REQUIP XL is an orally administered, non-ergoline dopamine agonist indicated for the treatment of signs and symptoms of idiopathic Parkinson’s disease. (1.1)

REQUIP XL (ropinirole extended-release tablets) is indicated for the treatment of the signs and symptoms of idiopathic Parkinson’s disease.

• REQUIP XL Tablets are taken once daily, with or without food. Tablets must be swallowed whole and must not be chewed, crushed, or divided. (2.1)
• The starting dose is 2 mg taken once daily for 1 to 2 weeks, followed by increases of 2 mg/day at 1 week or longer intervals as appropriate, depending on therapeutic response and tolerability, up to a maximally recommended dose of 24 mg/day. Patients should be assessed for therapeutic response and tolerability at a minimal interval of 1 week or longer after each dose increment. Caution should be exercised during dose titration because too rapid a rate of titration can lead to dose selection that does not provide additional benefit, but that increases the risk of adverse reactions. (2.2, 14.2)
• Patients may be switched directly from immediate-release ropinirole to REQUIP XL. The initial switching dose of REQUIP XL should most closely match the total daily dose of immediate-release ropinirole, see Table 1. (2.3)
• If REQUIP XL must be discontinued, it should be tapered gradually over a 7-day period. (2.2)

• REQUIP XL Extended-Release Tablets are taken once daily, with or without food. Taking REQUIP XL with food may reduce the occurrence of nausea; this has not been established in controlled clinical trials [see Clinical Pharmacology (12.3)].
• Tablets must be swallowed whole and must not be chewed, crushed, or divided.
• If a significant interruption in therapy with REQUIP XL has occurred, retitration of therapy may be warranted.

The starting dose is 2 mg taken once daily for 1 to 2 weeks, followed by increases of 2 mg/day at 1-week or longer intervals as appropriate, depending on therapeutic response and tolerability, up to a maximally recommended dose of 24 mg/day.

In clinical trials, dosage was initiated at 2 mg/day and gradually titrated based on individual therapeutic response and tolerability. Doses greater than 24 mg/day have not been studied in clinical trials. Patients should be assessed for therapeutic response and tolerability at a minimal interval of 1 week or longer after each dose increment. Caution should be exercised during dose titration because too rapid a rate of titration may lead to dose selection that may not provide additional benefit, but that may increase the risk of adverse reactions [see Clinical Studies (14.2)]. Due to the flexible dosing design used in clinical studies, specific dose response information could not be determined.

When REQUIP XL is administered as adjunct therapy to L-dopa, the concurrent dose of L-dopa may be decreased gradually as tolerated. In the placebo-controlled advanced Parkinson’s disease study, the L-dopa dose was reduced once patients reached a dose of REQUIP XL of 8 mg/day. Overall, L-dopa dose reduction was sustained in 93% of patients treated with REQUIP XL and in 72% of patients on placebo. On average the L-dopa dose was reduced by 34% in patients treated with REQUIP XL [see Clinical Studies (14)].

REQUIP XL should be discontinued gradually over a 7-day period.

Patients may be switched directly from immediate-release ropinirole to REQUIP XL Tablets. The initial dose of REQUIP XL should most closely match the total daily dose of the immediate-release formulation of REQUIP, as shown in Table 1.

Following conversion to REQUIP XL, the dose may be adjusted depending on therapeutic response and tolerability[see Dosage and Administration (2.2)].

None.

None

• Falling asleep during activities of daily living may occur, including the operation of motor vehicles, which sometimes resulted in accidents. Sudden onset of sleep may occur without apparent warning or daytime drowsiness. Sedating medications (such as alcohol or CNS depressants), the presence of sleeping disorders, or other medications that increase plasma levels of ropinirole, may increase the risk of somnolence or falling asleep while engaged in activities of daily living. Before initiating treatment, patients should be advised of the potential of sudden onset of sleep or to develop drowsiness and asked about risk factors they may have. If a patient develops sudden onset of sleep during activities that require active participation (e.g., conversations, eating, etc.) and/or cannot avoid high-risk activities in the future, REQUIP XL should ordinarily be discontinued. (5.1)
• Syncope, sometimes associated with bradycardia, may occur. (5.2)
• Symptomatic hypotension (including postural/orthostatic hypotension) may occur, especially during dose escalation. (5.3)
• Elevation of blood pressure and changes in heart rate may occur. (5.4)
• Hallucination may occur. (5.5)
• Dyskinesia may be caused or exacerbated. Decreasing the L-dopa dose may lessen or eliminate this side effect. (5.6)

Patients treated with ropinirole have reported falling asleep while engaged in activities of daily living, including the operation of motor vehicles, 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 of these events have been reported more than 1 year after initiation of treatment.

