Ropinirole 0.5 Mg Film-Coated Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Ropinirole 0.5 mg Film-Coated Tablets
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 0.57 mg ropinirole hydrochloride equivalent to 0.5 mg ropinirole.
Excipient: Contains 47.4 mg lactose monohydrate per film-coated tablet.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
Yellow coloured, circular, biconvex, film-coated tablets debossed with ‘F’ on one side and ‘62’ on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Treatment of Parkinson’s Disease:
•as montherapy in early phase in order to delay levodopa therapy.
•In combination with levodopa in later stage of the disease when the effect of levodopa is decreased or varies and fluctuations are seen (“end of dose” or “on-off’ fluctuations)
For 0.25, 0.5, 1, 2 mg strengths:
The symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome (See section 5.1).
4.2 Posology and method of administration
Oral use.
Individual dose titration against efficacy and tolerability is recommended.
For doses not realisable/practicable with this strength other strengths of this medicinal product are available.
In the treatment of Parkinson’s Disease
Ropinirole should be taken three times a day, preferably with meals to improve gastrointestinal tolerance.
Treatment initiation: The initial dose should be 0.25 mg three times daily for one week. Thereafter, the dose can be increased in 0.25 mg three times daily increments, according to the following regimen:
Table 1: Dose titration for treatment of Parkinson’s disease
|
Week | ||||
|
1 |
2 |
3 |
4 | |
|
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 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. If sufficient symptomatic control is not achieved, or maintained, the dose of ropinirole may be increased until an acceptable therapeutic response is established. Doses above 24 mg/day have not been investigated in clinical trials and this dose should not be exceeded.
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.
In the treatment of Restless Leg Syndrome
Individual dose titration against efficacy and tolerability is recommended. 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 0.25 mg 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 2:_Dose titration for treatment of Restless Legs Syndrome
|
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 efficacy of ropinirole treatment has not been shown beyond 12 weeks (see section 5.1). 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.
General instructions
As with other dopamine agonists, ropinirole should be discontinued gradually by reducing the number of daily doses over the period of one week.
Children and adolescents
Ropinirole is not recommended for use in children below 18 years due to lack of data on safety and efficacy.
Elderly:
The clearance of ropinirole is decreased by approximately 15% in patients over 65 years of age. Dosage increases should be gradual and titrated against the symptomatic 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 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 recommended initial dose of ropinirole is 0.25 mg once daily. Further dose escalations should be based on tolerability and efficacy. The recommended maximum dose of ropinirole is 3 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 <30 ml/min) without regular haemodialysis
Hepatic impairment.
4.4 Special warnings and precautions for use
Due to the pharmacological action of ropinirole, patients with severe cardiovascular (in particular coronary insufficiency) disease should be treated with caution. Blood pressure monitoring is recommended, particularly at the start of treatment (due to the risk of postural hypotension).
Ropinirole should be administered with caution to patients with moderate hepatic impairment. Undesirable effects should be closely monitored.
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.
Patients with a history or presence of major psychotic disorders should only be treated with dopamine agonists if the potential benefits outweigh the risks (see also Section 4.5).
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 and hypersexuality, compulsive spending or buying, binge eating and compulsive eating in patients treated with dopamine agonists including ropinirole. Dose reduction/tapered discontinuation should be considered if such symptoms develop.
Those 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).
Ropinirole has been associated with somnolence and episodes of sudden sleep onset, particularly in patients with Parkinson's Disease. In Restless Legs Syndrome, this phenomenon is very rare. 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.
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.
Lactose
The 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
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.
No pharmacokinetic interaction has been seen between ropinirole and levodopa or domperidone which would necessitate dosage adjustment of either medicinal product. 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 with centrally acting agonists.
No interaction has been seen between ropinirole and other drugs commonly used to treat Parkinson's disease but, as is common practice, care should be taken when adding a new drug to a treatment regimen. Other dopamine agonists may be used with caution.
In a study in parkinsonian patients receiving concurrent digoxin, no interaction was seen which would require dosage adjustment.
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.
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.
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.
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.
Lactation:
Ropinirole should not be used in nursing mothers as it might 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 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
Adverse reactions are listed below by system organ class and frequency. 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). Common and uncommon reactions were generally determined from pooled safety data from clinical trial populations of ropinirole and are quoted as excess incidence over placebo. Rare and very rare reactions were generally determined from post-marketing data and refer to reporting rate rather than true frequency.
Use of Ropinirole in Parkinson’s disease Immune system disorders
Not known: Hypersensitivity reactions (including urticaria, angioedema, rash, pruritus)
Psychiatric disorders:
Common: hallucinations
Uncommon: psychotic reactions (other than hallucinations), including delusion, paranoia, delirium.
Impulse control disorders
Pathological gambling, increased libido and 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: excessive daytime solmnolence, sudden onset of sleep 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 (seesection 4.2).
Vascular disorders:
Common: hypotension, postural hypotension.
Gastrointestinal disorders:
Very common: nausea Common: heartburn
Use in monotherapy studies:
Common: vomiting, abdominal pain.
Hepatobiliary disorders:
Very rare: hepatic reactions, mainly increased liver enzymes
General disorders:
Use in monotherapy studies:
Common: leg oedema
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.
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 are summarised below. These adverse drug reactions were 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
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 (see Section 4.4).
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: N04B C04
Ropinirole is a non-ergoline D2/D3 dopamine agonist which stimulates striatal dopamine receptors.
Clinical efficacy in the treatment of Parkinson’s disease
Parkinson's disease is characterised by a marked dopamine deficiency in the nigral striatal system. Ropinirole alleviates this deficiency by stimulating striatal dopamine receptors.
Ropinirole acts in the hypothalamus and pituitary to inhibit the secretion of prolactin.
Clinical efficacy in the treatment of Restless Leg Syndrome
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.
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
Oral absorption of ropinirole is rapid and essentially complete. Bioavailability of ropinirole is approximately 50% (36 to 57%) and average peak concentrations (Cmax) of the drug are achieved at a median time of 1.5 hours post-dose. Wide interindividual variability in the pharmacokinetic parameters has been seen but, overall, there is a proportional increase in the systemic exposure (Cmax and AUC) to the drug with an increase in dose, over the therapeutic dose range. 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
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 about six 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 the drug is low (10-40%).
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.
Linearity
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 (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 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 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.
Reproductive Toxicity:
Administration of ropinirole to pregnant rats at maternally toxic doses resulted in decreased fetal body weight at 60 mg/kg/day (approximately 15 times the AUC at the maximum dose in humans), increased fetal 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:
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 cores:
Lactose monohydrate Cellulose microcrystalline Crosscarmellose sodium Magnesium stearate
Film-coating:
Hypromellose 6cP Titanium dioxide (E171) Macrogol 400 Iron oxide Yellow (E172) Iron oxide red (E172)
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
In use shelf life for HDPE bottle pack: 45 days
6.4 Special precautions for storage
Store below 25°C.
For Blister pack:
Store in the original package in order to protect from moisture. For HDPE bottle pack:
Keep the bottle tightly closed in order to protect from moisture.
6.5 Nature and contents of container
Aluminium foil blister: 12, 14, 20, 21, 28, 30, 42, 50, 56, 60, 63, 84, 90, 100, 126 or 210 film-coated tablets
HDPE Bottle:
Pack sizes: 100 film-coated tablets Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Amneal Pharma Europe Limited 70 Sir John Rogerson’s Quay,
Dublin 2,
Ireland.
8 MARKETING AUTHORISATION NUMBER(S)
PL 42357/0117
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 16/07/2012
10 DATE OF REVISION OF THE TEXT
06/09/2013