- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
AdultsIndividual dose titration against efficacy and tolerability is recommended. Aimpart XL prolonged-release tablets should be taken once a day, at a similar time each day. The prolonged-release tablets may be taken with or without food (see section 5.2).Aimpart XL prolonged-release tablets must be swallowed whole and must not be chewed, crushed or divided.
Initial titrationThe starting dose of Aimpart XL prolonged-release tablets is 2 mg once daily for the first week; this should be increased to 4 mg once daily from the second week of treatment. A therapeutic response may be seen at a dose of 4 mg once daily of Aimpart XL prolonged-release tablets.Patients who initiate treatment with a dose of 2 mg/day of Aimpart XL prolonged-release tablets and who experience undesirable effects that they cannot tolerate, may benefit from switching to treatment with ropinirole immediate-release tablets at a lower daily dose, divided into three equal doses.
Therapeutic regimenPatients should be maintained on the lowest dose of Aimpart XL prolonged-release tablets that achieve symptomatic control.If sufficient symptomatic control is not achieved or maintained at a dose of 4 mg once daily of Aimpart XL prolonged-release tablets, the daily dose may be increased by 2 mg at weekly or longer intervals up to a dose of 8 mg once daily of Aimpart XL prolonged-release tablets.If sufficient symptomatic control is still not achieved or maintained at a dose of 8 mg once daily of Aimpart XL prolonged-release tablets, the daily dose may be increased by 2 mg to 4 mg at two weekly or longer intervals. The maximum daily dose of Aimpart XL prolonged-release tablets is 24 mg.It is recommended that patients are prescribed the minimum number of Aimpart XL prolonged-release tablets that are necessary to achieve the required dose by utilising the highest available strengths of Aimpart XL prolonged-release tablets.If treatment is interrupted for one day or more, re-initiation by dose titration should be considered (see above).When Aimpart XL prolonged-release tablets are administered as adjunct therapy to levodopa, it may be possible to reduce gradually the levodopa dose, depending on the clinical response. In clinical trials, the levodopa dose was reduced gradually by approximately 30% in patients receiving ropinirole prolonged-release tablets concurrently. In patients with advanced Parkinson's disease, receiving Aimpart XL prolonged-release tablets in combination with levodopa, dyskinesias can occur during the initial titration of Aimpart XL prolonged-release tablets. In clinical trials it was shown that a reduction of the levodopa dose may ameliorate dyskinesia (see section 4.8). When switching treatment from another dopamine agonist to ropinirole, the marketing authorisation holder's guidance on discontinuation should be followed before initiating Aimpart XL.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 film-coated (immediate release) tablets to Aimpart XL prolonged-release tabletsPatients may be switched overnight from ropinirole film-coated (immediate-release) tablets to Aimpart XL prolonged-release tablets. The dose of Aimpart XL prolonged-release tablets should be based on the total daily dose of ropinirole film-coated (immediate- release) tablets that the patient was taking. The table below shows the recommended dose of Aimpart XL prolonged-release tablets for patients switching from ropinirole film-coated (immediate-release) tablets:
Switching from ropinirole film-coated (immediate-release) tablets to Aimpart XL prolonged-release tablets
|Ropinirole film-coated (immediate-release) tablets Total daily dose (mg)||Aimpart XL prolonged-release tablets Total daily dose (mg)|
|0.75 - 2.25||2|
|3 - 4.5||4|
|7.5 - 9||8|
|15 - 18||16|
Children and adolescentsAimpart XL 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.
ElderlyThe clearance of ropinirole is decreased by approximately 15% in patients 65 years of age 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.
Renal impairmentIn 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 Aimpart XL is 2mg once daily. Further dose escalations should be based on tolerability and efficacy. The recommended maximum dose of Aimpart XL is 18mg/day in patients receiving regular haemodialysis.Supplemental doses after haemodialysis are not required (see section 5.2).The use of ropinirole in patients with severe renal impairment (creatinine clearance less than 30 ml/min) without regular haemodialysis has not been studied.
