REQUIP

Ropinirole hydrochloride is a white to yellow solid with a melting range of 243° to 250°C and a solubility of 133 mg/mL in water.

REQUIP XL extended-release tablets are formulated as a three-layered tablet with a central, active-containing, slow-release layer, and 2 placebo outer layers acting as barrier layers which control the surface area available for drug release. Each biconvex, capsule-shaped tablet contains 2.28 mg, 4.56 mg, 6.84 mg, 9.12 mg, or 13.68 mg ropinirole hydrochloride equivalent to ropinirole 2 mg, 4 mg, 6 mg, 8 mg, or 12 mg, respectively. Inactive ingredients consist of carboxymethylcellulose sodium, colloidal silicon dioxide, glyceryl behenate, hydrogenated castor oil, hypromellose, lactose monohydrate, magnesium stearate, maltodextrin, mannitol, povidone, and one or more of the following: FD&C Yellow No. 6 aluminum lake, FD&C Blue No. 2 aluminum lake, ferric oxides (black, red, yellow), polyethylene glycol 400, titanium dioxide.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Ropinirole is a non-ergoline dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D₂ and D₃ dopamine receptor subtypes, binding with higher affinity to D₃ than to D₂ or D₄ receptor subtypes.

Ropinirole has moderate in vitro affinity for opioid receptors. Ropinirole and its metabolites have negligible in vitro affinity for dopamine D₁, 5-HT₁, 5-HT₂, benzodiazepine, GABA, muscarinic, alpha₁-, alpha₂-, and beta-adrenoreceptors.

The precise mechanism of action of ropinirole as a treatment for Parkinson’s disease is unknown, although it is believed to be due to stimulation of postsynaptic dopamine D₂-type receptors within the caudate-putamen in the brain. This conclusion is supported by studies that show that ropinirole improves motor function in various animal models of Parkinson’s disease. In particular, ropinirole attenuates the motor deficits induced by lesioning the ascending nigrostriatal dopaminergic pathway with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in primates. The relevance of D₃ receptor binding in Parkinson’s disease is unknown.

12.2 Pharmacodynamics

Clinical experience with dopamine agonists, including ropinirole, suggests an association with impaired ability to regulate blood pressure with resulting postural 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 postural 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.

12.3 Pharmacokinetics

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

Ropinirole displayed linear kinetics up to doses of 24 mg/day (8 mg immediate-release, 3 times a day). 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.

Relative bioavailability of REQUIP XL extended-release tablets compared with immediate-release tablets was approximately 100%. In a repeat-dose study in patients with Parkinson’s disease using REQUIP XL 8 mg, the dose-normalized AUC_(0-24) and C_min for REQUIP XL and immediate-release ropinirole were similar. Dose-normalized C_max 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 study, administration of REQUIP XL to healthy volunteers with food (i.e., high-fat meal) increased AUC by approximately 30% and C_max by approximately 44%, compared with dosing under fasted conditions. In a repeat-dose study in patients with Parkinson’s disease, food (i.e., high-fat meal) increased AUC by approximately 20% and C_max by approximately 44%; T_max was prolonged by 3 hours (median prolongation) compared with dosing under fasted conditions [see Dosage and Administration (2.1)].

Distribution: Ropinirole is widely distributed throughout the body, with an apparent volume of distribution of 7.5 L/kg (cv = 32%). 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 isozyme 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 to patients is 47 L/hr (cv = 45%) 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%).

Drug Interactions: Ciprofloxacin: Coadministration of ciprofloxacin (500 mg twice daily), an inhibitor of CYP1A2, with immediate-release ropinirole (2 mg 3 times daily) increased ropinirole AUC by 84% on average and C_max by 60% (n = 12 patients).

Digoxin: Coadministration of immediate-release ropinirole (2 mg 3 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 3 times daily) in 12 patients with Parkinson’s disease. Immediate-release ropinirole (2 mg 3 times daily) did not alter the pharmacokinetics of theophylline (5 mg/kg IV) in 12 patients with Parkinson’s disease.

