Decentralised Procedure. Public Assessment Report. Pramipexol-neuraxpharm 0,26 / 0,52 / 1,05 / 1,57 / 2,1 / 2,62 / 3,15 mg Retardtabletten

Transcription

1 Decentralised Procedure Public Assessment Report Pramipexol-neuraxpharm 0,26 / 0,52 / 1,05 / 1,57 / 2,1 / 2,62 / 3,15 mg Retardtabletten Pramipexole dihydrochloride monohydrate DE/H/4703/ /DC Applicant: neuraxpharm Arzneimittel GmbH, Germany Reference Member State DE

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.4 III. SCIENTIFIC OVERVIEW AND DISCUSSION... 4 III.1 Quality aspects... 4 III.2 Non clinical aspects... 5 III.3 Clinical aspects... 5 IV. BENEFIT RISK ASSESSMENT... 8

3 ADMINISTRATIVE INFORMATION Proposed name of the medicinal product(s) in the RMS Name of the drug substance (INN name): Pharmaco-therapeutic group (ATC Code): Pharmaceutical form(s) and strength(s): Reference Number(s) for the Decentralised Procedure Reference Member State: Member States concerned: Applicant (name and address) Pramipexol-neuraxpharm 0,26 / 0,52 / 1,05 / 1,57 / 2,1 / 2,62 / 3,15 mg Retardtabletten Pramipexole dihydrochloride monohydrate N04BC05 Prolonged-release tablet 0,26 / 0,52 / 1,05 / 1,57 / 2,1 / 2,62 / 3,15 mg DE/H/4703/ /DC DE LU: withdrawn neuraxpharm Arzneimittel GmbH Elisabeth-Selbert-Straße 23, Langenfeld, Germany Pramipexol-neuraxpharm, DE/H/4703/ /DC Public AR Page 3/8

4 I. INTRODUCTION Based on the review of the data on quality, safety and efficacy, the application for Pramipexolneuraxpharm 0,26 / 0,52 / 1,05 / 1,57 / 2,1 / 2,62 / 3,15 mg Retardtabletten, indicated in adults for treatment of the signs and symptoms of idiopathic Parkinson s disease, alone (without levodopa) or in combination with levodopa, i.e. over the course of the disease, through to late stages when the effect of levodopa wears off or becomes inconsistent and fluctuations of the therapeutic effect occur (end of dose or on off fluctuations), is approved. II. II.1 N/A EXECUTIVE SUMMARY Problem statement II.2 About the product Pramipexole is indicated in adults for treatment of the signs and symptoms of idiopathic Parkinson s disease. Doses should be increased gradually from a starting dose of 0.26 mg of base (0.375 mg of salt) per day up to a maximum dose of 3.15 mg of base (4.5 mg of salt) per day. Pramipexole is a dopamine agonist that binds with high selectivity and specificity to the D2 subfamily of dopamine receptors of which it has a preferential affinity to D3 receptors, and has full intrinsic activity. Pramipexole alleviates parkinsonian motor deficits by stimulation of dopamine receptors in the striatum. Animal studies have shown that Pramipexole inhibits dopamine synthesis, release, and turnover. II.3 General comments on the submitted dossier The application for Pramipexole, prolonged-release tablets, 0,26 mg, 0,52 mg, 1,05 mg, 1,57 mg, 2,1 mg, 2,62 mg, 3,15 mg, are generic applications made according to Article 10(1) of Directive 2001/83/EC. The applicant, neuraxpharm Arzneimittel GmbH, Germany applies through the Decentralised Procedure with Germany acting as reference member state (RMS) and concerned member state (CMS) LU. However, the applicant decided to withdraw the application in LU. The reference medicinal product chosen for the purposes of establishing the expiry of the data protection period is SIFROL, 1,1 mg, tablets authorised via the centralised procedure in 1997, with Boehringer Ingelheim International GmbH, as marketing authorisation holder. The reference product used in the bioequivalence study is SIFROL 0,26 mg, 0,52 mg, 3,15 mg, prolonged-release tablets with the Member state of source being DE with Boehringer Ingelheim International GmbH, as marketing authorisation holder. 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. 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. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Drug substance The chemical-pharmaceutical documentation and Expert Report in relation to Pramipexole dihydrochloride monohydrate are of sufficient quality in view of the present European regulatory requirements. Both manufacturers of the drug substance have been granted a CEP. The control tests and specifications for drug substance product are adequately drawn up. Pramipexol-neuraxpharm, DE/H/4703/ /DC Public AR Page 4/8

