INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Ropinirole extended-release tablets are indicated for the treatment of Parkinsons disease.. Ropinirole extended-release tablets are non-ergoline dopamine agonist indicated for the treatment of Parkinsons disease. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).Dosing Instructions Instruct patients to take ropinirole extended-release tablets only as prescribed. If dose is missed, advise patients not to double their next dose. Ropinirole extended-release tablets can be taken with or without food. Inform patients to swallow ropinirole extended-release tablets whole and not to chew, crush, or divide the tablets [see Dosage and Administration (2.1)]. Ropinirole is the active ingredient in ropinirole extended-release tablets. Ask your patients if they are taking another medication containing ropinirole.Hypersensitivity/Allergic Reactions Advise patients about the potential for developing hypersensitivity/allergic reaction including manifestations such as urticaria, angioedema, rash, and pruritus when taking any ropinirole product. Inform patients who experience these or similar reactions after starting ropinirole extended-release tablets, to immediately contact their healthcare professional [see Contraindications (4)]. Falling Asleep during Activities of Daily Living and Somnolence Alert patients to the potential sedating effects caused by ropinirole extended-release tablets, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Because somnolence is frequent adverse reaction with potentially serious consequences, patients should not drive car, operate machinery, or engage in other potentially dangerous activities until they have gained sufficient experience with ropinirole extended-release tablets to gauge whether or not it adversely affects their mental and/or motor performance. Advise patients that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., conversations, eating, driving 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. Advise patients of possible additive effects when patients are taking other sedating medications, alcohol, or other central nervous system depressants (e.g., benzodiazepines, antipsychotics, antidepressants, etc.) in combination with ropinirole extended-release tablets or when taking concomitant medication (e.g., ciprofloxacin) that increases plasma levels of ropinirole [see Warnings and Precautions (5.1)]. Syncope and Hypotension/Orthostatic Hypotension Advise patients that they may experience syncope and may develop hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating while taking ropinirole extended-release tablets, especially if they are elderly. 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). Postural/orthostatic symptoms may be related to sitting up or standing. Accordingly, caution patients against standing rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with ropinirole extended-release tablets [see Warnings and Precautions (5.2, 5.3)].Elevation of Blood Pressure and Changes in Heart Rate Alert patients to the possibility of increases in blood pressure during treatment with 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. Alert patients with cardiovascular disease, who may not tolerate marked changes in heart rate to the possibility that they may experience significant increases or decreases in heart rate during treatment with ropinirole extended-release tablets [see Warnings and Precautions( 5.4)]. Hallucinations/Psychotic-like Behavior Inform patients that they may experience hallucinations (unreal visions, sounds, or sensations) and other psychotic-like behavior can occur while taking ropinirole extended-release tablets. The elderly are at greater risk than younger patients with Parkinsons disease. This risk is greater in patients who are taking ropinirole extended-release tablets with L-dopa or taking higher doses of ropinirole extended-release tablets, and may also be further increased in patients taking any other drugs that increase dopaminergic tone. Tell patients to report hallucinations or psychotic-like behavior to their healthcare provider promptly should they develop [see Warnings and Precautions( 5.5)]. Dyskinesia Inform patients that ropinirole extended-release tablets may cause and/or exacerbate pre-existing dyskinesias [see Warnings and Precautions 5.6)]. Impulse Control/Compulsive BehaviorsAdvise patients that they may experience impulse control and/or compulsive behaviors while taking or more of the medications (including ropinirole extended-release tablets) that increase central dopaminergic tone, that are generally used for the treatment of Parkinsons disease. Advise patients to inform their physician or healthcare provider if they develop new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with ropinirole extended-release tablets. Physicians should consider dose reduction or stopping the medication if patient develops such urges while taking ropinirole extended-release tablets [see Warnings and Precautions 5.7)]. Withdrawal-Emergent Hyperpyrexia and Confusion Advise patients to contact their healthcare provider if they wish to discontinue ropinirole extended-release tablets or decrease the dose of ropinirole extended-release tablets [see Warnings and Precautions 5.8)]. Melanoma Advise patients with Parkinsons disease that they have higher risk of developing melanoma. Advise patients to have their skin examined on regular basis by qualified healthcare provider (e.g., dermatologist) when using ropinirole extended-release tablets [see Warnings and Precautions 5.9)]. Nursing Mothers Because of the possibility that ropinirole may be excreted in breast milk, discuss the developmental and health benefits of breastfeeding along with the mothers clinical need for ropinirole extended-release tablets and any potential adverse effects on the breastfed child from ropinirole or from the underlying maternal condition [see Use In Specific Populations 8.2 )]. Advise patients that ropinirole extended-release tablets could inhibit lactation because ropinirole inhibits prolactin secretion.Pregnancy Because experience with ropinirole in pregnant women is limited and ropinirole has been shown to have adverse effects on embryofetal development in animals, including teratogenic effects, advise patients of this potential risk. Advise patients to notify their physician if they become pregnant or intend to become pregnant during therapy [see Use In Specific Populations 8.1)]. The brands listed are the registered trademarks of their respective owners and are not trademarks of Sandoz Inc.Manufactured in India by Sandoz Private Ltd. for Sandoz Inc., Princeton NJ 08540Rev.: April 2017. Instruct patients to take ropinirole extended-release tablets only as prescribed. If dose is missed, advise patients not to double their next dose. Ropinirole extended-release tablets can be taken with or without food. Inform patients to swallow ropinirole extended-release tablets whole and not to chew, crush, or divide the tablets [see Dosage and Administration (2.1)].. Ropinirole is the active ingredient in ropinirole extended-release tablets. Ask your patients if they are taking another medication containing ropinirole.. Advise patients about the potential for developing hypersensitivity/allergic reaction including manifestations such as urticaria, angioedema, rash, and pruritus when taking any ropinirole product. Inform patients who experience these or similar reactions after starting ropinirole extended-release tablets, to immediately contact their healthcare professional [see Contraindications (4)]. Advise patients of possible additive effects when patients are taking other sedating medications, alcohol, or other central nervous system depressants (e.g., benzodiazepines, antipsychotics, antidepressants, etc.) in combination with ropinirole extended-release tablets or when taking concomitant medication (e.g., ciprofloxacin) that increases plasma levels of ropinirole [see Warnings and Precautions (5.1)]. Advise patients that they may experience syncope and may develop hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating while taking ropinirole extended-release tablets, especially if they are elderly. 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). Postural/orthostatic symptoms may be related to sitting up or standing. Accordingly, caution patients against standing rapidly after sitting or lying down, especially if they have been doing so for prolonged periods and especially at the initiation of treatment with ropinirole extended-release tablets [see Warnings and Precautions (5.2, 5.3)].

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Ropinirole is non-ergoline dopamine agonist. The precise mechanism of action of ropinirole as treatment for Parkinsons disease is unknown, although it is thought to be related to its ability to stimulate dopamine D2 receptors within the caudate-putamen in the brain.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisTwo-year carcinogenicity studies of ropinirole were conducted in mice at oral doses of 0, 5, 15, and 50 mg/kg/day and in rats at oral doses of 0, 1.5, 15, and 50 mg/kg/day.In rats, there was an increase in testicular Leydig cell adenomas at all doses tested. The lowest dose tested (1.5 mg/kg/day) is less than the MRHD (24 mg/day) on mg/m2 basis. The endocrine mechanisms believed to be involved in the production of these tumors in rats are not considered relevant to humans. In mice, there was an increase in benign uterine endometrial polyps at dose of 50 mg/kg/day. The highest dose not associated with this finding (15 mg/kg/day) is three times the MRHD on mg/m2 basis.Mutagenesis Ropinirole was not mutagenic or clastogenic in in vitro (Ames, chromosomal aberration in human lymphocytes, mouse lymphoma tk) assays, or in the in vivo mouse micronucleus test. Impairment of FertilityWhen administered to female rats prior to and during mating and throughout pregnancy, ropinirole caused disruption of implantation at oral doses of 20 mg/kg/day (8 times the MRHD on mg/m2 basis) or greater. This effect in rats is thought to be due to the prolactin-lowering effect of ropinirole. In rat studies using low oral dose (5 mg/kg) during the prolactin-dependent phase of early pregnancy (gestation days to 8), ropinirole did not affect female fertility at oral doses up to 100 mg/kg/day (40 times the MRHD on mg/m2 basis). No effect on male fertility was observed in rats at oral doses up to 125 mg/kg/day (50 times the MRHD on mg/m2 basis).

OVERDOSAGE SECTION.

