ROPINIROLE: 4,239 Adverse Event Reports & Safety Profile

Ropinirole tablets, USP contains ropinirole, a non-ergoline dopamine agonist, as the hydrochloride salt. The chemical name of ropinirole hydrochloride, USP is 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one and the empirical formula is C 16 H 24 N 2 O•HCl. The molecular weight is 296.84 (260.38 as the free base). The structural formula is: Ropinirole hydrochloride, USP is a pale cream to yellow powder with a melting range of 243°C to 250°C and a solubility of 133 mg/mL in water. Each modified oval shaped, biconvex film-coated tablet contains 0.29 mg, 0.57 mg, 1.14 mg, 2.28 mg, 3.42 mg, 4.56 mg, or 5.70 mg ropinirole hydrochloride, USP equivalent to ropinirole, 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, or 5 mg. Inactive ingredients consist of microcrystalline cellulose, lactose monohydrate, citric acid monohydrate, croscarmellose sodium, magnesium stearate. 0.25 mg tablet contains opadry white. The components of opadry white are hypromellose, titanium dioxide, polyethylene glycol 6000 and polysorbate 80. 0.5 mg tablet contains opadry yellow. The components of opadry yellow are hypromellose, titanium dioxide, polyethylene glycol 6000, iron oxide yellow and polysorbate 80. 1 mg tablet contains opadry green. The components of opadry green are hypromellose, titanium dioxide, triacetin, iron oxide yellow and FD&C Blue No. 2. 2 mg tablet contains opadry pink. The components of opadry pink are hypromellose, titanium dioxide, polyethylene glycol 6000, iron oxide red and polysorbate 80. 3 mg tablet contains opadry purple. The components of opadry purple are hypromellose, titanium dioxide, carmine, polyethylene glycol 400, polysorbate 80 and FD&C Blue No. 1. 4 mg tablet contains opadry brown. The components of opadry brown are hypromellose, titanium dioxide, iron oxide red, polyethylene glycol 400, FD&C Blue No. 2, polysorbate 80 and iron oxide black. Also contains FD&C yellow No. 6 as a color additive. 5 mg tablet contains opadry blue. The components of opadry blue are hypromellose, titanium dioxide, polyethylene glycol 400, FD&C Blue No. 2 and polysorbate 80. molecular structure

INDICATIONS & USAGE Parkinson’s Disease Ropinirole Tablets are indicated for the treatment of the signs and symptoms of idiopathic Parkinson’s disease. The effectiveness of Ropinirole Tablets were demonstrated in randomized, controlled trials in patients with early Parkinson’s disease who were not receiving concomitant L-dopa therapy as well as in patients with advanced disease on concomitant L-dopa (see CLINICAL PHARMACOLOGY: Clinical Trials).

Restless Legs Syndrome Ropinirole

Tablets are indicated for the treatment of moderate-to-severe primary Restless Legs Syndrome (RLS). Key diagnostic criteria for RLS are: an urge to move the legs usually accompanied or caused by uncomfortable and unpleasant leg sensations; symptoms begin or worsen during periods of rest or inactivity such as lying or sitting; symptoms are partially or totally relieved by movement such as walking or stretching at least as long as the activity continues; and symptoms are worse or occur only in the evening or night. Difficulty falling asleep may frequently be associated with moderate-to-severe RLS.

AND ADMINISTRATION

• Ropinirole extended-release tablets are taken once daily, with or without food; tablets must be swallowed whole and not be chewed, crushed, or divided. ( 2.1 )
• The recommended starting dose is 2 mg taken once daily for 1 to 2 weeks; the dose should be increased by 2 mg/day at 1 week or longer intervals. The maximum recommended dose of ropinirole extended-release tablets is 24 mg/day. ( 2.2 , 14.2 )
• Renal Impairment: In patients with end-stage renal disease on hemodialysis, the maximum recommended dose is 18 mg/day. ( 2.2 )
• If ropinirole extended-release tablets must be discontinued, it should be tapered gradually over a 7-day period; retitration of ropinirole extended-release tablets may be warranted if therapy is interrupted. ( 2.1 , 2.2 )
• Patients 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

• Ropinirole extended-release tablets are taken once daily, with or without food [see Clinical Pharmacology ( 12.3 )] .
• Tablets must be swallowed whole and must not be chewed, crushed, or divided.
• If a significant interruption in therapy with ropinirole extended-release tablets has occurred, retitration of therapy may be warranted.

2.2 Dosing for Parkinson’s Disease The recommended starting dose of ropinirole extended-release tablets is 2 mg taken once daily for 1 to 2 weeks, followed by increases of 2 mg/day at weekly or longer intervals, based on therapeutic response and tolerability. Monitor patients at least weekly during dose titration. Too rapid a rate of titration may lead to the selection of a dose that does not provide additional benefit, but increases the risk of adverse reactions. In fixed-dose studies designed to characterize the dose response to ropinirole extended-release tablets, there was no additional therapeutic benefit shown in patients with advanced stage Parkinson’s disease taking daily doses greater than 8 mg/day, or with early stage Parkinson’s disease taking doses greater than 12 mg/day <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 and 14.2 )]</span> . Although the maximum recommended dose of ropinirole extended-release tablets is 24 mg, patients with advanced Parkinson’s disease should generally be maintained at daily doses of 8 mg or lower and patients with early Parkinson’s disease should generally be maintained at daily doses 12 mg or lower. Ropinirole extended-release tablets should be discontinued gradually over a 7-day period <span class="opacity-50 text-xs">[see Warnings and Precautions (5.9)]</span> .

Renal

Impairment No dose adjustment is necessary in patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min). The recommended initial dose of ropinirole extended-release tablets for patients with end-stage renal disease on hemodialysis is 2 mg once daily. Further dose escalations should be based on tolerability and need for efficacy. The recommended maximum total daily dose is 18 mg/day in patients receiving regular dialysis. Supplemental doses after dialysis are not required. The use of 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 Tablets to Ropinirole Extended-Release Tablets Immediate-Release Ropinirole Tablets Total Daily Dose (mg)

Ropinirole

Extended-Release Tablets Total Daily Dose (mg) 0.75 to 2.25 2 3 to 4.5 4 6 6 7.5 to 9 8 12 12 15 16 18 18 21 20 24 24 Following 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 a 24-hour period. If rapid gastrointestinal transit occurs, there may be risk of incomplete release of medication and medication residue being passed in the stool.

Ropinirole extended-release tablets are contraindicated in patients known to have a 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 )

ADVERSE REACTIONS Parkinson’s Disease During the premarketing development of Ropinirole Tablets, patients received Ropinirole Tablets either without L-dopa (early Parkinson’s disease studies) or as concomitant therapy with L-dopa (advanced Parkinson’s disease studies). Because these 2 populations may have differential risks for various adverse events, this section will, in general, present adverse event data for these 2 populations separately.

