Ropinirole

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 Requip.

Population pharmacokinetic analysis revealed that higher doses of estrogens (usually associated with hormone replacement therapy (HRT)) reduced the clearance of ropinirole. Starting or stopping HRT may require adjustment of dosage of Requip.

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

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

For more Interactions (Complete) data for ROPINIROLE (12 total), please visit the HSDB record page.

Ropinirole has been reported to cause serum aminotransferase or alkaline phosphatase elevations in a small proportion of patients, but these abnormalities are usually mild, asymptomatic and self-limiting even without dose adjustment. Ropinirole has been implicated in a small number of cases of acute liver injury, but the clinical characteristics and typical pattern of enzyme elevations has not been characterized. In one case report, the time to onset was 2 months and the pattern of liver enzyme elevations was mixed and associated with marked jaundice. Immunoallergic and autoimmune features were not present. The injury resolved within 2 months of stopping. Thus, ropinirole can cause acute, clinically apparent liver injury with jaundice, but it is rare.；Likelihood score: D (possible, rare cause of clinically apparent liver injury).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1700(SRC), determined from a log Kow of 2.70(2) and a regression-derived equation(3), indicates that ropinirole is expected to have low mobility in soil(SRC). The estimated pKa of the tertiary amine of ropinirole is 10.17(4), indicating that this compound will exist almost in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5). Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Ropinirole is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.3X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(3). Biodegradation data in soil were not available(SRC, 2015).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1700(SRC), determined from a log Kow of 2.70(2) and a regression-derived equation(3), indicates that ropinirole is expected to adsorb to suspended solids and sediment(SRC). An estimated pKa of the tertiary amine of 10.17(4) indicates ropinirole will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(5), an estimated BCF of 28(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2015).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), ropinirole, which has an estimated vapor pressure of 6.3X10-8 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase ropinirole may be removed from the air by wet and dry deposition(SRC). Ropinirol contains chromophores that absorb at wavelengths >290 nm(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Rare cases of hypersensitivity reactions, falling asleep during activities of daily living, somnolence (especially if concomitantly using CNS depressants), hallucinations, compulsive behaviors, augmentation, early morning rebound RLS, fibrotic complications, and retinal degeneration are also reported in clinical trials and postmarketing experience.；Peripheral edema: Peripheral edema has been reported in up to one-third of the patients on the extended-release form.；Anterocollis: The definition of this condition is the head positioned in flexion, resembling a "drooping head," a rare side effect reported in a patient taking ropinirole. Discontinuation of the medication progressively reversed the symptoms within 4 months.；Pisa syndrome: Cases of ropinirole-induced Pisa syndrome, referred to as "pleurothotonus," have been recorded. The condition is characterized by an abnormal lateral flexion of the trunk to the right or left. This condition occurred after a year on the medication and resolved 3 months after cessation of treatment. However, some reports maintain that Pisa syndrome is irreversible despite discontinuing this medication.；Reversible dyskinesias: Another movement disorder observed with ropinirole is severe reversible dyskinesias, which is very rare. This dose-dependent choreoform dyskinesia occurred in ropinirole monotherapy up to a dose of 15 mg daily but was also observed at a dose of 6 mg daily.；Dermal eruptions: Similar to other D2 agonists, ropinirole rarely caused fixed dermal eruptions. This adverse effect is thought to be due to the inactivation of T cells.；Dopamine-agonist withdrawal syndromes: Withdrawal-emergent hyperpyrexia and confusion are reported in patients where ropinirole treatment is abruptly stopped or the dose is rapidly tapered down. This condition resembles neuroleptic malignant syndrome without specific etiology. Withdrawal symptoms include insomnia, anxiety, apathy, depression, sweating, fatigue, and pain, which do not respond to treatment with levodopa. Recommendations include informing patients about the potential for withdrawal symptoms and monitoring symptoms during taper down and after treatment cessation.；Impulse control disorders: Case reports of increased sexual drive, gambling, and binge eating have been reported. The mechanism of action is thought to be the stimulation of dopamine D3 receptors by dopamine agonists. Patients have reported an inability to control their urges. Patients may not convey problems to clinicians due to embarrassment. In severe cases, clinicians should consider decreasing the dose of ropinirole; severe cases may require cessation of therapy. It acts as a dopamine agonist, which can trigger manic symptoms in susceptible patients.；Drug-Drug Interactions；CYP1A2 enzyme is induced by omeprazole and smoking and can decrease the plasma concentration of ropinirole. CYP1A2 is inhibited by fluoroquinolones (eg, ciprofloxacin and norfloxacin), fluvoxamine, and mexiletine. The administration of these drugs may increase the plasma level of this drug.；Hormone replacement therapy (HRT, high dose estrogens) reduces the clearance of ropinirole; dose adjustment may be required when starting or stopping HRT.；Dopamine antagonists phenothiazines, thioxanthenes, butyrophenones, and metoclopramide can reduce the efficacy of ropinirole. Concurrent administration of ropinirole and metoclopramide should be avoided.；As with most dopamine agonists, ropinirole's most frequently reported adverse effects include nausea, vomiting, dyspepsia, abdominal pain, hallucinations, drowsiness, dizziness, leg edema, viral infection, syncope, orthostatic hypotension, and asthenic condition (ie, weakness, fatigue, and malaise).

