19 April 2012 EMA/453346/2012 Committee for Medicinal Products for Human Use (CHMP) Final CHMP assessment report Folotyn International non-proprietary name: pralatrexate Procedure No. EMEA/H/C/002096 Note 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 7523 7455 E-mail [email protected] Website www.ema.europa.eu An agency of the European Union Table of contents 1. Background information on the procedure .............................................. 8 1.1. Submission of the dossier.................................................................................... 8 Information on Paediatric requirements ....................................................................... 8 Information relating to orphan market exclusivity.......................................................... 8 Applicant’s requests for consideration .......................................................................... 8 Conditional Marketing Authorisation ............................................................................ 8 New active Substance status ...................................................................................... 9 Protocol Assistance ................................................................................................... 9 Licensing status ..................................................................................................... 10 1.2. Steps taken for the assessment of the product ..................................................... 10 1.3. Steps taken for the re-examination procedure ...................................................... 11 2. Scientific discussion .............................................................................. 11 2.1. Introduction .................................................................................................... 11 Problem statement ................................................................................................. 11 About the product................................................................................................... 12 2.2. Quality aspects ................................................................................................ 12 2.2.1. Introduction ................................................................................................. 12 2.2.2. Active Substance........................................................................................... 12 Manufacture .......................................................................................................... 13 Specification .......................................................................................................... 13 Stability ................................................................................................................ 14 2.2.3. Finished Medicinal Product .............................................................................. 14 Pharmaceutical Development ................................................................................... 14 Adventitious agents ................................................................................................ 15 Manufacture of the product ...................................................................................... 15 Product specification ............................................................................................... 15 Stability of the product............................................................................................ 15 2.2.4. Discussion on chemical, pharmaceutical and biological aspects............................. 16 2.2.5. Conclusions on the chemical, pharmaceutical and biological aspects ..................... 16 2.2.6. Recommendation(s) for future quality development............................................ 16 2.3. Non-clinical aspects .......................................................................................... 16 2.3.1. Pharmacology ............................................................................................... 16 Primary pharmacodynamic studies ............................................................................ 16 Secondary pharmacodynamic studies ........................................................................ 19 Safety pharmacology programme ............................................................................. 19 Pharmacodynamic drug interactions .......................................................................... 20 2.3.2. Pharmacokinetics .......................................................................................... 20 Methods of analysis ................................................................................................ 20 Absorption............................................................................................................. 20 Distribution............................................................................................................ 21 Metabolism ............................................................................................................ 21 Excretion............................................................................................................... 21 Pharmacokinetic drug interactions............................................................................. 22 Folotyn CHMP assessment report Page 2/85 Rev10.11 Other pharmacokinetic studies ................................................................................. 22 2.3.3. Toxicology.................................................................................................... 22 Single dose toxicity................................................................................................. 22 Repeat dose toxicity................................................................................................ 22 Genotoxicity .......................................................................................................... 25 Carcinogenicity....................................................................................................... 25 Reproduction Toxicity.............................................................................................. 26 Fertility and early embryonic development ................................................................. 26 Embryo-foetal development ..................................................................................... 26 Prenatal and postnatal development, including maternal function .................................. 26 Studies in which the offspring (juvenile animals) are dosed and/or further evaluated........ 26 Toxicokinetic data................................................................................................... 26 Local Tolerance ...................................................................................................... 27 Other toxicity studies .............................................................................................. 27 Immunotoxicity ...................................................................................................... 27 Studies on impurities .............................................................................................. 27 2.3.4. Ecotoxicity/environmental risk assessment........................................................ 28 2.3.5. Discussion on non-clinical aspects.................................................................... 28 2.3.6. Conclusion on non-clinical aspects ................................................................... 32 2.4. Clinical aspects ................................................................................................ 33 2.4.1. Introduction ................................................................................................. 33 GCP...................................................................................................................... 33 2.4.2. Pharmacokinetics .......................................................................................... 34 Absorption............................................................................................................. 34 Distribution............................................................................................................ 34 Elimination ............................................................................................................ 34 Dose proportionality and time dependencies............................................................... 35 Special populations ................................................................................................. 36 Pharmacokinetic interaction studies........................................................................... 37 Pharmacokinetics using human biomaterials ............................................................... 38 2.4.3. Pharmacodynamics........................................................................................ 38 Mechanism of action ............................................................................................... 38 Primary and Secondary pharmacology ....................................................................... 38 2.4.4. Discussion on clinical pharmacology ................................................................. 39 2.4.5. Conclusions on clinical pharmacology ..............................................................