Early

Parkinson’s Disease (Without L-dopa) The most commonly observed adverse events (>5%) in the double-blind, placebo-controlled early Parkinson’s disease trials associated with the use of Ropinirole Tablets (n = 157) not seen at an equivalent frequency among the placebo-treated patients (n = 147) were, in order of decreasing incidence: nausea, dizziness, somnolence, headache, vomiting, syncope, fatigue, dyspepsia, viral infection, constipation, pain, increased sweating, asthenia, dependent/leg edema, orthostatic symptoms, abdominal pain, pharyngitis, confusion, hallucinations, urinary tract infections, and abnormal vision.

Approximately

24% of 157 patients treated with Ropinirole Tablets who participated in the double-blind, placebo-controlled early Parkinson’s disease (without L-dopa) trials discontinued treatment due to adverse events compared to 13% of 147 patients who received placebo. The adverse events most commonly causing discontinuation of treatment by patients treated with Ropinirole Tablets were: nausea (6.4%), dizziness (3.8%), aggravated Parkinson’s disease (1.3%), hallucinations (1.3%), somnolence (1.3%), vomiting (1.3%), and headache (1.3%). Of these, hallucinations appear to be dose-related. While other adverse events leading to discontinuation may be dose-related, the titration design utilized in these trials precluded an adequate assessment of the dose response. For example, in the larger of the 2 trials described in CLINICAL PHARMACOLOGY: Clinical Trials, the difference in the rate of discontinuations emerged only after 10 weeks of treatment, suggesting, although not proving, that the effect could be related to dose.

Adverse Event

Incidence in Controlled Clinical Studies Table 2 lists treatment-emergent adverse events that occurred in ≥2% of patients with early Parkinson’s disease (without L-dopa) treated with Ropinirole Tablets participating in the double-blind, placebo-controlled studies and were numerically more common in the group treated with Ropinirole Tablets. In these studies, either Ropinirole Tablets or placebo was used as early therapy (i.e., without L-dopa). The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse-events incidence rate in the population studied.

Table

2. Treatment-Emergent Adverse Event * Incidence in Double-Blind, Placebo-Controlled Early Parkinson’s Disease (Without L-dopa) Trials (Events ≥2% of Patients Treated With Ropinirole Tablets and Numerically More Frequent Than the Placebo Group)

Adverse Experience Ropinirole

Tablets (n = 157) (%) Placebo (n = 147) (%) Autonomic nervous system Flushing 3 1 Dry mouth 5 3 Increased sweating 6 4 Body as a whole Asthenia 6 1 Chest pain 4 2 Dependent edema 6 3 Leg edema 7 1 Fatigue 11 4 Malaise 3 1 Pain 8 4 Cardiovascular general Hypertension 5 3 Hypotension 2 0 Orthostatic symptoms 6 5 Syncope 12 1 Central/peripheral nervous system Dizziness 40 22 Hyperkinesia 2 1 Hypesthesia 4 2 Vertigo 2 0 Gastrointestinal system Abdominal pain 6 3 Anorexia 4 1 Dyspepsia 10 5 Flatulence 3 1 Nausea 60 22 Vomiting 12 7 Heart rate/rhythm Extrasystoles 2 1 Atrial fibrillation 2 0 Palpitation 3 2 Tachycardia 2 0 Metabolic/nutritional Increased alkaline phosphatase 3 1 Psychiatric Amnesia 3 1 Impaired concentration 2 0 Confusion 5 1 Hallucination 5 1 Somnolence 40 6 Yawning 3 0 Reproductive male Impotence 3 1 Resistance mechanism Viral infection 11 3 Respiratory system Bronchitis 3 1 Dyspnea 3 0 Pharyngitis 6 4 Rhinitis 4 3 Sinusitis 4 3 Urinary system Urinary tract infection 5 4 Vascular extracardiac Peripheral ischemia 3 0 Vision Eye abnormality 3 1 Abnormal vision 6 3 Xerophthalmia 2 0 * Patients may have reported multiple adverse experiences during the study or at discontinuation; thus, patients may be included in more than one category. Other events reported by 1% or more of early Parkinson’s disease (without L-dopa) patients treated with Ropinirole Tablets, but that were equally or more frequent in the placebo group, were: headache, upper respiratory infection, insomnia, arthralgia, tremor, back pain, anxiety, dyskinesias, aggravated Parkinsonism, depression, falls, myalgia, leg cramps, paresthesias, nervousness, diarrhea, arthritis, hot flushes, weight loss, rash, cough, hyperglycemia, muscle spasm, arthrosis, abnormal dreams, dystonia, increased salivation, bradycardia, gout, basal cell carcinoma, gingivitis, hematuria, and rigors. Among the treatment-emergent adverse events in patients treated with Ropinirole Tablets, hallucinations appear to be dose-related. The incidence of adverse events was not materially different between women and men.

Advanced

Parkinson’s Disease (With L-dopa) The most commonly observed adverse events (>5%), in the double-blind, placebo-controlled advanced Parkinson’s disease (with L-dopa) trials associated with the use of Ropinirole Tablets (n = 208) as an adjunct to L-dopa not seen at an equivalent frequency among the placebo-treated patients (n = 120) were, in order of decreasing incidence: dyskinesias, nausea, dizziness, aggravated Parkinsonism, somnolence, headache, insomnia, injury, hallucinations, falls, abdominal pain, upper respiratory infection, confusion, increased sweating, vomiting, viral infection, increased drug level, arthralgia, tremor, anxiety, urinary tract infection, constipation, dry mouth, pain, hypokinesia, and paresthesia.

Approximately

24% of 208 patients who received Ropinirole Tablets in the double-blind, placebo-controlled advanced Parkinson’s disease (with L-dopa) trials discontinued treatment due to adverse events compared to 18% of 120 patients who received placebo. The events most commonly (≥1%) causing discontinuation of treatment by patients treated with Ropinirole Tablets were: dizziness (2.9%), dyskinesias (2.4%), vomiting (2.4%), confusion (2.4%), nausea (1.9%), hallucinations (1.9%), anxiety (1.9%), and increased sweating (1.4%). Of these, hallucinations and dyskinesias appear to be dose-related.

Adverse Event

Incidence in Controlled Clinical Studies Table 3 lists treatment-emergent adverse events that occurred in ≥2% of patients with advanced Parkinson’s disease (with L-dopa) treated with Ropinirole Tablets who participated in the double-blind, placebo-controlled studies and were numerically more common in the group treated with Ropinirole Tablets. In these studies, either Ropinirole Tablets or placebo was used as an adjunct to L-dopa. Adverse events were usually mild or moderate in intensity. The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse events incidence rate in the population studied.

