Aleta

Aleta is indicated for the symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome.

Oral use.

Adults

Individual 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

* To achieve optimal improvement in some patients.

The efficacy of ropinirole treatment has not been shown beyond 12 weeks. Patient response should be evaluated after 12 weeks treatment and the need for treatment continuation reconsidered. If treatment is interrupted for more than a few days it should be re-initiated by dose titration as noted above.

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.

Children and adolescents

Aleta is not recommended for use in children below 18 years of age due to a lack of data on safety and efficacy.

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.

Renal impairment

No 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 Aleta is 0.25 mg once daily. Further dose escalations should be based on tolerability and efficacy. The recommended maximum dose of Aleta is 3 mg/day in patients receiving regular haemodialysis. Supplemental doses after haemodialysis 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.

Severe renal impairment (creatinine clearance <30 ml/min) without regular haemodialysis.

Severe hepatic impairment.

Ropinirole should not be used to treat neuroleptic akathisia, tasikinesia (neuroleptic-induced compulsive tendency to walk), or secondary Restless Legs Syndrome (e.g. caused by renal failure, iron deficiency anaemia or pregnancy).

Paradoxical worsening of Restless Legs Syndrome symptoms described as augmentation (either earlier onset, increased intensity, or spread of symptoms to previously unaffected limbs), or early morning rebound (reoccurrence of symptoms in the early morning hours), have been observed during treatment with ropinirole. If this occurs, the adequacy of ropinirole treatment should be reviewed and dosage adjustment or discontinuation of treatment may be considered.

In Parkinson's disease, ropinirole has been associated uncommonly with somnolence and episodes of sudden sleep onset however, in Restless Legs Syndrome, this phenomenon is very rare. Nevertheless, patients must be informed of this phenomenon 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. A reduction of dosage or termination of therapy may be considered.

Patients with major psychotic disorders should not be treated with dopamine agonists unless the potential benefits outweigh the risks.

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 Aleta. 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.

Dopamine agonist withdrawal syndrome

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.

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.

Patients being treated with ropinirole and presenting with somnolence and/or sudden sleep episodes must be informed to refrain from driving or engaging in activities where impaired alertness may put themselves or others at risk of serious injury or death (e.g. operating machines) until such effects have resolved.

Adverse drug reactions are listed below by system organ class and frequency. Frequencies from clinical trials are determined as excess incidence over placebo and are classed as very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Use of ropinirole in Restless Legs Syndrome

In 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)

Table 3 Adverse drug reactions reported in other Restless Legs Syndrome clinical trials

Management of undesirable effects

Dose 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 ropinirole

Ropinirole 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

Post marketing reports

Hypersensitivity 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)

Dopamine agonist withdrawal syndrome (frequency not known)

Including apathy, anxiety, depression, fatigue, sweating and pain. Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists including ropinirole.

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 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.

The symptoms of ropinirole overdose are related to its dopaminergic activity. These symptoms may be alleviated by appropriate treatment with dopamine antagonists such as neuroleptics or metoclopramide.

Pharmacotherapeutic group: Dopamine agonist, ATC code: N04BC04.

Mechanism of action

Ropinirole is a non ergoline D2/D3 dopamine agonist which stimulates striatal dopamine receptors.

Clinical efficacy

Aleta 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 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 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.

Absorption

The bioavailability of ropinirole is about 50% (36% to 57%), with C_max 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 T_max by 2.6 hours and an average 25% decrease in C_max

Distribution

Plasma protein binding of ropinirole is low (10 - 40%). Consistent with its high lipophilicity, ropinirole exhibits a large volume of distribution (approx. 7 l/kg).

Biotransformation

Ropinirole 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.

Elimination

Ropinirole 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-linearity

The pharmacokinetics of ropinirole are linear overall (C_max and AUC) in the therapeutic range between 0.25 mg and 4 mg, after a single dose and after repeated dosing.

Population-related characteristics

Oral 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 Impairment

In 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.

Paediatric population

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 the usual 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/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 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 (mean AUC in rats approximately 15 times the highest AUC at the Maximum Recommended Human Dose (MRHD)), increased foetal death at 90 mg/kg/day (approximately 25 times the highest AUC at the MRHD) and digit malformations at 150 mg/kg/day (approximately 40 times the highest AUC at the MRHD). There were no teratogenic effects in the rat at 120 mg/kg/day (approximately 30 times the maximum AUC at the MRHD) and no indication of an effect during organogenesis in the rabbit when given alone at 20 mg/kg (60 times the mean human C_max at the MRHD). However, ropinirole at 10 mg/kg (30 times the mean human C_max 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.

Safety Pharmacology

In 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).

Not applicable.

No special requirements for disposal.