10 OVERDOSAGE. The symptoms of overdose with ropinirole extended-release tablets are related to its dopaminergic activity. General supportive measures are recommended. Vital signs should be maintained, if necessary. In clinical trials, 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 7-day period (62.1 mg/day). Of patients who received dose greater than 24 mg/day, reported symptoms included adverse events commonly reported during dopaminergic therapy (nausea, dizziness), as well as visual hallucinations, hyperhidrosis, claustrophobia, chorea, palpitations, asthenia, and nightmares. Additional symptoms reported for overdoses included vomiting, increased coughing, fatigue, syncope, vasovagal syncope, dyskinesia, agitation, chest pain, orthostatic hypotension, somnolence, and confusional state.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. NDC 0781-5780-31rOPINIRole Extended-Release Tablets2 mgRx Only30 Tablets. 2mg label.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. 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 healthy volunteer, transient sinus arrest with syncope [see Warnings and Precautions (5.2, 5.3)]. The mechanism of orthostatic hypotension induced by ropinirole is presumed to be due to D2-mediated blunting of the noradrenergic response to standing and subsequent decrease in peripheral vascular resistance. Nausea is 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 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.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Increase in systemic exposure of ropinirole following oral administration of to 12 mg of ropinirole extended-release tablets was approximately dose-proportional. For ropinirole extended-release tablets, steady-state concentrations of ropinirole are expected to be achieved within days of dosing.AbsorptionIn clinical trials with immediate-release ropinirole, more than 88% of radiolabeled dose was recovered in urine, and the absolute bioavailability was 45% to 55%, indicating approximately 50% first-pass effect.The bioavailability of ropinirole extended-release tablets is similar to that of immediate-release ropinirole tablets. In repeat-dose trial in subjects with Parkinsons disease using ropinirole extended-release tablets mg, the dose-normalized AUC(0-24) and Cmin for ropinirole extended-release tablets and immediate-release ropinirole were similar. Dose-normalized Cmax was, on average, 12% lower for ropinirole extended-release tablets than for the immediate-release formulation and the median time-to-peak concentration was to 10 hours. In single-dose trial, administration of ropinirole extended-release tablets 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 repeat-dose trial in patients with Parkinsons disease, food (i.e., high-fat meal) increased AUC by approximately 20% and Cmax by approximately 44%; Tmax was prolonged by hours (median prolongation) compared with dosing under fasted conditions [see Dosage and Administration (2)]. DistributionRopinirole 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 blood-to-plasma ratio of 1:1.MetabolismRopinirole 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.EliminationThe clearance of ropinirole after oral administration is 47 L/h and its elimination half-life is approximately 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 InteractionsDigoxinCoadministration 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.TheophyllineAdministration of theophylline (300 mg twice daily, substrate of CYP1A2) did not alter the steady-state pharmacokinetics of immediate-release ropinirole (2 mg three times daily) in 12 patients with Parkinsons disease. Immediate-release ropinirole (2 mg three times daily) did not alter the pharmacokinetics of theophylline (5 mg/kg intravenously) in 12 patients with Parkinsons disease.CiprofloxacinCoadministration 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).EstrogensPopulation pharmacokinetic analysis revealed that estrogens (mainly ethinylestradiol: intake 0.6 to mg over 4-month to 23-year period) reduced the oral clearance of ropinirole by 36% in 16 patients.L-dopaCoadministration 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 mg three times daily increased mean steady-state Cmax of L-dopa by 20%, but its AUC was unaffected (n 23 patients).Commonly Administered DrugsPopulation 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 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 P450 mechanism.Specific PopulationsBecause therapy with ropinirole extended-release tablets is initiated at 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.AgeOral clearance of ropinirole is reduced by 15% in patients older than 65 years compared with younger patients. Dosage adjustment is not necessary in the elderly (older than 65 years), as the dose of ropinirole is to be individually titrated to clinical response.GenderFemale and male patients showed similar clearance.RaceThe influence of race on the pharmacokinetics of ropinirole has not been evaluated.Cigarette SmokingSmoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking. In trial in patients with Restless Legs Syndrome, smokers (n =7) had an approximately 30% lower Cmax and 38% lower AUC than did nonsmokers (n 11) when those parameters were normalized for dose.Renal ImpairmentBased on population pharmacokinetic analysis, no difference was observed in the pharmacokinetics of ropinirole in subjects 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. trial of immediate-release ropinirole in subjects with end-stage renal disease on hemodialysis has shown that clearance of ropinirole was reduced by approximately 30%. The recommended maximum dose is lower in these patients [see Dosage and Administration (2.2)]. The use of ropinirole in subjects with severe renal impairment (creatinine clearance less than 30 mL/min) without regular dialysis has not been studied. Hepatic ImpairmentThe pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment. Because ropinirole is extensively metabolized by the liver, these patients may have higher plasma levels and lower clearance of ropinirole than patients with normal hepatic function.Other DiseasesPopulation pharmacokinetic analysis revealed no change in the clearance of ropinirole in patients with concomitant diseases such as hypertension, depression, osteoporosis/arthritis, and insomnia compared with patients with Parkinsons disease only.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.2)3/2017 Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.6)3/2017. Dosage and Administration (2.2)3/2017. Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5, 5.6)3/2017.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are described in more detail in other sections of the label:oHypersensitivity [see Contraindications (4)]oFalling Asleep during Activities of Daily Living and Somnolence [see Warnings and Precautions (5.1)]oSyncope [see Warnings and Precautions (5.2)]oHypotension/Orthostatic Hypotension [see Warnings and Precautions (5.3)]oElevation of Blood Pressure and Changes in Heart Rate [see Warnings and Precautions (5.4)]oHallucinations/Psychotic-like Behavior [see Warnings and Precautions (5.5)]oDyskinesia [see Warnings and Precautions (5.6)]oImpulse Control/Compulsive Behaviors [see Warnings and Precautions (5.7)]oWithdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.8)]oMelanoma [see Warnings and Precautions (5.9)]oFibrotic Complications [see Warnings and Precautions (5.10)]oRetinal Pathology [see Warnings and Precautions (5.11)]. oHypersensitivity [see Contraindications (4)]. oFalling Asleep during Activities of Daily Living and Somnolence [see Warnings and Precautions (5.1)]. oSyncope [see Warnings and Precautions (5.2)]. oHypotension/Orthostatic Hypotension [see Warnings and Precautions (5.3)]. oElevation of Blood Pressure and Changes in Heart Rate [see Warnings and Precautions (5.4)]. oHallucinations/Psychotic-like Behavior [see Warnings and Precautions (5.5)]. oDyskinesia [see Warnings and Precautions (5.6)]. oImpulse Control/Compulsive Behaviors [see Warnings and Precautions (5.7)]. oWithdrawal-Emergent Hyperpyrexia and Confusion [see Warnings and Precautions (5.8)]. oMelanoma [see Warnings and Precautions (5.9)]. oFibrotic Complications [see Warnings and Precautions (5.10)]. oRetinal Pathology [see Warnings and Precautions (5.11)]. oMost common adverse reactions (incidence for ropinirole extended-release tablets all doses at least 5% greater than placebo in either flexible- or fixed-dose study) in patients with advanced Parkinsons disease were nausea, dyskinesia, dizziness, and hallucination.(6.1)oMost common adverse reactions (incidence for ropinirole extended-release tablets all doses at least 5% greater than placebo in fixed-dose study) in patients with early Parkinsons disease not taking L-dopa were nausea, somnolence, sudden onset of sleep, hypertension, and headache. In flexible-dose study in patients with early Parkinsons, the most common adverse reactions (at least 5% incidence for ropinirole extended-release tablets) were nausea, somnolence, abdominal pain/discomfort, dizziness, headache, and constipation. 6.1 To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. oMost common adverse reactions (incidence for ropinirole extended-release tablets all doses at least 5% greater than placebo in either flexible- or fixed-dose study) in patients with advanced Parkinsons disease were nausea, dyskinesia, dizziness, and hallucination.(6.1). oMost common adverse reactions (incidence for ropinirole extended-release tablets all doses at least 5% greater than placebo in fixed-dose study) in patients with early Parkinsons disease not taking L-dopa were nausea, somnolence, sudden onset of sleep, hypertension, and headache. In flexible-dose study in patients with early Parkinsons, the most common adverse reactions (at least 5% incidence for ropinirole extended-release tablets) were nausea, somnolence, abdominal pain/discomfort, dizziness, headache, and constipation. 6.1 . 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug (or of another development program of different formulation of the same drug) and may not reflect the rates observed in practice.During the premarketing development of ropinirole extended-release tablets, patients with advanced Parkinsons disease received ropinirole extended-release tablets or placebo as adjunctive therapy with L-dopa in flexible-dose clinical trial. In flexible-dose trial, patients with early Parkinsons disease were treated with ropinirole extended-release tablets or the immediate-release formulation of ropinirole without L-dopa. In addition, placebo-controlled, fixed-dose, postmarketing trials evaluated the dose response of ropinirole extended-release tablets in patients with advanced Parkinsons disease taking L-dopa and in patients with early Parkinsons disease without concomitant L-dopa. Advanced Parkinsons Disease (With L-dopa)Study was 24-week, double-blind, placebo-controlled, flexible-dose trial in patients with advanced Parkinsons disease. In Study 1, the most commonly observed adverse reactions in patients treated with ropinirole extended-release tablets (incidence at least 5% greater than placebo) were dyskinesia, nausea, dizziness, and hallucinations.In Study 1, approximately 6% of patients treated with ropinirole extended-release tablets discontinued treatment due to adverse reactions, compared with 5% of patients who received placebo. The most common adverse reaction in patients treated with ropinirole extended-release tablets causing discontinuation of treatment with ropinirole extended-release tablets in Study 1was hallucination (2%). Table lists adverse reactions that occurred in at least 2% (and were numerically greater than placebo) of patients with advanced Parkinsons disease treated with ropinirole extended-release tablets who participated in Study 1. In this trial, either ropinirole extended-release tablets or placebo was used as an adjunct to L-dopa.Table 2. Incidence of Adverse Reactions in Placebo-Controlled Flexible-Dose Trial in Advanced Stage Parkinsons Disease in Patients Taking L-dopa (Study 1) (Events >=2% of Patients Treated with Ropinirole Extended-Release Tablets and More Common than on Placebo)Body System/Adverse ReactionRopinirole Extended-releaseTablets(n 202)%Placebo(n 191)%Ear and labyrinth disorders Vertigo 42Gastrointestinal disorders Nausea114 Abdominal pain/discomfort 63 Constipation 42 Diarrhea 32 Dry mouth 2<1General disorders Edema peripheral 41Injury, poisoning, and procedural complications FallDose-related. 