Decentralised Procedure. Public Assessment Report. Ropinirole Teva. Ropinirole hydrochloride DE/H/1483/ /DC. Applicant: Teva Pharma B.V.

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1 Bundesinstitut für Arzneimittel und Medizinprodukte Decentralised Procedure Public Assessment Report Ropinirole Teva Ropinirole hydrochloride DE/H/1483/ /DC Applicant: Teva Pharma B.V. Reference Member State DE The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health. 1/8 Public AR

2 TABLE OF CONTENTS I. INTRODUCTION 4 II. EXECUTIVE SUMMARY 4 II.1 PROBLEM STATEMENT 4 II.2 ABOUT THE PRODUCT 4 II.3 GENERAL COMMENTS ON THE SUBMITTED DOSSIER 4 II.4 GENERAL COMMENTS ON COMPLIANCE WITH GMP, GLP, GCP AND AGREED ETHICAL PRINCIPLES. 5 III. SCIENTIFIC OVERVIEW AND DISCUSSION 5 III.1 QUALITY ASPECTS 5 III.2 NON-CLINICAL ASPECTS 6 III.3 CLINICAL ASPECTS 7 IV. BENEFIT RISK ASSESSMENT 8 DE/H/1483/01-05/DC Ropinirole Teva 2/8 Public AR

3 ADMINISTRATIVE INFORMATION Proposed name of the medicinal product in the RMS INN (or common name) of the active substance(s): Pharmaco-therapeutic group (ATC Code): Pharmaceutical form(s) and strength(s): Reference Number for the Decentralised Procedure Reference Member State: Member States concerned: Applicant (name and address) Names and addresses of manufacturers responsible for batch release in the EEA Ropinirole Teva Ropinirole hydrochloride N04BC04 Film-coated tablets; 0.25, 0.5, 1, 2 and 5 mg DE/H/1483/ /DC DE AT, BE, BG, CZ, DK, EE, EL, ES, FR, HU, IE, IT, LT, LU, LV, MT, NL, NO, PL, PT, RO, SI, SK, UK Teva Pharma B.V. Computerweg 10, 3542 DR Utrecht The Netherlands Teva Pharmaceutical Works Private Limited Company Pallagi út 13 Debrecen H-4042, Hungary DE/H/1483/01-05/DC Ropinirole Teva 3/8 Public AR

4 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Ropinirole, in the treatment of Parkinson s disease and restless leg syndrome (RLS), is approved. The applicant has removed Finland and Sweden as concerned member states from the decentralized procedure. II. EXECUTIVE SUMMARY II.1 Problem statement This is a decentralised application for Ropinirol 0.25 mg, 0.5 mg, 1 mg, 2 mg and 5 mg tablets with Germany as the reference member state (RMS) submitted in accordance with article 10(1) of Directive 2001/83/EC claiming essential similarity to the Ropinirole tablets marketed under the brand leader Requip by GlaxoSmithKline. The first authorisation for Requip 0.25 mg film coated tablets with the indication Parkinson s disease was granted on 2 nd July 1996 in the United Kingdom. Consequently, data protection period is already expired and reference can be made to the documentation of the originator. In addition to Requip, Glaxo Smith Kline holds a stand alone marketing authorisation for Adartrel (0.25, 0.5, 1 and 2 mg) for the approved indication RLS. The first marketing authorisation for Adartrel was granted in France on 6 th June 2004 in a MR-Procedure. This application includes the authorisation of Ropinirole in the strengths of 0.25, 0.5, 1 and 2 mg for both Parkinson's disease and RLS, whereas the 5 mg strength comprises only the authorisation for the indication Parkinson s disease. 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 receptors. 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 D2 receptors within the caudateputamen in the brain. This conclusion is supported by studies showing improved motor function after ropinirole treatment in various animal models of Parkinson's disease. The efficacy of Ropinirole was demonstrated as a monotherapy or in combination with levodopa (L-DOPA) in several randomized controlled clinical trials in patients with early or advanced stage Parkinson s disease, respectively. Moreover, Ropinirole was also beneficial in the long term management of moderate to severe RLS. II.3 General comments on the submitted dossier This application based on Art 10 (generics): It has to be shown that Ropinirol Teva is essentially similar to the authorised medicinal product Requip (originator). For this application no Scientific Advice was given. DE/H/1483/01-05/DC Ropinirole Teva 4/8 Public AR