L-dopa: Coadministration of carbidopa + l-dopa (SINEMET 10/100 mg twice daily) with immediate-release ropinirole (2 mg 3 times daily) had no effect on the steady-state pharmacokinetics of ropinirole (n = 28 patients). Oral administration of immediate-release ropinirole 2 mg 3 times daily increased mean steady-state C_max of l-dopa by 20%, but its AUC was unaffected (n = 23 patients).

Estrogens: Population pharmacokinetic analysis revealed that higher doses of estrogens (usually associated with hormone replacement therapy [HRT]) reduced the oral clearance of ropinirole by approximately 35%.

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 oral clearance of ropinirole.

Population Subgroups: Because therapy with REQUIP XL 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.

Age: Oral clearance of ropinirole is reduced by approximately 15% in patients above 65 years of age compared with younger patients. Dosage adjustment is not necessary in the elderly (above 65 years), as the dose of ropinirole is individually titrated to clinical response.

Gender: Female and male patients showed similar oral clearance.

Race: The influence of race on the pharmacokinetics of ropinirole has not been evaluated.

Renal Impairment: Based on population pharmacokinetic analysis, no difference was observed in the pharmacokinetics of ropinirole in patients with moderate renal impairment (creatinine clearance between 30 to 50 mL/min) compared with an age-matched population with creatinine clearance above 50 mL/min. Therefore, no dosage adjustment is necessary in patients with moderate renal impairment. The use of ropinirole in patients with severe renal impairment has not been studied.

The effect of hemodialysis on ropinirole clearance is not known, but because of the relatively high apparent volume of distribution of ropinirole (7.5 L/kg), significant removal of ropinirole by hemodialysis is unlikely.

Hepatic Impairment: The pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment. These patients may have higher plasma levels and lower clearance of ropinirole than patients with normal hepatic function. REQUIP XL should be titrated with caution in this population.

Other Diseases: Population pharmacokinetic analysis revealed no change in the oral clearance of ropinirole in patients with concomitant diseases such as hypertension, depression, osteoporosis/arthritis, and insomnia compared with patients who had Parkinson’s disease only.

13 NONCLINICAL TOXICOLOGY

13.1 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 vitro chromosome 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).

14 CLINICAL STUDIES

The effectiveness of the immediate-release formulation of ropinirole (REQUIP tablets) in the treatment of early and advanced Parkinson’s disease was initially established in 3 randomized, double-blind, placebo-controlled trials.

The effectiveness of REQUIP XL in the treatment of Parkinson’s disease was supported by 2 randomized, double-blind, multicenter clinical trials and clinical pharmacokinetic considerations. One trial conducted in advanced Parkinson’s disease patients compared REQUIP XL with placebo as adjunctive therapy to L-dopa. A second trial compared REQUIP XL with REQUIP tablets in early phase Parkinson’s disease patients not receiving L-dopa.

In these studies a variety of measures were used to assess the effects of treatment (e.g., patient diaries recording time “on” and “off,” tolerability of L-dopa dose reductions, and the Unified Parkinson’s Disease Rating Scale [UPDRS] scores). The UPDRS is a multi-item rating scale evaluating 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, etc.) scored for different body regions and has a maximum (worst) score of 108.

14.1 Study in Patients With Advanced Parkinson’s Disease (With L-dopa)

The effectiveness of REQUIP XL as adjunctive therapy to L-dopa in patients with Parkinson’s disease was established in a randomized, double-blind, placebo-controlled, parallel group, 24-week clinical trial in 393 patients (Hoehn & Yahr criteria Stages II-IV) who were not adequately controlled by L-dopa therapy. Patients were allowed to be on concomitant selegiline, amantadine, anticholinergics, and catechol-O-methyltransferase (COMT) inhibitors provided the doses were stable for at least 4 weeks prior to screening and throughout the trial. The primary efficacy endpoint evaluated was the mean change from baseline in total awake time spent “off”.

