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19 November 2015 EMA/PRAC/711550/2015 Pharmacovigilance Risk Assessment Committee (PRAC) Adopted at the PRAC meeting of 3-6 November 2015 This document provides an overview of the recommendations adopted by the Pharmacovigilance Risk Assessment Committee (PRAC) on the signals discussed during the meeting of 3-6 November 2015 (including the signal European Pharmacovigilance Issues Tracking Tool [EPITT] 1 reference numbers). PRAC recommendations to provide supplementary information are directly actionable by the concerned marketing authorisation holders (s). PRAC recommendations for regulatory action (e.g. amendment of the product information) are submitted to the Committee for Medicinal Products for Human Use (CHMP) for endorsement when the signal concerns Centrally Authorised Products (CAPs), and to the Co-ordination Group for Mutual Recognition and Decentralised Procedures Human (CMDh) for information in the case of Nationally Authorised Products (NAPs). Thereafter, s are expected to take action according to the PRAC recommendations. When appropriate, the PRAC may also recommend the conduct of additional analyses by the Agency or Member States. s are reminded that in line with Article 16(3) of Regulation No (EU) 726/2004 and Article 23(3) of Directive 2001/83/EC, they shall ensure that their product information is kept up to date with the current scientific knowledge including the conclusions of the assessment and recommendations published on the European Medicines Agency (EMA) website (currently acting as the EU medicines webportal). For CAPs, at the time of publication, PRAC recommendations for update of product information have been agreed by the CHMP at their plenary meeting (16-19 November 2015) and corresponding variations will be assessed by the CHMP. For nationally authorised medicinal products, it is the responsibility of the National Competent Authorities (NCAs) of the Member States to oversee that are adhered to. Variations for CAPs are handled according to established EMA procedures. s are referred to the available guidance. Variations for NAPs (including via mutual recognition and decentralised procedures) are handled at national level in accordance with the provisions of the Member States. 1 The relevant EPITT reference number should be used in any communication related to a signal. 30 Churchill Place Canary Wharf London E14 5EU United Kingdom Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website www.ema.europa.eu/contact An agency of the European Union European Medicines Agency, 2015. Reproduction is authorised provided the source is acknowledged.

The timeline recommended by PRAC for submission of variations following signal assessment is applicable to both innovator and generic medicinal products, unless otherwise specified. For procedural aspects related to the handling of (e.g. submission requirements, contact points, etc.) please refer to the Questions and Answers on signal management. EMA/PRAC/711550/2015 Page 2/5

1. Recommendations for update of the product information Palifermin Signal of infection (EPITT no 18401): request for a type II variation (see section 3 on page 5). 2. Recommendations for submission of supplementary information INN Signal (EPITT No) PRAC Axitinib Nephrotic syndrome (18484) Ingebjørg Buajordet (NO) Pfizer Limited Bevacizumab Generalized tonicclonic seizures (18485) Doris I. Stenver (DK) Assess in the next PSUR 05/05/2016) Roche Registration Ltd Human fibrinogen, human thrombin Intestinal obstruction (18373) Brigitte Keller- Stanislawski (DE) Proposal for summary of product characteristics wording and communication plan requested 18/11/2015) Takeda Austria GmbH Human normal immunoglobulin Posterior reversible encephalopathy syndrome (PRES) Brigitte Keller- Stanislawski (DE) Baltic Therapeutic Service, Baxter / Baxalta Innovations, Bio Products Laboratory, Biomed-Lublin Wsisz, Biotest Pharma GmbH / Vianex S.A., CSL Behring, Demo Abee, Grifols, Hi- Med Solutions (Cyprus) Ltd / Jana Pharm D.O.O. / Octapharma AG, Human Bioplazma Manufacturing and Trading LLC, Imed Poland SP.Z.O.O., Jasika D.O.O. / Kedrion S.p.A., LFB Biomedicaments, Narodowe centrum badań jądrowych, Oxbridge Pharma Limited, Sanquin/CAFDCF EMA/PRAC/711550/2015 Page 3/5

INN Signal (EPITT No) PRAC Mercaptopurine; azathioprine Lymphoproliferative disorders (18503) Ulla Wändel Liminga (SE) Aspen Pharma Methotrexate Congenital cardiovascular Doris I. Stenver (DK) Pfizer anomaly (18481) Oxybutynin Psychiatric disorders (18342) Veerle Verlinden (BE) Proposal for summary of product characteristics wording Nicobrand Limited (including frequencies) requested (submission by 10/12/2015) Selective serotonin Risk of autism spectrum disorders Lundbeck, Eli Lilly, Abbott, (ASD) after maternal GlaxoSmithKline, (SSRIs) and Serotonin use of SSRI/SNRI (14082) 10/02/2016) Organon, Pfizer norepinephrine (SNRIs): citalopram; duloxetine; escitalopram; fluoxetine ; fluvoxamine; mirtazapine; paroxetine; sertraline; venlafaxine Somatropin Hypersensitivity reactions (18486) Torbjörn Callreus (DK) Assess in the next PSUR 29/12/2015) Ipsen Pharma, Sandoz GmbH, BioPartners GmbH, Pfizer, Novo Nordisk A/S, Merck KGaA, Eli Lilly Nederland B.V., Ferring Pharmaceuticals EMA/PRAC/711550/2015 Page 4/5

INN Signal (EPITT No) PRAC Tigecycline Hypofibrinogenaemi Miguel A. Pfizer Limited a (18479) Maciá (ES) 3. Other recommendations INN Signal (EPITT No) PRAC Aflibercept Higher systemic No action Bayer Pharma AG exposure compared to ranibizumab after intravitreal injection (18112) Palifermin Infection (18401) Rafe Suvarna (UK) Submission of type II variation including update of product information, Direct Healthcare Professional Communication, drug utilisation study and update of risk management plan Swedish Orphan Biovitrum AB (publ) Selective New malformative Routine s of SSRIs serotonin risks in newborn pharmacovigilance (14082) (SSRIs): citalopram; escitalopram; fluoxetine ; fluvoxamine; paroxetine; sertraline Warfarin Bone density Torbjörn Routine s of warfarin- decreased (18173) Callreus pharmacovigilance containing (DK) products EMA/PRAC/711550/2015 Page 5/5