Requip (Ropinirole HCL)

REQUIP™

SmithKline Beecham

Ropinirole HCl

Antiparkinsonian Agent – Dopamine Agonist

Action And Clinical Pharmacology: Ropinirole is a non-ergoline dopamine agonist, which activates postsynaptic dopamine receptors.

In vitro studies have shown that ropinirole binds with high affinity to cloned human D2, D3, and D4 receptors. The antiparkinson activity of ropinirole is believed to be due to its stimulatory effects on central postsynaptic dopamine D2 receptors within the caudate-putamen.

Ropinirole is a potent agonist both in vitro and in vivo and restores motor function in animal models of Parkinson’s disease. Ropinirole has been shown to reverse the motor deficits induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in primates.

Neither ropinirole nor its metabolites bind with high affinity to dopamine D1 receptors. Ropinirole also has very low affinity for 5-HT1, 5-HT2, benzodiazepine, GABAA, muscarinic, a-or b-adrenoreceptors. Ropinirole binds to opiate receptors with low affinity, however, studies show that this weak opiate activity has no consequences at pharmacological doses in vivo.

In rats, ropinirole binds to melanin-containing tissues (e.g., the eye) to a greater degree than nonpigmented tissues, and tissue levels decline with a half-life of 16 to 20 days. It is unknown whether or not ropinirole accumulates in these tissues over time.

In healthy normotensive subjects, single oral doses of ropinirole, in the range of 0.01 to 2.5 mg, had little or no effect on supine blood pressure and pulse rate. Upon standing, ropinirole caused decreases in systolic and mainly 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 1 case, transient sinus arrest in the context of a severe vasovagal syncope. The effect of repeat dosing and slow titration of ropinirole was not studied in healthy volunteers. The mechanism of ropinirole-induced orthostatic symptoms probably relates to its dopamine D2-mediated blunting of the noradrenergic response to standing and subsequent decrease in peripheral vascular resistance. Orthostatic signs and symptoms were often accompanied by nausea.

Ropinirole had no dose-related effect on ECG wave form and rhythm in young healthy male volunteers.

At doses ³ 0.8 mg ropinirole suppressed serum prolactin concentrations in healthy male volunteers.

Pharmacokinetics: Absorption, Bioavailability and Distribution: Ropinirole is rapidly absorbed with median peak concentrations occurring within 1.5 hours after oral dosing. Despite complete absorption, absolute bioavailability of ropinirole is reduced to approximately 50% as a result of first-pass metabolism. Relative bioavailability from a tablet compared to an oral solution is 85%. Over the therapeutic dose range, Cmax and AUC values increase in proportion to the increase in dose (see Table I).

The average oral clearance is approximately 47 L/h (range 17 to 113 L/h) and is constant over the entire dosage range. The terminal elimination half-life is approximately 6 h (range 2 to 27 h) and the volume of distribution at steady-state is approximately 480 L (range 216 to 891 L) or 7 L/kg (range 3.1 to 12.9 L/kg).

Steady-state concentrations are expected to be achieved within 2 days of dosing. There is, on average, a 2-fold higher steady-state plasma concentration of ropinirole following the recommended t.i.d. regimen compared to those observed following a single oral dose.

Food delayed the rate of absorption of ropinirole (median Tmax was increased by 2.6 hours and Cmax was decreased by 25%) in Parkinsonian patients. However, there was no marked change in the overall systemic availability of the drug. Ropinirole may be given with or without food. While administration of the drug with food may improve gastrointestinal tolerance, in severely fluctuating patients, the morning dose may be given without food in order to avoid a delay in time to switch “ON”.

Population pharmacokinetic analyses have shown that frequently coadministered medications, such as levodopa, selegiline, amantadine, anticholinergic drugs, ibuprofen, benzodiazepines and antidepressants did not alter the pharmacokinetics of ropinirole.

Plasma protein binding is low (10 to 40%).

Ropinirole has a blood to plasma ratio of 1.2.

Metabolism: Ropinirole is extensively metabolized by the liver. The N-despropyl metabolite is the major metabolite circulating in the plasma. Based on AUC data, the plasma levels of the metabolite were consistently higher than those of the parent drug suggesting a nonsaturable conversion of ropinirole to the N-despropyl metabolite. The affinity of the N-despropyl metabolite for human cloned D2 receptors is lower than the affinity of ropinirole. In addition the metabolite does not cross the blood-brain barrier; thus, it is unlikely to contribute to the therapeutic effects of ropinirole. The plasma concentrations of the hydroxylated metabolite are low and account for about 1 to 5% of the ropinirole concentrations. Although the hydroxylated metabolite was more active than ropinirole in in vitro D2 receptor binding studies, at therapeutic doses it is not expected to contribute to the activity of ropinirole.