Among the 613 patients who received REQUIP XL in clinical trials, there were 5 cases of sudden onset of sleep and 2 cases of motor vehicle accident in which it is not known if falling asleep was a contributing factor.

During the 6-month trial in advanced Parkinson’s disease, somnolence was reported in 7% (14 of 202) of patients receiving REQUIP XL compared with 4% (7 of 191) of patients receiving placebo. During the 36-week trial in early Parkinson’s disease, somnolence was reported in 11% (16 of 140) of patients receiving REQUIP XL compared with 15% (22 of 149) of patients receiving the immediate-release formulation of REQUIP [see Adverse Reactions (6)]. However, because dose-response was not systematically studied with REQUIP XL, the occurrence of somnolence at the highest recommended doses may be higher than these reported frequencies [see Adverse Reactions (6)].

Many clinical experts believe that falling asleep while engaged in activities of daily living always occurs in a setting of preexisting somnolence, although patients may not give such a history. For this reason, prescribers should continually 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 REQUIP XL, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with REQUIP XL such as concomitant sedating medications, the presence of sleep disorders, 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, etc.), REQUIP XL should ordinarily be discontinued [see Dosage and Administration for guidance in discontinuing REQUIP XL (2.2)]. If a decision is made to continue REQUIP XL, 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.

Syncope, sometimes associated with bradycardia, was observed during treatment with ropinirole in Parkinson’s disease patients.

In a placebo-controlled study involving patients with advanced Parkinson’s disease, syncope occurred in 2 of the 202 patients (1%) who received REQUIP XL, and in none of the 191 patients who received placebo.

Because the study of REQUIP XL excluded patients with significant cardiovascular disease, it is not known to what extent the estimated incidence figure applies to patients with Parkinson’s disease in clinical practice. Therefore, patients with significant cardiovascular disease should be treated with caution.

Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting postural 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 being treated with dopaminergic agonists ordinarily (1) require careful monitoring for signs and symptoms of postural hypotension, especially during dose escalation, and (2) should be informed of this risk [see Patient Counseling Information (17.2)].

In a placebo-controlled trial involving patients with advanced Parkinson’s disease, hypotension was reported as an adverse event in 5 of 202 patients (2%) receiving REQUIP XL and in none of the 191 patients receiving placebo. Orthostatic hypotension was reported as an adverse event in 5% of patients receiving REQUIP XL, and in 1% of placebo recipients.

An analysis of the randomized, double-blinded, placebo-controlled study in advanced Parkinson’s disease was conducted using a variety of adverse event terms possibly suggestive of hypotension, including hypotension, orthostatic hypotension, dizziness, vertigo, and blood pressure decreased. This analysis showed a higher incidence of these events with REQUIP XL (7%, 15 of 202) vs. placebo (3%, 6 of 191). This increased incidence was observed in a setting in which patients were very carefully titrated, and patients with clinically relevant cardiovascular disease or symptomatic orthostatic hypotension at baseline had been excluded from this study.

Orthostatic vital signs (semi-supine to standing) were monitored throughout the study in the advanced Parkinson’s disease study and changes related to REQUIP XL (compared with placebo) from baseline were assessed.

The frequency of any orthostatic hypotension at any time during the study was 38% for REQUIP XL vs. 31% for placebo for mild to moderate systolic blood pressure decrements (≥20 mm Hg), 63% for REQUIP XL vs. 58% for placebo for mild to moderate diastolic blood pressure decrements (≥10 mm Hg), 10% for REQUIP XL vs. 7% for placebo for severe diastolic blood pressure decrements (≥20 mm Hg), and 23% for REQUIP XL vs. 19% for placebo for mild to moderate combined systolic and diastolic blood pressure decrements.

Significant decrements in blood pressure unrelated to standing were also reported in some patients taking REQUIP XL. In the semi-supine position, the frequency was 10% for REQUIP XL vs. 8% for placebo for severe systolic blood pressure decrease (≥40 mm Hg), and was 25% for REQUIP XL vs. 21% for placebo for severe diastolic blood pressure decrease (≥20 mm Hg).

The increased incidence for hypotension and/or orthostatic hypotension was observed in both the titration and maintenance phases and in some cases persisted into the maintenance period after developing in the titration phase.

In the placebo-controlled study in advanced Parkinson’s disease, there were no clear effects of REQUIP XL on average changes in blood pressure or heart rate compared with placebo. However, there was an increased incidence of patients treated with REQUIP XL who met various outlier criteria, as described below.

In the semi-supine position, the frequency was 8% for REQUIP XL vs. 5% for placebo for severe systolic blood pressure increase (≥40 mm Hg). In the standing position, the frequency was 9% for REQUIP XL vs. 6% for placebo for severe systolic blood pressure increase (≥40 mm Hg).

