1. Name Of The Medicinal Product
Ropinirole 0.25 mg film-coated tablets
2. Qualitative And Quantitative Composition
One film-coated tablet contains 0.285 mg ropinirole hydrochloride, equivalent to 0.25 mg of ropinirole.
Excipient(s):
One film-coated tablet contains 101.85 mg lactose.
.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet.
White, round film-coated tablets.
4. Clinical Particulars
4.1 Therapeutic Indications
Ropinirole is indicated for the symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome (RLS) (see section 5.1).
4.2 Posology And Method Of Administration
Oral use.
Ropinirole may be taken with food, to improve gastrointestinal tolerance.
Individual dose titration against efficacy and tolerability is recommended.
Restless Legs Syndrome:
Ropinirole should be taken just before bedtime, however the dose can be taken up to 3 hours before retiring.
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 remaining 5 days 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 the table below.
Doses above 4 mg once daily have not been investigated in Restless Legs Syndrome (RLS) patients.
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* To achieve optimal improvement in some patients.
The patient's response to ropinirole should be evaluated after 3 months treatment (see section 5.1).
At this time the dose prescribed and the need for continued treatment should be considered. If treatment is interrupted for more than a few days it should be re-initiated by dose titration carried out as above.
Children and adolescents
Ropinirole is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.
Elderly
The clearance of ropinirole is decreased in patients over 65 years of age. The increase in dosage should be gradual and titrated against the symptomatic response.
Renal impairment
No dosage adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance between 30 and 50 ml/min).
For doses not realisable/practicable with this strength other strengths of this medicinal product are available.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Severe renal impairment (creatinine clearance <30 ml/min).
Severe hepatic impairment.
4.4 Special Warnings And Precautions For Use
Ropinirole has been associated with somnolence and episodes of sudden sleep onset (see section 4.8). Sudden onset of sleep during daily activities, in some cases without awareness or warning signs, has been reported uncommonly. 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.
Impulse control disorders including pathological gambling and hypersexuality, and increased libido, have been reported in patients treated with dopamine agonists, including ropinirole, principally for Parkinson' s disease. Those disorders were reported especially at high doses and were generally reversible upon reduction of the dose or treatment discontinuation.
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).
During treatment with ropinirole, paradoxical worsening of Restless Legs Syndrome symptoms occurring with earlier onset (augmentation), and reoccurrence of symptoms in the early morning hours (early morning rebound), may be observed. If this occurs, treatment should be reviewed and dosage adjustment or discontinuation of treatment may be considered.
Patients with major psychotic disorders or a history of major psychotic disorders should not be treated with dopamine agonists unless the potential benefits outweigh the risks.
Ropinirole should be administered with caution to patients with moderate hepatic impairment. Undesirable effects should be closely monitored.
This medicinal product contains lactose monohydrate.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Patients with severe cardiovascular disease (in particular coronary insufficiency) should be treated with caution; blood pressure monitoring is recommended, particularly at the start of treatment (due to the risk of postural hypotension).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Ropinirole is principally metabolised by the cytochrome P450 isoenzyme CYP1A2. A pharmacokinetic study (with a ropinirole dose of 2 mg, three times a day) revealed that ciprofloxacin increased the Cmax and AUC of ropinirole by 60% and 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 known to inhibit CYP1A2, e.g. ciprofloxacin, enoxacin, cimetidine or fluvoxamine, are introduced or withdrawn.
A pharmacokinetic interaction study between ropinirole (at a 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. Therefore, it is not expected that ropinirole will compete with the metabolism of other medicinal products which are metabolised by CYP1A2.
Based on in-vitro data, ropinirole has little potential to inhibit cytochrome P450 at therapeutic doses. Hence, ropinirole is unlikely to affect the pharmacokinetics of other medicinal products, via a cytochrome P450 mechanism.
Smoking is known to induce CYP1A2 metabolism, therefore if patients stop or start smoking during treatment with ropinirole, dose adjustment maybe required.
Increased plasma concentrations of ropinirole have been observed in patients treated with hormone replacement therapy. In patients already receiving hormone replacement therapy, ropinirole treatment may be initiated in the usual manner. However, it may be necessary to adjust the ropinirole dose, in accordance with clinical response, if hormone replacement therapy is stopped or introduced during treatment with ropinirole.
There is no pharmacokinetic interaction between ropinirole and levodopa or domperidone which would necessitate dosage adjustment of any of these medicinal products.
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 with ropinirole should be avoided.
No information is available on the potential for interaction between ropinirole and alcohol. As with other centrally active medications, patients should be cautioned against taking ropinirole with alcohol.
4.6 Pregnancy And Lactation
Pregnancy
There are no adequate data from the use of ropinirole in pregnant women.
Studies in animals have shown reproductive toxicity (see section 5.3). As the potential risk for humans is unknown, it is recommended that ropinirole is not used during pregnancy. If pregnancy is detected during treatment with ropinirole, a specialist should be consulted.
Lactation
Ropinirole should not be used in nursing mothers as it may inhibit lactation.
4.7 Effects On Ability To Drive And Use Machines
Ropinirole may have major influence on the ability to drive and use machines.
Patients being treated with ropinirole and presenting with dizziness (including vertigo), 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 (see section 4.4).
4.8 Undesirable Effects
The adverse drug reactions reported are listed below by system organ class and frequency.
The following convention has been utilised for the classification of undesirable effects:
Very common:
Common:
Uncommon:
Rare:
Very rare: <1/10,000, not known (cannot be estimated from the available data)
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 1 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 1 Adverse drug reactions reported in 12 week Restless Legs Syndrome clinical trials (ropinirole n=309, placebo n=307)
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Hallucinations were reported uncommonly in the open label long-term studies.
