Zusammenfassung der Merkmale des Arzneimittels - Ropinirol Genmed Pharma 4 mg Retardtabletten
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles.. 4
| Proposed name of the medicinal product in the RMS | Ropinirol Genmed Pharma 2, 3, 4, 8mg Retardtabletten |
| Name of the drug substance (INN name): | Ropinirole hydrochloride |
| Pharmaco-therapeutic group (ATC Code): | N04BC04 |
| Pharmaceutical form(s) and strength(s): | Prolonged-release tablet; 2, 3, 4, 8mg |
| Reference Number(s) for the Decentralised Procedure | DE/H/5831/001–004/DC |
| Reference Member State: | DE |
| Concerned Member States: | UK |
| Legal basis of application: | Article 10(3) hybrid application – DE5831 002 Article 10(1) Generic application – DE5831 001+003–004 |
| Applicant (name and address) | GENMED Pharma GmbH Gabriele-Tergit-Promenade 17 10963 Berlin, Germany |
| Names and addresses of all proposed manufacturer(s) responsible for batch release in the EEA | Pharmathen S.A 6, Dervenakion str. 15351 Pallini, Attiki, Greece Pharmathen International S.A Industrial Park Sapes, Rodopi Prefecture, Block No 5 69300 Rodopi, Greece |
Based on the review of the data on quality, safety and efficacy, the application for “Ropinirol Genmed Pharma 2, 3, 4, 8mg Retardtabletten” with the following indication:
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).is approved.
II.1 Problem statement
Not applicable.
II.2 About the product
Ropinirole is a non-ergoline dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 – and D3 -dopamine receptor subtypes, binding with higher affinity to D3 – than to D2 – or D4 – receptor subtypes.
The precise mode of action of ropinirole as a treatment for Parkinson's disease is unknown, although it is believed to be due to stimulation of postsynaptic dopamine D 2 -type receptors within the caudate-putamen in the brain. This conclusion is supported by studies that show that ropinirole improves motor function in various animal models of Parkinson's disease.
II.3 General comments on the submitted dossier
This application based on Art 10(1) of Directive 2001/83/EC so called generic applications claiming essential similarity to the reference product. It has to be shown that Ropinirol Genmed Pharma is essentially similar to the authorised medicinal product RequipModutab (originator).
This is a decentralised application with Germany as the reference member state (RMS) submitted in accordance with article 10(1) of Directive 2001/83/EC as amended for Ropinirol Genmed Pharma 2,
3, 4, 8 mg Retardtabletten claiming essential similarity to Requip Modutab tablets. The study package provided including the 4 studies RPL-P9–512, RPL-P9–513 and RPL-514 and study 1432 was already provided in procedure DE 2132 (CMS BG, HU, PL, RO, SK) and FR 484, 485 and FR 486 with the CMS (AT, BE, CZ, DE, DK, FI, IE, LU, SK); (DE, ES, IT, NL, PT, PL, RO, UK) and CZ, DK, EE, FI, HU, LT, LV, NO, PL, SE, SK, UK respectivly.
The first authorisation for Requip 0,25 mg film coated tablets with the indication Parkinson’s disease was granted on 2nd July 1996 in the United Kingdom. Consequently, data protection period is already expired and reference can be made to the documentation of the originator.
The originator product RequipModutab 2 mg, 4 mg and 8 mg prolonged release tablets manufactured by GlaxoSmithKline GmbH & CoKG, Germany is registered since March 2007.
II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles
The RMS has been assured that acceptable standards of GMP are in place for these product types at all sites responsible for the manufacture and assembly of this product.
For manufacturing sites within the Community, the RMS has accepted copies of current manufacturer authorisations issued by inspection services of the competent authorities as certification that acceptable standards of GMP are in place at those sites.
For manufacturing sites outside the Community, the RMS has accepted copies of current GMP Certificates of satisfactory inspection summary reports, ‘close-out letters’ or ‘exchange of information’ issued by the inspection services of the competent authorities (or those countries with which the EEA has a Mutual Recognition Agreement for their own territories) as certification that acceptable standards of GMP are in place at those non-Community sites.
