Summary of Product Characteristics (SmPC) - Ropinirole 5 mg film-coated tablets
1 NAME OF THE MEDICINAL PRODUCT
Ropinirole 5 mg film-coated tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 5 mg of ropinirole (as hydrochloride).
Excipient with known effect:
Each film-coated tablet contains 54.25 mg lactose
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet
Blue coloured, 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)
4.2 Posology and method of administration
Oral use.
Adults
Individual dose titration against efficacy and tolerability is recommended.
Ropinirole should be taken three times daily, preferably with meals to improve gastrointestinal tolerance.
Treatment initiation
The initial dose of ropinirole should be 0.25 mg three times daily for one week. Thereafter, the dose of ropinirole can be increased in 0.25 mg increments three times daily according to the following regimen:
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Week 1 2 3 4 ----------------------------------------------------------------------------------------------
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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 dose 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 is administered as adjunct therapy to levodopa, the concurrent dose of levodopa may be reduced gradually according to the symptomatic response. In clinical trials, the levodopa dose was reduced gradually by around 20% in patients treated with ropinirole as adjunct therapy.
In patients with advanced Parkinson's disease receiving ropinirole in combination with levodopa, 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 4.8).
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 number of daily doses over the period of one week (see section 4.4).
For doses not realisable/practicable with this medicinal product other strengths of this medicinal product are available.
Children and adolescents
Ropinirole is not recommended for the use in children and adolescents below 18 years of age due to a lack of data on safety and efficacy.
Elderly patients
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
In patients with mild-to-moderate renal impairment (creatinine clearance between 30 and 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.
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
Somnolence and episodes of sudden sleep onset
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. A reduction of dosage or termination of therapy may be considered.
Psychiatric or psychotic disorders
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.
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, aggressive behaviours, 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.
Mania
Patients should be regularly monitored for the development of mania. Patients and carers should be made aware that symptoms of mania can occur with or without the symptoms of impulse control disorders in patients treated with ropinirole. Dose reduction/tapered discontinuation should be considered if such symptoms develop.
Hypotension
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).
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).
Dopamine agonist withdrawal syndrome (DAWS)
DAWS has been reported with dopamine agonists, including ropinirole (see section 4.8).
To discontinue treatment in patients with Parkinson’s disease, ropinirole should be tapered off (see section 4.2). Limited data suggests that patients with impulse control disorders and those receiving high daily dose and/or high cumulative doses of dopamine agonists may be at higher risk for developing DAWS. Withdrawal symptoms may include apathy, anxiety, depression, fatigue, sweating and pain and do not respond to levodopa.
Prior to tapering off and discontinuing ropinirole, patients should be informed about potential withdrawal symptoms. Patients should be closely monitored during tapering and discontinuation. In case of severe and/or persistent withdrawal symptoms, temporary re-administration of ropinirole at the lowest effective dose may be considered.
Hallucinations
Hallucinations are known as a side effect of treatment with dopamine agonists and levodopa. Patients should be informed that hallucinations can occur.
Excipients
Lactose
This medicinal product also contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Sodium
This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium free”.
4.5 Interaction with other medicinal products and other forms of interaction
There is no pharmacokinetic interaction between ropinirole and levodopa or domperidone which would necessitate dosage adjustment 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 should be avoided.
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, it may be necessary to adjust the ropinirole dose, in accordance with clinical response, if HRT is stopped or introduced during treatment with ropinirole.
Ropinirole is principally metabolised by the cytochrome P450 isoenzyme 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 values for ropinirole by 60% and 84% respectively with a potential risk of adverse events. Hence, in patients already receiving ropinirole, the ropinirole dose may have to be adjusted when medicinal products known to inhibit CYP1A2 (such as 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 CYP1A2 substrate) – revealed no change in the pharmacokinetics of either ropinirole or theophylline.
Smoking is known to induce CYP1A2 metabolism, therefore if patients stop or start smoking during treatment with ropinirole, dose adjustment may be required.
In patients receiving the combination of vitamin K antagonists and ropinirole, cases of unbalanced INR have been reported. Increased clinical and biological surveillance (INR) is warranted.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate data from the use of ropinirole in pregnant women. Ropinirole concentrations may gradually increase during pregnancy (see section 5.2).