Paradoxical worsening of Restless Legs Syndrome symptoms occurring with earlier onset (augmentation), and reoccurrence of symptoms in the early morning hours (early morning rebound), may be observed during treatment with ropinirole.
Nervous system disorders
Uncommon: 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.
Gastrointestinal disorders
Use in monotherapy studies:
Common: vomiting, abdominal pain.
Hepatobiliary disorders
Not known: hepatic reactions, mainly increased liver enzymes.
General disorders
Common: leg oedema.
Patients treated with dopamine agonists for treatment of Parkinson's disease, including ropinirole, especially at high doses, have been reported as exhibiting signs of pathological gambling, increased libido and hypersexuality and are generally reversible upon reduction of the dose or treatment discontinuation.
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 reinstituted.
Anti-nausea medicinal products that are not centrally active dopamine antagonists, such as domperidone, may be used, if required.
4.9 Overdose
It is anticipated that the symptoms of ropinirole overdose will be 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 Properties
Pharmacotherapeutic group: Dopamine agonists, ATC code: N04BC04.
Mechanism of action
Ropinirole is a non ergoline D2/D3 dopamine agonist which stimulates striatal dopamine receptors.
Clinical efficacy in the treatment of Restless Legs Syndrome
Ropinirole 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.
Although sufficient data are not available to adequately demonstrate the long term efficacy of ropinirole in Restless Legs Syndrome (see section 4.2), in a 36-week study, patients who continued on ropinirole demonstrated a significantly lower relapse rate compared with patients randomised to placebo (33% versus 58%, p=0.0156).
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).
A rebound phenomenon following discontinuation of ropinirole treatment (end of treatment rebound) cannot be excluded. In clinical trials, although the average IRLS total scores 7-10 days after withdrawal of therapy were higher in ropinirole-treated patients than in placebo-treated patients, the severity of symptoms following withdrawal of therapy generally did not exceed the baseline assessment in ropinirole-treated patients.
In clinical studies most patients were of Caucasian origin.
Additional clinical effect
Ropinirole acts in the hypothalamus and pituitary to inhibit the secretion of prolactin.
5.2 Pharmacokinetic Properties
Absorption
The bioavailability of ropinirole is about 50% (36% to 57%), with Cmax reached on average 1.5 hours after the dose. In the presence of food, Cmax is delayed by about 2.6 hours and the peak plasma level is reduced by 25%, with no effect on the bioavailable quantity. The bioavailability of ropinirole varies greatly between individuals.
Distribution
The binding of ropinirole to plasma proteins is not high (<40%), with no effect on the distribution which is very extensive (volume of distribution in the order of 7 l/kg).
Metabolism
Ropinirole is mainly metabolised by the isoform CYP1A2 of cytochrome P450. None of the many metabolites formed are involved in the resulting activity of the product and the main metabolite is 100 times less potent than ropinirole in animal models examining dopaminergic function.
Elimination
Unchanged ropinirole and the metabolites are mainly excreted through the kidneys. The elimination half life of ropinirole is 6 hours on average.
Linearity
The pharmacokinetics of ropinirole are linear overall (Cmax and AUC) in the therapeutic range.
Population-related characteristics
In patients over 65 years of age, a reduction in the systemic clearance of ropinirole by about 30% is possible.
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. No data are available in patients with severe renal impairment.
5.3 Preclinical Safety Data
Toxicology:
The toxicology profile is principally determined by the pharmacological activity of the drug: 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 a high dose (50 mg/kg), 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 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.
Reproductive Toxicity:
Administration of ropinirole to pregnant rats at maternally toxic doses resulted in decreased foetal body weight at 60 mg/kg (approximately 15 times the AUC at the maximum dose in humans), increased foetal death at 90 mg/kg (approximately 25 times the AUC at the maximum dose in humans) and digit malformations at 150 mg/kg (approximately 40 times the AUC at the maximum dose in humans). There were no teratogenic effects in the rat at 120 mg/kg (approximately 30 times the AUC at the maximum dose in humans) and no indication of an effect on development in the rabbit.
6. Pharmaceutical Particulars
6.1 List Of Excipients
Tablet core:
Lactose monohydrate
Microcrystalline cellulose
Croscarmellose sodium
Magnesium stearate.
Film coating:
Hypromellose
Macrogol 400
Titanium dioxide (E171)
Polysorbate 80.
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
PVC/Aclar/Aluminium blister:
1 year.
HDPE bottles:
18 months.
6.4 Special Precautions For Storage
PVC/Aclar/Aluminium blister: Do not store above 25 °C. In order to protect from moisture store in the original package.
HDPE bottles: Do not store above 30 °C. In order to protect from moisture keep the bottle tightly closed.
6.5 Nature And Contents Of Container
PVC/Aclar/Aluminium blister.
Packs of 12, 21, 84 or 126 film-coated tablets.
HDPE bottle with child-resistant PP-closure.
Bottles with 12 or 84 film-coated tablets.
Not all pack sizes may be marketed.
6.6 Special Precautions For Disposal And Other Handling
No special requirements.
7. Marketing Authorisation Holder
Winthrop Pharmaceuticals UK Limited
One Onslow Street
Guildford
Surrey
GU1 4YS, UK
Trading as: Winthrop Pharmaceuticals, PO Box 611, Guildford, Surrey, GU1 4YS, UK
8. Marketing Authorisation Number(S)
PL 17780/0423
9. Date Of First Authorisation/Renewal Of The Authorisation
21/11/2008
10. Date Of Revision Of The Text
21/11/2008
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