In vitro studies indicate that the major cytochrome P450 isozyme involved in the metabolism of ropinirole is CYP1A2. In patients with Parkinson’s disease, ciprofloxacin, an inhibitor of CYP1A2, significantly increased the systemic availability of ropinirole, while theophylline, a substrate of CYP1A2, was devoid of such activity (see Precautions, Drug Interactions).

Elimination: Recovery of radioactivity after oral and i.v. administration of 4-ropinirole was approximately 88% and 90% of the dose, respectively. Urinary excretion of unchanged ropinirole is low and represents approximately 5 to 10% of the dose. N-despropyl ropinirole is the predominant metabolite found in the urine (40%), followed by the glucuronide of the hydroxy metabolite (10%), and the carboxylic acid metabolite (10%) formed from N-despropyl ropinirole.

Population Subgroups: Renal and Hepatic Impairment: Based on population pharmacokinetics, no clinically significant differences were observed in the pharmacokinetics of ropinirole in Parkinsonian patients with moderate renal impairment (creatinine clearance between 30 to 50 mL/min; n=18, mean age 74 years) compared to age-matched patients with creatinine clearance above 50 mL/min (n=44, mean age 70 years). Therefore, no dosage adjustment is necessary in Parkinsonian patients with mild to moderate renal impairment (see Precautions and Dosage).

The use of ropinirole in patients with severe renal impairment or hepatic impairment has not been studied. Administration of ropinirole to such patients is not recommended (see Precautions and Dosage).

Gender: Population pharmacokinetic analysis indicated that the oral clearance and volume of distribution of ropinirole at steady-state were similar in male patients (n=99, mean age 60 years) and female patients who were not taking concomitant estrogens (n=56, mean age 65 years).

Estrogen Replacement Therapy: In women, on long-term treatment with conjugated estrogens (n=16, mean age 63 years), the oral clearance of ropinirole was decreased by an average of 36% compared to the oral clearance in women not receiving supplemental estrogens (n=56, mean age 65 years). The average terminal elimination half-life was 9 hours in the estrogen group and 6.5 hours in patients not taking estrogens (see Precautions and Dosage).

Age: Population pharmacokinetic analysis revealed that the oral clearance of ropinirole, seen in patients under the age of 65 years (n=97), was reduced from 62.1 L/h to 45.5 L/h in patients between the ages of 65 and 75 years (n=63). In patients older than 75 years (n=11), oral clearance was similar to that seen in the 65 to 75 year age group (41.7 L/h). However, since the dose of ropinirole is to be individually titrated to clinical response, dosage adjustment is not necessary in the elderly (above 65 years).

Clinical Trials: Up to May 31, 1996, 1 599 patients have been exposed to ropinirole, with 481 patients being exposed for over 1 year and 241 patients being exposed for over 2 years.

Evidence to support the efficacy of ropinirole in treating the signs and symptoms of Parkinson’s disease was obtained in multicentre, double-blind studies. These studies included either patients who had minimal or no prior dopaminergic therapy, or patients who were not optimally controlled with current levodopa-decarboxylase inhibitor therapy. In patients with early disease, ropinirole improved motor function (assessed by the motor component of the UPDRS [Unified Parkinson’s Disease Rating Scale]) and delayed the need to initiate treatment with levodopa. In patients with more advanced disease, ropinirole reduced “off” time (based upon patient diaries recording time “on” and “off”) and permitted a reduction in levodopa dose. The subsequent section describes some of the studies in which ropinirole was titrated (see Dosage) to the maximal dose of 8 mg t.i.d.

In clinical trials where dosing was titrated to optimal clinical effect, the mean daily dose of ropinirole at 24 weeks was 9.5 mg in early therapy (n=282) and was 13.5 mg in adjunct therapy (n=303).

In the pivotal clinical trials, including studies where the dose was titrated to the target maximum of 24 mg/day, the mean daily dose of ropinirole at endpoint was 10.7 mg in early therapy (n=458) and 12.5 mg in adjunct therapy (n=456).

