1.1Parkinson’s Disease

Ropinirole Tablets USP are indicated for the treatment of Parkinson’s disease.

1.2Restless Legs Syndrome

Ropinirole Tablets USP are indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS).

2.1General Dosing Recommendations

Ropinirole can be taken with or without food [see Clinical Pharmacology (12.3)].

If a significant interruption in therapy with ropinirole has occurred, retitration of therapy may be warranted.

2.2Dosing for Parkinson’s Disease

The recommended starting dose for Parkinson’s disease is 0.25 mg three times daily. Based on individual patient therapeutic response and tolerability, if necessary, the dose should then be titrated with weekly increments as described in Table 1. After week 4, if necessary, the daily dose may be increased by 1.5 mg/day on a weekly basis up to a dose of 9 mg/day, and then by up to 3 mg/day weekly to a maximum recommended total daily dose of 24 mg/day (8 mg three time daily). Doses greater than 24 mg/day have not been tested in clinical trials.

Ropinirole should be discontinued gradually over a 7-day period in patients with Parkinson’s disease. The frequency of administration should be reduced from three times daily to twice daily for 4 days. For the remaining 3 days, the frequency should be reduced to once daily prior to complete withdrawal of ropinirole.

2.3Dosing for Restless Legs Syndrome

The recommended adult starting dose for RLS is 0.25 mg once daily 1 to 3 hours before bedtime. After 2 days, if necessary, the dose can be increased to 0.5 mg once daily and to 1 mg once daily at the end of the first week of dosing, then as shown in Table 2 as needed to achieve efficacy. Titration should be based on individual patient therapeutic response and tolerability, up to a maximum recommended dose of 4 mg daily. For RLS, the safety and effectiveness of doses greater than 4 mg once daily have not been established.

In clinical trials of patients treated for RLS with doses up to 4 mg once daily, ropinirole was discontinued without a taper.

5.1 Falling Asleep During Activities of Daily Living and Somnolence

Patients treated with ropinirole have reported falling asleep while engaged in activities of daily living, including driving or operating machinery, which sometimes resulted in accidents. Although many of these patients reported somnolence while on ropinirole, some perceived that they had no warning signs, such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some have reported these events more than 1 year after initiation of treatment.

In controlled clinical trials, somnolence was commonly reported in patients receiving ropinirole and was more frequent in Parkinson's disease (up to 40% ropinirole, 6% placebo) than in Restless Legs Syndrome (12% ropinirole, 6% placebo) [see Adverse Reactions (6.1)].

It has been reported that 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. For this reason, prescribers should reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities.

Before initiating treatment with ropinirole, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with ropinirole such as concomitant sedating medications, the presence of sleep disorders (other than RLS), and concomitant medications that increase ropinirole plasma levels (e.g., ciprofloxacin) [see Drug Interactions (7.1)]. If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving a motor vehicle, conversations, eating), ropinirole should ordinarily be discontinued [see Dosage and Administration (2.2, 2.3)]. If a decision is made to continue ropinirole, patients should be advised to not drive and to avoid other potentially dangerous activities. There is insufficient information to establish that dose reduction will eliminate episodes of falling asleep while engaged in activities of daily living.

5.2 Syncope

Syncope, sometimes associated with bradycardia, was observed in association with ropinirole in both patients with Parkinson’s disease and patients with RLS. In controlled clinical trials in patients with Parkinson’s disease, syncope was observed more frequently in patients receiving ropinirole than in patients receiving placebo (early Parkinson’s disease without L-dopa: ropinirole 12%, placebo 1%; advanced Parkinson’s disease: ropinirole 3%, placebo 2%). Syncope was reported in 1% of patients treated with ropinirole for RLS in 12-week, placebo-controlled clinical trials compared with 0.2% of patients treated with placebo [see Adverse Reactions (6.1)]. Most cases occurred more than 4 weeks after initiation of therapy with ropinirole, and were usually associated with a recent increase in dose.

Because the trials of ropinirole excluded patients with significant cardiovascular disease, patients with significant cardiovascular disease should be treated with caution.

