Ropinirole 0.25 Mg Film-Coated Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ropinirole 0.25 mg film-coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One Ropinirole 0.25 mg film-coated tablet contains 0.25 mg of ropinirole (as hydrochloride).
Excipient:
51.540 mg lactose/film-coated tablet For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet
Ropinirole 0.25 mg: White to off-white colour, capsule shaped biconvex, film-coated tablets with break-line on both sides.
The tablet can be divided into equal halves.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
For the treatment of Parkinson’s disease under the following conditions:
- Initial treatment as monotherapy, in order to delay the introduction of levodopa
- In combination with levodopa, over the course of the disease, when the effect of levodopa wears off or becomes inconsistent and fluctuations in the therapeutic effect occur ("end of dose" or "on-off" type fluctuations)
- for the symptomatic treatment of moderate to severe idiopathic Restless Legs
Syndrome (see section 5.1)
4.2 Posology and method of administration
Individual dose titration is recommended, based on efficacy and tolerability.
Parkinson’s disease
Ropinirole should be taken three times daily, preferably with meals to improve gastrointestinal tolerance.
Treatment initiation
During the first week, the initial dose should be 0.25 mg Ropinirole three times daily (t.i.d.) Thereafter, the dose can be increased upwards - in 0.25 mg t.i.d. increments -according to the following regimen:
|
Week |
1 |
2 |
3 |
4 |
|
Unit dose (mg) |
0.25 |
0.5 |
0.75 |
1.0 |
|
Total daily dose (mg) |
0.75 |
1.5 |
2.25 |
3.0 |
Therapeutic regimen
Following initial dose titration, the Ropinirole dose may be increased weekly, in 0.5 mg to 1 mg t.i.d. increments (1.5 to 3 mg/day).
Response to treatment can be expected at a daily Ropinirole dose of 3 mg to 9 mg. If this is insufficient in achieving or maintaining symptomatic control, escalation of the Ropinirole dose to a maximum of 24 mg /day is permitted. Doses above 24 mg/day have not been investigated in clinical trials.
If treatment is interrupted for one day or more re-initiation by dose titration should be considered (see above).
When Ropinirole is administered as an adjunct to L-dopa therapy, the coadministered L-dopa dose may be tapered off gradually by around 20%.
When switching from another dopamine agonist to Ropinirole, the manufacturer's guidelines on discontinuation should be followed prior to initiating Ropinirole therapy.
As with other dopamine agonists, Ropinirole should be tapered off gradually, by reducing the number of daily doses over a 1-week period.
For doses not realisable/practicable with this medicinal product other strengths of this medicinal product are available.
Restless Legs Syndrome
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 0.25mg 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
|
Week |
2 |
3 |
4 |
5* |
6* |
7* |
|
Dose (mg)/once daily |
1 |
1.5 |
2 |
2.5 |
3 |
4 |
* 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 the use in children and adolescents below 18 years due to a lack of data on safety and efficacy.
Elderly patients
Ropinirole clearance is diminished in patients over 65 years of age. Therefore, upward dose titration should be gradual and based on individual response to treatment.
Renal Impairment
In parkinsonian patients with mild-to-moderate renal impairment (creatinine clearance of 30-50 ml/min), no change in ropinirole clearance was observed, indicating that no dosage adjustment is necessary for this patient group.
4.3 Contraindications
- Hypersensitivity to ropinirole or to any of the excipients.
- Severe renal failure (creatinine clearance < 30 ml/min) and hepatic impairment.
4.4 Special warnings and precautions for use
Ropinirole has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease. There have been (uncommon) reports of sudden sleep onset during daily activities. In some cases, such episodes occurred without any warning signs or awareness by the patient. 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 dose reduction or discontinuation of therapy should be considered.
Patients with major psychiatric or psychotic disorders, or a history of these disorders should only be treated with dopamine agonists only if 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 Ropinirole. Dose reduction/tapered discontinuation should be considered if such symptoms develop.
Due to the risk of hypotension, blood pressure monitoring is recommended, particularly at the start of the treatment, in patients with severe cardiovascular disease (in particular coronary insufficiency).
Co-administration of Ropinirole with anti-hypertensive and anti-arrhythmic agents has not been studied. As with other dopaminergic drugs, caution should be exercised when these compounds are given concomitantly with Ropinirole because of the unknown potential for the occurrence of hypotension, bradycardias or other arrhythmias.
