Kinetica

Each prolonged-release tablet contains: Ropinirole (as hydrochloride) 2 mg, 4 mg, or 8 mg.

Anti-parkinson drug (dopamine agonist).
Pharmacology: Pharmacodynamics: Ropinirole, a dipropylaminoethyl indolone derivative, is a non-ergoline D₂/D₃ dopamine receptor agonist. Although the exact mechanism of action of ropinirole is unknown, its antiparkinson activity is thought to be associated with its ability to stimulate central postsynaptic dopamine D₂ receptors in the corpus striatum of the brain.
Ropinirole acts in the hypothalamus and pituitary to inhibit the secretion of prolactin. Neither ropinirole nor its metabolites has high affinity to dopamine D₁ receptors. Ropinirole binds to opiate receptors with low affinity. However, in vivo studies showed that the weak opiate activity has no effect at pharmacological doses. Ropinirole has little or no affinity for serotonin type 1 (5-HT₁), serotonin type 2 (5-HT₂), benzodiazepine, gamma-aminobutyric acid, muscarinic, alpha-or beta-adrenoceptors.
Pharmacokinetics: Bioavailability of ropinirole is approximately 50% (range: 36% to 57%). Following oral administration, ropinirole plasma concentrations increase slowly, with a median time to peak plasma concentration (t_max) generally achieved between 6 to 10 hours.
Ropinirole hydrochloride 2 mg, 4 mg, and 8 mg prolonged-release tablets (KRKA, Slovenia) were shown to be bioequivalent to the reference product (innovator).
In two different studies, a single dose of ropinirole hydrochloride 2 mg and 4 mg prolonged-release tablets were administered in adult male volunteers under fasting conditions. The results showed that 90% Confidence Interval for the geometric means of maximum plasma concentration (C_max), area under the concentration-time curve from time 0 to the last measurable concentration (AUC_0-1) and AUC from time 0 to infinity (AUC_0-inf) of ropinirole 2 mg and 4 mg prolonged-release tablets are within the predefined bioequivalence limits of 80 to 125%. (See Table 1.)

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In a separate study, 8 mg prolonged-release tablets were administered for five consecutive days. The results showed that 90% Confidence Interval for the geometric means of maximum plasma concentration at steady state (C_{max, ss}), minimum plasma concentration at steady state (C_{min, ss}), and area under the concentration-time curve from one dosing interval at steady-state (AUC_0-Tss) of ropinirole 8 mg prolonged-release tablet are within the predefined bioequivalence limits of 80 to 125%. (See Table 2.)

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Compared with dosing under fasting conditions, high-fat meal increased the systemic exposure of ropinirole 12 mg prolonged-release tablet in Parkinson's disease patients, as shown by the increase in the AUC and peak plasma concentration (C_max) by 20% and 44% on average, respectively. Although t_max was delayed by 3 hours, these changes are unlikely to be clinically relevant (e.g., increased incidence of adverse events) and patients were instructed to take ropinirole prolonged-release tablet without regard to food intake.
The systemic exposure of ropinirole prolonged-release tablets is comparable to that of ropinirole immediate-release tablets based on the same daily dose. Ropinirole is highly lipophilic, thus the drug has a large volume of distribution (approximately 7 L/kg). The plasma protein binding of ropinirole is 10 to 40%.
Steady-state concentrations of ropinirole are expected to be attained within 4 days of dosing. The increase in systemic exposure (C_max and AUC) to ropinirole is in proportion over the therapeutic dose range. Thus, patients taking ropinirole three times a day has two-fold higher steady-state plasma concentrations compared to those observed in patients taking a single oral dose. The average oral clearance (47 L/h) of ropinirole is constant over the entire dosage range and in single and repeated oral administration.
Wide inter-individual variability in the pharmacokinetic parameters has been observed. Following steady-state administration, the inter-individual variability for C_max was between 30% and 55% and for AUC was between 40% and 70%.
Ropinirole is primarily metabolized in the liver by CYP1A2. The major metabolic pathways are N-despropylation and hydroxylation to form the N-despropyl metabolite, which is the major metabolite. Animal models of dopaminergic function show that the N-despropyl metabolite is at least 100 times less potent than ropinirole. The N-despropyl metabolite is converted to carbamyl glucuronide, carboxylic acid, and N-despropyl hydroxyl metabolites, while the hydroxy metabolite of ropinirole is rapidly glucuronidated.
Ropinirole metabolites are mainly excreted in the urine. Ropinirole is cleared from the systemic circulation with an average elimination half-life of about 6 hours (ranging from 2 to 27 hours). N-despropyl ropinirole is the predominant metabolite found in the urine (40%), followed by the carboxylic acid metabolite (10%) and the glucuronide of the hydroxyl metabolite (10%). Less than 10% of the administered dose is excreted as unchanged drug.
Special Populations: Renal impairment: There was no clinically significant change observed in the pharmacokinetics of ropinirole in Parkinson's disease patients with mild to moderate renal impairment [creatinine clearance (CrCl) 30 to 50 mL/min].
In patients with end stage renal disease receiving regular hemodialysis, the oral clearance of ropinirole is decreased by approximately 30%. Oral clearance of the metabolites SKF-104557 and SKF-89124 were also reduced by approximately 80% and 60%, respectively.
Hepatic Impairment: The pharmacokinetics of ropinirole has not been studied in patients with hepatic impairment. Since ropinirole is extensively metabolized by the liver, higher plasma levels and lower clearance of ropinirole may be anticipated in patients with hepatic impairment.
Elderly: Compared with younger patients, the oral clearance of ropinirole is decreased by 15% in patients older than 65 years old.

