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Zytiga, INN-Abiraterone Acetate

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Zytiga, INN-Abiraterone Acetate 15 November 2012 EMA/CHMP/755312/2012 Committee for Medicinal Products for Human Use (CHMP) Assessment report Zytiga (abiraterone) Procedure no. EMEA/H/C/002321/II/0004/G Note Variation assessment report as adopted by the CHMP with all information of a commercially confidential nature deleted. 7 Westferry Circus ● Canary Wharf ● London E14 4HB ● United Kingdom Telephone +44 (0)20 7418 8400 Facsimile +44 (0)20 7418 8613 E -mail [email protected] Website www.ema.europa.eu An agency of the European Union © European Medicines Agency, 2013. Reproduction is authorised provided the source is acknowledged. Table of contents 1. Background information on the procedure .............................................. 4 1.1. Type II and group of variations ............................................................................ 4 1.2. Steps taken for the assessment of the product ....................................................... 5 2. Scientific discussion ................................................................................ 6 2.1. Introduction ...................................................................................................... 6 2.2. Non-clinical aspects ............................................................................................ 7 2.2.1. Introduction ................................................................................................... 7 2.2.2. Pharmacology ................................................................................................. 7 2.2.3. Pharmacokinetics ............................................................................................ 7 2.2.4. Toxicology ...................................................................................................... 8 2.2.5. Ecotoxicity/environmental risk assessment .......................................................... 9 2.2.6. Discussion on non-clinical aspects .................................................................... 11 2.2.7. Conclusion on the non-clinical aspects .............................................................. 12 2.3. Clinical aspects ................................................................................................ 12 2.3.1. Introduction ................................................................................................. 12 2.3.2. Pharmacokinetics .......................................................................................... 12 2.3.3. Discussion on clinical pharmacology ................................................................. 13 2.4. Clinical efficacy ................................................................................................ 14 2.4.1. Dose response studies.................................................................................... 14 2.4.2. Main study ................................................................................................... 14 2.4.3. Discussion on clinical efficacy .......................................................................... 31 2.4.4. Conclusions on the clinical efficacy ................................................................... 34 2.5. Clinical safety .................................................................................................. 34 2.5.1. Introduction ................................................................................................. 34 2.5.2. Discussion on clinical safety ............................................................................ 43 2.5.3. Conclusions on clinical safety .......................................................................... 44 2.5.4. PSUR cycle ................................................................................................... 44 2.6. Risk management plan ...................................................................................... 44 2.7. Update of the Product information ...................................................................... 48 3. Benefit-Risk Balance.............................................................................. 48 4. Recommendations ................................................................................. 51 Assessment report Page 2/52 List of abbreviations ACTH adrenocorticotrophic hormone ADT androgen deprivation therapy AE adverse event ALT alanine aminotransferase AST aspartate aminotransferase AR androgen receptor BPI-SF Brief Pain Inventory-Short Form CHMP Committee for Medicinal Products for Human Use CI confidence interval CRPC castration-resistant prostate cancer CT computed tomography CYP17α cytochrome P450 17α-hydroxylase/C17,20-lyase DHEA Dehydroepiandrosterone ECOG Eastern Cooperative Oncology Group FACT-P Functional Assessment of Cancer Therapy-Prostate FWB Functional well being HR hazard ratio IARC International Agency for Research on Cancer IDMC Independent Data Monitoring Committee ITT intent-to-treat LDH lactate dehydrogenase LFT liver function test LHRH luteinizing hormone releasing hormone mCRPC metastatic castration-resistant prostate cancer MRI magnetic resonance imaging OS overall survival PCS prostate cancer score PCWG2 Prostate Cancer Working Group 2 PSA prostate-specific antigen PRO patient-reported outcomes PWB Physical well being P-Y patient-years RECIST Response Evaluation Criteria In Solid Tumors rPFS radiographic progression-free survival SAE serious adverse event SmPC Summary of Product Characteristics SMQ Standardized MedDRA Queries SOC system organ class Assessment report Page 3/52 1. Background information on the procedure 1.1. Type II and group of variations Pursuant to Article 7.2 of Commission Regulation (EC) No 1234/2008, Janssen-Cilag International N V submitted to the European Medicines Agency on 13 June 2012 an application for a group of variations including an extension of indication. This application concerns the following medicinal product: Medicinal product: International non-proprietary Presentations: name: Zytiga abiraterone See Annex A The following variations were requested in the group: Variations requested Type C.I.6.a Change(s) to therapeutic indication(s) - Addition of a new II therapeutic indication or modification of an approved one C.I.4 Variations related to significant modifications of the SPC II due in particular to new quality, pre-clinical, clinical or pharmacovigilance data The MAH applied for an extension of the prostate cancer indication in combination with prednisone or prednisolone for the treatment of metastatic castration resistant prostate cancer in adult men who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy. Consequently, the MAH proposed the update of sections 4.1, 4.2, 4.4, 4.8 and 5.1 of the SmPC and the Package Leaflet was proposed to be updated accordingly. In the second variation in the group, updates to sections 4.6 and 5.3 of the SmPC have been proposed based on the results of reproductive and developmental non- clinical studies. Minor modifications to the SmPC, Labelling and Package Leaflet have also been proposed. The group of variations proposed amendments to the SmPC, Labelling and Package Leaflet. Information on paediatric requirements Pursuant to Article 8 of Regulation (EC) No 1901/2006, the application included an EMA Decision P/63/2010 on the granting of a class waiver. Information relating to orphan market exclusivity Similarity Pursuant to Article 8 of Regulation (EC) No. 141/2000 and Article 3 of Commission Regulation (EC) No 847/2000, the applicant did not submit a critical report addressing the possible similarity with authorised orphan medicinal products because there is no authorised orphan medicinal product for a condition related to the proposed indication. Assessment report Page 4/52 Applicant’s request for consideration Additional market protection The applicant requested consideration of its application in accordance with Article 14(11) of Regulation (EC) 726/2004 - one year of market protection for a new indication. Scientific advice The applicant received Scientific Advice from the CHMP on 20 November 2008. The Scientific Advice pertained to non-clinical and clinical aspects of the dossier. 1.2. Steps taken for the assessment of the product The Rapporteur and Co-Rapporteur appointed by the CHMP and the evaluation teams were: Rapporteur: Arantxa Sancho-Lopez Co-Rapporteur: Robert James Hemmings Submission date: 13 June 2012 Start of procedure: 24 June 2012 Rapporteur’s preliminary assessment report circulated on: 21 August 2012 CoRapporteur’s preliminary assessment report circulated on: 17 August 2012 Joint Rapporteur’s updated assessment report circulated on: 14 September 2012 Request for supplementary information and extension of timetable adopted by the CHMP on: 20 September 2012 MAH’s responses submitted to the CHMP on: 12 October 2012 Joint Rapporteur/Co-Rapporteur assessment report on the MAH’s responses circulated on: 29 October 2012 CHMP opinion: 15 November 2012 Assessment report Page 5/52 2. Scientific discussion 2.1. Introduction Prostate cancer is the most common cancer and the second leading cause of cancer deaths among males in most Western countries. In 2008, 323,000 men were diagnosed with prostate cancer in the European Union and 71,000 patients died from the disease (GLOBOCAN 2008 (IARC)). For men with disseminated disease, bone is the most common site of metastasis. Prostate cancer- related deaths occur as a result of complications of metastatic disease. The objective of therapy is control of disease while maintaining quality of life.
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