Drug Monograph
Requip (Ropinirole)
ropinirole hydrochloride
Pharmacokinetic Profile
Half-Life
~6 h (IR)
Metabolism
Hepatic via CYP1A2 (major)
Protein Binding
~40%
Bioavailability
~55% (first-pass effect)
Volume of Distribution
~480 L (7 L/kg)
Clinical Information
Drug Class
Non-ergot dopamine agonist
Available Doses (IR)
0.25, 0.5, 1, 2, 3, 4, 5 mg
Available Doses (ER)
2, 4, 6, 8, 12 mg
Route
Oral
Renal Adjustment
Not required for CrCl ≥30; severe not studied
Hepatic Adjustment
Not studied; use caution (CYP1A2 metabolised)
Pregnancy
Animal teratogenicity; limited human data
Lactation
Inhibits prolactin; excretion in human milk unknown
Schedule
Prescription only (not scheduled)
Generic Available
Yes (IR and ER)
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Parkinson’s disease | Adults | Monotherapy or adjunctive to levodopa | FDA Approved |
| Moderate-to-severe primary RLS | Adults (IR only) | Monotherapy | FDA Approved |
Ropinirole is a non-ergot dopamine agonist with selectivity for D3 over D2 receptor subtypes, approved for both Parkinson’s disease and moderate-to-severe restless legs syndrome. Like pramipexole, it is commonly used as initial monotherapy in younger PD patients to delay levodopa-associated motor complications, and as adjunctive therapy in advanced disease. A key pharmacological distinction from pramipexole is that ropinirole undergoes extensive hepatic metabolism via CYP1A2, making it susceptible to drug interactions involving this enzyme and to the effects of cigarette smoking.
Off-Label Uses
SSRI-induced sexual dysfunction: Low-dose ropinirole has been used to manage sexual side effects of serotonergic antidepressants. Evidence quality: Low (case series).
Extrapyramidal symptoms (antipsychotic-induced): Limited evidence supports dopamine agonist use in this context. Evidence quality: Very low.
Dosing
Parkinson’s Disease — Immediate-Release (IR) Tablets
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Early PD — monotherapy | 0.25 mg TID | 3–8 mg TID | 8 mg TID (24 mg/day) | Wk 1: 0.75 mg/d → Wk 2: 1.5 → Wk 3: 2.25 → Wk 4: 3. After Wk 4: increase by 1.5 mg/d weekly up to 9, then by 3 mg/d weekly Titrate to efficacy; adverse effects are dose-related |
| Advanced PD — adjunctive to levodopa | 0.25 mg TID | 3–8 mg TID | 8 mg TID (24 mg/day) | L-dopa dose may be reduced concurrently Mean L-dopa reduction in trials: significant proportion of patients |
Parkinson’s Disease — Extended-Release (ER) Tablets
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| PD — any stage (ER) | 2 mg once daily | 4–24 mg once daily | 24 mg once daily | Increase by 2 mg/day at intervals ≥1 week Swallow whole; do not crush, chew, or divide |
| Switching from IR to ER | Match total daily IR dose (see PI conversion table) | Adjust as needed | 24 mg once daily | Monitor closely during transition ER not approved for RLS |
Restless Legs Syndrome — IR Tablets Only
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Moderate-to-severe RLS | 0.25 mg once daily | 0.5–4 mg once daily | 4 mg once daily | Take 1–3 hours before bedtime; increase weekly per titration schedule Wk 2: 0.5 → Wk 3: 1 → Wk 4: 1.5 → Wk 5: 2 → Wk 6: 2.5 → Wk 7: 3 → max 4 mg/d |
Special Populations
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Moderate renal impairment (CrCl 30–50) | No adjustment | Standard dosing | 24 mg/day | PK not altered in moderate renal impairment (FDA PI) |
| Severe renal impairment (CrCl <30, no dialysis) | Not studied; use with caution | |||
| ESRD on haemodialysis (RLS) | 0.25 mg once daily | Titrate based on efficacy/tolerability | Individualise | Hemodialysis removal unlikely due to large Vd Per StatPearls; limited data |
| Hepatic impairment | Not studied; caution advised (CYP1A2 metabolised) | |||
| Elderly (≥65 years) | Standard starting dose | Titrate cautiously | 24 mg/day | Oral clearance ~15% lower; hallucination risk 10% vs 2% in non-elderly (ER trials) |
Clinical Pearl: CYP1A2 and Smoking
Ropinirole is primarily metabolised by CYP1A2. Cigarette smoking induces CYP1A2, reducing ropinirole exposure by approximately 30–38%. If a patient quits smoking during ropinirole therapy, plasma levels may rise significantly, requiring dose reduction. Conversely, initiation of smoking may reduce efficacy and necessitate dose increase.
