- 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
|0.25 mg:||White pentagonal-shaped, bevelled edge tablets, marked "SB" on one side and "4890" on the other.|
|0.5 mg:||Yellow pentagonal-shaped, bevelled edge tablets, marked "SB" on one side and "4891" on the other.|
|2.0 mg:||Pink pentagonal-shaped, bevelled edge tablets, marked "SB" on one side and "4893" on the other.|
AdultsIndividual dose titration against efficacy and tolerability is recommended. Ropinirole should be taken just before bedtime, however the dose can be taken up to 3 hours before retiring. Ropinirole may be taken with food, to improve gastrointestinal tolerance.
Treatment initiation (week 1)The recommended initial dose is 0.25 mg once daily (administered as above) for 2 days. If this dose is well tolerated the dose should be increased to 0.5 mg once daily for the remainder of week 1.
Therapeutic regimen (week 2 onwards)Following treatment initiation, the daily dose should be increased until optimal therapeutic response is achieved. The average dose in clinical trials, in patients with moderate to severe Restless Legs Syndrome, was 2 mg once a day. The dose may be increased to 1 mg once a day at week 2. The dose may then be increased by 0.5 mg per week over the next two weeks to a dose of 2 mg once a day. In some patients, to achieve optimal improvement, the dose may be increased gradually up to a maximum of 4 mg once a day. In clinical trials the dose was increased by 0.5 mg each week to 3 mg once a day and then by 1 mg up to the maximum recommended dose of 4 mg once a day as shown in table 1.Doses above 4 mg once daily have not been investigated in Restless Legs Syndrome patients.
Table 1 Dose titration
|Dose (mg)/once daily||1||1.5||2||2.5||3||4|
Children and adolescentsADARTREL is 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 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.
Renal impairmentNo dosage adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance between 30 and 50 ml/min).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 ADARTREL is 0.25 mg once daily. Further dose escalations should be based on tolerability and efficacy. The recommended maximum dose of ADARTREL is 3 mg/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.
Impulse control disordersPatients 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 Adartrel. Dose reduction/tapered discontinuation should be considered if such symptoms develop. 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 (see section 4.2). Ropinirole should be administered with caution to patients with moderate hepatic impairment. Undesirable effects should be closely monitored.Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.Due to the risk of hypotension, patients with severe cardiovascular disease (in particular coronary insufficiency) should be treated with caution.
Use of ropinirole in Restless Legs SyndromeIn Restless Legs Syndrome clinical trials the most common adverse drug reaction was nausea (approximately 30% of patients). Undesirable effects were normally mild to moderate and experienced at the start of therapy or on increase of dose and few patients withdrew from the clinical studies due to undesirable effects.Table 2 lists the adverse drug reactions reported for ropinirole in the 12-week clinical trials at ≥1.0% above the placebo rate or those reported uncommonly but known to be associated with ropinirole.
Table 2 Adverse drug reactions reported in 12-week Restless Legs Syndrome clinical trials (ropinirole n=309, placebo n=307)
|Nervous system disorders|
|Common||Syncope, somnolence, dizziness (including vertigo)|
|Uncommon||Postural hypotension, hypotension|
|Very common||Vomiting, nausea|
|General disorders and administration site conditions|
|Nervous system disorders|
|Common||Augmentation, Early morning rebound (see section 4.4)|
Management of undesirable effectsDose reduction should be considered if patients experience significant undesirable effects. If the undesirable effect abates, gradual up-titration can be re-instituted. Anti-nausea medicinal products that are not centrally active dopamine antagonists, such as domperidone, may be used, if required.
Other experience with ropiniroleRopinirole is also indicated for the treatment of Parkinson's disease. The adverse drug reactions reported in patients with Parkinson's disease on ropinirole monotherapy and adjunct therapy at doses up to 24 mg/day at an excess incidence over placebo are described below.
Table 4 Adverse drug reactions reported in Parkinson's disease clinical trials at doses up to 24 mg/day
|Nervous system disorders|
|Very common||Syncope, dyskinesia, somnolence|
|Common||Vomiting, abdominal pain, heartburn|
|General disorders and administration site conditions|
|Common||Oedema peripheral (including leg oedema)|
Post marketing reportsHypersensitivity reactions (including urticaria, angioedema, rash, pruritus)Psychotic reactions (other than hallucinations) including delirium, delusion and paranoia have been reported. Aggression* (frequency not known) *Aggression has been associated with psychotic reactions as well as compulsive symptoms. Psychiatric disorders: Dopamine dysregulation syndrome (frequency not known). Impulse control disorders (frequency not known) Pathological gambling, increased libido, hypersexuality, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including ADARTREL. (see section 4.4. 'Special warnings and precautions for use').In Parkinson's disease, ropinirole is associated with somnolence and has been associated uncommonly (≥1/1,000 to <1/100) with excessive daytime somnolence and sudden sleep onset episodes, however, in Restless Legs Syndrome, this phenomenon is very rare (<1/10,000).Following ropinirole therapy, postural hypotension or hypotension has been reported uncommonly (≥1/1,000 to <1/100), rarely severe.Very rare cases of hepatic reactions (<1/10,000), mainly increase of liver enzymes, have been reported.
Reporting of suspected adverse reactionsReporting 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.
Mechanism of actionRopinirole is a non ergoline D2/D3 dopamine agonist which stimulates striatal dopamine receptors.
