The symptoms of ropinirole overdose are generally related to its dopaminergic activity. These symptoms may be alleviated by appropriate treatment with dopamine antagonists such as neuroleptics or metoclopramide.
ReQuip XL 2mg prolonged-release tablets 2 years.
ReQuip XL 4mg prolonged-release tablets 3 years.
ReQuip XL 8mg prolonged-release tablets 3 years.
Severe renal impairment (creatinine clearance <30 ml/min) without regular haemodialysis.
Hepatic impairment.
Not applicable.
Tablet core
Hypromellose 2208, hydrogenated castor oil, carmellose sodium, povidone K29-32, maltodextrin, magnesium stearate, lactose monohydrate, anhydrous colloidal silica, mannitol (E421), ferric oxide yellow (E172) and glycerol dibehenate.
Film coat
2 mg: Hypromellose 2910, ferric oxide yellow (E172), titanium dioxide (E171), macrogol 400 and ferric oxide red (E172).
4 mg: Hypromellose 2910, titanium dioxide (E171), macrogol 400, sunset yellow (E110) and indigo carmine (E132).
8 mg: Hypromellose 2910, ferric oxide yellow (E172), titanium dioxide (E171), ferric oxide black (E172), macrogol 400 and ferric oxide red (E172).
When switching treatment from another dopamine agonist to ropinirole, the marketing authorisation holder's guidance on discontinuation should be followed before initiating ropinirole.
As with other dopamine agonists, it is necessary to discontinue ropinirole treatment gradually by reducing the daily dose over the period of one week.
Switching from ropinirole immediate release tablets to ropinirole prolonged-release tablets
Patients may be switched overnight from ropinirole immediate release tablets to ropinirole prolonged-release tablets.
The dose of ropinirole prolonged-release tablets should be based on the total daily dose of immediate release formulation that the patient was receiving. The recommended dose for switching from ropinirole immediate release tablets to ropinirole prolonged-release tablets are provided in the following table. If patients are taking a different total daily dose of ropinirole immediate release tablets to those typically prescribed doses as shown in the table, they should be switched to the nearest available dose of ropinirole prolonged-release tablets as stated in the table:
|
Ropinirole immediate release tablets (Requip) Total daily dose (mg) |
Ropinirole prolonged-release tablets (Requip XL) Total daily dose (mg) |
|
0.75 - 2.25 |
2 |
|
3 - 4.5 |
4 |
|
6 |
6 |
|
7.5 - 9 |
8 |
|
12 |
12 |
|
15 - 18 |
16 |
|
21 |
20 |
|
24 |
24 |
After switching to Requip XL prolonged-release tablets, the dose may be adjusted depending on the therapeutic response (see “Initial titration†and “Therapeutic regimen†above).
Dose interruption or discontinuation
If treatment is interrupted for one day or more, re-initiation by dose titration on ropinirole immediate release tablets should be considered.
If it is necessary to discontinue ropinirole treatment, this should be done gradually by reducing the daily dose over the period of one week.
Renal impairment
In parkinsonian patients with mild to moderate renal impairment (creatinine clearance between 30 and 50 ml/min) no change in the clearance of ropinirole was observed, indicating that no dosage adjustment is necessary in this population.
A study into the use of ropinirole in patients with end stage renal disease (patients on haemodialysis) has shown that a dose adjustment in these patients is required as follows:
The recommended initial dose of ReQuip XL 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 dialysis. Supplemental doses after dialysis are not required.
The use of ropinirole in patients with severe renal impairment (creatinine clearance less than 30 ml/min) without regular haemodialysis has not been studied.
Hepatic impairment
The use of ropinirole in patients with hepatic impairment has not been studied. Administration of ropinirole to such patients 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.
Children and adolescents
Ropinirole prolonged-release tablets are not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy.
4.3 ContraindicationsSevere renal impairment (creatinine clearance <30 ml/min) without regular haemodialysis.
Hepatic impairment.
4.4 Special warnings and precautions for useDue to the risk of hypotension, blood pressure monitoring is recommended, particularly at the start of treatment, in patients with severe cardiovascular disease (in particular coronary insufficiency).
Impulse control disorders
Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including ReQuip XL. Dose reduction/tapered discontinuation should be considered if such symptoms develop. Impulse control disorders were reported especially at high doses and were generally reversible upon reduction of the dose or treatment discontinuation. Risk factors such as a history of compulsive behaviours were present in some cases.
Ropinirole has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with ropinirole. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore, a reduction of dosage or termination of therapy may be considered.
Neuroleptic malignant syndrome
Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal of dopaminergic therapy. Therefore it is recommended to taper treatment.
Requip XL tablets are designed to release medication over a 24hr period. If rapid gastrointestinal transit occurs, there may be risk of incomplete release of medication, and of medication residue being passed in the stool.
Dopamine agonist withdrawal syndrome
To discontinue treatment in patients with Parkinson's disease, ropinirole should be tapered off. Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists including ropinirole. Symptoms include apathy, anxiety, depression, fatigue, sweating and pain which may be severe. Patients should be informed about this before tapering the dopamine agonist, and monitored regularly thereafter. In case of persistent symptoms, it may be necessary to increase the ropinirole dose temporarily.
Hallucinations
Hallucinations are known as a side effect of treatment with dopamine agonists and levodopa. Patients should be informed that hallucinations can occur.
