Agenda Prac Draft Agenda Meeting 7 10 February 2022 - en

07 February 2022
EMA/PRAC/76191/2022
Human Medicines Division
Pharmacovigilance Risk Assessment Committee (PRAC)

Draft agenda for the meeting on 07-10 February 2022
Chair: Sabine Straus – Vice-Chair: Martin Huber
07 February 2022, 10:30 – 19:30, via teleconference
Organisational, regulatory and methodological matters (ORGAM)
Disclaimers
Some of the information contained in this agenda is considered commercially confidential or sensitive
and therefore not disclosed. With regard to intended therapeutic indications or procedure scopes listed
against products, it must be noted that these may not reflect the full wording proposed by applicants
and may also change during the course of the review. Additional details on some of these procedures
will be published in the PRAC meeting highlights once the procedures are finalised.
Of note, this agenda is a working document primarily designed for PRAC members and the work the
Committee undertakes.
Note on access to documents
Some documents mentioned in the agenda cannot be released at present following a request for
access to documents within the framework of Regulation (EC) No 1049/2001 as they are subject to on-
going procedures for which a final decision has not yet been adopted. They will become public when
adopted or considered public according to the principles stated in the Agency policy on access to
documents (EMA/127362/2006 Rev.1).
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© European Medicines Agency, 2022. Reproduction is authorised provided the source is acknowledged.
Table of contents
1. Introduction 12
1.1. Welcome and declarations of interest of members, alternates and experts .......... 12
1.2. Agenda of the meeting on 07-10 February 2022 ................................................... 12
1.3. Minutes of the previous meeting on 10-13 January 2022 ..................................... 12
2. EU referral procedures for safety reasons: urgent EU procedures 12

2.1. Newly triggered procedures ................................................................................. 12
2.2. Ongoing procedures ............................................................................................. 12
2.3. Procedures for finalisation.................................................................................... 12
3. EU referral procedures for safety reasons: other EU referral

procedures 12
3.1. Newly triggered procedures ................................................................................. 12
3.1.1. Janus kinase (JAK) inhibitors: abrocitinib - CIBINQO (CAP); baricitinib - OLUMIANT (CAP);
filgotinib - JYSELECA (CAP); tofacitinib - XELJANZ (CAP); upadacitinib - RINVOQ (CAP) –
EMEA/H/A-20/1517.................................................................................................. 12
3.2. Ongoing procedures ............................................................................................. 13
3.2.1. Chlormadinone (NAP); chlormadinone, ethinylestradiol (NAP); nomegestrol (NAP);

nomegestrol, estradiol – ZOELY (CAP), NAP - EMEA/H/A-31/1510.................................. 13
3.3. Procedures for finalisation.................................................................................... 13
3.4. Re-examination procedures .................................................................................. 13
3.5. Others .................................................................................................................. 13
4. Signals assessment and prioritisation 13

4.1. New signals detected from EU spontaneous reporting systems ............................ 13
4.2. New signals detected from other sources ............................................................. 14
4.2.1. Coronavirus (COVID-19) mRNA vaccine (nucleoside-modified) - SPIKEVAX (CAP) ............ 14
4.2.2. Coronavirus (COVID-19) mRNA vaccine (nucleoside-modified) - SPIKEVAX (CAP) ............ 14
4.2.3. Tozinameran - COMIRNATY (CAP) .............................................................................. 14
4.2.4. Tozinameran - COMIRNATY (CAP) .............................................................................. 14
4.3. Signals follow-up and prioritisation ...................................................................... 15
4.3.1. Enzalutamide - XTANDI (CAP) - EMEA/H/C/002639/SDA/015 ........................................ 15
4.3.2. Obinutuzumab - GAZYVARO (CAP) - EMEA/H/C/002799/SDA/012 .................................. 15
4.3.3. Sorafenib - NEXAVAR (CAP) - EMEA/H/C/000690/SDA/041 ........................................... 15
4.3.4. Tocilizumab – ROACTEMRA (CAP) .............................................................................. 15
4.4. Variation procedure(s) resulting from signal evaluation ...................................... 16
4.4.1. Coronavirus (COVID-19) mRNA vaccine (nucleoside-modified) - SPIKEVAX (CAP) -

EMEA/H/C/005791/II/0028 ....................................................................................... 16

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5. Risk management plans (RMPs) 16
5.1. Medicines in the pre-authorisation phase ............................................................. 16
5.1.1. Bevacizumab - EMEA/H/C/005574 ............................................................................. 16
5.1.2. Coronavirus (COVID-19) Vaccine (inactivated, adjuvanted, adsorbed) - EMEA/H/C/00601916
5.1.3. Dabigatran etexilate - EMEA/H/C/005639 ................................................................... 16
5.1.4. Fosdenopterin - EMEA/H/C/005378, Orphan................................................................ 17
5.1.5. Insulin human - EMEA/H/W/005779 ........................................................................... 17
5.1.6. Insulin human - EMEA/H/W/005780 ........................................................................... 17
5.1.7. Molnupiravir – LAGEVRIO (CAP MAA) - EMEA/H/C/005789 ............................................ 17
5.1.8. Olipudase alfa - EMEA/H/C/004850, PRIME, Orphan ..................................................... 17
5.1.9. Pirfenidone - EMEA/H/C/005873 ................................................................................ 17
5.1.10. Ranibizumab - EMEA/H/C/005610 .............................................................................. 17
5.2. Medicines in the post-authorisation phase – PRAC-led procedures ....................... 18
5.2.1. Alogliptin - VIPIDIA (CAP) - EMEA/H/C/002182/WS2191/0029; alogliptin, metformin -

VIPDOMET (CAP) - EMEA/H/C/002654/WS2191/0036; alogliptin, pioglitazone - INCRESYNC
(CAP) - EMEA/H/C/002178/WS2191/0040 .................................................................. 18

EMEA/H/C/005791/II/0022 ....................................................................................... 18
5.2.3. Nintedanib - VARGATEF (CAP) - EMEA/H/C/002569/II/0044.......................................... 18
5.2.4. Pandemic influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) - FOCLIVIA
(CAP) - EMEA/H/C/001208/WS2151/0068; prepandemic influenza vaccine (H5N1) (surface
antigen, inactivated, adjuvanted) - AFLUNOV (CAP) - EMEA/H/C/002094/WS2151/0071 .. 18
5.3. Medicines in the post-authorisation phase – CHMP-led procedures ...................... 19
5.3.1. Acalabrutinib - CALQUENCE (CAP) - EMEA/H/C/005299/X/0009/G ................................. 19
5.3.2. Aflibercept - EYLEA (CAP) - EMEA/H/C/002392/II/0077/G ............................................ 19
5.3.3. Apalutamide - ERLEADA (CAP) - EMEA/H/C/004452/II/0017 ......................................... 19
5.3.4. Axicabtagene ciloleucel - YESCARTA (CAP) - EMEA/H/C/004480/II/0042, Orphan ............ 20
5.3.6. Baloxavir marboxil - XOFLUZA (CAP) - EMEA/H/C/004974/X/0003/G ............................. 20
5.3.7. Brolucizumab - BEOVU (CAP) - EMEA/H/C/004913/II/0010 ........................................... 21
5.3.8. Buprenorphine - BUVIDAL (CAP) - EMEA/H/C/004651/II/0017 ...................................... 21
5.3.9. Cabozantinib - CABOMETYX (CAP) - EMEA/H/C/004163/II/0023 .................................... 21
5.3.10. Cariprazine - REAGILA (CAP) - EMEA/H/C/002770/II/0023 ........................................... 21
5.3.11. Cemiplimab - LIBTAYO (CAP) - EMEA/H/C/004844/II/0026 ........................................... 22

EMEA/H/C/005791/II/0041 ....................................................................................... 22
5.3.13. Crizotinib - XALKORI (CAP) - EMEA/H/C/002489/II/0072 .............................................. 22
5.3.14. Denosumab - PROLIA (CAP) - EMEA/H/C/001120/II/0093 ............................................ 23
5.3.15. Doravirine - PIFELTRO (CAP) - EMEA/H/C/004747/WS2065/0019; doravirine, lamivudine,

tenofovir disoproxil - DELSTRIGO (CAP) - EMEA/H/C/004746/WS2065/0026 ................... 23
5.3.16. Eribulin - HALAVEN (CAP) - EMEA/H/C/002084/II/0060 ................................................ 23

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5.3.17. Gilteritinib - XOSPATA (CAP) - EMEA/H/C/004752/II/0007, Orphan ............................... 24
5.3.18. Ipilimumab - YERVOY (CAP) - EMEA/H/C/002213/WS2113/0090; nivolumab - OPDIVO (CAP) -

EMEA/H/C/003985/WS2113/0108; ............................................................................ 24
5.3.19. Ipilimumab - YERVOY (CAP) - EMEA/H/C/002213/WS2153/0093; nivolumab - OPDIVO (CAP) -

EMEA/H/C/003985/WS2153/0111; ............................................................................ 24
5.3.20. Ivacaftor, tezacaftor, elexacaftor - KAFTRIO (CAP) - EMEA/H/C/005269/II/0017/G, Orphan25
5.3.21. Lomitapide - LOJUXTA (CAP) - EMEA/H/C/002578/II/0046 ........................................... 25
5.3.22. Lumasiran - OXLUMO (CAP) - EMEA/H/C/005040/II/0008, Orphan ................................ 25
5.3.23. Mepolizumab - NUCALA (CAP) - EMEA/H/C/003860/X/0042 .......................................... 26
5.3.24. Neratinib - NERLYNX (CAP) - EMEA/H/C/004030/II/0027 .............................................. 26
5.3.25. Niraparib - ZEJULA (CAP) - EMEA/H/C/004249/II/0033, Orphan .................................... 26
5.3.26. Nivolumab - OPDIVO (CAP) - EMEA/H/C/003985/II/0107 ............................................. 26
5.3.27. Octocog alfa - KOVALTRY (CAP) - EMEA/H/C/003825/II/0038 ....................................... 27
5.3.28. Padeliporfin - TOOKAD (CAP) - EMEA/H/C/004182/II/0015 ........................................... 27
5.3.29. Palbociclib - IBRANCE (CAP) - EMEA/H/C/003853/II/0037 ............................................ 27
5.3.30. Parathyroid hormone - NATPAR (CAP) - EMEA/H/C/003861/II/0029, Orphan .................. 28
5.3.31. Polatuzumab vedotin - POLIVY (CAP) - EMEA/H/C/004870/II/0012, Orphan .................... 28
5.3.32. Selpercatinib - RETSEVMO (CAP) - EMEA/H/C/005375/II/0011 ...................................... 28
5.3.33. Tenofovir disoproxil - VIREAD (CAP) - EMEA/H/C/000419/II/0204 ................................. 29
5.3.34. Tildrakizumab - ILUMETRI (CAP) - EMEA/H/C/004514/X/0023 ....................................... 29
6. Periodic safety update reports (PSURs) 29

6.1. PSUR single assessment (PSUSA) procedures including centrally authorised products
(CAPs) only .......................................................................................................... 29
6.1.1. Aclidinium bromide - BRETARIS GENUAIR (CAP); EKLIRA GENUAIR (CAP) -

PSUSA/00009005/202107 ........................................................................................ 29
6.1.2. Alectinib - ALECENSA (CAP) - PSUSA/00010581/202107 .............................................. 30
6.1.3. Alirocumab - PRALUENT (CAP) - PSUSA/00010423/202107 ........................................... 30
6.1.4. Asfotase alfa - STRENSIQ (CAP) - PSUSA/00010421/202107 ........................................ 30
6.1.5. Atazanavir - REYATAZ (CAP) - PSUSA/00000258/202106 ............................................. 30
6.1.6. Autologous peripheral blood T cells CD4 and CD8 selected and CD3 and CD28 activated
transduced with retroviral vector expressing anti-CD19 CD28/CD3-zeta chimeric antigen
receptor and cultured - TECARTUS (CAP) - PSUSA/00010903/202107 ............................ 30
6.1.7. Avapritinib - AYVAKYT (CAP) - PSUSA/00010878/202107 ............................................. 31
6.1.8. Beclometasone, formoterol, glycopyrronium bromide - RIARIFY (CAP); TRIMBOW (CAP);

TRYDONIS (CAP) - PSUSA/00010617/202107 ............................................................. 31
6.1.9. Birch bark extract - EPISALVAN (CAP) - PSUSA/00010446/202107 ................................ 31
6.1.10. Brexpiprazole - RXULTI (CAP) - PSUSA/00010698/202107............................................ 31
6.1.11. Brodalumab - KYNTHEUM (CAP) - PSUSA/00010616/202107 ........................................ 31
6.1.12. Budesonide - JORVEZA (CAP) - PSUSA/00010664/202107 ............................................ 31

6.1.13. Canakinumab - ILARIS (CAP) - PSUSA/00000526/202106 ............................................ 32
6.1.14. Carfilzomib - KYPROLIS (CAP) - PSUSA/00010448/202107 ........................................... 32

