Mechanism of Action

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

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

Clinical Pharmacology Studies

In healthy normotensive subjects, single oral doses of ropinirole in the range 0.01 to 2.5 mg had little or no effect on supine blood pressure and pulse rates. Upon standing, ropinirole caused decreases in systolic and diastolic blood pressure at doses above 0.25 mg. In some subjects, these changes were associated with the emergence of orthostatic symptoms, bradycardia, and, in one case, transient sinus arrest with syncope. With repeat dosing and slow titration up to 4 mg once daily in healthy volunteers, postural hypotension or hypotension-related adverse events were noted in 13% of subjects on ropinirole and none of the subjects on placebo.

The mechanism of postural hypotension induced by ropinirole is presumed to be due to a D2-mediated blunting of the noradrenergic response to standing and subsequent decrease in peripheral vascular resistance. Nausea is a common concomitant symptom of orthostatic signs and symptoms.

At oral doses as low as 0.2 mg, ropinirole suppressed serum prolactin concentrations in healthy male volunteers.

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.

Ropinirole had no dose- or exposure-related effect on mean QT intervals in healthy male and female volunteers titrated to doses up to 4 mg/day. The effect of ropinirole on QT intervals at higher exposures achieved either due to drug interactions or at doses used in Parkinson’s disease has not been systematically evaluated.

Pharmacokinetics

Population Subgroups

Because therapy with ropinirole is initiated at a low dose and gradually titrated upward according to clinical tolerability to obtain the optimum therapeutic effect, adjustment of the initial dose based on gender, weight, or age is not necessary.

Clinical Trials 

Parkinson’s Disease

Ropinirole Tablets USP are indicated for the treatment of the signs and symptoms of idiopathic Parkinson’s disease.

The effectiveness of ropinirole was 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 USP 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.

Falling Asleep During Activities of Daily Living:

Patients treated with ropinirole havereported falling asleep while engaged in activities of daily living, including the operation ofmotor vehicles, which sometimes resulted in accidents. Although many of these patients reportedsomnolence while on ropinirole, some perceived that they had no warning signs such as excessivedrowsiness, and believed that they were alert immediately prior to the event. Some of theseevents have been reported as late as 1 year after initiation of treatment.

In controlled clinical trials, somnolence was a common occurrence in patients receivingropinirole and is more frequent in Parkinson's disease (up to 40% ropinirole, 6% placebo) than inRestless Legs Syndrome (12% ropinirole, 6% placebo). Many clinical experts believe that fallingasleep while engaged in activities of daily living always occurs in a setting of preexistingsomnolence, although patients may not give such a history. For this reason, prescribers shouldcontinually 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 notacknowledge drowsiness or sleepiness until directly questioned about drowsiness or sleepinessduring specific activities.

Before initiating treatment with ropinirole, patients should be advised of the potential to develop drowsiness and specifically asked about factors that may increase the risk with ropinirole such as concomitant sedating medications, the presence of sleep disorders (other than RestlessLegs Syndrome), and concomitant medications that increase ropinirole plasma levels (e.g.,ciprofloxacin—see PRECAUTIONS: Drug Interactions). If a patient develops significantdaytime sleepiness or episodes of falling asleep during activities that require active participation(e.g., conversations, eating, etc.), ropinirole should ordinarily be discontinued. (See DOSAGE AND ADMINISTRATION for guidance in discontinuing ropinirole.) If a decision is made tocontinue ropinirole, patients should be advised to not drive and to avoid other potentiallydangerous activities. There is insufficient information to establish that dose reduction willeliminate episodes of falling asleep while engaged in activities of daily living.

Syncope

Syncope, sometimes associated with bradycardia, was observed in association with ropinirole in both Parkinson’s disease patients and RLS patients. In the two double-blind, placebo-controlled studies of ropinirole in patients with Parkinson’s disease who were not being treated with L-dopa, 11.5% (18 of 157) of patients on ropinirole had syncope compared to 1.4% (2 of 147) of patients on placebo. Most of these cases occurred more than 4 weeks after initiation of therapy with ropinirole, and were usually associated with a recent increase in dose.

Of 208 patients being treated with both L-dopa and ropinirole in placebo-controlled advanced Parkinson’s disease trials, there were reports of syncope in 6 (2.9%) compared to 2 of 120 (1.7%) of placebo/L-dopa patients.

In patients with RLS, of 496 patients treated with ropinirole in 12-week placebo-controlled trials, there were reports of syncope in 5 (1%) compared with 1 of 500 (0.2%) patients treated with placebo.

