ReQuip XL

Dosage Forms And Strengths

• 2-mg, pink, biconvex, capsule-shaped, film-coated, tablets debossed with “GS” and “3V2”
• 4-mg, light brown, biconvex, capsule-shaped, film-coated, tablets debossed with “GS” and “WXG”
• 6-mg, white, biconvex, capsule-shaped, film-coated, tablets debossed with “GS” and “11F”
• 8-mg, red, biconvex, capsule-shaped, film-coated, tablets debossed with “GS” and “5CC”
• 12-mg, green, biconvex, capsule-shaped, film-coated, tablets debossed with “GS” and “YX7”

Storage And Handling

Each biconvex, capsule-shaped, film-coated tablet contains ropinirole hydrochloride equivalent to the labeled amount of ropinirole as follows:

2-mg: pink tablets debossed with “GS” and “3V2” in bottles of 30 (NDC 0007-4885-13)

4-mg: light brown tablets debossed with “GS” and “WXG” in bottles of 30 (NDC 00074887-13) and 90 (NDC 0007-4887-59).

6-mg: white tablets debossed with “GS” and “11F” in bottles of 30 (NDC 0007-4883-13).

8-mg: red tablets debossed with “GS” and “5CC” in bottles of 30 (NDC 0007-4888-13).

12-mg: green tablets debossed with “GS” and “YX7” in bottles of 30 (NDC 0007-4882-13).

Storage

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F).

Dispense in a tight, light-resistant container as defined in the USP.

GlaxoSmithKline: Research Triangle Park, NC 27709. For more information go to www.gsk.com or call 1-888-825-5249 (toll-free). Revised: Mar 2017

REQUIP XL® is indicated for the treatment of Parkinson's disease.

General Dosing Recommendations

• REQUIP XL extended-release tablets are taken once daily, with or without food.
• 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.

Dosing For Parkinson's Disease

The recommended starting dose of REQUIP XL is 2 mg taken once daily for 1 to 2 weeks, followed by increases of 2 mg/day at weekly or longer intervals, based on therapeutic response and tolerability. Monitor patients at least weekly during dose titration. Too rapid a rate of titration may lead to the selection of a dose that does not provide additional benefit, but increases the risk of adverse reactions.

In fixed-dose studies designed to characterize the dose-response to REQUIP XL, there was no additional therapeutic benefit shown in patients with advanced stage Parkinson's disease taking daily doses greater than 8 mg/day, or with early stage Parkinson's disease taking doses greater than 12 mg/day. Although the maximum recommended dose of REQUIP XL is 24 mg, patients with advanced Parkinson's disease should generally be maintained at daily doses of 8 mg or lower and patients with early Parkinson's disease should generally be maintained at daily doses 12 mg or lower.

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

Renal Impairment

No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The recommended initial dose of REQUIP XL for patients with end-stage renal disease on hemodialysis is 2 mg once daily. Further dose escalations should be based on tolerability and need for efficacy. The recommended maximum total daily dose is 18 mg/day in patients receiving regular dialysis. Supplemental doses after dialysis are not required. The use of REQUIP XL in patients with severe renal impairment without regular dialysis has not been studied.

Switching From Immediate-Release Ropinirole Tablets To REQUIP XL

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

Table 1: Conversion from Immediate-Release Ropinirole Tablets to REQUIP XL

Following conversion to REQUIP XL, the dose may be adjusted depending on therapeutic response and tolerability .

Effect Of Gastrointestinal Transit Time On Medication Release

REQUIP XL is designed to release medication over a 24-hour period. If rapid gastrointestinal transit occurs, there may be risk of incomplete release of medication and medication residue being passed in the stool.

None.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Falling Asleep During Activities of Daily Living

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 (ropinirole extended release tablets) 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 (ropinirole extended release tablets) 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. However, because dose-response was not systematically studied with REQUIP XL (ropinirole extended release tablets) , the occurrence of somnolence at the highest recommended doses may be higher than these reported frequencies .