In the total patient database (n=1 599) over 50% of patients were dosed between 6 and 15 mg of ropinirole per day in both early and adjunct therapy. Less than 22% of patients exceeded a total daily dose of 15 mg.

During the clinical trials, the dose of ropinirole was titrated to optimal clinical response and tolerance. Retrospective analysis showed that female patients required lower doses than male patients but were exposed to ropinirole for similar periods of time.

Early Therapy: In a double-blind, randomized, placebo-controlled, 6-month study, ropinirole-treated patients (n=116) demonstrated a 24% improvement in UPDRS motor scores from baseline, compared to placebo-treated patients (n=125), who demonstrated a 3% worsening in motor scores. On the Clinical Global Impression (CGI) scale, 33% of ropinirole-treated patients and 12% of placebo-treated patients were rated as “very much improved” and “much improved”. “Rescue levodopa” was needed by 11% of ropinirole-treated and 29% of placebo-treated patients. All differences were statistically significant.

In a double-blind, randomized 5-year study, at the 6-month interim analysis, ropinirole (n=179) was compared to levodopa-benserazide (n=89). The decrease in UPDRS motor scores versus baseline was greater with levodopa than with ropinirole. However, the proportion of “responders” (UPDRS improvement of at least 30%) did not differ between levodopa and ropinirole. Results on the CGI indicated that there was no difference between ropinirole and levodopa in less severely afflicted patients (Hoehn and Yahr stage I to II) but levodopa was more efficacious in patients with more severe disease.

Adjunct Therapy: In a double-blind, randomized, clinical trial of 6-month duration, ropinirole (n=94) was compared to placebo (n=54) as adjunct therapy to levodopa. The primary efficacy parameter, defined as both a 20% or greater reduction in levodopa dose and a 20% or greater reduction in “off” time, was achieved by 28% of ropinirole-treated patients and 11% of placebo-treated patients. This difference was statistically significant. The daily dose of levodopa was reduced by 19% and 2.8% in the ropinirole and placebo-treated patients, respectively.

Therapeutic Effect – Plasma Concentrations: The relationship between efficacy and plasma concentrations of ropinirole was assessed from population pharmacokinetic data obtained in 141 male and female patients who participated in 2 prospective studies.

In general, the average plasma concentrations of ropinirole at steady-state (Css) were higher in patients classified as responders versus non-responders, although considerable overlap in the range of Css between the 2 groups was noted. Mean (±SD) ropinirole Css for responders and non-responders were 22.8±10.8 ng/mL and 15.1±9.7 ng/mL, respectively.

Indications And Clinical Uses: In the treatment of the signs and symptoms of idiopathic Parkinson’s disease.

Ropinirole can be used both as early therapy, without concomitant levodopa and as an adjunct to levodopa.

Contra-Indications: Patients with a known hypersensitivity to ropinirole or the excipients of the drug product.

Manufacturers’ Warnings In Clinical States: Orthostatic Symptoms: Dopamine agonists appear to impair the systemic regulation of blood pressure with resulting orthostatic symptoms of dizziness or lightheadedness, with or without documented hypotension. These symptoms appear to occur especially during dose escalation. Therefore, patients treated with dopamine agonists should be carefully monitored for signs and symptoms of orthostatic hypotension, especially during dose escalation (see Dosage) and should be informed of this risk (see Blue Section, Information for the Patient).

Hallucinations: In controlled trials, ropinirole caused hallucination in 5.1% of patients during early therapy (1.4% in the placebo group) and in 10.1% of patients receiving ropinirole and levodopa (4.2% receiving placebo and levodopa). Hallucination was of sufficient severity that it led to discontinuation in 1.3% and 1.9% of patients during early and adjunct therapy, respectively. The incidence of hallucination was dose-dependent both in early and adjunct therapy studies.

Precautions: Cardiovascular: Since ropinirole has not been studied in patients with a history or evidence of significant cardiovascular disease including myocardial infarction, unstable angina, cardiac decompensation, cardiac arrhythmias, vaso-occlusive disease (including cerebral) or cardiomyopathy, it should be used with caution in such patients.

There is limited experience with ropinirole in patients treated with antihypertensive and antiarrhythmic agents. Consequently, in such patients, the dose of ropinirole should be titrated with caution.

Neuroleptic Malignant Syndrome: 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 antiparkinsonian therapy.

