole if patient develops such urges.

Hallucinations/Psychotic-like Behavior

Potential for hallucinations in patients with parkinson disease. Increased risk observed in geriatric patients.

During postmarketing experience, other new or worsening mental status and behavioral changes (e.g., paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, delirium) reported during therapy or after initiating or increasing dosage. Other antiparkinsonian agents can produce similar effects.

Use generally not advised in patients with a major psychotic disorder. Concomitant use with certain antipsychotic agents may exacerbate symptoms of parkinson disease and decrease effectiveness of pramipexole.

Dyskinesia

May cause or exacerbate preexisting dyskinesias.

Postural Deformity

Postural deformities, including antecollis, camptocormia (bent spine syndrome), and pleurothotonus (pisa syndrome), reported after initiating therapy or increasing dosage. In some cases, occurred after several months.

If postural deformity occurs, consider reducing dosage or discontinuing therapy.

Rhabdomyolysis

Rhabdomyolysis reported in at least one patient with advanced parkinson disease receiving pramipexole.

Advise patients to contact a clinician if they experience any possible symptoms of rhabdomyolysis (e.g., unexplained muscle pain, tenderness, weakness).

Ocular Effects

In animal studies, retinal changes and degeneration observed in rats; clinical importance not established.

Results of a clinical study did not reveal any clinically important differences in retinal effects between pramipexole and ropinirole.

Hyperpyrexia and Confusion

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

When discontinuing pramipexole therapy, gradually reduce dosage.

Fibrotic Effects

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

Possible fibrotic complications (e.g., peritoneal, pleural, or pulmonary fibrosis) reported during postmarketing experience with pramipexole. Causal relationship not established; however, possible contributory role of the drug cannot be excluded.

Augmentation and Rebound in RLS

Long-term use of dopaminergic agents in patients with RLS associated with augmentation (worsening of symptoms during treatment); augmentation can manifest as an increase in overall symptom severity or earlier time of symptom onset each day. In clinical studies, incidence of augmentation increased with increasing duration of pramipexole treatment.

Rebound symptoms following abrupt discontinuance of therapy also reported in patients with RLS; symptoms were generally mild.

Incidence, severity, and management of augmentation and/or rebound in patients receiving long-term pramipexole therapy not adequately evaluated.

FDA Drug Safety Communication on Possible Increased Risk of Heart Failure

FDA notified healthcare professionals about a possible increased risk of heart failure with pramipexole (Mirapex) on September 19, 2012. This was prompted by findings from a pooled analysis of randomized clinical trials and 2 epidemiologic studies. At this time, FDA has not concluded that pramipexole increases the risk of heart failure and is continuing to review this safety concern. For more information visit the FDA website at: [Web].

Specific Populations

Pregnancy

No adequate data in pregnant women; teratogenic potential not completely established in animal studies.

Lactation

Distributed into milk in rats. Not known whether pramipexole is distributed into human milk, affects milk production, or affects the breast-fed infant. Consider known benefits of breast-feeding along with woman's clinical need for pramipexole and any potential adverse effects of the drug or disease on the infant.

Because pramipexole inhibits prolactin secretion, the drug may inhibit lactation.

Pediatric Use

Safety and efficacy not established in pediatric patients.

Geriatric Use

Geriatric patients with parkinson disease may be at increased risk of hallucinations. No other apparent differences in efficacy or safety between geriatric patients and younger adults.

Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of pramipexole not evaluated to date. Because pramipexole is eliminated renally, hepatic impairment not expected to have a substantial effect.

Renal Impairment

Use with caution and adjust dosage if necessary.

Pramipexole is removed only to a negligible extent by dialysis.

Common Adverse Effects

Patients with early parkinson disease (not receiving levodopa): Nausea, dizziness, somnolence, insomnia, asthenia, fatigue, muscle spasms, dry mouth, constipation, hallucinations, general edema, peripheral edema.

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

Patients with RLS: Nausea, headache, fatigue, insomnia, somnolence, abnormal dreams, diarrhea, nasal congestion, influenza, pain in extremity.

Drugs Metabolized or Affected by Hepatic Microsomal Enzymes

Does not inhibit CYP isoenzymes 1A2, 2C9, 2C19, 2E1, 3A4, or 2D6 at clinically relevant concentrations.

Not appreciably metabolized by CYP isoenzymes; drugs that inhibit these enzymes not expected to affect pramipexole pharmacokinetics.

Drugs Eliminated via Renal Secretion

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

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

Drugs Affecting GI Motility or Gastric pH

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

Dopamine Antagonists

Possible pharmacodynamic interaction, resulting in diminished effectiveness of pramipexole.

Specific Drugs

Pramipexole Pharmacokinetics

Absorption

Bioavailability

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

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

Food

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

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

Distribution

Extent

Widely distributed throughout the body.

Plasma Protein Binding

15%.

Elimination

Metabolism

No metabolites have been identified in plasma or urine.

Elimination Route

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

Half-life

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

Special Populations

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

Pharmacokinetics not evaluated to date in patients with hepatic impairment; however, hepatic impairment not expected to have a significant effect on pramipexole elimination.

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 individuals.

Stability

Storage

Oral

Immediate-release Tablets

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

Extended-release Tablets

25°C (may be exposed to 15–30°C). Protect from high humidity.

Actions

• Exhibits high binding specificity for and intrinsic activity at dopamine D₂ receptors in vitro compared with other dopamine receptor agonists (e.g., bromocriptine, pergolide); has a higher affinity for the D₃ subtype than for the D₂ or D₄ subtypes.

• In parkinson disease, appears to act by directly stimulating postsynaptic dopamine receptors in the corpus striatum.

• In RLS, mechanism(s) of action is unknown; dopaminergic systems appear to be involved in pathogenesis.

• Importance of reading the manufacturer's patient information.

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

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

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

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

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

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

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

• 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.

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

• 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.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

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