Approximately 4% of patients with Parkinson’s disease enrolled in Phase 1 trials had syncope following a 1-mg dose of ropinirole. In two trials in patients with RLS that used a forced-titration regimen and orthostatic challenge with intensive blood pressure monitoring, 2% of RLS patients treated with ropinirole compared with 0% of patients receiving placebo reported syncope.

In Phase 1 trials including healthy volunteers, the incidence of syncope was 2%. Of note, 1 subject with syncope developed hypotension, bradycardia, and sinus arrest; the subject recovered spontaneously without intervention.

5.3 Hypotension/Orthostatic Hypotension

Dopamine agonists in clinical trials and clinical experience appear to impair the systemic regulation of blood pressure, with resulting orthostatic hypotension, especially during dose escalation. In addition, patients with Parkinson’s disease appear to have an impaired capacity to respond to a postural challenge. For these reasons, patients should be monitored for signs and symptoms of orthostatic hypotension, especially during dose escalation, and patients should be informed of the risk for syncope and hypotension [see Patient Counseling Information (17)].

Although the clinical trials were not designed to systematically monitor blood pressure, there were individual reported cases of orthostatic hypotension in early Parkinson’s disease (without L-dopa) in patients treated with ropinirole. Most of these cases occurred more than 4 weeks after initiation of therapy with ropinirole and were usually associated with a recent increase in dose.

In 12-week, placebo-controlled trials of patients with RLS, the adverse event orthostatic hypotension was reported by 4 of 496 patients (0.8%) treated with ropinirole compared with 2 of 500 patients (0.4%) receiving placebo.

In two Phase 2 studies in patients with RLS, 14 of 55 patients (25%) receiving ropinirole experienced an adverse event of hypotension or orthostatic hypotension compared with none of the 27 patients receiving placebo. In these studies, 11 of the 55 patients (20%) receiving ropinirole and 3 of the 26 patients (12%) who had post-dose blood pressure assessments following placebo, experienced an orthostatic blood pressure decrease of at least 40 mm Hg systolic and/or at least 20 mm Hg diastolic.

In Phase 1 trials of ropinirole with healthy volunteers who received single doses on more than one occasion without titration, 7% had documented symptomatic orthostatic hypotension. These episodes appeared mainly at doses above 0.8 mg and these doses are higher than the starting doses recommended for patients with either Parkinson’s disease or with RLS. In most of these individuals, the hypotension was accompanied by bradycardia but did not develop into syncope [see Warnings and Precautions (5.2)].

Although dizziness is not a specific manifestation of hypotension or orthostatic hypotension, patients with hypotension or orthostatic hypotension frequently reported dizziness. In controlled clinical trials, dizziness was a common adverse reaction in patients receiving ropinirole and was more frequent in patients with Parkinson’s disease or with RLS receiving ropinirole than in patients receiving placebo (early Parkinson’s disease without L-dopa: ropinirole 40%, placebo 22%; advanced Parkinson’s disease: ropinirole 26%, placebo 16%; RLS: ropinirole 11%, placebo 5%). Dizziness of sufficient severity to cause trial discontinuation of ropinirole was 4% in patients with early Parkinson’s disease without L-dopa, 3% in patients with advanced Parkinson’s disease, and 1% in patients with RLS [See Adverse Reactions (6.1)].

5.4 Hallucinations/Psychotic-Like Behavior

In double-blind, placebo-controlled, early-therapy trials in patients with Parkinson’s disease who were not treated with L-dopa, 5.2% (8 of 157) of patients treated with ropinirole reported hallucinations, compared with 1.4% of patients on placebo (2 of 147). Among those patients receiving both ropinirole and L-dopa in advanced Parkinson’s disease studies, 10.1% (21 of 208) were reported to experience hallucinations, compared with 4.2% (5 of 120) of patients treated with placebo and L-dopa.

The incidence of hallucination was increased in elderly patients (i.e., older than 65 years) treated with extended-release ropinirole [see Use in Specific Populations (8.5)].

Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with ropinirole or after starting or increasing the dose of ropinirole. Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.