Table

3. Treatment-Emergent Adverse Event* Incidence in Double-Blind, Placebo-Controlled Advanced Parkinson’s Disease (With L-dopa) Trials (Events ≥2% of Patients Treated With Ropinirole Tablets and Numerically More Frequent Than the Placebo Group)

Adverse Experience Ropinirole

Tablets (n = 208) (%) Placebo (n = 120) (%) Autonomic nervous system Dry mouth 5 1 Increased sweating 7 2 Body as a whole Increased drug level 7 3 Pain 5 3 Cardiovascular general Hypotension 2 1 Syncope 3 2 Central/peripheral nervous system Dizziness 26 16 Dyskinesia 34 13 Falls 10 7 Headache 17 12 Hypokinesia 5 4 Paresis 3 0 Paresthesia 5 3 Tremor 6 3 Gastrointestinal system Abdominal pain 9 8 Constipation 6 3 Diarrhea 5 3 Dysphagia 2 1 Flatulence 2 1 Nausea 30 18 Increased saliva 2 1 Vomiting 7 4 Metabolic/nutritional Weight decrease 2 1 Musculoskeletal system Arthralgia 7 5 Arthritis 3 1 Psychiatric Amnesia 5 1 Anxiety 6 3 Confusion 9 2 Abnormal dreaming 3 2 Hallucinations 10 4 Nervousness 5 3 Somnolence 20 8 Red blood cell Anemia 2 0 Resistance mechanism Upper respiratory tract infection 9 8 Respiratory system Dyspnea 3 2 Urinary system Pyuria 2 1 Urinary incontinence 2 1 Urinary tract infection 6 3 Vision Diplopia 2 1 * Patients may have reported multiple adverse experiences during the study or at discontinuation; thus, patients may be included in more than one category. Other events reported by 1% or more of patients treated with both Ropinirole Tablets and L-dopa, but equally or more frequent in the placebo/L-dopa group, were: myocardial infarction, orthostatic symptoms, virus infections, asthenia, dyspepsia, myalgia, back pain, depression, leg cramps, fatigue, rhinitis, chest pain, hematuria, vertigo, tinnitus, leg edema, hot flushes, abnormal gait, hyperkinesia, and pharyngitis. Among the treatment-emergent adverse events in patients treated with Ropinirole Tablets, hallucinations and dyskinesias appear to be dose-related.

Restless Legs Syndrome

The most commonly observed adverse events (>5%) in the 12-week double-blind, placebo-controlled trials in the treatment of Restless Legs Syndrome with Ropinirole Tablets (n = 496) and at least twice the rate for placebo-treated patients (n = 500) were, in order of decreasing incidence: nausea, somnolence, vomiting, dizziness, and fatigue (see Table 4). Occurrences of nausea in clinical trials were generally mild to moderate in intensity (see also DOSAGE AND ADMINISTRATION: General Dosing Considerations).

Approximately

5% of 496 patients treated with Ropinirole Tablets who participated in the double-blind, placebo-controlled trials in the treatment of RLS discontinued treatment due to adverse events compared to 4% of 500 patients who received placebo. The adverse events most commonly causing discontinuation of treatment by patients treated with Ropinirole Tablets were: nausea (1.6%), dizziness (0.8 %), and headache (0.8%).

Adverse Event

Incidence in Controlled Clinical Studies Table 4 lists treatment-emergent adverse events that occurred in ≥2% of patients with RLS treated with Ropinirole Tablets participating in the 12-week double-blind, placebo-controlled studies and were numerically more common in the group treated with Ropinirole Tablets. The prescriber should be aware that these figures cannot be used to predict the incidence of adverse events in the course of usual medical practice where patient characteristics and other factors differ from those that prevailed in the clinical studies. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses, and investigators. However, the cited figures do provide the prescribing physician with some basis for estimating the relative contribution of drug and non-drug factors to the adverse-events incidence rate in the population studied.

Table

4. Treatment-Emergent Adverse Event Incidence in Double-Blind, Placebo-Controlled RLS Trials (Events ≥2% of Patients Treated With Ropinirole Tablets and Numerically More Frequent Than the Placebo Group)

Adverse Experience Ropinirole

Tablets (n = 496) (%) Placebo (n =500) (%) Ear and labyrinth disorders Vertigo 2 1 Gastrointestinal disorders Nausea 40 8 Vomiting 11 2 Diarrhea 5 3 Dyspepsia 4 3 Dry mouth 3 2 Abdominal pain upper 3 1 General disorders and administration site conditions Fatigue 8 4 Edema peripheral 2 1 Infections and infestations Nasopharyngitis 9 8 Influenza 3 2 Musculoskeletal and connective tissue disorders Arthralgia 4 3 Muscle cramps 3 2 Pain in extremity 3 2 Nervous system disorders Somnolence 12 6 Dizziness 11 5 Paresthesia 3 1 Respiratory, thoracic, and mediastinal disorders Cough 3 2 Nasal congestion 2 1 Skin and subcutaneous tissue disorders Hyperhidrosis 3 1 Other events reported by 2% or more of patients treated with Ropinirole Tablets, but equally or more frequent in the placebo group, were headache, insomnia, restless legs syndrome, upper respiratory tract infection, back pain, and sinusitis.

Other Adverse Events Observed During

All Phase 2/3 Clinical Trials for Parkinson’s Disease Ropinirole Tablets have been administered to 1,599 individuals in clinical trials. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using modified WHOART dictionary terminology. These categories are used in the listing below. The frequencies presented represent the proportion of the 1,599 individuals exposed to Ropinirole Tablets who experienced events of the type cited on at least 1 occasion while receiving Ropinirole Tablets. All reported events that occurred at least twice (or once for serious or potentially serious events), except those already listed above, trivial events, and terms too vague to be meaningful, are included without regard to determination of a causal relationship to Ropinirole Tablets, except that events very unlikely to be drug-related have been deleted. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients and infrequent adverse events are those occurring in 1/100 to 1/1,000 patients and rare events are those occurring in fewer than 1/1,000 patients. Body as a Whole Infrequent: Cellulitis, peripheral edema, fever, influenza-like symptoms, enlarged abdomen, precordial chest pain, and generalized edema. Rare : Ascites.

Cardiovascular

Infrequent: Cardiac failure, bradycardia, tachycardia, supraventricular tachycardia, angina pectoris, bundle branch block, cardiac arrest, cardiomegaly, aneurysm, mitral insufficiency. Rare: Ventricular tachycardia.

Central/Peripheral

Nervous System Frequent: Neuralgia. Infrequent: Involuntary muscle contractions, hypertonia, dysphonia, abnormal coordination, extrapyramidal disorder, migraine, choreoathetosis, coma, stupor, aphasia, convulsions, hypotonia, peripheral neuropathy, paralysis. Rare: Grand mal convulsions, hemiparesis, hemiplegia.

Endocrine

Infrequent: Hypothyroidism, gynecomastia, hyperthyroidism. Rare: Goiter, SIADH.

