Ropinirole 5mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ropinirole 5 mg film-coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains ropinirole hydrochloride equivalent to 5.0 mg of ropinirole. Ropinirole 5 mg film-coated tablets:
Each film-coated tablet contains ropinirole hydrochloride equivalent to 5 mg of ropinirole Excipient with known effect: 67.55 mg lactose (as lactose monohydrate and lactose anhydrous).
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM Film-coated tablet.
5.0 mg Blue, circular, bevelled edged, biconvex film coated tablets with ‘259’ debossed on one side and ‘G’ on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
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).
4.2 Posology and method of administration
Oral use.
Adults
Individual dose titration against efficacy and tolerability is recommended.
Ropinirole 5mg film-coated tablets should be taken three times a day, preferably with meals to improve gastrointestinal tolerance.
Treatment, initiation
The initial dose of ropinirole should be 0.25 mg three times daily for 1 week. Thereafter, the dose of ropinirole can be increased in 0.25 mg three times daily increments, according to the following regimen:
|
1 |
2 |
Week 3 |
4 | |
|
Unit dose (mg) of ropinirole |
0.25 |
0.5 |
0.75 |
1.0 |
|
Total daily dose (mg) of ropinirole |
0.75 |
1.5 |
2.25 |
3.0 |
Therapeutic regimen
After the initial titration, weekly increments of 0.5 to 1 mg three times daily (1.5 to 3 mg/day) of ropinirole may be given.
A therapeutic response may be seen between 3 and 9 mg/day of ropinirole. If sufficient symptomatic control is not achieved, or maintained after the initial titration as described above, the dose of ropinirole may be increased up to 24 mg/day.
Doses of ropinirole above 24 mg/day have not been studied.
If treatment is interrupted for one day or more re-initiation by dose titration should be considered (see above).
When Ropinirole 5 mg film-coated tablets are administered as adjunct therapy to L-dopa, the concurrent dose of L-dopa may be reduced gradually according to the symptomatic response. In clinical trials, the L-dopadose was reduced gradually by around 20% in patients treated with Ropinirole 5 mg film-coated tablets as adjunct therapy. In patients with advanced Parkinson’s disease receiving ropinirole in combination with L-dopa, dyskinesias can occur during the initial titration of ropinirole. In clinical trials it was shown that a reduction of the L-dopa dose may ameliorate dyskinesia (see section 4.8).
When switching treatment from another dopamine agonist to ropinirole, the manufacturer’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 number of daily doses over the period of one week.
Renal impairment
In patients with mild to moderate renal impairment (creatinine clearance 30-50 ml/min) no change in the clearance of ropinirole was observed, indicating that no dosage adjustment is necessary in this population.
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 initial dose of ropinirole should be 0.25 mg three times a day. Further dose escalations should be based on tolerability and efficacy. The recommended maximum dose is 18 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.
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.
Children and adolescents
Ropinirole 5 mg film-coated tablets are 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 by approximately 15% in patients over 65 years of age. 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
In patients with mild to moderate renal impairment (creatinine clearance 30-50 ml/min) no change in the clearance of ropinirole was observed, indicating that no dose adjustment is necessary.
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 ropinirole is 0.25 mg three times a day. Further dose escalations should be based on tolerability and efficacy. The recommended maximum dose is 18 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.
4.3 Contraindications
Hypersensitivity to ropinirole or to any of the excipients listed in section 6.1.
Severe renal impairment (creatinine clearance <30ml/min) without regular haemodialysis.
Hepatic impairment.
4.4 Special warnings and precautions for use
Patients with major psychiatric or psychotic disorders, or a history of these disorders should only be treated with dopamine agonists if the potential benefits outweigh the risks.
Ropinirole has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's disease. 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 were reported especially at high doses and were generally reversible upon reduction of the dose or treatment discontinuation. Risk factors such as a history of compulsive behaviours were present in some cases (see section 4.8).
Due to the risk of hypotension, blood pressure monitoring is recommended, particularly at the start of treatment, in patients with severe cardiovascular disease (in particular coronary insufficiency).
This medicinal product also 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
Neuroleptics and other centrally active dopamine antagonists, such as sulpiride or metoclopramide, may diminish the effectiveness of ropinirole and, therefore, concomitant use of these drugs with ropinirole should be avoided.
There is no pharmacokinetic interaction has been seen between ropinirole and L-dopa or domperidone which would necessitate dosage adjustment of these medicinal products.
Ropinirole is principally metabolised by the cytochrome P450 enzyme CYP1A2. A pharmacokinetic study (with a ropinirole dose of 2 mg, three times a day in patients with Parkinson’s disease) 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 or fluvoxamine, are introduced or withdrawn.