Ropinirole is indicated for the following: Treatment of Parkinson's disease; early therapy in patients requiring dopaminergic therapy; as adjunctive treatment to levodopa, ropinirole enhances the efficacy of levodopa, including control of "on-off" fluctuations and "end of dose" effects associated with chronic levodopa therapy and permits reduction in daily levodopa dose.

The dose should be titrated according to individual clinical response and tolerability of the patient.
Ropinirole hydrochloride prolonged-release tablets should be taken once a day, at a similar time each day. The prolonged-release tablets may be taken with or without food.
Ropinirole hydrochloride prolonged-release tablets must be swallowed whole and must not be chewed, crushed, or divided because the coating is intended to ensure a prolonged release.
Ropinirole hydrochloride prolonged-release tablets are designed to release the medication over a 24-hour period. If a rapid gastrointestinal transit occurs, there may be a risk of incomplete release of medication, and of medication residue being passed in the stool.
Adults: Initial titration: The starting dose of ropinirole is 2 mg once daily for the first week; this should be increased to 4 mg once daily from the second week of treatment. A therapeutic response may be seen at a dose of 4 mg once daily.
Patients who initiate treatment with a dose of 2 mg/day and who experience undesirable effects that they cannot tolerate, may benefit from switching to treatment with ropinirole immediate-release tablets at a lower daily dose, divided into three equal doses.
Therapeutic regimen: Patients should be maintained on the lowest dose of ropinirole that achieves symptomatic control.
If sufficient symptomatic control is not achieved or maintained at a dose of 4 mg once daily, the daily dose may be increased by 2 mg at weekly intervals or longer, up to a dose of 8 mg once daily.
If sufficient symptomatic control is still not achieved or maintained at a dose of 8 mg once daily, the daily dose may be increased by 2 mg to 4 mg at every two-week intervals or longer. The maximum daily dose of ropinirole is 24 mg.
When ropinirole is administered as adjunct therapy to levodopa, it may be possible to gradually reduce the levodopa dose, depending on the clinical response. In clinical trials on patients receiving ropinirole, the levodopa dose was gradually reduced by approximately 30%.
It is recommended that patients are prescribed the minimum number of ropinirole prolonged-release tablets that are necessary to achieve the required dose by utilizing the highest available strengths of ropinirole prolonged-release tablets.
If treatment is interrupted for one day or more, re-initiation by dose titration should be considered.
Dose titration due to adverse events: Treatment with ropinirole should be down-titrated. If the patient experiences disabling somnolence at any dose level. For other adverse events, down-titration followed by gradual up-titration has been beneficial to patients.
Switching from another dopamine agonist to ropinirole hydrochloride prolonged-release tablets: When switching treatment from another dopamine agonist to ropinirole hydrochloride prolonged-release tablet, the instructions on discontinuation of the withdrawn treatment should be followed before initiating treatment with ropinirole.
Switching from ropinirole immediate-release tablets to ropinirole hydrochloride prolonged-release tablets: Patients may be switched overnight from ropinirole immediate-release tablets to ropinirole hydrochloride prolonged-release tablets. The dose of ropinirole hydrochloride prolonged-release tablets should be based on the total daily dose of ropinirole immediate-release tablets that the patient was taking. The following table shows the recommended dose of ropinirole hydrochloride prolonged-release tablets for patients switching from ropinirole immediate-release tablets: (See Table 3.)

