Approval date: February 24, 2014
Date of revision.
Year
February
Date
Ropinirole hydrochloride extended release tablets
Please read the instructions carefully and use under the guidance of a physician
Drug Name
Generic name: Ropinirole Hydrochloride Sustained-release Tablets
English name: Ropinirole Hydrochloride Sustained-release Tablets
Hanyu Pinyin: Yansuan Luopiniluo Huanshipian
Ingredients
Chemical name: 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one hydrochloride
Chemical structure formula.
Molecular formula: C16H24N2O- HCl
Molecular weight: 296.84
Properties
This product is pink (2mg specification) or light brown (4mg specification) or red (8mg specification) film-coated tablet, after removing the coating, it is a three-layer tablet, the first and third layer shows yellow, the middle layer shows white.
Indications
This product is used in combination with levodopa to treat the signs and symptoms of Parkinson’s disease.
It can be used when the efficacy of levodopa decreases or when there are repeated fluctuations in the therapeutic effect (end-of-dose phenomenon or “switch” fluctuations).
Specification
2mg, 4mg, 8mg (based on C16H24N2O)
Dosage and Administration
Take orally.
Individualized dose titration is recommended based on efficacy and tolerability. This product should be taken once a day at a similar time. This product must be swallowed whole, not chewed, crushed or broken.
This product may be taken with or without food. In some patients on a high-fat diet, it may increase bioavailability and double the AUC and Cmax (see [Pharmacokinetics] for details).
Adults
Initial titration
The starting dose of this product is 2 mg once daily in week 1; the dose is adjusted upward to 4 mg once daily starting in week 2 of treatment. A therapeutic effect may be observed at a dose of 4 mg once daily.
Treatment regimen
Patients should be maintained on the lowest dose of this product that is effective in controlling symptoms.
If symptoms are not effectively controlled or maintained at a dose of 4 mg/day, the dose may be gradually increased by 2 mg daily at intervals of one week or longer until 8 mg/day is reached.
If symptoms are not effectively controlled or maintained at the 8 mg/day dose, the dose may be continued to be increased by 2-4 mg/day at intervals of 2 weeks or longer. The maximum daily dose of this product is 24 mg.
The maximum size of this product is recommended so that the patient uses the fewest number of tablets to achieve the desired daily dose.
If treatment is interrupted for more than one day, a restart of treatment based on a dose adjustment regimen needs to be considered.
When administered as adjunctive therapy to levodopa, the dose of levodopa may be gradually reduced based on clinical response. In clinical trials, the dose of levodopa could be gradually reduced by approximately 30% in patients taking this product concurrently. In patients with advanced Parkinson’s disease receiving this product in combination with levodopa, xerostomia may occur during the initial titration of this product. Reducing the levodopa dose has been found to improve isokinetic disorder in clinical trials (see [Adverse Reactions]).
When switching from other dopamine receptor agonists to this product, refer to the appropriate product insert for discontinuation instructions prior to starting this product.
As with other dopamine agonists, treatment with this product must be discontinued gradually, with a gradual reduction in daily dose over a period of one week.
Interruption of Dosing or Discontinuation
If discontinuation of treatment is required, the daily dose should be gradually reduced over a one-week interval.
Renal impairment
No change in clearance of ropinirole has been observed in Parkinson’s disease patients with mild to moderate renal impairment (creatinine clearance of 30-50 ml/min), indicating that no dose adjustment is required in this population.
A study of ropinirole in patients with end-stage renal disease (dialysis patients) showed that the following dose adjustments were required in these patients.
The recommended initial dose of this product is 2 mg/day. Further dose escalation is required based on tolerability and efficacy. For patients receiving conventional dialysis, the recommended maximum dose is 18 mg/day. Supplemental dosing after dialysis is not required.
The use of ropinirole has not been studied in patients with severe renal impairment (creatinine clearance less than 30 ml/min) who are not on regular dialysis.
Hepatic impairment
The use of ropinirole has not been studied in patients with hepatic impairment. Ropinirole is not recommended in these patients.
Elderly
The clearance of ropinirole is reduced by approximately 15% in patients 65 years of age or older. Although no dose adjustment is required, the dose of ropinirole should be individually titrated while closely monitoring tolerability until optimal clinical outcomes are achieved. For patients aged 75 years or older, a slower titration rate at the beginning of treatment may be considered.
Children and Adolescents
Due to the lack of safety and efficacy data, this product is not recommended for use in children aged 18 years or younger.
[Adverse Reactions].
The overall safety profile of ropinirole includes adverse reactions from clinical trials and post-marketing dosing for all indications.
The following adverse reactions are described in more detail under [Precautions].
Falling asleep during daily activities
Syncope
Symptomatic hypotension, low blood pressure, upright hypotension
Elevated blood pressure and changes in heart rate
hallucinations
Hyperkinetic disorder
Serious mental disorder
Dopaminergic treatment events
Retinal pathological changes
The following adverse events are summarized by system organ classification and frequency. Frequency was defined as very common (≥1/10), common (≥1/100,<1/10), uncommon (≥1/1000,<1/100), rare (≥1/10,000,<1/1000), and very rare (<1/10,000, including isolated event reports).
