Ropinirole 5mg Film-Coated Tablets
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ropinirole 5mg Film-Coated Tablets
2. QUALITATIVE AND QUANTITATIVE COMPOSITION
One film-coated tablet contains 5.7mg ropinirole hydrochloride, equivalent to 5mg ropinirole.
Excipient(s) with known effect Lactose monohydrate - 113.2mg For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
Blue, irregular hexagonal shape film-coated tablets, debossed with ‘W’ on one side and ‘177’ 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
Posology
Adults
Individual dose titration against efficacy and tolerability is recommended.
Ropinirole should be taken three times a day (t.i.d.), 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 0.25mg three times daily increments, according to the following regimen:
|
1 |
2 |
Week 3 |
4 | |
|
Unit dose (mg) |
0.25 |
0.5 |
0.75 |
1.0 |
|
Unit dose presentation (mg) |
0.25 |
0.5 |
0.25, 0.5 |
1.0 |
|
Total daily dose (mg) |
0.75 |
1.5 |
2.25 |
3.0 |
Therapeutic regimen: After the initial titration, weekly increments of 0.5 to 1mg three times daily (1.5 to 3mg/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 24mg/day.
Doses of ropiniriole 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 L-dopa, the concurrent dose of L-dopa 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 L-dopa, 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).
Paediatric population
Ropinirole Tablets are 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 responses.
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 Tablets should be 0.25 mg three times a day. Further dose escalations should be based on tolerability and efficacy. The recommended maximum dose of Ropinirole Tablets 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 (creatinine clearance <30ml/min) or hepatic impairment impairment has not been studied.
Treatment discontinuation
Abrupt discontinuation of dopaminergic therapy can lead to the development of a neuroleptic malignant syndrome (see section 4.4).
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.
Method of Administration
Ropinirole Film-coated Tablets are for oral use. The tablets should be swallowed whole with a glass of water, preferably with food
4.3 Contraindications
Hypersensitivity to the active substance 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
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.
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, 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. These 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).
Dopamine Dysregulation Syndrome
Dopamine Dysregulation Syndrome (DDS) has been reported.
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). This is suggested to be a class effect.
Due to the risk of hypotension, blood pressure monitoring is recommended, particularly at the beginning of 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. 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.
Excipients:
The tablets contain 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
There is no pharmacokinetic interaction between ropinirole and levodopa or domperidone would necessitate dosage adjustment of these medicinal products. Domperidone antagonises the dopaminergic actions of ropinirole peripherally and does not cross the blood-brain barrier. Hence its value as an anti-emetic in patients treated with centrally acting dopamine agonists.
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.
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 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.
Smoking is known to induce CYP1A2 metabolism, therefore if patients stop or start smoking during treatment with ropinirole, dose adjustment maybe required.
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 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 fetus.
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
Ropinirole Film-coated Tablets has major influence on the ability to drive and use machines.
Patients should be warned about the possibility of dizziness (including vertigo). 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 ).
4.8 Undesirable effects
Undesirable effects 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, <1/10), uncommon (>1/1,000, <1/100), rare (>1/10,000, <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.
Tabulated List of adverse reactions reported from patients taking ropinirole in Parkinson’s Disease
|
Immune System Disorders | |
|
Not known |
Hypersensitivity reactions (including urticaria, angioedema, rash, pruritis) |
|
Psychiatric disorders | |
|
Common |
Confusion1, hallucinations |
|
Uncommon |
Psychotic reactions (other than hallucinations), including delusion, paranoia, delirium. 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 (see section 4.4 ‘Special warnings and precautions for use’) |
|
Not known |
Dopamine dysregulation syndrome |
|
Nervous system disorders | |
|
Very common |
Syncope2, somnolence, dyskinesia1 |
|
Common |
Dizziness (including vertigo) |
|
Uncommon |
Extreme daytime somnolence, sudden onset of sleep. |
|
Vascular disorders | |
|
Uncommon |
Hypotension, postural hypotension postural hypotension or hypotension is rarely severe |
|
Gastrointestinal disorders | |
|
Very common |
Nausea |
|
Common |
22 Abdominal pain , vomiting , heartburn |
|
Hepatobiliary disorders | |
|
Not known |
Hepatic reactions, hepatic enzymes increased |
|
General disorders and administrative site conditions | |
|
Common |
2 Oedema peripheral (including leg oedema ) |
1 Adjunct therapy studies
2 Monotherapy studies
*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 also section 4.2)
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 may be alleviated by appropriate treatment with dopamine antagonists such as neuroleptics or metoclopramide.
5. PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Dopaminergic agents, dopamine agonists, ATC code: N04BC04
Mechanism of action
Ropinirole is a non ergoline D2/D3 dopamine agonist which stimulates striatal dopamine receptors.
Pharmacodynamic effects
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.
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
The bioavailability of ropinirole is about 50% (36% to 57%). Oral absorption of ropinirole film-coated (immediate-release) tablets is rapid with peak concentrations of ropinirole achieved at a median time of 1.5 hours post-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).
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 six 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.
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 18 mg/day in these patients with Parkinson’s disease (see section 4.2).
5.3 Preclinical safety data
Reproductive Toxicity
Administration of ropinirole to pregnant rats at maternally toxic doses resulted in decreased fetal body weight at 60 mg/kg/day (approximately twice the AUC at the maximum dose in humans), increased fetal 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 30 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 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 (24mg/day), see section 5.1.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Tablet core:
Lactose monohydrate Microcrystalline cellulose Croscarmellose sodium Hypromellose (6cps)
Magnesium stearate
Film coat (opadry blue 03B20462): Hypromellose 6cps Titanium dioxide (E171)
Macrogol
Indigo carmine aluminium lake (E132)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Blisters: 18 months
HDPE bottles: 18 months. After first opening of the bottle use the medicinal product within one month.
6.4 Special precautions for storage
Blisters: Store below 25°C. Store in the original package (blister) in order to protect from moisture.
HDPE bottles: Store below 25 °C. Keep the bottle tightly closed in order to protect from moisture.
6.5 Nature and contents of container
ALU/ALU blister packs of 12, 28 or 100 tablets
HDPE container with child resistant closure of 30 or 84 tablets.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
MARKETING AUTHORISATION HOLDER
7
Wockhardt UK Ltd Ash Road North Wrexham LL13 9UF UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 29831/0417
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
10/02/2011
10 DATE OF REVISION OF THE TEXT
19/07/2016