Ropinirole 0.25mg Film-Coated Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT
Ropinirole 0.25mg Film coated Tablets.
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each film-coated tablet contains 0.25 mg, ropinirole (as hydrochloride). Excipient (s): Each film-coated tablet contains 46.276 mg of lactose.
For a full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Film-coated tablet.
White to off white, round biconvex, film-coated tablets plain on both sides.
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)”
Ropinirole is indicated for the symptomatic treatment of moderate to severe idiopathic Restless Legs Syndrome (see section 5.1)
4.2 Posology and method of administration
Oral use
Parkinson’s Disease:
Adults
Individual dose titration against efficacy and tolerability is recommended.
Ropinirole 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:
|
Table 1: Ropinirole dose titration (Parkinson’s t |
isease) | |||
|
Week |
1 |
2 |
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 tablet 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.
Children and adolescents
Ropinirole is 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 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 of ropinirole 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.
Idiopathic Restless Leg Syndrome:
Adults
Individual dose titration against efficacy and tolerability is recommended. Ropinirole should be taken just before bed time; however it 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 2.
Doses above 4 mg once daily have not been investigated in Restless Legs Syndrome patients.
Table 2: Ropinirole Dose titration (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 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.
Children and adolescent
Ropinirole is not recommended for use in children and 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
No dosage adjustment is necessary in patients with mild to moderate renal impairment (creatinine clearance between 30 and 50 ml/min).
4.3 Contraindications
Parkinson’s Disease:
Hypersensitivity to the active substance or to any of the excipients.
Severe renal impairment (creatinine clearance <30ml/min) without regular haemodialysis.
Hepatic impairment.
Restless Leg Syndrome:
Hypersensitivity to the active substance or to any of the excipients.
Severe renal impairment (creatinine clearance < 30ml/min).
Severe hepatic impairment.
4.4 Special warnings and special precautions for use
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, increased intensity, or spread of symptoms to previously unaffected limbs), 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.
In Parkinson's disease, ropinirole has been associated with somnolence and episodes of sudden sleep onset (see section 4.8). However, 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. Nevertheless, patients must be informed of this phenomenon 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 major psychotic disorders should not be treated with dopamine agonists unless 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 tablets. Dose reduction/tapered discontinuation should be considered if such symptoms develop.
Ropinirole should be administered with caution to patients with moderate hepatic impairment. Undesirable effects should be closely monitored.
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.
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) should be treated with caution.
4.5 Interaction with other medicinal products and other forms of interaction
Ropinirole is principally metabolised by the cytochrome P450 isoenzyme CYP1A2. A pharmacokinetic study (with a ropinirole dose of 2 mg, three times a day) 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 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.
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.
Increased plasma concentrations of ropinirole have been observed in patients treated with hormone replacement therapy. In patients already receiving hormone replacement therapy, ropinirole treatment may be initiated in the usual manner. However, it may be necessary to adjust the ropinirole dose, in accordance with clinical response, if hormone replacement therapy is stopped or introduced during treatment with ropinirole.
No pharmacokinetic interaction has been seen between ropinirole and domperidone (a medicinal product used to treat nausea and vomiting) that 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 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 medicinal products with ropinirole should be avoided.
4.6 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.
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).
4.8 Undesirable effects
Adverse drug reactions are listed below by system organ class and frequency. Frequencies from the clinical trials are determined as excess incidence over placebo and are classified as very common (>1/10) or common (>1/100, <1/10) or uncommon (>1/1,000, <1/100), rare (>1/10,000, <1/100) and very rare (<1/10,000), including isolated reports. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.
Use of ropinirole in Restless Legs Syndrome
In Restless Legs Syndrome clinical trials the most common adverse drug reaction is 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.
Table 3 lists the 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.
Table 3 Adverse drug reactions 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 |
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.
Management of undesirable effects
Dose reduction should be considered if patients experience significant undesirable effects. If the undesirable effect abates, gradual up-titration can be re-instituted. Antinausea medicinal products that are not centrally active dopamine antagonists, such as domperidone, may be used, if required.
Use of Ropinirole in Parkinson’s Disease
Ropinirole is also indicated for the treatment of Parkinson's disease. The adverse drug reactions reported in patients with Parkinson's disease on ropinirole monotherapy and adjunct therapy at doses up to 24 mg/day at an excess incidence over placebo are described below.