A single spontaneous report of a symptom complex resembling the neuroleptic malignant syndrome has been observed in a 66-year-old diabetic male patient with Parkinson’s disease, who developed fever, muscle stiffness, and drowsiness 8 days after beginning ropinirole treatment. The patient also experienced acute bronchitis, which did not respond to antibiotic treatment. Ropinirole was discontinued 3 days before the patient died. The reporting physician considered these events to be possibly related to ropinirole treatment (see Dosage).

A single spontaneous report of severe muscle pain has been reported in a 66-year-old male patient around his thigh. The reporting physician considered the event to be probably related to ropinirole treatment.

Retinal Pathology in Rats: In a 2-year carcinogenicity study in albino Sprague-Dawley rats, retinal atrophy was observed at incidences of 0, 4.4, 1.4 and 10% of male rats and 0, 4.4, 2.9 and 12.9% of female rats dosed at 0, 1.5, 15 and 50 mg/kg/day respectively. The incidence was significantly higher in both male and female animals dosed at 50 mg/kg/day. The 50 mg/kg/day dose represents a 2.8-fold greater exposure (AUC) and a 13.1-fold greater exposure (Cmax) to ropinirole in rats than the exposure would be in humans at the maximum recommended dose of 24 mg/day. The relevance of this finding to humans is not known.

Pregnancy: The use of ropinirole during pregnancy is not recommended.

Ropinirole given to pregnant rats during organogenesis (gestation days 8 through 15) resulted in decreased fetal body weight at 60 mg/kg/day (approximately 3 to 4 times the AUC at the maximal human dose of 8 mg t.i.d.), increased fetal death at 90 mg/kg/day (approximately 5 times the AUC at the maximal human dose of 8 mg t.i.d.) and digital malformations at 150 mg/kg/day (approximately 8 to 9 times the AUC at the maximal human dose of 8 mg t.i.d.). These effects occurred at maternally toxic doses. There was no indication of an effect on development of the conceptus at a maternally toxic dose of 20 mg/kg/day in the rabbit. In a perinatal-postnatal study in rats, 10 mg/kg/day of ropinirole (approximately 0.5 to 0.6 times the AUC at the maximal human dose of 8 mg t.i.d.) impaired growth and development of nursing offspring and altered neurological development of female offspring.

Lactation: Since ropinirole suppresses lactation, it should not be administered to mothers who wish to breast-feed infants.

Studies in rats have shown that ropinirole and/or its metabolites cross the placenta and are excreted in breast milk. Consequently, the human fetus and/or neonate may be exposed to dopamine agonist activity.

Use in Women receiving Estrogen Replacement Therapy: In female patients on long-term treatment with conjugated estrogens, oral clearance was reduced and elimination half-life prolonged compared to patients not receiving estrogens (see Pharmacology, Pharmacokinetics). In patients already receiving estrogen replacement therapy, ropinirole may be titrated in the recommended manner according to clinical response. However, if estrogen replacement therapy is stopped or introduced during treatment with ropinirole, adjustment of the ropinirole dosage may be required.

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

Renal and Hepatic Impairment: No dosage adjustment is needed in patients with mild to moderate renal impairment (creatinine clearance of 30 to 50 mL/min; see Pharmacology, Pharmacokinetics).

Because the use of ropinirole in patients with severe renal impairment or hepatic impairment has not been studied, administration of ropinirole to such patients is not recommended.

Drug Interactions: Psychotropic Drugs: Neuroleptics and other centrally active dopamine antagonists may diminish the effectiveness of ropinirole. Therefore, concomitant use of these products is not recommended.

Based on population pharmacokinetic assessment, no interaction was seen between ropinirole and tricyclic antidepressants or benzodiazepines.

Antiparkinson Drugs: Based on population pharmacokinetic assessment, there were no interactions between ropinirole and drugs commonly used to treat Parkinson’s disease, i.e., selegiline, amantadine, and anticholinergics.

Levodopa: The potential pharmacokinetic interaction of levodopa/carbidopa (100 mg/10 mg b.i.d.) and ropinirole (2 mg t.i.d.) was assessed in levodopa naive (de novo) male and female patients with Parkinson’s disease (n=30, mean age 64 years). The rate and extent of availability of ropinirole at steady-state were essentially the same with or without levodopa. Similarly, the rate and extent of availability of levodopa, as well as its elimination half-life, were essentially the same in the presence and absence of ropinirole.

