VA Class:CN500

AHFS Class:

• Nonergot-derivative Dopamine Receptor Agonists 28:36.20.08

Generic Name(s):

• rOPINIRole Hydrochloride

Chemical Name:

• 4-[2-(Dipropylamino)ethyl]-1,3-dihydro-2( H )-indol-2-one monohydrochloride

Molecular Formula:

• C₁₆H₂₄N₂O•HCl

Ropinirole hydrochloride is a nonergot-derivative dopamine receptor agonist.1,2,3,4,5,7,14,15,16

Parkinsonian Syndrome

Ropinirole is used for the symptomatic management of parkinson disease.1,2,3,4,5,7,8,11,13,14,15,30

Dopamine receptor agonists (e.g., pramipexole, ropinirole, rotigotine) are used as initial monotherapy in patients with early parkinson disease or as an adjunct to levodopa in patients with advanced disease.101,115,123,157 Levodopa is currently the most effective drug for relieving motor symptoms of parkinson disease.115,123,157 However, the effectiveness of levodopa decreases over time as the disease progresses, and most patients develop motor complications (e.g., end-of-dose failure, “on-off” phenomenon, dyskinesias) with long-term use.101,115,157 Strategies for reducing the risk of motor complications include adjusting the dosage of levodopa or adding other antiparkinsonian agents such as a dopamine receptor agonist; alternatively, a levodopa-sparing strategy may be used in which other antiparkinsonian agents are initiated first to delay use of levodopa.101,115,116,123,157 This latter approach is often used in younger patients who have a higher risk of developing motor complications and a longer life expectancy.101,116,123,157 The appropriate treatment approach should be individualized based on the patient's age, symptoms, degree of disability, and adverse effects of therapy.101,120,122,123,124,125 (For additional information on treatment options in parkinson disease, see Uses: Parkinsonian Syndrome, in Levodopa/Carbidopa 28:36.16.)

Efficacy of conventional (immediate-release) ropinirole for the management of parkinson disease has been established in several placebo-controlled studies of up to 6 months' duration in patients with early parkinson disease not receiving levodopa and in patients with advanced parkinson disease who were receiving concomitant levodopa therapy.1,2,4,8,13,14,15 In these studies, ropinirole improved activities of daily living (ADL) and reduced motor manifestations of parkinson disease such as tremor, rigidity, bradykinesia, and postural stability.1,2,4,6,8,13,14,15 Therapeutic response was assessed principally using the Unified Parkinson's Disease Rating Scale (UPDRS), a 4-part rating scale intended to evaluate mentation, ADL, motor performance, and complications of therapy.1,2,14

In studies evaluating immediate-release ropinirole in patients with early parkinson disease, the drug was more effective than placebo in reducing the severity of symptoms.1,2,13,14 In one of these studies, clinical response (defined as an improvement of at least 30% in UPDRS motor score) occurred after 12 weeks of treatment in 71% of patients receiving ropinirole (mean daily dosage of 7.4 mg) compared with 41% of those receiving placebo.1,14 In another study, 47% of patients receiving ropinirole (mean daily dosage of 15.7 mg) responded to therapy compared with 20% of those receiving placebo; average UPDRS motor score improved by 22% with ropinirole therapy and worsened by 4% with placebo.1,2,13 In this study, addition of levodopa therapy for symptomatic relief was required in 29% of patients treated with placebo versus 11% of those receiving ropinirole.2

In studies evaluating immediate-release ropinirole in patients with advanced parkinson disease who were receiving concomitant levodopa therapy, ropinirole reduced the severity of symptoms and allowed for a reduction in levodopa dosage.1,4,6,8,13,14 In addition, ropinirole was more effective than placebo in reducing “off” time in patients who were experiencing “on-off” phenomena (i.e., a deteriorating response to levodopa therapy).1,13,14,15 In one study, average daily “off” time was reduced by 1.5 hours following 6 months of therapy with ropinirole, while “off” time with placebo was reduced by 0.9 hours.1