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After switching to ropinirole hydrochloride prolonged-release tablets, the dose may be adjusted depending on the therapeutic response (see Initial titration and Therapeutic regimen as mentioned previously).
Treatment Discontinuation: As with other dopamine agonists, it is necessary to discontinue ropinirole treatment gradually by reducing the daily dose over the period of one week.
Special Populations: Renal impairment: In patients with mild to moderate renal impairment (CrCl 30 to 50 mL/min), no change in the clearance of ropinirole was observed, indicating that no dosage adjustment is necessary in this population.
For patients with end stage renal disease receiving hemodialysis, the recommended initial dose of is 2 mg once daily. Further dose escalations should be based on tolerability and efficacy. The recommended maximum dose is 18 mg/day in patients receiving regular hemodialysis. Supplemental doses after dialysis are not required.
The use of ropinirole is not recommended in patients with severe renal impairment (CrCl <30 mL/min) who are not undergoing regular hemodialysis.
Hepatic Impairment: The administration of ropinirole prolonged-release tablets is contraindicated in patients with hepatic impairment.
Children: The use of ropinirole prolonged-release tablets in children less than 18 years of age is not recommended.
Elderly: The clearance of ropinirole is decreased by approximately 15% in patients aged 65 years or above. Although a dose adjustment is not required, ropinirole dose should be individually titrated, with careful monitoring of tolerability, to the optimal clinical response. In patients aged 75 years and above, slower titration during treatment initiation may be considered.

Overdose and treatment: The largest accidental overdose reported in premarketing clinical trials was 435 mg ingested over for a seven-day period (62.1 mg/day). The following symptoms were observed in patients who had accidental ropinirole overdose of more than 24 mg/day: orofacial dyskinesia, intermittent nausea, agitation, increased dyskinesia, grogginess, sedation, orthostatic hypotension, chest pain, confusion, vomiting, visual hallucinations, hyperhidrosis, claustrophobia, chorea, palpitations, asthenia, and nightmares. Additional overdose symptoms include increased coughing, fatigue, syncope, and vasovagal syncope.
The symptoms of ropinirole overdose are related to its dopaminergic activity. Symptoms of overdose may be managed by appropriate treatment with dopamine antagonists, such as neuroleptics or metoclopramide. However, the efficacy of these drugs in reversing the effects of overdose has not been assessed. General supportive measures should be provided to the patient, and vital signs should be maintained, if necessary. Cardiovascular monitoring is also recommended.

Hypersensitivity to ropinirole or to any component in the product; patients with severe renal impairment (creatinine clearance <30 mL/min) who are not undergoing regular hemodialysis; hepatic impairment; pregnancy; breastfeeding.