Patients in this study had a mean disease duration of 8.6 years, a mean duration of exposure to L-dopa of 6.5 years, had experienced a minimum of 3 hours awake time “off” with a baseline average of approximately 7 hours awake time “off”, and had a mean baseline UPDRS motor score of approximately 30 points with similar mean data in each treatment group. The mean baseline dose of L-dopa in the group receiving REQUIP XL was 824 mg/day and 776 mg/day for the placebo group. Patients initiated treatment at 2 mg/day for 1 week followed by increases of 2 mg/day at weekly intervals to a minimum dose of 6 mg/day. The following week, the REQUIP XL total daily dose could be further increased (based upon therapeutic response and tolerability ) to 8 mg/day. Once a daily dose of 8 mg/day was reached, the background L-dopa dosage was reduced. Thereafter, the daily dose could be increased by up to 4 mg/day approximately every 2 weeks until an optimal dose was achieved (based upon therapeutic response and tolerability). The mean dose of REQUIP XL at the end of Week 24 was 18.8 mg/day. Dose titrations were based upon the degree of symptom control, planned L-dopa dosage reduction, and/or tolerability. The maximal allowed daily dosage for REQUIP XL was 24 mg/day.

The primary efficacy endpoint was mean change from baseline in total awake time spent “off” at Week 24. At baseline the mean total awake time spent “off” was approximately 7 hours in each treatment group. At Week 24, the total awake time spent “off”, on average, had decreased by approximately 2 hours in the group receiving REQUIP XL and by approximately half an hour in the placebo group. The adjusted mean difference in total awake time spent “off” between REQUIP XL and placebo was -1.7 hours, which was statistically significant (ANCOVA, p< 0.0001). Results for this endpoint showing the statistical superiority of REQUIP XL over Placebo are presented in Table 3.

The difference between groups in favor of REQUIP XL, with regard to a decrease in total “off” hours, was primarily related to an increase in total “on” hours without troublesome dyskinesia. Patients treated with REQUIP XL had a mean reduction in L-dopa dose of 278 mg/day (34%) while patients treated with placebo had a mean reduction of 164 mg/day (21%). In patients who reduced their L-dopa dose, reduction was sustained in 93% of patients treated with REQUIP XL and in 72% of patients treated with placebo (p<0.001).

14.2 Study in Patients With Early Parkinson’s Disease (Without L-dopa)

A 36-week multicenter, double-blind, titration/3-period maintenance, cross-over study compared the efficacy of REQUIP XL with the immediate-release formulation of REQUIP (IR) in 161 patients with early phase Parkinson’s disease (Hoehn & Yahr Stages I-III) with limited prior exposure to L-dopa or dopamine agonists. Eligible subjects were randomized (1:1:1:1) to 4 treatment sequences (2 were titrated on REQUIP IR and 2 on REQUIP XL). The REQUIP IR titration was slower in rate than that of the REQUIP XL. Patients were titrated, during the 12-week titration period, to their optimal dosage, based upon tolerance and therapeutic response. This was followed by 3 consecutive 8-week maintenance periods, during which patients were either maintained on the prior formulation or switched to the alternative formulation. All switches were performed overnight by using the approximately equivalent doses of ropinirole. The primary efficacy endpoint was the change of UPDRS motor score within each maintenance period.

Patients in all 4 groups started out with similar UPDRS motor scores (about 21) at baseline. All 4 groups exhibited similar improvement in UPDRS total motor scores from baseline until the completion of the titration phase, with a change in score of about -9 observed for the groups started on REQUIP IR and of about -10 for the groups started on REQUIP XL. No difference was observed between groups when switches were made between identical formulations or between different formulations. This suggests therapeutic dosage equivalence between REQUIP IR and REQUIP XL formulations.

The optimal daily dose at the end of the titration period for patients on REQUIP IR was substantially lower (mean 7 mg) compared to the dose at the end of the titration period for patients on REQUIP XL (mean 18 mg). In this study, the marked difference in the final optimal dosages suggests that the higher doses afforded no additional benefit when compared to the lower doses [see Dosage and Administration (2)].