Efficacy of ropinirole extended-release tablets has been evaluated in several randomized, double-blind studies of up to 36 weeks' duration.30 In one of these studies, ropinirole (mean dosage of 18.8 mg daily) was more effective than placebo in reducing total daily “off” time in patients with advanced parkinson disease who were receiving concomitant levodopa therapy; “off” time was reduced by 2 hours with ropinirole versus 0.5 hours with placebo.30 Another study that compared efficacy of immediate-release ropinirole to the extended-release formulation in patients with early parkinson disease found that both formulations produced similar improvement in UPDRS motor score; in addition, no loss of efficacy was observed in patients who were switched overnight from the immediate-release tablets given 3 times daily to the extended-release tablets given once daily at approximately equivalent dosages, suggesting therapeutic equivalence between the formulations.30 Additional randomized controlled studies supporting the use of extended-release ropinirole have been conducted in the postmarketing setting.30,31,32 The benefits observed with ropinirole in these studies were generally consistent with those reported in previous studies.30,31,32 The greatest treatment benefit was observed with a dosage of 8 mg daily in patients with advanced parkinson disease and 12 mg daily in patients with early parkinson disease; use of higher dosages did not provide further benefit.30,31,32

Restless Legs Syndrome

Ropinirole is used for the symptomatic management of moderate-to-severe primary restless legs syndrome (RLS; also known as Willis-Ekbom disease).1,21,25,26,27 Experts state that treatment of RLS should be considered if symptoms substantially interfere with sleep or daytime function.40 Nonergot-derivative dopamine receptor agonists (e.g., pramipexole, ropinirole, rotigotine) are considered one of several drugs of choice for reducing symptoms of RLS; there is moderate to strong evidence supporting the use of any of the currently available drugs in this class.40 Treatment should be individualized based on the patient's symptoms, age, comorbidities, preference, and adverse effects of therapy (e.g., risk of augmentation).40

Efficacy of ropinirole for this indication has been established in 3 randomized, placebo-controlled studies in adults with moderate-to-severe RLS (score of at least 15 on the International Restless Legs Syndrome [IRLS] scale and a history of symptoms on at least 15 nights per month).1,21 Patients were excluded from these studies if they had RLS associated with other conditions (e.g., end-stage renal failure, anemia, pregnancy).1,21 Ropinirole was initiated at a dosage of 0.25 mg once daily (given 1-3 hours before bedtime) and increased over 7 weeks to a maximum dosage of 4 mg once daily; the average dosage administered was 2 mg once daily.1,21 Response to therapy was assessed using the IRLS scale (designed to assess motor symptoms, sleep disturbance, daytime somnolence, ADL, and mood) and the Clinical Global Impression Improvement (CGI-I) scale.1,21 After 12 weeks of therapy, improvements in both the IRLS score and the percentage of patients rated as responders (defined as being much improved or very much improved) on the CGI-I scale were greater in patients receiving ropinirole than those receiving placebo.1,21,22,23,24 Ropinirole therapy also was associated with greater improvement in sleep and quality-of-life scores than placebo.21,22,24 Improvement was observed in ropinirole-treated patients as early as the first week of therapy.21

Long-term efficacy of ropinirole for the treatment of RLS was demonstrated in a study in which patients who achieved a response after 24 weeks of open-label ropinirole therapy were randomized to receive continued ropinirole or placebo for an additional 12 weeks of treatment; patients who continued receiving ropinirole had substantially reduced relapse rates compared with those who received placebo.1,25

Administration

Ropinirole is administered orally as conventional (immediate-release) tablets or extended-release tablets.1,30 The extended-release tablets are FDA-labeled for use only in the treatment of parkinson disease.30

For the management of parkinson disease, ropinirole is administered as immediate-release tablets in 3 equally divided doses daily or as extended-release tablets once daily.1,13,30 For the management of restless legs syndrome (RLS), ropinirole is administered as immediate-release tablets once daily, 1-3 hours before bedtime.1,21,22,23,24,25 Both formulations of the drug may be administered without regard to food.1,30

The extended-release tablets should be swallowed whole, and not chewed, crushed, or divided.30 The tablet is designed to slowly release ropinirole over a 24-hour period; if rapid GI transit occurs, incomplete release of the drug may occur, causing some tablet residue to appear in the stool.30