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 (ropinirole extended release tablets) , patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with REQUIP XL (ropinirole extended release tablets) such as concomitant sedating medications, the presence of sleep disorders, and concomitant medications that increase ropinirole plasma levels (e.g., ciprofloxacin). 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. If a decision is made to continue REQUIP XL (ropinirole extended release tablets) , 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

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 (ropinirole extended release tablets) , and in none of the 191 patients who received placebo.

Because the study of REQUIP XL (ropinirole extended release tablets) 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.

Hypotension

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.

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 (ropinirole extended release tablets) and in none of the 191 patients receiving placebo. Orthostatic hypotension was reported as an adverse event in 5% of patients receiving REQUIP XL (ropinirole extended release tablets) , 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 (ropinirole extended release tablets) (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 (ropinirole extended release tablets) (compared with placebo) from baseline were assessed.

The frequency of any orthostatic hypotension at any time during the study was 38% for REQUIP XL (ropinirole extended release tablets) vs. 31% for placebo for mild to moderate systolic blood pressure decrements ( ≥ 20 mm Hg), 63% for REQUIP XL (ropinirole extended release tablets) vs. 58% for placebo for mild to moderate diastolic blood pressure decrements ( ≥ 10 mm Hg), 10% for REQUIP XL (ropinirole extended release tablets) vs. 7% for placebo for severe diastolic blood pressure decrements ( ≥ 20 mm Hg), and 23% for REQUIP XL (ropinirole extended release tablets) 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 (ropinirole extended release tablets). In the semi-supine position, the frequency was 10% for REQUIP XL (ropinirole extended release tablets) vs. 8% for placebo for severe systolic blood pressure decrease ( ≥ 40 mm Hg), and was 25% for REQUIP XL (ropinirole extended release tablets) 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.

Elevation of Blood Pressure and Changes in Heart Rate

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

In the semi-supine position, the frequency was 8% for REQUIP XL (ropinirole extended release tablets) vs. 5% for placebo for severe systolic blood pressure increase ( ≥ 40 mm Hg). In the standing position, the frequency was 9% for REQUIP XL (ropinirole extended release tablets) 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 (ropinirole extended release tablets) vs. 18% for placebo for moderate pulse increase ( ≥ 15 beats/ minute), and 19% for REQUIP XL (ropinirole extended release tablets) vs. 17% for placebo for moderate pulse decrease ( ≥ 15 beats/minute). In the standing position, the frequency was 2% for REQUIP XL (ropinirole extended release tablets) vs. < 1% for placebo for severe pulse increase ( > 30 beats/minute), and 24% for REQUIP XL (ropinirole extended release tablets) 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 (ropinirole extended release tablets) should be considered when treating patients with cardiovascular disease.

Hallucination

In the double-blind, placebo-controlled, advanced Parkinson's disease trial 8% (17 of 202) of patients receiving REQUIP XL (ropinirole extended release tablets) 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 (ropinirole extended release tablets) 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 (ropinirole extended release tablets) plus L-dopa (6%), and in 7 of 47 patients taking entacapone with REQUIP XL (ropinirole extended release tablets) plus L-dopa (15%).

Dyskinesia

REQUIP XL (ropinirole extended release tablets) 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.

Major Psychotic Disorders

Patients with a major psychotic disorder should ordinarily not be treated with REQUIP XL (ropinirole extended release tablets) because of the risk of exacerbating the psychosis. In addition, many treatments for psychosis may decrease the effectiveness of REQUIP XL.

Events Reported With Dopaminergic Therapy

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.

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 (ropinirole extended release tablets) , 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 (ropinirole extended release tablets) 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 (ropinirole extended release tablets) and also levodopa/carbidopa developed melanoma. Patients using REQUIP XL (ropinirole extended release tablets) should be made aware of these results and undergo periodic dermatologic screening.

Retinal Pathology

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.

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.