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.
Ropinirole should be administered with caution to patients with moderate hepatic impairment. Undesirable effects should be closely monitored.
This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
4.5 Interaction with other medicinal products and other forms of interaction
No pharmacokinetic interaction has been observed between ropinirole and L-dopa or domperidone, which would necessitate dosage adjustment of either medicinal product.
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 should be avoided.
Elevated ropinirole plasma levels have been observed in women receiving high-dose oestrogen. In patients already receiving hormone replacement therapy (HRT), Ropinirole treatment may be initiated in the normal manner. However, if HRT is stopped or introduced during Ropinirole therapy, adjustment of the Ropinirole dose may be required, depending on the response to treatment.
Ropinirole is mainly metabolised by the cytochrome P450 isoenzyme CYP1A2. One pharmacokinetic study on parkinsonian patients (who were given a 2 mg ropinirole dose t.i.d.) revealed that, following concomitant administration of ciprofloxacin, Cmax and AUC values for ropinirole increased by 60% and 84% respectively. There is hence a potential risk of adverse effects. Therefore, in patients already receiving Ropinirole, the Ropinirole dose may have to be reduced, if active substances that inhibit CYP1A2 (such as ciprofloxacin, enoxacin or fluvoxamine) are concomitantly administered. This also applies when such medicinal products are being withdrawn.
A pharmacokinetic study on Parkinson patients - which set out to investigate interactions between ropinirole (at a dose of 2 mg t.i.d.) and theophylline (a CYP1A2 substrate) - revealed no changes in the pharmacokinetics of either ropinirole or theophylline.
Smoking is known to induce CYP1A2 metabolism, therefore if the patients stop or start smoking during treatment with Ropinirole, dose adjustment may be required.
Pregnancy and lactation
4.6
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 unless the potential benefit to the patient outweighs the potential risk to the foetus.
Ropinirole should not be used in nursing mothers as it may inhibit lactation
4.7 Effects on ability to drive and use machines
Ropinirole has major influence on the ability to drive and use machines. Patients, in whom somnolence and/or sudden sleep episodes occur - or have occurred - whilst receiving ropinirole treatment, 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); this shall apply until such recurrent episodes of sudden sleep onset and somnolence have resolved (see also section 4.4).
4.8 Undesirable effects
Undesirable effects are listed below by system organ class and frequency. Frequencies are defined 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: frequency 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 2Adverse drug reactions reported in 12-week Restless Legs Syndrome
|
clinical trials (ropinirole n=309, placebo n= |
=307) |
|
Psychiatric disorders | |
|
Common |
Nervousness |
|
Uncommon |
Confusion |
|
Nervous system disorders | |
|
Common |
Syncope, somnolence, dizziness (including vertigo) |
|
Vascular disorders | |
|
Uncommon |
Postural hypotension, hypotension |
|
Gastrointestinal disorders | |
|
Very common |
Vomiting, nausea |
|
Common |
Abdominal pain |
|
General disorders and administration site conditions | |
|
Common |
Fatigue |
|
Table 3 Adverse drug reactions reported |
in other Restless Legs Syndrome |
|
clinical trials | |
|
Psychiatric disorders | |
|
Uncommon |
Hallucinations |
|
Nervous system disorders | |
|
Common |
Augmentation, Early morning rebound (see section 4.4) |
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. 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.
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.
|
In monotherapy studies |
In adjunct therapy studies | ||
|
Immune system disorders | |||
|
Not known |
Hypersensitivity reactions including urticarial, angioedema, rash, pruritus | ||
|
Psychiatric disorders | |||
|
Common |
Hallucinations |
Confusion | |
|
Uncommon |
Psychotic reactions (other hallucinations) including delirium, delusion, paranoia. Impulse control disorders including pathological | ||
|
gambling and hypersexuality, and increased libido, have been reported in postmarketing reports (see section 4.4). | |||
|
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) | ||
|
Uncommon |
Excessive daytime somnolence, sudden onset of sleep Ropinirole is associated with somnolence and has been associated uncommonly with excessive daytime somnolence and sudden sleep onset episodes. | ||
|
Vascular disorders | |||
|
Uncommon |
Hypotension, postural hypotension Hypotension or postural hypotension is rarely severe | ||
|
Gastrointestinal disorders | |||
|
Very common |
Nausea | ||
|
Common |
Heartburn |
Vomiting, abdominal pain | |
|
Hepatobiliary disorders | |||
|
Not known |
Hepatic reactions, mainly increased liver enzymes | ||
|
General disorders and administration site conditions | |||
|
Common |
Leg oedema | ||
Hypersensitivity reactions (including urticaria, angioedema, rash, pruritus) Psychotic reactions (other than hallucinations) including delirium, delusion, paranoia have been reported.