Dispensing and Administration Precautions

FDA alerted healthcare professionals and patients of medication error reports in which patients were given risperidone (Risperdal^®), an antipsychotic agent, instead of ropinirole hydrochloride (Requip^®) and vice versa.28 As of June 2011, FDA had evaluated 226 wrong drug medication errors associated with confusion between these 2 drugs, all of which involved tablet formulations of the drugs.28 Several of these cases resulted in adverse effects (including confusion, lethargy, ataxia, hallucinations, tiredness, dizziness, tingling, numbness, and altered mental status) and some of the patients who took the wrong drug required hospitalization.28 FDA has determined that the factors contributing to the confusion between these 2 products include similarities in both the trade (brand) and generic (nonproprietary) names, similarities in the container labels and carton packaging, illegible handwriting on the prescriptions, and overlapping product characteristics (such as drug strengths, dosage forms, and dosing intervals).28 It is also possible that the 2 products may be stocked close to one another on pharmacy shelves whether they are alphabetized by brand or generic name.28 In addition, some generic manufacturers make both products.28 Healthcare professionals are therefore reminded to clearly print out or spell out the drug name on prescriptions and to make sure their patients know the name of their prescribed drug and the reason they are taking it.28

Dosage

Dosage of ropinirole hydrochloride is expressed in terms of ropinirole.1,17,30

Therapy should be initiated with a low dosage and titrated slowly until the maximum therapeutic response is achieved.1,30

If ropinirole therapy is interrupted for a substantial period of time, retitration may be warranted.1,30

Parkinson Disease

For the management of parkinson disease, the recommended initial adult dosage of ropinirole as immediate-release tablets is 0.25 mg 3 times daily.1 If needed, dosage may be increased in weekly increments based on response and tolerability up to a maximum daily dosage of 24 mg; the manufacturer recommends the following dosage titration schedule (see Table 1).1 In clinical studies, ropinirole dosages of 0.25-8 mg daily administered in 3 equally divided doses as immediate-release tablets were effective and well tolerated when administered with or without concomitant levodopa therapy.1,2,4,13

If the extended-release tablets are used, an initial dosage of 2 mg once daily for 1-2 weeks is recommended; if needed, dosage may be increased by increments of 2 mg daily at weekly (or longer) intervals based on patient response and tolerability.30 Although the maximum recommended dosage of ropinirole extended-release tablets is 24 mg daily, the manufacturer states that patients with advanced parkinson disease should generally be maintained at dosages no higher than 8 mg daily and patients with early parkinson disease should generally be maintained at dosages no higher than 12 mg daily; higher dosages have not been shown to provide greater benefit and may increase the risk of adverse effects.30

Dosage of ropinirole must be re-evaluated and adjusted according to the needs of the patient in a constant effort to find a dosage regimen that provides maximum relief of symptoms with minimum adverse effects.17

Since concomitant therapy with ropinirole and levodopa may cause or exacerbate preexisting dyskinesia, a reduction in dosage of the dopaminergic agents may reduce this effect.1,17,30 In a controlled study in patients with advanced parkinson disease, dosage of levodopa was reduced per protocol by an average of 19% from baseline with concomitant ropinirole therapy.1

When discontinuing therapy, dosage of ropinirole should be gradually reduced over a period of 1 week.1,29,30 If the conventional tablets are used, frequency of administration should be reduced from 3 times daily to twice daily for 4 days, then to once daily for the next 3 days, before complete discontinuance of the drug.1,29

Patients may be switched directly from the immediate-release to extended-release tablets at the same approximate total daily dosage (see Table 2).30 Following conversion, dosage should be adjusted if necessary based on patient response and tolerability.30

Restless Legs Syndrome

The recommended initial adult dosage of ropinirole for the management of RLS is 0.25 mg once daily 1-3 hours before bedtime (as immediate-release tablets).1 After 2 days, dosage may be increased if necessary based on patient response and tolerability according to the schedule in Table 3.1,24 The maximum recommended dosage of ropinirole is 4 mg daily for the treatment of RLS.1

When discontinuing therapy, dosage should be gradually reduced.1

Special Populations

Renal Impairment in Patients with Parkinson Disease

No dosage adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30-50 mL/minute).1,30 In patients with end-stage renal disease undergoing hemodialysis, the recommended initial dosage of ropinirole is 0.25 mg 3 times daily (as immediate-release tablets) or 2 mg once daily (as extended-release tablets); dosage may be increased based on patient response and tolerability up to a maximum total daily dosage of 18 mg.1,30 Supplemental doses are not required after dialysis.1,30