Because the studies of ropinirole excluded patients with significant cardiovascular disease, it is not known to what extent the estimated incidence figures apply to either Parkinson’s disease or RLS patients in clinical practice. Therefore, patients with severe cardiovascular disease should be treated with caution.

Two of 47 Parkinson’s disease patient volunteers enrolled in phase 1 studies had syncope following a 1 mg dose. In 2 studies in RLS patients that used a forced titration regimen and orthostatic challenge with intensive blood pressure monitoring, 1 of 55 RLS patients treated with ropinirole compared with 0 of 27 patients receiving placebo reported syncope. In phase 1 studies including 110 healthy volunteers, one patient developed hypotension, bradycardia, and sinus arrest of 26 seconds accompanied by syncope; the patient recovered spontaneously without intervention. One other healthy volunteer reported syncope.

Symptomatic Hypotension

Dopamine agonists, in clinical studies and clinical experience, appear to impair the systemic regulation of blood pressure, with resulting postural hypotension, especially during dose escalation. Parkinson’s disease patients, in addition, appear to have an impaired capacity to respond to a postural challenge. For these reasons, Parkinson’s patients being treated with dopaminergic agonists ordinarily (1) require careful monitoring for signs and symptoms of postural hypotension, especially during dose escalation, and (2) should be informed of this risk (see PRECAUTIONS: Information for Patients).

Although the clinical trials were not designed to systematically monitor blood pressure, there were individual reported cases of postural hypotension in early Parkinson’s disease (without L-dopa) in patients treated with ropinirole. Most of these cases occurred more than 4 weeks after initiation of therapy with ropinirole and were usually associated with a recent increase in dose.

In 12-week placebo-controlled trials of patients with RLS, the adverse event orthostatic hypotension was reported by 4 of 496 patients (0.8%) treated with ropinirole compared with 2 of 500 patients (0.4%) receiving placebo.

In two phase 2 studies in patients with RLS that used a force-titration regimen and orthostatic challenges with intensive blood pressure monitoring, 14 of 55 patients (25%) receiving ropinirole experienced an adverse event of hypotension or postural hypotension. As described above, one additional patient was noted to have an episode of vasovagal syncope (although no blood pressure recording was documented). None of the 27 patients receiving placebo had a similar adverse event. In these studies, 11 of the 55 patients (20%) receiving ropinirole and 3 of the 26 patients (12%) who had post-dose blood pressure assessments following placebo, experienced an orthostatic blood pressure decrease of at least 40 mm Hg systolic and/or at least 20 mm Hg diastolic; not all of these changes were associated with clinical symptoms. Except for its forced nature these studies used a similar titration schedule as those in the phase 3 efficacy trials.

In phase 1 studies of ropinirole that included 110 healthy volunteers, nine subjects had documented symptomatic postural hypotension. These episodes appeared mainly at doses above 0.8 mg and these doses are higher than the starting doses recommended for either Parkinson’s disease patients or RLS patients. In eight of these nine individuals, the hypotension was accompanied by bradycardia, but did not develop into syncope (see Syncope subsection). None of these events resulted in death or hospitalization.

One of 47 Parkinson’s disease patient volunteers enrolled in phase 1 studies had documented hypotension following a 2 mg dose on two occasions.

Hallucinations

In double-blind, placebo-controlled, early-therapy studies in patients with Parkinson’s disease who were not treated with L-dopa, 5.2% (8 of 157) of patients treated with ropinirole reported hallucinations, compared to 1.4% of patients on placebo (2 of 147). Among those patients receiving both ropinirole and L-dopa in advanced Parkinson’s disease (with L-dopa) studies, 10.1% (21 of 208) were reported to experience hallucinations, compared to 4.2% (5 of 120) of patients treated with placebo and L-dopa.

Hallucinations were of sufficient severity to cause discontinuation of treatment in 1.3% of the early Parkinson’s disease (without L-dopa) patients and 1.9% of the advanced Parkinson’s disease (with L-dopa) patients, compared to 0% and 1.7% of placebo patients, respectively.

In patients with RLS, hallucinations were reported by 0% of patients treated with ropinirole (0 of 496) compared with 0.2% of patients who received placebo (1 of 500) in the 12-week placebo-controlled trials; in premarketing long-term open-label studies, 0.5% of patients reported hallucinations during therapy with ropinirole (2 of 390) but did not discontinue treatment and symptoms resolved.

General

Information for Patients

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

Patients should be instructed to take ropinirole only as prescribed. If a dose is missed, patients should be advised not to double their next dose.

Ropinirole can be taken with or without food. Patients may be advised that taking ropinirole 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.