Inhibitors of CYP1A2: Ciprofloxacin: The effect of ciprofloxacin (500 mg b.i.d.) on the pharmacokinetics of ropinirole (2 mg t.i.d.) was studied in male and female patients with Parkinson’s disease (n=12, mean age 55 years). The extent of systemic availability of ropinirole was significantly increased when coadministered with ciprofloxacin (AUC increased by 1.84 fold). Thus, in patients already receiving CYP1A2 inhibitors such as ciprofloxacin, ropinirole therapy may be instituted in the recommended manner and the dose titrated according to clinical response. However, if therapy with a drug known to be an inhibitor of CYP1A2 is stopped or introduced during treatment with ropinirole, adjustment of the ropinirole dosage will be required.

Substrates of CYP1A2: Theophylline: The effect of oral theophylline (300 mg b.i.d.) on the pharmacokinetics of ropinirole (2 mg t.i.d.) was studied in male and female patients with Parkinson’s disease (n=12, mean age 59 years). There was no marked change in the rate or extent of availability of ropinirole when coadministered with theophylline. Similarly, coadministration of ropinirole with i.v. theophylline (5 mg/kg) did not result in any marked change in the pharmacokinetics of theophylline. It is therefore unlikely that substrates of CYP1A2 would significantly alter the pharmacokinetics of ropinirole, and vice-versa.

Digoxin: The effect of ropinirole (2 mg t.i.d.) on the pharmacokinetics of digoxin (0.125 to 0.25 mg once a day) was studied in male and female patients with Parkinson’s disease (n=10, mean age 72 years). Coadministration at steady-state with ropinirole resulted in a 10% decrease in digoxin AUC although mean trough digoxin plasma concentrations were unaltered. However, the effect of higher recommended doses of ropinirole on the pharmacokinetics of digoxin is not known.

Alcohol: No information is available on the potential for interaction between ropinirole and alcohol. As with other centrally active medications, patients should be cautioned against taking ropinirole with alcohol.

Occupational Hazards: Psychomotor Performance: As orthostatic symptoms of dizziness or lightheadedness as well as somnolence may occur during ropinirole therapy patients should be cautioned not to drive a motor vehicle or operate potentially hazardous machinery until they are reasonably certain that ropinirole therapy does not affect their ability to engage in such activities.

Adverse Reactions: Adverse Reactions Associated with Discontinuation of Treatment: Of 1 599 patients who received ropinirole during the premarketing clinical trials, 17.1% in early-therapy studies and 17.3% in adjunct-therapy studies discontinued treatment due to adverse reactions. The events resulting in discontinuation of ropinirole in 1% or more of patients were as follows: Early therapy: nausea (6.4%), dizziness (3.8%), aggravated Parkinson’s disease (1.3%), hallucination (1.3%), headache (1.3%), somnolence (1.3%) and vomiting (1.3%). Adjunct therapy: dizziness (2.9%), dyskinesia (2.4%), confusion (2.4%), vomiting (2.4%), hallucination (1.9%), nausea (1.9%), anxiety (1.9%), and increased sweating (1.4%). Patients over 75 years of age (n=130) showed slightly higher incidences of withdrawal due to hallucination, confusion and dizziness than patients less than 75 years of age.

Most Frequent Adverse Events: Adverse events occurring with an incidence of greater than, or equal to, 10% were as follows: Early therapy: nausea, dizziness, somnolence, headache, peripheral edema, vomiting, syncope, fatigue and viral infection. Adjunct therapy: dyskinesia, nausea, dizziness, somnolence and headache.

Dopamine agonists with an ergoline chemical structure have been associated with adverse experiences such as retroperitoneal fibrosis, erythromelalgia and pulmonary reactions. Ropinirole has a novel, non-ergoline chemical structure and no reports of such events have been observed in clinical trials.

Incidence of Adverse Events in Placebo-Controlled Trials: The incidence of postural hypotension, an event commonly associated with initiation of dopamine agonist therapy, was not notably different from placebo in clinical trials. However, decreases in systolic blood pressure to 75 years) of patients treated with ropinirole.

Adverse events that occurred at an incidence of 1% or more among ropinirole-treated patients who participated in placebo-controlled trials for up to 1 year. Patients were dosed in a range of 0.75 mg to 24 mg/day. Reported adverse events were classified using a standard World Health Organization (WHO)-based dictionary terminology.

