- 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 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.
Initial titrationThe starting dose of ropinirole 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 ropinirole prolonged-release tablets.Patients who initiate treatment with a dose of 2 mg/day of ropinirole 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 ropinirole 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 ropinirole 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 ropinirole prolonged- release tablets.If sufficient symptomatic control is still not achieved or maintained at a dose of 8 mg once daily of ropinirole 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 ropinirole prolonged-release tablets is 24 mg.It is recommended that patients are prescribed the minimum number of ropinirole prolonged-release tablets that are necessary to achieve the required dose by utilising the highest available strengths of ropinirole prolonged-release tablets.If treatment is interrupted for one day or more, re-initiation by dose titration should be considered (see above).When Ralnea 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 Ralnea XL prolonged-release tablets concurrently. In advanced Parkinson's disease, in combination treatment with levodopa, dyskinesias can occur during the initial titration of Ralnea XL prolonged-release tablets. If they occur, the dose of levodopa should be decreased.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 Ralnea XL prolonged-release tabletsPatients may be switched overnight from ropinirole immediate-release tablets to Ralnea XL prolonged-release tablets. The dose of Ralnea XL prolonged-release tablets should be based on the total daily dose of ropinirole immediate-release tablets that the patient was taking. The table below shows the recommended dose of Ralnea XL prolonged-release tablets for patients switching from ropinirole immediate-release tablets:
Switching from ropinirole immediate-release tablets to Ralnea XL prolonged-release tablets
|Ropinirole immediate-release tablets Total daily dose (mg)||Ralnea XL prolonged-release tablets Total daily dose (mg)|
|7,5 - 9||8|
|15 - 18||16|
ElderlyThe clearance of ropinirole is decreased in patients over 65 years of age. Any increase in dosage should be gradual and titrated against the symptomatic response. For the very elderly, 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.
Children and adolescentsRalnea XL prolonged-release tablets are not recommended for use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy.
Method of administrationOral use.Ralnea 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).Ralnea XL prolonged-release tablets must be swallowed whole and must not be chewed, crushed or divided because the coating is intended to ensure a prolonged release.
|In momotherapy||In adjunct therapy|
|Nervous system disorders|
|Common||Dizziness (including vertigo)||Somnolence, dizziness (including vertigo)|
|Common||Postural hypotension, hypotension|
|Uncommon||Postural hypotension, hypotension|
|General disorders and administration site conditions|
|Common||Oedema peripheral||Oedema peripheral|
|In momotherapy||In adjunct therapy|
|Immune system disorders|
|Not known||Hypersensitivity reactions (including urticaria, angioedema, rash, pruritus)||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, hypersexuality, increased libido, compulsive spending or buying, binge eating and compulsive eating (see section 4.4)||Impulse control disorders (pathological gambling, hypersexuality, increased libido, compulsive spending or buying, binge eating and compulsive eating (see section 4.4)|
|Nervous system disorders|
|Uncommon||Sudden onset of sleep, excessive daytime somnolence *||Sudden onset of sleep, excessive daytime somnolence *|
|Uncommon||Postural hypostension, hypotension (rarely severe)||Postural hypotension, hypotension (rarely severe)|
|Common||Vomiting, heartburn, abdominal pain||Heartburn|
|Not known||Hepatic reactions (mainly increased liver enzymes)||Hepatic reactions (mainly increased liver enzymes)|
|General disorders and administration site conditions|
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 (eg. increased incidence of adverse events).The systemic exposure to ropinirole is comparable for ropinirole prolonged-release tablets and ropinirole immediate-release tablets based on the same daily dose.
DistributionPlasma protein binding of ropinirole is low (1040%). Consistent with its high lipophilicity, ropinirole exhibits a large volume of distribution (approx. 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 6 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 for Cmax was between 30% and 55% and for AUC was between 40% and 70%.
Reproductive ToxicityAdministration of ropinirole to pregnant rats at maternally toxic doses resulted in decreased foetal body weight at 60 mg/kg/day (approximately twice 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 the usual 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/day 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 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:Hypromellose type 2208Lactose monohydrate Silica, colloidal anhydrous Carbomers 4,000-11,000 mPa.s Castor oil, hydrogenated Magnesium stearateFilm-coating:Hypromellose type 2910Titanium dioxide (E171) Macrogol 400Iron oxide, red (E172) Iron oxide, yellow (E172)
Consilient Health Ltd
No. 1 Church Road, Richmond upon Thames, Surrey, TW9 2QE, UK
+44(0)20 3751 1889
+44(0) 20 3751 1888