5 There is no need for paediatric development and development in other special populations such as the elderly, male/female and ethnic minorities because these subjects have been well examined by the originator. There are sufficient information about ropinirole concerning efficacy and safety. 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. III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The active substance is manufactured in five steps. The complete manufacturing process has been described in detail in the restricted part of the EDMF. The proposed specifications for impurities in the active substance are in accordance with EU/ICH Q6A and Q3A guidelines. The analytical methods for assay, related substances and residual solvents used for the active substance is satisfactorily described and validated in accordance with the relevant EU/ICH guidelines on Analytical validation. Reference standards are satisfactorily described, and packaging materials comply with requirements for plastics in contact with food stuffs. Ropinirole hydrochloride is a stable molecule. Stability studies according to the relevant EU/ICH stability guidelines have been submitted with batches of half production size. Significant changes are not observed at ICH conditions. Therefore a re-test period of 3 years with no special storage conditions is accepted. Drug Product The film coated tablets are formulated with well-known excipients. The pharmaceutical development work is acceptable and in accordance with relevant EU guidelines. The manufacturing process has been satisfactorily described and batch homogeneity is demonstrated. The manufacturing process is conventional using standard techniques. Although, the process is considered a non standard process due to the low active substance content. Therefore process validation on productions scale batches will be provided. The excipients lactose monohydrate, microcrystalline cellulose, hypromellose, purified water, croscarmellose sodium and magnesium stearate complies with the current version of the monograph in Ph.Eur. and are tested according to the analytical methods in Ph. Eur. The coating film is controlled by In House monographs. The only excipient stated by applicant derived from animal source is lactose monohydrate. It is confirmed that the preparation of lactose monohydrate is in accordance with the EU regulations. DE/H/1483/01-05/DC Ropinirole Teva 5/8 Public AR

6 Magnesium stearate is stated to be of vegetable origin. The proposed limits on degradation products are acceptable. Other requirements are justified according to relevant EU/ICH guidelines and Ph.Eur. The analytical methods used for the active substance is described and validated in accordance with the relevant EU/ICH guidelines. The description and choice of container closure system is in accordance with relevant directives. Two alternative container have deleted by the applicant due to poor stability performance. The stability studies have been carried out according to relevant EU/ICH stability guidelines. 2 batches per strengths (1 and 2 mg only one batch) have been stored for up to 12 months at ICH conditions. The product remains within its specified limits. Although some increasing trends in regard of the impurity content are detectable. The proposed shelf lifes (18 month) and storage recommendations ( Do not store above 25 C for 0.25 and 0.5 mg strengths and Do not store above 30 C for 1 mg, 2 mg and 5 mg strengths) are considered justified. Photostability stability studies showed significant degradation and therefore the drug product should be stored within its original container. III.2 Non-clinical aspects Pharmacology Dopamine is a major neurotransmitter in the central nervous system, especially in the basal ganglia, and is involved in the control of motor functions. Degeneration of dopaminergic neurons in the substantia nigra causes the movement disorders of idiopathic Parkinson s disease. Stimulation of dopamine receptors ameliorates these symptoms. This can be either achieved by administration of the dopamine precursor levodopa (L-DOPA), which passes the blood-brain-barrier and is then metabolised to dopamine, or by direct dopamine receptor agonists like the non-ergoline dopamine agonist ropinirole. Ropinirole binds with high affinity to dopamine D2- and D3-receptor subtypes with a higher affinity to the latter. The relevance of the activation of dopamine D3-receptors in Parkinson s disease has not yet been elucidated but activation of D2-receptors appears to be crucial for the therapeutic benefit. Apart from moderate binding to opioid receptors, ropinirole has no affinity for D1-, 5-HT 1 -, 5-HT 2 -, benzodiazepine-, muscarine- and α- and β-adrenergic receptors. In vivo, ropinirole was effective in several animal models of Parkinson s disease. Pharmacokinetics Following oral administration, ropinirole is almost completely absorbed. Peak blood levels are observed after about 1 to 2 hours. Due to first pass elimination, bioavailability is only about 50 %. Bioavailability increases with dose. The volume of distribution is more than unity and amounts to 6.7 L/kg in humans. Plasma protein binding is 10 to 40 %. Ropinirole is mainly metabolised by the cytochrome P450 isoform CYP1A2 and metabolites have only marginal dopaminergic activity. Ropinirole has a terminal half-life of about 6 hours and is predominantly excreted via the kidneys. Only 10 % of the dose is recovered as unchanged substance in the urine. Toxicology The toxicological profile of ropinirole is mainly reasoned in its pharmacological effects (behavioural changes, hypoprolactinaemia, decrease of blood pressure and heart rate, ptosis and salivation). In various in vitro and in vivo tests, no relevant signs of genotoxicity were observed. In a 2 years carcinogenicity study in mice, no carcinogenic effects were detected. In contrast, hyperplasia of Leydig cells and adenomas of the testis were found in a 2 years study in rats, probably as a consequence of the hypoprolactinemic effect of ropinirole. These lesions appear to be species-specific. Ropinirole reduced fetal weight, increased postimplatation loss and induced digit malformations at maternally toxic doses in a reproduction toxicity study in rats. At lower dosages, no teratogenicity was observed in rats and no signs of developmental impairments were apparent in rabbits. DE/H/1483/01-05/DC Ropinirole Teva 6/8 Public AR