Adverse drug reactions reported in Parkinson's disease clinical trials with ropinirole prolonged-release tablets at doses up to 24 mg/day.
|In monotherapy||In adjunct therapy|
|Nervous system disorders|
|Very common||Somnolence, syncope||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 (see section 4.2).|
|Common||Dizziness (including vertigo)||Somnolence, dizziness (including vertigo)|
|Common||Postural hypotension, hypotension|
|Uncommon||Postural hypotension, hypotension|
|General disorders and administrative site conditions|
|Common||Oedema peripheral||Oedema peripheral|
|In monotherapy||In adjunct therapy|
|Immune system disorders|
|Not known||Hypersensitivity reactions (including urticaria, angioedema, rash, pruritus)|
|Uncommon||Psychotic reactions (other than hallucinations) including delirium, delusion, paranoia.||Psychotic reactions (other than hallucinations) including delirium, delusion, paranoia.|
|Not known||Impulse control disorders: Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including ropinirole (see section 4.4).|
|Nervous system disorders|
|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.|
|Uncommon||Postural hypotension or hypotension is rarely severe|
|Common||Vomiting, heartburn, abdominal pain||Heartburn|
|Not known||Hepatic reactions, mainly increased liver enzymes|
|General disorders and administrative site conditions|
-Ropinirole is a non-ergoline D2/D3 dopamine agonist which stimulates striatal dopamine receptors. Ropinirole alleviates the dopamine deficiency which characterises Parkinson's disease by stimulating striatal dopamine receptors.Ropinirole acts in the hypothalamus and pituitary to inhibit the secretion of prolactin. Clinical efficacyA 36-week, double-blind, three-period crossover study, in monotherapy, conducted in 161 patients with early phase Parkinson's disease demonstrated that ropinirole prolonged-release tablets were non-inferior to immediate-release film-coated tablets on the primary endpoint, the treatment difference in change from baseline in the Unified Parkinson's Disease Rating Scale (UPDRS) motor score (a 3-point non-inferiority margin on the UPDRS motor score was defined). The adjusted mean difference between ropinirole prolonged-release tablets and immediate-release film-coated 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 decrease).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 repolarisationA thorough QT study conducted in male and female healthy volunteers who received doses of 0.5, 1, 2 and 4 mg of ropinirole immediate-release tablets once daily showed a maximum increase of the QT interval duration at 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.
AbsorptionBioavailability of ropinirole is approximately 50% (3657%). Following oral administration, of ropinirole prolonged-release tablets plasma concentrations increase slowly, with a median time to Cmax generally achieved between 6 and 10 hours.In a steady-state study in 25 Parkinson's disease patients receiving 12 mg of ropinirole prolonged release tablets once daily, a high fat meal increased the systemic exposure to ropinirole as shown by an average 20% increase in AUC and an average 44% increase in Cmax. Tmax was delayed by 3.0 hours. However, these changes are unlikely to be clinically relevant (e.g. increased incidence of adverse events).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.
DistributionPlasma protein binding of the drug is low (1040%). Consistent with its high lipophilicity, ropinirole exhibits a large volume of distribution (approximately 7 L/kg).
MetabolismRopinirole 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.
EliminationRopinirole 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-individualvariability for Cmax was between 30% and 55% and for AUC was between 40% and 70%.
Renal ImpairmentThere was no changed 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 haemodialysis, 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 (see section 4.2).
Reproductive ToxicityAdministration of ropinirole to pregnant rats at maternally toxic doses resulted in decreased foetal body weight at 60 mg/kg/day (approximately equivalent to the AUC at the maximum dose in humans), increased foetal death at 90 mg/kg/day (approximately 3 times the AUC at the maximum dose in humans) and digit malformations at 150 mg/kg/day (approximately 5 times the AUC at the maximum dose in humans). There were no teratogenic effects in the rat at 120 mg/kg/day (approximately 4 times the AUC at the maximum dose in humans) and no indication of an effect on development in the rabbit.
ToxicologyThe 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.
GenotoxicityGenotoxicity was not observed in a battery of in vitro and in vivo tests.
CarcinogenicityFrom 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 drug-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 PharmacologyIn vitro studies have shown that ropinirole inhibits hERG-mediated currents. The IC50 is 5-fold higher than the expected maximum plasma concentration in patients treated at the highest recommended dose (24 mg/day), see section 5.1.
Tablet core:Methacrylic acid copolymer type RS Hypromellose (E464)Sodium lauryl sulphateCopovidoneMagnesium stearate (E572)
8 mg Tablet coat:Titanium dioxide (E171)Hypromellose (E464)Macrogol 400Iron oxide red (E172)Iron oxide black (E172)Iron oxide yellow (E172)
The preparations being discontinued are:
- Aimpart XL 8mg tablets (Zentiva)
The pharmaceutical company has decided to discontinue the product and so it may not be available in the future. This document has been left on the eMC for information purposes.
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