16 HOW SUPPLIED/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) and 90 (NDC 0007-4885-59).
• • 4 mg: light brown tablets debossed with “GS” and “WXG”, in bottles of 30 (NDC 0007–4887–13) 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) and 90 (NDC 0007-4888-59).
• •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) [see USP Controlled Room Temperature].

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

17 PATIENT COUNSELING INFORMATION

See FDA-approved patient labeling (Patient Information).

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

17.1 Dosing Instructions

• •Patients should be instructed to take REQUIP XL only as prescribed. If a dose is missed, patients should be advised not to double their next dose.
• •REQUIP XL can be taken with or without food. Taking REQUIP XL with food may reduce the occurrence of nausea [see Dosage and Administration (2.1)].
• •REQUIP XL tablets should be swallowed whole. They should not be chewed, crushed, or divided [see Dosage and Administration (2.1)].
• •Ropinirole is the active ingredient that is in both REQUIP XL and REQUIP tablets (the immediate-release formulation). Ask your patient if they are taking another medication containing ropinirole.

17.2 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 [see Warnings and Precautions (5.2, 5.3)].

17.3 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. 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 [see Warnings and Precautions (5.4)].

17.4 Sedating Effects

Patients should be alerted to the potential sedating effects caused by REQUIP XL, 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 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) [see Warnings and Precautions (5.1)].

17.5 Hallucination

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 [see Warnings and Precautions (5.5)].

17.6 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 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. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking REQUIP XL. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking REQUIP XL.

17.7 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 [see Use in Specific Populations (8.3)].

Patients should be advised that ropinirole could inhibit lactation, as ropinirole inhibits prolactin secretion.

17.8 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 [see Use in Specific Populations (8.1)].

REQUIP XL is a registered trademark of GlaxoSmithKline.

SINEMET is a registered trademark of Merck & Co., Inc.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2012, GlaxoSmithKline. All rights reserved.

RXL:5PI

PATIENT INFORMATION

REQUIP^® (RE-qwip) (ropinirole tablets)

REQUIP XL^® (RE-qwip)

(ropinirole extended-release tablets)

IF YOU HAVE PARKINSON’S DISEASE, READ THIS SIDE

IF YOU HAVE RESTLESS LEGS SYNDROME, READ THE OTHER SIDE

IMPORTANT NOTE: REQUIP XL has not been studied in Restless Legs Syndrome (RLS) and is not approved for the treatment of RLS. However, an immediate-release form of ropinirole (REQUIP) is approved for the treatment of RLS (see other side of this leaflet).

Read this information completely before you start taking REQUIP or REQUIP XL. Read the information each time you get more medicine. There may be new information. This leaflet provides a summary about REQUIP and REQUIP XL. It does not include everything there is to know about your medicine. This information should not take the place of discussions with your healthcare provider about your medical condition or treatment with REQUIP or REQUIP XL.

What are REQUIP and REQUIP XL?

REQUIP is a short-acting prescription medicine containing ropinirole (usually taken 3 times a day) used to treat Parkinson’s disease. It is also used to treat a condition called Restless Legs Syndrome.

REQUIP XL is a long-acting prescription medicine containing ropinirole (taken once a day) used to treat Parkinson’s disease.

You should not be taking more than one medicine containing ropinirole. Inform your physician if you are taking any other medicine containing ropinirole.

REQUIP and REQUIP XL have not been studied in children.

What is the most important information I should know about REQUIP and REQUIP XL?

REQUIP and REQUIP XL can cause serious side effects including:

• • Falling asleep during normal activities. You may fall asleep while doing normal activities such as driving a car, doing physical tasks, or using hazardous machinery while taking REQUIP or REQUIP XL. You may suddenly fall asleep without being drowsy or without warning. This may result in having accidents. Your chances of falling asleep while doing normal activities while taking REQUIP or REQUIP XL are greater if you take other medicines that cause drowsiness. Tell your healthcare provider right away if this happens. Before starting REQUIP or REQUIP XL, be sure to tell your healthcare provider if you take any medicines that make you drowsy.
• • Changes in blood pressure. REQUIP and REQUIP XL can decrease or increase your blood pressure. Lowering of your blood pressure is of special concern. If you faint, feel dizzy, nauseated, or sweaty when you stand up from sitting or lying down, this may mean that your blood pressure is decreased. If you notice this, you should contact your healthcare provider. Also, when changing position from lying down or sitting to standing up, you should do it carefully and slowly. Lowering of your blood pressure can happen especially when you start taking REQUIP or REQUIP XL or when your dose is increased.
• • Fainting. Fainting can occur, and sometimes your heart rate may be decreased. This can happen especially when you start taking REQUIP or REQUIP XL or your dose is increased. Tell your healthcare provider if you faint or feel dizzy.
• • Hallucinations (unreal visions, sounds, or sensations) can occur in patients taking REQUIP or REQUIP XL. The chances of having hallucinations are higher in patients with Parkinson’s disease who are elderly, taking REQUIP or REQUIP XL with other Parkinson’s disease drugs, or taking higher doses of REQUIP or REQUIP XL. If you have hallucinations, talk with your healthcare provider.
• • Uncontrolled sudden movements. REQUIP or REQUIP XL may cause uncontrolled sudden movements or make such movements you already have worse or more frequent. Tell your healthcare provider if this happens. The doses of your anti-Parkinson’s medicines may need to be changed.

Unusual urges. Some patients taking REQUIP or REQUIP XL get urges to behave in a way unusual for them. Examples of this are an unusual urge to gamble or increased sexual urges and behaviors. If you notice or your family notices that you are developing any unusual behaviors, talk to your healthcare provider.

See “What are the possible side effects of REQUIP and REQUIP XL?”

What should I tell my healthcare provider before taking REQUIP or REQUIP XL?

Be sure to tell your healthcare provider if you:

• •have daytime sleepiness from a sleep disorder or have unexpected or unpredictable sleepiness or periods of sleep.
• •are taking any other prescription or over-the-counter medicines. Some of these medicines may increase your chances of getting side effects while taking REQUIP or REQUIP XL.
• •start or stop taking other medicines while you are taking REQUIP or REQUIP XL. This may increase your chances of getting side effects.
• •start or stop smoking while you are taking REQUIP or REQUIP XL. Smoking may decrease the treatment effect of REQUIP or REQUIP XL.
• •feel dizzy, nauseated, sweaty, or faint when you first stand up from sitting or lying down.
• •drink alcoholic beverages. This may increase your chances of becoming drowsy or sleepy while taking REQUIP or REQUIP XL.
• •have high or low blood pressure.
• •are pregnant or plan to become pregnant. REQUIP and REQUIP XL should only be used during pregnancy if needed.
• •are breastfeeding. It is not known if REQUIP or REQUIP XL passes into your breast milk. Talk to your healthcare provider to decide whether you will breastfeed or take REQUIP or REQUIP XL.
• •are allergic to any of the ingredients in REQUIP or REQUIP XL. See the end of this Patient Information leaflet for a complete list of the ingredients in REQUIP and REQUIP XL.

How should I take REQUIP or REQUIP XL for Parkinson’s disease?

• •Take REQUIP or REQUIP XL exactly as directed by your healthcare provider.
• •Do not suddenly stop taking REQUIP or REQUIP XL without talking to your healthcare provider. If you stop this medicine suddenly, you may develop fever, confusion, or severe muscle stiffness.
• •Before starting REQUIP or REQUIP XL, you should talk to your healthcare provider about what to do if you miss a dose. If you have missed the previous dose and it is time for your next dose, do not double the dose.
• •Your healthcare provider will start you on a low dose of REQUIP or REQUIP XL. Your healthcare provider will change the dose until you are taking the right amount of medicine to control your symptoms. It may take several weeks before you reach a dose that controls your symptoms.

If you are taking REQUIP:

• •REQUIP tablets are usually taken 3 times each day for Parkinson’s disease.

If you are taking REQUIP XL:

• •Take REQUIP XL tablets 1 time each day for Parkinson’s disease, preferably at or around the same time of day.
• •Swallow REQUIP XL tablets whole. Do not chew, crush, or split REQUIP XL tablets.