Patient Counseling Information

See FDA-Approved Patient Labeling

Physicians should instruct their patients to read the Patient Information leaflet before starting therapy with REQUIP XL (ropinirole extended release tablets) and to reread it upon prescription renewal for new information regarding the use of REQUIP XL (ropinirole extended release tablets).

Dosing Instructions

• Patients should be instructed to take REQUIP XL (ropinirole extended release tablets) only as prescribed. If a dose is missed, patients should be advised not to double their next dose.
• REQUIP XL (ropinirole extended release tablets) can be taken with or without food. Taking REQUIP XL (ropinirole extended release tablets) with food may reduce the occurrence of nausea
• REQUIP XL (ropinirole extended release tablets) Tablets should be swallowed whole. They should not be chewed, crushed, or divided
• Ropinirole is the active ingredient that is in both REQUIP XL (ropinirole extended release tablets) and REQUIP Tablets (the immediate-release formulation). Ask your patient if they are taking another medication containing ropinirole.

Postural (Orthostatic) Hypotension

Patients should be advised that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating. Hypotension and/or orthostatic symptoms may occur more frequently during initial therapy or with an increase in dose at any time (cases have been seen after weeks of treatment). Accordingly, patients should be cautioned against standing up rapidly after sitting or lying down, especially if they have been doing so for prolonged periods, and especially at the initiation of treatment with REQUIP XL.

Elevation of Blood Pressure and Changes in Heart Rate

Patients should be alerted to the possibility of increases in blood pressure during treatment with REQUIP XL (ropinirole extended release tablets). Exacerbation of hypertension may occur. Medication dose adjustment may be necessary if elevation of blood pressure is sustained over multiple evaluations. Patients with cardiovascular disease, who may not tolerate marked changes in heart rate, should also be alerted to the possibility that they may experience significant increases or decreases in heart rate during treatment with REQUIP XL (ropinirole extended release tablets).

Sedating Effects

Patients should be alerted to the potential sedating effects caused by REQUIP XL (ropinirole extended release tablets) , including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse reaction with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with REQUIP XL (ropinirole extended release tablets) to gauge whether or not it affects their mental and/or motor performance adversely. Patients should be advised that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., conversations, eating, driving a motor vehicle, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician.

Because of possible additive effects, caution should be advised when patients are taking other sedating medications, alcohol, or other CNS depressants (e.g., benzodiazepines, antipsychotics, antidepressants, etc.) in combination with REQUIP XL or when taking concomitant medications that increase plasma levels of ropinirole (e.g., ciprofloxacin).

Hallucinations

Patients should be informed they may experience hallucinations (unreal visions, sounds, or sensations) while taking ropinirole. The elderly are at greater risk than younger patients with Parkinson's disease; and the risk is greater in patients who are taking ropinirole with L-dopa or taking higher doses of ropinirole, and may also be further increased in patients taking any other drugs that increase dopaminergic tone.

Impulse Control Symptoms Including Compulsive Behaviors

There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone, that are generally used for the treatment of Parkinson's disease or Restless Legs Syndrome, including ropinirole. In the clinical development program (N = 613), 6 patients treated with REQUIP XL (ropinirole extended release tablets) exhibited compulsive behaviors consisting of pathological gambling and/or hypersexuality. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with REQUIP XL (ropinirole extended release tablets). Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking REQUIP XL (ropinirole extended release tablets). Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking REQUIP XL.

Nursing Mothers

Because of the possibility that ropinirole may be excreted in breast milk, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Patients should be advised that ropinirole could inhibit lactation, as ropinirole inhibits prolactin secretion.

Pregnancy

Because ropinirole has been shown to have adverse effects on embryo-fetal development, including teratogenic effects, in animals, and because experience in humans is limited, patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

FDA-Approved Patient Labeling

Patient labeling is reproduced in the PATIENT INFORMATION section.

Physicians should instruct their patients to read the Patient Information leaflet before starting therapy with REQUIP XL (ropinirole extended release tablets) and to reread it upon prescription renewal for new information regarding the use of REQUIP XL (ropinirole extended release tablets).