Do Not Stop Abruptly
Ropinirole should be tapered gradually. Abrupt discontinuation or rapid dose reduction may trigger a syndrome resembling neuroleptic malignant syndrome (hyperpyrexia, rigidity, altered consciousness) or dopamine agonist withdrawal syndrome (anxiety, depression, apathy, pain, insomnia). DAWS does not respond to levodopa.
Pharmacology
Mechanism of Action
Ropinirole is a non-ergoline dopamine receptor agonist that directly stimulates postsynaptic D2 and D3 receptors in the striatum, with approximately 20-fold selectivity for D3 over D2 subtypes at cloned human receptors. By activating these receptors independently of endogenous dopamine, ropinirole compensates for the progressive loss of nigrostriatal dopaminergic neurons in Parkinson’s disease. In RLS, its efficacy is thought to involve modulation of descending dopaminergic pathways that regulate sensorimotor function. Unlike ergot-derived agonists, ropinirole does not carry a clinically meaningful risk of fibrotic complications, though isolated postmarketing reports of pleural and peritoneal fibrosis exist and a causal relationship has not been established.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Rapidly absorbed; Tmax ~1–2 h (IR), 6–10 h (ER); absolute bioavailability ~55% (first-pass); food delays Tmax by ~2.5 h and reduces Cmax by ~25% but does not affect AUC | Significant first-pass metabolism distinguishes ropinirole from pramipexole (>90% bioavailability); can take with food to reduce nausea |
| Distribution | Vd ~480 L (7 L/kg); protein binding ~40%; binds to melanin-containing tissues (eyes, skin) | Extensive tissue distribution; moderate protein binding; melanin binding prompts periodic ophthalmological consideration |
| Metabolism | Extensively hepatic via CYP1A2 (major); N-despropylation and hydroxylation to inactive metabolites; no active circulating metabolites | CYP1A2 inhibitors (ciprofloxacin, fluvoxamine) increase levels; CYP1A2 inducers (smoking, omeprazole) decrease levels; HRT reduces clearance by ~36% |
| Elimination | t½ ~6 h (IR); oral clearance ~47 L/h; ~88% recovered in urine (predominantly as metabolites); <10% excreted as unchanged drug | Short half-life requires TID dosing (IR) or ER formulation for once-daily; renal impairment has minimal impact since elimination is metabolism-driven |
Side Effects
≥10%Very Common (Early PD Without Levodopa — IR Trials)
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Nausea | 38% | Most common adverse effect; usually transient; take with food; domperidone may help |
| Somnolence | 34% (up to 40% in some PD trials; 6% placebo) | Dose-related; warn about driving; higher in PD than RLS (12% in RLS) |
| Dizziness | 18% | Often related to orthostatic hypotension; slow positional changes |
| Syncope | 11% | Associated with bradycardia in some cases; cardiovascular patients excluded from trials |
1–10%Common
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Viral infection | 8% | Reported in early PD trials; clinical significance uncertain |
| Fatigue | 7% | Distinguish from PD apathy; consider dose timing |
| Leg oedema | 6% | Dopamine agonist class effect; assess for cardiac causes |
| Hallucinations | 5–10% (10% in elderly ≥65 vs 2% non-elderly) | Visual predominant; age is the strongest risk factor; may require dose reduction or discontinuation |
| Asthenia / malaise | 5% | General weakness; usually early in treatment |
| Dyspepsia | 5% | Take with food; consider antacid (avoid omeprazole if possible as it induces CYP1A2) |
| Vomiting | 4–5% | Usually transient; more common in RLS trials |
| Constipation | ~5% (5% in ER early PD trials) | Advise fluids and dietary fibre |
| Orthostatic hypotension | ~4% | More common during dose escalation; syncope occurred more frequently than with other DA agonists |
| Confusion | ~5% (advanced PD with LD) | More frequent in advanced disease with polypharmacy |
| Dyskinesia | Variable (common in advanced PD with LD) | Ropinirole may cause or exacerbate preexisting dyskinesia; reduce L-dopa dose |
SeriousSerious (Regardless of Frequency)
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Sudden onset of sleep (“sleep attacks”) | ~5% (ER fixed-dose); ~2% (IR) | Any time; may occur >1 year after initiation | Stop driving immediately; ordinarily discontinue ropinirole |
| Impulse control disorders (gambling, hypersexuality, compulsive spending/eating) | Class effect; estimates vary widely | Weeks to months | Screen at every visit; dose reduction or discontinuation usually resolves |
| Syncope with bradycardia | ~4% in early PD Phase 1 trials | Usually >4 weeks; often with dose increase | ECG if recurrent; caution in cardiovascular patients |
| NMS-like syndrome / DAWS | Rare (class effect) | During rapid dose reduction or abrupt withdrawal | Taper gradually; DAWS does not respond to levodopa |