This medicinal product also contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
The 4 mg tablets contain the azo colouring agent sunset yellow (E110), which may cause allergic reactions.
4.5 Interaction with other medicinal products and other forms of interactionThere is no pharmacokinetic interaction between ropinirole and L-dopa or domperidone which would necessitate dosage adjustment of these drugs. Neuroleptics and other centrally active dopamine antagonists, such as sulpiride or metoclopramide, may diminish the effectiveness of ropinirole and therefore, concomitant use of these medicinal products should be avoided.
Ropinirole is principally metabolised by the cytochrome P450 enzyme CYP1A2. A pharmacokinetic study (with a ropinirole film-coated (immediate-release) tablet dose of 2 mg, three times a day) in Parkinson's disease patients, revealed that ciprofloxacin increased the Cmax and AUC of ropinirole by 60% an 84% respectively, with a potential risk of adverse events. Hence, in patients already receiving ropinirole, the dose of ropinirole may need to be adjusted when medicinal products know to inhibit CYP1A2, e.g. ciprofloxacin, enoxacin, cimetidine or fluvoxamine, are introduced or withdrawn.
A pharmacokinetic interaction study in patients with Parkinson's disease between ropinirole (with a ropinirole film-coated (immediate-release) tablet dose of 2 mg, three times a day) and theophylline, a substrate of CYP1A2, revealed no change in the pharmacokinetics of either ropinirole or theophylline.
Increased plasma concentrations of ropinirole have been observed in patients treated with high doses of oestrogens. In patients already receiving hormone replacement therapy (HRT), ropinirole treatment may be initiated in the normal manner. However, if HRT is stopped or introduced during treatment with ropinirole, dosage adjustment may be required.
Smoking is known to induce CYP1A2 metabolism, therefore if patients stop or start smoking during treatment with ropinirole, adjustment of dose may be required.
4.6 Fertility, pregnancy and lactationPregnancy
There are no adequate data from the use of ropinirole in pregnant women.
Studies in animals have shown reproductive toxicity. As the potential risk for humans is unknown, it is recommended that ropinirole is not used during pregnancy unless the potential benefit to the patient outweighs the potential risk to the foetus.
Breast-feeding
Ropinirole-related material was shown to transfer into the milk of lactating rats. It is unknown whether ropinirole and its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded.
Ropinirole should not be used in nursing mothers as it may inhibit lactation.
Fertility
There are no data on the effects of ropinirole on human fertility. In female fertility studies in rats, effects were seen on implantation but no effects were seen on male fertility.
4.7 Effects on ability to drive and use machinesRopinirole may have a major effect on the ability to drive and use machines.
4.8 Undesirable effectsAdverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000) very rare (<1/10,000), not known (cannot be estimated from the available data).
During clinical trials, the most commonly reported undesirable effects for ropinirole prolonged-release tablets were during monotherapy and dyskinesia during adjunctive therapy with levodopa.
The following adverse events were reported during clinical trials with ReQuip XL up to 24 mg/day.
|
In monotherapy |
In adjunct therapy | |
|
Psychiatric disorders | ||
|
Common |
Hallucinations |
Hallucinations |
|
Nervous system disorders | ||
|
Very common |
Somnolence |
Dyskinesia In patients with advanced Parkinson's disease, dyskinesias can occur during the initial titration of ropinirole. In clinical trials it was shown that a reduction of the levodopa dose may ameliorate dyskinesia. |
|
Common |
Dizziness (including vertigo), sudden onset of sleep |
Somnolence, dizziness (including vertigo), sudden onset of sleep |
|
Vascular disorders | ||
|
Common |
Postural hypotension, hypotension | |
|
Uncommon |
Postural hypotension, hypotension | |
|
Gastrointestinal disorders | ||
|
Very common |
Nausea | |
|
Common |
Constipation |
Nausea, constipation |
|
General disorders and administrative site conditions | ||
|
Common |
Oedema peripheral |
Oedema peripheral |
In addition to the above adverse drug reactions, the following events have been reported with ReQuip film-coated (immediate-release) tablets in patients during clinical trials (at doses up to 24 mg/day) and/or post-marketing reports.
|
In monotherapy |
In adjunct therapy | |
|
Immune system disorders | ||
|
Not known |
Hypersensitivity reactions (including urticaria, angioedema, rash, pruritus). | |
|
Psychiatric disorders | ||
|
Common |
Confusion | |
|
Uncommon |
Psychotic reactions (other than hallucinations) including delirium, delusion, paranoia. |
Psychotic reactions (other than hallucinations) including delirium, delusion, paranoia. |
|
Not known |
Aggression* | |
|
Dopamine dysregulation syndrome | ||
|
* Aggression has been associated with psychotic reactions as well as compulsive symptoms | ||
|
Not known |
Impulse control disorders including pathological gambling, compulsive shopping, binge eating and hypersexuality and increased libido, have been reported in post marketing reports | |
|
Nervous system disorders | ||
|
Very common |
Syncope |
Somnolence |
|
Uncommon |
Sudden onset of sleep, excessive daytime somnolence |
Sudden onset of sleep, excessive daytime somnolence |
|
Ropinirole is associated with somnolence and has been associated uncommonly with excessive daytime somnolence and sudden sleep onset episodes. | ||
|
Vascular disorders | ||
|
Uncommon |
Postural hypotension or hypotension is rarely severe | |
|
Gastrointestinal disorders | ||
|
Very common |
Nausea | |
|
Common |
Vomiting, heartburn, abdominal pain |
Heartburn |
|
Hepatobiliary disorders | ||
|
Not known |
Hepatic reactions, mainly increased liver enzymes | |
|
General disorders and administrative site conditions | ||
|
Common |
Leg oedema | |
|
Not known |
Dopamine agonist withdrawal syndrome (including apathy, anxiety, depression, fatigue, sweating and pain) | |
Dopamine agonist withdrawal syndrome
Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists including ropinirole.