Clinical trial data
The following are adverse drug reactions to ropinirole that occurred at a higher rate than placebo, or at the same or higher rate than the control drug, in clinical trials. Unless otherwise noted, the following data are from reports of immediate-release and extended-release dosage forms.
Mental disturbances
Common: hallucinations, confusion1.
Neurological disorders
Very common: allodynia3.
Common: drowsiness2, dizziness (including vertigo)
Vascular disorders
common: postural hypotension2, hypotension2.
Gastrointestinal disorders
common: nausea, constipation2.
Systemic diseases and administration site reactions
Common: peripheral edema2.
1. clinical trial data for immediate-release dosage forms.
2. clinical trial data for extended-release dosage forms.
3. In patients with advanced Parkinson’s disease, xerostomia can occur at regular intervals during the initial titration of this product. Reducing the levodopa dose was found to alleviate the isokinetic disorder in clinical trials (see [Dosage]).
Post-marketing data
The following events were also reported in post-marketing reports of ropinirole hydrochloride in the treatment of patients with Parkinson’s disease.
Immune system disorders
Very rare: allergic reactions (including urticaria, angioneurotic edema, rash, pruritus)
Psychiatric disorders
Unusual: psychotic reactions (except hallucinations) including delirium, delusions, paranoia symptoms of impulse control disorders, impulse hyperactivity including increased sexual desire, compulsive shopping, binge drinking, pathological gambling (see [Caution]).
Neurological disorders
Extremely rare: extreme drowsiness, sudden sleep attacks*.
* As with other dopaminergic drugs, very few cases of excessive somnolence and sudden sleep attacks have been reported post-marketing, primarily in patients with Parkinson’s disease. Patients who present with sudden sleep attacks are unable to resist falling asleep and may not feel fatigued before falling asleep. For the available data, all cases recovered after dose reduction or withdrawal. In most cases patients were taking concomitant medications with sedative effects.
Vascular disorders
Common: hypotension, postural hypotension**.
** As with other dopamine agonists, hypotension including postural hypotension has been previously observed in ropinirole therapy.
Gastrointestinal disorders
Very common: nausea.
common: heartburn.
Hepatobiliary disorders
Unknown: hepatic reactions, mainly elevated liver enzymes. (Unknown: The frequency of adverse events is not available from the available data)
[Contraindicated].
Hypersensitivity to ropinirole or any of the excipients.
Precautions]
1. Sleeping during daily activities
Sleeping during daily activities (including operation of motor vehicles) has been reported in patients treated with this product, sometimes resulting in accidents. Although drowsiness has been reported in many patients using this product, some patients do not have warning signs such as excessive sleepiness and believe that they can be awake immediately before the event. Some of these events were reported more than one year after initiation of treatment.
Of the 613 patients who received ropinirole hydrochloride extended-release tablets in the clinical study, there were five cases of sudden sleepiness and two motor vehicle accidents, and it is unclear whether falling asleep was the cause of the accidents.
In the 6-month clinical study of advanced Parkinson’s disease, the incidence of somnolence was 7% (14/202) in the ropinirole hydrochloride extended-release tablet group and 4% (7/191) in the placebo group. However, because no systematic studies of dose response have been conducted with ropinirole hydrochloride extended-release tablets, the incidence of drowsiness at the highest recommended dose may be higher than the reported incidence (see [Adverse Reactions] for details).
Many clinical experts believe that falling asleep during daily activities usually occurs in the presence of preexisting drowsiness, although the patient may not have a history of such. Therefore, physicians should consistently repeat evaluations of patients regarding sleepiness or drowsiness, especially if some event occurs after initiation of therapy. The physician should also be aware that the patient may not be aware of being sleepy or drowsy until asked if he or she is sleepy or drowsy during a particular event.
Before initiating ropinirole hydrochloride extended-release tablet therapy, patients should be informed of the possibility of drowsiness and, in particular, asked about the presence of factors that may increase the risk of ropinirole hydrochloride extended-release tablets, such as the combination of sedative medications, the presence of sleep disorders, and the combination of medications that can increase plasma levels of this product (e.g., ciprofloxacin; see [Drug Interactions] for details). Ropinirole Hydrochloride Extended-Release Tablets should usually be discontinued if a patient experiences a significant episode of daytime sleepiness or sleepiness during activities that require active participation (e.g., driving a motor vehicle, talking, eating a meal, etc.). If the decision is made to continue ropinirole hydrochloride extended-release tablets, patients should be advised not to drive vehicles and to avoid other potentially hazardous activities. There is insufficient information to determine whether a dose reduction will eliminate sleep attacks during the performance of daily activities.
2 .Syncope
Syncopal reactions, sometimes associated with bradycardia, have been observed during the treatment of patients with Parkinson’s disease with this product.
In a placebo-controlled study in patients with advanced Parkinson’s disease, syncope occurred in 2 (1%) of 202 patients who received ropinirole hydrochloride extended-release tablets and none of the 191 patients who received placebo.
Because patients with severe cardiovascular disease were excluded from the clinical study, the incidence of syncope in patients with Parkinson’s disease in clinical practice cannot be estimated. Therefore, this product should be used with caution in patients with severe cardiovascular disease.