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6.1.15. Cenegermin - OXERVATE (CAP) - PSUSA/00010624/202107 ......................................... 32
6.1.16. Cladribine - MAVENCLAD (CAP) - PSUSA/00010634/202107 ......................................... 32
6.1.17. Gefitinib - IRESSA (CAP) - PSUSA/00001518/202107................................................... 32
6.1.18. Glecaprevir, pibrentasvir - MAVIRET (CAP) - PSUSA/00010620/202107 .......................... 33
6.1.19. Glucagon - BAQSIMI (CAP); OGLUO (CAP) - PSUSA/00010826/202107 .......................... 33
6.1.20. Guselkumab - TREMFYA (CAP) - PSUSA/00010652/202107 ........................................... 33
6.1.21. Human plasma protease C1 inhibitor - CINRYZE (CAP) - PSUSA/00010104/202106 ......... 33
6.1.22. Ibandronic acid - BONDRONAT (CAP); BONVIVA (CAP) - PSUSA/00001702/202106 ......... 33
6.1.23. Icosapent ethyl - VAZKEPA (CAP) - PSUSA/00010922/202107 ...................................... 33
6.1.24. Idursulfase - ELAPRASE (CAP) - PSUSA/00001722/202107 ........................................... 34
6.1.25. Imipenem, cilastatin, relebactam - RECARBRIO (CAP) - PSUSA/00010830/202107 .......... 34
6.1.26. Indacaterol, glycopyrronium, mometasone - ENERZAIR BREEZHALER (CAP); ZIMBUS

BREEZHALER (CAP) - PSUSA/00010861/202107.......................................................... 34
6.1.27. Inotersen - TEGSEDI (CAP) - PSUSA/00010697/202107 ............................................... 34
6.1.28. L-lysine hydrochloride, L-arginine hydrochloride - LYSAKARE (CAP) - PSUSA/00010786/202107

............................................................................................................................. 34
6.1.29. Lonoctocog alfa - AFSTYLA (CAP) - PSUSA/00010559/202107 ....................................... 35
6.1.30. Macimorelin - GHRYVELIN (CAP) - PSUSA/00010746/202107 ........................................ 35
6.1.31. Mirabegron - BETMIGA (CAP) - PSUSA/00010031/202106 ............................................ 35
6.1.32. Neratinib - NERLYNX (CAP) - PSUSA/00010712/202107 ............................................... 35
6.1.33. Nivolumab - OPDIVO (CAP) - PSUSA/00010379/202107 ............................................... 35
6.1.34. Osilodrostat - ISTURISA (CAP) - PSUSA/00010820/202107 .......................................... 35
6.1.35. Paliperidone - INVEGA (CAP); paliperidone palmitate - BYANNLI (CAP); TREVICTA (CAP);
XEPLION (CAP) - PSUSA/00002266/202106 ................................................................ 36
6.1.36. Peginterferon beta-1a - PLEGRIDY (CAP) - PSUSA/00010275/202107 ............................ 36
6.1.37. Perampanel - FYCOMPA (CAP) - PSUSA/00009255/202107 ........................................... 36
6.1.38. Remimazolam - BYFAVO (CAP) - PSUSA/00010924/202107 .......................................... 36
6.1.39. Romosozumab - EVENITY (CAP) - PSUSA/00010824/202107 ........................................ 36
6.1.40. Salmeterol, fluticasone propionate - BROPAIR SPIROMAX (CAP); SEFFALAIR SPIROMAX (CAP) -
PSUSA/00010928/202107 ........................................................................................ 37
6.1.41. Saxagliptin, dapagliflozin - QTERN (CAP) - PSUSA/00010520/202107 ............................ 37
6.1.42. Sofosbuvir, velpatasvir, voxilaprevir - VOSEVI (CAP) - PSUSA/00010619/202107 ............ 37
6.1.43. Spheroids of human autologous matrix-associated chondrocytes - SPHEROX (CAP) -

PSUSA/00010630/202107 ........................................................................................ 37
6.1.44. Tagraxofusp - ELZONRIS (CAP) - PSUSA/00010896/202107 ......................................... 37
6.1.45. Tasimelteon - HETLIOZ (CAP) - PSUSA/00010394/202107............................................ 38
6.1.46. Tobramycin - TOBI PODHALER (CAP) - PSUSA/00009315/202106 ................................. 38
6.1.47. Voretigene neparvovec - LUXTURNA (CAP) - PSUSA/00010742/202107.......................... 38
6.2. PSUR single assessment (PSUSA) procedures including centrally authorised products
(CAPs) and nationally authorised products (NAPs) .............................................. 38
6.2.1. 5-aminolevulinic acid - AMELUZ (CAP); NAP - PSUSA/00010006/202106 ........................ 38

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6.2.2. Amlodipine, valsartan - COPALIA (CAP), DAFIRO (CAP), EXFORGE (CAP), NAP; amlodipine,
hydrochlorothiazide, valsartan - COPALIA HCT (CAP), DAFIRO HCT (CAP), EXFORGE HCT (CAP)
- PSUSA/00010344/202106 ...................................................................................... 38
6.2.3. Cabazitaxel - CABAZITAXEL ACCORD (CAP); JEVTANA (CAP); NAP - PSUSA/00000476/202106

............................................................................................................................. 39
6.3. PSUR single assessment (PSUSA) procedures including nationally authorised

products (NAPs) only ........................................................................................... 39
6.3.1. Acenocoumarol (NAP) - PSUSA/00000027/202107....................................................... 39
6.3.2. Betula verrucosa (NAP) - PSUSA/00010815/202107 ................................................... 39
6.3.3. Bovine lung phospholipid (NAP) - PSUSA/00010791/202106 ......................................... 39
6.3.4. Calcifediol (NAP) - PSUSA/00000491/202106 .............................................................. 39
6.3.5. Calcitonin salmon (NAP); synthetic analogue of eel calcitonin (NAP) -

PSUSA/00000494/202106 ........................................................................................ 40
6.3.6. Cefepime (NAP) - PSUSA/00000593/202106 ............................................................... 40
6.3.7. Desogestrel (NAP) - PSUSA/00000966/202107 ........................................................... 40
6.3.8. Dexchlorpheniramine (NAP) - PSUSA/00000989/202106 .............................................. 40
6.3.9. Fosinopril (NAP); fosinopril, hydrochlorothiazide (NAP) - PSUSA/00010463/202107 ......... 40
6.3.10. Glibenclamide, metformin hydrochloride (NAP) - PSUSA/00002002/202106 .................... 41
6.3.11. Human fibrinogen (NAP) - PSUSA/00001624/202106 ................................................... 41
6.3.12. Ibuprofen, pseudoephedrine (NAP) - PSUSA/00001711/202107 .................................... 41
6.3.13. Lidocaine hydrochloride, phenylephrine hydrochloride, tropicamide (NAP) -

PSUSA/00010390/202107 ........................................................................................ 41
6.3.14. Manidipine (NAP) - PSUSA/00001932/202106 ............................................................. 41
6.3.15. Nimesulide (NAP) - PSUSA/00009236/202106 ............................................................. 41
6.3.16. Propranolol (NAP) - PSUSA/00010251/202106 ............................................................ 42
6.3.17. Rabbit anti-human T-lymphocyte immunoglobulin (NAP) - PSUSA/00010252/202106 ...... 42
6.3.18. Solifenacin, tamsulosin (NAP) - PSUSA/00010285/202107 ............................................ 42
6.3.19. Tamsulosin (NAP) - PSUSA/00002847/202107 ............................................................ 42
6.3.20. Thiocolchicoside (NAP); paracetamol, thiocolchicoside (NAP) - PSUSA/00010464/202107 . 42
6.3.21. Tiagabine (NAP) - PSUSA/00002942/202106 .............................................................. 43
6.3.22. Tianeptine (NAP) - PSUSA/00002943/202106 ............................................................. 43
6.3.23. Urapidil (NAP) - PSUSA/00003078/202107 ................................................................. 43
6.4. Follow-up to PSUR/PSUSA procedures ................................................................. 43
6.4.1. Dolutegravir - TIVICAY (CAP) - EMEA/H/C/002753/LEG 015.......................................... 43
6.4.2. Dolutegravir, abacavir, lamivudine - TRIUMEQ (CAP) - EMEA/H/C/002754/LEG 010 ......... 43
6.4.3. Dolutegravir, lamivudine - DOVATO (CAP) - EMEA/H/C/004909/LEG 005 ........................ 44
6.4.4. Sitagliptin - JANUVIA (CAP) - EMEA/H/C/000722/LEG 041.1 ......................................... 44
6.4.5. Sitagliptin - RISTABEN (CAP) - EMEA/H/C/001234/LEG 019.1 ....................................... 44
6.4.6. Sitagliptin - TESAVEL (CAP) - EMEA/H/C/000910/LEG 035.1 ......................................... 44

6.4.7. Sitagliptin - XELEVIA (CAP) - EMEA/H/C/000762/LEG 040.1.......................................... 45
6.4.8. Sitagliptin, metformin hydrochloride - EFFICIB (CAP) - EMEA/H/C/000896/LEG 020.1 ...... 45

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6.4.9. Sitagliptin, metformin hydrochloride - JANUMET (CAP) - EMEA/H/C/000861/LEG 020.1 .... 45
6.4.10. Sitagliptin, metformin hydrochloride - RISTFOR (CAP) - EMEA/H/C/001235/LEG 016.1 ..... 45
6.4.11. Sitagliptin, metformin hydrochloride - VELMETIA (CAP) - EMEA/H/C/000862/LEG 020.1 ... 46
6.5. Variation procedure(s) resulting from PSUSA evaluation ..................................... 46
6.5.1. Dolutegravir - TIVICAY (CAP) - EMEA/H/C/002753/WS2192/0075; dolutegravir, abacavir,

lamivudine - TRIUMEQ (CAP) - EMEA/H/C/002754/WS2192/0099; dolutegravir, lamivudine -
DOVATO (CAP) - EMEA/H/C/004909/WS2192/0026; dolutegravir, rilpivirine - JULUCA (CAP) -
EMEA/H/C/004427/WS2192/0040 ............................................................................. 46
6.5.2. Macitentan - OPSUMIT (CAP) - EMEA/H/C/002697/II/0042, Orphan ............................... 46
6.6. Expedited summary safety reviews ...................................................................... 47

EMEA/H/C/005791/MEA 011.10 ................................................................................. 47
6.6.2. Tozinameran - COMIRNATY (CAP) - EMEA/H/C/005735/MEA 002.11 .............................. 47
7. Post-authorisation safety studies (PASS) 47

7.1. Protocols of PASS imposed in the marketing authorisation(s) .............................. 47
7.1.1. Afamelanotide – SCENESSE (CAP) - EMEA/H/C/PSA/S/0076.1 ....................................... 47
7.1.2. Chlormadinone acetate, ethinylestradiol (NAP) – EMEA/H/N/PSA/J/0072.1...................... 48
7.1.3. Levonorgestrel (NAP) - EMEA/H/N/PSA/S/0073.1 ........................................................ 48
7.1.4. Teduglutide - REVESTIVE (CAP) - EMEA/H/C/PSA/S/0082 ............................................. 48
7.1.5. Tolvaptan - JINARC (CAP) - EMEA/H/C/PSA/S/0078.1 .................................................. 49
7.2. Protocols of PASS non-imposed in the marketing authorisation(s) ...................... 49
7.2.1. Filgotinib - JYSELECA (CAP) - EMEA/H/C/005113/MEA 011.1 ......................................... 49
7.2.2. Liraglutide - SAXENDA (CAP) - EMEA/H/C/003780/MEA 015.4 ....................................... 49
7.2.3. Naltrexone hydrochloride, bupropion hydrochloride - MYSIMBA (CAP) - EMEA/H/C/003687/MEA

003.11 ................................................................................................................... 49
7.2.4. Risdiplam - EVRYSDI (CAP) - EMEA/H/C/005145/MEA 007.1 ......................................... 50
7.2.5. Setmelanotide - IMCIVREE (CAP) - EMEA/H/C/005089/MEA 001 .................................... 50
7.2.6. Tozinameran - COMIRNATY (CAP) - EMEA/H/C/005735/MEA 010.2 ................................ 50
7.2.7. Tozinameran - COMIRNATY (CAP) - EMEA/H/C/005735/MEA 041 ................................... 50
7.2.8. Upadacitinib – RINVOQ (CAP) – EMEA/H/C/004760/MEA 012 ........................................ 51
7.2.9. Upadacitinib - RINVOQ (CAP) - EMEA/H/C/004760/MEA 013 ......................................... 51
7.3. Results of PASS imposed in the marketing authorisation(s) ................................. 51
7.3.1. Aprotinin (NAP) - EMEA/H/N/PSR/S/0030 ................................................................... 51
7.3.2. Human normal immunoglobulin - HYQVIA (CAP) - EMEA/H/C/PSR/S/0037 ...................... 51
7.3.3. Hydroxyethyl starch (HES) (NAP) - EMEA/H/N/PSR/J/0031 ........................................... 52
7.4. Results of PASS non-imposed in the marketing authorisation(s).......................... 52
7.4.2. Coronavirus (COVID-19) vaccine (ChAdOx1-S [recombinant]) - VAXZEVRIA (CAP) -