Impulse control disorders
'Special warnings and precautions for use').Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Reproductive toxicity
In fertility studies in female rats, effects were seen on implantation due to the prolactin-lowering effect of ropinirole. It should be noted that prolactin is not essential for implantation in humans.
Administration of ropinirole to pregnant rats at maternally toxic doses resulted in decreased foetal body weight at 60 mg/kg/day (approximately twice the highest AUC at the Maximum Recommended Human Dose (MRHD)), increased foetal death at 90 mg/kg/day (mean AUC in rats is approximately 3 times the highest AUC at the MRHD) and digit malformations at 150 mg/kg/day (approximately 5 times the highest AUC at the MRHD). There were no teratogenic effects in the rat at 120 mg/kg/day (approximately 4 times the highest AUC at the MRHD) and no indication of an effect during organogenesis in the rabbit when given alone at 20 mg/kg (9.5 times the mean human Cmax at the MRHD). However, ropinirole at 10 mg/kg (4.8 times the mean human Cmax at the MRHD) administered to rabbits in combination with oral L-dopa produced a higher incidence and severity of digit malformations than L-dopa alone.
Toxicology
The toxicology profile is principally determined by the pharmacological activity of ropinirole behavioural changes, hypoprolactinaemia, decrease in blood pressure and heart rate, ptosis and salivation. In the albino rat only, retinal degeneration was observed in a long term study at the highest dose (50 mg/kg/day), and was probably associated with an increased exposure to light.
Genotoxicity
Genotoxicity was not observed in a battery of in vitro and in vivo tests.
Carcinogenicity
From two-year studies conducted in the mouse and rat at dosages up to 50 mg/kg there was no evidence of any carcinogenic effect in the mouse. In the rat, the only ropinirole-related lesions were Leydig cell hyperplasia and testicular adenoma resulting from the hypoprolactinaemic effect of ropinirole. These lesions are considered to be a species specific phenomenon and do not constitute a hazard with regard to the clinical use of ropinirole.
Safety pharmacology
In vitro studies have shown that ropinirole inhibits hERG-mediated currents.
Pharmacotherapeutic group
Dopamine agonist.
ATC code: N04BC04
Mechanism of action
Parkinson's disease is characterised by a marked dopamine deficiency in the nigral striatal system. Ropinirole is a non-ergoline D2/D3 dopamine agonist that alleviates this deficiency by stimulating striatal dopamine receptors.
Ropinirole acts in the hypothalamus and pituitary to inhibit the secretion of prolactin.
Clinical efficacy
A 36-week, double-blind, three-period crossover study, in monotherapy with a primary end point of change from period baseline in Unified Parkinson's Disease Rating Scale (UPDRS) total motor score was conducted in 161 patients with early phase Parkinson's disease. A subgroup analysis of patients initiated on monotherapy treatment with ropinirole immediate release tablets and switched overnight to the nearest equivalent dose of ropinirole prolonged-release tablets was consistent with similar efficacy from equivalent mg for mg doses. The adjusted mean difference between ropinirole prolonged-release tablets and Requip film-coated (immediate-release) tablets at study-endpoint was 0.7 points (95% CI: [-1.51, 0.10], p=0.0842).
Following the overnight switch to a similar dose of the alternative tablet formulation, there was no difference in the adverse event profile and less than 3% of patients required a dose adjustment (all dose adjustments were increases by one dose level. No patients required a dose increase).
A 24-week, double-blind, placebo-controlled, parallel group study in patients with Parkinson's disease who were not optimally controlled on levodopa demonstrated that adjunctive therapy of ropinirole prolonged-release tablets results in clinically relevant and statistically significant superiority over placebo in a change from baseline in awake time “off†(adjusted mean treatment difference -1.7 hours (95% CI: [-2.34, -1.09], p<0.0001). This was supported by secondary efficacy parameters of change from baseline in total awake time “on†(+1.7 hours (95% CI [1.06, 2.33], p<0.0001) and total awake time “on†without troublesome dyskinesias (+1.5 hours (95% CI: [0.85, 2.13], p<0.0001). Importantly, there was no indication of an increase from baseline in awake time “on†with troublesome dyskinesias, either from diary card data or from the UPDRS items.
Study of the effect of ropinirole on cardiac repolarisation
A thorough QT study conducted in male and female healthy volunteers who received doses of 0.5, 1, 2 and 4 mg of ropinirole film-coated (immediate release) tablets once daily showed a maximum increase of the QT interval duration nat the 1 mg dose of 3.46 milliseconds (point estimate) as compared to placebo. The upper bound of the one sided 95% confidence interval for the largest mean effect was less than 7.5 milliseconds. The effect of ropinirole at higher doses has not been systematically evaluated.