Use of ropinirole in patients with severe renal impairment not undergoing regular dialysis has not been evaluated.1,30

Renal Impairment in Patients with Restless Legs Syndrome

No dosage adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30-50 mL/minute).1 In patients with end-stage renal disease on hemodialysis, the recommended initial dosage of ropinirole (as immediate-release tablets) is 0.25 mg once daily; dosage may be increased based on patient response and tolerability up to a maximum total daily dosage of 3 mg.1 Supplemental doses are not required after dialysis.1

Use of ropinirole in patients with severe renal impairment not undergoing regular dialysis has not been evaluated.1

Dosage Adjustment in Geriatric Patients

Because dosage of ropinirole is titrated to clinical response, routine dosage adjustment based solely on age is not necessary in geriatric patients.1

Contraindications

• Known hypersensitivity to ropinirole hydrochloride or any ingredient in the formulation.1,30

Warnings/Precautions

Falling Asleep During Activities of Daily Living and Somnolence

Falling asleep while engaged in activities of daily living, including operating a motor vehicle, has been reported in patients receiving ropinirole; such events have sometimes resulted in accidents.1,20,30 Some of the cases were reported as late as 1 year after initiation of ropinirole therapy.1 Although many patients reported somnolence while receiving the drug, some patients did not perceive warning signs, such as excessive drowsiness, and believed they were alert prior to sudden sleep onset.1,20 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.1

Somnolence commonly occurs in patients receiving ropinirole and appears to be more frequent in patients with parkinson disease than in patients with restless legs syndrome (RLS).1 However, patients may not acknowledge drowsiness or sleepiness until directly questioned about such adverse effects during specific activities.1

Before initiating ropinirole therapy, patients should be advised of the potential to develop drowsiness and specifically asked about any factors that may increase the risk of somnolence (e.g., concomitant use of sedating drugs or drugs that can increase plasma concentrations of ropinirole, presence of sleep disorders).1 Patients should be continually reassessed for drowsiness or sleepiness during therapy, especially since some of these episodes occur well after starting treatment.1 If a patient develops daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., conversations, eating), ropinirole generally should be discontinued.1 If a decision is made to continue therapy, the patient should be advised not to drive and to avoid other potentially dangerous activities.1 There is insufficient information to establish whether dosage reduction will eliminate this adverse event.1

Syncope

Syncope, sometimes associated with bradycardia, was reported more frequently in patients receiving ropinirole than those receiving placebo in clinical studies; most cases occurred more than 4 weeks after initiation of ropinirole and were associated with a recent dosage increase.1,8,9,10,11,13,15,30 In a phase 1 study, one individual with syncope developed hypotension, bradycardia, and sinus arrest, but recovered spontaneously without intervention.1

Patients with significant cardiovascular disease were excluded from clinical studies; therefore, ropinirole should be used with caution in such patients.1

Hypotension and Orthostatic Hypotension

Dopaminergic agents appear to impair systemic regulation of blood pressure, which can cause orthostatic hypotension, particularly during dosage escalation.1,30,123 Orthostatic hypotension can also be a manifestation of parkinson disease.1,123

In clinical studies of patients with parkinson disease or RLS, hypotension and orthostatic hypotension were reported more frequently with ropinirole than with placebo.1,30 Most cases of orthostatic hypotension that were reported in patients with parkinson disease occurred more than 4 weeks after initiation of therapy and were usually associated with a recent dosage increase.1 Substantial decreases in blood pressure not related to standing also have been reported in some patients receiving the extended-release formulation of the drug.1,30 Patients with hypotension or orthostatic hypotension frequently reported dizziness.1

Patients receiving ropinirole should be monitored for signs and symptoms of orthostatic hypotension, particularly during dosage escalation.1

Hallucinations/Psychotic-like Behavior

Hallucinations have been reported in patients with parkinson disease receiving ropinirole.1,13,14,30 In clinical studies, an increased risk of hallucinations was observed in geriatric patients and in patients receiving concomitant levodopa.1,30

Other new or worsening mental status and behavioral changes, which can be severe and include psychotic-like behavior, have been reported during ropinirole therapy or after initiating or increasing dosage of the drug in the postmarketing setting.1 Such abnormal thinking and behavior may consist of one or more of the following manifestations: paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.1 Other drugs used in the treatment of parkinson disease can produce similar effects on thinking and behavior.1

