PUBLIC ASSESSMENT REPORT Decentralised Procedure Pemetrexed ODS 100 mg & 500mg Pemetrexed Xellex 100 mg & 500mg Pemetrexed PhaRes 100 mg & 500mg Pemetrexed Profusio 100 mg & 500mg Pemetrexed Heumann 100 mg & 500mg Pemetrexed Bhardwaj 100 mg & 500mg Pemetrexed PhaRes 100 mg & 500mg Pemetrexed Vitane 100 mg & 500mg Pulver für ein Konzentrat zur Herstellung einer Infusionslösung Procedure Numbers: DE/H/4277/01-02/DC – DE/H/4284/01- 02/DC Active Substance: Pemetrexed Dosage Form: Powder For Concentrate For Solution For Infusion Marketing Authorisation Holder in the RMS, Germany: Pharma Resources GmbH; ZytoService Deutschland GmbH Leipzig; Aristo Pharma GmbH & Co. Generica KG; Bhardwaj GmbH; Vitane Pharma GmbH Publication: 02.07.2019 TABLE OF CONTENTS I. INTRODCUTION ....................................................................................................................... 5 II. EXECUTIVE SUMMARY ..................................................................................................... 5 II.1 Problem statement ................................................................................................................... 5 II.2 About the product ................................................................................................................... 5 II.3 General comments on the submitted dossier ........................................................................ 5 II.4 General comments on compliance with GMP, GLP, GCP and agreed ethical principles 6 III. SCIENTIFIC OVERVIEW AND DISCUSSION ................................................................. 6 III.1 Quality aspects ......................................................................................................................... 6 III.2 Non-clinical aspects ................................................................................................................. 8 III.3 Clinical aspects ........................................................................................................................ 8 IV. BENEFIT RISK ASSESSMENT ........................................................................................... 9 Pemetrexed 100 mg& 500mg, DE/H/4277/01-02/DC – DE/H/4284/01-02/DC Public Assessment Report Page 2/9 ADMINISTRATIVE INFORMATION Pemetrexed ODS 100 mg & 500mg; DE/H/4277/01-02/DC Proposed name of the medicinal Pemetrexed Xellex 100 mg & 500mg; DE/H/4278/01- product(s) in the RMS 02/DC Pemetrexed PhaRes 100 mg & 500mg; DE/H/4279/01- 02/DC Pemetrexed Profusio 100 mg & 500mg; DE/H/4280/01- 02/DC Pemetrexed Heumann 100 mg & 500mg; DE/H/4281/01- 02/DC Pemetrexed Bhardwaj 100 mg & 500mg; DE/H/4282/01- 02/DC Pemetrexed PhaRes 100 mg & 500mg; DE/H/4283/01- 02/DC Pemetrexed Vitane 100 mg & 500mg; DE/H/4284/01- 02/DC Name of the drug substance (INN Pemetrexed name): Pharmaco-therapeutic group L01BA004 (ATC Code): Pharmaceutical form(s) and POWDER FOR CONCENTRATE FOR SOLUTION FOR strength(s): INFUSION Reference Number(s) for the DE/H/4277/01-02/DC – DE/H/4284/01-02/DC Decentralised Procedure Reference Member State: DE Member States concerned: LU DE/H/4277/01-02/DC; Marketing Authorisation Holder DE/H/4278/01-02/DC; (name and address) DE/H/4279/01-02/DC Pharma Resources GmbH Domeierstraße 29/31 31785 Hameln Germany DE/H/4280/01-02/DC ZytoService Deutschland GmbH Leipzig Mommsenstr. 4 04329 Leipzig Germany DE/H/4281/01-02/DC Aristo Pharma GmbH Wallenroder Str. 8-10 13435 Berlin Germany DE/H/4282/01-02/DC; DE/H/4283/01-02/DC Bhardwaj GmbH Grootmoor 180 a 22175 Hamburg Germany Pemetrexed 100 mg& 500mg, DE/H/4277/01-02/DC – DE/H/4284/01-02/DC Public Assessment Report Page 3/9 DE/H/4284/01-02/DC Vitane Pharma GmbH Pfaffenrieder Str. 7 82515 Wolfratshausen Germany Thymoorgan Pharmazie GmbH Names and addresses of all Schiffgraben 23 manufacturer(s) responsible for 38690 Goslar batch release in the EEA Germany Pemetrexed 100 mg& 500mg, DE/H/4277/01-02/DC – DE/H/4284/01-02/DC Public Assessment Report Page 4/9 I. INTRODCUTION Based on the review of the data and the Applicant’s response to the questions raised by RMS and CMSs on quality, safety and efficacy, the RMS considers that the application for ‘Pemetrexed PhaRes’, in the treatment of Malignant pleural mesothelioma Pemetrexed in combination