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Two-year carcinogenicity studies were conducted in Charles River CD-1 mice at doses of 5, 15, and 50 mg/kg/day and in Sprague-Dawley rats at doses of 1.5, 15, and 50 mg/kg/day (top doses which, based on mg/m², are equivalent to 10 and 20 times, respectively, the MRHD of 24 mg/day). In the male rat, there was a significant increase in testicular Leydig cell adenomas at all doses tested, i.e., ≥ 1.5 mg/kg (0.6 times the MRHD on a mg/m² basis). This finding is of questionable significance because the endocrine mechanisms believed to be involved in the production of Leydig cell hyperplasia and adenomas in rats are not relevant to humans. In the female mouse, there was an increase in benign uterine endometrial polyps at a dose of 50 mg/kg/day (10 times the MRHD on a mg/m² basis). Ropinirole was not mutagenic or clastogenic in the in vitro Ames test, the in vitrochromosome aberration test in human lymphocytes, the in vitro mouse lymphoma (L1578Y cells) assay, and the in vivo mouse micronucleus test.

When administered to female rats prior to and during mating and throughout pregnancy, ropinirole caused disruption of implantation at doses of 20 mg/kg/day (8 times the MRHD on a mg/m² basis) or greater. This effect is thought to be due to the prolactin-lowering effect of ropinirole. In humans, chorionic gonadotropin, not prolactin, is essential for implantation. In rat studies using low doses (5 mg/kg) during the prolactin-dependent phase of early pregnancy (gestation days 0 to 8), ropinirole did not affect female fertility at dosages up to 100 mg/kg/day (40 times the MRHD on a mg/m² basis). No effect on male fertility was observed in rats at dosages up to 125 mg/kg/day (50 times the MRHD on a mg/m² basis).

Use In Specific Populations

Pregnancy

Pregnancy Category C. There are no adequate and well-controlled studies using ropinirole in pregnant women. REQUIP XL (ropinirole extended release tablets) should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

In animal reproduction studies, ropinirole has been shown to have adverse effects on embryo-fetal development, including teratogenic effects. 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 the MRHD, respectively. The combined 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. 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.

Nursing Mothers

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

Ropinirole has been detected in the milk of lactating rats. Although many drugs are excreted in human milk, transfer of ropinirole into human milk has not been demonstrated. Due to the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of ropinirole to the mother.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established.

Geriatric use

Dosage adjustment is not necessary in the elderly (above 65 years), as the dose of REQUIP XL (ropinirole extended release tablets) is to be individually titrated to clinical response. Pharmacokinetic studies conducted in patients demonstrated that oral clearance of ropinirole is reduced by 15% in patients above 65 years of age compared to younger patients.

Of the total number of patients who participated in clinical trials of REQUIP XL (ropinirole extended release tablets) for Parkinson's disease, 387 patients were 65 and over and 107 patients were 75 and over. Among patients receiving REQUIP XL (ropinirole extended release tablets) , hallucination was more common in elderly subjects (10%) compared with non-elderly subjects (2%). The incidence of overall adverse events increased with increasing age for both patients receiving REQUIP XL and placebo.

Renal Impairment

No dosage adjustment of ropinirole is needed in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The use of ropinirole in patients with severe renal impairment has not been studied.

Hepatic Impairment

The pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment. Since patients with hepatic impairment may have higher plasma levels and lower clearance, ropinirole should be titrated with caution in these patients.

Digoxin: Coadministration of immediate-release ropinirole (2 mg three times daily) with digoxin (0.125 to 0.25 mg once daily) did not alter the steady-state pharmacokinetics of digoxin in 10 patients.

Theophylline: Administration of theophylline (300 mg twice daily, a substrate of CYP1A2) did not alter the steady-state pharmacokinetics of immediate-release ropinirole (2 mg three times daily) in 12 patients with Parkinson's disease. Immediate-release ropinirole (2 mg three times daily) did not alter the pharmacokinetics of theophylline (5 mg/kg intravenously) in 12 patients with Parkinson's disease.