21Musculoskeletal and connective tissue disorders Back pain 32Nervous system disorders Dyskinesia 133 Dizziness 83 Somnolence 74Psychiatric disorders Hallucination 82 Anxiety 21Vascular disorders Orthostatic hypotension 51 Hypertension 32 Hypotension 20 Patients may have reported multiple adverse reactions during the trial or at discontinuation; thus, patients may be included in more than one category.Although this trial was not designed for optimally characterizing dose-related adverse reactions, there was suggestion (based upon comparison of incidence of adverse reactions across dose ranges for ropinirole extended-release tablets and placebo) that the incidence for dyskinesia, hypertension, and fall was dose-related to ropinirole extended-release tablets. 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 was an 18-week, double-blind, placebo-controlled, fixed-dose, dose-response trial in patients with advanced Parkinsons disease. In Study 2, approximately 7% of patients treated with any dose of ropinirole extended-release tablets 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 ropinirole extended-release tablets mg, 9% for ropinirole extended-release tablets mg, 8% for ropinirole extended-release tablets 12 mg, 8% for ropinirole extended-release tablets 16 mg, and 0% for ropinirole extended-release tablets 24 mg [see Warnings and Precautions 5.2, 5.5)]. Table lists adverse reactions with an incidence of at least 5% of patients in any dose group of ropinirole extended-release tablets and numerically higher than on placebo in Study 2. The most common adverse reaction (incidence for ropinirole extended-release tablets all doses at least 5% greater than placebo) was dyskinesia.Table 3. Incidence of Adverse Reactions in Placebo-Controlled Fixed-Dose Trial in Advanced Stage Parkinsons Disease in Patients Taking L-dopa (Study 2) (Events >=5% of Patients Treated with any Dose of Ropinirole Extended-Release Tablets and More Common Than on Placebo)Adverse Reaction Placebo N=74 Ropinirole Extended-Release Tablets4 mg N=25 8 mg N=76 12 mg N=75 16 mg N=75 24 mg N=25 All Doses N=276 Nervous system disorders Somnolence 545121108Dyskinesia 14471147Dizziness3848546Sudden onset of sleep 3854104Vascular disordersHypertension 1811483Infections and infestations Nasopharyngitis 1033082Musculoskeletal and connective tissue disordersArthralgia 0030382Psychiatric disordersInsomnia 0001502Early Parkinsons Disease (Without L-dopa) Study was 36-week, flexible-dose crossover trial in patients with early Parkinsons disease who were first treated with ropinirole extended-release tablets or the immediate-release formulation of ropinirole and then crossed over to treatment with the other formulation. In Study 3, the most commonly observed adverse reactions (>=5%) in patients treated with ropinirole extended-release tablets were nausea (19%), somnolence (11%), abdominal pain/discomfort (7%), dizziness (6%), headache (6%), and constipation (5%).Study was an 18-week, double-blind, placebo-controlled, fixed-dose, dose-response trial in patients with early Parkinsons disease. Overall, 7% of patients treated with any dose of ropinirole extended-release tablets, 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 ropinirole extended-release tablets mg, 5% for ropinirole extended-release tablets mg, 8% for ropinirole extended-release tablets mg, 5% for ropinirole extended-release tablets 12 mg, and 15% for ropinirole extended-release tablets 24 mg. Table lists adverse reactions with an incidence of at least 10% of patients in any dose group of ropinirole extended-release tablets and numerically higher than on placebo in Study 4. The most common adverse reactions (incidence for ropinirole extended-release tablets 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 Double-Blind, Placebo-Controlled, Fixed-Dose, Trial in Early Stage Parkinsons Disease (Study 4) (Events >=10% of Patients Treated With any Dose of Ropinirole Extended-Release Tablets and Greater Than on Placebo)Adverse Reactions PlaceboN=40 Ropinirole Extended-Release Tablets2 mg N=13 4 mg N=41 8 mg N=40 12 mg N=39 24 mg N=13 All Doses N=146 Gastrointestinal disorders Nausea 881533101518Vomiting 50510004Nervous system disorders Somnolence 515 12 10 8810Headache 381085158Dizziness 50510887Sudden onset of sleep00501085Vascular disordersHypertension00553155Musculoskeletal and connective tissue disordersBack pain 30533154Laboratory Abnormalities In the fixed-dose trial in advanced Parkinsons disease (Study 2), 11% of patients on ropinirole extended-release tablets exhibited 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 Parkinsons disease in either fixed-dose trial. In the fixed-dose trial in early Parkinsons disease patients (Study 4), serum CPK shifted during treatment from normal to above the normal reference range in 10% of patients on ropinirole extended-release tablets and in 5% of patients on placebo.. 6.2 Adverse Reactions Observed During the Clinical Development of the Immediate-Release Formulation of Ropinirole for Parkinsons Disease (Advanced and Early). Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared with rates in the clinical trials of another drug (or of another development program of different formulation of the same drug) and may not reflect the rates observed in practice.In patients with advanced Parkinsons disease who were treated with the immediate-release formulation of ropinirole, 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 Parkinsons disease who were treated with the immediate-release formulation of ropinirole, 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%).

BOXED WARNING SECTION.

Important Note: Ropinirole extended-release tablets have not been studied in Restless Legs Syndrome (RLS) and is not approved for the treatment of RLS.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisTwo-year carcinogenicity studies of ropinirole were conducted in mice at oral doses of 0, 5, 15, and 50 mg/kg/day and in rats at oral doses of 0, 1.5, 15, and 50 mg/kg/day.In rats, there was an increase in testicular Leydig cell adenomas at all doses tested. The lowest dose tested (1.5 mg/kg/day) is less than the MRHD (24 mg/day) on mg/m2 basis. The endocrine mechanisms believed to be involved in the production of these tumors in rats are not considered relevant to humans. In mice, there was an increase in benign uterine endometrial polyps at dose of 50 mg/kg/day. The highest dose not associated with this finding (15 mg/kg/day) is three times the MRHD on mg/m2 basis.Mutagenesis Ropinirole was not mutagenic or clastogenic in in vitro (Ames, chromosomal aberration in human lymphocytes, mouse lymphoma tk) assays, or in the in vivo mouse micronucleus test. Impairment of FertilityWhen administered to female rats prior to and during mating and throughout pregnancy, ropinirole caused disruption of implantation at oral doses of 20 mg/kg/day (8 times the MRHD on mg/m2 basis) or greater. This effect in rats is thought to be due to the prolactin-lowering effect of ropinirole. In rat studies using low oral dose (5 mg/kg) during the prolactin-dependent phase of early pregnancy (gestation days to 8), ropinirole did not affect female fertility at oral doses up to 100 mg/kg/day (40 times the MRHD on mg/m2 basis). No effect on male fertility was observed in rats at oral doses up to 125 mg/kg/day (50 times the MRHD on mg/m2 basis).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Ropinirole is non-ergoline dopamine agonist. The precise mechanism of action of ropinirole as treatment for Parkinsons disease is unknown, although it is thought to be related to its ability to stimulate dopamine D2 receptors within the caudate-putamen in the brain. 12.2 Pharmacodynamics. 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 healthy volunteer, transient sinus arrest with syncope [see Warnings and Precautions (5.2, 5.3)]. The mechanism of orthostatic hypotension induced by ropinirole is presumed to be due to D2-mediated blunting of the noradrenergic response to standing and subsequent decrease in peripheral vascular resistance. Nausea is 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 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. Increase in systemic exposure of ropinirole following oral administration of to 12 mg of ropinirole extended-release tablets was approximately dose-proportional. For ropinirole extended-release tablets, steady-state concentrations of ropinirole are expected to be achieved within days of dosing.AbsorptionIn clinical trials with immediate-release ropinirole, more than 88% of radiolabeled dose was recovered in urine, and the absolute bioavailability was 45% to 55%, indicating approximately 50% first-pass effect.The bioavailability of ropinirole extended-release tablets is similar to that of immediate-release ropinirole tablets. In repeat-dose trial in subjects with Parkinsons disease using ropinirole extended-release tablets mg, the dose-normalized AUC(0-24) and Cmin for ropinirole extended-release tablets and immediate-release ropinirole were similar. Dose-normalized Cmax was, on average, 12% lower for ropinirole extended-release tablets than for the immediate-release formulation and the median time-to-peak concentration was to 10 hours. In single-dose trial, administration of ropinirole extended-release tablets 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 repeat-dose trial in patients with Parkinsons disease, food (i.e., high-fat meal) increased AUC by approximately 20% and Cmax by approximately 44%; Tmax was prolonged by hours (median prolongation) compared with dosing under fasted conditions [see Dosage and Administration (2)]. DistributionRopinirole 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 blood-to-plasma ratio of 1:1.MetabolismRopinirole 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.EliminationThe clearance of ropinirole after oral administration is 47 L/h and its elimination half-life is approximately 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 InteractionsDigoxinCoadministration 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.TheophyllineAdministration of theophylline (300 mg twice daily, substrate of CYP1A2) did not alter the steady-state pharmacokinetics of immediate-release ropinirole (2 mg three times daily) in 12 patients with Parkinsons disease. Immediate-release ropinirole (2 mg three times daily) did not alter the pharmacokinetics of theophylline (5 mg/kg intravenously) in 12 patients with Parkinsons disease.CiprofloxacinCoadministration 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).EstrogensPopulation pharmacokinetic analysis revealed that estrogens (mainly ethinylestradiol: intake 0.6 to mg over 4-month to 23-year period) reduced the oral clearance of ropinirole by 36% in 16 patients.L-dopaCoadministration 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 mg three times daily increased mean steady-state Cmax of L-dopa by 20%, but its AUC was unaffected (n 23 patients).Commonly Administered DrugsPopulation 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 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 P450 mechanism.Specific PopulationsBecause therapy with ropinirole extended-release tablets is initiated at 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.AgeOral clearance of ropinirole is reduced by 15% in patients older than 65 years compared with younger patients. Dosage adjustment is not necessary in the elderly (older than 65 years), as the dose of ropinirole is to be individually titrated to clinical response.GenderFemale and male patients showed similar clearance.RaceThe influence of race on the pharmacokinetics of ropinirole has not been evaluated.Cigarette SmokingSmoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking. In trial in patients with Restless Legs Syndrome, smokers (n =7) had an approximately 30% lower Cmax and 38% lower AUC than did nonsmokers (n 11) when those parameters were normalized for dose.Renal ImpairmentBased on population pharmacokinetic analysis, no difference was observed in the pharmacokinetics of ropinirole in subjects 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. trial of immediate-release ropinirole in subjects with end-stage renal disease on hemodialysis has shown that clearance of ropinirole was reduced by approximately 30%. The recommended maximum dose is lower in these patients [see Dosage and Administration (2.2)]. The use of ropinirole in subjects with severe renal impairment (creatinine clearance less than 30 mL/min) without regular dialysis has not been studied. Hepatic ImpairmentThe pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment. Because ropinirole is extensively metabolized by the liver, these patients may have higher plasma levels and lower clearance of ropinirole than patients with normal hepatic function.Other DiseasesPopulation pharmacokinetic analysis revealed no change in the clearance of ropinirole in patients with concomitant diseases such as hypertension, depression, osteoporosis/arthritis, and insomnia compared with patients with Parkinsons disease only.