If you are taking either REQUIP or REQUIP XL:

• •Contact your healthcare provider if you stop taking REQUIP or REQUIP XL for any reason. Do not restart without talking with your healthcare provider.
• •Your healthcare provider may prescribe REQUIP or REQUIP XL alone, or add REQUIP or REQUIP XL to medicine that you are already taking for Parkinson’s disease.
• •You should not substitute REQUIP for REQUIP XL or REQUIP XL for REQUIP without talking with your healthcare provider.
• •You can take REQUIP or REQUIP XL with or without food. If you experience nausea you may try taking REQUIP or REQUIP XL with food.

What are the possible side effects of REQUIP and REQUIP XL?

Serious side effects in people taking REQUIP and REQUIP XL are described in the section “REQUIP and REQUIP XL can cause serious side effects including” and include:

• •Falling asleep during normal activities
• •Changes in blood pressure
• •Fainting
• •Hallucinations
• •Uncontrolled sudden movements

Some patients taking REQUIP or REQUIP XL get urges to behave in a way unusual for them. Examples of this are an unusual urge to gamble or increased sexual urges and behaviors. If you notice or your family notices that you are developing any unusual behaviors, talk to your healthcare provider.

You should be careful until you know if REQUIP or REQUIP XL affects your ability to remain alert while doing normal daily activities, driving a car, operating machinery, or working at heights. You should also watch for the development of significant daytime sleepiness or episodes of falling asleep.

Common side effects in people taking REQUIP and REQUIP XL include:

• •Fainting
• •Sleepiness
• •Hallucinations
• •Dizziness
• •Nausea or vomiting
• •Uncontrolled sudden movements
• •Leg swelling
• •Fatigue
• •Headache
• •Upset stomach
• •Increased sweating

This is not a complete list of side effects and should not take the place of discussions with your healthcare providers. Your healthcare provider or pharmacist can give you a more complete list of possible side effects.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store REQUIP and REQUIP XL?

• •Store REQUIP tablets between 68°-77°F (20°-25°C).
• •Store REQUIP XL tablets between 59°-86°F (15°-30°C).
• •Store REQUIP or REQUIP XL at room temperature out of direct sunlight.
• •Keep REQUIP or REQUIP XL in a tightly closed container.
• •Keep REQUIP or REQUIP XL out of the reach of children.

Other Information about REQUIP and REQUIP XL:

• •Do not share REQUIP or REQUIP XL with other people, even if they have the same symptoms you have.
• •Studies of people with Parkinson’s disease show that they may be at an increased risk of developing melanoma, a form of skin cancer, when compared to people without Parkinson’s disease. It is not known if this problem is associated with Parkinson’s disease or the medicines used to treat Parkinson’s disease. REQUIP and REQUIP XL are two of the medicines used to treat Parkinson’s disease; therefore, patients being treated with REQUIP or REQUIP XL should have periodic skin examinations.

This patient information leaflet summarizes the most important information about REQUIP and REQUIP XL for Parkinson’s disease. Medicines are sometimes prescribed for purposes other than those listed in this leaflet. Do not take REQUIP or REQUIP XL for a condition for which it was not prescribed. For more information, talk with your healthcare provider or pharmacist. They can give you information about REQUIP and REQUIP XL that is written for healthcare professionals. For more information call 1-888-825-5249 (toll-free) or visit www.requipxl.com.

What are the ingredients in REQUIP and REQUIP XL?

The following ingredients are in REQUIP:

Active ingredient: ropinirole (as ropinirole hydrochloride)

Inactive ingredients: croscarmellose sodium, hydrous lactose, magnesium stearate, microcrystalline cellulose, and one or more of the following: carmine, FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake, hypromellose, iron oxides, polyethylene glycol, polysorbate 80, titanium dioxide.

The following ingredients are in REQUIP XL:

Active ingredient: ropinirole (as ropinirole hydrochloride)

Inactive ingredients: carboxymethylcellulose sodium, colloidal silicon dioxide, glycerol behenate, hydrogenated castor oil, hypromellose, lactose monohydrate, magnesium stearate, maltodextrin, mannitol, povidone, and one or more of the following: FD&C Yellow No. 6 aluminum lake, FD&C Blue No. 2 aluminum lake, ferric oxides (black, red, yellow), polyethylene glycol 400, titanium dioxide.

