Introduction
Neupro (rotigotine) is a transdermal delivery system indicated for the treatment of Parkinson's disease and restless legs syndrome. It is a non-ergoline dopamine agonist that provides continuous drug delivery through the skin over 24 hours. The patch formulation offers advantages in medication adherence and stable plasma concentrations compared to oral dopamine agonists.
Mechanism of Action
Rotigotine acts as a dopamine receptor agonist with high affinity for D3, D2, and D1 receptors, in that order. It also exhibits agonist activity at α2-adrenergic receptors and antagonist activity at 5-HT2A and 5-HT2C receptors. By stimulating dopamine receptors in the striatum, rotigotine helps restore dopamine neurotransmission that is deficient in Parkinson's disease. For restless legs syndrome, its dopaminergic action modulates sensory and motor symptoms through central nervous system pathways.
Indications
FDA-approved indications:- Treatment of Parkinson's disease (early and advanced stages)
- Treatment of moderate-to-severe primary restless legs syndrome
- Some evidence supports use in periodic limb movement disorder
- Investigational use in other movement disorders
Dosage and Administration
Parkinson's disease:- Initial dose: 2 mg/24 hours
- Titration: Increase by 2 mg/24 hours weekly
- Maintenance: 6-8 mg/24 hours (early stage); up to 8 mg/24 hours (advanced stage)
- Maximum dose: 8 mg/24 hours
- Initial dose: 1 mg/24 hours
- Titration: Increase by 1 mg/24 hours weekly as needed
- Maintenance: 1-3 mg/24 hours
- Maximum dose: 3 mg/24 hours
- Apply once daily to clean, dry, intact skin on abdomen, thigh, hip, shoulder, or upper arm
- Rotate application sites to avoid skin reactions
- Avoid applying to areas where tight clothing may rub the patch
- Do not cut the patch
- Renal impairment: No dose adjustment needed
- Hepatic impairment: Use with caution in severe impairment
- Elderly: No specific dose adjustment required
- Pediatrics: Safety and efficacy not established
Pharmacokinetics
Absorption: Rotigotine is continuously absorbed through the skin with approximately 45% absolute bioavailability. Steady-state concentrations are reached within 1-2 days. Distribution: Volume of distribution is ~84 L/kg. Protein binding is approximately 92% (mainly albumin and α1-acid glycoprotein). Rotigotine crosses the blood-brain barrier. Metabolism: Extensive hepatic metabolism via N-dealkylation, conjugation, and CYP-mediated metabolism (primarily CYP1A2, 2C19, 3A4). Elimination: Terminal half-life is 5-7 hours. Approximately 71% excreted in urine and 23% in feces as metabolites.Contraindications
- Hypersensitivity to rotigotine or any component of the transdermal system
- History of dermatologic reactions to transdermal preparations
- Concomitant use with antipsychotics that are dopamine antagonists
- Patients with magnetic resonance imaging (MRI) or cardioversion needs (patch contains aluminum)
Warnings and Precautions
Sleep attacks/sudden onset of sleep: Patients may fall asleep during activities of daily living without warning signs. Orthostatic hypotension: Monitor blood pressure, especially during dose titration. Hallucinations/psychotic symptoms: More common in elderly patients and those with cognitive impairment. Impulse control disorders: Pathological gambling, increased libido, binge eating, and other compulsive behaviors may occur. Skin reactions: Application site reactions are common. Severe reactions including allergic contact dermatitis may require discontinuation. Withdrawal-emergent hyperpyrexia and confusion: Similar to neuroleptic malignant syndrome upon abrupt withdrawal. Melanoma risk: Increased risk in Parkinson's patients; regular dermatologic monitoring recommended. Augmentation in RLS: Worsening of symptoms, earlier onset, or spread to other body parts may occur.Drug Interactions
Dopamine antagonists: (e.g., antipsychotics, metoclopramide) May diminish therapeutic effects. CYP1A2 inhibitors: (e.g., fluvoxamine, ciprofloxacin) May increase rotigotine concentrations. CYP1A2 inducers: (e.g., smoking, omeprazole) May decrease rotigotine concentrations. CNS depressants: (e.g., alcohol, benzodiazepines, opioids) Additive sedative effects. Antihypertensics: Enhanced hypotensive effects. Levodopa: May enhance efficacy but also increase risk of adverse effects.Adverse Effects
Very common (>10%):- Application site reactions (erythema, pruritus, irritation)
- Nausea
- Somnolence
- Headache
- Dizziness
- Vomiting
- Insomnia
- Orthostatic hypotension
- Fatigue
- Edema
- Constipation
- Hallucinations
- Dyskinesias
- Impulse control disorders
- Sudden sleep attacks
- Neuroleptic malignant syndrome (upon withdrawal)
- Severe skin reactions
- Symptomatic hypotension
- Psychotic symptoms
- Fibrotic complications
Monitoring Parameters
- Efficacy assessment using UPDRS for Parkinson's disease or IRLS for restless legs syndrome
- Blood pressure (sitting and standing) during titration
- Mental status changes and psychiatric symptoms
- Skin examination at application sites
- Signs of impulse control disorders
- Sleep patterns and daytime somnolence
- Motor complications and dyskinesias
- Signs of augmentation in RLS patients
- Regular dermatologic exams for melanoma screening
Patient Education
Application instructions:- Apply to clean, dry, hairless, intact skin
- Press firmly for 30 seconds to ensure adhesion
- Remove backing and avoid touching adhesive surface
- Change application site daily
- Do not apply to same site for 14 days
- Avoid exposing application site to direct heat sources
- Avoid alcohol and other CNS depressants
- Rise slowly from sitting/lying positions
- Report any skin reactions, new moles, or skin changes
- Be aware of potential for sudden sleep attacks
- Do not drive or operate machinery until effects are known
- Report any new or increased gambling urges, sexual urges, or other compulsive behaviors
- Store at room temperature
- Keep unused patches in sealed pouch
- Fold used patch with adhesive sides together and dispose properly
- Wash hands after application and removal
- Apply as soon as remembered unless almost time for next dose
- Do not apply two patches simultaneously
References
1. FDA Prescribing Information: Neupro (rotigotine) transdermal system 2. Jankovic J, et al. Neurology. 2007;68(16):1262-1267 3. Oertel WH, et al. Lancet Neurol. 2011;10(6):513-520 4. Trenkwalder C, et al. Sleep Med. 2011;12(12):1144-1151 5. LeWitt PA, et al. Clin Neuropharmacol. 2013;36(1):6-11 6. Antonini A, et al. Expert Opin Drug Saf. 2015;14(6):895-908 7. National Comprehensive Cancer Network. Guidelines Version 1.2024 8. Micromedex Solutions. Truven Health Analytics. 2024 9. Clinical Pharmacology [database online]. Tampa, FL: Elsevier; 2024