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-related material was shown to transfer into the milk of lactating rats. It is unknown whether ropinirole and its metabolites are excreted in human milk. A risk to the suckling child cannot be excluded. Ropinirole should not be used in nursing mothers as it may inhibit lactation.
Fertility
There are no data on the effects of ropinirole on human fertility. In female fertility studies in rats, effects were seen on implantation but no effects were seen on male fertility (see section 5.3).
4.7 Effects on ability to drive and use machines
Patients being treated with ropinirole and presenting with hallucination 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 section 4.4).
4.8 Undesirable effect
Undesirable effects reported 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: frequency cannot be estimated from the available.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
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 and paranoia. Not known: aggression*, dopamine dysregulation syndrome, mania (see section
4.4), impulse control disorders** (see section 4.4.).
* Aggression has been associated with psychotic reactions as well as compulsive symptoms.
** Impulse control disorders: pathological gambling, increased libido, hypersexuality, aggression, compulsive spending or buying, binge eating, and compulsive eating can occur in patients treated with dopamine agonists including ropinirole (see section 4.4.).
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.
Respiratory, thoracic and mediastinal disorders
Uncommon: hiccups
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.
Reproductive system and breast disorders
Not known: spontaneous penile erection
General disorders
Use in
monotherapy
studies:
Common: Oedema peripheral (including leg oedema).
Not known: Dopamine agonist withdrawal syndrome (including apathy, anxiety, depression, fatigue, sweating and pain).
Dopamine agonist withdrawal syndrome
Non-motor adverse effects may occur when tapering or discontinuing dopamine agonists including ropinirole (see section 4.4).
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 related to its dopaminergic activity.
These symptoms can be alleviated by appropriate treatment with dopamine antagonists, such as neuroleptics or metoclopramide.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: dopaminergic agents, dopamine agonist. ATC code: N04BC04.
Mechanism of action
Ropinirole is a non-ergoline D2/D3 dopamine agonist which stimulates striatal dopamine receptors.
Ropinirole alleviates the symptoms of dopamine deficiency, which characterises Parkinson’s disease, by stimulating striatal dopamine receptors.
Due to its action in the hypothalamus and pituitary, ropinirole inhibits prolactin secretion.
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.
5.2 Pharmacokinetic properties
Absorption
Bioavailability of ropinirole is approximately 50 % (36 to 57 %). Oral absorption of ropinirole film-coated (immediate release) tablet is rapid with peak concentrations of ropinirole are achieved at a median time of 1.5 hours post-dose. A high fat meal decreases the rate of absorption or ropinirole, as shown by a delay in median Tmax by 2.6 hours and an average 25% decrease in Cmax.
Distribution
The binding of ropinirole to plasma proteins 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. The increase in systemic exposure (Cmax and AUC) to ropinirole is approximately proportional over the therapeutic dose range. 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.
Renal Impairment
There was no change observed in the pharmacokinetics of ropinirole in Parkinson's disease patients with mild to moderate renal impairment.
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 18mg/day in these patients with Parkinson's disease (see section 4.2).
Pregnancy
Physiological changes in pregnancy (including decreased CYP1A2 activity) are predicted to gradually lead to an increased maternal systemic exposure of ropinirole (see also section 4.6).
5.3 Preclinical safety data
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 twice the highest AUC at the Maximum Recommended Human Dose (MRHD)), increased foetal death at 90 mg/kg/day (approximately 3 times the highest AUC at the MRHD) and digit malformations at 150 mg/kg/day (approximately 5 times the highest AUC at the MRHD). There were no teratogenic effects in the rat at 120 mg/kg/day (approximately 4 times the highest AUC at the MRHD) and no indication of an effect during organogenesis in the rabbit when given alone at 20 mg/kg (9.5 times the mean human Cmax at the MRHD). However, ropinirole at 10 mg/kg (4.8 times the mean human Cmax 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.
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.
Safety Pharmacology
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).
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Cellulose, microcrystalline
Lactose monohydrate
Croscarmellose sodium
Hypromellose
Magnesium stearate
Film Coat
Hypromellose
Titanium dioxide (E 171)
Macrogol
Polysorbate
Indigo carmine (E 132)
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
21, 28, 84 and 126 film-coated tablets
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Generics [UK] Ltd t/a Mylan
Station Close
Potters Bar
Hertfordshire
EN6 1TL
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 04569/0816
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
04/04/2008
10 DATE OF REVISION OF THE TEXT
13/07/2026