PATIENT INFORMATION

REQUIP^® (RE-qwip)

(ropinirole tablets)

IF YOU HAVE RESTLESS LEGS SYNDROME (RLS), READ THIS SIDE

IF YOU HAVE PARKINSON’S DISEASE, READ THE OTHER SIDE

Read this information completely before you start taking REQUIP. Read the information each time you get more medicine. There may be new information. This leaflet provides a summary about REQUIP. It does not include everything there is to know about your medicine. This information should not take the place of discussions with your healthcare provider about your medical condition or treatment with REQUIP.

Patients with RLS should take REQUIP differently than patients with Parkinson’s disease (see How should I take REQUIP for RLS? for the recommended dosing for RLS). A lower dose of REQUIP is generally needed for patients with RLS, and is taken once daily before bedtime.

What is the most important information I should know about REQUIP?

REQUIP can cause serious side effects including:

• • Falling asleep during normal activities. You may fall asleep while doing normal activities such as driving a car, doing physical tasks, or using hazardous machinery while taking REQUIP. You may suddenly fall asleep without being drowsy or without warning. This may result in having accidents. Your chances of falling asleep while doing normal activities while taking REQUIP are greater if you take other medicines that cause drowsiness. Tell your healthcare provider right away if this happens. Before starting REQUIP, be sure to tell your healthcare provider if you take any medicines that make you drowsy.
• • Decrease in blood pressure. REQUIP can decrease your blood pressure. Lowering of your blood pressure is of special concern. If you faint, feel dizzy, nauseated, or sweaty when you stand up from sitting or lying down, this may mean that your blood pressure is decreased. If you notice this, you should contact your healthcare provider. Also, when changing position from lying down or sitting to standing up, you should do it carefully and slowly. Lowering of your blood pressure can happen especially when you start taking REQUIP or when your dose is increased.
• • Fainting. Fainting can occur, and sometimes your heart rate may be decreased. This can happen especially when you start taking REQUIP or your dose is increased. Tell your healthcare provider if you faint or feel dizzy.
• • Hallucinations (unreal visions, sounds, or sensations) can occur in patients taking REQUIP. If you have hallucinations, talk with your healthcare provider.

Unusual urges. Some patients taking REQUIP get urges to behave in a way unusual for them. Examples of this are an unusual urge to gamble or increased sexual urges and behaviors. If you notice or your family notices that you are developing any unusual behaviors, talk to your healthcare provider.

See “What are the possible side effects of REQUIP?”

What is REQUIP?

REQUIP is a prescription medicine containing ropinirole used to treat moderate-to-severe primary Restless Legs Syndrome. It is also used to treat Parkinson’s disease. Having one of these conditions does not mean you have or will develop the other.

REQUIP has not been studied in children.

What should I tell my healthcare provider before taking REQUIP?

Be sure to tell your healthcare provider if you:

• •have daytime sleepiness from a sleep disorder or have unexpected or unpredictable sleepiness or periods of sleep.
• •are taking any other prescription or over-the-counter medicines. Some of these medicines may increase your chances of getting side effects while taking REQUIP.
• •start or stop taking other medicines while you are taking REQUIP. This may increase your chances of getting side effects.
• •start or stop smoking while you are taking REQUIP. Smoking may decrease the treatment effect of REQUIP.
• •feel dizzy, nauseated, sweaty, or faint when you first stand up from sitting or lying down.
• •drink alcoholic beverages. This may increase your chances of becoming drowsy or sleepy while taking REQUIP.
• •have high or low blood pressure.
• •are pregnant or plan to become pregnant. REQUIP should only be used during pregnancy if needed.
• •are breastfeeding. It is not known if REQUIP passes into your breast milk. Talk to your healthcare provider to decide whether you will breastfeed or take REQUIP.
• •are allergic to any of the ingredients in REQUIP. See the end of this Patient Information leaflet for a complete list of the ingredients in REQUIP.