The available clinical data from a thorough QT study do not indicate a risk of QT prolongation at doses of ropinirole up to 4 mg/day. A risk of QT prolongation cannot be excluded as a thorough QT study at doses up to 24 mg/day has not been conducted.
Absorption
Bioavailability of ropinirole is approximately 50% (36-57%). Following oral administration of ropinirole prolonged-release tablets, plasma concentrations of ropinirole increase slowly, with a median time to Cmax of between six and ten hours.
In a steady-state study in Parkinson's disease patients receiving 12 mg of Requip XL once daily, a high fat meal increased the systemic exposure to ropinirole as shown by an average 20% increase in AUC (90% CI [1.12, 1.28]) and an average 44% increase in Cmax (90% CI[1.34, 1.56]). Tmax was delayed by 3.0 hours. However, in the studies that established the safety and efficacy of Requip XL, patients were instructed to take study medication without regard to food intake.
The systemic exposure to ropinirole is comparable for ropinirole prolonged-release tablets and ropinirole film-coated (immediate-release) tablets based on the same daily dose.
Distribution
Plasma protein binding of the drug is low (10-40%). Consistent with its high lipophilicity, ropinirole exhibits a large volume of distribution (approximately 7 l/kg).
Biotransformation
Ropinirole is primarily cleared by CYP1A2 metabolism and its metabolites are mainly excreted in the urine. The major metabolite is at least 100-times less potent than ropinirole in animal models of dopaminergic function.
Elimination
Ropinirole is cleared from the systemic circulation with an average elimination half-life of about six hours. The increase in systemic exposure (Cmax and AUC) to ropinirole is approximately proportional over the therapeutic dose range. No change in the oral clearance of ropinirole is observed following single and repeated oral administration. Wide inter-individual variability in the pharmacokinetic parameters has been observed. Following steady-state administration of ropinirole prolonged-release tablets, the inter-individual variability of Cmax was between 30% and 55% and for AUC was between 40% and 70%.
Special Patient Populations
Renal impairment: There was no change observed in the pharmacokinetics of ropinirole in Parkinson's disease patients with mild to moderate renal impairment.
In patients with end stage renal disease receiving regular dialysis, oral clearance of ropinirole is reduced by approximately 30%. Oral clearance of the metabolites SKF-104557 and SKF-89124 were also reduced by approximately 80% and 60%, respectively. Therefore, the recommended maximum dose is limited to 18 mg/day in these patients with Parkinson's disease.
03 November 2017
As with other dopamine agonists, it is necessary to discontinue ropinirole treatment gradually by reducing the daily dose over the period of one week.
Switching from ropinirole immediate release tablets to ropinirole prolonged-release tablets
Patients may be switched overnight from ropinirole immediate release tablets to ropinirole prolonged-release tablets.
The dose of ropinirole prolonged-release tablets should be based on the total daily dose of immediate release formulation that the patient was receiving. The recommended dose for switching from ropinirole immediate release tablets to ropinirole prolonged-release tablets are provided in the following table. If patients are taking a different total daily dose of ropinirole immediate release tablets to those typically prescribed doses as shown in the table, they should be switched to the nearest available dose of ropinirole prolonged-release tablets as stated in the table:
|
Ropinirole immediate release tablets (Requip) Total daily dose (mg) |
Ropinirole prolonged-release tablets (Requip XL) Total daily dose (mg) |
|
0.75 - 2.25 |
2 |
|
3 - 4.5 |
4 |
|
6 |
6 |
|
7.5 - 9 |
8 |
|
12 |
12 |
|
15 - 18 |
16 |
|
21 |
20 |
|
24 |
24 |
After switching to Requip XL prolonged-release tablets, the dose may be adjusted depending on the therapeutic response (see “Initial titration†and “Therapeutic regimen†above).
Dose interruption or discontinuation
If treatment is interrupted for one day or more, re-initiation by dose titration on ropinirole immediate release tablets should be considered.
If it is necessary to discontinue ropinirole treatment, this should be done gradually by reducing the daily dose over the period of one week.
Renal impairment
In parkinsonian patients with mild to moderate renal impairment (creatinine clearance between 30 and 50 ml/min) no change in the clearance of ropinirole was observed, indicating that no dosage adjustment is necessary in this population.
A study into the use of ropinirole in patients with end stage renal disease (patients on haemodialysis) has shown that a dose adjustment in these patients is required as follows:
The recommended initial dose of ReQuip XL 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 dialysis. Supplemental doses after dialysis are not required.
The use of ropinirole in patients with severe renal impairment (creatinine clearance less than 30 ml/min) without regular haemodialysis has not been studied.
Hepatic impairment
The use of ropinirole in patients with hepatic impairment has not been studied. Administration of ropinirole to such patients 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.
Children and adolescents
Ropinirole prolonged-release tablets are not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy.
4.3 ContraindicationsSevere renal impairment (creatinine clearance <30 ml/min) without regular haemodialysis.
Hepatic impairment.
4.4 Special warnings and precautions for useDue to the risk of hypotension, blood pressure monitoring is recommended, particularly at the start of treatment, in patients with severe cardiovascular disease (in particular coronary insufficiency).