IDENTIFICATION AND USE: Ropinirole hydrochloride, a dipropylaminoethyl indolone derivative, is a nonergot-derivative dopamine receptor agonist. It is used for the symptomatic management of idiopathic parkinsonian syndrome. It is also used for the symptomatic management of moderate-to-severe primary restless legs syndrome (RLS).HUMAN EXPOSURE AND TOXICITY: The largest overdose reported with ropinirole in 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, reported symptoms included adverse events commonly reported during dopaminergic therapy (nausea, dizziness), as well as visual hallucinations, hyperhidrosis, claustrophobia, chorea, palpitations, asthenia, and nightmares. Additional symptoms reported for doses of 24 mg or less or for overdoses of unknown amount included vomiting, increased coughing, fatigue, syncope, vasovagal syncope, dyskinesia, agitation, chest pain, orthostatic hypotension, somnolence, and confusional state. Postmarketing reports indicate that patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior during treatment with ropinirole or after starting or increasing the dose of ropinirole. 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, disorientation, aggressive behavior, agitation, and delirium. Case 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, that increase central dopaminergic tone and that are generally used for the treatment of Parkinson's disease and RLS. In some cases, although not all, these urges were reported to have

Ropinirole can cause death when taken with alcohol, and persons who excessively consume alcohol should not use the drug. A lethal level up to 6 times the therapeutic dose correlates with death.；Patients with liver insufficiency require close monitoring; a case report of liver toxicity exists. The medication is metabolized primarily in the liver, and the toxicity may be due to an immune reaction or a possible toxic metabolite.；Signs and Symptoms of Overdose；Of these patients who used doses exceeding 24 mg per day, commonly reported adverse reactions were related to its dopaminergic activity, ie, nausea, dizziness, hyperhidrosis, visual hallucinations, claustrophobia, palpitations, chorea, asthenia, and nightmares. Additional symptoms reported in overdose patients included vomiting, agitation, chest pain, increased coughing, fatigue, orthostatic hypotension, syncope, dyskinesia, somnolence, and a confusional state. A recent study describes shock and arrhythmias as the probable reason for mortality associated with ropinirole overdose.；Management of Overdose；There have been reports of patients who intentionally or accidentally took more than the maximum recommended daily dose of ropinirole in clinical trials. General supportive measures are recommended, and vitals should be maintained when necessary. In clinical trials, the most significant overdose reported with ropinirole was 62 mg daily for 7 days (total dose 435 mg).

Symptoms of overdose include agitation, chest pain, confusion, drowsiness, facial muscle movements, grogginess, increased jerkiness of movement, symptoms of low blood pressure (dizziness, light-headedness)upon standing, nausea, and vomiting.

The Koc of ropinirole is estimated as 1700(SRC), using a log Kow of 2.70(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that ropinirole is expected to have low mobility in soil. The estimated pKa of the tertiary amine of ropinirole is 10.17(4), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(5).