Gastrointestinal

Infrequent: Increased hepatic enzymes, bilirubinemia, cholecystitis, cholelithiasis colitis, dysphagia, periodontitis, fecal incontinence, gastroesophageal reflux, hemorrhoids, toothache, eructation, gastritis, esophagitis, hiccups, diverticulitis, duodenal ulcer, gastric ulcer, melena, duodenitis, gastrointestinal hemorrhage, glossitis, rectal hemorrhage, pancreatitis, stomatitis and ulcerative stomatitis, tongue edema. Rare: Biliary pain, hemorrhagic gastritis, hematemesis, salivary duct obstruction.

Hematologic

Infrequent: Purpura, thrombocytopenia, hematoma, Vitamin B12 deficiency, hypochromic anemia, eosinophilia, leukocytosis, leukopenia, lymphocytosis, lymphopenia, lymphedema.

Metabolic/Nutritional

Frequent: Increased BUN. Infrequent: Hypoglycemia, increased alkaline phosphatase, increased LDH, weight increase, hyperphosphatemia, hyperuricemia, diabetes mellitus, glycosuria, hypokalemia, hypercholesterolemia, hyperkalemia, acidosis, hyponatremia, thirst, increased CPK, dehydration. Rare: Hypochloremia.

Musculoskeletal

Infrequent: Aggravated arthritis, tendonitis, osteoporosis, bursitis, polymyalgia rheumatica, muscle weakness, skeletal pain, torticollis. Rare: Dupuytren’s contracture requiring surgery.

Neoplasm

Infrequent: Malignant breast neoplasm. Rare: Bladder carcinoma, benign brain neoplasm, esophageal carcinoma, malignant laryngeal neoplasm, lipoma, rectal carcinoma, uterine neoplasm.

Psychiatric

Infrequent: Increased libido, agitation, apathy, impaired concentration, depersonalization, paranoid reaction, personality disorder, euphoria, delirium, dementia, delusion, emotional lability, decreased libido, manic reaction, somnambulism, aggressive reaction, neurosis. Rare: Suicide attempt.

Genitourinary

Infrequent: Amenorrhea, vaginal hemorrhage, penile disorder, prostatic disorder, balanoposthitis, epididymitis, perineal pain, dysuria, micturition frequency, albuminuria, nocturia, polyuria, renal calculus. Rare: Breast enlargement, mastitis, uterine hemorrhage, ejaculation disorder, Peyronie’s disease, pyelonephritis, acute renal failure, uremia.

Resistance Mechanism

Infrequent: Herpes zoster, otitis media, sepsis, abscess, herpes simplex, fungal infection, genital moniliasis.

Respiratory

Infrequent: Asthma, epistaxis, laryngitis, pleurisy, pulmonary edema.

Skin/Appendage

Infrequent: Pruritus, dermatitis, eczema, skin ulceration, alopecia, skin hypertrophy, skin discoloration, urticaria, fungal dermatitis, furunculosis, hyperkeratosis, photosensitivity reaction, psoriasis, maculopapular rash, psoriaform rash, seborrhea.

Special Senses

Infrequent: Tinnitus, earache, decreased hearing, abnormal lacrimation, conjunctivitis, blepharitis, glaucoma, abnormal accommodation, blepharospasm, eye pain, photophobia. Rare: Scotoma.

Vascular Extracardiac

Infrequent: Varicose veins, phlebitis, peripheral gangrene. Rare: Limb embolism, pulmonary embolism, gangrene, subarachnoid hemorrhage, deep thrombophlebitis, leg thrombophlebitis, thrombosis.

Falling Asleep During

Activities of Daily Living Patients treated with Ropinirole Tablets have reported falling asleep while engaged in activities of daily living, including operation of a motor vehicle which sometimes resulted in accidents (see bolded WARNING).

Other Adverse Events Observed During

Phase 2/3 Clinical Trials for RLS Ropinirole Tablets has been administered to 911 individuals in clinical trials. During these trials, all adverse events were recorded by the clinical investigators using terminology of their own choosing. To provide a meaningful estimate of the proportion of individuals having adverse events, similar types of events were grouped into a smaller number of standardized categories using MedDRA dictionary terminology. These categories are used in the listing below. The frequencies presented represent the proportion of the 911 individuals exposed to Ropinirole Tablets who experienced events of the type cited on at least one occasion while receiving Ropinirole Tablets. All reported events that occurred at least twice (or once for serious or potentially serious events), except those already listed, trivial events, and terms too vague to be meaningful, are included without regard to determination of a causal relationship to Ropinirole Tablets, except that events very unlikely to be drug-related have been deleted. Events are further classified within body system categories and enumerated in order of decreasing frequency using the following definitions: frequent adverse events are defined as those occurring in at least 1/100 patients and infrequent adverse events are those occurring in 1/100 to 1/1,000 patients. Blood and Lymphatic System Disorders Infrequent: Anemia, lymphadenopathy.

Cardiac Disorders

Frequent: Palpitations. Infrequent: Acute coronary syndrome, angina pectoris, angina unstable, bradycardia, cardiac failure, cardiovascular disorder, coronary artery disease, myocardial infarction, sick sinus syndrome, tachycardia. Congenital, Familial, and Genetic Disorders Infrequent: Pigmented nevus. Ear and Labyrinth Disorders Infrequent: Ear pain, middle ear effusion, tinnitus.

Endocrine Disorders

Infrequent: Goiter, hypothyroidism.

Eye Disorders

Infrequent: Blepharitis, conjunctival hemorrhage, conjunctivitis, eye irritation, eye pain, keratoconjunctivitis sicca, vision blurred, visual acuity reduced, visual disturbance.

Gastrointestinal Disorders

Frequent: Abdominal pain, constipation, gastroesophageal reflux disease, stomach discomfort, toothache. Infrequent: Abdominal adhesions, abdominal discomfort, abdominal distension, abdominal pain lower, duodenal ulcer, dysphagia, eructation, flatulence, gastric disorder, gastric hemorrhage, gastric polyps, gastric ulcer, gastritis, gastrointestinal pain, hematemesis, hemorrhoids, hiatus hernia, intestinal obstruction, irritable bowel syndrome, loose stools, mouth ulceration, pancreatitis acute, peptic ulcer, rectal hemorrhage, reflux esophagitis.

General

Disorders and Administration Site Conditions Frequent: Asthenia, chest pain, influenza-like illness, rigors. Infrequent: Chest discomfort, feeling cold, feeling hot, hunger, lethargy, malaise, edema, pain, pyrexia.

Hepatobiliary Disorders

Infrequent: Cholecystitis, cholelithiasis, ischemic hepatitis.

Immune System Disorders

Infrequent: Hypersensitivity. Infections and Infestations Frequent: Bronchitis, gastroenteritis, gastroenteritis viral, lower respiratory tract infection, rhinitis, tooth abscess, urinary tract infection. Infrequent: Appendicitis, bacterial infection, bladder infection, bronchitis acute, candidiasis, cellulitis, cystitis, diarrhea infectious, diverticulitis, ear infection, folliculitis, fungal infection, gastrointestinal infection, herpes simplex, infected cyst, laryngitis, localized infection, mastitis, otitis externa, otitis media, pharyngitis, pneumonia, postoperative infection, respiratory tract infection, tonsillitis, tooth infection, vaginal candidiasis, vaginal infection, vaginal mycosis, viral infection, viral upper respiratory tract infection, wound infection. Injury, Poisoning, and Procedural Complications Infrequent: Concussion, lower limb fracture, post procedural hemorrhage, road traffic accident.