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The effectiveness of ropinirole was initially established with the immediate-release formulation (ropinirole tablets) for the treatment of early and advanced Parkinsons disease in three randomized, double-blind, placebo-controlled trials.The effectiveness of ropinirole extended-release tablets in the treatment of Parkinsons disease was supported by two randomized, double-blind, multicenter, flexible-dose clinical trials and clinical pharmacokinetic considerations. One trial conducted in patients with advanced Parkinsons disease compared ropinirole extended-release tablets with placebo as adjunctive therapy to L-dopa (Study 1). second trial compared ropinirole extended-release tablets with ropinirole immediate-release in patients with early Parkinsons disease not receiving L-dopa (Study 3). Ropinirole extended-release tablets has also been evaluated in postmarketing, randomized, double-blind, multicenter, fixed-dose, dose-response clinical trials conducted in advanced and early Parkinsons disease patients (Study and Study 4, respectively).In these trials, variety of measures were used to assess the effects of treatment (e.g., Unified Parkinsons Disease Rating Scale [UPDRS] scores, and patient diaries recording time on and off, tolerability of L-dopa dose reductions). The UPDRS is multi-text rating scale intended to evaluate mentation (Part I), activities of daily living (Part II), motor performance (Part III), and complications of therapy (Part IV). Part III of the UPDRS contains 14 texts designed to assess the severity of the cardinal motor findings in patients with Parkinsons disease (e.g., tremor, rigidity, bradykinesia, postural instability) scored for different body regions and has maximum (worst) score of 108. 14.1 Trials in Patients With Advanced Parkinsons Disease (With L-dopa). Study (Flexible-Dose Trial)The effectiveness of ropinirole extended-release tablets as adjunctive therapy to L-dopa in patients with Parkinsons disease was established in 24-week, randomized, double-blind, placebo-controlled, parallel-group, flexible-dose, 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 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 trial had mean disease duration of 8.6 years, had mean duration of exposure to L-dopa of 6.5 years, had experienced minimum of hours awake time off with baseline average of approximately hours awake time off, and had mean baseline UPDRS motor score of approximately 30 points. The mean baseline dose of L-dopa was 824 mg/day in the group receiving ropinirole extended-release tablets and 776 mg/day for the placebo group. Patients initiated treatment at mg/day for week, followed by increases of mg/day at weekly intervals, to minimum dose of mg/day. The following week, the total daily dose of ropinirole extended-release tablets could be further increased (based upon therapeutic response and tolerability) to mg/day. Once daily dose of mg/day was reached, the background L-dopa dosage was reduced. Thereafter, the daily dose could be increased by up to mg/day approximately every weeks until an optimal dose was achieved (based upon therapeutic response and tolerability). The mean dose of ropinirole extended-release tablets 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 maximum allowed daily dosage for ropinirole extended-release tablets 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 hours in each treatment group. At Week 24, the total awake time spent off, on average, had decreased by approximately hours in the group receiving ropinirole extended-release tablets and by approximately one-half hour in the placebo group. The adjusted mean difference in total awake time spent off between ropinirole extended-release tablets and placebo was -1.7 hours, which was statistically significant (analysis of covariance [ANCOVA], P<0.0001). Results for this endpoint showing the statistical superiority of ropinirole extended-release tablets over placebo, are presented in Table 5. Table 5. Change from Baseline in Total Awake Time Spent Off (Primary Efficacy Endpoint) at Week 24 (Study 1)Ropinirole Extended-Release Tablets (n=201)Placebo (n=190)Mean Off Time at Baseline (hours) 7 Mean Change from Baseline in Off Time (hours) -2.1 -0.4 Treatment Difference (Ropinirole Extended-release Tablets PLACEBO) -1.7The difference between groups in favor of ropinirole extended-release tablets, with regard to decrease in total off hours, was primarily related to an increase in total on hours without troublesome dyskinesia. Patients treated with ropinirole extended-release tablets had mean reduction in L-dopa dose of 278 mg/day (34%), while patients treated with placebo had mean reduction of 164 mg/day (21%). In patients who reduced their L-dopa dose, reduction was sustained in 93% of patients treated with ropinirole extended-release tablets and in 72% of patients treated with placebo (P<0.001).Study (Fixed-Dose, Dose-Response Trial) double-blind, placebo-controlled, fixed-dose, parallel-group trial evaluated the dose-response of ropinirole extended-release tablets as adjunctive therapy to L-dopa in 352 randomized patients with advanced Parkinsons disease (Hoehn Yahr criteria Stages II-IV) over total dosing period of 18 weeks. Patients initiated treatment with placebo or ropinirole extended-release tablets at mg/day for week, and increased to target dose of mg/day, mg/day, 12 mg/day, 16 mg/day, or 24 mg/day over 13-week up-titration period. The dose remained stable over an additional 4-week maintenance period, followed by 1-week down-titration period. The L-dopa dose was kept constant during the study, if possible. The primary efficacy endpoint was the mean change from baseline in total awake time spent off at Week of the maintenance period with daily doses of mg, mg, 12 mg, 16 mg, and 24 mg compared with placebo. The primary statistical analysis of the primary efficacy endpoint was Mixed Model Repeated Measures (MMRM). At baseline, the mean off time ranged from 5.6 to 6.5 hours across groups on ropinirole extended-release tablets and placebo. Table shows the results for the primary efficacy endpoint. The greatest treatment difference (ropinirole extended-release tablets PLACEBO) for the primary efficacy endpoint was observed with the mg dose; however, higher doses were not shown to provide additional benefit. Table 6. Change from Baseline in Total Awake Time Spent Off (Primary Efficacy Endpoint) at the End of the Maintenance Period (Study 2)Endpoint Placebo N=65Daily Ropinirole Extended-Release Tablets Dose4 mg N=21 mg N=60 12 mg N=61 16 mg N=65 24 mg N=25 LS Mean Change from Baseline for Off Time -1.91-2.04 -2.92 -2.34 -2.80 -2.37 Treatment Difference (Ropinirole Extended-release Tablets PLACEBO) -0.13 -1.01-0.43-0.89 -0.46P value 0.81 0.01 0.290.03 0.39 value not adjusted for multiple comparisons. hierarchical step-down approach for statistical testing was used starting with 16-mg dose.. Table 5. Change from Baseline in Total Awake Time Spent Off (Primary Efficacy Endpoint) at Week 24 (Study 1). Table 6. Change from Baseline in Total Awake Time Spent Off (Primary Efficacy Endpoint) at the End of the Maintenance Period (Study 2). 14.2 Trials in Patients With Early Parkinsons Disease (Without L-dopa). Study (Flexible-Dose Trial)A 36-week, multicenter, double-blind, titration/3-period maintenance, flexible-dose, crossover trial compared the efficacy of ropinirole extended-release tablets with the immediate-release formulation of ropinirole in 161 patients with early phase Parkinsons disease (Hoehn Yahr Stages I-III) with limited prior exposure to L-dopa or dopamine agonists. Eligible patients were randomized (1:1:1:1) to treatment sequences (2 were titrated on immediate-release formulation of ropinirole and on ropinirole extended-release tablets). Titration rate of immediate-release formulation of ropinirole was slower than that of the ropinirole extended-release. Patients were titrated, during the 12-week titration period, to their optimal dosage, based upon tolerance and therapeutic response. This was followed by 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 four groups started out with similar UPDRS motor scores (about 21) at baseline. All groups exhibited similar improvement in UPDRS total motor scores from baseline until the completion of the titration phase, with change in score of about -9 observed for the groups started on immediate-release formulation of ropinirole and of about -10 for the groups started on ropinirole extended-release tablets. No difference was observed between groups when switches were made between identical formulations or between different formulations. This suggests therapeutic dosage equivalence between the immediate-release formulation of ropinirole and ropinirole extended-release tablets.The optimal daily dose at the end of the titration period for patients on immediate release formulation of ropinirole was substantially lower (mean: mg) compared with the dose at the end of the titration period for patients on ropinirole extended-release tablets (mean: 18 mg). In this trial, the marked difference in the final optimal dosages suggests that the higher doses afforded no additional benefit when compared with the lower doses [see Dosage and Administration 2.2 )]. Study (Fixed-Dose, Dose-Response Trial) double-blind, placebo-controlled, fixed-dose, parallel-group trial evaluated the dose response of ropinirole extended-release tablets without L-dopa in 186 randomized patients with early Parkinsons disease (Hoehn Yahr Stages I-III) over total dosing period of 18 weeks. Patients initiated treatment with placebo or ropinirole extended-release tablets at mg/day for week and were either maintained at target dose of mg/day or further increased to target dose of mg/day, mg/day, 12 mg/day, or 24 mg/day over 13-week up-titration period. The dose remained stable over an additional week maintenance period, followed by 1-week down-titration period. The primary statistical analysis of the primary efficacy endpoint was Mixed Model Repeated Measures (MMRM). The primary efficacy endpoint was the change from baseline in UPDRS motor score at Week of the maintenance period with daily doses of mg, mg, mg, 12 mg, and 24 mg compared with placebo. At baseline, the mean UPDRS motor score ranged from approximately 21 to 25 across all groups receiving ropinirole extended-release tablets and placebo. Table shows results for the primary efficacy endpoint. The greatest treatment difference (ropinirole extended-release tablets PLACEBO) for the primary efficacy endpoint occurred with the 12-mg dose. At Week of the maintenance period, the primary efficacy analysis (MMRM) did not show significant difference between placebo (mean adjusted change: -3.98) and any dose of ropinirole extended-release tablets (mean adjusted changes ranged from -4.09 to -6.14). Data were also analyzed by nonparametric ANCOVA as pre-specified because of non-normality. This analysis and showed that there was significant reduction from baseline in the UPDRS motor score for the group receiving ropinirole extended-release tablets 12 mg/day (P 0.047); however, higher doses were not shown to provide additional benefit.Table 7. Change from Baseline in UPDRS Part III Motor Score (Primary Efficacy Endpoint) at the End of the Maintenance Period (Study 4)Endpoint Placebo = 35Daily Ropinirole Extended-Release Tablets Dose2 mgN=13 mg N=35 mg N=33 12 mg N=34 24 mg N=10 LS Mean Change from Baseline in UPDRS Part III Motor Score -3.98-4.09 -4.97 -5.90 -6.14 -4.85 Treatment Difference (Ropinirole Extended-release Tablets PLACEBO) -0.11 -0.99-1.92-2.16-0.87P value 0.950.480.180.130.68 value not adjusted for multiple comparisons. hierarchical step-down approach for statistical testing was used starting with 12-mg dose.