Patients should be alerted to the potential sedating effects associated with ropinirole, 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 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 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.

Patients should be informed they may experience hallucinations (unreal visions, sounds, or sensations) while taking ropinirole. These were uncommon in patients taking ropinirole 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 with L-dopa, or taking higher doses of ropinirole.

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

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

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 clinical 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 in pregnant women. Ropinirole should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus.

Nursing Mothers

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

Studies in rats have shown that ropinirole 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, 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.

Parkinson’s Disease

During the premarketing development of ropinirole, patients received ropinirole 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.

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 participating in the double-blind, placebo-controlled studies and were numerically more common in the group treated with ropinirole. In these studies, either ropinirole 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.

Other events reported by 1% or more of early Parkinson’s disease (without L-dopa) patients treated with ropinirole, 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, hallucinations appear to be dose-related.

The incidence of adverse events was not materially different between women and men.

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 (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 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 were: nausea (1.6%), dizziness (0.8%), and headache (0.8%).

Other Adverse Events Observed During All Phase 2/3 Clinical Trials for Parkinson’s Disease

Ropinirole has 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 who experienced events of the type cited on at least one occasion while receiving ropinirole. 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 hydrochloride, 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 have reported falling asleep while engaged in activities of daily living, including operation of a motor vehicle which sometimes resulted in accidents (see bolded WARNINGS).

Other Adverse Events Observed During Phase 2/3 Clinical Trials for RLS

Ropinirole 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 who experienced events of the type cited on at least one occasion while receiving ropinirole. 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, 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 to1/1,000 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.

Controlled Substance

Ropinirole is not a controlled substance.

Physical and Psychological Dependence

Animal studies and human clinical trials with ropinirole hydrochloride did not reveal any potential for drug-seeking behavior or physical dependence.

Overdose Management

 It is anticipated that the symptoms of overdose with ropinirole will be related to its dopaminergic activity. General supportive measures are recommended. Vital signs should be maintained, if necessary. Removal of any unabsorbed material (e.g., by gastric lavage) should be considered.

General Dosing Considerations for Parkinson's Disease and RLS

Ropinirole can be taken with or without food. Patients may be advised that taking ropinirole with food may reduce the occurrence of nausea. However, this has not been established in controlled clinical trials.

If a significant interruption in therapy with ropinirole has occurred, retitration of therapy may be warranted.

Dosing for Parkinson’s Disease

In all clinical studies, dosage was initiated at a subtherapeutic level and gradually titrated to therapeutic response. The dosage should be increased to achieve a maximum therapeutic effect, balanced against the principal side effects of nausea, dizziness, somnolence, and dyskinesia.

The recommended starting dose for Parkinson’s Disease is 0.25 mg three times daily. Based on individual patient response, dosage should then be titrated with weekly increments as described in Table 5. After week 4, if necessary, daily dosage may be increased by 1.5 mg/day on a weekly basis up to a dose of 9 mg/day, and then by up to 3 mg/day weekly to a total dose of 24 mg/day. Doses greater than 24 mg/day have not been tested in clinical trials.

When ropinirole is administered as adjunct therapy to L-dopa, the concurrent dose of L-dopa may be decreased gradually as tolerated. L-dopa dosage reduction was allowed during the advanced Parkinson’s disease (with L-dopa) study if dyskinesias or other dopaminergic effects occurred. Overall, reduction of L-dopa dose was sustained in 87% of patients treated with ropinirole and in 57% of patients on placebo. On average the L-dopa dose was reduced by 31% in patients treated with ropinirole.

Ropinirole for Parkinson’s disease patients should be discontinued gradually over a 7-day period. The frequency of administration should be reduced from three times daily to twice daily for 4 days. For the remaining 3 days, the frequency should be reduced to once daily prior to complete withdrawal of ropinirole.

Dosing for Restless Legs Syndrome

In all clinical trials, the dose for ropinirole was initiated at 0.25 mg once daily, 1 to 3 hours before bedtime. Patients were titrated based on clinical response and tolerability.

The recommended adult starting dosage for RLS is 0.25 mg once daily, 1 to 3 hours before bedtime. After 2 days, the dosage can be increased to 0.5 mg once daily and to 1 mg once daily at the end of the first week of dosing, then as shown in Table 6 as needed to achieve efficacy. For RLS, the safety and effectiveness of doses greater than 4 mg once daily have not been established.

In clinical trials of patients being treated for RLS with doses up to 4 mg once daily, ropinirole was discontinued without a taper.

Storage

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature].Protect from light and moisture. Close container tightly after each use.