Ciprofloxacin: Coadministration of ciprofloxacin (500 mg twice daily), an inhibitor of CYP1A2, with immediate-release ropinirole (2 mg three times daily) increased ropinirole AUC by 84% on average and Cmax by 60% (n = 12 patients).

Estrogens: Population pharmacokinetic analysis revealed that estrogens (mainly ethinylestradiol: intake 0.6 to 3 mg over 4-month to 23-year period) reduced the oral clearance of ropinirole by 36% in 16 patients.

L-dopa: Coadministration of carbidopa + L-dopa (10/100 mg twice daily) with immediate-release ropinirole (2 mg three times daily) had no effect on the steady-state pharmacokinetics of ropinirole (n = 28 patients). Oral administration of immediate-release ropinirole 2 mg three times daily increased mean steady-state Cmax of L-dopa by 20%, but its AUC was unaffected (n = 23 patients).

Commonly Administered Drugs: Population analysis showed that commonly administered drugs, e.g., selegiline, amantadine, tricyclic antidepressants, benzodiazepines, ibuprofen, thiazides, antihistamines, and anticholinergics, did not affect the clearance of ropinirole. An in vitro study indicates that ropinirole is not a substrate for P-gp. Ropinirole and its circulating metabolites do not inhibit or induce P450 enzymes; therefore, ropinirole is unlikely to affect the pharmacokinetics of other drugs by a P450 mechanism.

Because ropinirole has been shown to have adverse effects on embryo-fetal development, including teratogenic effects, in animals, and because experience in humans is limited, patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.

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

• Hypersensitivity
• Falling Asleep during Activities of Daily Living and Somnolence
• Syncope
• Hypotension/Orthostatic Hypotension
• Elevation of Blood Pressure and Changes in Heart Rate
• Hallucinations/Psychotic-like Behavior
• Dyskinesia
• Impulse Control/Compulsive Behaviors
• Withdrawal-Emergent Hyperpyrexia and Confusion
• Melanoma
• Fibrotic Complications
• Retinal Pathology

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.

During the premarketing development of REQUIP XL, patients with advanced Parkinson's disease received REQUIP XL or placebo as adjunctive therapy with L-dopa in a flexible-dose clinical trial. In a flexible-dose trial, patients with early Parkinson's disease were treated with REQUIP XL or the immediate-release formulation of REQUIP without L-dopa. In addition, placebo-controlled, fixed-dose, postmarketing trials evaluated the dose response of REQUIP XL in patients with advanced Parkinson's disease taking L-dopa and in patients with early Parkinson's disease without concomitant L-dopa.

Advanced Parkinson's Disease (with L-dopa)

Study 1 was a 24-week, double-blind, placebo-controlled, flexible-dose trial in patients with advanced Parkinson's disease. In Study 1, the most commonly observed adverse reactions in patients treated with REQUIP XL (incidence at least 5% greater than placebo) were dyskinesia, nausea, dizziness, and hallucinations.

In Study 1, approximately 6% of patients treated with REQUIP XL discontinued treatment due to adverse reactions, compared with 5% of patients who received placebo. The most common adverse reaction in patients treated with REQUIP XL causing discontinuation of treatment with REQUIP XL in Study 1 was hallucination (2%).

Table 2 lists adverse reactions that occurred in at least 2% (and were numerically greater than placebo) of patients with advanced Parkinson's disease treated with REQUIP XL who participated in Study 1. In this trial, either REQUIP XL or placebo was used as an adjunct to L-dopa.

Table 2: Incidence of Adverse Reactions in a Placebo-Controlled Flexible-Dose Trial in Advanced Stage Parkinson's Disease in Patients Taking L-dopa (Study 1) (Events ≥ 2% of Patients Treated with REQUIP XL and More Common than on Placebo)^a

Although this trial 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.