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Ropinirole extended-release tablets are contraindicated in patients known to have hypersensitivity allergic reaction (including urticaria, angioedema, rash, pruritus) to ropinirole or any of the excipients.. History of hypersensitivity/allergic reaction (including urticaria, angioedema, rash, pruritus) to ropinirole or to any of the excipients. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Ropinirole extended-release tablets contain ropinirole, non-ergoline dopamine agonist as the hydrochloride salt. The chemical name of ropinirole hydrochloride is 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one and the molecular formula is C16H24N2OoHCl. The molecular weight is 296.84 (260.38 as the free base).The structural formula is:Ropinirole hydrochloride is white to cream colored crystalline powder with melting range of 241 to 245C and solubility of 134 mg/mL in water.Ropinirole extended-release tablets are formulated as single layer matrix tablets coated with functional polymer. 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 mg, mg, mg, mg, or 12 mg, respectively. Inactive ingredients consist of carboxymethyl cellulose sodium, colloidal silicon dioxide, diethyl phthalate, ethyl cellulose, hydrogenated castor oil, hydroxypropyl cellulose, hypromellose, lactose anhydrous, magnesium stearate, maltodextrin, polyethylene glycol, talc, titanium dioxide and ferric oxide. The film coating contains: iron oxide red (for the mg, mg, and mg strengths), iron oxide black (for the mg and mg strengths), iron oxide yellow (for the mg, mg, and 12 mg strengths), polysorbate 80 (for the mg strength), and FD&C Blue No. aluminum lake (for the 12 mg strength).. Chemical structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oRopinirole extended-release tablets are taken once daily, with or without food; tablets must be swallowed whole and must not be chewed, crushed, or divided. (2.1)oThe recommended starting dose is mg taken once daily for to weeks; the dose should be increased by mg/day at week or longer intervals. The maximum recommended dose of ropinirole extended-release tablets is 24 mg/day. (2.2, 14.2)oRenal Impairment: In patients with end-stage renal disease on hemodialysis, the maximum recommended dose is 18 mg/day. (2.2)oIf ropinirole extended-release tablets must be discontinued, it should be tapered gradually over 7-day period; retitration of ropinirole extended-release tablets may be warranted if therapy is interrupted. (2.1, 2.2)oPatients may be switched directly from immediate-release ropinirole to ropinirole extended-release tablets; the initial switching dose of ropinirole extended-release tablets should approximately match the total daily dose of immediate-release ropinirole. (2.3). oRopinirole extended-release tablets are taken once daily, with or without food; tablets must be swallowed whole and must not be chewed, crushed, or divided. (2.1). oThe recommended starting dose is mg taken once daily for to weeks; the dose should be increased by mg/day at week or longer intervals. The maximum recommended dose of ropinirole extended-release tablets is 24 mg/day. (2.2, 14.2). oRenal Impairment: In patients with end-stage renal disease on hemodialysis, the maximum recommended dose is 18 mg/day. (2.2). oIf ropinirole extended-release tablets must be discontinued, it should be tapered gradually over 7-day period; retitration of ropinirole extended-release tablets may be warranted if therapy is interrupted. (2.1, 2.2). oPatients may be switched directly from immediate-release ropinirole to ropinirole extended-release tablets; the initial switching dose of ropinirole extended-release tablets should approximately match the total daily dose of immediate-release ropinirole. (2.3). 2.1 General Dosing Recommendations oRopinirole extended-release tablets are taken once daily, with or without food [see Clinical Pharmacology (12.3) ].oTablets must be swallowed whole and must not be chewed, crushed, or divided.oIf significant interruption in therapy with ropinirole extended-release tablets has occurred, retitration of therapy may be warranted. oRopinirole extended-release tablets are taken once daily, with or without food [see Clinical Pharmacology (12.3) ].. oTablets must be swallowed whole and must not be chewed, crushed, or divided.. oIf significant interruption in therapy with ropinirole extended-release tablets has occurred, retitration of therapy may be warranted. 2.2 Dosing for Parkinsons Disease. The recommended starting dose of ropinirole extended-release tablets is mg taken once daily for to weeks, followed by increases of mg/day at weekly or longer intervals, based on therapeutic response and tolerability. Monitor patients at least weekly during dose titration. Too rapid rate of titration may lead to the selection of 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 ropinirole extended-release tablets, there was no additional therapeutic benefit shown in patients with advanced stage Parkinsons disease taking daily doses greater than mg/day, or with early stage Parkinsons disease taking doses greater than 12 mg/day [see Clinical Studies (14.1 and 14.2)]. Although the maximum recommended dose of ropinirole extended-release tablets is 24 mg, patients with advanced Parkinsons disease should generally be maintained at daily doses of mg or lower and patients with early Parkinsons disease should generally be maintained at daily doses 12 mg or lower.Ropinirole extended-release tablets should be discontinued gradually over 7-day period.Renal ImpairmentNo dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The recommended initial dose of ropinirole extended-release tablets for patients with end-stage renal disease on hemodialysis is 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 ropinirole extended-release tablets in patients with severe renal impairment without regular dialysis has not been studied.. 2.3 Switching From Immediate-Release Ropinirole Tablets to Ropinirole Extended-Release Tablets. Patients may be switched directly from immediate-release ropinirole to ropinirole extended-release tablets. The initial dose of ropinirole extended-release tablets 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 to Ropinirole Extended-Release Tablets Immediate-Release Ropinirole Tablets Total Daily Dose (mg)Ropinirole Extended-Release TabletsTotal Daily Dose (mg)0.75 to 2.2523 to 4.54667.5 to 98121215 16181821202424Following conversion to ropinirole extended-release tablets, the dose may be adjusted depending on therapeutic response and tolerability [see Dosage and Administration (2.2) ]. 2.4 Effect of Gastrointestinal Transit Time on Medication Release. Ropinirole extended-release tablets are designed to release medication over 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. o2 mg, light pink coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 770 debossed on other side.o4 mg, light brown coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 796 debossed on other side.o6 mg, white to off-white coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 797 debossed on other side.o8 mg, dark brown coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 161 debossed on other side.o12 mg, light green coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 162 debossed on other side.. o2 mg, light pink coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 770 debossed on other side.. o4 mg, light brown coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 796 debossed on other side.. o6 mg, white to off-white coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 797 debossed on other side.. o8 mg, dark brown coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 161 debossed on other side.. o12 mg, light green coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 162 debossed on other side.. Tablets: mg, mg, mg, mg, and 12 mg (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. oInhibitors or inducers of CYP1A2: May alter the clearance of ropinirole; dose adjustment of ropinirole extended-release tablets may be required. (7.1, 12.3) oHormone replacement therapy (HRT): Starting or stopping HRT treatment may require dose adjustment of ropinirole extended-release tablets. (7.3, 12.3)oDopamine antagonists (e.g., neuroleptics, metoclopramide): May reduce efficacy of ropinirole extended-release tablets. (7.3). oInhibitors or inducers of CYP1A2: May alter the clearance of ropinirole; dose adjustment of ropinirole extended-release tablets may be required. (7.1, 12.3) oHormone replacement therapy (HRT): Starting or stopping HRT treatment may require dose adjustment of ropinirole extended-release tablets. (7.3, 12.3). oDopamine antagonists (e.g., neuroleptics, metoclopramide): May reduce efficacy of ropinirole extended-release tablets. (7.3). 7.1 CYP1A2 Inhibitors and Inducers. In vitro metabolism studies showed that CYP1A2 is the major enzyme responsible for the metabolism of ropinirole. There is thus the potential for inducers or inhibitors of this enzyme to alter the clearance of ropinirole. Therefore, if therapy with drug known to be potent inducer or inhibitor of CYP1A2 is stopped or started during treatment with ropinirole extended-release tablets, adjustment of the dose of ropinirole extended-release tablets may be required. Coadministration of ciprofloxacin, an inhibitor of CYP1A2, with immediate-release ropinirole increases the AUC and Cmax of ropinirole [see Clinical Pharmacology (12.3) ]. Cigarette smoking is expected to increase the clearance of ropinirole since CYP1A2 is known to be induced by smoking [see Clinical Pharmacology (12.3) ]. 7.2 Estrogens. Population pharmacokinetic analysis revealed that higher doses of estrogens (usually associated with hormone replacement therapy [HRT]) reduced the clearance of ropinirole. Starting or stopping HRT may require adjustment of dosage of ropinirole extended-release tablets [see Clinical Pharmacology (12.3)].. 7.3 Dopamine Antagonists. Because ropinirole is dopamine agonist, it is possible that dopamine antagonists such as neuroleptics (e.g., phenothiazines, butyrophenones, thioxanthenes) or metoclopramide may reduce the efficacy of ropinirole extended-release tablets.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. Ropinirole exended-release tablets are biconvex, capsule-shaped, film-coated tablets that contain ropinirole hydrochloride equivalent to the labeled amount of ropinirole as follows:o2 mg, light pink coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 770 debossed on other side. NDC 0781-5780-31, bottle of 30 tablets NDC 0781-5780-92, bottle of 90 tabletso4mg, light brown coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 796 debossed on other side. NDC 0781-5782-31, bottle of 30 tablets NDC 0781-5782-92, bottle of 90 tabletso6 mg, white to off-white coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 797 debossed on other side. NDC 0781-5784-31, bottle of 30 tablets NDC 0781-5784-92, bottle of 90 tabletso8mg, dark brown coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 161 debossed on other side. NDC 0781-5786-31, bottle of 30 tablets NDC 0781-5786-92, bottle of 90 tabletso12 mg, light green coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 162 debossed on other side. NDC 0781-5788-31, bottle of 30 tablets NDC 0781-5788-92, bottle of 90 tabletsStorage Store at 20o to 25oC (68o to 77oF) [see USP Controlled Room Temperature].Dispense in tight, light-resistant container as defined in the USP.. o2 mg, light pink coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 770 debossed on other side.. NDC 0781-5780-31, bottle of 30 tablets. NDC 0781-5780-92, bottle of 90 tablets. o4mg, light brown coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 796 debossed on other side.. NDC 0781-5782-31, bottle of 30 tablets. NDC 0781-5782-92, bottle of 90 tablets. o6 mg, white to off-white coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 797 debossed on other side.. NDC 0781-5784-31, bottle of 30 tablets. NDC 0781-5784-92, bottle of 90 tablets. o8mg, dark brown coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 161 debossed on other side.. NDC 0781-5786-31, bottle of 30 tablets. NDC 0781-5786-92, bottle of 90 tablets. o12 mg, light green coloured, capsule shaped, biconvex film-coated tablets with SZ debossed on one side and 162 debossed on other side.. NDC 0781-5788-31, bottle of 30 tablets. NDC 0781-5788-92, bottle of 90 tablets.

SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATIONRopinirole Extended-release Tablets (roe-PIN-ih-role). Important Note: Ropinirole extended-release tablets have not been studied in Restless Legs Syndrome (RLS) and is not approved for the treatment of RLS. What is the most important information should know about ropinirole extended-release tablets Ropinirole extended-release tablets can cause serious side effects, including: oFalling asleep during normal activities. You may fall asleep while doing normal activities such as driving car, doing physical tasks, or using hazardous machinery while taking ropinirole extended-release tablets. 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 ropinirole extended-release tablets are greater if you take other medicines that cause drowsiness. Tell your healthcare provider right away if this happens. Before starting ropinirole extended-release tablets, be sure to tell your healthcare provider if you take any medicines that make you drowsy. oFainting. Fainting can happen, and sometimes your heart rate may be decreased. This can happen especially when you start taking ropinirole extended-release tablets or your dose is increased. Tell your healthcare provider if you faint, feel dizzy, or feel light-headed. oDecrease in blood pressure. Ropinirole extended-release tablets can decrease your blood pressure (hypotension), especially when you start taking ropinirole extended-release tablets or when your dose is changed. If you faint or feel dizzy, nauseated, or sweaty when you stand up from sitting or lying down (orthostatic hypotension), this may mean that your blood pressure is decreased. When you change position from lying down or sitting to standing up, you should do it carefully and slowly. Call your healthcare provider if you have any of the symptoms of decreased blood pressure listed above. oIncrease in blood pressure. Ropinirole extended-release tablets may increase your blood pressure. oChanges in heart rate (decrease or increase). Ropinirole extended-release tablets can decrease or increase your heart rate. oHallucinations and other psychotic-like behavior. Ropinirole extended-release tablets can cause or worsen psychotic-like behavior including hallucinations (seeing or hearing things that are not real), confusion, excessive suspicion, aggressive behavior, agitation, delusional beliefs (believing things that are not real), and disorganized thinking. The chances of having hallucinations or these other psychotic-like changes are higher in people with Parkinsons disease who are taking ropinirole extended-release tablets or taking higher doses of these drugs. If you have hallucinations or any of these other psychotic-like changes, talk with your healthcare provider. oUncontrolled sudden movements. Ropinirole extended-release tablets 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-Parkinsons medicine may need to be changed. oUnusual urges. Some patients taking ropinirole extended-release tablets get urges to behave in way unusual for them. Examples of this are an unusual urge to gamble, increased sexual urges and behaviors, or an uncontrollable urge to shop, spend money, or eat. If you notice or your family notices that you are developing any unusual behaviors, talk to your healthcare provider. oIncreased chance of skin cancer (melanoma). People with Parkinsons disease may have higher chance of getting melanoma. It is not known if ropinirole extended-release tablets increase your chances of getting melanoma. You and your healthcare provider should check your skin on regular basis. Tell your healthcare provider right away if you notice any changes in your skin such as change in the size, shape, or color of moles on your skin. What are ropinirole extended-release tabletsRopinirole extended-release tablets are long-acting prescription medicine containing ropinirole (taken time day) that is used only to treat Parkinsons disease but not to treat RLS. Having one of these conditions does not mean you have or will develop the other condition.You should not be taking more than medicine containing ropinirole. Tell your healthcare provider if you are taking any other medicine containing ropinirole.It is not known if ropinirole extended-release tablets are safe and effective for use in children younger than 18 years of age.Do not take ropinirole extended-release tablets if you: oare allergic to ropinirole or any of the ingredients in ropinirole extended-release tablets. See the end of this page for complete list of the ingredients in ropinirole extended-release tablets.oGet help right away if any of the symptoms of an allergic reaction cause problems swallowing or breathing. Call your healthcare provider if you have any of the symptoms of an allergic reaction. Symptoms of an allergic reaction may include: ohives orash oswelling of the face, lips, mouth, tongue, or throat oitching Before taking ropinirole extended-release tablets, tell your healthcare provider about all of your medical conditions including if you: ohave daytime sleepiness from sleep disorder or have unexpected or unpredictable sleepiness or periods of sleep. ostart or stop taking other medicines while you are taking ropinirole extended-release tablets. This may increase your chances of getting side effects.ostart or stop smoking while you are taking ropinirole extended-release tablets. Smoking may decrease the treatment effect of ropinirole extended-release tablets. ofeel dizzy, nauseated, sweaty, or faint when you first stand up from sitting or lying down.odrink alcoholic beverages. This may increase your chances of becoming drowsy or sleepy while taking ropinirole extended-release tablets.ohave high or low blood pressure.ohave or have had heart problems.oare pregnant or plan to become pregnant. It is not known if ropinirole extended-release tablets can harm your unborn baby. oare breastfeeding or plan to breastfeed. It is not known if ropinirole passes into your breast milk. The amount of breast milk you make may be decreased while taking ropinirole exended-release tablets. Talk to your healthcare provider to decide if you should breastfeed while taking ropinirole extended-release tablets.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Some of these medicines may increase your chances of getting side effects while taking ropinirole extended-release tablets. How should take ropinirole extended-release tabletsoTake ropinirole extended-release tablets exactly as directed by your healthcare provider. oTake ropinirole extended-release tablets with or without food.oDo not suddenly stop taking ropinirole extended-release tablets without talking to your healthcare provider. If you stop this medicine suddenly, you may develop fever, confusion, or severe muscle stiffness.oBefore starting ropinirole extended-release tablets, you should talk to your healthcare provider about what to do if you miss dose. If you have missed the previous dose and it is time for your next dose, do not double the dose.oYour healthcare provider will start you on low dose of ropinirole extended-release tablets. 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 dose that controls your symptoms.oContact your healthcare provider if you stop taking ropinirole extended-release tablets for any reason. Do not restart without talking with your healthcare provider.oYour healthcare provider may prescribe ropinirole extended-release tablets alone, or add ropinirole extended-release tablets to medicine that you are already taking for Parkinsons disease. oYou should not substitute ropinirole immediate-release for ropinirole extended-release tablets or ropinirole extended-release tablets for ropinirole immediate-release without talking with your healthcare provider. If you are taking ropinirole extended-release tablets:oTake ropinirole extended-release tablets time each day for Parkinsons disease, preferably at or around the same time of day.oSwallow ropinirole extended-release tablets whole. Do not chew, crush, or split ropinirole extended-release tablets.oRopinirole extended-release tablets release drug over 24-hour period. If you have condition where medicine passes through your body too quickly, such as diarrhea, the tablet(s) may not dissolve completely and you may see tablet residue in your stool. If this happens, let your healthcare provider know as soon as possible. What are the possible side effects of ropinirole extended-release tabletsRopinirole extended-release tablets can cause serious side effects including:See What is the most important information should know about ropinirole extended-release tablets The most common side effects of ropinirole extended-release tablets include:ofaintingosleepiness or drowsiness ohallucinations (seeing or hearing things that are not real) odizziness onausea or vomiting ouncontrolled sudden movements oupset stomach, abdominal pain or discomfortofatigue, tiredness, or weakness oconfusion oheadache oleg swellingoincreased sweating oconstipationosuddenly falling asleepohigh blood pressure (hypertension)Tell your healthcare provider about any side effect that bothers you or does not go away. These are not all of the possible side effects with ropinirole extended-release tablets. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. How should store ropinirole extended-release tablets oStore ropinirole extended-release tablets at room temperature between 68F to 77F (20C to 25C). oKeep ropinirole extended-release tablets in tightly closed container and out of direct sunlight. Keep ropinirole extended-release tablets and all medicines out of the reach of children.General information about the safe and effective use of ropinirole extended-release tablets:Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use ropinirole extended-release tablets for condition for which it was not prescribed. Do not give ropinirole extended-release tablets to other people, even if they have the same symptoms that you have. It may harm them.You can ask your pharmacist or healthcare provider for information about ropinirole extended-release tablets that is written for health professionals. What are the ingredients in ropinirole extended-release tabletsActive ingredient: ropinirole (as ropinirole hydrochloride)Inactive ingredients: carboxymethyl cellulose sodium, colloidal silicon dioxide, diethyl phthalate, ethyl cellulose, hydrogenated castor oil, hydroxypropyl cellulose, hypromellose, lactose anhydrous, magnesium stearate, maltodextrin, polyethylene glycol, talc, titanium dioxide and ferric oxide. The film coating contains: iron oxide red (for the mg, mg, and mg strengths), iron oxide black (for the mg and mg strengths), iron oxide yellow (for the mg, mg, and 12 mg strengths), polysorbate 80 (for the mg strength), and FD&C Blue No. aluminum lake (for the 12 mg strength).The brands listed are the registered trademarks of their respective owners and are not trademarks of Sandoz Inc.Manufactured in India by Sandoz Private Ltd. for Sandoz Inc., Princeton NJ 08540Rev.: April 2017. oFalling asleep during normal activities. You may fall asleep while doing normal activities such as driving car, doing physical tasks, or using hazardous machinery while taking ropinirole extended-release tablets. 