Patients with a major psychotic disorder should ordinarily not be treated with ropinirole because of the risk of exacerbating the psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinson’s disease and may decrease the effectiveness of ropinirole [see Drug Interactions (7.3)].

5.5 Dyskinesia

Ropinirole may potentiate the dopaminergic side effects of L-dopa and may cause and/or exacerbate pre-existing dyskinesia in patients treated with L-dopa for Parkinson's disease. In double-blind, placebo-controlled trials in advanced Parkinson’s disease, dyskinesia was much more common in patients treated with ropinirole than in those treated with placebo. Among those patients receiving both ropinirole and L-dopa in advanced Parkinson’s disease trials, 34% were reported to experience dyskinesia, compared with 13% of patients treated with placebo [see Adverse Reactions (6.1)]. Decreasing the dose of dopaminergic drug may ameliorate this adverse reaction.

5.6 Impulse Control/Compulsive Behaviors

Case reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge or compulsive eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including ropinirole, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease and RLS. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with ropinirole. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ropinirole.

5.7 Withdrawal-Emergent Hyperpyrexia and Confusion

A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in dopaminergic therapy. Therefore, it is recommended that the dose be tapered at the end of treatment with ropinirole for Parkinson’s disease as a prophylactic measure [see Dosage and Administration (2.2)].

5.8 Melanoma

Epidemiological studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear.

For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using ropinirole for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).

5.9 Augmentation and Early-Morning Rebound in Restless Legs Syndrome

Reports in the literature indicate treatment of RLS with dopaminergic medications can result in recurrence of symptoms in the early morning hours, referred to as rebound. Augmentation has also been described during therapy for RLS. Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities. Rebound refers to new onset of symptoms in the early morning hours. Augmentation and/or early-morning rebound have been observed in a postmarketing trial. If augmentation or early-morning rebound occurs, the use of ropinirole should be reviewed and dosage adjustment or discontinuation of treatment should be considered.

5.10 Fibrotic Complications

Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur.

Although these adverse reactions are believed to be related to the ergoline structure of these compounds, whether other, non-ergot-derived dopamine agonists such as ropinirole can cause them is unknown.

Cases of possible fibrotic complications, including pleural effusion, pleural fibrosis, interstitial lung disease, and cardiac valvulopathy, have been reported in the development program and postmarketing experience for ropinirole. While the evidence is not sufficient to establish a causal relationship between ropinirole and these fibrotic complications, a contribution of ropinirole cannot be excluded.

5.11 Retinal Pathology

Retinal degeneration was observed in albino rats in the 2-year carcinogenicity study at all doses tested (equivalent to 0.6 to 20 times the maximum recommended human dose [MRHD] for Parkinson’s disease [24 mg/day] on a mg/m2 basis), but was statistically significant at the highest dose (50 mg/kg/day). Retinal degeneration was not observed in a 3-month study in pigmented rats, in a 2-year carcinogenicity study in albino mice, or in 1-year studies in monkeys or albino rats. The significance of this effect for humans has not been established, but involves disruption of a mechanism that is universally present in vertebrates (e.g., disk shedding).

Ocular electroretinogram (ERG) assessments were conducted during a 2-year, double-blind, multicenter, flexible dose, L-dopa-controlled clinical study of ropinirole in patients with Parkinson's diseas; 156 patients (78 on ropinirole, mean dose 11.9 mg/day and 78 on L-dopa, mean dose 555.2 mg/day) were evaluated for evidence of retinal dysfunction through electroretinograms. There was no clinically meaningful difference between the treatment groups in retinal function over the duration of the trial.

5.12 Binding to Melanin

Ropinirole binds to melanin-containing tissues (i.e., eyes, skin) in pigmented rats. After a single dose, long-term retention of drug was demonstrated, with a half-life in the eye of 20 days.