Impulse control disorders
Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including ReQuip XL. Dose reduction/tapered discontinuation should be considered if such symptoms develop. Impulse control disorders were reported especially at high doses and were generally reversible upon reduction of the dose or treatment discontinuation. Risk factors such as a history of compulsive behaviours were present in some cases.
Ropinirole has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with ropinirole. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore, a reduction of dosage or termination of therapy may be considered.
Neuroleptic malignant syndrome
Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal of dopaminergic therapy. Therefore it is recommended to taper treatment.
Requip XL tablets are designed to release medication over a 24hr period. If rapid gastrointestinal transit occurs, there may be risk of incomplete release of medication, and of medication residue being passed in the stool.
Dopamine agonist withdrawal syndrome
To discontinue treatment in patients with Parkinson's disease, ropinirole should be tapered off. Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists including ropinirole. Symptoms include apathy, anxiety, depression, fatigue, sweating and pain which may be severe. Patients should be informed about this before tapering the dopamine agonist, and monitored regularly thereafter. In case of persistent symptoms, it may be necessary to increase the ropinirole dose temporarily.
Hallucinations
Hallucinations are known as a side effect of treatment with dopamine agonists and levodopa. Patients should be informed that hallucinations can occur.
This medicinal product also contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
The 4 mg tablets contain the azo colouring agent sunset yellow (E110), which may cause allergic reactions.
4.5 Interaction with other medicinal products and other forms of interactionThere is no pharmacokinetic interaction between ropinirole and L-dopa or domperidone which would necessitate dosage adjustment of these drugs. Neuroleptics and other centrally active dopamine antagonists, such as sulpiride or metoclopramide, may diminish the effectiveness of ropinirole and therefore, concomitant use of these medicinal products should be avoided.
Ropinirole is principally metabolised by the cytochrome P450 enzyme CYP1A2. A pharmacokinetic study (with a ropinirole film-coated (immediate-release) tablet dose of 2 mg, three times a day) in Parkinson's disease patients, revealed that ciprofloxacin increased the Cmax and AUC of ropinirole by 60% an 84% respectively, with a potential risk of adverse events. Hence, in patients already receiving ropinirole, the dose of ropinirole may need to be adjusted when medicinal products know to inhibit CYP1A2, e.g. ciprofloxacin, enoxacin, cimetidine or fluvoxamine, are introduced or withdrawn.
A pharmacokinetic interaction study in patients with Parkinson's disease between ropinirole (with a ropinirole film-coated (immediate-release) tablet dose of 2 mg, three times a day) and theophylline, a substrate of CYP1A2, revealed no change in the pharmacokinetics of either ropinirole or theophylline.
Increased plasma concentrations of ropinirole have been observed in patients treated with high doses of oestrogens. In patients already receiving hormone replacement therapy (HRT), ropinirole treatment may be initiated in the normal manner. However, if HRT is stopped or introduced during treatment with ropinirole, dosage adjustment may be required.
Smoking is known to induce CYP1A2 metabolism, therefore if patients stop or start smoking during treatment with ropinirole, adjustment of dose may be required.
4.6 Fertility, pregnancy and lactationPregnancy
There are no adequate data from the use of ropinirole in pregnant women.
Studies in animals have shown reproductive toxicity. As the potential risk for humans is unknown, it is recommended that ropinirole is not used during pregnancy unless the potential benefit to the patient outweighs the potential risk to the foetus.
Breast-feeding
Ropinirole-related material was shown to transfer into the milk of lactating rats. It is unknown whether ropinirole and its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded.
Ropinirole should not be used in nursing mothers as it may inhibit lactation.
Fertility
There are no data on the effects of ropinirole on human fertility. In female fertility studies in rats, effects were seen on implantation but no effects were seen on male fertility.
4.7 Effects on ability to drive and use machinesRopinirole may have a major effect on the ability to drive and use machines.
4.8 Undesirable effectsAdverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/1,000) very rare (<1/10,000), not known (cannot be estimated from the available data).
During clinical trials, the most commonly reported undesirable effects for ropinirole prolonged-release tablets were during monotherapy and dyskinesia during adjunctive therapy with levodopa.
The following adverse events were reported during clinical trials with ReQuip XL up to 24 mg/day.
|
In monotherapy |
In adjunct therapy | |
|
Psychiatric disorders | ||
|
Common |
Hallucinations |
Hallucinations |
|
Nervous system disorders | ||
|
Very common |
Somnolence |
Dyskinesia In patients with advanced Parkinson's disease, dyskinesias can occur during the initial titration of ropinirole. In clinical trials it was shown that a reduction of the levodopa dose may ameliorate dyskinesia. |
|
Common |
Dizziness (including vertigo), sudden onset of sleep |
Somnolence, dizziness (including vertigo), sudden onset of sleep |
|
Vascular disorders | ||
|
Common |
Postural hypotension, hypotension | |
|
Uncommon |
Postural hypotension, hypotension | |
|
Gastrointestinal disorders | ||
|
Very common |
Nausea | |
|
Common |
Constipation |
Nausea, constipation |
|
General disorders and administrative site conditions | ||
|
Common |
Oedema peripheral |
Oedema peripheral |
In addition to the above adverse drug reactions, the following events have been reported with ReQuip film-coated (immediate-release) tablets in patients during clinical trials (at doses up to 24 mg/day) and/or post-marketing reports.