Clinical efficacyADARTREL should only be prescribed to patients with moderate to severe idiopathic Restless Legs Syndrome. Moderate to severe idiopathic Restless Legs Syndrome is typically represented by patients who suffer with insomnia or severe discomfort in the limbs.In the four 12-week efficacy studies, patients with Restless Legs Syndrome were randomised to ropinirole or placebo, and the effects on the IRLS scale scores at week 12 were compared to baseline. The mean dose of ropinirole for the moderate to severe patients was 2.0 mg/day. In a combined analysis of moderate to severe Restless Legs Syndrome patients from the four 12-week studies, the adjusted treatment difference for the change from baseline in IRLS scale total score at week 12 Last Observation Carried Forward (LOCF) Intention To Treat population was -4.0 points (95% CI -5.6, -2.4, p<0.0001; baseline and week 12 LOCF mean IRLS points: ropinirole 28.4 and 13.5; placebo 28.2 and 17.4).A 12-week placebo-controlled polysomnography study in Restless Legs Syndrome patients examined the effect of treatment with ropinirole on periodic leg movements of sleep. A statistically significant difference in the periodic leg movements of sleep was seen between ropinirole and placebo from baseline to week 12.A combined analysis of data from moderate to severe Restless Legs Syndrome patients, in the four 12-week placebo-controlled studies, indicated that ropinirole-treated patients reported significant improvements over placebo on the parameters of the Medical Outcome Study Sleep Scale (scores on 0-100 range except sleep quantity). The adjusted treatment differences between ropinirole and placebo were: sleep disturbance (-15.2, 95% CI -19.37, -10.94; p<0.0001), sleep quantity (0.7 hours, 95% CI 0.49, 0.94); p<0.0001), sleep adequacy (18.6, 95% CI 13.77, 23.45; p<0.0001) and daytime somnolence (-7.5, 95% CI -10.86, -4.23; p<0.0001). Long term efficacy was evaluated in a randomised, double-blind, placebo-controlled clinical trial of 26 weeks. Overall results were difficult to interpret due to significant centre treatment interaction and the high proportion of missing data. No maintenance of efficacy at 26 weeks compared to placebo could be shown.
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 film-coated (immediate release) tablets once daily showed a maximum increase of the QT interval duration at the 1mg 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.In clinical studies most patients were of Caucasian origin.
AbsorptionThe bioavailability of ropinirole is about 50% (36% to 57%), with Cmax reached on average 1.5 hours after the dose. A high fat meal decreases the rate of absorption of ropinirole, as shown by a delay in median Tmax by 2.6 hours and an average 25% decrease in Cmax
DistributionPlasma protein binding of ropinirole is low (10 40%). Consistent with its high lipophilicity, ropinirole exhibits a large volume of distribution (approx. 7 l/kg).
BiotransformationRopinirole is primarily cleared by the cytochrome P450 enzyme, CYP1A2, 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 approximately 6 hours. 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.
Linearity/non-linearityThe pharmacokinetics of ropinirole are linear overall (Cmax and AUC) in the therapeutic range between 0.25 mg and 4 mg, after a single dose and after repeated dosing.
Population-related characteristicsOral clearance of ropinirole is reduced by approximately 15% in elderly patients (65 years or above) compared to younger patients. Dosage adjustment is not necessary in the elderly.
Renal ImpairmentIn patients with mild to moderate renal impairment (creatinine clearance between 30 and 50 ml/min), no change in the pharmacokinetics of ropinirole is observed. 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 3 mg/day in these patients with RLS (see section 4.2).
Paediatric populationLimited pharmacokinetic data obtained in adolescents (12-17 years, n=9) showed that the systemic exposure following single doses of 0.125 mg and 0.25 mg was similar to that observed in adults (see also section 4.2; subparagraph "Children and adolescents")
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.
Reproductive ToxicityAdministration of ropinirole to pregnant rats at maternally toxic doses resulted in decreased foetal body weight at 60 mg/kg/day (approximately 15 times the AUC at the maximum dose in humans), increased foetal death at 90 mg/kg/day (approximately 25 times the AUC at the maximum dose in humans) and digit malformations at 150 mg/kg/day (approximately 40 times the AUC at the maximum dose in humans). There were no teratogenic effects in the rat at 120 mg/kg/day (approximately 30 times the AUC at the maximum dose in humans) and no indication of an effect on development in the rabbit.
Safety PharmacologyIn vitro studies have shown that ropinirole inhibits hERG-mediated currents. The IC50 is at least 30-fold higher than the expected maximum plasma concentration in patients treated at the highest recommended dose (4 mg/day) (see section 5.1).
Tablet cores:Lactose monohydrateMicrocrystalline celluloseCroscarmellose sodiumMagnesium stearate.
Film coating:0.25mg (white): Hypromellose, Macrogol 400, Titanium dioxide (E171), Polysorbate 80 (E433). 0.5mg (yellow): Hypromellose, Macrogol 400, Titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172), indigo carmine aluminium lake (E132). 2.0 mg (pink): Hypromellose, Macrogol 400, Titanium dioxide (E171), iron oxide yellow (E172), iron oxide red (E172).
|0.25mg:||PVC/PCTFE/Aluminium blister or PVC/PCTFE/PVC-Aluminium /paper child-resistant blister in cartons of 2 or 12 tablets|
|0.5mg :||PVC/PCTFE/Aluminium blister or PVC/PCTFE/PVC-Aluminium/paper child-resistant blister in cartons of 28 or 84 tablets|
|2.0 mg:||PVC/PCTFE/Aluminium blister or PVC/PCTFE/PVC-Aluminium/paper child-resistant blister in cartons of 28 or 84 tablets|
|Adartrel 0.25 mg film coated tablets||PL 19494/0033|
|Adartrel 0.5 mg film coated tablets||PL 19494/0034|
|Adartrel 2.0 mg film coated tablets||PL 19494/0036|
Stockley Park West, Uxbridge, Middlesex, UB11 1BT
+44 (0)208 990 4328
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0800 221 441