Investigations

Infrequent: Blood cholesterol increased, blood iron decreased, blood pressure increased, blood urine present, hemoglobin decreased, heart rate increased, protein urine present, weight decreased, weight increased. Metabolism and Nutrition Disorders Infrequent: Anorexia, decreased appetite, diabetes mellitus non-insulin-dependent, fluid retention, gout, hypercholesterolemia. Musculoskeletal and Connective Tissue Disorders Frequent: Muscle spasms, musculoskeletal stiffness, myalgia, neck pain, osteoarthritis, tendonitis. Infrequent: Arthritis, aseptic necrosis bone, bone pain, bone spur, bursitis, groin pain, intervertebral disc degeneration, intervertebral disc protrusion, joint stiffness, joint swelling, localized osteoarthritis, monoarthritis, muscle contracture, muscle tightness, muscle twitching, osteoporosis, rotator cuff syndrome, sacroiliitis, synovitis.

Neoplasms

Benign, Malignant, and Unspecified Infrequent: Anaplastic thyroid cancer, angiomyolipoma, basal cell carcinoma, breast cancer, gastric cancer, gastrointestinal stromal tumor, malignant melanoma, prostate cancer, skin papilloma, squamous cell carcinoma, uterine leiomyoma.

Nervous System Disorders

Frequent: Hypoesthesia, migraine. Infrequent : Amnesia, aphasia, ataxia, balance disorder, benign intracranial hypertension, burning sensation, carpal tunnel syndrome, disturbance in attention, dizziness postural, dysgeusia, dyskinesia, head discomfort, hyperesthesia, hypersomnia, lethargy, loss of consciousness, memory impairment, migraine with aura, migraine without aura, neuralgia, sciatica, sedation, sinus headache, sleep apnea syndrome, syncope vasovagal, tension headache, transient ischemic attack, tremor.

Psychiatric Disorders

Frequent: Anxiety, depression, irritability, sleep disorder. Infrequent: Abnormal dreams, agitation, bruxism, confusional state, depressed mood, disorientation, early morning awakening, libido decreased, loss of libido, mood swings, nervousness, nightmare, panic attack, stress symptoms, tension. Renal and Urinary Disorders Infrequent: Dysuria, hematuria, hypertonic bladder, micturition disorder, nephrolithiasis, nocturia, pollakiuria, proteinuria, urinary retention.

Reproductive

System and Breast Disorders Frequent: Erectile dysfunction. Infrequent: Breast cyst, dysmenorrhea, menorrhagia, pelvic peritoneal adhesions, postmenopausal hemorrhage, premenstrual syndrome, prostatitis. Respiratory, Thoracic and Mediastinal Disorders Frequent: Asthma, pharyngolaryngeal pain. Infrequent: Dry throat, dyspnea, epistaxis, hemoptysis, hoarseness, interstitial lung disease, nasal mucosal disorder, nasal polyps, respiratory tract congestion, rhinorrhea, sinus congestion, sneezing, wheezing, yawning. Skin and Subcutaneous Tissue Disorders Frequent: Night sweats, rash. Infrequent: Acne, actinic keratosis, alopecia, cold sweat, dermatitis, dermatitis allergic, dermatitis contact, eczema, exanthem, face edema, photosensitivity reaction, pruritus, psoriasis, rash pruritic, skin lesion, urticaria.

Vascular Disorders

Frequent: Hot flush, hypertension, hypotension. Infrequent: Atherosclerosis, circulatory collapse, flushing, hematoma, thrombosis, varicose vein.

Postmarketing Reports Psychiatric

Disorders: Impulse control symptoms, pathological gambling, increased libido including hypersexuality.

AND PRECAUTIONS Sudden onset of sleep and somnolence may occur (5.1) Syncope may occur (5.2) Hypotension, including orthostatic hypotension may occur (5.3) Elevation of blood pressure and changes in heart rate may occur (5.4) May cause hallucinations and psychotic-like behaviors (5.5) May cause or exacerbate dyskinesia (5.6) May 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 tablets have reported falling asleep while engaged in activities of daily living, including driving or operating machinery, which sometimes resulted in accidents. Although many of these patients reported somnolence while on ropinirole, some perceived that they had no warning signs such as excessive drowsiness, and believed that they were alert immediately prior to the event. Some have reported these events more than 1 year after initiation of treatment. Among the 613 patients who received ropinirole extended-release tablets in flexible-dose clinical trials (Study 1 and Study 3), &lt;1% of patients reported sudden onset of sleep and &lt; 1% of patients reported a motor vehicle accident in which it is not known if falling asleep was a contributing factor. In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s 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 a placebo-controlled fixed-dose trial in patients with early Parkinson’s 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . The incidence of sudden onset of sleep was not dose-related in either trial. During a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s 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 a flexible-dose, active-control, crossover trial in early Parkinson’s 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 REQUIP <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s 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 a placebo-controlled fixed-dose trial in patients with early Parkinson’s disease (Study 4), somnolence was reported in 10% of 146 patients on ropinirole extended-release tablets compared with 5% of 40 patients on placebo <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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 a setting of pre-existing somnolence, although patients may not give such a history. For this reason, prescribers should reassess patients for drowsiness or sleepiness, especially since some of the events occur well after the start of treatment. Prescribers should also be aware that patients may not acknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepiness during specific activities. Before initiating treatment with ropinirole 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) <span class="opacity-50 text-xs">[see Drug Interactions (7.1 )]</span> . If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving a motor vehicle, conversations, eating), ropinirole extended-release tablets should ordinarily be discontinued <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> . If a 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 Parkinson’s disease. In a placebo-controlled flexible-dose trial in patients with advanced Parkinson&apos;s disease (Study 1), syncope occurred in 1% of patients on ropinirole extended-release tablets compared with 0% of patients on placebo <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . In the placebo-controlled fixed-dose trials (Study 2 and Study 4), one patient on ropinirole extended-release tablets with advanced Parkinson&apos;s disease) and one patient on ropinirole extended-release tablets with early Parkinson&apos;s 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 Parkinson&apos;s disease may have impaired ability to respond normally to a 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 <span class="opacity-50 text-xs">[see Patient Counseling Information ( 17 )]</span> . In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . Some patients experienced hypotension or orthostatic hypotension that started in the titration and persisted into the maintenance period. There was also a higher incidence for the combined adverse reaction terms of “hypotension”, “orthostatic hypotension”, “dizziness”, “vertigo”, and &quot;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 a setting in which patients were very carefully titrated, and patients with clinically relevant cardiovascular disease or symptomatic orthostatic hypotension at baseline had been excluded from this 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 a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), a 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 a placebo-controlled fixed-dose trial of patients with early Parkinson&apos;s disease (Study 4), a 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 a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s 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 a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . In a placebo-controlled, fixed-dose trial in patients with early Parkinson’s 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> .