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 which prevailed in the clinical trials. Similarly, the cited frequencies cannot be compared with figures obtained from other clinical investigations involving different treatments, uses and investigators. The cited figures, however, do provide the prescribing physician with some basis for estimating the relative contribution of drug and nondrug factors to the adverse events incidence rate in the population studied.

The following adverse events were recorded with rates equal to, or more common in, placebo-treated patients:

Early Therapy: fever, hot flushes, injury, rigors, ataxia, dyskinesia, dystonia, hyperkinesia, involuntary muscle contractions, paresthesia, aggravated Parkinsonism, tremor, diarrhea, gingivitis, increased saliva, bradycardia, gout, hyperglycemia, decreased weight, arthralgia, arthritis, back pain, myalgia, basal cell carcinoma, anxiety, depression, abnormal dreaming, insomnia, nervousness, prostatic disorder, upper respiratory tract infection, coughing, rash, hematuria and leg cramps.

Adjunct Therapy: asthenia, chest pain, fatigue, hot flushes, postural hypotension, abnormal gait, hyperkinesia, aggravated Parkinsonism, vertigo, abdominal pain, constipation, back pain, myalgia, depression, insomnia, paroniria (WHO dictionary term for nightmares), viral infection, upper respiratory tract infection, pharyngitis, rhinitis, rash, rash erythematous, taste perversion, hematuria, leg cramps and diplopia, myocardial infarction, extrasystoles supraventricular.

Events Observed During the Premarketing Evaluation of Ropinirole: Of the 1 599 patients who received ropinirole in therapeutic studies, the following adverse events have been noted up to May 1996. In the absence of appropriate controls in some of the studies, a causal relationship between these events and treatment with ropinirole cannot be determined.

Events are categorized by body system and listed in order of decreasing frequency according to the following definitions: frequent adverse events are those occurring on one or more occasions in at least 1/100 patients; infrequent adverse events are those occurring in 1/100 to 1/1 000 patients; rare events are those occurring in fewer than 1/1 000 patients.

Autonomic Nervous System: rare, cold clammy skin.

Body as a Whole: infrequent, pallor, allergy, enlarged abdomen, substernal chest pain, edema, allergic reaction, ascites, precordial chest pain, therapeutic response increased, ischemic necrosis, edema generalised; rare, periorbital edema, face edema, halitosis.

Cardiovascular: infrequent, cardiac failure, heart disorder, specific abnormal ECG, aneurysm, cardiomegaly, abnormal ECG, aggravated hypertension; rare, cyanosis, fluid overload, heart valve disorder.

Central and Peripheral Nervous System: frequent, neuralgia; infrequent, hypertonia, speech disorder, choreoathetosis, abnormal coordination, dysphonia, extrapyramidal disorder, migraine, aphasia, coma, convulsions, hypotonia, nerve root lesion, peripheral neuropathy, paralysis, stupor; rare, cerebral atrophy, grand mal convulsions, hemiparesis, hemiplegia, hyperreflexia, neuropathy, ptosis, sensory disturbance, hydrocephaly.

Collagen: rare, rheumatoid arthritis.

Endocrine: infrequent, gynecomastia, hypothyroidism; rare, SIADH (syndrome of inappropriate antidiuretic hormone secretion), increased thyroxine, goitre, hyperthyroid.

Gastrointestinal: frequent, gastrointestinal disorder (NOS); infrequent, gastritis, gastroenteritis, gastroesophageal reflux, increased appetite, esophagitis, peptic ulcer, diverticulitis, hemorrhoids, hiccup, tooth caries, increased amylase, duodenal ulcer, duodenitis, fecal incontinence, gastrointestinal hemorrhage, glossitis, rectal hemorrhage, melena, pancreatitis, rectal disorder, altered saliva, stomatitis, ulcerative stomatitis, tongue edema, gastric ulcer, tooth disorder; rare, esophageal stricture, esophageal ulceration, hemorrhagic gastritis, gingival bleeding, hematemesis, lactose intolerance, salivary duct obstruction, tenesmus, tongue disorder, hemorrhagic duodenal ulcer, aggravated tooth caries.

Hearing: infrequent, earache, decreased hearing, vestibular disorder, ear disorder (NOS); rare, hyperacusis, deafness.

Heart Rate and Rhythm: infrequent, arrhythmia, bundle branch block, cardiac arrest, supraventricular extrasystoles, ventricular tachycardia; rare, atrioventricular block.