| Postural deformity (camptocormia, Pisa syndrome) | Rare (postmarketing) | Months after initiation | Consider dose reduction or discontinuation |
| RLS augmentation | Variable; up to 40–50% long-term | Months to years of chronic use | If augmentation occurs, consider switching to alpha-2-delta ligand (gabapentin enacarbil, pregabalin) |
| Possible fibrotic complications | Very rare (postmarketing; causality not established) | Variable | Monitor for unexplained dyspnoea, cough, or abdominal symptoms |
| Retinal pathology | Unknown (animal data in albino rats) | Chronic exposure | Consider periodic ophthalmological examination |
DiscontinuationDiscontinuation Rates
Early PD (IR trials)
~24% vs ~13% placebo
Top reasons: Nausea, dizziness, somnolence, hallucinations, syncope
RLS (IR trials)
~5% (lower doses used)
Top reasons: Nausea, somnolence, dizziness
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Nausea | Most frequent | Top individual reason per FDA PI; early onset during titration |
| Dizziness / syncope | Second most frequent | Per FDA PI, nausea and dizziness were the most common DC causes (≥2% above placebo) |
| Hallucinations | ~3% | Predominantly elderly patients; led to DC in 3.1% of early PD and 2.7% of advanced PD patients per FDA PI |
Managing Nausea and Somnolence
Nausea (38%) and somnolence (34%) are the most common adverse effects in early PD and frequently limit titration. Taking ropinirole with food may reduce nausea without affecting total absorption. If domperidone is used as an antiemetic, avoid metoclopramide (D2 antagonist). Somnolence is dose-related; patients exceeding 1.5 mg/day total are at particularly elevated risk per FDA PI data.
Drug Interactions
Ropinirole is primarily metabolised by CYP1A2, making it susceptible to interactions with inhibitors and inducers of this enzyme. This is a key pharmacological distinction from pramipexole, which has no CYP involvement and is eliminated renally.
MajorCiprofloxacin (CYP1A2 Inhibitor)
MechanismPotent inhibition of CYP1A2, the major metabolising enzyme for ropinirole
Effect84% increase in ropinirole AUC; 60% increase in Cmax
ManagementDose adjustment of ropinirole required; consider alternative antibiotic; monitor for toxicity (somnolence, nausea, hypotension)
FDA PIMajorFluvoxamine / Other CYP1A2 Inhibitors (mexiletine, norfloxacin)
MechanismCYP1A2 inhibition reducing ropinirole hepatic clearance
EffectIncreased ropinirole plasma levels; magnitude variable but potentially clinically significant
ManagementAdjust ropinirole dose when initiating or stopping; monitor for dose-related adverse effects
FDA PIModerateCigarette Smoking (CYP1A2 Inducer)
MechanismPolycyclic aromatic hydrocarbons in smoke induce CYP1A2
Effect~30% lower Cmax, ~38% lower AUC in smokers vs non-smokers
ManagementIf patient quits smoking, reduce ropinirole dose (risk of toxicity); if starts smoking, may need dose increase
FDA PIModerateHormone Replacement Therapy (Estrogens)
MechanismEstrogens reduce oral clearance of ropinirole by ~36%
EffectIncreased ropinirole exposure; higher risk of dose-related adverse effects
ManagementMay need dose adjustment when starting or stopping HRT; clinical titration is key
FDA PIMajorDopamine D2 Antagonists (haloperidol, risperidone, metoclopramide)
MechanismPharmacodynamic antagonism at dopamine receptors
EffectReduced ropinirole efficacy; worsening of PD or RLS
ManagementAvoid; use quetiapine/clozapine/pimavanserin for psychosis; domperidone for nausea
FDA PIMinorLevodopa / Carbidopa-Levodopa
MechanismAdditive dopaminergic stimulation; ropinirole increases L-dopa Cmax by ~20%
EffectMay cause or exacerbate dyskinesia
ManagementReduce L-dopa dose as ropinirole is titrated upward; monitor for dyskinesia
FDA PIMonitoring
- Daytime SleepinessEach visit
RoutineDirectly ask about somnolence and sleep attacks; somnolence up to 40% in PD trials; discontinue if sleep attacks occur. - Blood PressureBaseline, each titration
RoutineLying and standing; syncope (11%) and orthostatic hypotension are notable in early PD trials. Also monitor for hypertension (reported in ER trials). - Impulse ControlEach visit
RoutineScreen for gambling, hypersexuality, compulsive spending/eating. Involve caregivers. - NeuropsychiatricEach visit
RoutineHallucinations (5–10%), confusion, psychosis. Risk highest in elderly (≥65 yrs: 10%). - CYP1A2 StatusAt each med change
Trigger-BasedReview concurrent CYP1A2 inhibitors/inducers, smoking status, and HRT use at each visit. Adjust ropinirole dose accordingly. - RLS AugmentationEach visit (RLS patients)
RoutineWatch for symptom onset earlier in the day, spread to arms, or dose escalation need. Consider switching class if augmentation confirmed. - Skin ExaminationAnnually
RoutineMelanoma risk elevated in PD (disease-related); ropinirole binds melanin-containing tissues. - OphthalmologicalConsider periodically
Trigger-BasedRetinal degeneration in albino rats; ropinirole binds melanin in eyes; clinical significance unclear.