3 .Low blood pressure
In clinical studies and clinical experience, dopamine agonists can impair the systemic regulation of blood pressure, resulting in postural hypotension, especially during dose escalation. In addition, patients with Parkinson’s disease often have an impaired ability to respond to postural excitation. The mechanism of action of ropinirole-induced postural hypotension is thought to be due to a blunted D2-mediated noradrenergic response to standing and a subsequent decrease in peripheral vascular resistance. Nausea is a common concomitant of uprightness signs and symptoms. For these reasons, patients treated with dopamine agonists should generally: (1) need to be monitored for signs and symptoms of postural hypotension, especially during dose escalation; and (2) patients should be informed of this risk .
Changes in blood pressure in some patients in clinical studies were associated with the development of erectile symptoms and bradycardia, and one healthy subject experienced a transient sinus arrest with syncope. In a placebo-controlled study involving patients with advanced Parkinson’s disease, hypotensive adverse events were reported in 5 of 202 patients in the ropinirole hydrochloride extended-release tablet group and were not reported in 191 patients in the placebo group. Upright hypotension was reported in 5% of the ropinirole hydrochloride extended-release tablet group and 1% of the placebo group.
A randomized, double-blind, placebo-controlled study of patients with advanced Parkinson’s disease enrolled in the study was analyzed using various terms for adverse events that may suggest hypotension, including hypotension, upright hypotension, dizziness, vertigo, and decreased blood pressure. This analysis showed a higher incidence of these events in the ropinirole hydrochloride extended-release tablet group (7%, 15/202) than in the placebo group (3%, 6/191). The context for this difference in incidence was that patients were all receiving very careful dose titration and the study excluded patients with clinically relevant cardiovascular disease or symptomatic upright hypotension at baseline.
Monitoring of upright vital signs (recumbent to standing) was maintained throughout the course of the Advanced Parkinson’s Disease Study, and changes from baseline associated with ropinirole hydrochloride extended-release tablets (compared with placebo) were evaluated.
Regarding the frequency of any upright hypotension at any time during the study: the incidence of mild to moderate systolic blood pressure reduction (≥20 mm Hg) was 38% in the ropinirole hydrochloride extended-release tablet group and 31% in the placebo group; the incidence of mild to moderate diastolic blood pressure reduction (≥10 mm Hg) was 63% in the ropinirole hydrochloride extended-release tablet group and 58% in the placebo group; and the incidence of severe diastolic blood pressure reduction (≥20 mm Hg) was 10% in the ropinirole hydrochloride extended-release group and 7% in the placebo group, and the incidence of mild to moderate combined systolic and diastolic blood pressure reductions was 23% in the ropinirole hydrochloride extended-release group and 19% in the placebo group.
Some patients taking ropinirole hydrochloride extended-release tablets also reported significant reductions in blood pressure unrelated to rising and standing. In the reclined position, the incidence of major systolic blood pressure reductions (≥40 mm Hg) was 10% in the ropinirole hydrochloride extended-release tablet group and 8% in the placebo group, and the incidence of major diastolic blood pressure reductions (≥20 mm Hg) was 25% in the ropinirole hydrochloride extended-release tablet group and 21% in the placebo group.
An increased incidence of hypotension and/or upright hypotension was observed in some cases during the titration and maintenance phases and in the transition to the maintenance phase after the titration phase.
4. Elevated blood pressure and heart rate changes
In placebo-controlled studies in advanced Parkinson’s disease, ropinirole hydrochloride extended-release tablets had no significant effect on mean changes in blood pressure or heart rhythm compared with placebo. However, there was an increased probability of abnormalities in ropinirole hydrochloride extended-release tablet-treated patients, as described below.
In the reclined position, the incidence of severe systolic blood pressure elevation (≥40 mm Hg) was 8% in the ropinirole hydrochloride extended-release tablet group and 5% in the placebo group; in the standing position, the incidence of severe systolic blood pressure elevation (≥40 mm Hg) was 9% in the ropinirole hydrochloride extended-release tablet group and 6% in the placebo group.
In the reclined position, the incidence of moderate pulse rate elevation (≥15 beats/min) was 23% in the ropinirole hydrochloride extended-release tablet group and 18% in the placebo group, and the incidence of moderate pulse rate reduction (≥15 beats/min) was 19% in the ropinirole hydrochloride extended-release tablet group and 17% in the placebo group. In the standing position, the incidence of severe pulse rate elevation (≥30 beats/min) was 2% in the ropinirole hydrochloride extended-release tablet group and <1% in the placebo group; the incidence of moderate pulse rate reduction (≥15 beats/min) was 24% in the ropinirole hydrochloride extended-release tablet group and 19% in the placebo group.
Increases in the incidence of various systolic and/or diastolic blood pressure elevations and/or increases in the incidence of pulse rate changes were observed during the titration and maintenance phases and during the transition to the maintenance phase after the titration phase.
Elevated blood pressure and/or heart rate changes should be considered in patients taking ropinirole hydrochloride extended-release tablets when treating patients with comorbid cardiovascular disease.