EMEA/H/C/005675/II/0038 ....................................................................................... 52
7.4.3. Edoxaban - LIXIANA (CAP) - EMEA/H/C/002629/WS2078/0034; ROTEAS (CAP) -
EMEA/H/C/004339/WS2078/0020 ............................................................................. 53

EMA/PRAC/76191/2022 Page 7/69
7.4.4. Empagliflozin - JARDIANCE (CAP) - EMEA/H/C/002677/WS2196/0063; empagliflozin, linagliptin
- GLYXAMBI (CAP) - EMEA/H/C/003833/WS2196/0042; empagliflozin, metformin - SYNJARDY
(CAP) - EMEA/H/C/003770/WS2196/0060 .................................................................. 53
7.4.5. Etanercept - ENBREL (CAP) - EMEA/H/C/000262/II/0244 ............................................. 53
7.4.6. Human papillomavirus vaccine [types 16, 18] (recombinant, adjuvanted, adsorbed) –
CERVARIX (CAP) - EMEA/H/C/000721/II/0114 ............................................................ 54
7.4.7. Naltrexone hydrochloride, bupropion hydrochloride - MYSIMBA (CAP) -

EMEA/H/C/003687/II/0054 ....................................................................................... 54
7.4.8. Romiplostim - NPLATE (CAP) - EMEA/H/C/000942/II/0083 ........................................... 54
7.4.9. Ustekinumab - STELARA (CAP) - EMEA/H/C/000958/II/0091......................................... 54
7.5. Interim results of imposed and non-imposed PASS submitted before the entry into
force of the revised variation regulation ............................................................... 55
7.5.1. Adalimumab - HUMIRA (CAP) - EMEA/H/C/000481/MEA 075.10 .................................... 55
7.5.2. Adalimumab - HUMIRA (CAP) - EMEA/H/C/000481/MEA 080.8 ...................................... 55
7.5.3. Dapagliflozin - EDISTRIDE (CAP) - EMEA/H/C/004161/MEA 009.3 ................................. 55
7.5.4. Dapagliflozin - FORXIGA (CAP) - EMEA/H/C/002322/MEA 004.8 .................................... 55
7.5.5. Filgrastim - NIVESTIM (CAP) - EMEA/H/C/001142/MEA 015.6 ....................................... 56
7.5.6. Pitolisant - WAKIX (CAP) - EMEA/H/C/002616/ANX 001.4 ............................................. 56
7.5.7. Sebelipase alfa - KANUMA (CAP) - EMEA/H/C/004004/ANX 001.5 .................................. 56
7.5.8. Teriflunomide - AUBAGIO (CAP) - EMEA/H/C/002514/MEA 005.3 ................................... 56
7.5.9. Turoctocog alfa pegol - ESPEROCT (CAP) - EMEA/H/C/004883/ANX 001.1 ...................... 57
7.6. Others .................................................................................................................. 57
7.6.1. Acalabrutinib - CALQUENCE (CAP) - EMEA/H/C/005299/MEA 002.2 ................................ 57

EMEA/H/C/005675/MEA 007.4 .................................................................................. 57
7.6.3. Eribulin - HALAVEN (CAP) - EMEA/H/C/002084/MEA 024.2 ........................................... 57
7.6.4. Insulin detemir - LEVEMIR (CAP) - EMEA/H/C/000528/MEA 045.11 ................................ 58
7.7. New Scientific Advice ........................................................................................... 58
7.8. Ongoing Scientific Advice ..................................................................................... 58
7.9. Final Scientific Advice (Reports and Scientific Advice letters) .............................. 58
8. Renewals of the marketing authorisation, conditional renewal and

annual reassessments 58
8.1. Annual reassessments of the marketing authorisation ......................................... 58
8.1.1. Defibrotide - DEFITELIO (CAP) - EMEA/H/C/002393/S/0057 (with RMP) ......................... 58
8.1.2. Lomitapide - LOJUXTA (CAP) - EMEA/H/C/002578/S/0048 (without RMP) ....................... 58
8.1.3. Obiltoxaximab - OBILTOXAXIMAB SFL (CAP) - EMEA/H/C/005169/S/0004 (without RMP) . 59
8.1.4. Susoctocog alfa - OBIZUR (CAP) - EMEA/H/C/002792/S/0044 (without RMP) .................. 59
8.1.5. Tafamidis - VYNDAQEL (CAP) - EMEA/H/C/002294/S/0076 (without RMP) ...................... 59
8.1.6. Tocofersolan - VEDROP (CAP) - EMEA/H/C/000920/S/0041 (without RMP) ...................... 59

8.2. Conditional renewals of the marketing authorisation ........................................... 59

EMA/PRAC/76191/2022 Page 8/69
8.2.1. Onasemnogene abeparvovec - ZOLGENSMA (CAP) - EMEA/H/C/004750/R/0021 (without RMP)
............................................................................................................................. 59
8.2.2. Selumetinib - KOSELUGO (CAP) - EMEA/H/C/005244/R/0003 (without RMP) ................... 60
8.3. Renewals of the marketing authorisation ............................................................. 60
8.3.1. Adalimumab - IMRALDI (CAP) - EMEA/H/C/004279/R/0050 (without RMP) ..................... 60
8.3.2. Atezolizumab - TECENTRIQ (CAP) - EMEA/H/C/004143/R/0069 (without RMP) ................ 60
8.3.3. Brodalumab - KYNTHEUM (CAP) - EMEA/H/C/003959/R/0019 (with RMP) ....................... 60
8.3.4. Cladribine - MAVENCLAD (CAP) - EMEA/H/C/004230/R/0022 (with RMP) ........................ 60
8.3.5. Fampridine - FAMPYRA (CAP) - EMEA/H/C/002097/R/0050 (without RMP) ...................... 61
8.3.6. Ivacaftor - KALYDECO (CAP) - EMEA/H/C/002494/R/0106 (without RMP) ....................... 61
8.3.7. Meningococcal group b vaccine (recombinant, adsorbed) - TRUMENBA (CAP) -

EMEA/H/C/004051/R/0036 (with RMP) ....................................................................... 61
8.3.8. Midostaurin - RYDAPT (CAP) - EMEA/H/C/004095/R/0023 (without RMP) ........................ 61
8.3.9. Rituximab - BLITZIMA (CAP) - EMEA/H/C/004723/R/0049 (without RMP) ....................... 61
8.3.10. Sarilumab - KEVZARA (CAP) - EMEA/H/C/004254/R/0029 (with RMP) ............................ 61
8.3.11. Sofosbuvir, velpatasvir, voxilaprevir - VOSEVI (CAP) - EMEA/H/C/004350/R/0053 (with RMP)

............................................................................................................................. 62

EMEA/H/C/002736/R/0024 (with RMP) ....................................................................... 62
8.3.13. Telotristat ethyl - XERMELO (CAP) - EMEA/H/C/003937/R/0032 (without RMP) ............... 62
9. Product related pharmacovigilance inspections 62

9.1. List of planned pharmacovigilance inspections ..................................................... 62
9.2. Ongoing or concluded pharmacovigilance inspections .......................................... 62
9.3. Others .................................................................................................................. 62
10. Other safety issues for discussion requested by CHMP or EMA 63

10.1. Safety related variations of the marketing authorisation...................................... 63
10.1.1. Infliximab – REMICADE (CAP) - EMEA/H/C/000240/IB/0233 ......................................... 63
10.2. Timing and message content in relation to Member States’ safety announcements63
10.3. Other requests ...................................................................................................... 63
10.4. Scientific Advice ................................................................................................... 63
11. Other safety issues for discussion requested by the Member States63
11.1. Safety related variations of the marketing authorisation...................................... 63
11.2. Other requests ...................................................................................................... 63
12. Organisational, regulatory and methodological matters 64

12.1. Mandate and organisation of the PRAC ................................................................. 64
12.1.1. PRAC membership ................................................................................................... 64

12.1.2. PRAC working group - Best practice guide on using PRAC plenary time efficiently and
effectively – update on the implementation of quantitative goals – Q4 2021 ................... 64

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12.1.3. Vote by proxy ......................................................................................................... 64
12.2. Coordination with EMA Scientific Committees or CMDh-v ..................................... 64
12.3. Coordination with EMA Working Parties/Working Groups/Drafting Groups ......... 64
12.3.1. Classification of post-authorisation studies group (CPAS) - activities overview ................. 64
12.4. Cooperation within the EU regulatory network ..................................................... 64
12.4.1. Coronavirus (COVID-19) pandemic - update ............................................................... 64
12.5. Cooperation with International Regulators........................................................... 64
12.6. Contacts of the PRAC with external parties and interaction with the Interested
Parties to the Committee ...................................................................................... 64
12.7. PRAC work plan .................................................................................................... 65
12.8. Planning and reporting ......................................................................................... 65
12.8.1. EU Pharmacovigilance system - quarterly workload measures and performance indicators – Q4

2021 and predictions ............................................................................................... 65
12.8.2. PRAC workload statistics – Q4 2021 ........................................................................... 65
12.9. Pharmacovigilance audits and inspections ........................................................... 65
12.9.1. Pharmacovigilance systems and their quality systems .................................................. 65
12.9.2. Pharmacovigilance inspections .................................................................................. 65
12.9.3. Pharmacovigilance audits.......................................................................................... 65
12.10. Periodic safety update reports (PSURs) & Union reference date (EURD) list ........ 65
12.10.1. Periodic safety update reports ................................................................................... 65
12.10.2. Granularity and Periodicity Advisory Group (GPAG) ...................................................... 65
12.10.3. PSURs repository ..................................................................................................... 65
12.10.4. Union reference date list – consultation on the draft list ............................................... 66
12.11. Signal management .............................................................................................. 66
12.11.1. Signal management – feedback from Signal Management Review Technical (SMART) Working
Group .................................................................................................................... 66
12.12. Adverse drug reactions reporting and additional reporting .................................. 66
12.12.1. Management and reporting of adverse reactions to medicinal products ........................... 66
12.12.2. Additional monitoring ............................................................................................... 66
12.12.3. List of products under additional monitoring – consultation on the draft list .................... 66
12.13. EudraVigilance database ...................................................................................... 66
12.13.1. Activities related to the confirmation of full functionality ............................................... 66
12.14. Risk management plans and effectiveness of risk minimisations ......................... 66
12.14.1. Risk management systems ....................................................................................... 66
12.14.2. Tools, educational materials and effectiveness measurement of risk minimisations .......... 66
12.14.3. Coronavirus (COVID-19) pandemic - coreRMP19: update.............................................. 67
12.15. Post-authorisation safety studies (PASS) ............................................................. 67
12.15.1. Post-authorisation Safety Studies – imposed PASS ...................................................... 67

12.15.2. Post-authorisation Safety Studies – non-imposed PASS ................................................ 67
12.16. Community procedures ......................................................................................... 67

EMA/PRAC/76191/2022 Page 10/69
12.16.1. Referral procedures for safety reasons ....................................................................... 67
12.17. Renewals, conditional renewals, annual reassessments ....................................... 67
12.18. Risk communication and transparency ................................................................. 67
12.18.1. Public participation in pharmacovigilance .................................................................... 67
12.18.2. Safety communication .............................................................................................. 67
12.19. Continuous pharmacovigilance ............................................................................. 67
12.19.1. Incident management .............................................................................................. 67
12.20. Impact of pharmacovigilance activities ................................................................ 68
12.21. Others .................................................................................................................. 68
12.21.1. EU pharmaceutical legislation – revision of Directive 2001/83/EC and Regulation (EC) No

726/2004 ............................................................................................................... 68
13. Any other business 68

14. Explanatory notes 69

EMA/PRAC/76191/2022 Page 11/69
1. Introduction
1.1. Welcome and declarations of interest of members, alternates and

experts
Pre-meeting list of participants and restrictions in relation to declarations of interests

applicable to the items of the agenda for the PRAC plenary session to be held 07-10
February 2022. See February 2022 PRAC minutes (to be published post March 2022 PRAC
meeting).
1.2. Agenda of the meeting on 07-10 February 2022
Action: For adoption
1.3. Minutes of the previous meeting on 10-13 January 2022
2. EU referral procedures for safety reasons: urgent EU

procedures
2.1. Newly triggered procedures
None
2.2. Ongoing procedures
None
2.3. Procedures for finalisation
None
3. EU referral procedures for safety reasons: other EU referral

procedures
3.1. Newly triggered procedures
3.1.1. Janus kinase (JAK) inhibitors1:

abrocitinib - CIBINQO (CAP); baricitinib - OLUMIANT (CAP); filgotinib - JYSELECA
1
Indicated for the treatment of inflammatory disorders