Contraindications & Cautions
Absolute Contraindications
- Hypersensitivity to ropinirole or any excipient (including urticaria, angioedema, rash, pruritus).
Relative Contraindications (Specialist Input Recommended)
- Active psychotic disorder: Dopamine agonists can exacerbate psychosis.
- Significant cardiovascular disease: Syncope occurred in ~4% of early PD patients; patients with active CVD were excluded from trials.
- Severe hepatic impairment: Not studied; ropinirole is extensively hepatically metabolised.
Use with Caution
- Elderly (≥65 yrs): 15% reduced clearance; hallucination rate 10% vs 2% in non-elderly.
- Severe renal impairment (CrCl <30 mL/min): Not studied; removal by haemodialysis unlikely.
- Concurrent CYP1A2 inhibitors: Ciprofloxacin increases AUC by 84%; dose adjustment essential.
- Smokers starting or stopping: Major shift in ropinirole clearance.
- Pregnancy: Teratogenic in animal studies; use only if benefit clearly outweighs risk.
FDA Class-Wide Regulatory Warning
Falling Asleep During Activities of Daily Living
Patients treated with dopamine agonists, including ropinirole, have reported suddenly falling asleep without warning while driving, sometimes resulting in accidents. Events have been reported more than one year after treatment initiation. The FDA PI warns that if significant daytime sleepiness or sleep attacks occur, ropinirole should ordinarily be discontinued.
Patient Counselling
Purpose of Therapy
Ropinirole mimics the action of dopamine in the brain, helping to improve movement in Parkinson’s disease or reduce the uncomfortable leg sensations in restless legs syndrome. It does not cure these conditions but helps manage their symptoms. The extended-release tablet provides once-daily dosing for convenience.
How to Take
Immediate-release tablets are taken three times daily for PD, or once daily before bedtime for RLS. Extended-release tablets are taken once daily and must be swallowed whole. The medication can be taken with food to reduce nausea.
Drowsiness & Sleep Attacks
Tell patientThis medication commonly causes sleepiness, and some patients have fallen asleep suddenly during activities like driving. Do not drive until you know how this medication affects you.
Call prescriberIf excessive sleepiness occurs, if you fall asleep unexpectedly, or if you have any close calls while driving.
Dizziness & Fainting
Tell patientBlood pressure may drop when standing. Rise slowly, especially during dose increases. Fainting has been reported in about 1 in 10 patients in clinical trials.
Call prescriberIf you faint, feel very light-headed, or notice your heart beating unusually slowly.
Unusual Urges & Compulsive Behaviours
Tell patientThis medication can cause strong urges to gamble, increased sexual behaviour, compulsive shopping, or binge eating. Caregivers should be informed and asked to watch for changes.
Call prescriberIf you or your family notice new or increased gambling, spending, sexual urges, or compulsive eating.
Nausea
Tell patientNausea is very common at the start but usually improves. Taking the medication with food helps reduce it.
Call prescriberIf nausea is severe, persistent, or causes vomiting that prevents you from taking the medication.
Smoking Changes
Tell patientCigarette smoking affects how your body processes this medication. If you quit smoking or start smoking, tell your prescriber immediately as your dose may need to change.
Call prescriberBefore or immediately after any change in smoking habits.