GMP active substance
Regarding the statement on GMP for the active substance a statement/declaration is provided from the manufacturer(s) responsible for manufacture of the finished product and batch release situated in the EU.
III.1 Quality aspects
The general impression of the documentation is that it has been satisfactorily elaborated and justified in accordance with relevant guidelines.
The active substance is a chemical derived molecule. The medicinal product is formulated as prolonged release tablet tablets which are manufactured by conventional techniques using well-known excipients and packaging materials.
Ropinirole hydrochloride drug substance is described in Ph. Eur. For this decentralised registration procedure the DMF procedure has been applied for both drug substance sources.
Ropinirole hydrochloride is relatively stable substance. Raw materials which might be present in the drug substance, residual intermediates inorganic impurities have thoroughly discussed.
The control tests and specifications are acceptable.
Stability studies results have been submitted by both manufacturers. A re-test period of 5 years for both is justified by relevant long-term data.
ROPINIROL SR 2 mg, 3 mg, 4 mg and 8 mg prolonged release tablets, containing ropinirole hydrochloride, are a generic product of Requip Modutab 2 mg, 4 mg and 8 mg prolonged release tablets of GlaxoSmithKline.
Ropinirole HCl is freely soluble in water and its characteristic predicts good dissolution. However, prolonged dissolution is assured by matrix created by hypromellose, sodium lauryl sulfate and carbomers (Eudragit RS). Dissolution test with suitable analytical conditions can approve slow release of ropinirole HCl – <15% in 1 hour, 40–60% in 8 hours and minimum 80% in 24hours. All used excipients are well known, described in current Ph. Eur. and function of all excipients has been properly described. Coating material Opadry has controlled by in-house specifications.
The product specifications covered appropriate tests for modified release tablets. Validation of all used analytical methods have been performed and the results have been submitted.
Batch analysis and process validation have been provide on production scale batches.
A risk assessment for nitrosamines has been provided. The results indicate that the risk for nitrosamine contamination is low.
The conditions used in the stability studies have been set according to ICH stability guideline on existing active substances and related finished products. The product remained stable under long-term conditions, however under accelerating conditions the results for impurities showed significant increases.
The proposed 36 months shelf-life is supported by relevant long-term stability data.
III.2 Non clinical aspects
The pharmacological and toxicological properties of ropinirole have been described satisfactorily and it has been assured that none of the impurities for Ropinirole SR/Pharmathen tabs are considered potentially mutagenic, nor do they possess other serious and unusual toxicity.
The instructions on use of the active substance during pregnancy and lactation and the preclinical safety data contained in the proposed SmPC and PL, respectively, essentially reflect these characteristics and they have been harmonised with the most recent version of the texts approved for the reference product “Requip-Modutab” (FR/H/111/01–05).
Since “Ropinirol Genmed Pharma 2, 3, 4, 8mg Retardtabletten” is intended for generic substitution, this will not lead to an increased exposure to the environment. An environmental risk assessment is therefore not deemed necessary.
III.3 Clinical aspects
Parkinson’s disease results from a selective loss of dopaminergic neurons in the pars compacta of the substantia nigra, a midbrain structure with projections to the striatum. Parkinson’s disease affects about 1–2% of individuals over the age of 65 years. The cardinal signs of Parkinson’s disease include tremor, rigidity, akinesia or bradykinesia and postural instability. These symptoms of Parkinson’s disease do not develop until approximately 70–80% of the nigral dopaminergic neurons have degenerated.
So far medical strategies have focused mainly on either dopamine replacement or otherwise enhancing the dopaminergic response. Current research on anti-parkinsonian drugs focuses on palliative therapy and several drugs are presently in use for the symptomatic therapy of Parkinson’s disease.
Levodopa is the most effective drug in the treatment of Parkinson disease. It improves significantly the symptoms of Parkinson disease, but it cannot stop the progression of the disease.
The other drugs used in the treatment of Parkinson disease are synthetic dopamine receptor agonists, amantadine and monoamine oxidase B inhibitors like seligiline. The dopamine agonists being ergot derivatives are bromocriptine, pergolide, lisuride and cabergoline and non-ergot derivatives like pramipexole, ropinirole, piribedil and apomorphine.