Sudden Onset of Sleep: Ropinirole has been associated with somnolence and episodes of suddenly falling asleep while engaging in activities of daily living, such as driving or operating machinery, which has sometimes resulted in accidents. Although cases of sudden onset of sleep while engaged in daily living usually occur in a setting of pre-existing somnolence, others may not give such a history. Thus, prescribers should reassess patients for drowsiness or sleepiness, especially since some of the events occur well after treatment initiation. However, some of these adverse events have been reported as late as one year after starting ropinirole therapy. Patients may not be aware of excessive drowsiness or sleepiness, perceived that they had no warning signs (e.g., excessive drowsiness), and that they were alert immediately prior to the event until directly questioned about drowsiness or sleepiness during specific activities.
Many Parkinson's disease patients experience alterations in sleep architecture, resulting to excessive daytime sleepiness or spontaneous dozing; however, the exact cause of these events is not yet known. In addition, dopaminergic agents can also induce sleepiness. There is insufficient information to determine whether this event is associated with ropinirole, all dopaminergic agents or Parkinson's disease itself.
Patients should be advised of the potential occurrence of drowsiness before starting treatment with ropinirole. In addition, the patient should be specifically asked about the factors that may increase the risk of drowsiness, such as concomitant use of sedating medications or alcohol; sleep disorders; or coadministration of drugs that may increase ropinirole plasma levels (see Interactions).
If a patient develops significant daytime sleepiness or episodes of falling asleep during activities that require active participation (e.g., driving, conversation, eating), dose reduction or treatment discontinuation should be considered (see Dosage & Administration). However, there is insufficient information to establish that dose reduction will lessen the risk of falling asleep while engaged in activities of daily living. If a decision is made to continue treatment with ropinirole, patients should be advised to avoid driving and other potentially dangerous activities. Physicians should inform patients of the reported cases of sudden onset of sleep, since these events are not limited to treatment initiation. Patients should also be advised that sudden onset of sleep may occur even without warning signs. Patients should contact their physician immediately if drowsiness or sudden onset of sleep occurs.
Cardiovascular Effects: Patients with pre-existing cardiovascular conditions: Ropinirole has not been studied in patients with a history or evidence of significant cardiovascular disease, such as myocardial infarction, unstable angina, cardiac decompensation, cardiac arrhythmias, vaso-occlusive disease (including cerebral) or cardiomyopathy. Due to its pharmacologic action, ropinirole should be used with caution in patients with these conditions or those with severe cardiovascular disease.
Hypotension/Orthostatic hypotension: Patients with Parkinson's disease may have impaired capacity to respond to hypotension after standing from a seated position or from lying down. In addition, dopamine agonists may impair the systemic regulation of blood pressure with resulting orthostatic symptoms of dizziness or light-headedness, with or without documented hypotension. These symptoms occur particularly during dose initiation and escalation. Significant decrements in blood pressure unrelated to standing were also reported. Therefore, patients treated with ropinirole and other dopamine agonists should be informed of this risk and be carefully monitored for signs and symptoms of orthostatic hypotension, especially during dose initiation/escalation and in patients at risk of hypotension, those receiving antihypertensive and antiarrhythmic drugs (see Interactions), those who poorly tolerate transient hypotensive episodes, and those with severe cardiovascular disease, particularly coronary insufficiency.
Syncope: Syncope, sometimes associated with bradycardia, has been observed in patients with Parkinson's disease during ropinirole therapy.
Elevation of Blood Pressure and Changes in Heart Rate: Increased incidence of elevations of systolic and/or diastolic blood pressure and/or change in pulse occurred in both titration and maintenance phase of ropinirole therapy. In some cases, this effect developed in the titration phase and persisted up to the maintenance period. The elevations of blood pressure and/or changes in heart rate should be considered in patients with cardiovascular disease.
Fibrotic Complications: Ergot-derived dopamine agonists have been associated with cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusion, pleural thickening, pericarditis, and cardiac valvulopathy. Although ropinirole is not an ergot, possible fibrotic complications (i.e., pleural effusion, pleural fibrosis, interstitial lung diseases, and cardiac valvulopathy) have been reported with ropinirole in postmarketing studies. Patients should be closely monitored for signs and symptoms of fibrosis.
While discontinuation may resolve these complications, complete resolution does not always occur.
Effects on the Central Nervous System: Withdrawal-Emergent Hyperpyrexia and Confusion: A symptom complex resembling neuroleptic malignant syndrome with no other obvious etiology has been reported with significant dose reduction in, or abrupt withdrawal of antiparkinsonian therapy after long-term use. The syndrome is characterized by elevated temperature, muscular rigidity, altered consciousness, and autonomic instability. It is recommended that the dose must be tapered at the end of treatment.