During the titration phase, the incidence of adverse reactions in descending order of percent treatment difference was dyskinesia, nausea, abdominal pain/discomfort, orthostatic hypotension, dizziness, vertigo, hypertension, peripheral edema, and dry mouth. During the maintenance phase, the most frequently observed adverse reactions were 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 similar in women and men.

Study 2 was an 18-week, double-blind, placebo-controlled, fixed-dose, dose-response trial in patients with advanced Parkinson's disease. In Study 2, approximately 7% of patients treated with any dose of REQUIP XL discontinued prematurely during the titration phase because of adverse reactions, compared with 4% of patients on placebo. The percentage of patients who discontinued from the study because of an adverse reaction was 4% for REQUIP XL 4 mg, 9% for REQUIP XL 8 mg, 8% for REQUIP XL 12 mg, 8% for REQUIP XL 16 mg, and 0% for REQUIP XL 24 mg. Table 3 lists adverse reactions with an incidence of at least 5% of patients in any dose group of REQUIP XL and numerically higher than on placebo in Study 2. The most common adverse reaction (incidence for REQUIP XL all doses at least 5% greater than placebo) was dyskinesia.

Table 3: Incidence of Adverse Reactions in a Placebo-Controlled Fixed-Dose Trial in Advanced Stage Parkinson's Disease in Patients Taking L-dopa (Study 2) (Events ≥ 5% of Patients Treated with any Dose of REQUIP XL and More Common than on Placebo)

Early Parkinson's Disease (without L-dopa)

Study 3 was a 36-week, flexible-dose crossover trial in patients with early Parkinson's disease who were first treated with REQUIP XL or the immediate-release formulation of REQUIP and then crossed over to treatment with the other formulation. In Study 3, the most commonly observed adverse reactions ( ≥ 5%) in patients treated with REQUIP XL were nausea (19%), somnolence (11%), abdominal pain/discomfort (7%), dizziness (6%), headache (6%), and constipation (5%).

Study 4 was an 18-week, double-blind, placebo-controlled, fixed-dose, dose-response trial in patients with early Parkinson's disease. Overall, 7% of patients treated with any dose of REQUIP XL, including 6% during the titration phase, discontinued prematurely from the study because of adverse reactions compared with 5% of patients on placebo. The percentage of patients discontinuing prematurely because of an adverse reaction was 8% for REQUIP XL 2 mg, 5% for REQUIP XL 4 mg, 8% for REQUIP XL 8 mg, 5% for REQUIP XL 12 mg, and 15% for REQUIP XL 24 mg.

Table 4 lists adverse reactions with an incidence of at least 10% of patients in any dose group of REQUIP XL and numerically higher than on placebo in Study 4. The most common adverse reactions (incidence for REQUIP XL all doses at least 5% greater than placebo) were nausea, somnolence, sudden onset of sleep, hypertension, and headache.

Table 4: Incidence of Adverse Reactions in a Double-Blind, Placebo-Controlled, Fixed-Dose, Trial in Early Stage Parkinson's Disease (Study 4) (Events ≥ 10% of Patients Treated with any Dose of REQUIP XL and Greater % than on Placebo)

Laboratory Abnormalities

In the fixed-dose trial in advanced Parkinson's disease (Study 2), 11% of patients on REQUIP XL exhibited a shift in serum creatine phosphokinase (CPK) from normal at baseline to above the normal reference range during treatment, compared with 6% of patients on placebo. There was no clear dose-response for abnormal shifts in CPK levels in patients with early or advanced stage Parkinson's disease in either fixed-dose trial.

In the fixed-dose trial in early Parkinson's disease patients (Study 4), serum CPK shifted during treatment from normal to above the normal reference range in 10% of patients on REQUIP XL and in 5% of patients on placebo.

Adverse Reactions Observed During The Clinical Development Of The Immediate-Release Formulation Of REQUIP For Parkinson's Disease (Advanced and Early)

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.

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%), asthenic condition (11%), viral infection (8%), leg edema (6%), vomiting (5%), and dyspepsia (5%).