with cisplatin is indicated for the treatment of chemotherapy naive patients with unresectable malignant pleural mesothelioma. Non-small cell lung cancer Pemetrexed in combination with cisplatin is indicated for the first line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. Pemetrexed is indicated as monotherapy for the maintenance treatment of locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology in patients whose disease has not progressed immediately following platinum-based chemotherapy. Pemetrexed is indicated as monotherapy for the second line treatment of patients with locally advanced or metastatic non-small cell lung cancer other than predominantly squamous cell histology. is approved. II. EXECUTIVE SUMMARY II.1 Problem statement N/A (generic application) II.2 About the product Pemtrexed (ATC code: L01BA04) is a so called multi-targeted antifolate related to the folic acid analogue methotrexate (L01BA01) used in anticancer treatment (mesothelioma & NSCLC). The indications claimed are identical with the reference product Alimta. II.3 General comments on the submitted dossier These current decentralised applications consist of 8 duplicate applications and concern a generic version of Pemetrexed. Marketing Authorisation for the reference product “Alimta 100mg and 500mg powder for concentrate for solution for infusion” was first granted on 20 September 2004. The present applications (Pemetrexed 100mg, 500mg powder for concentrate for solution for infusion) deal with the essential similarity claim of the proposed product with the reference product “Alimta 100mg and 500mg powder for concentrate for solution for infusion”. The same therapeutic indications are intended to be authorized as for the reference product. The applicant seeks biowaiver for the test product pursuant to guideline “Investigation of bioequivalence” (CPMP/EWP/QWP/1401/98 Rev.1) which states that “The applicant is not required to submit a bioequivalence study if the product is to be administered as an aqueous intravenous solution containing the same active substance in the same concentration as the currently authorised product.” RMS’ assessor agrees that the requirement for a BE study can be waived. Data has been presented in application to support the claimed essential similarity with the innovator. Pemetrexed 100 mg& 500mg, DE/H/4277/01-02/DC – DE/H/4284/01-02/DC Public Assessment Report Page 5/9 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. III. SCIENTIFIC OVERVIEW AND DISCUSSION III.1 Quality aspects Introduction The medicinal product applied for is a generic medicinal product in accordance with Article 10(1) of Directive 2001/83/EC as amended. Essential similarity is claimed with the reference medicinal product Alimta 100 mg & 500 mg Powder for concentrate for solution for infusion, Eli Lilly Nederland B.V. The proposed product is indicated for treatment of Malignant pleural mesothelioma and Non-small cell lung cancer and contains the Folic acid analogue (ATC code: L01BA04), Pemetrexed as the active moiety. After reconstitution, each vial contains 25 mg/ml of Pemetrexed. The dosage form is a powder for concentrate for solution for infusion. Drug substance For the quality of the active drug substance, Pemetrexed disodium (hemipentahydrate), the applicant refers to an ASMF. The ASMF-holder has provided an applicant’s part and a restricted part of the ASMF which is assessed in separate assessment reports. The substance is a white or off-white hygroscopic powder, soluble in water and hygroscopic in nature. It is polymorphic and the hemipentahydrate form is produced by the manufacturer. The Pemetrexed molecule exhibits asymmetric nature due to the presence of one chiral centre. The enantiomer is suitable controlled in the API. The synthesis of Pemetrexed Disodium hemipentahydrate involves overall seven stages beginning with the designated starting materials 4-iodo ethyl benzoate, allyl alcohol, 2,4-diamino 6- hydroxypyrimidine and L-Glutamic Acid Diethyl ester HCl. Intermediate D and the final API are manufactured at different manufacturing sites. For both sites GMP compliance is assured. The manufacturing process is overall acceptably described. The API is acceptably characterised. The information presented regarding