Table 4 Adverse drug reactions reported in Parkinson's disease clinical trials at doses up to 24 mg/day
|
Immune system disorders | |
|
Very rare |
Hypersensitivity reactions (including 3 urticaria, angioedema, rash, pruritus) |
|
Psychiatric disorders | |
|
Common |
Hallucinations, confusion1 |
|
Uncommon |
Psychotic reactions, (other than hallucinations) including delirium, delusion, paranoia. |
|
Impulse control disorders: Pat hypersexuality, compulsive spending eating can occur in patients treated w tablets (see section 4.4. ‘Special warni |
lological gambling, increased libido, or buying, binge eating and compulsive ith dopamine agonists including Ropinirole ngs and precautions for use’) |
|
Nervous system disorders | |
|
Very common |
Dyskinesia , somnolence , syncope |
|
Common |
Dizziness1,2 (including vertigo), |
|
Uncommon |
Sudden onset of sleep, extreme day time somnolence3 |
|
Vascular disorders | |
|
Uncommon |
Postural hypotension, hypotension. postural hypotension or hypotension is |
|
rarely severe. | |
|
Gastrointestinal disorders | |
|
Very common |
Nausea |
|
Common |
Vomiting2, abdominal pain2, heart burn2 |
|
General disorders and administration site conditions | |
|
Common |
Leg oedema2 |
|
Hepatobiliary disorders: | |
|
Not known |
Hepatic reactions, mainly increased liver enzymes3. |
'Adjunct therapy studies
2Monotherapy studies
3Post -marketing data (See section 4.4)
* In patients with advanced Parkinson’s disease, dyskinesia’s 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 also section 4.2).
4.9 Overdose
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 antagonist such as neuroleptics or metoclopramide.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Dopamine agonist, Dopaminergic agents ATC code: N04BC04.
Mechanism of action
Ropinirole is a non ergoline D2/D3 dopamine agonist which stimulates striatal dopamine receptors.
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. Parkinson’s disease
Ropinirole alleviates this deficiency which characterises Parkinson's disease by stimulating striatal dopamine receptors.
Ropinirole acts in the hypothalamus and pituitary to inhibit the secretion of prolactin. Restless Legs Syndrome Clinical efficacy
Ropinirole tablets 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.
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 1.5 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
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).
Metabolism
Ropinirole is mainly metabolised by the isoform CYP1A2 of cytochrome P450, and its metabolites are mainly excreted in the urine, and The main metabolite is 100 times less potent than ropinirole in animal models examining dopaminergic function.
Elimination
Ropinirole is cleared from the systemic circulation with elimination half “life of ropinirole is 6 hours on average. 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.
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
In patients over 65 years of age, a reduction in the systemic clearance of ropinirole by about 30% is possible.
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).”
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 the drug: 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), 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 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 diseases:
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 (approximately 15 times the AUC at the maximum dose in humans), increased foetal death at 90 mg/kg (approximately 25 times the AUC at the maximum dose in humans), and digit malformations at 150 mg/kg (approximately 40 times the AUC at the maximum dose in humans). There were no teratogenic effects in the rat at 120 mg/kg (approximately 30 times the AUC at the maximum dose in humans) and no indication of an effect on development in the rabbit
Parkinson’s Diseases:
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.
Restless Legs Syndrome
In vitro studies have shown that ropinirole inhibits hERG-mediated currents. 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) (see section 5.1).
6.1 List of excipients
Core Tablet:
Lactose monohydrate Cellulose microcrystalline Croscarmellose sodium Magnesium stearate
Film coating:
Hypromellose 6cp (E464) Macrogol 400 Titanium dioxide (E171) Polysorbate 80
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years.
For HDPE container:
Shelf-life after date of first opening is 6 months.
6.4 Special precautions for storage
Do not store above 250C.
6.5. Nature and contents of container
Tablets are in Alu-Alu blister and packed in final carton along with package insert.The carton contains either 21 or 42 tablets.
Ropinirole 0.25 mg tablets are packed in HDPE bottles containing either 12 or 84 tablets with silica gel canister which acts as a desiccant and packed in a carton with a package insert.
Not all packs may be marketed
6.6 Special precautions for disposal
Any unused product or waste material should be disposed of in accordance with local requirements
7 MARKETING AUTHORISATION HOLDER
Accord Healthcare Limited Sage House 319 Pinner Road North Harrow Middlesex HA1 4HF UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 20075/0002
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
30/03/2012
10 DATE OF REVISION OF THE TEXT
30/03/2012