Ropinirole is rapidly absorbed after oral administration, reaching peak concentration in approximately 1–2 hours. In clinical studies, over 88% of a radio-labeled dose was recovered in urine and the absolute bioavailability was 55%, indicating a first-pass effect. Relative bioavailability from a tablet compared to an oral solution is 85%. Food does not affect the extent of absorption of ropinirole, although its Tmax is increased by 2.5 hours and its Cmax is decreased by approximately 25% when the drug is taken with a high-fat meal. The clearance of ropinirole after oral administration to patients is 47 l/hr (cv = 45%) and its elimination half-life is approximately 6 hours. Ropinirole is extensively metabolized by the liver to inactive metabolites. Steady-state concentrations are expected to be achieved within 2 days of dosing.
Ropinirole is widely distributed throughout the body, with an apparent volume of distribution of 7.5 l/kg (cv = 32%). It is up to 40% bound to plasma proteins and has a blood-to-plasma ratio of 1:1.
This Marketing Authorization application concerns a generic application according to Article 10(1) of Directive 2001/83/EC. In vivo bioequivalence between the product that should be marketed and the originator product Requip-Modutab prolonged release tablets has been demonstrated. Four in vivo bioequivalence studies have been provided:
1. Study fasting condition, Ref-N° RPL-P9–512:
Single dose crossover comparative bioavailability study of Ropinirole 2 mg prolonged-release tablets in healthy male and female volunteers; fasting state.
Results
Table 1: Results of the 90% confidence intervals of study RPL-P9–512
| Pharmacokinetic Parameter | Geometric Mean Ratio Test Refer ence | 90% Confidence Intervals | CV%* |
| AUC | 96.7 | 86.07–108.65 | 27.0 |
| AUCmf | 9691 | 8610–109 08 | 269 |
| Cmax | 94 84 | 86.32–104.2 | 21.7 |
Estimated from the Residual Mean Squares.
2. Study fed condition, Ref-N° RPL-P9–513:
Single dose, replicate, crossover comparative bioavailability study of Ropinirole 2mg prolonged release tablets in healthy male and female volunteers, fed state.
Table 2: Results of the 90% confidence intervals of study RPL-P9–513
| Pharmacokinetic Parameter | Geometric Mean Ratio TestReference | 90% Confidence Intervals | CV%* |
| AUC | 94.26 | 90.84–97 81 | 12.8 |
| AUCinf | 94.24 | 90.82–97.79 | 12.7 |
| Cmax | 110.59 | 102.32–119.52 | 30.5 |
'Estimated from the Residual Mean Squares.
3. Steady state study, Ref-N° RPL-P9–514:
Multiple dose, crossover comparative bioavailability study of Ropinirole 2 mg prolonged release tablets
in healthy male volunteers; steady state.
Table 3: Results of the 90% confidence intervals of study RPL-P9–514
| Pharmacokinetic Parameter | Geometric Mean Ratio Test Reference | 90% Confidence Intervals | CV%* |
| AUC™ | 102.07 | 97.99– 106.33 | 12.1 |
| Cmax | 108.81 | 103.65–114.24 | 14.4 |
| Cmin | 93.48 | 80.26– 108.88 | 47.4 |
'Estimated from the Residual Mean Squares.
The analytic procedures of the studies RPL-P9–512, RPL-P9–513 and RPL-P9–514 were conducted in the years 2009 and 2010. At that time no ISR have been performed, but this is not in line with today’s requirements according to the guideline EMEA/CHMP/EWP/192217/2009 Rev. 1 Corr. 2**. The Applicant now has answered the additional questions with regard to the lacking ISR controls sufficiently.
4. Study fasting condition, Ref-N° 1432:
This was a pivotal, steady-state, randomized, open-label, two-period, two-sequence, two-treatment, single-centre, crossover study designed to evaluate the comparative bioavailability of ropinirole from Ropinirole Hydrochloride 8 mg Prolonged-Release Tablets (Pharmathen S.A., Greece) and Requip-Modutab® 8 mg (Ropinirole Hydrochloride) Tablets (GlaxoSmithKline, Germany) administered under fasting conditions at steady state.