5. Hallucinations
In double-blind, placebo-controlled, clinical studies of advanced Parkinson’s disease, hallucinations were reported in 8% (17/202) of the ropinirole hydrochloride extended-release tablet group and 2% (4/191) of the placebo group. The incidence of hallucinations leading to discontinuation of treatment was 2% (4/202) in the ropinirole hydrochloride extended-release tablet group and 1% (2/191) in the placebo group.
The incidence of hallucinations was increased in patients over 65 years of age. Concomitant administration of this product with entacapone and levodopa also increased the risk of hallucinations. In placebo-controlled clinical studies, none of the 43 patients taking entacapone plus levodopa had hallucinations, 9 (6%) of the 155 patients taking ropinirole hydrochloride extended-release tablets + levodopa and 7 (15%) of the 47 patients taking ropinirole hydrochloride extended-release tablets + entacapone + levodopa had hallucinations.
6. Heterokinesia
Ropinirole hydrochloride extended-release tablets can enhance the dopaminergic adverse effects of levodopa and lead to the occurrence of xerostomia and/or exacerbation of existing xerostomia in patients treated with levodopa for Parkinson’s disease. Reducing the dose of dopamine drug may reduce this adverse effect.
7.Severe psychiatric disorders
Patients with severe psychiatric disorders are usually not treated with ropinirole hydrochloride extended-release tablets because of the risk of worsening psychosis. In addition, many antipsychotic drugs can reduce the efficacy of ropinirole hydrochloride extended-release tablets (see [Drug Interactions] for details).
8. Events reported with dopaminergic therapy
Withdrawal-induced hyperthermia and confusion: Although no such events were reported during the clinical development of this product, syndromes resembling neuroblocker malignant syndrome (manifested by elevated body temperature, muscle rigidity, impaired consciousness, and autonomic dysregulation) associated with rapid dose reduction, withdrawal, or changes in dopaminergic therapy with no other apparent etiology have been reported. Therefore, as a precautionary measure, a gradual dose reduction at the end of treatment with ropinirole hydrochloride extended-release tablets is recommended (see [Dosage] for details).
Complications of Fibrosis: Some patients treated with ergot dopamine preparations have reported cases of retroperitoneal fibrosis, pulmonary infiltrates, pleural effusions, pleural thickening, pericarditis, and cardiac valvular lesions. These complications may subside when the drug is discontinued, but generally do not subside completely.
Although these adverse reactions are thought to be related to the ergot structure of the complex, it is unclear whether other non-ergot dopamine agonists (such as ropinirole hydrochloride tablets or ropinirole hydrochloride extended-release tablets) may cause these reactions.
A few reports of possible complications of fibrosis have been received in the development program and post-marketing experience with this product, including pleural effusion, pleural fibrosis, interstitial lung disease, and cardiac valvular lesions. In the clinical development program (N = 613), pleural effusions occurred in 2 patients treated with ropinirole hydrochloride extended-release tablets. Although this evidence is insufficient to establish a causal relationship between this product and these fibrotic complications, an association cannot be completely ruled out.
Melanoma: Several epidemiologic studies have shown a higher risk of melanoma in patients with Parkinson’s disease than in the general population. It is unclear whether this observed increased risk is due to Parkinson’s disease or other factors (e.g., medications used to treat Parkinson’s disease). This product is one of the dopamine agonists used to treat Parkinson’s disease. Although not specifically associated with an increased risk of melanoma, its potential role as a risk factor has not been systematically studied. In the clinical development program (N = 613), melanoma occurred in 1 patient using ropinirole hydrochloride extended-release tablets with concomitant levodopa/carbidopa. Users of ropinirole hydrochloride extended-release tablets should be informed of these findings and should be screened dermatologically on a regular basis.
9. Retinal pathological changes
Human: As a result of findings in albino rats, electroretinography (ERG) was evaluated in a 2-year, double-blind, multicenter, fixed-dose, levodopa-controlled clinical study of immediate-release ropinirole tablets in patients with Parkinson’s disease. A total of 156 patients (78 on immediate-release ropinirole tablets at a mean dose of 11.9 mg/day and 78 on levodopa at a mean dose of 555.2 mg/day) were evaluated by ERG for retinal dysfunction. There were no clinically significant differences in retinal function between treatment groups during the study period.
Rats: In the 2-year carcinogenicity study, retinal degeneration was observed in rats at all doses tested (equivalent to 0.6 to 20 times the maximum recommended human dose (MRHD) of 24 mg/day based on mg/m2), but was statistically significant at the highest dose (50 mg/kg/day). However, no retinal degeneration was observed in colored rats after 3 months in a 2-year carcinogenicity study in mice, or in a 1-year study in monkeys or rats. The significance of this effect has not been established in humans, but this should not be overlooked, as the disruption of mechanisms normally seen in vertebrates (e.g., disc detachment) also occurs in humans.
10 , Binding to melanin
In colored rats, the product was found to bind to melanin-containing tissues (e.g., eyes, skin). After single-dose administration, the drug proved to remain in the body for a long time, with a half-life of 20 days in the eyes.
11, Effects on driving and mechanical ability
There are no data on the effect of ropinirole on driving or mechanical handling ability. Patients should be aware of their ability to drive or operate machinery because of the possibility of drowsiness and dizziness (including vertigo) while taking this product.