EMA/PRAC/76191/2022 Page 12/69
(CAP); tofacitinib - XELJANZ (CAP); upadacitinib - RINVOQ (CAP) – EMEA/H/A-
20/1517
Applicant(s): AbbVie Deutschland GmbH & Co. KG (Rinvoq), Eli Lilly Nederland B.V.
(Olumiant), Galapagos N.V. (Jyseleca), Pfizer Europe MA EEIG (Cibinqo, Xeljanz)
PRAC Rapporteur: To be appointed; PRAC Co-rapporteur: To be appointed
Scope: Review of the benefit-risk balance following notification by the European

Commission (EC) of a referral under Article 20 of Regulation (EC) No 726/2004, based on
pharmacovigilance data
Action: For adoption of a list of questions (LoQ)
3.2. Ongoing procedures
3.2.1. Chlormadinone (NAP); chlormadinone, ethinylestradiol (NAP); nomegestrol (NAP);

nomegestrol, estradiol – ZOELY (CAP), NAP - EMEA/H/A-31/1510
Applicant(s): Theramex Ireland Limited (Zoely), various
PRAC Rapporteur: Martin Huber; PRAC Co-rapporteur: Željana Margan Koletić
Scope: Review of the benefit-risk balance following notification by France of a referral under
Article 31 of Directive 2001/83/EC, based on pharmacovigilance data
Action: For adoption of a list of outstanding issues (LoOI)
3.3. Procedures for finalisation
None
3.4. Re-examination procedures2
None
3.5. Others
None
4. Signals assessment and prioritisation3
4.1. New signals detected from EU spontaneous reporting systems
None
2Re-examination of PRAC recommendation under Article 32 of Directive 2001/83/EC

3Each signal refers to a substance or therapeutic class. The route of marketing authorisation is indicated in brackets (CAP for
Centrally Authorised Products; NAP for Nationally Authorised Products including products authorised via Mutual Recognition
Procedures and Decentralised Procedure). Product names are listed for reference Centrally Authorised Products (CAP) only.
PRAC recommendations will specify the products concerned in case of any regulatory action required

EMA/PRAC/76191/2022 Page 13/69
4.2. New signals detected from other sources
4.2.1. Coronavirus (COVID-19) mRNA4 vaccine (nucleoside-modified) - SPIKEVAX (CAP)
Applicant: Moderna Biotech Spain, S.L.
PRAC Rapporteur: To be appointed
Scope: Signal of amenorrhea
Action: For adoption of PRAC recommendation
EPITT 19781 – New signal
Lead Member State(s): DE, DK
4.2.2. Coronavirus (COVID-19) mRNA5 vaccine (nucleoside-modified) - SPIKEVAX (CAP)
Scope: Signal of heavy menstrual bleeding
Lead Member State(s): DE, DK
4.2.3. Tozinameran - COMIRNATY (CAP)
Applicant: BioNTech Manufacturing GmbH
Scope: Signal of amenorrhea
Lead Member State(s): NL, NO
4.2.4. Tozinameran - COMIRNATY (CAP)
Scope: Signal of heavy menstrual bleeding
Lead Member State(s): NL, NO
4 Messenger ribonucleic acid

5
Messenger ribonucleic acid

EMA/PRAC/76191/2022 Page 14/69
4.3. Signals follow-up and prioritisation
4.3.1. Enzalutamide - XTANDI (CAP) - EMEA/H/C/002639/SDA/015
Applicant: Astellas Pharma Europe B.V.
PRAC Rapporteur: Eva Segovia
Scope: Signal of erythema multiforme
EPITT 19734 – Follow-up to October 2021
4.3.2. Obinutuzumab - GAZYVARO (CAP) - EMEA/H/C/002799/SDA/012
Applicant: Roche Registration GmbH
PRAC Rapporteur: Annika Folin
Scope: Signal of non-overt disseminated intravascular coagulation (DIC)
EPITT 19711 – Follow-up to September 2021
4.3.3. Sorafenib - NEXAVAR (CAP) - EMEA/H/C/000690/SDA/041
Applicant: Bayer AG
Scope: Signal of tumour lysis syndrome (TLS)
EPITT 19733 – Follow-up to October 2021
4.3.4. Tocilizumab – ROACTEMRA (CAP)
PRAC Rapporteur: Brigitte Keller-Stanislawski
Scope: Signal of drug reaction with eosinophilia and systemic symptoms
EPITT 19360 – Follow-up to September 2019

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4.4. Variation procedure(s) resulting from signal evaluation
4.4.1. Coronavirus (COVID-19) mRNA6 vaccine (nucleoside-modified) - SPIKEVAX (CAP) -

EMEA/H/C/005791/II/0028
PRAC Rapporteur: Hans Christian Siersted
Scope: Submission of an updated RMP (version 2.1) to include myocarditis and pericarditis
in the list of the safety concerns as an important identified risk, as requested in the
outcome of the signal procedure on myocarditis and pericarditis (EPITT 19713) adopted in
July 2021 (SDA 033)
Action: For adoption of PRAC Assessment Report
5. Risk management plans (RMPs)
5.1. Medicines in the pre-authorisation phase
5.1.1. Bevacizumab - EMEA/H/C/005574
Scope: Treatment of metastatic carcinoma of the colon or rectum, metastatic breast cancer
and recurrence of platinum-sensitive epithelial ovarian, fallopian tube or primary peritoneal
cancer; first-line treatment of patients with unresectable advanced, metastatic or recurrent
non-small cell lung cancer; first line treatment of patients with advanced and/or metastatic
renal cell cancer
Action: For adoption of PRAC RMP AR, PRAC RMP assessment overview and advice to CHMP
5.1.2. Coronavirus (COVID-19) Vaccine (inactivated, adjuvanted, adsorbed) -

EMEA/H/C/006019
Scope: Active immunisation for prevention of coronavirus disease-2019 (COVID-19) caused

by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in individuals 18 years
of age and older
5.1.3. Dabigatran etexilate - EMEA/H/C/005639
Scope: Prevention of venous thromboembolic events
6

EMA/PRAC/76191/2022 Page 16/69
5.1.4. Fosdenopterin - EMEA/H/C/005378, Orphan
Applicant: Comharsa Life Sciences Ltd
Scope (accelerated assessment): Treatment of molybdenum cofactor deficiency type A
5.1.5. Insulin human - EMEA/H/W/005779
Scope: Treatment of diabetes mellitus
5.1.6. Insulin human - EMEA/H/W/005780
Scope: Treatment of diabetes mellitus
5.1.7. Molnupiravir – LAGEVRIO (CAP MAA) - EMEA/H/C/005789
Scope: Treatment of coronavirus disease 2019 (COVID-19)
5.1.8. Olipudase alfa - EMEA/H/C/004850, PRIME, Orphan
Applicant: Genzyme Europe BV
Scope (accelerated assessment): Treatment of non-central nervous system (CNS)

manifestations of acid sphingomyelinase deficiency (ASMD) in paediatric and adult patients
with type A/B or type B
5.1.9. Pirfenidone - EMEA/H/C/005873
Scope: Treatment of mild to moderate idiopathic pulmonary fibrosis (IPF)
5.1.10. Ranibizumab - EMEA/H/C/005610
Scope: Treatment of neovascular age-related macular degeneration in adults

EMA/PRAC/76191/2022 Page 17/69
5.2. Medicines in the post-authorisation phase – PRAC-led procedures
5.2.1. Alogliptin - VIPIDIA (CAP) - EMEA/H/C/002182/WS2191/0029; alogliptin,

metformin - VIPDOMET (CAP) - EMEA/H/C/002654/WS2191/0036; alogliptin,
pioglitazone - INCRESYNC (CAP) - EMEA/H/C/002178/WS2191/0040
Applicant: Takeda Pharma A/S
PRAC Rapporteur: Menno van der Elst
Scope: Submission of an updated RMP (version 11) in order to consolidate it within a single
RMP for Vipidia (alogliptin), Vipdomet (alogliptin/metformin) and Incresync
(alogliptin/pioglitazone) as requested in the conclusions of the PSUR single assessment
(PSUSA) procedure (PSUSA/00010061/202104) finalised in November 2021. The
consolidated RMP is also updated in line with revision 2 of GVP module V on ‘Risk
management systems’ and the targeted follow up questionnaires (FUQ) of severe
hypersensitivity and skin reactions, pancreatitis, hepatic events and follow up
gastrointestinal events and infections is removed. Finally, the removal of the inverted black
triangle as agreed other procedures is reflected in the RMP

EMEA/H/C/005791/II/0022
Scope: Submission of an updated RMP (version 2.0) to include clinical safety data from
study mRNA-1273 P203 (NCT04649151): a phase 2/3, randomised, observer-blind,
placebo-controlled study evaluating the safety, reactogenicity and effectiveness of the
mRNA-1273 vaccine in healthy adolescents aged ≥ 12 to < 18 years
5.2.3. Nintedanib - VARGATEF (CAP) - EMEA/H/C/002569/II/0044
Applicant: Boehringer Ingelheim International GmbH
PRAC Rapporteur: Georgia Gkegka
Scope: Submission of an updated RMP (version 10.0) in order to remove safety concerns
that were classified as important identified risks, important potential risks and missing
information, based on cumulative post-marketing experience. The MAH also proposed an
update of the anatomical therapeutic chemical (ATC) code, an update of post-marketing
exposure, the removal of adverse event follow-up forms and an update of search strategies
5.2.4. Pandemic influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted) -

FOCLIVIA (CAP) - EMEA/H/C/001208/WS2151/0068; prepandemic influenza vaccine
7

EMA/PRAC/76191/2022 Page 18/69
(H5N1) (surface antigen, inactivated, adjuvanted) - AFLUNOV (CAP) -
EMEA/H/C/002094/WS2151/0071
Applicant: Seqirus S.r.l
PRAC Rapporteur: Amelia Cupelli
Scope: Submission of an updated RMP (version 3.9) in order to align safety concerns of
Aflunov (prepandemic influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted))
and Foclivia (pandemic influenza vaccine (H5N1) (surface antigen, inactivated, adjuvanted))
and to reclassify some potential risks in line with revision 2 of GVP module V on ‘Risk
management systems’. In addition, reference to adverse drug reaction follow-up forms for
routine pharmacovigilance activity are removed
5.3. Medicines in the post-authorisation phase – CHMP-led procedures
5.3.1. Acalabrutinib - CALQUENCE (CAP) - EMEA/H/C/005299/X/0009/G
Applicant: AstraZeneca AB
PRAC Rapporteur: Željana Margan Koletić
Scope: Grouped application consisting of: 1) extension application to introduce a new

pharmaceutical form, film-coated tablet; 2) change of the anatomical therapeutic chemical
(ATC) code for acalabrutinib from L01XE51 to L01EL02. The RMP (version 4.1) is updated
accordingly
5.3.2. Aflibercept - EYLEA (CAP) - EMEA/H/C/002392/II/0077/G
Applicant: Bayer AG
PRAC Rapporteur: Nathalie Gault
Scope: Grouped applications consisting of: 1) extension of indication to include as a

paediatric indication retinopathy of prematurity (ROP). As a consequence, sections 2, 4.1,
4.2, 4.4, 4.5, 4.8, 5.1, 5.2, 5.3 and 6.6 of the SmPC are updated. The package leaflet and
the RMP (version 32.1) are updated in accordance. Separate package leaflet is proposed for
the guardians of preterm babies; 2) addition of a stand-alone paediatric dosing device,
which will be CE marked and cross-labelled to the EU product information
5.3.3. Apalutamide - ERLEADA (CAP) - EMEA/H/C/004452/II/0017
Applicant: Janssen-Cilag International N.V.
PRAC Rapporteur: Tiphaine Vaillant
Scope: Update of section 5.3 of the SmPC in order to update non-clinical information based
on final results from study TOX11338 (in completion of MEA 006): a 2-year study to better

EMA/PRAC/76191/2022 Page 19/69
characterize the carcinogenic potential of JNJ-56021927-AAA (apalutamide) by oral gavage
in rats. The RMP (version 4.1) is updated accordingly. In addition, the MAH took the
opportunity to include general information in the RMP regarding study TITAN (PCR3002): a
phase 3 randomized, placebo-controlled, double-blind study of apalutamide plus androgen
deprivation therapy (ADT) versus ADT in subjects with metastatic hormone-sensitive
prostate cancer (mHSPC)
5.3.4. Axicabtagene ciloleucel - YESCARTA (CAP) - EMEA/H/C/004480/II/0042, Orphan
Applicant: Kite Pharma EU B.V., ATMP8
PRAC Rapporteur: Anette Kirstine Stark
Scope: Extension of indication to include the treatment of adult patients with relapsed or
refractory follicular lymphoma (FL) after three or more lines of systemic therapy. As a
consequence, sections 4.1, 4.8, 5.1 and 5.2 of the SmPC, Annex II-D on ‘Conditions or
restrictions with regard to the safe and effective use of the medicinal product’ and the
package leaflet are updated. The RMP (version 5.1) is updated in accordance. In addition,
the applicant took the opportunity to make minor editorial corrections throughout the SmPC
and package leaflet to align with the latest quality review of documents (QRD) template
(version 10.2)
Action: For adoption of PRAC RMP AR, PRAC RMP assessment overview and advice to CAT
and CHMP
Scope: Extension of indication to include treatment of adult patients with relapsed or

refractory (r/r) diffuse large B-cell lymphoma (DLBCL) and high-grade B-cell lymphoma
(HGBL). As a consequence, sections 4.1, 4.2, 4.8, 5.1 and 5.2 of the SmPC are updated.
The package leaflet and the RMP (version 5.3) are updated in accordance. In addition, the
MAH took the opportunity to update the product information with minor editorial changes
Action: For adoption of PRAC RMP AR, PRAC RMP assessment overview and advice to CAT
and CHMP
5.3.6. Baloxavir marboxil - XOFLUZA (CAP) - EMEA/H/C/004974/X/0003/G
PRAC Rapporteur: Sonja Hrabcik
Scope: Grouped applications consisting of: 1) extension application to add a new strength of
80 mg; 2) addition of a new pack size of 1 tablet for 40 mg strength. The RMP (version 1.2)
is updated in accordance. Furthermore, the product information is brought in line with the
latest quality review of documents (QRD) template (version 10.2) to update the local
8 Advanced therapy medicinal product