Table 4: Results of the 90% confidence intervals of study 1432
| Pharmacokinetic Parameter | Geometric Mean Ratio Test Reference | 9014 Confidence Intervals | CWo1 |
| AUCtau | 97.98 | 91.59– 104.82 | 18.74 |
| ^ max | 104.48 | 99.61–109.59 | 13.21 |
| C mm | 99.83 | 84.28– 118.26 | 49.30 |
'Estimated from the Residual Mean Squares.
The Test/Reference ratio of geometric means and the corresponding 90% confidence interval for AUCτ, Cmax and Cmin were entirely contained within the acceptance range of 80.00% to125.00%. Thus regarding the 8 mg strength Ropinirole Retardtabletten bioequivalence between the test and reference product has been shown.
Summarizing:
In total 4 bioequivalence studies have been provided and in all studies bioequivalence between the test and the reference product has been demonstrated. However regarding the studies RPL-P9–512, RPL-P9–513 and RPL-514 ISR analysis were not conducted during pharmacokinetic analysis because these studies have already been carried out in the years 2009 and 2010 before the entry into force of the “Guideline on bioanalytical method validation”. Meanwhile the Applicant has answered the additional questions with regard to the lacking ISR controls sufficiently.
Beside that it has to be mentioned that in contrast to the studies study RPL-P9–512, RPL-P9–513 and RPL-514 the multiple dose study 1432 includes a proper ISR analysis and this study established bioequivalence between the 8 mg strength of test and the reference product.
Condition of biowaiver
In general the results of the bioequivalence studies can be extrapolated to the other dose strengths according to the guideline CPMP/EWP/QWP/1401/98 Rev. 1/ Corr ** and acceptable dissolution profiles have been presented.
The medicinal product is subject to medical prescription.
The applicant has provided a bridging report written by momaja s.r.o. (elc group), Prague, Czech Republik. In this bridging report the daughter PL of Ropinirole Retardtablette 2, 3, 4, 8 mg manufactured by Pharmathen was compared with the parent PL Ropinirole film-coated tablet 0,25, 0,5,
1, 2, 5 mg manufactured by Pharmathen.
A user testing of the parent PL was performed in June 2009 by Magmapharma, Ireland resulting that the PL is understandable and comprehensible and that it complies with the “Guideline on the readability of the label and the package leaflet of medical products for human use”. This user testing has been already accepted in former procedures (e.g. DE/H/2132, PL/H/102/01–05/DC).
In the bridging report each section of the daughter PL was compared with the parent PL in a table. It was concluded that the daughter PL is similar to the parent PL. Furthermore the layout and the fonts of the PLs have been compared.
Summarizing the bridging study report shows that the daughter PL is strongly similar to the parent PL and the RMS agrees that no separate user testing is necessary.
The Applicant has submitted a signed Summary of the Applicant's and/or Proposed Future MAH's Pharmacovigilance System. Provided that the Pharmacovigilance System Master File fully complies with the new legal requirements as set out in the Commission Implementing Regulation and as detailed in the GVP module, the RMS considers the Summary acceptable.
The MAH has submitted a risk management plan, in accordance with the requirements of Directive 2001/83/EC as amended, describing the pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to the medicinal product(s) applied for authorisation.
Safety specification
According to the Applicant the safety specification is in full accordance with the current safety specification agreed and published for a similar product which is acceptable.
Pharmacovigilance Plan
Routine pharmacovigilance is suggested and no additional pharmacovigilance activities are proposed by the applicant, which is endorsed.
Risk minimisation measures
Routine risk minimisation is suggested and no additional risk minimisation activities are proposed by the applicant, which is endorsed.
Summary of the RMP
The submitted Risk Management Plan is considered acceptable.
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent updates of the RMP.
An updated RMP should be submitted:
At the request of the RMS; Whenever the risk management system is modified, especially as the result of new information being received that may lead to a significant change to the benefit/risk profile or as the result of an important (pharmacovigilance or risk minimisation) milestone being reached. If the dates for submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time, but via different procedures.