5 Batch results for the drug substance should be for three batches tested by the manufacturer of the drug products. The reference standards used by the manufacturer of the drug product for control of the drug substance should be described. Stability studies have been performed with the drug substance. No significant changes in any parameters were observed. The proposed retest period of 5 years is justified. Drug Product The development of the product has been described, the choice of excipients is justified and their functions explained. The product specifications cover appropriate parameters for this dosage form. Validations of the analytical methods have been presented. Batch analysis has been performed on 42 batches. The batch analysis results show that the finished products meet the specifications proposed. The amount of drug substance is low for all strengths (0.1% up to 0.6%). Unit dose products containing drugs in low content ( 2% of composition) and prolonged release preparations could be defined as non standard processes according to Annex II NfG on process validation CHMP/QWP848/99. Process validation should be performed at production scale unless otherwise justified. The process validation is accepted for the scale of the batches included in the process validation ( and ) performed. The conditions used in the stability studies are according to the ICH stability guideline. The control tests and specifications for drug product are adequately drawn up. A shelf-life of 3 years without temperature restriction is accepted for the drug product. III.2 Non clinical aspects The pharmacological and toxicological properties of pramipexole are well known and have been satisfactorily summarised in the Non-clinical Overview. The instructions on use of the compound during pregnancy and lactation and the preclinical safety data contained in the proposed SmPC and PL, respectively, essentially reflect the characteristics delineated in the nonclinical overview and have been brought in line with the currently approved product information of the reference products Sifrol (EMEA/H/C/000133) and Mirapexin (EMEA/H/C/000134). Environmental Risk Assessment (ERA) Since Pramipexol-neuraxpharm 0,26 / 0,52 / 1,05 / 1,57 / 2,1 / 2,62 / 3,15 mg Retardtabletten are 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 Pharmacokinetics The application concerns the following strengths: 0.26, 0.52, 1.05, 1.57, 2.1, 2.62 and 3.15 mg. To support the application, the applicant has submitted four bioequivalence studies. In accordance with the guideline (CPMP/EWP/QWP/1401/98, REV.1, CORR. COMMITTEE, January 2010) four studies with three strengths (lowest and medium (fasted/fed) strength in single dose and a multiple dose study with the highest strength) were conducted. A justification for not performing single-dose fasted studies with the higher strengths based on safety concerns has been submitted. In the fed state the 0.52 mg strength is the highest strength possible to give to healthy volunteers due to an increase in C max of 20% when the product is co-administered with food. Also, a multiple dose study with highest strength is adequate. 1. Single dose fasted on the 0.26 mg strength: OPEN LABEL, TWO PERIODS, TWO SEQUENCES, CROSSOVER, CONTROLLED, RANDOMIZED, SINGLE DOSE PIVOTAL BIOEQUIVALENCE STUDY OF PRAMIPEXOL XR 0.26 mg PROLONGED RELEASE TABLETS (TEST FORMULATION) vs. EQUAL DOSE OF PROLONGED RELEASE REFERENCE FORMULATION IN HEALTHY MALE VOLUNTEERS UNDER FASTING CONDITIONS Study code: PRA-BESD-18-ITQ/12 Pramipexol-neuraxpharm, DE/H/4703/ /DC Public AR Page 5/8