5.5 Hallucinations/Psychotic-Like Behavior In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), 8% of patients on ropinirole extended-release tablets reported hallucination, compared with 2% of patients on placebo <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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 <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.5 )]</span> . In a placebo-controlled fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), the incidence of hallucination was 3% in patients on ropinirole extended-release tablets compared with 0% in patients on placebo <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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 with Parkinson’s disease may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with ropinirole extended-release tablets or after starting or increasing the dose of ropinirole extended-release tablets. Other drugs prescribed to improve the symptoms of Parkinson’s disease can have similar effects on thinking and behavior. This abnormal thinking and behavior can consist of one or more of a variety of manifestations including paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, symptoms of mania (e.g., insomnia, psychomotor agitation), disorientation, aggressive behavior, agitation, and delirium. Patients with a 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 Parkinson’s disease and may decrease the effectiveness of ropinirole extended-release tablets <span class="opacity-50 text-xs">[see Drug Interactions ( 7.3 )]</span> .

5.6 Dyskinesia Ropinirole extended-release tablets may cause or exacerbate pre-existing dyskinesia in patients treated with L-dopa for Parkinson’s disease. In a placebo-controlled flexible-dose trial in patients with advanced Parkinson’s disease (Study 1), the incidence of dyskinesia was 13% in patients on ropinirole extended-release tablets and 3% in patients on placebo <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . In a placebo-controlled, fixed-dose trial in patients with advanced Parkinson’s disease (Study 2), the incidence of dyskinesia was 7% in patients on ropinirole extended-release tablets compared with 1% in patients on placebo <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> . 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. 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 for Parkinson&apos;s disease. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking ropinirole extended-release tablets.

5.8 Withdrawal-Emergent Hyperpyrexia and Confusion A symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction 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 a prophylactic measure <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span> .

5.9 Withdrawal Symptoms Symptoms including insomnia, apathy, anxiety, depression, fatigue, sweating, and pain have been reported during taper or after discontinuation of dopamine agonists, including ropinirole extended-release tablets. These symptoms generally do not respond to levodopa. Prior to discontinuation of ropinirole extended-release tablets, patients should be informed about the potential withdrawal symptoms and monitored during and after discontinuation. In case of severe withdrawal symptoms, a trial re-administration of a dopamine agonist at the lowest effective dose may be considered.

5.10 Fibrotic Complications Cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy have been reported in some patients treated with ergot-derived dopaminergic agents. While these complications may resolve when the drug is discontinued, complete resolution does not always occur. Although these adverse reactions are believed to be related to the ergoline structure of these compounds, whether other, non-ergot-derived dopamine agonists such as ropinirole, can cause them is unknown. Cases of possible fibrotic complications, including pleural effusion, pleural fibrosis, interstitial lung disease, and cardiac valvulopathy have been reported in the development program and postmarketing experience for ropinirole. In the clinical development program (N=613), 2 patients treated with ropinirole extended-release tablets had pleural effusion. While the evidence is not sufficient to establish a causal relationship between ropinirole and these fibrotic complications, a contribution of ropinirole cannot be excluded.

5.11 Retinal Pathology Retinal degeneration was observed in albino rats in the 2-year carcinogenicity study at all dose stested. The lowest dose tested (1.5 mg/kg/day) is less than the maximum recommended human dose (MRHD) of 24 mg/day on a mg/m 2 basis. Retinal degeneration was not observed in a 3-month study in pigmented rats, in a 2-year carcinogenicity study in albino mice, or in 1-yearstudies in monkeys or albino rats. The significance of this effect for humans has not been established, but involves disruption of a mechanism that is universally present in vertebrates(e.g., disk shedding). Ocular electroretinogram assessments were conducted during a 2-year, double-blind, multicenter, flexible-dose, L-dopa-controlled clinical trial of immediate-release ropinirole in patients with Parkinson’s 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 (e.g., eyes, skin) in pigmented rats. After a single dose, long-term retention of drug was demonstrated, with a half-life in the eye of 20 days.

PRECAUTIONS GENERAL Dyskinesia Ropinirole Tablets may potentiate the dopaminergic side effects of L-dopa and may cause and/or exacerbate preexisting dyskinesia in patients treated with L-dopa for Parkinson's disease. Decreasing the dose of L-dopa may ameliorate this side effect.

Renal

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

Hepatic Impairment

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

Events Reported With Dopaminergic Therapy

Withdrawal-Emergent Hyperpyrexia and Confusion Although not reported with Ropinirole Tablets, a symptom complex resembling the neuroleptic malignant syndrome (characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability), with no other obvious etiology, has been reported in association with rapid dose reduction, withdrawal of, or changes in anti-Parkinsonian therapy.

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 events are believed to be related to the ergoline structure of these compounds, whether other, nonergot-derived dopamine agonists can cause them is unknown. A small number of reports have been received of possible fibrotic complications, including pleural effusion, pleural fibrosis, interstitial lung disease, and cardiac valvulopathy, in the development program and postmarketing experience for Ropinirole Tablets. While the evidence is not sufficient to establish a causal relationship between Ropinirole Tablets and these fibrotic complications, a contribution of Ropinirole Tablets cannot be completely ruled out in rare cases.

Melanoma

Epidemiologic studies have shown that patients with Parkinson’s disease have a higher risk (2- to approximately 6-fold higher) of developing melanoma than the general population. Whether the increased risk observed was due to Parkinson’s disease or other factors, such as drugs used to treat Parkinson’s disease, is unclear. For the reasons stated above, patients and providers are advised to monitor for melanomas frequently and on a regular basis when using Ropinirole Tablets for any indication. Ideally, periodic skin examinations should be performed by appropriately qualified individuals (e.g., dermatologists). Augmentation and Rebound in RLS Reports in the literature indicate treatment of RLS with dopaminergic medications can result in a worsening of symptoms in the early morning hours, referred to as rebound. Augmentation has also been described during therapy for RLS. Augmentation refers to the earlier onset of symptoms in the evening (or even the afternoon), increase in symptoms, and spread of symptoms to involve other extremities. The controlled trials of Ropinirole Tablets in patients with RLS excluded patients with augmentation and rebound and were generally not of sufficient duration to capture these phenomena. The frequency of augmentation and/or rebound after longer use of Ropinirole Tablets and the appropriate management of these events, have not been evaluated in controlled clinical trials.