Dyskinesia with Adjunctive Levodopa: Ropinirole may cause or exacerbate pre-existing dyskinesia due to its potentiation of the dopaminergic adverse effects of levodopa. Decreasing the dose of levodopa may ameliorate this effect.
Psychiatric Effects: Impulse Control/Compulsive Behaviors: Impulse control symptoms, including compulsive behaviors (e.g., pathological gambling, increased libido, hypersexuality, compulsive shopping, and binge eating), have been reported in patients treated with ropinirole or other dopamine agonists, especially at high doses. In some cases, these symptoms were generally reversible upon dose reduction or treatment discontinuation. Other factors that may increase these urges, such as a history of compulsive behaviors or concurrent dopaminergic treatment, may also be present.
Since patients may not recognize that these behaviors were abnormal, patients should be regularly monitored for the development of impulse control disorders. It is also important for prescribers to specifically ask patients or their caregivers about the development of new or increased incidences of compulsive behaviors while being treated with ropinirole. Dose reduction or tapered discontinuation should be considered if the patient develops such compulsive behaviors.
Aggression has been associated with psychotic reactions as well as compulsive symptoms.
Hallucinations/Psychotic-like Behavior: Patients may experience new or worsening mental status and behavioral changes, which may be severe, including psychotic-like behavior, during initiation of treatment with ropinirole or after increasing the dose. Other drugs prescribed to improve the symptoms of Parkinson's disease can have similar effects on thinking and behavior. The manifestations of abnormal thinking and behavior include paranoid ideation, delusions, hallucinations, confusion, psychotic-like behavior, disorientation, aggressive behavior, agitation, and delirium.
Since ropinirole may exacerbate psychosis, it should only be used in patients with a history or presence of major psychotic disorder if the potential benefits outweigh the risks of treatment. In addition, certain medications used to treat psychosis may aggravate the symptoms of Parkinson's disease and may decrease the effectiveness of ropinirole (see Interactions).
Hallucination is a known adverse effect of treatment with dopamine agonist and levodopa. Patients and caregivers should be informed that hallucinations may occur during ropinirole treatment.
Dermatologic Effects: Epidemiological studies demonstrated that patients with Parkinson's disease have a 2- to 6-fold higher risk of developing melanoma compared with the general population. However, it is unclear if the increased risk observed was due to Parkinson's disease or to the drugs used to manage the disease. Patients and caregivers are advised to monitor for melanomas frequently and regularly during ropinirole treatment. Skin examinations should be performed periodically.
Dopamine Agonist Withdrawal Syndrome: Non-motor adverse effects, such as apathy, anxiety, depression, fatigue, sweating, and pain, may occur when tapering or discontinuing dopamine agonists; these effects may be severe. Treatment with ropinirole should not be abruptly discontinued (see Dosage & Administration). Patients should be informed of this risk before tapering ropinirole therapy, and monitored regularly thereafter. In case of persistent symptoms, it may be necessary to temporarily increase the dose of ropinirole.
Effects on Ability to Drive and Use Machines: Ropinirole may have a significant effect on the ability to drive and use machines since it may cause sudden onset of sleep without any prior warning or apparent daytime somnolence and dizziness, including vertigo. Patients should be informed of this risk and be warned not to drive or engage in other activities where impaired alertness could put themselves and others at risk of serious injury or death (e.g., operating machines), until these episodes and somnolence have been resolved. Since cases of falling asleep while engaged in activities of daily living also occurred in patients taking other dopaminergic agents, symptoms may not be alleviated by substituting these products.
Hepatic Impairment: Since the use of ropinirole in patients with hepatic impairment has not been studied, the use of ropinirole in such patients is not recommended.
Renal Impairment: Dose adjustments are not necessary for patient with mild to moderate renal impairment. Since the use of ropinirole in patients with severe renal impairment (CrCl <30 mL/min without regular dialysis) has not been studied, the use of ropinirole in such patients is not recommended. In patients with end stage renal disease on hemodialysis, a lower maximum dose is recommended which, compared to the maximum exposure evaluated in clinical trials, results in similar exposure to ropinirole, and to a 4.5-fold increased exposure to the N-despropyl inactive metabolite (see Dosage & Administration).
Use in Children: The effectiveness and safety of ropinirole in children below 18 years of age have not been established.
Use in the Elderly: The oral clearance of ropinirole is decreased in patients older than 65 years of age. The dosing of ropinirole for elderly patients should be titrated individually based on clinical therapeutic response and tolerability. For patients 75 years and older, slower titration during treatment initiation is recommended (see Dosage & Administration).