Human Overdose Experience

In the Parkinson's disease program, there have been patients who accidentally or intentionally took more than their prescribed dose of ropinirole. The largest overdose reported with immediate-release ropinirole in clinical trials was 435 mg taken over a 7-day period (62.1 mg/day). Of patients who received a dose greater than 24 mg/day, reported symptoms included adverse events commonly reported during dopaminergic therapy (nausea, dizziness), as well as visual hallucination, hyperhidrosis, claustrophobia, chorea, palpitations, asthenia, and nightmares. Additional symptoms reported for doses of 24 mg or less or for overdoses of unknown amount included vomiting, increased coughing, fatigue, syncope, vasovagal syncope, dyskinesia, agitation, chest pain, orthostatic hypotension, somnolence, and confusional state.

Overdose Management

The symptoms of overdose with ropinirole are generally related to its dopaminergic activity; these symptoms may be alleviated by appropriate treatment with dopamine antagonists such as neuroleptics or metoclopramide. General supportive measures are recommended. Vital signs should be maintained, if necessary. Removal of any unabsorbed material (e.g., by gastric lavage) may be considered.

Clinical experience with dopamine agonists, including ropinirole, suggests an association with impaired ability to regulate blood pressure resulting in orthostatic hypotension, especially during dose escalation. In some subjects 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.

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.

Immediate-release 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.

Immediate-release 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.

Increase in systemic exposure of ropinirole following oral administration of 2 to 12 mg of REQUIP XL was approximately dose-proportional. For REQUIP XL, steady-state concentrations of ropinirole are expected to be achieved within 4 days of dosing.

Absorption

In clinical trials with immediate-release ropinirole, more than 88% of a radiolabeled dose was recovered in urine, and the absolute bioavailability was 45% to 55%, indicating approximately 50% first-pass effect.

The bioavailability of REQUIP XL extended-release tablets is similar to that of immediate-release ropinirole tablets. In a repeat-dose trial in subjects with Parkinson's disease using REQUIP XL 8 mg, the dose-normalized AUC(0-24) and Cmin for REQUIP XL and immediate-release ropinirole were similar. Dose-normalized Cmax was, on average, 12% lower for REQUIP XL than for the immediate-release formulation and the median time-to-peak concentration was 6 to 10 hours. In a single-dose trial, administration of REQUIP XL to healthy volunteers with food (i.e., high-fat meal) increased AUC by approximately 30% and Cmax by approximately 44%, compared with dosing under fasted conditions. In a repeat-dose trial in patients with Parkinson's disease, food (i.e., high-fat meal) increased AUC by approximately 20% and Cmax by approximately 44%; Tmax was prolonged by 3 hours (median prolongation) compared with dosing under fasted conditions.

Distribution

Ropinirole is widely distributed throughout the body, with an apparent volume of distribution of 7.5 L/kg. It is up to 40% bound to plasma proteins and has a blood-to-plasma ratio of 1:1.

Metabolism

Ropinirole is extensively metabolized by the liver. The major metabolic pathways are N-despropylation and hydroxylation to form the inactive N-despropyl metabolite and hydroxy metabolites. The N-despropyl metabolite is converted to carbamyl glucuronide, carboxylic acid, and N-despropyl hydroxy metabolites. The hydroxy metabolite of ropinirole is rapidly glucuronidated.

In vitro studies indicate that the major cytochrome P450 enzyme involved in the metabolism of ropinirole is CYP1A2, an enzyme known to be induced by smoking and omeprazole and inhibited by, for example, fluvoxamine, mexiletine, and the older fluoroquinolones such as ciprofloxacin and norfloxacin.

Elimination

The clearance of ropinirole after oral administration is 47 L/h and its elimination half-life is approximately 6 hours. Less than 10% of the administered dose is excreted as unchanged drug in urine. N-despropyl ropinirole is the predominant metabolite found in urine (40%), followed by the carboxylic acid metabolite (10%) and the glucuronide of the hydroxy metabolite (10%).