Patients must be advised that there have been rare cases of sudden sleep attacks without any warning or cases of significant daytime drowsiness (see [ADVERSE REACTIONS]), primarily in patients with Parkinson’s disease, and that patients should be aware of the risk to their own and others’ safety if such events occur while driving or operating machinery. Patients should be advised not to drive and to avoid other potentially risky activities if they experience significant episodes of daytime sleepiness or drowsiness during activities that require active participation.
12 , This product also contains lactose. Patients with rare genetic galactose intolerance, Lapp lactase deficiency, or glucose
–
This product should not be used in patients with rare genetic galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption.
13, 4 mg tablets contain azo coloring agent sunset yellow (E110), which may cause allergic reactions.
14, Drug dependence
Animal and human studies of this product have not shown any possibility of drug seeking behavior or physical dependence.
Pregnant women and nursing mothers
Pregnant women
Pregnancy Classification C. Adequate and rigorously controlled studies of ropinirole have not been conducted in women during pregnancy. Therefore, ropinirole hydrochloride extended-release tablets should be administered during pregnancy only if the potential benefit outweighs the potential risk to the fetus.
Lactating Women
Ropinirole hydrochloride inhibits prolactin secretion in humans and therefore may inhibit lactation. Studies in rats have shown that ropinirole hydrochloride and/or its metabolites are excreted through breast milk. It is not known whether it is excreted in human milk. Because many drugs are excreted in human milk, and because ropinirole hydrochloride may cause serious adverse effects in nursing infants, women should not breastfeed while taking the drug.
Pediatric Dosage]
The safety and efficacy of the drug in pediatric patients have not been established.
Geriatric use]
No dose adjustment is required in elderly patients (65 years of age or older) because the dose of ropinirole hydrochloride extended-release tablets is individually titrated based on clinical response (see [Pharmacokinetics] for details). Pharmacokinetic studies in patients have demonstrated a 15% reduction in oral clearance of ropinirole in patients 65 years of age and older compared to younger patients.
Of all Parkinson’s disease patients enrolled in the clinical study of ropinirole hydrochloride extended-release tablets, 387 were 65 years of age and older, and 107 patients were 75 years of age and older. In patients receiving ropinirole hydrochloride extended-release tablets, hallucinations were more common in older subjects (10%) than in non-older subjects (2%). The incidence of overall adverse events increased with age in both patients receiving ropinirole hydrochloride extended-release tablets and placebo.
[Drug Interactions].
P450 enzymes
In vitro metabolism studies have shown that CYP1A2 is the primary enzyme responsible for the metabolism of ropinirole. Therefore inducers or inhibitors of this enzyme have the potential to alter the clearance of ropinirole. A pharmacokinetic study in patients with Parkinson’s disease showed that ciprofloxacin (CYP1A2 inhibitor) increased the Cmax and AUC of ropinirole by 60% and 84%, respectively. Therefore, for patients already receiving this product, dose adjustment may be required when drugs known to inhibit CYP1A2 (ciprofloxacin, enoxacin, cimetidine, or fluvoxamine, etc.) are used or discontinued.
A pharmacokinetic interaction trial in patients with Parkinson’s disease studied the interaction of ropinirole with theophylline, a representative CYP1A2 substrate, and showed no change in the pharmacokinetics of either ropinirole or theophylline. Therefore, concomitant administration with other CYP1A2 substrates did not alter the pharmacokinetics of ropinirole.
Because CYP1A2 is known to be induced by smoking, smoking is expected to increase the clearance of this product. In a study conducted in patients with restless legs syndrome, smokers had an approximately 30% lower Cmax and an approximately 38% lower AUC than nonsmokers when the parameters were dose normalized.
This product and its circulating metabolites do not inhibit or induce P450 enzymes; therefore, it is not likely to affect the pharmacokinetics of other drugs metabolized by P450 (see [Pharmacokinetics] for details).
Levodopa
There was no effect on the steady-state pharmacokinetic behavior of ropinirole when ropinirole hydrochloride (2 mg, 3 times daily) was coadministered with carbidopa + levodopa (SINEMET® 10/100 mg, 2 times daily) (n=28). Oral administration of ropinirole hydrochloride (2 mg, 3 times daily) increased the mean steady-state Cmax of levodopa by 20%, but its AUC was unaffected (n = 23) (see [Pharmacokinetics] for details).
Estrogen
Population pharmacokinetic studies showed that estrogens (mainly ethinylestradiol: intake of 0.6 mg to 3 mg over 4 months to 23 years) reduced the clearance of oral ropinirole by 36% in patients (n = 16). It is not necessary to adjust the dose of ropinirole hydrochloride extended-release tablets when treating with estrogen, as it will be prudent to increment the patient’s dose based on tolerability and whether optimal therapeutic effect is achieved. However, if estrogen is discontinued or started during treatment with ropinirole hydrochloride extended-release tablets, the dose of ropinirole hydrochloride extended-release tablets will need to be adjusted.