Liver and Biliary: Infrequent, abnormal hepatic function, increased ALT, bilirubinemia, cholecystitis, cholelithiasis, hepatocellular damage, increased AST; rare, biliary pain, aggravated bilirubinemia, gallbladder disorder.

Metabolic and Nutritional: frequent, increased blood urea nitrogen; infrequent, increased LDH, increased NPN, hyperuricemia, increased weight, hyperphosphatemia, diabetes mellitus, glycosuria, hypercholesterolemia, acidosis, hypokalemia, hyponatremia, thirst, increased creatine phosphokinase, dehydration, aggravated diabetes mellitus, hyperkalemia; rare, electrolyte abnormality, enzyme abnormality, hypochloremia, obesity, increased phosphatase acid, decreased serum iron.

Musculoskeletal: frequent, arthrosis; infrequent, arthropathy, osteoporosis, tendinitis, bone disorder, bursitis, muscle weakness, polymyalgia rheumatica, skeletal pain, torticollis, rare, muscle atrophy, myositis, Dupuytren’s contracture, spine malformation.

Myocardial, Endocardial, Pericardial Valve: frequent, angina pectoris; infrequent, myocardial infarction, aggravated angina pectoris; rare, mitral insufficiency.

Neoplasm: infrequent, carcinoma, malignant female breast neoplasm, dermoid cyst, malignant skin neoplasm, prostate adenocarcinoma, adenocarcinoma, neoplasm (NOS); rare, bladder carcinoma, benign brain neoplasm, breast fibroadenosis, malignant endometrial neoplasm, esophageal carcinoma, malignant larynx neoplasm, malignant lymphoma, malignant neoplasm, neuroma, lipoma, rectal carcinoma, uterine neoplasm.

Platelet Bleeding and Clotting: infrequent, purpura, thrombocytopenia, hematoma.

Psychiatric: frequent, aggravated depression, agitation; infrequent, increased libido, sleep disorder, apathy, dementia, delirium, emotional lability, psychosis, aggressive reaction, delusion, psychotic depression, euphoria, decreased libido, manic reaction, neurosis, personality disorder, somnambulism; rare, suicide attempt.

Red Blood Cell: infrequent, hypochromic anemia, anemia B12 deficiency; rare, polycythemia.

Female Reproductive: infrequent, amenorrhea, menstrual disorder, vaginal hemorrhage, uterine disorders (NOS); rare, female breast enlargement, intermenstrual bleeding, mastitis, uterine hemorrhage, dysmenorrhea.

Male Reproductive: Infrequent, epididymitis, balanoposthitis, ejaculation failure, penis disorder, perineal pain; rare, Peyronie’s disease, ejaculation disorder, testis disorder.

Resistance Mechanism: frequent, infection; infrequent, herpes zoster, moniliasis, otitis media, sepsis, herpes simplex, fungal infection, abscess, bacterial infection, genital moniliasis; rare, poliomyelitis.

Respiratory: frequent, pneumonia; infrequent, asthma, epistaxis, laryngitis, pleurisy, increased sputum, pulmonary edema; rare, hypoxia, respiratory insufficiency, vocal cord paralysis.

Skin and Appendages: infrequent, dermatitis, alopecia, skin discoloration, dry skin, skin hypertrophy, skin ulceration, fungal dermatitis, eczema, hyperkeratosis, photosensitivity reaction, psoriasis, maculopapular rash, psoriaform rash, seborrhea, skin disorder, urticaria, furunculosis; rare, bullous eruption, nail disorder, nevus, photosensitivity allergic reaction, aggravated psoriasis, skin exfoliation, abnormal skin odor.

Other Special Senses: rare, parosmia.

Urinary: infrequent, albuminuria, dysuria, nocturia, polyuria, renal calculus, abnormal urine, micturition disorder; rare, oliguria, pyelonephritis, renal cyst, acute renal failure, renal pain, uremia, urethral disorder, urinary casts, bladder calculus, nephritis.

Vascular Extracardiac: infrequent, cerebrovascular disorder, vein disorder, varicose vein, peripheral gangrene, phlebitis, vascular disorder; rare, atherosclerosis, limb embolism, pulmonary embolism, gangrene, superficial phlebitis, subarachnoid hemorrhage, deep thrombophlebitis, leg thrombophlebitis, thrombosis, arteritis.

Vision: infrequent, conjunctivitis, blepharitis, abnormal accommodation, blepharospasm, eye pain, glaucoma, photophobia, scotoma; rare, blindness, blindness temporary, hemianopia, keratitis, photopsia, macula lutea degeneration, vitreous detachment, retinal disorder.