Pregnancy: Ropinirole has been shown to have developmental and teratogenic effects in animals. There are no adequate or well-controlled studies in pregnant women. Ropinirole concentrations may also gradually increase during pregnancy. Thus, ropinirole should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Patients should also notify their physicians if they become pregnant or intent to become pregnant during ropinirole therapy.
Lactation: There are no data regarding the excretion of ropinirole in human milk. Suppression of lactation is anticipated because ropinirole inhibits prolactin secretion in humans. Since the infant may be exposed to dopamine agonist activity, ropinirole should not be used by breastfeeding patients.

The most common adverse events associated with ropinirole include nausea, dizziness (including vertigo), somnolence, sudden onset of sleep, headache, hallucinations, peripheral edema, vomiting, abdominal pain or discomfort, syncope, fatigue, viral infection, and dyskinesia.
Infections and infestations: Abscess, bacterial infection, bronchitis, candidiasis, fungal infection, herpes simplex, infections, nasopharyngitis, periodontitis, poliomyelitis, sepsis, upper respiratory tract infection, urinary tract infection.
Neoplasms benign, malignant and unspecified (including cysts and polyps): Adenocarcinoma, basal cell carcinoma, benign brain neoplasm, bladder carcinoma, brain neoplasm, breast fibroadenosis, carcinoma, dermoid cyst, esophageal carcinoma, lipoma, malignant female breast neoplasm, fungal dermatitis, malignant endometrial neoplasm, malignant larynx neoplasm, malignant lymphoma, malignant neoplasm, malignant skin neoplasm, neoplasm, prostate adenocarcinoma, rectal carcinoma, uterine neoplasm.
Blood and lymphatic system disorders: Anemia, eosinophilia, granulocytopenia, hypochromic anemia, leukocytosis, leukopenia, lymphadenopathy, lymphopenia, lymphedema, lymphocytosis, polycythemia, thrombocytopenia, vitamin B12 deficiency anemia.
Immune system disorders: Angioedema, hypersensitivity.
Endocrine disorders: Goiter, hypothyroidism, syndrome of inappropriate antidiuretic hormone secretion, hyperthyroidism.
Metabolism and nutrition disorders: Acidosis, aggravated diabetes mellitus, anorexia, dehydration, diabetes mellitus, electrolyte imbalance, enzyme abnormality, fluid overload, generalized edema, gout, hypercholesterolemia, hyperglycemia, hyperkalemia, hyperphosphatemia, hyperuricemia, hypochloremia, hypoglycemia, hypokalemia, hyponatremia, increased appetite, lactose intolerance, obesity, thirst, weight loss.
Psychiatric disorders: Abnormal dreams, agitation, aggravated depression, aggression, anxiety, apathy, binge eating, compulsive shopping, confusion, delirium, delusion, depersonalization, depression, disturbance in attention, dopamine dysregulation syndrome, drowsiness, emotional lability, euphoria, gambling disorder, hypersexuality, illusion, impulse control disorder, insomnia, manic reaction, major depression, neurosis, nightmare, paranoia, personality disorder, psychosis, psychotic disorder, sleep disorder, somnambulism, suicide attempt, thinking abnormal.
Nervous system disorders: Abnormal coordination, abnormal gait, aggravated Parkinson's disease, amnesia, aphasia, ataxia, blepharospasm, carpal tunnel syndrome, cerebral atrophy, choreoathetosis, coma, convulsions, dementia, dysphonia, dystonia, extrapyramidal disorder, generalized tonic-clonic seizure, hemiparesis, hemiplegia, hydrocephalus, hypoesthesia, hyperesthesia, hyperkinesia, hyperreflexia, hypertonia, hypokinesia, hypotonia, involuntary muscle contractions, migraine, mental status change, neuroma, nervousness, neuralgia, nerve root lesion, neuropathy, paresis, paresthesia, peripheral neuropathy, paralysis, ptosis, sensory disturbance, speech disorder, stupor, tremor, vocal cord paralysis.
Eye disorders: Accommodation disorder, abnormal lacrimation, blepharitis, blindness, cataract, conjunctivitis, diplopia, eye disorder, eye pain, hemianopia, glaucoma, keratitis, macular degeneration, periorbital edema, photophobia, retinal disorder, scotoma, transient blindness, visual impairment, xerophthalmia.
Ear and labyrinth disorders: Deafness, ear disorder, ear pain, hyperacusis, hypoacusis, otitis media, tinnitus, vestibular disorder.
Cardiac disorders: Aggravated angina pectoris, angina pectoris, arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, bundle branch block, cardiac arrest, cardiac failure, cardiac valve disease, cardiomegaly, chest pain (precordial, substernal), extrasystoles, heart disorder, mitral valve incompetence, myocardial infarction, palpitations, supraventricular extrasystoles, supraventricular tachycardia, tachycardia, ventricular tachycardia.