|
In monotherapy |
In adjunct therapy | |
|
Immune system disorders | ||
|
Not known |
Hypersensitivity reactions (including urticaria, angioedema, rash, pruritus). | |
|
Psychiatric disorders | ||
|
Common |
Confusion | |
|
Uncommon |
Psychotic reactions (other than hallucinations) including delirium, delusion, paranoia. |
Psychotic reactions (other than hallucinations) including delirium, delusion, paranoia. |
|
Not known |
Aggression* | |
|
Dopamine dysregulation syndrome | ||
|
* Aggression has been associated with psychotic reactions as well as compulsive symptoms | ||
|
Not known |
Impulse control disorders including pathological gambling, compulsive shopping, binge eating and hypersexuality and increased libido, have been reported in post marketing reports | |
|
Nervous system disorders | ||
|
Very common |
Syncope |
Somnolence |
|
Uncommon |
Sudden onset of sleep, excessive daytime somnolence |
Sudden onset of sleep, excessive daytime somnolence |
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Ropinirole is associated with somnolence and has been associated uncommonly with excessive daytime somnolence and sudden sleep onset episodes. | ||
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Vascular disorders | ||
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Uncommon |
Postural hypotension or hypotension is rarely severe | |
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Gastrointestinal disorders | ||
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Very common |
Nausea | |
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Common |
Vomiting, heartburn, abdominal pain |
Heartburn |
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Hepatobiliary disorders | ||
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Not known |
Hepatic reactions, mainly increased liver enzymes | |
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General disorders and administrative site conditions | ||
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Common |
Leg oedema | |
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Not known |
Dopamine agonist withdrawal syndrome (including apathy, anxiety, depression, fatigue, sweating and pain) | |
Dopamine agonist withdrawal syndrome
Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists including ropinirole.
Impulse control disorders
'Special warnings and precautions for use').Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
4.9 OverdoseThe symptoms of ropinirole overdose are generally related to its dopaminergic activity. These symptoms may be alleviated by appropriate treatment with dopamine antagonists such as neuroleptics or metoclopramide.
5. Pharmacological properties 5.1 Pharmacodynamic propertiesPharmacotherapeutic group
Dopamine agonist.
ATC code: N04BC04
Mechanism of action
Parkinson's disease is characterised by a marked dopamine deficiency in the nigral striatal system. Ropinirole is a non-ergoline D2/D3 dopamine agonist that alleviates this deficiency by stimulating striatal dopamine receptors.
Ropinirole acts in the hypothalamus and pituitary to inhibit the secretion of prolactin.
Clinical efficacy
A 36-week, double-blind, three-period crossover study, in monotherapy with a primary end point of change from period baseline in Unified Parkinson's Disease Rating Scale (UPDRS) total motor score was conducted in 161 patients with early phase Parkinson's disease. A subgroup analysis of patients initiated on monotherapy treatment with ropinirole immediate release tablets and switched overnight to the nearest equivalent dose of ropinirole prolonged-release tablets was consistent with similar efficacy from equivalent mg for mg doses. The adjusted mean difference between ropinirole prolonged-release tablets and Requip film-coated (immediate-release) tablets at study-endpoint was 0.7 points (95% CI: [-1.51, 0.10], p=0.0842).
Following the overnight switch to a similar dose of the alternative tablet formulation, there was no difference in the adverse event profile and less than 3% of patients required a dose adjustment (all dose adjustments were increases by one dose level. No patients required a dose increase).
A 24-week, double-blind, placebo-controlled, parallel group study in patients with Parkinson's disease who were not optimally controlled on levodopa demonstrated that adjunctive therapy of ropinirole prolonged-release tablets results in clinically relevant and statistically significant superiority over placebo in a change from baseline in awake time “off†(adjusted mean treatment difference -1.7 hours (95% CI: [-2.34, -1.09], p<0.0001). This was supported by secondary efficacy parameters of change from baseline in total awake time “on†(+1.7 hours (95% CI [1.06, 2.33], p<0.0001) and total awake time “on†without troublesome dyskinesias (+1.5 hours (95% CI: [0.85, 2.13], p<0.0001). Importantly, there was no indication of an increase from baseline in awake time “on†with troublesome dyskinesias, either from diary card data or from the UPDRS items.
Study of the effect of ropinirole on cardiac repolarisation
A thorough QT study conducted in male and female healthy volunteers who received doses of 0.5, 1, 2 and 4 mg of ropinirole film-coated (immediate release) tablets once daily showed a maximum increase of the QT interval duration nat the 1 mg dose of 3.46 milliseconds (point estimate) as compared to placebo. The upper bound of the one sided 95% confidence interval for the largest mean effect was less than 7.5 milliseconds. The effect of ropinirole at higher doses has not been systematically evaluated.
The available clinical data from a thorough QT study do not indicate a risk of QT prolongation at doses of ropinirole up to 4 mg/day. A risk of QT prolongation cannot be excluded as a thorough QT study at doses up to 24 mg/day has not been conducted.
5.2 Pharmacokinetic propertiesAbsorption
Bioavailability of ropinirole is approximately 50% (36-57%). Following oral administration of ropinirole prolonged-release tablets, plasma concentrations of ropinirole increase slowly, with a median time to Cmax of between six and ten hours.