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 ropinirole extended-release tablets are greater if you take other medicines that cause drowsiness. Tell your healthcare provider right away if this happens. Before starting ropinirole extended-release tablets, be sure to tell your healthcare provider if you take any medicines that make you drowsy. oFainting. Fainting can happen, and sometimes your heart rate may be decreased. This can happen especially when you start taking ropinirole extended-release tablets or your dose is increased. Tell your healthcare provider if you faint, feel dizzy, or feel light-headed. oDecrease in blood pressure. Ropinirole extended-release tablets can decrease your blood pressure (hypotension), especially when you start taking ropinirole extended-release tablets or when your dose is changed. If you faint or feel dizzy, nauseated, or sweaty when you stand up from sitting or lying down (orthostatic hypotension), this may mean that your blood pressure is decreased. When you change position from lying down or sitting to standing up, you should do it carefully and slowly. Call your healthcare provider if you have any of the symptoms of decreased blood pressure listed above. oIncrease in blood pressure. Ropinirole extended-release tablets may increase your blood pressure. oChanges in heart rate (decrease or increase). Ropinirole extended-release tablets can decrease or increase your heart rate. oHallucinations and other psychotic-like behavior. Ropinirole extended-release tablets can cause or worsen psychotic-like behavior including hallucinations (seeing or hearing things that are not real), confusion, excessive suspicion, aggressive behavior, agitation, delusional beliefs (believing things that are not real), and disorganized thinking. The chances of having hallucinations or these other psychotic-like changes are higher in people with Parkinsons disease who are taking ropinirole extended-release tablets or taking higher doses of these drugs. If you have hallucinations or any of these other psychotic-like changes, talk with your healthcare provider. oUncontrolled sudden movements. Ropinirole extended-release tablets 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-Parkinsons medicine may need to be changed. oUnusual urges. Some patients taking ropinirole extended-release tablets get urges to behave in way unusual for them. Examples of this are an unusual urge to gamble, increased sexual urges and behaviors, or an uncontrollable urge to shop, spend money, or eat. If you notice or your family notices that you are developing any unusual behaviors, talk to your healthcare provider. oIncreased chance of skin cancer (melanoma). People with Parkinsons disease may have higher chance of getting melanoma. It is not known if ropinirole extended-release tablets increase your chances of getting melanoma. You and your healthcare provider should check your skin on regular basis. Tell your healthcare provider right away if you notice any changes in your skin such as change in the size, shape, or color of moles on your skin. oare allergic to ropinirole or any of the ingredients in ropinirole extended-release tablets. See the end of this page for complete list of the ingredients in ropinirole extended-release tablets.. oGet help right away if any of the symptoms of an allergic reaction cause problems swallowing or breathing. Call your healthcare provider if you have any of the symptoms of an allergic reaction. Symptoms of an allergic reaction may include: ohives orash oswelling of the face, lips, mouth, tongue, or throat oitching ohave daytime sleepiness from sleep disorder or have unexpected or unpredictable sleepiness or periods of sleep. ostart or stop taking other medicines while you are taking ropinirole extended-release tablets. This may increase your chances of getting side effects.. ostart or stop smoking while you are taking ropinirole extended-release tablets. Smoking may decrease the treatment effect of ropinirole extended-release tablets. ofeel dizzy, nauseated, sweaty, or faint when you first stand up from sitting or lying down.. odrink alcoholic beverages. This may increase your chances of becoming drowsy or sleepy while taking ropinirole extended-release tablets.. ohave high or low blood pressure.. ohave or have had heart problems.. oare pregnant or plan to become pregnant. It is not known if ropinirole extended-release tablets can harm your unborn baby. oare breastfeeding or plan to breastfeed. It is not known if ropinirole passes into your breast milk. The amount of breast milk you make may be decreased while taking ropinirole exended-release tablets. Talk to your healthcare provider to decide if you should breastfeed while taking ropinirole extended-release tablets.. oTake ropinirole extended-release tablets exactly as directed by your healthcare provider. oTake ropinirole extended-release tablets with or without food.. oDo not suddenly stop taking ropinirole extended-release tablets without talking to your healthcare provider. If you stop this medicine suddenly, you may develop fever, confusion, or severe muscle stiffness.. oBefore starting ropinirole extended-release tablets, you should talk to your healthcare provider about what to do if you miss dose. If you have missed the previous dose and it is time for your next dose, do not double the dose.. oYour healthcare provider will start you on low dose of ropinirole extended-release tablets. 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 dose that controls your symptoms.. oContact your healthcare provider if you stop taking ropinirole extended-release tablets for any reason. Do not restart without talking with your healthcare provider.. oYour healthcare provider may prescribe ropinirole extended-release tablets alone, or add ropinirole extended-release tablets to medicine that you are already taking for Parkinsons disease. oYou should not substitute ropinirole immediate-release for ropinirole extended-release tablets or ropinirole extended-release tablets for ropinirole immediate-release without talking with your healthcare provider. . oTake ropinirole extended-release tablets time each day for Parkinsons disease, preferably at or around the same time of day.. oSwallow ropinirole extended-release tablets whole. Do not chew, crush, or split ropinirole extended-release tablets.. oRopinirole extended-release tablets release drug over 24-hour period. If you have condition where medicine passes through your body too quickly, such as diarrhea, the tablet(s) may not dissolve completely and you may see tablet residue in your stool. If this happens, let your healthcare provider know as soon as possible. ofainting. osleepiness or drowsiness ohallucinations (seeing or hearing things that are not real) odizziness onausea or vomiting ouncontrolled sudden movements oupset stomach, abdominal pain or discomfort. ofatigue, tiredness, or weakness oconfusion oheadache oleg swelling. oincreased sweating oconstipation. osuddenly falling asleep. ohigh blood pressure (hypertension). oStore ropinirole extended-release tablets at room temperature between 68F to 77F (20C to 25C). oKeep ropinirole extended-release tablets in tightly closed container and out of direct sunlight.

SPL UNCLASSIFIED SECTION.

2.1 General Dosing Recommendations oRopinirole extended-release tablets are taken once daily, with or without food [see Clinical Pharmacology (12.3) ].oTablets must be swallowed whole and must not be chewed, crushed, or divided.oIf significant interruption in therapy with ropinirole extended-release tablets has occurred, retitration of therapy may be warranted. oRopinirole extended-release tablets are taken once daily, with or without food [see Clinical Pharmacology (12.3) ].. oTablets must be swallowed whole and must not be chewed, crushed, or divided.. oIf significant interruption in therapy with ropinirole extended-release tablets has occurred, retitration of therapy may be warranted.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Pregnancy: Based on animal data, may cause fetal harm. (8.1). 8.1 Pregnancy. Risk SummaryThere are no adequate data on the developmental risk associated with the use of ropinirole extended-release tablets in pregnant women. In animal studies, ropinirole had adverse effects on development when administered to pregnant rats at doses similar to (neurobehavioral impairment) or greater than (teratogenicity and embryolethality at >36 times) the maximum recommended human dose (MRHD) for Parkinsons disease. Ropinirole doses associated with teratogenicity and embryolethality in pregnant rats were associated with maternal toxicity. In pregnant rabbits, ropinirole potentiated the teratogenic effects of L-dopa when these drugs were administered in combination [see Data]. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage in the indicated populations is unknown.Data Animal DataOral administration of ropinirole (0, 20, 60, 90, 120, or 150 mg/kg/day) to pregnant rats during organogenesis resulted in embryolethality, increased incidence of fetal malformations (digit, cardiovascular, and neural tube defects) and variations, and decreased fetal weight at the two highest doses. These doses were also associated with maternal toxicity. The highest no-effect dose for adverse effects on embryofetal development (90 mg/kg/day) is approximately 36 times the MRHD for Parkinsons disease (24 mg/day) on body surface area (mg/m2) basis. No effect on embryofetal development was observed in rabbits when ropinirole was administered alone during organogenesis at oral doses of 0, 1, 5, or 20 mg/kg/day (up to 16 times the MRHD on mg/m2 basis). In pregnant rabbits, there was greater incidence and severity of fetal malformations (primarily digit defects) when ropinirole (10 mg/kg/day) was administered orally during gestation in combination with L-dopa (250 mg/kg/day) than when L-dopa was administered alone. This drug combination was also associated with maternal toxicity. Oral administration of ropinirole (0, 0.1, 1, or 10 mg/kg/day) to rats during late gestation and continuing throughout lactation resulted in neurobehavioral impairment (decreased startle response) and decreased body weight in offspring at the highest dose. The no-effect dose of mg/kg/day is less than the MRHD on mg/m2 basis.. 8.2 Lactation. Risk SummaryThere are no data on the presence of ropinirole in human milk, the effects of ropinirole on the breastfed infant, or the effects of ropinirole on milk production. However, inhibition of lactation is expected because ropinirole inhibits secretion of prolactin in humans. Ropinirole or metabolites, or both, are present in rat milk.The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for ropinirole extended-release tablets and any potential adverse effects on the breastfed infant from ropinirole or from the underlying maternal condition.. 8.4 Pediatric Use. Safety and effectiveness in pediatric patients have not been established.. 8.5 Geriatric Use. Dose adjustment is not necessary in elderly (65 years and older) patients, as the dose of ropinirole extended-release tablets is individually titrated to clinical therapeutic response and tolerability. Pharmacokinetic trials conducted in patients demonstrated that oral clearance of ropinirole is reduced by 15% in patients older than 65 years compared with younger patients [see Clinical Pharmacology (12.3)]. In flexible-dose clinical trials of ropinirole extended-release tablets, 387 patients were 65 years and older and 107 were 75 and older. Among patients receiving ropinirole extended-release tablets, hallucination was more common in elderly patients (10%) compared with non-elderly patients (2%). In these trials, the incidence of overall adverse reactions increased with increasing age for both patients receiving ropinirole extended-release tablets and placebo. In the fixed-dose clinical trials of ropinirole extended-release tablets, 176 patients were 65 years and older and 73 were 75 and older. Among patients with advanced Parkinsons disease receiving ropinirole extended-release tablets, vomiting and nausea were more common in patients greater than 65 years (5% and 9%, respectively) compared with patients less than 65 (1% and 7%, respectively).. 8.6 Renal Impairment. No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). For patients with end-stage renal disease on hemodialysis, reduced maximum dose is recommended [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)]. The use of ropinirole extended-release tablets in patients with severe renal impairment (creatinine clearance less than 30 mL/min) without regular dialysis has not been studied.. 8.7 Hepatic Impairment. The pharmacokinetics of ropinirole have not been studied in patients with hepatic impairment.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oSudden onset of sleep and somnolence may occur (5.1)oSyncope may occur (5.2)oHypotension, including orthostatic hypotension may occur (5.3)oElevation of blood pressure and changes in heart rate may occur (5.4)oMay cause hallucinations and psychotic-like behaviors (5.5)oMay cause or exacerbate dyskinesia (5.6)oMay cause problems with impulse control or compulsive behaviors (5.7). oSudden onset of sleep and somnolence may occur (5.1). oSyncope may occur (5.2). oHypotension, including orthostatic hypotension may occur (5.3). oElevation of blood pressure and changes in heart rate may occur (5.4). oMay cause hallucinations and psychotic-like behaviors (5.5). oMay cause or exacerbate dyskinesia (5.6). oMay cause problems with impulse control or compulsive behaviors (5.7). 