In the semi-supine position, the frequency was 23% for REQUIP XL vs. 18% for placebo for moderate pulse increase (≥15 beats/minute), and 19% for REQUIP XL vs. 17% for placebo for moderate pulse decrease (≥15 beats/minute). In the standing position, the frequency was 2% for REQUIP XL vs. <1% for placebo for severe pulse increase (≥30 beats/minute), and 24% for REQUIP XL vs. 19% for placebo for moderate pulse decrease (≥15 beats/minute).

The increased incidence for various elevations of systolic and/or diastolic blood pressure and/or changes in pulse was observed in both the titration and maintenance phases as well as persisting into the maintenance period after developing in the titration phase.

Elevation of blood pressure and/or changes in heart rate in patients taking REQUIP XL should be considered when treating patients with cardiovascular disease.

In the double-blind, placebo-controlled, advanced Parkinson’s disease trial 8% (17 of 202) of patients receiving REQUIP XL reported hallucination compared with 2% (4 of 191) patients receiving placebo. Hallucination led to discontinuation of treatment in 2% (4 of 202) of patients on REQUIP XL and 1% (2 of 191) of patients on placebo.

The incidence of hallucination is increased in patients over age 65. Coadministration of entacapone and L-dopa with ropinirole may also increase the risk of hallucination. In a placebo-controlled clinical trial, hallucination occurred in 0 of 43 patients taking entacapone plus L-dopa, in 9 of 155 patients taking REQUIP XL plus L-dopa (6%), and in 7 of 47 patients taking entacapone with REQUIP XL plus L-dopa (15%).

REQUIP XL may potentiate the dopaminergic side effects of L-dopa and may cause and/or exacerbate preexisting dyskinesia in patients treated with L-dopa for Parkinson’s disease. Decreasing the dose of a dopaminergic drug may ameliorate this side effect.

Patients with a major psychotic disorder should ordinarily not be treated with REQUIP XL because of the risk of exacerbating the psychosis. In addition, many treatments for psychosis may decrease the effectiveness of REQUIP XL [see Drug Interactions (7.4)].

Withdrawal-Emergent Hyperpyrexia and Confusion: Although not reported during the clinical development of ropinirole, 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 REQUIP XL as a prophylactic measure [see Dosage and Administration (2.2)].

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, nonergot-derived dopamine agonists, such as REQUIP or REQUIP XL, can cause them is unknown.

A small number of reports have been received of possible fibrotic complications, including pleural effusion, pleural fibrosis, interstitial lung disease, and cardiac valvulopathy, in the development program and postmarketing experience for ropinirole. In the clinical development program (N = 613), 2 patients treated with REQUIP XL had pleural effusion. While the evidence is not sufficient to establish a causal relationship between ropinirole and these fibrotic complications, a contribution of ropinirole cannot be completely ruled out in rare cases.

Melanoma: Some epidemiologic studies have shown that patients with Parkinson’s disease have a higher risk (perhaps 2- to 4-fold higher) of developing melanoma than the general population. Whether the observed increased risk was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, was unclear. Ropinirole is one of the dopamine agonists used to treat Parkinson’s disease. Although ropinirole has not been associated with an increased risk of melanoma specifically, its potential role as a risk factor has not been systematically studied. In the clinical development program (N = 613), one patient treated with REQUIP XL and also levodopa/carbidopa developed melanoma. Patients using REQUIP XL should be made aware of these results and undergo periodic dermatologic screening.

Human: Because of observations made in albino rats (see below), ocular electroretinogram (ERG) assessments were conducted during a 2-year, double-blind, multicenter, flexible-dose, l-dopa controlled clinical study of immediate-release ropinirole in patients with Parkinson’s disease. A total of 156 patients (78 on immediate-release 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 study.

Albino Rats: 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) of 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 pigmented rats after 3 months in a 2-year carcinogenicity study in albino mice, or in 1-year studies in monkeys or albino rats. The potential significance of this effect for humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (e.g., disk shedding) may be involved.

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.

The following adverse reactions are described in more detail in the Warnings and Precautions section of the label:

• Falling asleep during activities of daily living (5.1)
• Syncope (5.2)
• Symptomatic hypotension, hypotension, postural/orthostatic hypotension (5.3)
• Elevation of blood pressure and changes in heart rate (5.4)
• Hallucination (5.5)
• Dyskinesia (5.6)
• Major psychotic disorders (5.7)
• Events with dopaminergic therapy (5.8)
• Retinal pathology (5.9)

• Most common adverse reactions (incidence ≥5% and greater than placebo) in advanced Parkinson’s disease with concomitant L-dopa were dyskinesia, nausea, dizziness, hallucination, somnolence, abdominal pain/discomfort, and orthostatic hypotension. (6.1)
• Most common adverse reactions (incidence ≥5%) in early Parkinson’s disease without L-dopa were nausea, somnolence, abdominal pain/discomfort, dizziness, headache, and constipation. (6.1)

  To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

During the premarketing development of REQUIP XL, patients with advanced Parkinson’s disease received REQUIP XL or placebo as adjunctive therapy in 1 clinical trial. In a second trial, patients with early Parkinson’s disease were treated with REQUIP XL or the immediate-release formulation of REQUIP without L-dopa.