Adverse Reactions

The following adverse reactions are described in more detail in other sections of the label:

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Hypersensitivity [see Contraindications (4)]

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Falling Asleep during Activities of Daily Living and Somnolence [see Warnings and Precautions (5.1)]

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Syncope [see Warnings and Precautions (5.2)]

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Hypotension/Orthostatic Hypotension [see Warnings and Precautions (5.3)]

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Hallucinations/Psychotic-like Behavior [see Warnings and Precautions (5.4)]

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Dyskinesia [see Warnings and Precautions (5.5)]

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Impulse Control/Compulsive Behaviors [see Warnings and Precautions (5.6)]

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Withdrawal-emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.7)]

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Melanoma [see Warnings and Precautions (5.8)]

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Augmentation and Early-morning rebound in RLS [see Warnings and Precautions (5.9)]

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Fibrotic Complications [see Warnings and Precautions (5.10)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug (or of another development program of a different formulation of the same drug) and may not reflect the rates observed in practice.

Restless Legs Syndrome

In the double-blind, placebo-controlled trials in patients with RLS, the most commonly observed adverse reactions in patients treated with ropinirole (incidence at least 5% greater than placebo) were nausea, vomiting, somnolence, dizziness, and asthenic condition (i.e., asthenia, fatigue, and/or malaise).

Approximately 5% of patients treated with ropinirole who participated in the double-blind, placebo-controlled trials in the treatment of RLS discontinued treatment due to adverse reactions compared with 4% of patients who received placebo. The most common adverse reaction in patients treated with ropinirole (incidence at least 2% greater than placebo) of sufficient severity to cause discontinuation was nausea.

Table 5 lists treatment-emergent adverse reactions that occurred in at least 2% of patients with RLS treated with ropinirole participating in the 12-week, double-blind, placebo-controlled trials and were numerically more common than the incidence for placebo-treated patients.

7.1 CYP1A2 Inhibitors and Inducers

In vitro metabolism studies showed that CYP1A2 was the major enzyme responsible for the metabolism of ropinirole. There is thus the potential for inducers or inhibitors of this enzyme to alter the clearance of ropinirole. Therefore, if therapy with a drug known to be a potent inducer or inhibitor of CYP1A2 is stopped or started during treatment with ropinirole, adjustment of the dose of ropinirole may be required. Coadministration of ciprofloxacin, an inhibitor of CYP1A2, increases the AUC and Cmax of ropinirole [see Clinical Pharmacology (12.3)]. Cigarette smoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking [see Clinical Pharmacology (12.3)].

7.2 Estrogens

Population pharmacokinetic analysis revealed that higher doses of estrogens (usually associated with hormone replacement therapy [HRT]) reduced the clearance of ropinirole. Starting or stopping HRT may require adjustment of dosage of ropinirole [see Clinical Pharmacology (12.3)].

7.3 DopamineAntagonists

Because ropinirole is a dopamine agonist, it is possible that dopamine antagonists such as neuroleptics (e.g., phenothiazines, butyrophenones, thioxanthenes) or metoclopramide may reduce the efficacy of ropinirole.

8.1 Pregnancy

Pregnancy Category C. There are no adequate and well-controlled studies in pregnant women. In animal reproduction studies, ropinirole has been shown to have adverse effects on embryo-fetal development, including teratogenic effects. Ropinirole should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Oral treatment of pregnant rats with ropinirole during organogenesis resulted in decreased fetal body weight, increased fetal death, and digital malformations at 24, 36, and 60 times, respectively, the maximum recommended human dose (MRHD) for Parkinson’s disease (24 mg/day) on a mg/m2basis. The combined oral administration of ropinirole at 8 times the MRHD and a clinically relevant dose of L-dopa to pregnant rabbits during organogenesis produced a greater incidence and severity of fetal malformations (primarily digit defects) than were seen in the offspring of rabbits treated with L-dopa alone. No effect on fetal development was observed in rabbits when ropinirole was administered alone at an oral dose 16 times the MRHD on a mg/m2basis. In a perinatal-postnatal study in rats, impaired growth and development of nursing offspring and altered neurological development of female offspring were observed when dams were treated with 4 times the MRHD on a mg/m2basis.