In a steady-state study in Parkinson's disease patients receiving 12 mg of Requip XL once daily, a high fat meal increased the systemic exposure to ropinirole as shown by an average 20% increase in AUC (90% CI [1.12, 1.28]) and an average 44% increase in Cmax (90% CI[1.34, 1.56]). Tmax was delayed by 3.0 hours. However, in the studies that established the safety and efficacy of Requip XL, patients were instructed to take study medication without regard to food intake.
The systemic exposure to ropinirole is comparable for ropinirole prolonged-release tablets and ropinirole film-coated (immediate-release) tablets based on the same daily dose.
Distribution
Plasma protein binding of the drug is low (10-40%). Consistent with its high lipophilicity, ropinirole exhibits a large volume of distribution (approximately 7 l/kg).
Biotransformation
Ropinirole is primarily cleared by CYP1A2 metabolism and its metabolites are mainly excreted in the urine. The major metabolite is at least 100-times less potent than ropinirole in animal models of dopaminergic function.
Elimination
Ropinirole is cleared from the systemic circulation with an average elimination half-life of about six hours. The increase in systemic exposure (Cmax and AUC) to ropinirole is approximately proportional over the therapeutic dose range. No change in the oral clearance of ropinirole is observed following single and repeated oral administration. Wide inter-individual variability in the pharmacokinetic parameters has been observed. Following steady-state administration of ropinirole prolonged-release tablets, the inter-individual variability of Cmax was between 30% and 55% and for AUC was between 40% and 70%.
Special Patient Populations
Renal impairment: There was no change observed in the pharmacokinetics of ropinirole in Parkinson's disease patients with mild to moderate renal impairment.
In patients with end stage renal disease receiving regular dialysis, oral clearance of ropinirole is reduced by approximately 30%. Oral clearance of the metabolites SKF-104557 and SKF-89124 were also reduced by approximately 80% and 60%, respectively. Therefore, the recommended maximum dose is limited to 18 mg/day in these patients with Parkinson's disease.
5.3 Preclinical safety dataReproductive toxicity
In fertility studies in female rats, effects were seen on implantation due to the prolactin-lowering effect of ropinirole. It should be noted that prolactin is not essential for implantation in humans.
Administration of ropinirole to pregnant rats at maternally toxic doses resulted in decreased foetal body weight at 60 mg/kg/day (approximately twice the highest AUC at the Maximum Recommended Human Dose (MRHD)), increased foetal death at 90 mg/kg/day (mean AUC in rats is approximately 3 times the highest AUC at the MRHD) and digit malformations at 150 mg/kg/day (approximately 5 times the highest AUC at the MRHD). There were no teratogenic effects in the rat at 120 mg/kg/day (approximately 4 times the highest AUC at the MRHD) and no indication of an effect during organogenesis in the rabbit when given alone at 20 mg/kg (9.5 times the mean human Cmax at the MRHD). However, ropinirole at 10 mg/kg (4.8 times the mean human Cmax at the MRHD) administered to rabbits in combination with oral L-dopa produced a higher incidence and severity of digit malformations than L-dopa alone.
Toxicology
The toxicology profile is principally determined by the pharmacological activity of ropinirole behavioural changes, hypoprolactinaemia, decrease in blood pressure and heart rate, ptosis and salivation. In the albino rat only, retinal degeneration was observed in a long term study at the highest dose (50 mg/kg/day), and was probably associated with an increased exposure to light.
Genotoxicity
Genotoxicity was not observed in a battery of in vitro and in vivo tests.
Carcinogenicity
From two-year studies conducted in the mouse and rat at dosages up to 50 mg/kg there was no evidence of any carcinogenic effect in the mouse. In the rat, the only ropinirole-related lesions were Leydig cell hyperplasia and testicular adenoma resulting from the hypoprolactinaemic effect of ropinirole. These lesions are considered to be a species specific phenomenon and do not constitute a hazard with regard to the clinical use of ropinirole.
Safety pharmacology
In vitro studies have shown that ropinirole inhibits hERG-mediated currents.
6. Pharmaceutical particulars 6.1 List of excipientsTablet core
Hypromellose 2208, hydrogenated castor oil, carmellose sodium, povidone K29-32, maltodextrin, magnesium stearate, lactose monohydrate, anhydrous colloidal silica, mannitol (E421), ferric oxide yellow (E172) and glycerol dibehenate.
Film coat
2 mg: Hypromellose 2910, ferric oxide yellow (E172), titanium dioxide (E171), macrogol 400 and ferric oxide red (E172).
4 mg: Hypromellose 2910, titanium dioxide (E171), macrogol 400, sunset yellow (E110) and indigo carmine (E132).
8 mg: Hypromellose 2910, ferric oxide yellow (E172), titanium dioxide (E171), ferric oxide black (E172), macrogol 400 and ferric oxide red (E172).
6.2 IncompatibilitiesNot applicable.
6.3 Shelf lifeReQuip XL 2mg prolonged-release tablets 2 years.
ReQuip XL 4mg prolonged-release tablets 3 years.
ReQuip XL 8mg prolonged-release tablets 3 years.
6.4 Special precautions for storageDo not store above 25°C. Store in the original package.
6.5 Nature and contents of containerPVC/PCTFE/Aluminium blister packs or PVC/PE/PVdC-Aluminium/Paper child-resistant blister packs
Packs of 28 or 84 prolonged-release tablets.