9
Advanced therapy medicinal product

EMA/PRAC/76191/2022 Page 20/69
representatives with ‘United Kingdom (Northern Ireland)’
5.3.7. Brolucizumab - BEOVU (CAP) - EMEA/H/C/004913/II/0010
Applicant: Novartis Europharm Limited
Scope: Extension of indication to include treatment of visual impairment due to diabetic

macular oedema (DME). As a consequence, sections 4.1, 4.4, 4.8 and 5.1 of the SmPC are
updated. The package leaflet and the RMP (version 4.0) are updated in accordance
5.3.8. Buprenorphine - BUVIDAL (CAP) - EMEA/H/C/004651/II/0017
Applicant: Camurus AB
Scope: Extension of indication to include treatment of moderate to severe chronic pain in

patients with opioid dependence. As a consequence, sections 4.1, 4.2, 4.5, 5.1 and 6.6 of
the SmPC are updated. The package leaflet and the RMP (version 2.1) are updated
accordingly
5.3.9. Cabozantinib - CABOMETYX (CAP) - EMEA/H/C/004163/II/0023
Applicant: Ipsen Pharma
Scope: Extension of indication to include monotherapy treatment of adults and adolescent

patients aged 12 years and older, with locally advanced or metastatic differentiated thyroid
carcinoma (DTC), refractory or not eligible to radioactive iodine (RAI) who have progressed
during or after prior systemic therapy. As a consequence, sections 4.1, 4.2, 4.4, 4.8, 5.1
and 5.2 of the SmPC are updated. The package leaflet and the RMP (version 6.0) are
updated in accordance
5.3.10. Cariprazine - REAGILA (CAP) - EMEA/H/C/002770/II/0023
Applicant: Gedeon Richter Plc.
PRAC Rapporteur: Ana Sofia Diniz Martins
Scope: Update of sections 4.4, 4.5, 4.6 and 5.2 of the SmPC in order to update
pharmacokinetic information based on final results from RGH-188-302 (CAROLA) study
(listed as a category 3 study in the RMP): an open-label, single-arm, fixed-sequence, phase
1 trial in female schizophrenia patients to investigate the effect of multiple-dose
administration of cariprazine on the pharmacokinetics of a combined oral contraceptive

EMA/PRAC/76191/2022 Page 21/69
containing ethinylestradiol and levonorgestrel. The package leaflet and the RMP (version
2.0) are updated accordingly. In addition, the MAH took the opportunity to implement minor
editorial changes in the SmPC and the package leaflet
5.3.11. Cemiplimab - LIBTAYO (CAP) - EMEA/H/C/004844/II/0026
Applicant: Regeneron Ireland Designated Activity Company (DAC)
Scope: Extension of indication to include monotherapy treatment of adult patients with

recurrent or metastatic cervical cancer with disease progression on or after chemotherapy.
As a consequence, sections 4.1, 4.2, 4.4, 4.5, 4.8, 5.1 and 5.2 of the SmPC are updated.
The package leaflet and the RMP (version 3.0) are updated in accordance

EMEA/H/C/005791/II/0041
Scope: Extension of indication to include use in children of 6-11 years of age based on data
from study mRNA-1273-P204: an ongoing phase 2/3, 2-part, open-label, dose-escalation,
age de-escalation and subsequent randomised, observer-blind, placebo-controlled
expansion study to evaluate the safety, tolerability, reactogenicity, and effectiveness of
mRNA-1273 in healthy children. As a consequence, sections 4.1, 4.2, 4.8 and 5.1 of the
SmPC are updated. The package leaflet and the RMP (version 1.3) are updated in
accordance
5.3.13. Crizotinib - XALKORI (CAP) - EMEA/H/C/002489/II/0072
Applicant: Pfizer Europe MA EEIG
Scope: Extension of indication to include treatment of paediatric patients aged ≥ 6 to < 18

years with relapsed or refractory systemic anaplastic lymphoma kinase (ALK)-positive
anaplastic large cell lymphoma (ALCL) and with unresectable, recurrent, or refractory ALK-
positive inflammatory myofibroblastic tumour (IMT) based on the results from: 1) study
ADVL0912: a phase 1/2 study of crizotinib, an oral small molecule inhibitor of ALK and C-
Met, in children with relapsed/refractory solid tumours and anaplastic large cell lymphoma;
2) study A8081013: a phase 1b open-label study of the safety and clinical activity of
crizotinib in tumours with genetic events involving the ALK gene locus. As a consequence,
sections 4.1, 4.2, 4.4, 4.8, 5.1 and 5.2 of the SmPC are updated. The package leaflet and
the RMP (version 8.0) are updated in accordance. In addition, the MAH took the opportunity
10

EMA/PRAC/76191/2022 Page 22/69
to update the anatomical therapeutic chemical (ATC) code for crizotinib. Moreover, the MAH
took the opportunity to implement a minor change in the list of local representatives in the
package leaflet
5.3.14. Denosumab - PROLIA (CAP) - EMEA/H/C/001120/II/0093
Applicant: Amgen Europe B.V.
PRAC Rapporteur: Ulla Wändel Liminga
Scope: Update of sections 4.2 and 4.4 of the SmPC in order to change the posology
recommendation for paediatric population and add a new warning on hypercalcaemia in
paediatric patients with osteogenesis imperfecta (OI) following an urgent safety measure
regarding the risk of hypercalcaemia reported very commonly in ongoing clinical trials in
paediatric patients with OI treated with denosumab. The package leaflet and the RMP
(version 29.0) are updated accordingly. In addition, the MAH took the opportunity to update
the list of local representatives in the package leaflet and to implement minor editorial
changes in the labelling
5.3.15. Doravirine - PIFELTRO (CAP) - EMEA/H/C/004747/WS2065/0019; doravirine,

lamivudine, tenofovir disoproxil - DELSTRIGO (CAP) -
EMEA/H/C/004746/WS2065/0026
Applicant: Merck Sharp & Dohme B.V.
Scope: Extension of indication to extend the indication to the paediatric population weighing
at least 35 kg. As a consequence, sections 4.1, 4.2, 4.8, 5.1 and 5.2 of the SmPC are
updated. The package leaflet and the RMP (version 2.1) are updated in accordance. In
addition, the MAH took the opportunity to make minor editorial corrections and to update
the list of local representatives in the package leaflet
5.3.16. Eribulin - HALAVEN (CAP) - EMEA/H/C/002084/II/0060
Applicant: Eisai GmbH
Scope: Update of sections 4.2, 5.1 and 5.2 of the SmPC in order to update efficacy and
pharmacokinetic information based on results in the paediatric population (6 months to <18
years) from: 1) study E7389-A001-113: A phase 1 study of eribulin mesylate, a novel
microtubule targeting chemotherapeutic agent in children with refractory or recurrent solid
tumours, including lymphomas; 2) study E7389-G000-223: a phase 2, multicentre, open-
label study to assess safety and preliminary activity of eribulin mesylate in paediatric
subjects with relapsed/refractory rhabdomyosarcoma (RMS), non-rhabdomyosarcoma soft
tissue sarcoma (NRSTS) and Ewing sarcoma (EWS); 3) study E7389-G000-213: a phase 1/2
single-arm study evaluating the safety and efficacy of eribulin mesilate in combination with

EMA/PRAC/76191/2022 Page 23/69
irinotecan in children with refractory or recurrent solid tumours. The package leaflet and the
RMP (version 6.0) are updated accordingly
5.3.17. Gilteritinib - XOSPATA (CAP) - EMEA/H/C/004752/II/0007, Orphan
PRAC Rapporteur: Martin Huber
Scope: Submission of the report of an integrated analysis to demonstrate the safety of long
term treatment with gilteritinib when all patients enrolled in studies 2215-CL-0101, 2215-
CL-0102 and 2215-CL-0301 have completed at least 3 years of treatment with gilteritinib or
have withdrawn prior to completing at least 3 years of treatment. The studies refer to: 1)
study 2215-CL-0101: a phase 1/2 open-label, dose escalation study investigating the
safety, tolerability, pharmacokinetics, and pharmacodynamics of ASP2215 (gilteritinib) in
patients with relapsed or refractory acute myeloid leukaemia (AML); 2) study 2215-CL-
0102: a phase 1 open-label, dose escalation study investigating the safety, tolerability,
pharmacokinetics, and pharmacodynamics of ASP2215 in Japanese patients with relapsed or
refractory AML; 3) study 2215-CL-0301: a phase 3 open-label, multicentre, randomized
study of ASP2215 versus salvage chemotherapy in patients with relapsed or refractory AML
with FMS-like tyrosine kinase 3 (FLT3) mutation. The RMP (version 2.0) is updated in order
to address the missing information regarding the safety of Xospata (gilteritinib)
5.3.18. Ipilimumab - YERVOY (CAP) - EMEA/H/C/002213/WS2113/0090; nivolumab -

OPDIVO (CAP) - EMEA/H/C/003985/WS2113/0108;
Applicant: Bristol-Myers Squibb Pharma EEIG
Scope: Extension of indication to include first-line treatment of adult patients with

unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma
(OSCC) for Opdivo (nivolumab) in combination with Yervoy (ipilimumab). As a consequence,
sections 4.1, 4.2, 4.4, 4.8 and 5.1 of the SmPC are updated. The package leaflet and the
RMP (version 24.0 for Opdivo and version 33.0 for Yervoy) are updated in accordance
5.3.19. Ipilimumab - YERVOY (CAP) - EMEA/H/C/002213/WS2153/0093; nivolumab -

OPDIVO (CAP) - EMEA/H/C/003985/WS2153/0111;
Scope: Update of sections 4.2, 4.8 and 5.1 of the SmPC based on final results from study
CA209908: a phase 1b/2 clinical trial of nivolumab monotherapy and nivolumab in
combination with ipilimumab in paediatric subjects with high grade primary central nervous
system (CNS) malignancies. The RMP (version 22.3 for Opdivo) is updated in accordance

EMA/PRAC/76191/2022 Page 24/69
5.3.20. Ivacaftor, tezacaftor, elexacaftor - KAFTRIO (CAP) - EMEA/H/C/005269/II/0017/G,
Orphan
Applicant: Vertex Pharmaceuticals (Ireland) Limited
Scope: Grouped variations consisting of: 1) update of section 5.3 of the SmPC in order to
update the non-clinical information based on final results from study VX-445-TX-015: a 2-
year oral carcinogenicity study in rats evaluating the carcinogenic potential of up to
10 mg/kg/day of elexacaftor. The RMP (version 6.0) is updated accordingly; 2) submission
of the final report for study VX-661-TX-038: a tezacaftor juvenile toxicity study
5.3.21. Lomitapide - LOJUXTA (CAP) - EMEA/H/C/002578/II/0046
Applicant: Amryt Pharmaceuticals DAC
Scope: Submission of an alternative study: an evaluation of the effect of lomitapide

treatment on major adverse cardiovascular events (MACE) in patients with homozygous
familial hypercholesterolemia (LILITH) to the currently agreed protocol for study on the
effects of lomitapide on carotid and aortic atherosclerosis in patients treated with lomitapide
in usual care (CAPTURE) in order to propose an evaluation of the effect of lomitapide
treatment on MACE in patients with homozygous familial hypercholesterolemia. As a
consequence, Annex II-D and the RMP (version 6.4) are updated accordingly. In addition,
the MAH took the opportunity to bring the product information in line with the latest quality
review of documents (QRD) template (version 10.2)
5.3.22. Lumasiran - OXLUMO (CAP) - EMEA/H/C/005040/II/0008, Orphan
Applicant: Alnylam Netherlands B.V.
Scope: Update of sections 4.2, 4.4, 4.8, 5.1 and 5.2 of the SmPC in order to clarify
administration instructions, remove an existing warning on metabolic acidosis in patients
with severe or end stage renal impairment, update the description of adverse reactions
injection site reactions, abdominal pain and immunogenicity, update efficacy and
pharmacokinetic information based on: 1) interim results from study ALN-GO1-005
(ILLUMINATE-C) (listed as a category 3 study in the RMP): a single arm study to evaluate
efficacy, safety, pharmacokinetics, and pharmacodynamics of lumasiran in patients with
advanced primary hyperoxaluria type 1 (PH1); 2) available long-term efficacy and safety
data from ongoing studies: study ALN-GO1-003 (ILLUMINATE-A): a phase 3 randomized,
double-blind, placebo-controlled study with an extended dosing period to evaluate the
efficacy and safety of lumasiran in children and adults with PH1 and study ALN-GO1-004
(ILLUMINATE-B): an open-label study to evaluate the efficacy, safety, pharmacokinetics,
and pharmacodynamics of lumasiran in infants and young children with primary PH1; 3)
study ALN-GO1-002: a phase 2, multicentre, open-label, extension study to evaluate the
long-term administration of ALN-GO1 (lumasiran) in patients with PH. The package leaflet

