Ropinirole 5 Mg Film-Coated Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ropinirole 5mg Film-Coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Ropinirole 5 mg: Each film-coated tablet contains 5.70 mg ropinirole hydrochloride, equivalent to 5 mg ropinirole
Excipient(s) with known effect:
Lactose and Ponceau 4R Aluminium Lake (E124):
99.94 mg lactose & 0.0189 mg Ponceau 4R Aluminium Lake (E124) / film-coated tablet
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
Blue, round slightly arched film-coated tablets, debossed “R 5” on one side and plain on the other.
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
For oral use
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 should be 0.25mg three times daily for 1 week. Thereafter, the dose can be increased in 0.25mg 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
After the initial titration, weekly increments of 0.5 to 1mg t.i.d (1.5 to 3mg/day) may be given.
A therapeutic response may be seen between 3 and 9mg/day. If sufficient symptomatic control is not achieved, or maintained, the dose of ropinirole may be increased up to 24mg/day. Doses above 24mg/day have not been studied.
When ropinirole is administered as adjunct therapy to levodopa, the concurrent dose of levodopa may be reduced gradually by around 20%.
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.
General information for all therapeutic indications 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
In parkinsonian patients with mild to moderate renal impairment (creatinine clearance between 30 and 50ml/min) no change in the clearance of ropinirole was observed, indicating that no dosage adjustment is necessary in this population.
4.3 Contraindications
Hypersensitivity to ropinirole, Ponceau 4R or to any of the excipients Severe renal impairment (creatinine clearance <30ml/min)
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. Furthermore, a reduction of dosage or termination of therapy may be considered.
Patients with psychiatric or psychotic 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, hypersexuality, increased libido, compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists, including Ropinirole (see section 4.8). Dose reduction/tapered discontinuation should be considered if such symptoms develop.
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.
Precautions for Use
Severe cardiovascular disease (in particular coronary insufficiency). 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
No pharmacokinetic interaction has been seen between ropinirole and levodopa or domperidone which would necessitate dosage adjustment of either medicinal product.
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 2mg, three times a day) in Parkinson patients revealed that ciprofloxacine 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. ciprofloxacine, enoxacin or fluvoxamine, are introduced or withdrawn.
A pharmacokinetic interaction study in Parkinson patients between ropinirole (at a dose of 2mg, three times a day) and theophylline, a substrate of CYP 1A2, revealed no change in the pharmacokinetics of either ropinirole or theophylline.
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.
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.
4.6 Fertility, pregnancy and lactation
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 machine. 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. 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. Common and uncommon events were generally determined from pooled safety data from clinical trial populations and are quoted as excess incidence over placebo. Rare and very rare undesirable effects were generally determined from postmarketing data and refer to reporting rate rather than true frequency.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
|
Organ Class System |
Monotherapy or Adjunct therapy |
Frequency | |||
|
Very Common (>1/10) |
Common (>1/100 to <1/10) |
Uncommon (>1/1,000 to <1/100) |
Not known | ||
|
Nervous system disorders |
Both |
Somnolence |
Dizziness (including vertigo) |
Excessive daytime somnolence and sudden onset of sleep | |
|
Monotherapy |
Syncope | ||||
|
Adjunct therapy |
Dyskinesia | ||||
|
Gastro intestinal disorders |
Both |
Nausea |
Heartburn | ||
|
Monotherapy |
Abdominal pain, vomiting and heartburn | ||||
|
Vascular disorders |
Both |
Hypotension and postural hypotension (rarely severe) | |||
|
General disorders and administration site conditions |
Monotherapy |
Leg oedema | |||
|
Hepatobiliary disorders |
Both |
Hepatic reactions and increased liver enzymes | |||
|
Psychiatric disorders |
Both |
Hallucinations |
Psychotic reactions (other than hallucinations) including delirium, delusion, and paranoia | ||
|
Adjunct therapy |
Confusion, hallucination | ||||
Both: Monotherapy and adjunct therapy
Impulse control disorders
Pathological gambling, hypersexuality and increased libido compulsive spending or buying, binge eating and compulsive eating can occur in patients treated with dopamine agonists including Ropinirole (see section 4.4).
Ponceau 4R may cause allergic reactions
4.9 Overdose
There have been no incidences of intentional overdose with ropinirole in clinical trials. 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: Dopaminergic agents, dopamine agonists; ATC code: N04BC04
Ropinirole is a non-ergoline dopamine agonist.
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.
5.2 Pharmacokinetic properties
Oral absorption of ropinirole is rapid. Bioavailability of ropinirole is approximately 50 % (36 to 57 %) and average peak concentrations of the drug are achieved at a median time of 1.5 hours post-dose. 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. 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). Plasma protein binding of ropinirole is low (10 - 40 %). 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.
Population-related characteristics 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 a high dose (50mg/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 50mg/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 60mg/kg (approximately 15 times the AUC at the maximum dose in humans), increased foetal death at 90mg/kg (approximately 25 times the AUC at the maximum dose in humans) and digit malformations at 150mg/kg (approximately 40 times the AUC at the maximum dose in humans). There were no teratogenic effects in the rat at 120mg/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 Hydroxypropylcellulose Croscarmellose sodium Magnesium stearate
Tablet coating (Opadry II 85F30590):
Poly(vinyl alcohol) - partially hydrolyzed Titanium dioxide (E171)
Macrogol 3350 Talc
FD&C Blue #2/ Indigo Carmine Aluminium (E132) Ponceau 4R Aluminium Lake (E124)
6.2 Incompatibilities
Not applicable
6.3 Shelf life
18 months
6.4 Special precautions for storage
Do not store above 30°C. Store in the original container.
6.5 Nature and contents of container
OPA/Alu/PVC - aluminium blisters. The pack sizes available are 15, 21, 30, 60, 84, 90 and 100.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Teva UK Limited,
Brampton Road,
Hampden Park,
Eastbourne,
BN22 9AG,
United Kingdom
8 MARKETING AUTHORISATION NUMBER
PL 00289/1196
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
13/01/2009
10 DATE OF REVISION OF THE TEXT
14/02/2013