Because of the risk of exacerbating psychosis, ropinirole should generally not be used in patients with a major psychotic disorder.1 In addition, concomitant use of ropinirole with certain antipsychotic agents may exacerbate parkinsonian symptoms and result in decreased efficacy of ropinirole.1

Dyskinesia

Ropinirole may cause or exacerbate preexisting dyskinesia in patients with parkinson disease receiving concomitant levodopa therapy.1,30 A reduction in dosage of the dopaminergic agents may alleviate this effect.1,17

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 the inability to control these urges have been reported in patients receiving dopaminergic agents.1 These urges stopped in some cases when dosage was reduced or the drug was discontinued.1 If a patient develops any such behaviors while receiving ropinirole, consideration should be given to reducing the dosage or discontinuing therapy.1

Hyperpyrexia and Confusion

A symptom complex resembling neuroleptic malignant syndrome (NMS; 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 dopaminergic therapy.1,30 To reduce this risk, gradual withdrawal of therapy is recommended when ropinirole treatment is discontinued.1

Melanoma

Data from epidemiologic studies indicate that patients with parkinson disease have an approximately twofold to sixfold greater risk of developing melanoma than the general population.1,30 It is unclear whether this increased risk is due to the disease or other factors (e.g., drugs used to treat the disease).1 In the clinical development program for extended-release ropinirole, one patient who received the drug and also was receiving levodopa/carbidopa developed melanoma.30 Because of these findings, the manufacturer recommends that patients and clinicians monitor for melanoma on a frequent and regular basis during ropinirole therapy.1 Periodic skin examinations should ideally be performed by qualified clinicians (e.g., dermatologists).1

Augmentation and Rebound in Restless Legs Syndrome

Long-term use of dopaminergic agents in patients with RLS has been associated with augmentation (i.e., worsening of symptoms during treatment); augmentation can manifest as an increase in overall symptom severity, earlier time of symptom onset each day, or extension of symptoms to other extremities.1,26 Augmentation has been reported during postmarketing experience with ropinirole.1

In addition, rebound (i.e., new onset of symptoms during the early morning hours) also has been reported in patients with RLS receiving ropinirole in a postmarketing study.1

If augmentation or rebound occurs during ropinirole therapy, consideration should be given to adjusting the dosage or discontinuing treatment; when discontinuing therapy, dosage should be gradually reduced whenever possible.1,21

Fibrotic Effects

Retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, thickening of pleura, pericarditis, and cardiac valvulopathy have been reported in patients receiving ergot-derivative dopamine agonists, presumably related to the ergoline structure of these agents.1,30 It is not known whether nonergot-derived dopamine agonists may induce similar changes.1

Cases of possible fibrotic complications (e.g., pleural effusion or fibrosis, interstitial lung disease, cardiac valvulopathy) have been reported in clinical trials and during postmarketing experience with ropinirole.1 A causal relationship has not been established; however, the possibility that ropinirole may have a contributory role cannot be excluded.1

Ocular Effects

Retinal degeneration has been reported in albino rats receiving ropinirole for 2 years at dosages less than the maximum recommended human dosage on a mg/m² basis; similar changes were not observed in pigmented rats, albino mice, or in rats or monkeys treated for 1 year.1,30 The clinical importance of these animal findings has not been established; however, the mechanism involves disruption of a process that is universally present in all vertebrates.1

A 2-year study in patients with parkinson disease did not reveal any clinically important differences with regard to retinal effects between ropinirole and levodopa.1

Binding to Melanin

Binding to melanin-containing tissues (e.g., eyes, skin) has been reported following administration of a single dose of ropinirole in pigmented rats.1,30 Long-term retention was observed with a half-life of 20 days in the eye.1

Specific Populations

Pregnancy

There are no adequate data on the developmental risks associated with the use of ropinirole in pregnant women.1 In animal studies, adverse developmental effects (e.g., teratogenicity, embyrolethality) were observed when the drug was administered to pregnant rats at dosages similar to or greater than the recommended maximum human dosa these dosages also were associated with maternal toxicity.1 In pregnant rabbits, oral administration of ropinirole had no effect on embryofetal development, but when administered in combination with levodopa, an increased incidence of fetal malformations was observed.1