Not all pack sizes may be marketed
6.6 Special precautions for disposal and other handlingNo special requirements for disposal.
7. Marketing authorisation holderSmithKline Beecham Limited
Great West Road,
Brentford,
Middlesex TW8 9GS
Trading as:
GlaxoSmithKline UK
Stockley Park West,
Uxbridge,
Middlesex UB11 1BT
Do not store above 25°C. Store in the original package.
PVC/PCTFE/Aluminium blister packs or PVC/PE/PVdC-Aluminium/Paper child-resistant blister packs
Packs of 28 or 84 prolonged-release tablets.
Not all pack sizes may be marketed
Requip XL 2 mg prolonged-release tablets PL 10592/0293
Requip XL 4 mg prolonged-release tablets PL 10592/0295
Requip XL 8 mg prolonged-release tablets PL 10592/0296
Pregnancy
There are no adequate data from the use of ropinirole in pregnant women.
Studies in animals have shown reproductive toxicity. As the potential risk for humans is unknown, it is recommended that ropinirole is not used during pregnancy unless the potential benefit to the patient outweighs the potential risk to the foetus.
Breast-feeding
Ropinirole-related material was shown to transfer into the milk of lactating rats. It is unknown whether ropinirole and its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded.
Ropinirole should not be used in nursing mothers as it may inhibit lactation.
Fertility
There are no data on the effects of ropinirole on human fertility. In female fertility studies in rats, effects were seen on implantation but no effects were seen on male fertility.
Due to the risk of hypotension, blood pressure monitoring is recommended, particularly at the start of treatment, in patients with severe cardiovascular disease (in particular coronary insufficiency).
Impulse control disorders
Patients should be regularly monitored for the development of impulse control disorders. Patients and carers should be made aware that behavioural symptoms of impulse control disorders including pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including ReQuip XL. Dose reduction/tapered discontinuation should be considered if such symptoms develop. Impulse control disorders were reported especially at high doses and were generally reversible upon reduction of the dose or treatment discontinuation. Risk factors such as a history of compulsive behaviours were present in some cases.
Ropinirole has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease. Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported. Patients must be informed of this and advised to exercise caution while driving or operating machines during treatment with ropinirole. Patients who have experienced somnolence and/or an episode of sudden sleep onset must refrain from driving or operating machines. Furthermore, a reduction of dosage or termination of therapy may be considered.
Neuroleptic malignant syndrome
Symptoms suggestive of neuroleptic malignant syndrome have been reported with abrupt withdrawal of dopaminergic therapy. Therefore it is recommended to taper treatment.
Requip XL tablets are designed to release medication over a 24hr period. If rapid gastrointestinal transit occurs, there may be risk of incomplete release of medication, and of medication residue being passed in the stool.
Dopamine agonist withdrawal syndrome
To discontinue treatment in patients with Parkinson's disease, ropinirole should be tapered off. Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists including ropinirole. Symptoms include apathy, anxiety, depression, fatigue, sweating and pain which may be severe. Patients should be informed about this before tapering the dopamine agonist, and monitored regularly thereafter. In case of persistent symptoms, it may be necessary to increase the ropinirole dose temporarily.
Hallucinations
Hallucinations are known as a side effect of treatment with dopamine agonists and levodopa. Patients should be informed that hallucinations can occur.
This medicinal product also contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
The 4 mg tablets contain the azo colouring agent sunset yellow (E110), which may cause allergic reactions.
Ropinirole may have a major effect on the ability to drive and use machines.
No special requirements for disposal.
07th May 2008/7th September 2016
There is no pharmacokinetic interaction between ropinirole and L-dopa or domperidone which would necessitate dosage adjustment of these drugs. Neuroleptics and other centrally active dopamine antagonists, such as sulpiride or metoclopramide, may diminish the effectiveness of ropinirole and therefore, concomitant use of these medicinal products should be avoided.
Ropinirole is principally metabolised by the cytochrome P450 enzyme CYP1A2. A pharmacokinetic study (with a ropinirole film-coated (immediate-release) tablet dose of 2 mg, three times a day) in Parkinson's disease patients, revealed that ciprofloxacin increased the Cmax and AUC of ropinirole by 60% an 84% respectively, with a potential risk of adverse events. Hence, in patients already receiving ropinirole, the dose of ropinirole may need to be adjusted when medicinal products know to inhibit CYP1A2, e.g. ciprofloxacin, enoxacin, cimetidine or fluvoxamine, are introduced or withdrawn.
A pharmacokinetic interaction study in patients with Parkinson's disease between ropinirole (with a ropinirole film-coated (immediate-release) tablet dose of 2 mg, three times a day) and theophylline, a substrate of CYP1A2, revealed no change in the pharmacokinetics of either ropinirole or theophylline.
Increased plasma concentrations of ropinirole have been observed in patients treated with high doses of oestrogens. In patients already receiving hormone replacement therapy (HRT), ropinirole treatment may be initiated in the normal manner. However, if HRT is stopped or introduced during treatment with ropinirole, dosage adjustment may be required.
Smoking is known to induce CYP1A2 metabolism, therefore if patients stop or start smoking during treatment with ropinirole, adjustment of dose may be required.