EMA/PRAC/76191/2022 Page 25/69
and the RMP (version 1.1) are updated in accordance
5.3.23. Mepolizumab - NUCALA (CAP) - EMEA/H/C/003860/X/0042
Applicant: GlaxoSmithKline Trading Services Limited
Scope: Extension application to introduce a new strength of 40 mg for Nucala

(mepolizumab) solution for injection in a pre-filled syringe for subcutaneous use to be used
in children aged 6 to 11 years. The RMP (version 8.0) is updated accordingly
5.3.24. Neratinib - NERLYNX (CAP) - EMEA/H/C/004030/II/0027
Applicant: Pierre Fabre Medicament
Scope: Update of section 5.1 of the SmPC in order to update the pharmacokinetic
information with descriptive diarrhoea characteristics based on final results from study
PUMA-NER-6201 (CONTROL) (listed as a category 3 study in the RMP):an open-label study
to characterize the incidence and severity of diarrhoea in patients with early stage human
epidermal growth factor receptor-2+ (HER2+) breast cancer treated with neratinib and
loperamide. The RMP (version 2.1) is updated accordingly. In addition, the MAH took the
opportunity to introduce editorial updates in the product information
5.3.25. Niraparib - ZEJULA (CAP) - EMEA/H/C/004249/II/0033, Orphan
Applicant: GlaxoSmithKline (Ireland) Limited
PRAC Rapporteur: Jan Neuhauser
Scope: Update of sections 4.4 and 4.8 of the SmPC in order to amend an existing warning
and add myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) to the list of
adverse drug reactions (ADRs) with a frequency common, and update of section 5.1 based
on final results from study 213356 (NOVA): a phase 3 randomized double-blind trial of
maintenance with niraparib versus placebo in patients with platinum sensitive ovarian
cancer. In addition, the MAH also took this opportunity to amend section 4.4 and 4.6 to
update information on contraception based on EMA and Clinical Trials Facilitation and
Coordination Group (CTFG) recommendations. The package leaflet and the RMP (version
6.0) are updated accordingly
5.3.26. Nivolumab - OPDIVO (CAP) - EMEA/H/C/003985/II/0107

EMA/PRAC/76191/2022 Page 26/69
Scope: Extension of indication to include in combination with fluoropyrimidine- and
platinum-based combination chemotherapy the first-line treatment of adult patients with
unresectable advanced, recurrent or metastatic oesophageal squamous cell carcinoma
(OSCC) based on study CA209648: a randomized phase 3 study of nivolumab plus
ipilimumab or nivolumab combined with fluorouracil plus cisplatin versus fluorouracil plus
cisplatin in subjects with unresectable advanced, recurrent or metastatic previously
untreated oesophageal squamous cell carcinoma. As a consequence, sections 4.1, 4.2, 4.4,
4.8, 5.1 and 6.6 of the SmPC are updated. The package leaflet and the RMP (version 25.0)
are updated in accordance
5.3.27. Octocog alfa - KOVALTRY (CAP) - EMEA/H/C/003825/II/0038
Applicant: Bayer AG
Scope: Update of sections 4.8 and 5.1 of the SmPC to include data from LEOPOLD kids part
B: a long term efficacy open-label programme in severe haemophilia A disease (previously
submitted as Art 46; an addendum on biomarker data is included in this submission) and
extension study results. In addition, an editorial revision in section 4.2 and a clarification in
section 6.5 of the SmPC are proposed. The package leaflet is updated accordingly. The MAH
took the opportunity to correct a typo in the Greek product information. The RMP (version
4.1) is updated and brought in line with revision 2.0.1 of the guidance on the format of RMP
in the EU (template)
5.3.28. Padeliporfin - TOOKAD (CAP) - EMEA/H/C/004182/II/0015
Applicant: STEBA Biotech S.A
PRAC Rapporteur: Maia Uusküla
Scope: Submission of the clinical study report for study CLIN1001 PCM301FU5 (listed as a
post-authorisation efficacy study (PAES), category 1 study in Annex II): a European
randomised phase 3 study to assess the efficacy and safety of Tookad (padeliporfin) soluble
for localised prostate cancer compared to active surveillance. Annex II is updated to remove
reference to this study. The RMP (version 8.0) is updated accordingly
5.3.29. Palbociclib - IBRANCE (CAP) - EMEA/H/C/003853/II/0037
Scope: Submission of the final report from study A5481027 (listed as a category 3 study in
the RMP): a multicentre, randomized, double-blind, phase 3 study of palbociclib plus
letrozole versus placebo plus letrozole for the treatment of previously untreated Asian
postmenopausal women with estrogen receptor (ER)-positive, human epidermal growth
factor receptor-2 (HER2)-negative advanced breast cancer to evaluate the effect of

EMA/PRAC/76191/2022 Page 27/69
palbociclib on hyperglycaemia (in fulfilment of MEA 001). The RMP (version 1.8) is updated
accordingly
5.3.30. Parathyroid hormone - NATPAR (CAP) - EMEA/H/C/003861/II/0029, Orphan
Applicant: Takeda Pharmaceuticals International AG
PRAC Rapporteur: Rhea Fitzgerald
Scope: Submission of the final results of study SHP634-101: an open-label, randomised,

crossover study to assess the pharmacokinetic and pharmacodynamic profiles of once-daily
and twice-daily dose regimens of recombinant human parathyroid hormone (rhPTH[1-84])
administered subcutaneously to subjects with hypoparathyroidism. Further clinical
evaluation of an alternative dosing regimen is no longer warranted, as outlined in the
current specific obligation (study SHP634-403). The conditional marketing authorisation can
therefore be converted into a standard marketing authorisation (no longer subject to a
specific obligation) valid for 5 years. The RMP (version 3.2) is updated accordingly
5.3.31. Polatuzumab vedotin - POLIVY (CAP) - EMEA/H/C/004870/II/0012, Orphan
Scope: Extension of indication to include treatment of adult patients with previously

untreated diffuse large B-cell lymphoma (DLBCL) in combination with rituximab,
cyclophosphamide, doxorubicin, and prednisone based on the efficacy and safety data from
pivotal study GO39942 (POLARIX): a phase 3, multicentre, randomized, double-blind,
placebo-controlled trial comparing the efficacy and safety of polatuzumab vedotin in
combination with rituximab and cyclophosphamide, doxorubicin and prednisone (CHP) (R-
CHP) versus rituximab and cyclophosphamide, doxorubicin, vincristine and prednisone
(CHOP) (R-CHOP) in previously untreated patients with diffuse large B-cell lymphoma. This
submission fulfils SOB003 supporting the switch from conditional marketing authorisation to
full marketing authorisation. As a consequence, the SmPC, Annex II and the package leaflet
are revised. The RMP (version 2.0) is updated in accordance
5.3.32. Selpercatinib - RETSEVMO (CAP) - EMEA/H/C/005375/II/0011
Applicant: Eli Lilly Nederland B.V.
Scope: Extension of indication to include first-line treatment of rearranged during

transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) based on results from
study LIBRETTO-001: an open-label, multicentre, global phase 1/2 study of selpercatinib in
patients with RET-altered advanced solid tumours. As a consequence, sections 4.1, 4.5, 4.8
and 5.1 of the SmPC are updated. The package leaflet and the RMP (version 1.1) are
updated in accordance

EMA/PRAC/76191/2022 Page 28/69
5.3.33. Tenofovir disoproxil - VIREAD (CAP) - EMEA/H/C/000419/II/0204
Applicant: Gilead Sciences Ireland UC
Scope: Submission of the final study report for study GS-US-174-0144 (listed as category 3
study in the RMP): a randomised, double-blind evaluation of the antiviral efficacy, safety
and tolerability of tenofovir disporoxil fumarate. This application fulfils the Article 46
commitment to provide the final week 192 study results for clinical measure ‘study 5’ (study
GS_US_174-0144) listed in the paediatric investigation plan (PIP). As a consequence,
section 5.1 of the SmPC is updated accordingly. Additionally, the risk minimisation
measures for paediatrics are removed from the RMP and Annex II of the product
information. The package leaflet and the RMP (version 25.1) are updated accordingly. In
addition, the MAH took the opportunity to implement minor linguistic amendments
throughout the product information. Furthermore, the expression of lactose content in
Annex I for the tablets was changed to refer to lactose base (not as monohydrate) in line
with current practice
5.3.34. Tildrakizumab - ILUMETRI (CAP) - EMEA/H/C/004514/X/0023
Applicant: Almirall S.A
PRAC Rapporteur: Adam Przybylkowski
Scope: Extension application to introduce a new strength (200 mg solution for injection).
The RMP (version 1.0) is updated accordingly
6. Periodic safety update reports (PSURs)
6.1. PSUR single assessment (PSUSA) procedures including centrally

authorised products (CAPs) only
6.1.1. Aclidinium bromide - BRETARIS GENUAIR (CAP); EKLIRA GENUAIR (CAP) -

PSUSA/00009005/202107
Applicant(s): AstraZeneca AB
Scope: Evaluation of a PSUSA procedure
Action: For adoption of recommendation to CHMP

EMA/PRAC/76191/2022 Page 29/69
6.1.2. Alectinib - ALECENSA (CAP) - PSUSA/00010581/202107
PRAC Rapporteur: Jana Lukacisinova
6.1.3. Alirocumab - PRALUENT (CAP) - PSUSA/00010423/202107
Applicant: Sanofi-aventis groupe
6.1.4. Asfotase alfa - STRENSIQ (CAP) - PSUSA/00010421/202107
Applicant: Alexion Europe SAS
6.1.5. Atazanavir - REYATAZ (CAP) - PSUSA/00000258/202106
6.1.6. Autologous peripheral blood T cells CD114 and CD8 selected and CD3 and CD28
activated transduced with retroviral vector expressing anti-CD19 CD28/CD3-zeta
chimeric antigen receptor and cultured - TECARTUS (CAP) -
PSUSA/00010903/202107
Action: For adoption of recommendation to CAT and CHMP
11 Cluster of differentiation
12

EMA/PRAC/76191/2022 Page 30/69
6.1.7. Avapritinib - AYVAKYT (CAP) - PSUSA/00010878/202107
Applicant: Blueprint Medicines (Netherlands) B.V.
6.1.8. Beclometasone, formoterol, glycopyrronium bromide - RIARIFY (CAP); TRIMBOW

(CAP); TRYDONIS (CAP) - PSUSA/00010617/202107
Applicant(s): Chiesi Farmaceutici S.p.A.
6.1.9. Birch bark extract13 - EPISALVAN (CAP) - PSUSA/00010446/202107
Applicant: Amryt GmbH
PRAC Rapporteur: Zane Neikena
6.1.10. Brexpiprazole - RXULTI (CAP) - PSUSA/00010698/202107
Applicant: Otsuka Pharmaceutical Netherlands B.V.
PRAC Rapporteur: Marek Juracka
6.1.11. Brodalumab - KYNTHEUM (CAP) - PSUSA/00010616/202107
Applicant: LEO Pharma A/S
6.1.12. Budesonide14 - JORVEZA (CAP) - PSUSA/00010664/202107
Applicant: Dr. Falk Pharma GmbH
13 Centrally authorised product(s) only

14
Centrally authorised product(s) only

EMA/PRAC/76191/2022 Page 31/69
PRAC Rapporteur: Zane Neikena
6.1.13. Canakinumab - ILARIS (CAP) - PSUSA/00000526/202106
6.1.14. Carfilzomib - KYPROLIS (CAP) - PSUSA/00010448/202107
PRAC Rapporteur: Nikica Mirošević Skvrce
6.1.15. Cenegermin - OXERVATE (CAP) - PSUSA/00010624/202107
Applicant: Dompe farmaceutici S.p.A.
6.1.16. Cladribine15 - MAVENCLAD (CAP) - PSUSA/00010634/202107
Applicant: Merck Europe B.V.
PRAC Rapporteur: Marcia Sofia Sanches de Castro Lopes Silva
6.1.17. Gefitinib - IRESSA (CAP) - PSUSA/00001518/202107
15
For treatment of multiple sclerosis only