Lactation

It is not known whether ropinirole is distributed into human milk; however, the drug is distributed into milk in rats.1 The effects of ropinirole on the breast-fed infant or on milk production are not known.1 The known benefits of breast-feeding should be considered along with the mother's clinical need for ropinirole and any potential adverse effects on the breast-fed infant from the drug or underlying maternal condition.1

Because ropinirole inhibits prolactin secretion, the drug is expected to inhibit lactation.1

Pediatric Use

Safety and efficacy of ropinirole have not been established in pediatric patients.1

Geriatric Use

Oral clearance of ropinirole is reduced by 15% in geriatric patients older than 65 years of age compared with younger patients.1 In clinical studies of ropinirole in patients with parkinson disease, some adverse effects were more frequent in geriatric patients (e.g., hallucinations, vomiting, nausea) than in younger patients receiving the drug.1

Hepatic Impairment

The pharmacokinetics of ropinirole have not been evaluated in patients with hepatic impairment.1 Because ropinirole is extensively metabolized by the liver, such patients may have reduced clearance and increased plasma concentrations of the drug.1

Renal Impairment

Moderate renal impairment (creatinine clearance of 30-50 mL/minute) is not expected to alter the pharmacokinetics of ropinirole.1 Clearance of ropinirole is reduced by approximately 30% in patients with end-stage renal disease undergoing hemodialysis; a reduced dosage is recommended in such patients.1

Use of ropinirole in patients with severe renal impairment (creatinine clearance less than 30 mL/minute) who are not undergoing hemodialysis has not been studied.1

Common Adverse Effects

Common adverse effects of immediate-release ropinirole in patients with early parkinson disease include nausea, somnolence, dizziness, syncope, asthenic condition, viral infection, leg edema, vomiting, and dyspepsia.1

Common adverse effects of the extended-release tablets in patients with early parkinson disease include nausea, somnolence, sudden onset of sleep, hypertension, headache, abdominal pain/discomfort, dizziness, and constipation.30

Common adverse effects of immediate-release ropinirole in patients with advanced parkinson disease receiving concomitant levodopa include dyskinesia, somnolence, nausea, dizziness, confusion, hallucinations, sweating, and headache.1

Common adverse effects with the extended-release ropinirole tablets in patients with advanced parkinson disease include nausea, dyskinesia, dizziness, and hallucinations.30

Common adverse effects of immediate-release ropinirole in patients with RLS include nausea, somnolence, vomiting, dizziness, and fatigue.1

Drugs Affecting Hepatic Microsomal Enzymes

Ropinirole is metabolized principally by cytochrome P-450 (CYP) 1A2.1 CYP1A2 inhibitors (e.g., ciprofloxacin, fluvoxamine, mexiletine, norfloxacin) or CYP1A2 inducers (e.g., omeprazole) may alter clearance of ropinirole; dosage adjustment of ropinirole may be required if a potent inhibitor or inducer of CYP1A2 is initiated or discontinued during ropinirole therapy.1

Ropinirole does not inhibit or induce CYP isoenzymes, and is therefore not likely to interact with drugs metabolized by these enzymes.1

Antipsychotic Agents

Certain antipsychotic agents may exacerbate symptoms of parkinson disease and diminish the effectiveness of ropinirole.1

Cigarette Smoking

Cigarette smoking, which is a known inducer of CYP1A2, is expected to increase the clearance of ropinirole1

Ciprofloxacin

Concomitant administration of ciprofloxacin (a CYP1A2 inhibitor) and ropinirole increased systemic exposure and peak plasma concentrations of ropinirole by 84 and 60%, respectively.1

CNS Depressants

Concomitant use of ropinirole and CNS depressants (including alcohol) can cause additive sedative effects.1

Digoxin

A study in a limited number of patients showed that the steady-state pharmacokinetics of digoxin were not altered when the drug was administered concomitantly with ropinirole.1

Dopamine Antagonists

Dopamine antagonists (e.g., phenothiazines, butyrophenones, thioxanthenes, metoclopramide) may reduce efficacy of ropinirole.1

Estrogens

Population pharmacokinetic analysis indicates that high dosages of estrogens (e.g., those used for hormone replacement therapy) may reduce clearance of ropinirole by 36%.1 Dosage adjustment of ropinirole may be necessary if hormone replacement therapy is initiated or discontinued during treatment with ropinirole.1