Dopamine antagonists
Because ropinirole is a dopamine agonist, dopamine antagonists such as psychostimulants (phenothiazines, phenylbutazones, and thiophanes) or metoclopramide may reduce the efficacy of ropinirole hydrochloride extended-release tablets. The benefits/risks need to be fully evaluated if dopamine agonists are to be used during treatment with psychostimulants in patients with severe psychiatric disorders.
Other
There are no pharmacokinetic interactions between ropinirole and levodopa or domperidone, so no dose adjustment of these drugs is required. There are also no interactions between ropinirole and other drugs commonly used in the treatment of Parkinson’s disease. In a trial of patients with Parkinson’s disease who were combined with digoxin, there were no interactions between the two drugs, and therefore no dose adjustment was required.
No information is available on potential interactions between ropinirole and alcohol. As with other centrally active drugs, patients should use caution when consuming alcohol while taking this product.
Overdose]
Human drug overdose experience
Patients have overdosed unintentionally or intentionally with this product in Parkinson’s disease research projects. The largest overdose of immediate-release ropinirole tablets reported in clinical studies was 435 mg (62.1 mg/day) taken over 7 days. Symptoms reported in patients receiving more than 24 mg/day included common adverse events reported during dopaminergic therapy (nausea, dizziness), as well as hallucinations, hyperhidrosis, claustrophobia, chorea, palpitations, syncope, weakness, nightmares, vasovagal syncope, isokinetic disorder, agitation, chest pain, rising hypotension, drowsiness, and a state of confusion.
Overdose management
Symptoms of drug overdose are generally associated with its dopaminergic activity; they may be alleviated by appropriate treatment with dopamine antagonists (e.g., neuroleptics or gastrodynamics). Management with general supportive measures is recommended. Vital signs must be maintained if necessary. Remove unabsorbed drugs.
Clinical trials]
The efficacy of ropinirole immediate-release tablets in the treatment of early and advanced Parkinson’s disease was initially established in three randomized, double-blind, placebo-controlled clinical studies.
The efficacy of ropinirole hydrochloride extended-release tablets for the treatment of advanced Parkinson’s disease was supported by 1 randomized, double-blind, multicenter clinical study and a clinical pharmacokinetic study.
Study in patients with advanced Parkinson’s disease (in combination with levodopa)
The efficacy of ropinirole hydrochloride extended-release tablets in combination with levodopa in the treatment of patients with Parkinson’s disease was established in a 24-week randomized, double-blind, placebo-controlled, parallel-group clinical study. The study was conducted in 393 patients with inadequate symptom control with levodopa (Hoehn & Yahr Criteria Stages II to IV). Patients were allowed to combine sregiline, amantadine, anticholinergics, and catechol-O -methyltransferase (COMT) inhibitors provided that the doses of these drugs had been stable for at least 4 weeks prior to screening and throughout the study period. The primary efficacy endpoint evaluated was the mean change from baseline in total awake “off” time.
Patients in this study had a mean duration of disease of 8.6 years and a mean duration of levodopa use of 6.5 years, experienced at least 3 hours of wakefulness “off” time, had a mean wakefulness “off” time of approximately 7 hours at baseline, had a mean baseline UPDRS motor examination score of approximately 30, and had similar mean data across treatment groups. The mean baseline dose of levodopa was 824 mg/day in the ropinirole hydrochloride extended-release tablet group and 776 mg/day in the placebo group. Patients began treatment at a dose of 2 mg/day for one week, followed by weekly increments of 2 mg/day until a minimum dose of 6 mg/day was reached. The total daily dose of ropinirole hydrochloride extended-release tablets (based on treatment response and tolerability) may then be further increased to 8 mg/day. After reaching a daily dose of 8 mg/day, the levodopa dose for background therapy is reduced. Thus, the dose can be increased by up to 4 mg/day approximately every 2 weeks until the optimal dose (based on treatment response and tolerability) is reached. The average dose of ropinirole hydrochloride extended-release tablets at the end of week 24 was 18.8 mg/day. Dose titration was based on symptom control level, planned levodopa dose reduction and/or tolerability. The maximum allowable daily dose of ropinirole hydrochloride extended-release tablets is 24 mg/day.
The primary efficacy endpoint was the mean change from baseline in total wakefulness “off” time at week 24. At week 24, the mean reduction in total wakefulness “off-time” was approximately 2 hours in the ropinirole hydrochloride extended-release group and approximately 1 hour in the placebo group. The corrected mean difference in total wakefulness “off time” between the ropinirole hydrochloride extended-release group and the placebo group was -1.7 hours, which was statistically significant (ANCOVA, p<0.0001). For results indicating that ropinirole hydrochloride extended-release tablets were statistically superior to placebo for this endpoint, see the table below.
Table Change from Baseline in Total Waking “Off” Time at Week 24
Mean “off” time (hours) at baseline for ropinirole hydrochloride extended-release tablets (n = 201) and placebo (n = 190) 7.07.0 Mean change in “off” time from baseline (hours) -2.1 – 0.4 Favorable group differences for ropinirole hydrochloride extended-release tablets, i.e., a decrease in total “off” time (hours), primarily associated with an increase in total “on” time (hours) in the absence of anhedonia. The decrease in total “off” time (hours) was mainly associated with an increase in total “on” time (hours) in the absence of athexia. Levodopa dose was reduced by a mean of 278 mg/day (34%) in ropinirole hydrochloride extended-release tablets-treated patients, compared with a mean reduction of 164 mg/day (21%) in placebo-treated patients. Of the patients who reduced their levodopa dose, 93% of ropinirole hydrochloride extended-release tablet-treated patients maintained their dose reduction compared with 72% of placebo-treated patients (p<0.001).