Vascular disorders: Aggravated hypertension, aneurysm, angiopathy, arteritis, atherosclerosis, cerebrovascular disorder, cyanosis, deep vein thrombosis, flushing, gangrene, hematoma, hemorrhoids, hypertension, hypotension, ischemic necrosis, orthostatic hypotension, pallor, peripheral embolism, peripheral ischemia, phlebitis, superficial phlebitis, systolic hypertension, systolic orthostatic hypotension, thrombophlebitis, thrombosis, varicose vein, vein disorder.
Respiratory, thoracic, and mediastinal disorders: Asthma, bronchitis, cough, dyspnea, epistaxis, hypoxia, increased sputum, influenza, interstitial pulmonary disease, laryngitis, nasal congestion, parosmia, pharyngitis, pleural effusion, pleurisy, pneumonia, pulmonary edema, pulmonary embolism, respiratory disorder, respiratory failure, rhinitis, sinusitis, yawning.
Gastrointestinal disorders: Abdominal distension, aggravated tooth caries, altered saliva, constipation, colitis, diarrhea, diverticulitis, dry mouth, duodenal ulcer, duodenal ulcer hemorrhage, duodenitis, dysgeusia, dyspepsia, dysphagia, esophageal stricture, esophageal ulcer, esophagitis, fecal incontinence, flatulence, gastric ulcer, gastritis, gastroenteritis, gastroesophageal reflux disorder, gastrointestinal disorder, gastrointestinal hemorrhage, gingival bleeding, gingivitis, glossitis, halitosis, hematemesis, hemorrhagic gastritis, hiccup, increased salivation, melena, mouth ulceration, pancreatitis, peptic ulcer, rectal disorder, rectal hemorrhage, salivary duct obstruction, salivary hypersecretion, stomatitis, tenesmus, tongue disorder, tongue edema, toothache, tooth caries, tooth disorder, xerostomia.
Hepatic and hepatobiliary disorders: Abnormal hepatic function, aggravated bilirubinemia, ascites, biliary colic, bilirubinemia, cholecystitis, cholelithiasis, gall bladder disorder, hepatic reactions, hepatocellular damage.
Skin and subcutaneous tissue disorders: Aggravated psoriasis, alopecia, bullous eruption, cellulitis, dermatitis, dry skin, eczema, furuncle, herpes zoster, hyperkeratosis, nail disorder, nevus, photosensitivity allergic reaction, photosensitivity reaction, pruritus, psoriasis, purpura, rash, rash erythematous, rash maculopapular, rash psoriaform, seborrhea, skin discoloration, skin disorder, skin exfoliation, skin hypertrophy, skin ulcer, urticaria.
Musculoskeletal and connective tissue disorders: Aggravated arthritis, arthralgia, arthritis, arthropathy, back pain, bone disorder, bursitis, Dupuytren's contracture, leg cramps, limb pain, muscle atrophy, muscle cramps, muscle spasms, muscular weakness, myalgia, myositis, osteoporosis, polymyalgia rheumatica, rheumatoid arthritis, rigors, skeletal pain, spine malformation, tendonitis, torticollis.
Renal and urinary disorders: Abnormal urine, acute renal failure, albuminuria, bladder calculus, cystitis, dysuria, glycosuria, hematuria, micturition disorder, micturition frequency, nephritis, nocturia, oliguria, polyuria, pyelonephritis, pyuria, renal calculus, renal cyst, renal pain, uremia, urethral disorder, urinary incontinence, urinary retention.
Reproductive system and breast disorders: Amenorrhea, balanoposthitis, decreased libido, dysmenorrhea, epididymitis, ejaculation disorder, ejaculation failure, female breast enlargement, genital candidiasis, gynecomastia, impotence, increased libido, metrorrhagia, mastitis, menstrual disorder, penis disorder, perineal pain, Peyronie's disease, prostatic disorder, testicular disorder, uterine disorders, uterine hemorrhage, vaginal hemorrhage.
General disorders and administration site conditions: Asthenia, cold sweat, decreased therapeutic response, dopamine agonist withdrawal syndrome, face edema, fever, gravitational edema, hyperhidrosis, increased therapeutic response, influenza-like illness, malaise, pain.
Investigations: Abnormal electrocardiogram, decreased blood pressure, decreased diastolic blood pressure, decreased heart rate, decreased serum iron, decreased systolic blood pressure, decreased weight, increased alanine aminotransferase, increased alkaline phosphatase, increased amylase, increased aspartate aminotransferase, increased blood urea nitrogen, increased creatine phosphokinase, increased drug level, increased gamma-glutamyltranspeptidase levels, increased heart rate, increased hepatic enzymes, increased lactate dehydrogenase, increased phosphokinase, increased thyroxine, increased weight, urinary casts.
Injury, poisoning and procedural complications: Fall, injury, subarachnoid hemorrhage, vitreous detachment.