8.3 Nursing Mothers

Ropinirole inhibits prolactin secretion in humans and could potentially inhibit lactation.

Ropinirole has been detected in rat milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when ropinirole is administered to a nursing woman.

8.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use

Dose adjustment is not necessary in elderly (65 years and older) patients, as the dose of ropinirole is individually titrated to clinical therapeutic response and tolerability. Pharmacokinetic trials conducted in patients demonstrated that oral clearance of ropinirole is reduced by 15% in patients older than 65 years compared with younger patients [see Clinical Pharmacology (12.3)].

In clinical trials of extended-release ropinirole for Parkinson’s disease, 387 patients were 65 years and older and 107 patients were 75 years and older. Among patients receiving extended-release ropinirole, hallucination was more common in elderly patients (10%) compared with non-elderly patients (2%). The incidence of overall adverse reactions increased with increasing age for both patients receiving extended-release ropinirole and placebo.

8.6 Renal Impairment

No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). For patients with end-stage renal disease on hemodialysis, a reduced maximum dose is recommended [see Dosage and Administration (2.2, 2.3), Clinical Pharmacology (12.3)].

The use of ropinirole in patients with severe renal impairment (creatinine clearance less than 30 mL/min) without regular dialysis has not been studied.

8.7 Hepatic Impairment

The pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment.

12.1 Mechanism of Action

Ropinirole is a non-ergoline dopamine agonist. The precise mechanism of action of ropinirole as a treatment for Parkinson’s disease is unknown, although it is thought to be related to its ability to stimulate dopamine D2 receptors within the caudate-putamen in the brain. The precise mechanism of action of ropinirole as a treatment for Restless Legs Syndrome is unknown, although it is thought to be related to its ability to stimulate dopamine receptors.

12.2 Pharmacodynamics

Clinical experience with dopamine agonists, including ropinirole, suggests an association with impaired ability to regulate blood pressure with resulting orthostatic hypotension, especially during dose escalation. In some patients in clinical trials, blood pressure changes were associated with the emergence of orthostatic symptoms, bradycardia, and, in one case in a healthy volunteer, transient sinus arrest with syncope [see Warnings and Precautions (5.2, 5.3)].

The mechanism of orthostatic hypotension induced by ropinirole is presumed to be due to a D2-mediated blunting of the noradrenergic response to standing and subsequent decrease in peripheral vascular resistance. Nausea is a common concomitant symptom of orthostatic signs and symptoms.

At oral doses as low as 0.2 mg, ropinirole suppressed serum prolactin concentrations in healthy male volunteers.

Ropinirole had no dose-related effect on ECG wave form and rhythm in young, healthy, male volunteers in the range of 0.01 to 2.5 mg.

Ropinirole had no dose- or exposure-related effect on mean QT intervals in healthy male and female volunteers titrated to doses up to 4 mg/day. The effect of ropinirole on QTc intervals at higher exposures achieved either due to drug interactions, hepatic impairment, or at higher doses has not been systematically evaluated.

12.3 Pharmacokinetics

Ropinirole displayed linear kinetics over the dosing range of 1 to 8 mg three times daily. Steady-state concentrations are expected to be achieved within 2 days of dosing. Accumulation upon multiple dosing is predictive from single dosing.

Population Subgroups

Because therapy with ropinirole is initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight, or age is not necessary.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 Parkinson’s Disease

The effectiveness of ropinirole in the treatment of Parkinson’s disease was evaluated in a multinational drug development program consisting of 11 randomized, controlled trials. Four trials were conducted in patients with early Parkinson’s disease and no concomitant levodopa (L-dopa) and seven trials were conducted in patients with advanced Parkinson’s disease with concomitant L-dopa.

Three placebo-controlled trials provide evidence of effectiveness of ropinirole in the management of patients with Parkinson’s disease who were and were not receiving concomitant L-dopa. Two of these three trials enrolled patients with early Parkinson’s disease (without L-dopa) and one enrolled patients receiving L-dopa.