/HUMAN EXPOSURE STUDIES/ Ropinirole, SK&F 101468 has been characterized preclinically as a specific dopamine D2-receptor agonist. Nine male healthy subjects were investigated for the effects on supine and erect heart rate and blood pressure, catecholamines and prolactin, of a single dose of 800 micrograms ropinirole preceded by a single dose of 20 mg domperidone or domperidone-placebo, and those of a single dose of domperidone followed by ropinirole-placebo. Single doses of 800 micrograms ropinirole did not cause clinically significant changes in supine resting heart rate and blood pressure. However, they caused postural faintness on 3 min immobile upright standing on 10/26 occasions. Pretreatment with 20 mg domperidone 1 hr before administration of ropinirole prevented the postural symptoms in all but one subject. It did not alter ropinirole's plasma pharmacokinetics. Ropinirole did not alter supine or standing catecholamine concentrations. Domperidone increased the plasma concentrations of prolactin whereas ropinirole administered alone reduced them. A single dose of 800 micrograms ropinirole did not attenuate the prolactin increase induced by a single dose of 20 mg domperidone administered 1 hr earlier.

/HUMAN EXPOSURE STUDIES/ Pramipexole and ropinirole are ... dopamine agonists, both of which have proven efficacy in the treatment of Parkinson's disease. There is, however, uncertainty regarding differences in the adverse event profiles associated with each drug. ... We systematically reviewed the medical literature to identify randomised controlled trials of pramipexole and ropinirole used in the management of Parkinson's disease. Computerised databases (including Medline, Embase, the Cochrane Library, and the International Pharmaceutical Abstracts) were used to identify pertinent articles for inclusion in this study. Trials that compared the dopamine agonists to either levodopa or placebo were included. Adverse events with these drugs included dizziness, nausea, hypotension, hallucinations, and somnolence. We made two separate analyses. In the first analysis, we estimated the pooled relative risk (RR) of adverse events with either pramipexole or ropinirole as compared with levodopa. In the second analysis, the pooled RRs of adverse events with pramipexole and ropinirole were compared with placebo. We used the random-effects model of DerSimonian and Laird to estimate the RRs and their corresponding 95% CIs. We tested for study heterogeneity using Q statistics. RESULTS: There was no significant difference in the risk of dizziness, nausea, or hypotension with either drug individually or in combination when compared with levodopa. The risk of hypotension was approximately four times higher with ropinirole than pramipexole when each drug was individually compared with placebo (6.46 [95% CI 1.47-28.28] for ropinirole, and 1.65 [0.88-3.08] for pramipexole). The pooled RR (for pramipexole and ropinirole combined) of hallucinations was 1.92 (95% CI 1.08-3.43) when compared with levodopa. Relative to placebo, pramipexole had a significantly higher risk of hallucinations than ropinirole (pramipexole 5.2 (95% CI 1.97-13.72) vs ropinirole 2.75 (95% CI 0.55-13.73)). There was

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including ropinirole hydrochloride, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act. /Ropinirole hydrochloride/

MEDICATION

Antiparkinson Agents; Dopamine Agonists

Use (kg; approx.) in Germany (2009): >75；Consumption (g per capita; approx.) in Germany (2009): 0.000916；Calculated removal (%): 11.8

For the treatment of the signs and symptoms of idiopathic Parkinson's disease. Also used for the treatment of restless legs syndrome.

The acid chloride of 2-(2-methyl-3-nitrophenyl)acetic acid is prepared with thionyl chloride, then treated with dipropylamine to form the amide. The carbonyl group is reduced with borane in THF and then reacted with diethyl oxalate and sodium in alcohol in a Claisen-type reaction to produce the ethyl ester of 3-[[2-(dipropylamino)ethyl]-6-nitrophenyl]pyruvic acid. Hydrolysis and decarboxylation of the acid with peroxide and base removes the ethoxycarbonyl group and forms 2-[2-(dipropylamino)ethyl]-6-nitrophenylacetic acid. Cyclization to the product is effected by catalytic reduction of the nitro group, using palladium/hydrogen to give the amine, which through loss of water forms the lactam (indolone). Heating with HCl forms ... /ropinirole hydrochloride/. /Ropinirole hydrochloride/

Preparation: G. Gallagher, Jr., United States of America patent 4452808 (1984 to SmithKline Beckman)