A pharmacokinetic interaction study in patients with Parkinson’s disease 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.
Increased plasma concentrations of ropinirole have been observed in patients treated with high doses of oestrogens. 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 treatment with ropinirole, dosage adjustment may be required, in accordance with clinical response.
Smoking is known to induce CYP1A2 metabolism, therefore if patients stop or start smoking during treatment with ropinirole, adjustment of dose maybe required.
4.6 Fertility, 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 unless the potential benefit to the patient outweighs the potential risk to the foetus.
Breast feeding
Ropinirole should not be used in nursing mothers as it may inhibit lactation.
4.7 Effects on ability to drive and use machines
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 recurrent episodes and somnolence have resolved (see also Section 4.4).
Adverse events are listed below by system organ class and frequency. It is noted if these undesirable effects were reported in clinical trials as monotherapy or adjunct therapy to levodopa.
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 (cannot be estimated from the available data).
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
It is noted if these undesirable effects were reported in clinical trials as monotherapy or adjunct therapy to levodopa.
Immune system disorders
Not known: hypersensitivity reactions (including urticaria, angioedema, rash, pruritus).
Psychiatric disorders Common: hallucinations.
Uncommon: psychotic reactions (other than hallucinations) including delirium, delusion,
paranoia.
Not known: aggression*
*aggression has been associated with psychotic reactions as well as compulsive symptoms.
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’).
Use in adjunct therapy studies:
Common: confusion.
Nervous system disorders
Very common: somnolence
Common: dizziness (including vertigo).
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.
Use in monotherapy studies:
Very common: syncope.
Use in adjunct therapy studies:
Very common: 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).
Vascular disorders
Uncommon: postural hypotension, hypotension.
Postural hypotension or hypotension is rarely severe.
Gastrointestinal disorders Very common: nausea.
Common: heartburn.
Use in monotherapy studies:
Common: vomiting, abdominal pain.
Hepatobiliary disorders
Not known: hepatic reactions, mainly increased liver enzymes.
General disorders
Use in monotherapy studies: Common: leg oedema.
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.
4.9 Overdose
The symptoms of ropinirole overdose are generally 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.
Ropinirole alleviates the dopamine deficiency which characterises Parkinson’s disease by stimulating striatal dopamine receptors.
Ropinirole acts in the hypothalamus and pituitary to inhibit the secretion of prolactin.
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.
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 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.
In clinical studies most patients were of Caucasian origin.
5.2 Pharmacokinetic properties
Absorption
The bioavailability of ropinirole is about 50% (36% to 57%), with Cmax reached on average 1.54 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.
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).
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.
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.
Linearitv/non-linearitv
The 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 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 and 18 mg/day in patients with Parkinson’s disease (see section 4.2).
Paediatric population
Limited 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").
5.3 Preclinical safety data
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 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
Parkinson’s disease
Administration 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.
Restless Legs Syndrome
Administration 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 Pharmacology Restless Legs Syndrome
In vitro studies have shown that ropinirole inhibits hERG-mediated currents. However, 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), and the available clinical data with ropinirole do not suggest a risk of QT prolongation at therapeutic doses (see section 5.1).
Parkinson’s disease
In 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).
PHARMACEUTICAL PARTICULARS
6
6.1 List of excipients
Tablet Cores Lactose, Anhydrous Lactose Monohydrate Cellulose, microcrystalline (E460) Citric acid, anhydrous (E330) Croscarmellose sodium (E468) Magnesium Stearate (E572)
Film Coating
5.0 mg
Hypromellose (E464), Titanium dioxide (E171), Macrogol 400, Talc, Indigo carmine aluminium lake (E132), Brilliant blue FCF Aluminium lake (E133)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
6.4 Special precautions for storage
Do not store above 30°C.
Blisters
Store in the original package in order to protect from moisture.
Bottles
Keep the bottle tightly closed in order to protect from moisture.
6.5 Nature and contents of container
Blisters:
Plain Aluminium/Aluminium blisters; White, opaque Triplex(PVC/PE/Aclar)/Aluminium blisters. Bottles:
White opaque HDPE bottle with polypropylene child-resistant closure.
Pack Sizes Blister: 21 and 84 Bottle: 84
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements for disposal.
7 MARKETING AUTHORISATION HOLDER
Glenmark Pharmaceuticals Europe Limited, Laxmi House, 2 B Draycott Avenue, Kenton, Middlesex HA3 0BU, United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL25258/0051
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
17/12/2009
10 DATE OF REVISION OF THE TEXT
20/05/2015