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 ‘Special warnings and precautions for use’).
Ropinirole is associated with somnolence and has been associated very rarely with excessive daytime somnolence and sudden sleep onset episodes.
Very rarely, hepatic reactions, mainly increased liver enzymes, have been reported.
4.9 Overdose
It is anticipated that the symptoms of ropinirole overdose will be related to the dopaminergic activity.
These symptoms can be alleviated by appropriate treatment with dopamine antagonists, such as a neuroleptic or metoclopramide.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Anti-Parkinson drug, dopamine agonist.
ATC code: N04BC04.
Parkinson’s disease
Ropinirole is a non-ergoline dopamine agonist. Ropinirole alleviates the symptoms of dopamine deficiency, which characterises Parkinson’s disease, by stimulating dopamine receptors in the striatum.
Due to its action in the hypothalamus and pituitary, ropinirole inhibits prolactin secretion.
Restless Legs Syndrome
Mechanism of action
Ropinirole is a non ergoline D2/D3 dopamine agonist which stimulates striatal dopamine receptors.
Clinical efficacy
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.
5.2 Pharmacokinetic properties
Absorption
Oral absorption of ropinirole is rapid. Bioavailability of ropinirole is approximately 50% (36 to 57%) and average peak concentrations of ropinirole are achieved at a median time of 1.5 hours post-dose.
Distribution
The binding of ropinirole to plasma proteins is low (10 - 40%).
Consistent with its high lipophilicity, ropinirole exhibits a large volume of distribution (mean value 6.7 l/kg, range 3.4 - 19.5 l/kg) and is cleared from the systemic circulation with an average elimination half-life of approximately 6 hours (range 3.4 - 10.2 h) and an apparent oral clearance of 58.7 l/h (range
18.5 - 132 l/h).
Metabolism
The cytochrome P450 isoenzyme CYP1A2 is primarily responsible for the oxidative metabolism of ropinirole. Ropinirole is mainly excreted in the urine as metabolites. The major metabolite is at least 100 times less potent than ropinirole in animal models of dopaminergic function.
Elimination
Wide inter-individual variability in the pharmacokinetic parameters has been seen and the increase in systemic exposure (Cmax and AUC) to ropinirole with an increase in dose over the therapeutic dose range is proportional after single administration.
Paediatric population
Limited pharmacokinetic data obtained in adolescents (12-17 years, n=9) showed that the systemic exposure following single doses of 0.125mg and 0.25mg was similar to that observed in adults (see also section 4.2; subparagraph “Children and adolescents).
5.3 Preclinical safety data
Reproductive Toxicity
Administration 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 2 times the AUC at the maximum dose in humans) and digit malformations at 150 mg/kg/day (approximately 3 times the AUC at the maximum dose in humans). There were no teratogenic effects in the rat at 120 mg/kg/day (approximately 2.5 times the AUC at the maximum dose in humans) and no indication of an effect on development in the rabbit.
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 a high 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.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Cellulose, Microcrystalline Lactose Monohydrate Croscarmellose Sodium Hypromellose Magnesium stearate
Film Coat:
0.25 mg:
Hypromellose Titanium Dioxide (E 171)
Macrogol 400 Polysorbate 80
6.2 Incompatibilities
Not applicable
6.3 Shelf life
3 years
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions
6.5 Nature and contents of container
HDPE multidose container with child resistant closure (PP)
Silica gel canister
Ropinirole 0.25mg: 21, 28, 84 and 126 film-coated tablets
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Generics [UK] Limited t/a Mylan
Station Close
Potters Bar
Hertfordshire
EN6 1TL
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 04569/0812
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
04/04/2008
10 DATE OF REVISION OF THE TEXT
26/11/2013