In these trials a variety of measures were used to assess the effects of treatment (e.g., the Unified Parkinson’s Disease Rating Scale [UPDRS], Clinical Global Impression [CGI] scores, patient diaries recording time “on” and “off,” tolerability of L-dopa dose reductions).

In both trials of patients with early Parkinson’s disease (without L-dopa), the motor component (Part III) of the UPDRS was the primary outcome assessment. The UPDRS is a multi-item rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor performance (Part III), and complications of therapy (Part IV). Part III of the UPDRS contains 14 items designed to assess the severity of the cardinal motor findings in patients with Parkinson’s disease (e.g., tremor, rigidity, bradykinesia, postural instability) scored for different body regions and has a maximum (worst) score of 108. In the trial of patients with advanced Parkinson’s disease (with L-dopa), both reduction in percent awake time spent “off” and the ability to reduce the daily use of L-dopa were assessed as a combined endpoint and individually.

14.2 Restless Legs Syndrome

The effectiveness of ropinirole in the treatment of RLS was demonstrated in randomized, double-blind, placebo-controlled trials in adults diagnosed with RLS using the International Restless Legs Syndrome Study Group diagnostic criteria. Patients were required to have a history of a minimum of 15 RLS episodes/month during the previous month and a total score of ≥15 on the International RLS Rating Scale (IRLS scale) at baseline. Patients with RLS secondary to other conditions (e.g., pregnancy, renal failure, anemia) were excluded. All trials employed flexible dosing, with patients initiating therapy at 0.25 mg ropinirole once daily. Patients were titrated based on clinical response and tolerability over 7 weeks to a maximum of 4 mg once daily. All doses were taken between 1 and 3 hours before bedtime.

A variety of measures were used to assess the effects of treatment, including the IRLS scale and Clinical Global Impression-Global Improvement (CGI-I) scores. The IRLS scale contains 10 items designed to assess the severity of sensory and motor symptoms, sleep disturbance, daytime somnolence, and impact on activities of daily living and mood associated with RLS. The range of scores is 0 to 40, with 0 being absence of RLS symptoms and 40 the most severe symptoms. Three of the controlled trials utilized the change from baseline in the IRLS scale at the Week 12 endpoint as the primary efficacy outcome.

Three hundred eighty patients were randomized to receive ropinirole (n=187) or placebo (n=193) in a US trial (RLS-1); 284 were randomized to receive either ropinirole (n=146) or placebo (n=138) in a multinational trial (excluding US) (RLS-2); and 267 patients were randomized to ropinirole (n=131) or placebo (n=136) in a multinational trial (including US) (RLS-3). Across the three trials, the mean duration of RLS was 16 to 22 years (range: 0 to 65 years), mean age was approximately 54 years (range: 18 to 79 years), and approximately 61% were women. The mean dose at Week 12 was approximately 2 mg/day for the three trials.

At baseline, mean total IRLS score was 22.0 for ropinirole and 21.6 for placebo in RLS-1, was 24.4 for ropinirole and 25.2 for placebo in RLS-2, and was 23.6 for ropinirole and 24.8 for placebo in RLS-3. In all three trials, a statistically significant difference between the treatment group receiving ropinirole and the treatment group receiving placebo was observed at Week 12 for both the mean change from baseline in the IRLS scale total score and the percentage of patients rated as responders (much improved or very much improved) on the CGI-I (see Table 9).

Long-term maintenance of efficacy in the treatment of RLS was demonstrated in a 36-week trial. Following a 24-week, single-blind treatment phase (flexible dosages of ropinirole of 0.25 to 4 mg once daily), patients who were responders (defined as a decrease of >6 points on the IRLS scale total score relative to baseline) were randomized in double-blind fashion to placebo or continuation of ropinirole for an additional 12 weeks. Relapse was defined as an increase of at least 6 points on the IRLS scale total score to a total score of at least 15, or withdrawal due to lack of efficacy. For patients who were responders at Week 24, the mean dose of ropinirole was 2 mg (range: 0.25 to 4 mg). Patients continued on ropinirole demonstrated a significantly lower relapse rate compared with patients randomized to placebo (32.6% versus 57.8%, P = 0.0156).