Pramipexole - Drug Monograph

Introduction

Pramipexole is a non-ergot dopamine agonist medication primarily used in the treatment of Parkinson's disease and restless legs syndrome. First approved by the FDA in 1997, it has become a cornerstone therapy for managing motor symptoms in Parkinson's disease. As a selective D3/D2 dopamine receptor agonist, pramipexole offers both symptomatic relief and potential neuroprotective effects, though the latter remains investigational.

Mechanism of Action

Pramipexole exerts its therapeutic effects through selective agonism of dopamine D2-type receptors, particularly D2, D3, and D4 subtypes. It has highest affinity for D3 receptors. In Parkinson's disease, it compensates for depleted dopamine levels in the nigrostriatal pathway by directly stimulating postsynaptic dopamine receptors. For restless legs syndrome, its mechanism is thought to involve modulation of dopaminergic pathways in the spinal cord and central nervous system, though the exact pathophysiology remains incompletely understood.

Indications

• Treatment of Parkinson's disease (both initial monotherapy and adjunct therapy to levodopa)
• Treatment of moderate-to-severe primary restless legs syndrome (RLS)

• Depression (particularly treatment-resistant cases)
• Bipolar depression
• Fibromyalgia (investigational)

Dosage and Administration

• Initial dose: 0.125 mg three times daily
• Titration: Increase by 0.125 mg per dose every 5-7 days
• Maintenance dose: 1.5-4.5 mg daily in divided doses
• Maximum dose: 4.5 mg daily

• Initial dose: 0.125 mg once daily 2-3 hours before bedtime
• Titration: May increase to 0.25 mg after 4-7 days, then to 0.5 mg if needed
• Maximum dose: 0.5 mg daily

• Renal impairment: Dose adjustment required based on creatinine clearance

- CrCl >50 mL/min: No adjustment - CrCl 30-50 mL/min: Initial dose 0.125 mg twice daily - CrCl 15-29 mL/min: Initial dose 0.125 mg once daily - CrCl <15 mL/min: Not recommended

• Hepatic impairment: No dosage adjustment necessary
• Elderly: Use caution during titration due to increased fall risk

Pharmacokinetics

Contraindications

• Hypersensitivity to pramipexole or any component of the formulation
• Concomitant use with other dopamine agonists (additive effects)
• History of pathologic gambling, hypersexuality, or other impulse control disorders (relative contraindication)

Warnings and Precautions

• Falling asleep during activities of daily living, including operation of motor vehicles, which has resulted in accidents

• Orthostatic hypotension: Monitor blood pressure, especially during dose escalation
• Hallucinations and psychosis: More common in elderly patients and those with cognitive impairment
• Impulse control disorders: Pathological gambling, hypersexuality, compulsive spending/eating
• Dopamine agonist withdrawal syndrome: May occur with abrupt discontinuation
• Melanoma risk: Increased incidence in Parkinson's patients; regular dermatologic screening recommended
• Fibrotic complications: Although less common than with ergot-derived dopamine agonists, monitor for retroperitoneal fibrosis, pleural effusion, etc.

Drug Interactions

• CNS depressants (alcohol, benzodiazepines, opioids): Additive sedative effects
• Antipsychotics (typical and atypical): May diminish pramipexole efficacy
• Antihypertensives: Enhanced hypotensive effects
• Dopamine antagonists (metoclopramide, phenothiazines): Reduced efficacy of pramipexole
• Cimetidine: May decrease renal clearance of pramipexole

Adverse Effects

• Nausea (28%)
• Dizziness (25%)
• Somnolence (22%)
• Insomnia (17%)
• Constipation (14%)
• Fatigue (14%)
• Hallucinations (9%)
• Orthostatic hypotension (8%)

• Sudden sleep attacks (1-4%)
• Syncope (2%)
• Compulsive behaviors (5-10%)
• Neuroleptic malignant syndrome (upon withdrawal)
• Rhabdomyolysis (rare)

Monitoring Parameters

• Efficacy assessment: UPDRS scores for Parkinson's disease, RLS severity scales
• Blood pressure (sitting and standing) regularly, especially during titration
• Mental status examination for hallucinations, psychosis, or impulse control disorders
• Daytime somnolence and sleep attacks
• Renal function (baseline and periodically)
• Dermatologic examination annually for melanoma screening
• Assessment for developing tolerance or need for dose adjustment

Patient Education

• Take medication as prescribed; do not abruptly discontinue
• Rise slowly from sitting/lying position to prevent dizziness
• Be aware of potential for sudden sleepiness during daily activities
• Avoid alcohol and other CNS depressants
• Report any new or increased gambling urges, sexual desires, or other compulsive behaviors
• Use caution when driving or operating machinery until response is known
• Regular skin examinations recommended
• May take with food if nausea occurs
• Keep regular follow-up appointments for monitoring and dose adjustments

References

1. FDA Prescribing Information: Pramipexole Dihydrochloride Tablets 2. National Institute for Health and Care Excellence (NICE). Parkinson's disease in adults: diagnosis and management. NICE guideline [NG71]. 2017 3. Trenkwalder C, et al. Expert Consensus Group report on the use of apomorphine in the treatment of Parkinson's disease - clinical practice recommendations. Parkinsonism Relat Disord. 2015 4. Garcia-Borreguero D, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: A combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med. 2016 5. Weintraub D, et al. Impulse control disorders in Parkinson's disease: a cross-sectional study of 3090 patients. Arch Neurol. 2010 6. Clinical Pharmacokinetics of Pramipexole: A Systematic Review. Clin Pharmacokinet. 2020