Do Not Stop Suddenly
Tell patientStopping this medication suddenly can cause withdrawal symptoms (anxiety, depression, pain, sweating) or a dangerous condition with high fever and muscle rigidity. Always follow the prescribed tapering schedule.
Call prescriberIf you run out of medication or develop withdrawal symptoms during tapering.
RLS Symptom Worsening (Augmentation)
Tell patientOver time, RLS symptoms may start earlier in the day, spread to other body parts, or become more intense. This is called augmentation and may require a change in treatment approach.
Call prescriberIf your RLS symptoms begin occurring earlier in the day, worsen despite treatment, or spread to your arms.
Sources
Regulatory (PI / SmPC)
- REQUIP XL (ropinirole) Extended-Release Tablets — FDA Prescribing Information. Revised 2021. accessdata.fda.govPrimary source for ER dosing, adverse reaction tables, CYP1A2 interactions, and renal/elderly PK data.
- REQUIP (ropinirole) Tablets — FDA Prescribing Information. Revised 2021. accessdata.fda.govSource for IR-specific dosing (PD and RLS), adverse reaction incidence in early/advanced PD and RLS trials, and ciprofloxacin PK data.
- Ropinirole Tablets — FDA Prescribing Information (generic). drugs.com/proGeneric label confirming dosing schedules, contraindications, and postmarketing adverse reactions.
Key Clinical Trials
- Rascol O, Brooks DJ, Korczyn AD, et al. A five-year study of the incidence of dyskinesia in patients with early Parkinson’s disease who were treated with ropinirole or levodopa. N Engl J Med. 2000;342(20):1484–1491. doi:10.1056/NEJM200005183422004Landmark 5-year trial demonstrating lower dyskinesia risk with initial ropinirole vs levodopa monotherapy.
- Trenkwalder C, Garcia-Borreguero D, Montagna P, et al. Ropinirole in the treatment of restless legs syndrome: results from the TREAT RLS 1 study. J Neurol Neurosurg Psychiatry. 2004;75(1):92–97. PubMed: 14707315Pivotal RCT supporting the RLS indication; source for RLS adverse reaction data and efficacy endpoints.
- Pahwa R, Stacy MA, Factor SA, et al. Ropinirole 24-hour prolonged release: randomized, controlled study in advanced Parkinson disease. Neurology. 2007;68(14):1108–1115. doi:10.1212/01.wnl.0000258660.74391.c1Key trial for the ER formulation in advanced PD; primary source for ER adverse reaction data.
Guidelines
- Fox SH, Katzenschlager R, Lim SY, et al. International Parkinson and Movement Disorder Society Evidence-Based Medicine Review: Update on Treatments for the Motor Symptoms of Parkinson’s Disease. Mov Disord. 2018;33(8):1248–1266. doi:10.1002/mds.27372MDS evidence review classifying ropinirole as “efficacious” for motor symptoms of PD.
- Silber MH, Becker PM, Earley C, et al. Willis–Ekbom Disease Foundation Revised Consensus Statement on the Management of Restless Legs Syndrome. Mayo Clin Proc. 2013;88(9):977–986. doi:10.1016/j.mayocp.2013.06.016RLS consensus statement recommending dopamine agonists as first-line for moderate-to-severe symptoms.
Mechanistic / Basic Science
- Kaye CM, Nicholls B. Clinical pharmacokinetics of ropinirole. Clin Pharmacokinet. 2000;39(4):243–254. doi:10.2165/00003088-200039040-00001Comprehensive PK review defining bioavailability (~55% per FDA PI), t½ (~6 h), CYP1A2 dependence, and ciprofloxacin interaction data.
- Weintraub D, Koester J, Potenza MN, et al. Impulse control disorders in Parkinson disease: a cross-sectional study of 3090 patients. Arch Neurol. 2010;67(5):589–595. doi:10.1001/archneurol.2010.65DOMINION study quantifying ICD prevalence across dopamine agonists including ropinirole.
Pharmacokinetics / Special Populations
- Ropinirole. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024. NCBI BookshelfClinical pharmacology review covering PK parameters, renal/hepatic considerations, and adverse effect profile.
- Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of augmentation. Sleep Med. 2016;21:1–11. doi:10.1016/j.sleep.2016.01.017International guideline addressing augmentation risk with dopamine agonists and management strategies.
- Rascol O, Brooks DJ, Brunt ER, et al. Ropinirole in the treatment of early Parkinson’s disease: a 6-month interim report of a 3-year study. Mov Disord. 1998;13(1):39–45. doi:10.1002/mds.870130111Early efficacy data from ropinirole monotherapy trials informing the FDA PI adverse reaction tables.