White Cell and Reticuloendothelial System: infrequent, leukocytosis, leukopenia, lymphopenia, lymphedema, lymphocytosis; rare, lymphadenopathy, granulocytopenia.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: There were no reports of intentional overdose of ropinirole in the premarketing clinical trials. A total of 27 patients accidentally took more than their prescribed dose of ropinirole, with 10 patients ingesting more than 24 mg/day. The largest overdose reported in premarketing clinical trials was 435 mg taken over a 7-day period (62.1 mg/day). Of patients who received a dose greater than 24 mg/day, one experienced mild oro-facial dyskinesia, another patient experienced intermittent nausea. Other symptoms reported with accidental overdoses were: agitation, increased dyskinesia, grogginess, sedation, orthostatic hypotension, chest pain, confusion, vomiting and nausea.

It is anticipated that the symptoms of ropinirole overdose 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.

Dosage And Administration: Ropinirole should be taken 3 times daily. While administration of ropinirole with meals may improve gastrointestinal tolerance, ropinirole may be taken with or without food (see Pharmacology, Pharmacokinetics).

The recommended starting dosage is 0.25 mg 3 times daily. Based on individual patient response, dosage should then be titrated by weekly increments of 0.25 mg/dose. After week 4, daily dosage may be increased by 0.5 to 1 mg/dose on a weekly basis up to 24 mg/day. Doses greater than 24 mg/day have not been tested in clinical trials. Smaller dose increments are recommended for patients who may be at risk for orthostatic symptoms. In clinical trials, initial benefits were observed with 3 mg/day and higher doses.

When ropinirole is administered as adjunct therapy to levodopa, the dose of levodopa may be decreased gradually as tolerated once a therapeutic effect with ropinirole has been observed (see Pharmacology, Clinical Trials).

Ropinirole should be discontinued gradually over a 7-day period. The frequency of administration should be reduced from 3 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.

Renal and Hepatic Impairment: In patients with mild to moderate renal impairment, ropinirole may be titrated in the recommended manner according to clinical response. Patients with severe renal impairment or on hemodialysis have not been studied and administration of ropinirole to such patients is not recommended.

Patients with hepatic impairment have not been studied and administration of ropinirole to such patients is not recommended.

Estrogen Replacement Therapy: In patients already receiving estrogen replacement therapy, ropinirole may be titrated in the recommended manner according to clinical response. However, if estrogen replacement therapy is stopped or started during treatment with ropinirole, adjustment of the ropinirole dosage may be required.

Availability And Storage: 0.25 mg: Each white, pentagonal, film-coated, beveled-edged Tiltab tablet, imprinted with SB and 4890, contains: ropinirole HCl 0.25 mg. Nonmedicinal ingredients: croscarmellose sodium, hydrous lactose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80 and titanium dioxide. Sucrose-, tartrazine- or any other azo dyes-free. Bottles of 100.

1 mg: Each pale green, pentagonal, film-coated, beveled-edged Tiltab tablet, imprinted with SB and 4892, contains: ropinirole HCl 1 mg. Nonmedicinal ingredients: croscarmellose sodium, FD&C Blue No. 2 aluminum lake, hydrous lactose, hydroxypropyl methylcellulose, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide. Sucrose-, tartrazine- or any other azo dyes-free. Bottles of 100.

2 mg: Each pale pink, pentagonal, film-coated, beveled-edged Tiltab tablet, imprinted with SB and 4893, contains: ropinirole HCl 2 mg. Nonmedicinal ingredients: croscarmellose sodium, hydrous lactose, hydroxypropyl methylcellulose, iron oxide red, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol and titanium dioxide. Sucrose-, tartrazine- or any other azo dyes-free. Bottles of 100.

5 mg: Each pale blue, pentagonal, film-coated, beveled-edged Tiltab tablet, imprinted with SB and 4894, contains: ropinirole HCl 5 mg. Nonmedicinal ingredients: croscarmellose sodium, FD&C Blue No. 2 aluminum lake, hydrous lactose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, talc and titanium dioxide. Sucrose-, tartrazine- or any other azo dyes-free. Bottles of 100.

Store between 15 and 30°C, in tightly closed containers. Protect from light.

REQUIP™ SmithKline Beecham Ropinirole HCl Antiparkinsonian Agent – Dopamine Agonist

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