[Pharmacology and Toxicology].
Pharmacological effects
Ropinirole is a dopamine receptor agonist of non-ergotrin structure with high relative specificity in vitro, with full intrinsic activity for D2 and D3 dopamine receptor subtypes and higher affinity for binding to D3 receptor subtypes than D2 or D4 receptor subtypes.
Ropinirole has a moderate affinity for opioid receptors in vitro. Ropinirole and its metabolites have negligible affinity for dopamine receptors D1, 5-HT1, 5-HT2, benzodiazepine, GABA, muscarinic, α1-, α2-, and β-adrenergic receptors in vitro.
The exact mechanism of action of ropinirole in the treatment of Parkinson’s disease is not known, but is thought to be due to the stimulatory effect on postsynaptic dopamine D2 receptors in the caudate nucleus of the brain. This conclusion is supported by studies in various animal models of Parkinson’s disease, showing that ropinirole improves motor function. In particular, ropinirole reduced motor deficits caused by neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced impairment of the nigrostriatal dopaminergic pathway in primates. The relevance of D3 receptor binding in Parkinson’s disease is not known.
Toxicological studies
Genotoxicity
Ropinirole did not show mutagenic or chromosome-breaking activity in the Ames test, human lymphocyte chromosome aberration test, mouse lymphoma cell (L1578Y cell) test, or mouse micronucleus test.
Reproductive toxicity
Administration of ropinirole to female rats before and during mating and throughout gestation disrupted implantation at doses of 20 mg/kg/day (equivalent to 8 times the maximum recommended human dose of MRHD (24 mg/day) in mg/m2) or higher. The effect is thought to be due to the hypogammaglobulinemic effect of ropinirole. In humans, it is chorionic gonadotropin, not lactogen, that plays an important role in female fertilization. In rats given low doses (5 mg/kg) of ropinirole during the prolactin-dependent phase of early gestation (days 0-8 of gestation), ropinirole was not seen to affect female fertility at doses up to 100 mg/kg/day (40 times the MRHD in mg/m2). No effect of ropinirole on male rat fertility was seen at doses up to 125 mg/kg/day (50 times the MRHD in mg/m2).
In animal reproductive toxicity studies, ropinirole was shown to have adverse effects on embryo-fetal development, including teratogenic effects. In pregnant rats given 24, 36, and 60-fold MRHD doses of ropinirole during fetal organogenesis, reduced fetal body weight, increased fetal mortality, and toe deformities occurred. In pregnant rabbits given 8 times the MRHD dose of ropinirole in combination with clinically relevant doses of levodopa during fetal organogenesis, a greater incidence and severity of fetal malformations (mainly toe defects) were observed compared to levodopa alone. In a perinatal toxicity study in rats, impaired growth and development in lactating offspring and altered neurological development in female offspring were observed when the parental generation was given 4x MRHD.
Carcinogenicity
Carcinogenicity studies were conducted for 2 years in CD-1 mice at doses of 5, 15 and 50 mg/kg/day, and in SD rats at doses of 1.5, 15 and 50 mg/kg/day (in mg/m2, the highest dose corresponding to 10 and 20 times MRHD, respectively). Male rats showed a significant increase in testicular mesenchymal cell adenomas at all reagent doses, i.e. ≥1.5 mg/kg (in mg/m2, equivalent to 0.6 times the MRHD). Because the endocrine mechanisms involved in testicular mesenchymal cell proliferation and adenoma formation in rats are not relevant to humans, the above animal results are not very suggestive for humans.
Benign endometrial polyps were increased in female mice at a dose of 50 mg/kg/day (in mg/m2, equivalent to 10 times the MRHD).
[Pharmacokinetics].
Absorption: In clinical studies of immediate-release ropinirole, more than 88% of the radiolabeled dose was recovered via urine, and the absolute bioavailability was 36% to 57%, indicating that approximately 50% of the first-pass effect occurred.
Ropinirole showed linear kinetics over a dose range of 24 mg/day (8 mg immediate-release tablets three times daily). Systemic exposure to ropinirole increased approximately dose-proportionally after oral administration of 2 to 12 mg of this product. When administered orally, ropinirole is expected to reach steady-state concentrations within 4 days of dosing.
The relative bioavailability of this product is approximately 100% compared to immediate-release tablets. In a repeat dose study in patients with Parkinson’s disease given 8 mg of this product, the dose normalized AUC (0-24) and Cmin were similar for this product and immediate-release ropinirole tablets. The dose normalized Cmax was on average 12% lower than the immediate-release form, with a median time to peak concentration of 6 to 10 hours. In single-dose studies, the AUC increased by approximately 30% and Cmax increased by approximately 44% in healthy subjects when the product was taken with a meal (i.e., high-fat meal) compared to fasting. In repeat dose studies in Parkinson’s patients, food (i.e., high-fat meal) increased AUC by 20% and Cmax by 44% compared to fasting administration; Tmax was prolonged by 3 hours (median prolongation).