Advanced Parkinson’s Disease (With L-dopa): The most commonly observed adverse reactions (≥5% and numerically greater than placebo) in the 24-week, double-blind, placebo-controlled trial for the treatment of advanced Parkinson’s disease during treatment with REQUIP XL were, in order of decreasing incidence: dyskinesia, nausea, dizziness, hallucination, somnolence, abdominal pain/discomfort, and orthostatic hypotension.

Approximately 6% of 202 patients treated with REQUIP XL discontinued treatment due to adverse event(s) compared with 5% of 191 patients who received placebo. The adverse event most commonly causing discontinuation of treatment with REQUIP XL was hallucination (2%).

Table 2 lists adverse reactions that occurred with a frequency of at least 2% (and were numerically greater than placebo) in patients with advanced Parkinson’s disease treated with REQUIP XL who participated in the 26-week, double-blind, placebo-controlled study. In this study, either REQUIP XL or placebo was used as an adjunct to L -dopa. Adverse reactions were generally mild or moderate in intensity.

^*Dose-related.

Although this study was not designed for optimally characterizing dose-related adverse reactions, there was a suggestion (based upon comparison of incidence of adverse reactions across dose ranges for REQUIP XL and placebo) that the incidence for dyskinesia, hypertension, and fall was dose-related to REQUIP XL.

The incidence for many adverse reactions with REQUIP XL treatment was increased relative to placebo (i.e., REQUIP XL % - Placebo % = treatment difference ≥2%) in either the titration or maintenance phases of the study. During the titration phase, an increased incidence (shown in descending order of % treatment difference) was observed for dyskinesia, nausea, abdominal pain/discomfort, orthostatic hypotension, dizziness, vertigo, hypertension, peripheral edema, and dry mouth. During the maintenance phase, an increased incidence was observed for dyskinesia, nausea, dizziness, hallucination, somnolence, fall, hypertension, abnormal dreams, constipation, chest pain, bronchitis, and nasopharyngitis. Some adverse reactions developing in the titration phase persisted (≥7 days) into the maintenance phase. These “persistent” adverse reactions included dyskinesia, hallucination, orthostatic hypotension, and dry mouth.

The incidence of adverse reactions was not clearly different between women and men.

Early Parkinson’s Disease (Without L-dopa): The most commonly observed adverse reactions (≥5%) in the 36-week early Parkinson’s disease trial during treatment with REQUIP XL were, in order of decreasing incidence: nausea (19%), somnolence (11%), abdominal pain/discomfort (7%), dizziness (6%), headache (6%), and constipation (5%). The type of adverse reactions and the frequency (i.e. incidence) with which they occurred were generally similar over the whole treatment period in this study of early Parkinson’s disease patients who were initially treated with REQUIP XL or the immediate-release formulation of REQUIP and subsequently crossed over to treatment with the other formulation.

During the titration phase, an increased incidence with REQUIP XL compared with the immediate-release formulation of REQUIP (i.e., REQUIP XL % - REQUIP IR % = treatment difference ≥2%), shown in descending order of % treatment difference, was observed for: constipation, hallucination, vertigo, abdominal pain/discomfort, nausea, vomiting, fall, headache, diarrhea, pyrexia, and flatulence. During the maintenance phase, an increased incidence was observed for fall, myalgia, and sleep disorder. Several adverse reactions developing in the titration phase persisted (≥7 days) into the maintenance phase. These “persistent” adverse reactions included: constipation, hallucination, muscle spasms, flatulence, insomnia, sleep disorder, abdominal pain/discomfort, cough, and nasopharyngitis.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to 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.

In patients with advanced Parkinson’s disease who were treated with the immediate-release formulation of REQUIP, the most common adverse reactions (≥5% treatment difference from placebo; presented in order of decreasing treatment difference frequency) were dyskinesia (21%), somnolence (12%), nausea (12%), dizziness (10%), confusion (7%), hallucinations (6%), headache (5%), and increased sweating (5%). In patients with early Parkinson’s disease who were treated with the immediate-release formulation of REQUIP, the most common adverse reactions (≥5% treatment difference from placebo; presented in order of decreasing treatment difference frequency) were nausea (38%), somnolence (34%), dizziness (18%), syncope (11%), viral infection (8%), fatigue (7%), leg edema (6%), asthenia (5%), and dyspepsia (5%).