Levodopa

Concomitant administration of ropinirole and levodopa did not alter steady-state pharmacokinetics of ropinirole; peak plasma concentrations of levodopa were increased by 20%, but systemic exposure of the drug was not affected.1

Concomitant use of levodopa and ropinirole may increase the risk of dyskinesia in patients with parkinson disease.1

Theophylline

A study in a limited number of patients with parkinson disease showed that concomitant administration of ropinirole and theophylline (a CYP1A2 substrate) did not alter the pharmacokinetics of either drug.1

Other Commonly Administered Drugs

Population pharmacokinetic analysis suggests that clearance of ropinirole is not affected by commonly coadministered drugs such as selegiline, amantadine, tricyclic antidepressants, benzodiazepines, ibuprofen, thiazide diuretics, antihistamines, and anticholinergics.1

Description

Ropinirole, a dipropylaminoethyl indolone derivative,8,13,14 is a nonergot-derivative dopamine receptor agonist.1,2,3,4,5,7,14,15,16 In in vitro binding studies, ropinirole demonstrated high binding specificity for and intrinsic activity at dopamine D₂ receptors9,10,11,13,14,15 compared with other dopamine receptor agonists (e.g., bromocriptine, pergolide), having a higher affinity for the D₃ subtype than for the D₂ or D₄ subtypes.1,7 Ropinirole binds with moderate affinity to opiate receptors but has little or no affinity for α₁-,1,6,11,15α₂-,1,6,11,15 or β-adrenergic;1,6,11,15 dopamine D₁;1,6,7 benzodiazepine;1,7γ-aminobutyric acid (GABA);1,7 serotonin type 1 (5-hydroxytryptamine [5-HT₁]);1,6,7,11,15 serotonin type 2 (5-HT₂);1,6,7,11,15 or muscarinic receptors.1,7

The exact mechanism of action of ropinirole in the management of parkinson disease has not been fully elucidated.1 There is considerable evidence that manifestations of parkinson disease, regardless of the cause of the syndrome, are related to depletion of dopamine in the corpus striatum.6,8 While levodopa is believed to act principally by increasing dopamine concentrations in the brain, ropinirole appears to act by directly stimulating postsynaptic dopamine receptors in the corpus striatum.8,10,17

The exact mechanism of action of ropinirole in the management of restless legs syndrome (RLS) is not known, but is thought to be related to its ability to stimulate dopamine receptors.1,24

Advice to Patients

• Importance of reading the manufacturer's patient information.1
• Importance of taking ropinirole as prescribed; if a dose is missed, advise patient not to double next dose.1 Advise patients that ropinirole may be taken with or without food.1 Advise patients to contact their clinician if they wish to discontinue therapy or decrease dosage.1
• Risk of hypersensitivity reactions; importance of advising patients to immediately contact their clinician if they experience any manifestations of such reactions (e.g., urticaria, angioedema, rash, pruritus).1
• 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.1,14,15,20 Patients should avoid driving, operating machinery, or participating in other potentially dangerous activities until effects on the individual are known.1 Importance of advising patients that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., conversations, eating, driving) occur at any time during therapy, they should not drive or participate in potentially dangerous activities until they have contacted their clinician.1
• Potential for hypotension or orthostatic hypotension with or without symptoms (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 ropinirole therapy.1
• Risk of hallucinations, particularly in geriatric patients with parkinson disease, those receiving concomitant levodopa, and those receiving higher dosages of ropinirole.1
• Importance of informing patients with restless legs syndrome (RLS) that augmentation and rebound may occur.1
• Importance of informing patients of the risk of new onset or exacerbation of dyskinesia.1
• 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 ropinirole and of advising them of the importance of reporting such urges.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
• 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.1 (See Cautions.)

Additional Information

Overview^® (see Users Guide). For additional information on this drug until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

1. GlaxoSmithKline. Requip^® (ropinirole hydrochloride) tablets prescribing information. Research Triangle Park, NC; 2018 Feb.

2. Adler CH, Sethi KD, Hauser RA et al. Ropinirole for the treatment of early Parkinson's disease. Neurology . 1997; 49:393-9. [PubMed 9270567]

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