Retinal Pathology Albino Rats

Retinal degeneration was observed in albino rats in the 2-year carcinogenicity study at all doses tested (equivalent to 0.6 to 20 times the maximum recommended human dose on a mg/m2 basis), but was statistically significant at the highest dose (50 mg/kg/day). Additional studies to further evaluate the specific pathology (e.g., loss of photoreceptor cells) have not been performed. Similar changes were not observed in a 2-year carcinogenicity study in albino mice or in rats or monkeys treated for 1 year. The potential significance of this effect in humans has not been established, but cannot be disregarded because disruption of a mechanism that is universally present in vertebrates (e.g., disk shedding) may be involved. Human In order to evaluate the effect of Ropinirole Tablets in humans, ocular electroretinogram (ERG) assessments were conducted during a 2-year, double-blind, multicenter, flexible dose, L-dopa controlled clinical study of Ropinirole Tablets in patients with Parkinson's disease. A total of 156 patients (78 on ropinirole, mean dose 11.9 mg/day and 78 on L-dopa, mean dose 555.2 mg/day) were evaluated for evidence of retinal dysfunction through electroretinograms. There was no clinically meaningful difference between the treatment groups in retinal function over the duration of the study. Binding to Melanin Ropinirole Hydrochloride binds to melanin-containing tissues (i.e., eyes, skin) in pigmented rats. After a single dose, long-term retention of drug was demonstrated, with a half-life in the eye of 20 days. It is not known if Ropinirole Hydrochloride accumulates in these tissues over time.

Information For Patients

Physicians should instruct their patients to read the Patient Information leaflet before starting therapy with Ropinirole Tablets and to reread it upon prescription renewal for new information regarding the use of Ropinirole Tablets. Patients should be instructed to take Ropinirole Tablets only as prescribed. If a dose is missed, patients should be advised not to double their next dose.

Ropinirole

Tablets can be taken with or without food. Patients may be advised that taking Ropinirole Tablets with food may reduce the occurrence of nausea. However, this has not been established in controlled clinical trials. Patients should be advised that they may develop postural (orthostatic) hypotension with or without symptoms such as dizziness, nausea, syncope, and sometimes sweating. Hypotension and/or orthostatic symptoms may occur more frequently during initial therapy or with an increase in dose at any time (cases have been seen after weeks of treatment). Accordingly, patients should be cautioned against rising 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 Tablets. Patients should be alerted to the potential sedating effects associated with Ropinirole Tablets, including somnolence and the possibility of falling asleep while engaged in activities of daily living. Since somnolence is a frequent adverse event with potentially serious consequences, patients should neither drive a car nor engage in other potentially dangerous activities until they have gained sufficient experience with Ropinirole Tablets to gauge whether or not it affects their mental and/or motor performance adversely. Patients should be advised that if increased somnolence or episodes of falling asleep during activities of daily living (e.g., watching television, passenger in a car, etc.) are experienced at any time during treatment, they should not drive or participate in potentially dangerous activities until they have contacted their physician. Because of possible additive effects, caution should be advised when patients are taking other sedating medications or alcohol in combination with Ropinirole Tablets and when taking concomitant medications that increase plasma levels of ropinirole (e.g., ciprofloxacin). Because of the possible additive sedative effects, caution should also be used when patients are taking alcohol or other CNS depressants (e.g., benzodiazepines, antipsychotics, antidepressants, etc.) in combination with Ropinirole Tablets. Patients should be informed they may experience hallucinations (unreal visions, sounds, or sensations) while taking Ropinirole Tablets. These were uncommon in patients taking Ropinirole Tablets for Restless Legs Syndrome. The risk is greater in patients with Parkinson's disease; the elderly are at greater risk than younger patients with Parkinson's disease; and the risk is greater in patients who are taking Ropinirole Tablets with L-dopa, or taking higher doses of Ropinirole Tablets.

Impulse Control Symptoms Including Compulsive

Behaviors: There have been reports of patients experiencing intense urges to gamble, increased sexual urges, and other intense urges and the inability to control these urges while taking one or more of the medications that increase central dopaminergic tone, that are generally used for the treatment of Parkinson’s disease, including Ropinirole Tablets. Although it is not proven that the medications caused these events, these urges were reported to have stopped in some cases when the dose was reduced or the medication was stopped. Prescribers should ask patients about the development of new or increased gambling urges, sexual urges or other urges while being treated with Ropinirole Tablets. Patients should inform their physician if they experience new or increased gambling urges, increased sexual urges or other intense urges while taking Ropinirole Tablets. Physicians should consider dose reduction or stopping the medication if a patient develops such urges while taking Ropinirole Tablets. Because of the possibility that ropinirole may be excreted in breast milk, patients should be advised to notify their physicians if they intend to breastfeed or are breastfeeding an infant. Because ropinirole has been shown to have adverse effects on embryo-fetal development, including teratogenic effects, in animals, and because experience in humans is limited, patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy (see PRECAUTIONS: Pregnancy). DRUG INTERACTIONS P 450 Interaction In vitro metabolism studies showed that CYP1A2 was the major enzyme responsible for the metabolism of ropinirole. There is thus the potential for substrates or inhibitors of this enzyme when coadministered with ropinirole to alter its clearance. Therefore, if therapy with a drug known to be a potent inhibitor of CYP1A2 is stopped or started during treatment with Ropinirole Tablets, adjustment of the dose of Ropinirole Tablets may be required. L-dopa Co-administration of carbidopa + L-dopa (SINEMET® 10/100 mg twice daily) with ropinirole (2 mg 3 times daily) had no effect on the steady-state pharmacokinetics of ropinirole (n = 28 patients). Oral administration of Ropinirole Tablets 2 mg 3 times daily increased mean steady state Cmax of L-dopa by 20%, but its AUC was unaffected (n = 23 patients). Digoxin Co-administration of Ropinirole Tablets (2 mg 3 times daily) with digoxin (0.125 to 0.25 mg once daily) did not alter the steady-state pharmacokinetics of digoxin in 10 patients.

Theophylline

Administration of theophylline (300 mg twice daily, a substrate of CYP1A2) did not alter the steady-state pharmacokinetics of ropinirole (2 mg 3 times daily) in 12 patients with Parkinson’s disease. Ropinirole (2 mg 3 times daily) did not alter the pharmacokinetics of theophylline (5 mg/kg IV) in 12 patients with Parkinson’s disease. Ciprofloxacin Co-administration of ciprofloxacin (500 mg twice daily), an inhibitor of CYP1A2, with ropinirole (2 mg 3 times daily) increased ropinirole AUC by 84% on average and Cmax by 60% (n = 12 patients).

Estrogens

Population pharmacokinetic analysis revealed that estrogens (mainly ethinyl estradiol: intake 0.6 to 3 mg over 4-month to 23-year period) reduced the oral clearance of ropinirole by 36% in 16 patients. Dosage adjustment may not be needed for Ropinirole Tablets in patients on estrogen therapy because patients must be carefully titrated with ropinirole to tolerance or adequate effect. However, if estrogen therapy is stopped or started during treatment with Ropinirole Tablets, then adjustment of the dose of Ropinirole Tablets may be required.