EMA/PRAC/76191/2022 Page 32/69
6.1.18. Glecaprevir, pibrentasvir - MAVIRET (CAP) - PSUSA/00010620/202107
Applicant: AbbVie Deutschland GmbH & Co. KG
6.1.19. Glucagon16 - BAQSIMI (CAP); OGLUO (CAP) - PSUSA/00010826/202107
Applicant(s): Eli Lilly Nederland B.V. (Baqsimi), Tetris Pharma B.V. (Ogluo)
6.1.20. Guselkumab - TREMFYA (CAP) - PSUSA/00010652/202107
6.1.21. Human plasma protease C1 inhibitor - CINRYZE (CAP) - PSUSA/00010104/202106
Applicant: Shire Services BVBA
6.1.22. Ibandronic acid - BONDRONAT (CAP); BONVIVA (CAP) - PSUSA/00001702/202106
Applicant(s): Atnahs Pharma Netherlands B.V.
6.1.23. Icosapent ethyl - VAZKEPA (CAP) - PSUSA/00010922/202107
Applicant: Amarin Pharmaceuticals Ireland Limited
16
Centrally authorised product(s) only

EMA/PRAC/76191/2022 Page 33/69
6.1.24. Idursulfase - ELAPRASE (CAP) - PSUSA/00001722/202107
Applicant: Shire Human Genetic Therapies AB
PRAC Rapporteur: Liana Gross-Martirosyan
6.1.25. Imipenem, cilastatin, relebactam - RECARBRIO (CAP) - PSUSA/00010830/202107
6.1.26. Indacaterol, glycopyrronium, mometasone - ENERZAIR BREEZHALER (CAP);

ZIMBUS BREEZHALER (CAP) - PSUSA/00010861/202107
Applicant(s): Novartis Europharm Limited
6.1.27. Inotersen - TEGSEDI (CAP) - PSUSA/00010697/202107
Applicant: Akcea Therapeutics Ireland Limited
6.1.28. L-lysine hydrochloride, L-arginine hydrochloride - LYSAKARE (CAP) -

PSUSA/00010786/202107
Applicant: Advanced Accelerator Applications

EMA/PRAC/76191/2022 Page 34/69
6.1.29. Lonoctocog alfa - AFSTYLA (CAP) - PSUSA/00010559/202107
Applicant: CSL Behring GmbH
PRAC Rapporteur: Sonja Hrabcik
6.1.30. Macimorelin - GHRYVELIN (CAP) - PSUSA/00010746/202107
Applicant: Consilient Health Limited
6.1.31. Mirabegron - BETMIGA (CAP) - PSUSA/00010031/202106
PRAC Rapporteur: Maria del Pilar Rayon
6.1.32. Neratinib - NERLYNX (CAP) - PSUSA/00010712/202107
Applicant: Pierre Fabre Medicament
6.1.33. Nivolumab - OPDIVO (CAP) - PSUSA/00010379/202107
6.1.34. Osilodrostat - ISTURISA (CAP) - PSUSA/00010820/202107
Applicant: Recordati Rare Diseases

EMA/PRAC/76191/2022 Page 35/69
6.1.35. Paliperidone - INVEGA (CAP); paliperidone palmitate - BYANNLI (CAP); TREVICTA

(CAP); XEPLION (CAP) - PSUSA/00002266/202106
Applicant(s): Janssen-Cilag International N.V.
6.1.36. Peginterferon beta-1a - PLEGRIDY (CAP) - PSUSA/00010275/202107
Applicant: Biogen Netherlands B.V.
6.1.37. Perampanel - FYCOMPA (CAP) - PSUSA/00009255/202107
6.1.38. Remimazolam - BYFAVO (CAP) - PSUSA/00010924/202107
Applicant: PAION Netherlands B.V.
6.1.39. Romosozumab - EVENITY (CAP) - PSUSA/00010824/202107
Applicant: UCB Pharma S.A.

EMA/PRAC/76191/2022 Page 36/69
6.1.40. Salmeterol, fluticasone propionate17 - BROPAIR SPIROMAX (CAP); SEFFALAIR
SPIROMAX (CAP) - PSUSA/00010928/202107
Applicant(s): Teva B.V.
PRAC Rapporteur: Ilaria Baldelli
6.1.41. Saxagliptin, dapagliflozin - QTERN (CAP) - PSUSA/00010520/202107
PRAC Rapporteur: Ilaria Baldelli
6.1.42. Sofosbuvir, velpatasvir, voxilaprevir - VOSEVI (CAP) - PSUSA/00010619/202107

PSUSA/00010630/202107
Applicant: CO.DON AG, ATMP18
6.1.44. Tagraxofusp - ELZONRIS (CAP) - PSUSA/00010896/202107
Applicant: Stemline Therapeutics B.V.
17 Centrally authorised product(s) only

18

EMA/PRAC/76191/2022 Page 37/69
6.1.45. Tasimelteon - HETLIOZ (CAP) - PSUSA/00010394/202107
Applicant: Vanda Pharmaceuticals Netherlands B.V.
6.1.46. Tobramycin19 - TOBI PODHALER (CAP) - PSUSA/00009315/202106
Applicant: Mylan IRE Healthcare Limited
6.1.47. Voretigene neparvovec - LUXTURNA (CAP) - PSUSA/00010742/202107
Applicant: Novartis Europharm Limited, ATMP20
6.2. PSUR single assessment (PSUSA) procedures including centrally

authorised products (CAPs) and nationally authorised products
(NAPs)
6.2.1. 5-aminolevulinic acid21 - AMELUZ (CAP); NAP - PSUSA/00010006/202106
Applicants: Biofrontera Bioscience GmbH (Ameluz), various
6.2.2. Amlodipine, valsartan - COPALIA (CAP), DAFIRO (CAP), EXFORGE (CAP), NAP;
amlodipine, hydrochlorothiazide, valsartan - COPALIA HCT (CAP), DAFIRO HCT
(CAP), EXFORGE HCT (CAP) - PSUSA/00010344/202106
Applicants: Novartis Europharm Limited (Copalia, Copalia HCT, Dafiro, Dafiro HCT, Exforge,
Exforge HCT), various
19 Inhalation powder, capsules only

20 Advanced therapy medicinal product
21
For treatment of keratosis only

EMA/PRAC/76191/2022 Page 38/69
6.2.3. Cabazitaxel - CABAZITAXEL ACCORD (CAP); JEVTANA (CAP); NAP -

PSUSA/00000476/202106
Applicants: Accord Healthcare S.L.U. (Cabazitaxel Accord), Sanofi-aventis groupe (Jevtana),

various
6.3. PSUR single assessment (PSUSA) procedures including nationally

authorised products (NAPs) only
6.3.1. Acenocoumarol (NAP) - PSUSA/00000027/202107
Applicant(s): various
PRAC Lead: Maria Popova-Kiradjieva
Action: For adoption of recommendation to CMDh
6.3.2. Betula verrucosa22 23

(NAP) - PSUSA/00010815/202107
PRAC Lead: Kirsti Villikka
6.3.3. Bovine lung phospholipid (NAP) - PSUSA/00010791/202106
PRAC Lead: Kirsti Villikka
6.3.4. Calcifediol (NAP) - PSUSA/00000491/202106
22 Allergen for therapy

23
Sublingual tablet(s) only

EMA/PRAC/76191/2022 Page 39/69
PRAC Lead: Martin Huber
6.3.5. Calcitonin salmon (NAP); synthetic analogue of eel calcitonin (NAP) -

PSUSA/00000494/202106
PRAC Lead: Eva Segovia
6.3.6. Cefepime (NAP) - PSUSA/00000593/202106
PRAC Lead: Ana Sofia Diniz Martins
6.3.7. Desogestrel (NAP) - PSUSA/00000966/202107
PRAC Lead: Annika Folin
6.3.8. Dexchlorpheniramine (NAP) - PSUSA/00000989/202106
PRAC Lead: Ana Sofia Diniz Martins
6.3.9. Fosinopril (NAP); fosinopril, hydrochlorothiazide (NAP) - PSUSA/00010463/202107
PRAC Lead: Eva Segovia

EMA/PRAC/76191/2022 Page 40/69
6.3.10. Glibenclamide, metformin hydrochloride (NAP) - PSUSA/00002002/202106
PRAC Lead: Nathalie Gault
6.3.11. Human fibrinogen (NAP) - PSUSA/00001624/202106
PRAC Lead: Brigitte Keller-Stanislawski
6.3.12. Ibuprofen, pseudoephedrine (NAP) - PSUSA/00001711/202107
PRAC Lead: Nathalie Gault
6.3.13. Lidocaine hydrochloride, phenylephrine hydrochloride, tropicamide (NAP) -

PSUSA/00010390/202107
PRAC Lead: Anette Kirstine Stark
6.3.14. Manidipine (NAP) - PSUSA/00001932/202106
PRAC Lead: Amelia Cupelli
6.3.15. Nimesulide24 (NAP) - PSUSA/00009236/202106
PRAC Lead: Ilaria Baldelli
24
Systemic formulation(s) only

EMA/PRAC/76191/2022 Page 41/69
6.3.16. Propranolol25 (NAP) - PSUSA/00010251/202106
PRAC Lead: Guðrún Stefánsdóttir
6.3.17. Rabbit anti-human T-lymphocyte immunoglobulin (NAP) -

PSUSA/00010252/202106
PRAC Lead: Maia Uusküla
6.3.18. Solifenacin, tamsulosin (NAP) - PSUSA/00010285/202107
PRAC Lead: Menno van der Elst
6.3.19. Tamsulosin (NAP) - PSUSA/00002847/202107
PRAC Lead: Menno van der Elst
6.3.20. Thiocolchicoside (NAP); paracetamol, thiocolchicoside (NAP) -

PSUSA/00010464/202107
PRAC Lead: Ilaria Baldelli
25
All except centrally authorised product(s) only

EMA/PRAC/76191/2022 Page 42/69
6.3.21. Tiagabine (NAP) - PSUSA/00002942/202106
PRAC Lead: Tiphaine Vaillant
6.3.22. Tianeptine (NAP) - PSUSA/00002943/202106
PRAC Lead: Tiphaine Vaillant
6.3.23. Urapidil (NAP) - PSUSA/00003078/202107
PRAC Lead: Eva Jirsová
6.4. Follow-up to PSUR/PSUSA procedures
6.4.1. Dolutegravir - TIVICAY (CAP) - EMEA/H/C/002753/LEG 015
Applicant: ViiV Healthcare B.V.
Scope: Submission of all available data/results for study RESPOND (International Cohort
Consortium of Infectious Disease): a prospective, multi-cohort collaboration study of people
living with human immunodeficiency virus (HIV) across Europe and Australia as requested in
the conclusions of the PSUR single assessment (PSUSA) procedure
(PSUSA/00010075/202101) adopted in September 2021
Action: For adoption of advice to CHMP
6.4.2. Dolutegravir, abacavir, lamivudine - TRIUMEQ (CAP) - EMEA/H/C/002754/LEG 010

EMA/PRAC/76191/2022 Page 43/69
6.4.3. Dolutegravir, lamivudine - DOVATO (CAP) - EMEA/H/C/004909/LEG 005
PRAC Rapporteur: David Olsen
6.4.4. Sitagliptin - JANUVIA (CAP) - EMEA/H/C/000722/LEG 041.1
Scope: MAH’s response to LEG 041.1 [cumulative review and analysis on the risk of
malignancies/neoplasms particularly pancreatic carcinoma from clinical trials, literature and
post-marketing data as requested in the conclusions of the PSUR single assessment
(PSUSA) procedure (PSUSA/00010673/202008) adopted in March 2021] as per the request
for supplementary information (RSI) adopted in September 2021
6.4.5. Sitagliptin - RISTABEN (CAP) - EMEA/H/C/001234/LEG 019.1
Scope: MAH’s response to LEG 019 [cumulative review and analysis on the risk of
6.4.6. Sitagliptin - TESAVEL (CAP) - EMEA/H/C/000910/LEG 035.1

EMA/PRAC/76191/2022 Page 44/69
6.4.7. Sitagliptin - XELEVIA (CAP) - EMEA/H/C/000762/LEG 040.1
6.4.8. Sitagliptin, metformin hydrochloride - EFFICIB (CAP) - EMEA/H/C/000896/LEG

020.1
6.4.9. Sitagliptin, metformin hydrochloride - JANUMET (CAP) - EMEA/H/C/000861/LEG

020.1
6.4.10. Sitagliptin, metformin hydrochloride - RISTFOR (CAP) - EMEA/H/C/001235/LEG

016.1

EMA/PRAC/76191/2022 Page 45/69
6.4.11. Sitagliptin, metformin hydrochloride - VELMETIA (CAP) - EMEA/H/C/000862/LEG