How should I take REQUIP for RLS?

• •Take REQUIP exactly as directed by your healthcare provider.
• •The usual way to take REQUIP is once in the evening, 1 to 3 hours before bedtime.
• •Your healthcare provider will start you on a low dose of REQUIP. Your healthcare provider may change the dose until you are taking the right amount of medicine to control your symptoms.
• • If you miss your dose, do not double your next dose. Take only your usual dose 1 to 3 hours before your next bedtime.
• •Contact your healthcare provider if you stop taking REQUIP for any reason. Do not restart without consulting your healthcare provider.
• •You can take REQUIP with or without food. Taking REQUIP with food may decrease the chances of feeling nauseated.

What are the possible side effects of REQUIP?

Serious side effects in people taking REQUIP are described in the section “REQUIP can cause serious side effects including” and include:

• •Falling asleep during normal activities
• •Decrease in blood pressure
• •Fainting
• •Hallucinations

Some patients taking REQUIP get urges to behave in a way unusual for them. Examples of this are an unusual urge to gamble or increased sexual urges and behaviors. If you notice or your family notices that you are developing any unusual behaviors, talk to your healthcare provider.

You should be careful until you know if REQUIP affects your ability to remain alert while doing normal daily activities, driving a car, operating machinery, or working at heights. You should also watch for the development of significant daytime sleepiness or episodes of falling asleep.

Common side effects in people taking REQUIP include:

• •Nausea or vomiting
• •Sleepiness or drowsiness
• •Dizziness
• •Fatigue

This is not a complete list of side effects and should not take the place of discussions with your healthcare providers. Your healthcare provider or pharmacist can give you a more complete list of possible side effects.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store REQUIP?

• •Store REQUIP tablets between 68°-77°F (20°-25°C).
• •Store REQUIP at room temperature out of direct sunlight.
• •Keep REQUIP in a tightly closed container.
• •Keep REQUIP out of the reach of children.

Other Information about REQUIP

• •Do not share REQUIP with other people, even if they have the same symptoms you have.
• •Studies of people with Parkinson’s disease show that they may be at an increased risk of developing melanoma, a form of skin cancer, when compared to people without Parkinson’s disease. It is not known if this problem is associated with Parkinson’s disease or the medicines used to treat Parkinson’s disease. REQUIP is one of the medicines used to treat Parkinson’s disease; therefore, patients being treated with REQUIP should have periodic skin examinations.

This patient information leaflet summarizes important information about REQUIP for Restless Legs Syndrome. Medicines are sometimes prescribed for purposes other than those listed in this leaflet. Do not take REQUIP for a condition for which it was not prescribed. For more information, talk with your healthcare provider or pharmacist. They can give you information about REQUIP that is written for healthcare professionals. For more information call 1-888-825-5249 (toll-free) or visit www.requip.com.

What are the ingredients in REQUIP?

The following ingredients are in REQUIP:

Active ingredient: ropinirole (as ropinirole hydrochloride)

Inactive ingredients: croscarmellose sodium, hydrous lactose, magnesium stearate, microcrystalline cellulose, and one or more of the following: carmine, FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake, hypromellose, iron oxides, polyethylene glycol, polysorbate 80, titanium dioxide.

GlaxoSmithKline

Research Triangle Park, NC 27709

©2012, GlaxoSmithKline. All rights reserved.

RXL:3PIL

December 2012

Principal Display Panel

NDC 0007-4885-13

REQUIP XL^®

(ropinirole extended-release tablets)

2 mg

R_x only

30 Tablets

Each tablet contains 2.28 mg ropinirole HCl equivalent to 2 mg ropinirole.

Dosage: See Prescribing Information for complete dosing instructions.

Do not use if safety seal under cap is broken or missing.

Store at 25^oC (77^oF); excursions permitted to 15-30^oC (59-86^oF) [see USP Controlled Room Temperature].

GlaxoSmithKline

Research Triangle Park, NC 27709

Made in Ireland

Rev. 3/13

10000000114273