7 The applicant revised the SPC in accordance with the text approved for the originator product Requip (FR/H/111/01-05/R/02; see also DE/H/957/ /DC). III.3 Clinical aspects Generic application: For Ropinirole film coated tablets with a systemic effect an appropriate bioequivalence study is needed. About ropinirole in the therapy of Parkinson s disease and RLS. Ropinirole is in use for treatment of idiopathic Parkinson s disease and RLS. 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 like are bromocriptine, pergolide, lisuride and carbagoline and non-ergot derivatives like are pramipexole, ropinirole, piribedil and apomorphine. Patients with Parkinson disease on long term levodopa treatment have close to 80% frequency of dyskinesias. To minimize end-of-dose effects encountered with levodopa therapy, dopamine agonists with relative long half-lives were introduced in the US, beginning with bromocriptine in 1976 and pergolide in Both agonists have been used primarily as adjuncts to levodopa. Ropinirole is used without levodopa and as an adjuvant to levodopa therapy. In the early stages of the disease ropinirole is as effective as levodopa, in the later stages the effectivness of ropinirole is less than levodopa. Concomitant use of ropinirole with levodopa reduces the off-phases. Furthermore ropinirole is used for treatment of RLS and efficacy was demonstrated in several studies. RLS, a sleep-related disorder with an estimated prevalence of 1 % to 5 % is characterized by unpleasant sensations experienced predominantly in the legs, which occur only at rest and become more pronounced in the evening or at night. The onset of this disorder is usually after 30 years of age and the prevalence increases with age. The etiology of RLS is unknown. It is hypothesized that periodic limb movements during sleep (a similar disease) results from a disinhibition of descending inhibitory pathways. Disturbances in dopaminergic, adrenergic and opiate systems may contribute to RLS. Pharmacokinetics The pharmacokinetics of ropinirole is similar in Parkinson's disease patients and patients with Restless Legs Syndrome. 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 T max is increased by 2.5 hours and its C max 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 DE/H/1483/01-05/DC Ropinirole Teva 7/8 Public AR

8 extensively metabolized by the liver to inactive metabolites. Steady-state concentrations are expected to be achieved within 2 days of dosing. Accumulation upon multiple dosing is predictive from single 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. Clinical efficacy and Clinical safety: No specific clinical studies in patients were required for the applications submitted in accordance with Article 10(1) of Directive 2001/83/EEC as amended. An appropriate literature review has been conducted which supports the use of Ropinirole in the proposed indications Parkinson s disease and RLS. Safety issues have also been appropriately addressed in the clinical overview. The active substance and the excipients included in the formulation Ropinirole Teva have a long history of safe and problem-free use, so that in conclusion none of the compounds contained in the generic formulations gives reasons for safety problems. Bioequivalence study To support the application, the applicant has submitted one bioequivalence study. Study No. RPL-P7-067 is a bioequivalence study submitted to support applicant s claim that Ropinirole Teva 0,25 mg tablets are bioequivalent with Requip 0,25 mg tablets. It is a randomized, two period, two sequence, cross-over single dose, open label bioequivalence study in healthy human adult male and female subjects, under fasting conditions. Bioequivalence between Ropinirole Teva 0,25 mg tablets and Requip 0,25 mg tablets could be shown. Pharmacovigilance system The Pharmacovigilance system as described by the applicant fulfils the requirements and provides adequate evidence that the applicant has the services of a qualified person responsible for pharmacovigilance and has the necessary means for the notification of any adverse reaction suspected of occurring either in the Community or in a third country. IV. BENEFIT RISK ASSESSMENT Ropinirole is a well examined medicinal product. Efficacy is demonstrated in several studies, furthermore safety is observed over many years and in the studies fullfilled safety data are gathered. Widespread information exists concerning the optimal dose range and dosage regimes, efficacy and safety of subpopulations, interactions with other medicinal products and adverse events. Ropinirole is a medicinal product that meanwhile is used in several European countries over ten years and summerizing the benefit/risk ratio is to be judged positive. The application is approved. DE/H/1483/01-05/DC Ropinirole Teva 8/8 Public AR