Alcohol: As with other centrally-active medications, patients should be cautioned not to concomitantly take ropinirole with alcohol.
Antihypertensives: 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.
Central nervous system (CNS) depressants: Because of the possible additive sedative effects, caution should be observed when coadministering ropinirole with CNS depressants (e.g., benzodiazepines, antipsychotics, antidepressants).
CYP1A2 inhibitors or inducers: In vitro studies demonstrated that CYP1A2 was the major enzyme responsible for the metabolism of ropinirole. Thus, coadministration of the inhibitors or inducers of this enzyme may alter the clearance of ropinirole. Dose adjustments may be necessary if a potent inhibitor of CYP1A2 is discontinued or initiated during treatment with ropinirole.
The extent of systemic availability and peak plasma concentration of ropinirole 2 mg immediate-release tablet given three times a day was increased by 60% and 84%, respectively, with the coadministration of ciprofloxacin. Cigarette smoking is expected to increase the clearance of ropinirole since it is known that smoking induces CYP1A2 activity. Adjustments in ropinirole doses may be required in patients who are smoking or in those planning to stop smoking.
In patients already administered with CYP1A2 inhibitor (e.g., ciprofloxacin, enoxacin, cimetidine, fluvoxamine), ropinirole may be started in the recommended manner and the dose be titrated according to clinical response. However, ropinirole dosage adjustments will be required if therapy with a CYP1A2 is discontinued or introduced during ropinirole treatment.
CYP1A2 substrates: A pharmacokinetic study revealed that there is no change in the pharmacokinetics of both ropinirole and theophylline, a representative of substrates of CYP1A2. Therefore, there are no expected changes in the pharmacokinetics of ropinirole coadministered with other CYP1A2 substrates.
Digoxin: At steady state, coadministration of ropinirole 2 mg given three times daily resulted in a 10% decrease in digoxin AUC, while mean trough digoxin plasma concentrations were not altered. The effect of higher recommended ropinirole doses on the pharmacokinetics of digoxin is not yet known.
Domperidone: No dose adjustment is needed during the coadministration of ropinirole with domperidone, a peripherally-active dopamine agonist.
Drugs used to treat Parkinson's disease: No interaction was observed between ropinirole and other drugs commonly used to manage Parkinson's disease.
Hormone Replacement Therapy (HRT): Higher doses of estrogens (0.6 to 3 mg), predominantly conjugated estrogens, decreased the clearance of ropinirole by 33% in postmenopausal women receiving HRT. Ropinirole treatment may be started in the normal manner. However, adjustments of ropinirole dosage may be required when concomitant HRT is initiated or discontinued.
Levodopa: In levodopa-naive patients, the rate and extent of availability of ropinirole 2 mg administered three times a day at steady state were the same with or without levodopa. The rate and extent of availability, as well as the elimination half-life of levodopa, were unchanged in the presence and absence of ropinirole. There is no pharmacokinetic interaction between ropinirole and levodopa that would require dosage adjustments of either drugs.
Psychotropic Drugs: The concomitant use of ropinirole with neuroleptics (e.g., phenothiazines, butyrophenones, thioxanthenes) or other centrally-active dopamine antagonists (e.g., metoclopramide, sulpiride) is not recommended because these drugs may diminish the effect of ropinirole.
Vitamin K antagonists: Cases of unbalanced international normalized ratio (INR) have been reported in patients receiving ropinirole with vitamin K. Increased clinical and biological surveillance of INR is recommended.

Store at temperatures not exceeding 30°C.
Store in the original package in order to protect from moisture.

Antiparkinsonian Drugs

N04BC04 - ropinirole ; Belongs to the class of dopamine agonist. Used in the management of Parkinson's disease.

Rx