5.1 Falling Asleep During Activities of Daily Living and Somnolence Patients treated with ropinirole extended-release have reported falling asleep while engaged in activities of daily living, including driving or operating machinery, which sometimes resulted in accidents. Although many of these patients reported somnolence while on ropinirole, some perceived that they had no warning signs such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some have reported these events more than year after initiation of treatment. Among the 613 patients who received ropinirole extended-release in flexible-dose clinical trials (Study and Study 3), <1% of patients reported sudden onset of sleep and <1% of patients reported motor vehicle accident in which it is not known if falling asleep was contributing factor.In placebo-controlled fixed-dose trial in patients with advanced Parkinsons disease (Study 2), sudden onset of sleep was reported in 4% of 276 patients on ropinirole extended-release tablets compared with 3% of 74 patients on placebo. In placebo-controlled fixed-dose trial in patients with early Parkinsons disease (Study 4), sudden onset of sleep was reported in 5% of 146 patients on ropinirole extended-release tablets compared with 0% of 40 patients on placebo [see Adverse Reactions (6.1)]. The incidence of sudden onset of sleep was not dose-related in either trial.During placebo-controlled flexible-dose trial in patients with advanced Parkinsons disease (Study 1), somnolence was reported in 7% of 202 patients on ropinirole extended-release tablets compared with 4% of 191 patients on placebo. During flexible-dose, active-control, crossover trial in early Parkinsons disease (Study 3), somnolence was reported in 11% of 140 patients on ropinirole extended-release tablets compared with 15% of 149 patients on an immediate-release formulation of ropinirole [see Adverse Reactions 6.1)].In placebo-controlled fixed-dose trial in patients with advanced Parkinsons disease (Study 2), somnolence was reported in 8% of 276 patients on ropinirole extended-release tablets compared with 5% of 74 patients on placebo. In placebo-controlled fixed-dose trial in patients with early Parkinsons disease (Study 4), somnolence was reported in 10% of 146 patients on ropinirole extended-release tablets compared with 5% of 40 patients on placebo [see Adverse Reactions (6.1)]. The frequency of reported somnolence was not dose-related.It has been reported that falling asleep while engaged in activities of daily living usually occurs in setting of pre-existing somnolence, although patients may not give such history. For this reason, prescribers should reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Before initiating treatment with ropinirole extended-release tablets, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with ropinirole extended-release tablets such as concomitant sedating medications or alcohol, the presence of sleep disorders, and concomitant medications that increase ropinirole plasma levels (e.g., ciprofloxacin) [see Drug Interactions (7.1) ]. If patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving motor vehicle, conversations, eating), ropinirole extended-release tablets should ordinarily be discontinued [see Dosage and Administration (2.2)]. If decision is made to continue 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. 5.2 Syncope. Syncope, sometimes associated with bradycardia, was observed in association with treatment with ropinirole extended-release tablets in patients with Parkinsons disease. In placebo-controlled flexible-dose trial in patients with advanced Parkinsons disease (Study 1), syncope occurred in 1% of patients on ropinirole extended-release tablets compared with 0% of patients on placebo [see Adverse Reactions (6.1)]. In the placebo-controlled fixed-dose trials (Study and Study 4), one patient on ropinirole extended-release tablets with advanced Parkinsons disease) and one patient on ropinirole extended-release tablets with early Parkinsons disease experienced syncope during the titration period for ropinirole extended-release tablets. Both patients discontinued prematurely from the respective trials.Because the trials conducted with ropinirole extended-release tablets excluded patients with significant cardiovascular disease, patients with significant cardiovascular disease should be treated with caution.. 5.3 Hypotension/Orthostatic Hypotension. Patients with Parkinsons disease may have impaired ability to respond normally to fall in blood pressure after standing from lying down or seated position. Patients on ropinirole extended-release tablets should be monitored for signs and symptoms of orthostatic hypotension, especially during dose escalation, and should be informed of the risk for syncope and hypotension [see Patient Counseling Information 17)]. In placebo-controlled flexible-dose trial in patients with advanced Parkinsons disease (Study 1), hypotension was reported as an adverse reaction in 2% of patients on ropinirole extended-release tablets, compared with 0% of patients on placebo. In this study, orthostatic hypotension was reported as an adverse reaction in 5% of patients on ropinirole extended-release tablets and 1% of patients on placebo [see Adverse Reactions 6.1)]. Some patients experienced hypotension or orthostatic hypotension that started in the titration and persisted into the maintenance period. There was also higher incidence for the combined adverse reaction terms of hypotension, orthostatic hypotension, dizziness, vertigo, and blood pressure decreased in 7% of patients on ropinirole extended-release tablets compared with 3% of patients on placebo. The increased incidence of those events with ropinirole extended-release tablets was observed in 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 trial. The frequency of orthostatic hypotension (systolic blood pressure decrements >=20 mm Hg) at any time during the trial was 38% for ropinirole extended-release tablets vs. 31% for placebo.In placebo-controlled fixed-dose trial in patients with advanced Parkinsons disease (Study 2), decrease in standing systolic blood pressure of >=20 mm Hg was observed in 26% of patients on ropinirole extended-release tablets compared with 18% of patients on placebo.In placebo-controlled fixed-dose trial of patients with early Parkinsons disease (Study 4), decrease in standing systolic blood pressure of >=20 mm Hg was observed in 14% of patients on ropinirole extended-release tablets compared with 10% of patients on placebo.Significant decrements in blood pressure unrelated to standing were also reported in some patients taking ropinirole extended-release tablets. 5.4 Elevation of Blood Pressure and Changes in Heart Rate. The potential for elevation in blood pressure and changes in heart rate should be considered when treating patients with cardiovascular disease with ropinirole extended-release tablets.In placebo-controlled flexible-dose trial in patients with advanced Parkinsons disease (Study 1), the frequency of systolic blood pressure increase (>=40mm Hg) in the semi-supine position was 8% of patients on ropinirole extended-release tablets vs. 5% of patients on placebo. In the standing position, the frequency of systolic blood pressure increase (>=40 mm Hg) was 9% for ropinirole extended-release tablets vs. 6% for placebo. There was no clear effect of ropinirole extended-release tablets on average heart rate.In placebo-controlled fixed-dose trial in patients with advanced Parkinsons disease (Study 2), hypertension was reported as an adverse reaction in 3% of patients on ropinirole extended-release tablets, compared with 1% of patients on placebo [see Adverse Reactions (6.1)].In placebo-controlled, fixed-dose trial in patients with early Parkinsons disease (Study 4), hypertension was reported as an adverse reaction in 5% of patients on ropinirole extended-release tablets, compared with 0% of patients on placebo [see Adverse Reactions (6.1)].. 5.5 Hallucinations/Psychotic-like Behavior. In placebo-controlled flexible-dose trial in patients with advanced Parkinsons disease (Study 1), 8% of patients on ropinirole extended-release tablets reported hallucination, compared with 2% of patients on placebo [see Adverse Reactions 6.1)]. Hallucinations led to discontinuation of treatment in 2% of patients on ropinirole extended-release tablets and 1% of patients on placebo. The incidence of hallucination was increased in elderly patients (i.e., older than 65 years) treated with ropinirole extended-release tablets [see Use in Specific Populations 8.5)].In placebo-controlled fixed-dose trial in patients with advanced Parkinsons disease (Study 2), the incidence of hallucination was 3% in patients on ropinirole extended-release tablets compared with 0% in patients on placebo [see Adverse Reactions (6.1)]. The most common adverse reaction associated with study discontinuation for any dose of ropinirole extended-release tablets was hallucination (2%).Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with ropinirole or after starting or increasing the dose of ropinirole. Other drugs prescribed to improve the symptoms of Parkinsons disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.Patients with major psychotic disorder should ordinarily not be treated with ropinirole extended-release tablets because of the risk of exacerbating the psychosis. In addition, certain medications used to treat psychosis may exacerbate the symptoms of Parkinsons disease and may decrease the effectiveness of ropinirole extended-release tablets [see Drug Interactions (7.3)]. 5.6 Dyskinesia. Ropinirole extended-release tablets may cause or exacerbate pre-existing dyskinesia in patients treated with L-dopa for Parkinsons disease.In placebo-controlled flexible-dose trial in patients with advanced Parkinsons disease (Study 1), the incidence of dyskinesia was 13% in patients on ropinirole extended-release tablets and 3% in patients on placebo [see Adverse Reactions 6.1)].In placebo-controlled, fixed-dose trial in patients with advanced Parkinsons disease (Study 2), the incidence of dyskinesia was 7% in patients on ropinirole extended-release tablets compared with 1% in patients on placebo [see Adverse Reactions (6.1)].Decreasing the dose of dopaminergic medications may ameliorate this adverse reaction.. 5.7 Impulse Control/Compulsive Behaviors. Reports suggest that patients can experience intense urges to gamble, increased sexual urges, intense urges to spend money, binge or compulsive eating, and/or other intense urges, and the inability to control these urges while taking one or more of the medications, including ropinirole extended-release tablets, that increase central dopaminergic tone and that are generally used for the treatment of Parkinsons disease. In some cases, although not all, these urges were reported to have stopped when the dose was reduced or the medication was discontinued. Because patients may not recognize these behaviors as abnormal, it is important for prescribers to specifically ask patients or their caregivers about the development of new or increased gambling urges, sexual urges, uncontrolled spending, binge or compulsive eating, or other urges while being treated with ropinirole extended-release tablets. Physicians should consider dose reduction or stopping the medication if patient develops such urges while taking ropinirole extended-release tablets. 5.8 Withdrawal-Emergent Hyperpyrexia and Confusion. 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 of, withdrawal of, or changes in, dopaminergic therapy. Therefore, it is recommended that the dose be tapered at the end of treatment with ropinirole extended-release tablets as prophylactic measure [see Dosage and Administration 2.2)]. 5.9 Melanoma. Epidemiological studies have shown that patients with Parkinsons disease have higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinsons disease or other factors, such as drugs used to treat Parkinsons disease, is unclear. In the clinical development program (N 613), patient treated with ropinirole extended-release tablets and also levodopa/carbidopa developed melanoma. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on regular basis when using ropinirole extended-release tablets. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists).. 5.10 Fibrotic Complications. Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse reactions are believed to be related to the ergoline structure of these compounds, whether other, non-ergot-derived dopamine agonists, such as ropinirole, can cause them is unknown. Cases of possible fibrotic complications, including pleural effusion, pleural fibrosis, interstitial lung disease, and cardiac valvulopathy have been reported in the development program and postmarketing experience for ropinirole. In the clinical development program (N 613), patients treated with ropinirole extended-release tablets had pleural effusion. While the evidence is not sufficient to establish causal relationship between ropinirole and these fibrotic complications, contribution of ropinirole cannot be excluded. 5.11 Retinal Pathology. Retinal degeneration was observed in albino rats in the 2-year carcinogenicity study at all doses tested. The lowest dose tested (1.5 mg/kg/day) is less than the maximum recommended human dose (MRHD) of 24 mg/day on mg/m2 basis. Retinal degeneration was not observed in 3-month study in pigmented rats, in 2-year carcinogenicity study in albino mice, or in 1-year studies in monkeys or albino rats. The significance of this effect for humans has not been established, but involves disruption of mechanism that is universally present in vertebrates (e.g., disk shedding). Ocular electroretinogram (ERG) assessments were conducted during 2-year, double-blind, multicenter, flexible-dose, L-dopa-controlled clinical trial of immediate-release ropinirole in patients with Parkinsons disease; 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 trial.. 5.12 Binding to Melanin. Ropinirole binds to melanin-containing tissues (i.e., eyes, skin) in pigmented rats. After single dose, long-term retention of drug was demonstrated, with half-life in the eye of 20 days.