Distribution: Ropinirole is widely distributed in humans with an apparent volume of distribution of 7.5 L/kg (CV= 32%). Of this, 10-40% is bound to plasma proteins with a blood plasma ratio of 1:1.
Metabolism: The majority of ropinirole is metabolized by the liver. The main metabolic pathways are N-despropylation and hydroxylation to form depropylated metabolites and hydroxylated metabolites. the N-despropylated metabolites are converted to carbamoyl glucosinolates, carboxylic acids and depropylated hydroxylated metabolites. The hydroxyl metabolites of ropinirole were rapidly glucuronidated.
In vitro studies have shown that the major cytochrome P450 isoenzyme involved in ropinirole metabolism is CYP1A2, which is known to be induced by smoking and omeprazole, and is inhibited by fluvoxamine, mexilate and older generation fluoroquinolones such as ciprofloxacin and norfloxacin.
Elimination: The oral clearance of ropinirole is 47 L/hr (CV = 45%), and the elimination half-life is approximately 6 hours. Less than 10% of the oral dose is excreted in the urine as prodrug. The major metabolite found in urine was N-despropyl ropinirole (40%), followed by the carboxylic acid metabolite (10%) and the hydroxyl metabolite glucosinolate (10%).
Drug interactions.
Ciprofloxacin: Combining immediate-release ropinirole (2 mg three times daily) with ciprofloxacin (500 mg twice daily) (CYP1A2 inhibitor) increased the AUC of ropinirole by a mean of 84% and the Cmax by 60% (n = 12 patients).
Digoxin: The combination of immediate-release ropinirole (2 mg three times daily) with digoxin (0.125 to 0.25 mg once daily) in 10 patients did not alter the steady-state pharmacokinetics of digoxin.
Theophylline: The use of theophylline (300 mg twice daily, CYP1A2 substrate) in 12 patients with Parkinson’s disease did not alter the steady-state pharmacokinetics of immediate-release ropinirole (2 mg three times daily). Immediate release ropinirole (2 mg three times daily) did not alter the pharmacokinetics of theophylline (5 mg/kg IV) in 12 patients with Parkinson’s disease.
Levodopa: The combination of immediate-release ropinirole (2 mg three times daily) with carbidopa + levodopa (xylazine 10/100 mg twice daily) had no effect on the steady-state pharmacokinetics of ropinirole (n = 28 patients). Immediate release oral ropinirole 2 mg three times daily increased the mean steady-state Cmax of levodopa by 20%, but its AUC was unaffected (n = 23 patients).
Estrogen: Population pharmacokinetic analysis showed that higher doses of estrogen (usually associated with hormone replacement therapy [HRT]) decreased oral clearance of ropinirole by approximately 35%.
Commonly used medications: Population analysis showed that commonly used medications such as sregiline, amantadine, tricyclic antidepressants, benzodiazepines, ibuprofen, thiazide diuretics, antihistamines, and anticholinergics did not affect the oral clearance of ropinirole.
Population subgroups.
Because this treatment is administered at a low dose to begin with and then titrated gradually upward for optimal efficacy based on clinical tolerability, there is no need to adjust the initial dose based on gender, weight, or age.
Age: Oral clearance is reduced by approximately 15% in patients over 65 years of age compared to younger patients. Because ropinirole dosing is individually titrated based on clinical response, no dose adjustment is required for older patients (65 years of age or older).
Gender: Female and male patients showed similar oral clearance.
Ethnicity: The effect of ethnicity on the pharmacokinetics of ropinirole has not been evaluated.
Renal impairment: Based on population pharmacokinetic analysis, there was no difference in the pharmacokinetics of ropinirole between patients with moderate renal impairment (creatinine clearance of 30 to 50 mL/min) and an age-matched population with creatinine clearance greater than 50 mL/min. Therefore, no dose adjustment is required for patients with moderate renal impairment. Ropinirole has not been studied in patients with severe renal impairment.
The effect of hemodialysis on ropinirole clearance is not known, but due to the relatively high apparent volume of distribution of ropinirole (7.5 L/kg), significant clearance of ropinirole by hemodialysis is not expected.
Liver injury: The pharmacokinetics of ropinirole has not been studied in patients with liver injury.
Other diseases: Population pharmacokinetic analysis showed no change in oral clearance of ropinirole in patients with comorbidities such as hypertension, depression, osteoporosis/arthritis and insomnia compared to patients with Parkinson’s disease only.
Storage】Store below 25℃ in a dry place.
Package】Aluminum-plastic package, 28 tablets/box
Expiration date】2mg, 24 months; 4mg, 36 months; 8mg, 36 months.
Execution Standard
Approval number】
【Manufacturer】
Company name: GLAXO WELLCOME, S.A.
Production Address: Avda.de EXTREMADURA,no 3 09400-ARANDA DE DUERO(BURGOS) SPAIN
Office in China: 6th Floor, Metropolitan Headquarters Building, 168 Xizang Middle Road, Shanghai, 200001, P.R. China
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