6 2. Two separate (test/reference - fed and fasted) studies in healthy volunteers, in both studies 0.52 mg strength: OPEN LABEL, TWO PERIODS, TWO SEQUENCES, CROSSOVER, CONTROLLED, RANDOMIZED, SINGLE DOSE PIVOTAL BIOEQUIVALENCE STUDY OF PRAMIPEXOL XR 0.52 mg PROLONGED RELEASE TABLETS (TEST FORMULATION) vs. EQUAL DOSE OF PROLONGED RELEASE REFERENCE FORMULATION IN HEALTHY MALE VOLUNTEERS UNDER FASTING CONDITIONS, Study code: PRA-BESD-03-ITQ/11 3. OPEN LABEL, TWO PERIODS, TWO SEQUENCES, CROSSOVER, CONTROLLED, RANDOMIZED, SINGLE DOSE PIVOTAL BIOEQUIVALENCE STUDY OF PRAMIPEXOL XR 0.52 mg PROLONGED RELEASE TABLETS (TEST FORMULATION) vs. EQUAL DOSE OF PROLONGED RELEASE REFERENCE FORMULATION IN HEALTHY MALE VOLUNTEERS IN FED CONDITION, Study code: PRA-BEFI-04-ITQ/11 4. Multiple dose steady state study on the strength 0.52 mg and 3.15 mg conducted in healthy volunteers (up-titration and tapering down according to the pivotal study of Sifrol): AN OPEN LABEL, TWO PERIODS/STRENGTH, TWO SEQUENCES/STRENGTH, CROSSOVER, DOUBLERANDOMIZED MULTIPLE DOSES BIOEQUIVALENCE STUDY OF PRAMIPEXOL XR 0.75mg tablets (TEST1) vs. EQUAL DOSE OF SIFROL (REFERENCE1 FORMULATION) AND OF PRAMIPEXOL XR 4.5mg tablets (TEST2) vs. EQUAL DOSE OF SIFROL (REFERENCE2 FORMULATION) IN HEALTHY MALE VOLUNTEERS UNDER FASTING CONDITIONS, Study code: PRA-BEMD-07-ITQ/11 The number and kind of bioequivalence studies provided is regarded accptable. The bioequivalence criteria were met for all four bioequivalence studies. Taking into consideration, that the bioequivalence criteria were consistently met in each of the bioequivalence studies, performed with the lowest (s.d.), the highest (m.d.) and an intermediate strength of the intended range of tablet strengths, and the similarity of dissolution profiles, it is considered acceptable, that the results of the performed bio-equivalence studies are extrapolated to the additional strength 1.05, 1.57, 2.10 and 2.62 mg strengths of the intended Pramipexole prolongedrelease tablets. The respective waiver is thus considered acceptable. SmPC is in line with the original product referred to, thus it is acceptable. Pharmacodynamics/ Clinical efficacy/ Clinical safety No new studies on pharmacodynamics, clinical efficacy or safety have been submitted and new studies are not needed, because this decentralized procedure concerns a generic application. Legal Status Medicinal product is subject to medical prescription. User Testing In the first as well as in the second round a satisfactory test outcome was reached for each question, thus the condition 90% of all participants are able to find the information requested within the PL and 90% of all participants can show that they understand and can act upon it is fulfilled. This user testing indicates that the tested PL of pramipexole 0,26/0,52/1,05/1,57/2,1/2,62/3,15 mg prolonged release tablets is easy to understand and written in a comprehensible manner. The leaflet is readable and the users are able to act on the information that it contains. No changes of the PL were required. Mock-up of the PL used in the readability testing has been provided by Aristo Pharma GmbH (tradename not specified). The applicant has confirmed that layout and content of the PL is the same as provided as mock-up for the readability user testing by Aristo Pharma GmbH, thus user testing is accepted. Pramipexol-neuraxpharm, DE/H/4703/ /DC Public AR Page 6/8

7 Summary Pharmacovigilance system The Applicant/Proposed Future MAH has submitted a signed Summary of the Applicant's/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. Risk Management Plan 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 pramipexol-neuraxpharm. Summary of safety concerns The MAH provided the following updated summary of safety concerns to ensure that the safety concerns meet the definitions of important risks as per GVP module V and to align with the RMP of the originator s medicinal product: Summary of safety concerns Important identified risks impulse control disorder (binge eating, compulsive shopping, pathological gambling, hypersexuality and other abnormal behavior) inappropriate antidiuretic hormone secretion (SIADH) cardiac failure hallucination and confusion Important potential risks suicide-related behaviour delirium/mania retinal degeneration skin melanoma fibrotic events response-related behaviour Missing information use during pregnancy and lactation Risk minimisation plan The Applicant does not propose additional risk minimisation measures. This is endorsed. Currently routine risk minimisation measures are considered sufficient to address the risks of the medicinal product in the proposed indication(s). Periodic Safety Update Report (PSUR) With regard to PSUR submission, the MAH should take the following into account: PSURs shall be submitted in accordance with the requirements set out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. Marketing authorisation holders shall continuously check the European medicines web-portal for the DLP and frequency of submission of the next PSUR. For medicinal products authorized under the legal basis of Article 10(1) or Article 10a of Directive 2001/83/EC, no routine PSURs need to be submitted, unless otherwise specified in the EURD list. For medicinal products that do not fall within the categories waived of the obligation to submit routine PSURs by the revised pharmacovigilance legislation, the MAH should follow the DLP according to the EURD list. Pramipexol-neuraxpharm, DE/H/4703/ /DC Public AR Page 7/8

8 IV. BENEFIT RISK ASSESSMENT The application contains an adequate review of published clinical data. Bioequivalence of the products Pramipexole neuraxpharm 0.26/0.52 and 3.15 mg prolonged release tablets with the Reference products Sifrol 0.26/0.52 and 3.15 mg prolonged release tablets has been shown. The results of the studies provided with 0.26/0.52 and 3.15 mg prolonged release tablets can be extrapolated to other strengths 1.05, 1.57, 2.1, 2.62 mg prolonged release tablets, according to conditions in Guideline on the Investigation of Bioequivalence CPMP/EWP/QWP/1401/98 Rev. 1/Corr*, section The application is approved. For intermediate amendments see current product information. Pramipexol-neuraxpharm, DE/H/4703/ /DC Public AR Page 8/8