Dopamine Antagonists

Since ropinirole is a dopamine agonist, it is possible that dopamine antagonists such as neuroleptics (phenothiazines, butyrophenones, thioxanthenes) or metoclopramide may diminish the effectiveness of Ropinirole Tablets. Patients with major psychotic disorders treated with neuroleptics should only be treated with dopamine agonists if the potential benefits outweigh the risks. Population analysis showed that commonly administered drugs, e.g., selegiline, amantadine, tricyclic antidepressants, benzodiazepines, ibuprofen, thiazides, antihistamines, and anticholinergics, did not affect the oral clearance of ropinirole. CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY Two-year carcinogenicity studies were conducted in Charles River CD-1 mice at doses of 5, 15, and 50 mg/kg/day and in Sprague-Dawley rats at doses of 1.5, 15, and 50 mg/kg/day (top doses equivalent to 10 and 20 times, respectively, the maximum recommended human dose of 24 mg/day on a mg/m2 basis). In the male rat, there was a significant increase in testicular Leydig cell adenomas at all doses tested, i.e., ≥1.5 mg/kg (0.6 times the maximum recommended human dose on a mg/m2 basis). This finding is of questionable significance because the endocrine mechanisms believed to be involved in the production of Leydig cell hyperplasia and adenomas in rats are not relevant to humans. In the female mouse, there was an increase in benign uterine endometrial polyps at a dose of 50 mg/kg/day (10 times the maximum recommended human dose on a mg/m2 basis). Ropinirole was not mutagenic or clastogenic in the in vitro Ames test, the in vitro chromosome aberration test in human lymphocytes, the in vitro mouse lymphoma (L1578Y cells) assay, and the in vivo mouse micronucleus test. When administered to female rats prior to and during mating and throughout pregnancy, ropinirole caused disruption of implantation at doses of 20 mg/kg/day (8 times the maximum recommended human dose on a mg/m2 basis) or greater. This effect is thought to be due to the prolactin-lowering effect of ropinirole. In humans, chorionic gonadotropin, not prolactin, is essential for implantation. In rat studies using low doses (5 mg/kg) during the prolactin-dependent phase of early pregnancy (gestation days 0 to 8), ropinirole did not affect female fertility at dosages up to 100 mg/kg/day (40 times the maximum recommended human dose on a mg/m2 basis). No effect on male fertility was observed in rats at dosages up to 125 mg/kg/day (50 times the maximum recommended human dose on a mg/m2 basis).

Pregnancy

Pregnancy Category C. In animal reproduction studies, ropinirole has been shown to have adverse effects on embryo-fetal development, including teratogenic effects. Ropinirole given to pregnant rats during organogenesis (20 mg/kg on gestation days 6 and 7 followed by 20, 60, 90, 120, or 150 mg/kg on gestation days 8 through 15) resulted in decreased fetal body weight at 60 mg/kg/day, increased fetal death at 90 mg/kg/day, and digital malformations at 150 mg/kg/day (24, 36, and 60 times the maximum recommended human dose on a mg/m2 basis, respectively). The combined administration of ropinirole (10 mg/kg/day, 8 times the maximum recommended human dose on a mg/m2 basis) and L-dopa (250 mg/kg/day) to pregnant rabbits during organogenesis produced a greater incidence and severity of fetal malformations (primarily digit defects) than were seen in the offspring of rabbits treated with L-dopa alone. No indication of an effect on development of the conceptus was observed in rabbits when a maternally toxic dose of ropinirole was administered alone (20 mg/kg/day, 16 times the maximum recommended human dose on a mg/m2 basis). In a perinatal-postnatal study in rats, 10 mg/kg/day (4 times the maximum recommended human dose on a mg/m2 basis) of ropinirole impaired growth and development of nursing offspring and altered neurological development of female offspring. There are no adequate and well-controlled studies using Ropinirole Tablets in pregnant women.

Ropinirole

Tablets should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Nursing Mothers

Ropinirole Tablets inhibit prolactin secretion in humans and could potentially inhibit lactation. Studies in rats have shown that Ropinirole Tablets and/or its metabolite(s) is excreted in breast milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Ropinirole Tablets, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

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

INTERACTIONS

• Inhibitors or inducers of CYP1A2: May alter the clearance of ropinirole; dose adjustment of ropinirole may be required. ( 7.1 , 12.3)
• Hormone replacement therapy (HRT): Starting or stopping HRT may require dose adjustment of ropinirole. ( 7.2 , 12.3 )
• Dopamine antagonists (e.g., neuroleptics, metoclopramide): May reduce efficacy of ropinirole. ( 7.3 )

7.1 Cytochrome P450 1A2 Inhibitors and Inducers In vitro metabolism studies showed that cytochrome P450 1A2 (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 a drug known to be a potent inducer or inhibitor of CYP1A2 is stopped or started during treatment with ropinirole, adjustment of the dose of ropinirole may be required. Coadministration of ciprofloxacin, an inhibitor of CYP1A2, increases the AUC and C max 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 hormone replacement therapy [ see Clinical Pharmacology ( 12.3 ) ].

7.2 Estrogens Population pharmacokinetic analysis revealed that higher doses of estrogens (usually associated with hormone replacement therapy) reduced the clearance of ropinirole. Starting or stopping may require adjustment of dosage of ropinirole <span class="opacity-50 text-xs">[see Clinical Pharmacology ( 12.3 )]</span> .

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

Drug Interaction Studies

Digoxin: Coadministration of ropinirole (2 mg 3 times daily) with digoxin (0.125 to 0.25 mg once daily) did not alter the steady-state pharmacokinetics of digoxin in 10 patients. Theophylline: Administration of theophylline (300 mg twice daily), a substrate of CYP1A2, did not alter the steady-state pharmacokinetics of ropinirole (2 mg 3 times daily) in 12 patients with Parkinson’s disease. Ropinirole (2 mg 3 times daily) did not alter the pharmacokinetics of theophylline (5 mg/kg intravenously) in 12 patients with Parkinson’s disease. Ciprofloxacin: Coadministration of ciprofloxacin (500 mg twice daily), an inhibitor of CYP1A2, with ropinirole (2 mg 3 times daily) increased ropinirole AUC by 84% on average and C max by 60% (n = 12 patients). Estrogens: Population pharmacokinetic analysis revealed that estrogens (mainly ethinylestradiol: intake 0.6 to 3 mg over 4-month to 23-year period) reduced the oral clearance of ropinirole by 36% in 16 patients. L-dopa : Coadministration of carbidopa + L-dopa (10/100 mg twice daily) with ropinirole (2 mg 3 times daily) had no effect on the steady-state pharmacokinetics of ropinirole (n = 28 patients). Oral administration of ropinirole 2 mg 3 times daily increased mean steady-state C max of L-dopa by 20%, but its AUC was unaffected (n = 23 patients).

Commonly Administered

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