020.1
6.5. Variation procedure(s) resulting from PSUSA evaluation
6.5.1. Dolutegravir - TIVICAY (CAP) - EMEA/H/C/002753/WS2192/0075; dolutegravir,

abacavir, lamivudine - TRIUMEQ (CAP) - EMEA/H/C/002754/WS2192/0099;
dolutegravir, lamivudine - DOVATO (CAP) - EMEA/H/C/004909/WS2192/0026;
dolutegravir, rilpivirine - JULUCA (CAP) - EMEA/H/C/004427/WS2192/0040
Scope: Update of section 4.8 of the SmPC to add completed suicide to the list of adverse
drug reactions (ADRs) with a frequency rare to Tivicay (dolutegravir), Dovato
(dolutegravir/lamivudine) and Triumeq (dolutegravir/ abacavir/lamivudine) following the
finalisation of the PSUR single assessment (PSUSA) procedure (PSUSA/00010075/202101)
in September 2021. As the changes impact all doletugravir-containing products, Juluca
(dolutegravir/rilpivirine) is also updated in accordance. The package leaflets are updated
accordingly
6.5.2. Macitentan - OPSUMIT (CAP) - EMEA/H/C/002697/II/0042, Orphan
Scope: Update of Annex II of the product information and of the RMP (version 12.1) in line
with the outcome of the last PSUR single assessment (PSUSA) procedure
(PSUSA/00010115/202010) adopted in June 2021 to remove the controlled distribution
system and prescriber kit (prescribing check list and healthcare professional (HCP)

EMA/PRAC/76191/2022 Page 46/69
brochure) as additional risk minimisation measures (aRMM) while the patient alert card is
kept as an aRMM. In addition, the RMP is updated to remove off-label use from the list of
safety concerns, elderly patients aged over 75 years, patients with moderate to severe
hepatic impairment and patients with severe renal impairment and/or undergoing dialysis as
missing information. The MAH took the opportunity to include in the RMP updated specific
follow-up questionnaires forms (in line with internal company template. Finally, the MAH
took the opportunity to bring the product information in line with the latest quality review of
documents (QRD) template (version 10.2)
6.6. Expedited summary safety reviews26

EMEA/H/C/005791/MEA 011.10
Scope: Eleventh expedited summary safety report (SSR) for Spikevax (COVID-19 mRNA
vaccine (nucleoside-modified)) during the coronavirus disease (COVID-19) pandemic
6.6.2. Tozinameran - COMIRNATY (CAP) - EMEA/H/C/005735/MEA 002.11
Scope: Twelfth expedited summary safety report (SSR) for Comirnaty (COVID-19 mRNA
vaccine (nucleoside-modified)) during the coronavirus disease (COVID-19) pandemic
7. Post-authorisation safety studies (PASS)
7.1. Protocols of PASS imposed in the marketing authorisation(s)28
7.1.1. Afamelanotide – SCENESSE (CAP) - EMEA/H/C/PSA/S/0076.1
Applicant: Clinuvel Europe Limited
Scope: MAH’s response to PSA/S/0076 [substantial amendment to a protocol previously
26 Submission of expedited summary safety reports for review in addition to the requirements for submission of PSUR(s) falling
within the pandemic period and requirements set out in the list of Union reference dates (EURD list) provided for under Article
107c(7) of Directive 2001/83/EC
27 Messenger ribonucleic acid
28
In accordance with Article 107n of Directive 2001/83/EC

EMA/PRAC/76191/2022 Page 47/69
agreed in March 2016 (PSP/0022.1.A.1 (PSA/0002)) for study CUV-PA001: a post-
authorisation disease registry safety study to generate data on the long-term safety and
clinical effectiveness of Scenesse (afamelanotide) in patients with erythropoietic
protoporphyria (EPP)] as per the request for supplementary information (RSI) adopted in
October 2021
Action: For adoption of PRAC Assessment Report, PRAC outcome letter
7.1.2. Chlormadinone acetate, ethinylestradiol (NAP) – EMEA/H/N/PSA/J/0072.1
Applicant: Gedeon Richter PLC
Scope: MAH’s response to PSA/J/0072 [substantial amendment to a joint protocol

previously agreed in October 2018 for a case control study comparing levonorgestrel and
chlormadinone acetate to compare the risk of venous thromboembolism (VTE) of combined
hormonal contraceptives (COCs) containing chlormadinone (CMA) 2mg / ethinylestradiol
(EE) 30 μg, compared to COCs containing levonorgestrel (LNG) 0.15mg, both combined
with 30 μg ethinylestradiol (EE)] as per the request for supplementary information (RSI)
adopted in July 2021
7.1.3. Levonorgestrel (NAP) - EMEA/H/N/PSA/S/0073.1
Applicant: Bayer Pharma AG (Jaydess, Luadei)

agreed in November 2019 (PSA/S/0044) for study EURAS-LCS12: a European active
surveillance study of LCS-12 (levonorgestrel intrauterine contraceptive system releasing 12
μg levonorgestrel/24h in vitro), an intra-uterine device (IUD) for Jaydess and Luadei
(levonorgestrel) to investigate whether LCS-12 is associated with an increased risk of
unintended pregnancy compared to Mirena (levonorgestrel-releasing intrauterine system)
and to copper IUDs] as per the request for supplementary information (RSI) adopted in
September 2021
7.1.4. Teduglutide - REVESTIVE (CAP) - EMEA/H/C/PSA/S/0082
Applicant: Shire Pharmaceuticals Ireland Limited
Scope: Substantial amendment to a protocol previously agreed in July 2019 (PSA/S/0040)

for study TED-R13-002: a prospective, multicentre registry for patients with short bowel
syndrome

EMA/PRAC/76191/2022 Page 48/69
7.1.5. Tolvaptan - JINARC (CAP) - EMEA/H/C/PSA/S/0078.1
Applicant: Otsuka Pharmaceutical Europe Ltd
PRAC Rapporteur: Amelia Cupelli

agreed in March 2016 (PSP/0028.2) for a 7.5-year, multicentre, non-interventional PASS to
characterise and quantify the identified risk of idiosyncratic liver injury in Jinarc (tolvaptan)
treated patients with autosomal dominant polycystic kidney disease (ADPKD) in routine
clinical practice] as per the request for supplementary information (RSI) adopted in
November 2021
7.2. Protocols of PASS non-imposed in the marketing authorisation(s)29
7.2.1. Filgotinib - JYSELECA (CAP) - EMEA/H/C/005113/MEA 011.1
Applicant: Galapagos N.V.
Scope: MAH’s response to MEA 011 [protocol for study GS-EU-417-9050: a non-
interventional post-authorisation cross-sectional safety study evaluating the effectiveness of
the additional risk minimisation measures for filgotinib use in patients with rheumatoid
arthritis within the German registry Rheumatoide Arthritis: Beobachtung der Biologika-
Therapie (RABBIT)] as per the request for supplementary information (RSI) adopted in
September 2021
7.2.2. Liraglutide - SAXENDA (CAP) - EMEA/H/C/003780/MEA 015.4
Applicant: Novo Nordisk A/S
Scope: Amendment to a protocol previously agreed in September 2018 for study NN8022-
4246: a drug utilisation study (DUS) in the United Kingdom using UK clinical practice
research datalink (CPRD) database evaluating if liraglutide (Saxenda) is used according to
approved indication and posology and if liraglutide (Victoza) is used for weight management

EMEA/H/C/003687/MEA 003.11
Applicant: Orexigen Therapeutics Ireland Limited
29In accordance with Article 107m of Directive 2001/83/EC, supervised by PRAC in accordance with Article 61a (6) of
Regulation (EC) No 726/2004

EMA/PRAC/76191/2022 Page 49/69
Scope: MAH’s response to MEA 003.10 [third feasibility assessment report and protocol for
study NB-451: an observational retrospective drug utilisation study (DUS) of Mysimba
(naltrexone hydrochloride/bupropion hydrochloride) in Europe and the United States to
describe the demographic and baseline characteristics of users of Mysimba (naltrexone
hydrochloride/bupropion hydrochloride), evaluate patterns of Mysimba (naltrexone
hydrochloride/bupropion hydrochloride) initiation and use] as per the request for
supplementary information (RSI) adopted in September 2021
7.2.4. Risdiplam - EVRYSDI (CAP) - EMEA/H/C/005145/MEA 007.1
Scope: MAH’s response to MEA 007 [protocol for study BN42833 - Risdiplam pregnancy
surveillance study: a phase 4, non-interventional surveillance study [final study report
expected in Q4/2031] (from initial opinion/marketing authorisation (MA)] as per request for
supplementary information (RSI) adopted in October 2021
7.2.5. Setmelanotide - IMCIVREE (CAP) - EMEA/H/C/005089/MEA 001
Applicant: Rhythm Pharmaceuticals Netherlands B.V.
PRAC Rapporteur: Marek Juracka
Scope: Protocol for study RM-IMC-901 (listed as a category 3 study in the RMP): a registry
of patients with biallelic homozygous pro-opiomelanocortin (POMC), proprotein convertase
subtilisin/kexin type 1 (PCSK1), or leptin receptor (LEPR) deficiency obesity treated with
setmelanotide (from initial opinion/marketing authorisation)
7.2.6. Tozinameran - COMIRNATY (CAP) - EMEA/H/C/005735/MEA 010.2
Scope: MAH’s response to MEA 010.1 [amendment to a protocol previously agreed in the
initial marketing authorisation application (MAA)/marketing authorisation for study
C4591012 assessing the occurrence of safety events of interest, including severe or atypical
COVID-19 in real-world use of COVID-19 mRNA vaccine to include the booster dose [final
clinical study report (CSR) expected in December-2023]] as per the request for
supplementary information (RSI) adopted in November 2021
7.2.7. Tozinameran - COMIRNATY (CAP) - EMEA/H/C/005735/MEA 041

EMA/PRAC/76191/2022 Page 50/69
Scope: Protocol for study C4591036 (former paediatric heart network study): a safety
surveillance study of myocarditis and myopericarditis associated with Comirnaty
(tozinameran) in persons less than 21 years of age to characterize the clinical course, risk
factors, long-term sequelae, and quality of life in children and young adults under 21 years
with acute post-vaccine myocarditis
7.2.8. Upadacitinib – RINVOQ (CAP) – EMEA/H/C/004760/MEA 012
Scope: Protocol for study P21-825: an evaluation of the effectiveness of additional risk
minimisation measures for upadacitinib in the treatment of atopic dermatitis
7.2.9. Upadacitinib - RINVOQ (CAP) - EMEA/H/C/004760/MEA 013
Scope: Protocol for study P20-390: a cohort study of long-term safety of upadacitinib in the
treatment of atopic dermatitis in Denmark and Sweden
7.3. Results of PASS imposed in the marketing authorisation(s)30
7.3.1. Aprotinin (NAP) - EMEA/H/N/PSR/S/0030
Applicant: Nordic Group BV (Trasylol)
PRAC Rapporteur: Laurence de Fays
Scope: MAH’s response to PSR/S/0030 [results for a Nordic aprotinin patient registry to
record utilisation information on patients at cardiac surgery centres] as per the request for
supplementary information (RSI) adopted in September 2021
Action: For adoption of recommendation to CMDh (or request for supplementary

information (RSI))
7.3.2. Human normal immunoglobulin - HYQVIA (CAP) - EMEA/H/C/PSR/S/0037
Applicant: Baxalta Innovations GmbH
Scope: Results of study number 161302 (listed as a category 1 study in Annex II and the
30
In accordance with Article 107p-q of Directive 2001/83/EC

EMA/PRAC/76191/2022 Page 51/69
RMP): non-interventional post-authorization safety study on the long-term safety of Hyqvia
in subjects treated with Hyqvia (human normal immunoglobulin)
Action: For adoption of recommendation to CHMP (or request for supplementary

information (RSI))
7.3.3. Hydroxyethyl starch (HES) (NAP) - EMEA/H/N/PSR/J/0031
Applicant(s): B. Braun Melsungen AG (Tetraspan, Venofundin), Fresenius Kabi Deutschland

GmbH (Volulyte, Voluven)
Scope: MAH’s response to PSR/J/0031 [results for a joint retrospective, multinational, drug
utilisation study (DUS) to assess the non-adherence of physicians in hydroxyethyl starch
(HES) accredited hospitals to the approved European product information [regarding
indication for use, contraindications and posology (dosage)] for HES 130-containing
medicinal products in clinical routine after implementation of a set of risk minimisation
measures as required in the outcome of the referral procedure under Article 107i of
Directive 2001/83/EC for HES completed in 2018 (EMEA/H/A-107i/1457)] as per the request
for supplementary information (RSI) adopted in January 2022
Action: For adoption of recommendation to CMDh (or request for supplementary

information (RSI))
7.4. Results of PASS non-imposed in the marketing authorisation(s)31
Scope: Submission of the final study report for non-interventional study KT-EU-471-0116
(listed as category 3 study in the RMP): a quantitative testing of healthcare provider
knowledge about Yescarta (axicabtagene ciloleucel) risk minimisation measures

EMEA/H/C/005675/II/0038
PRAC Rapporteur: Jean-Michel Dogné
Scope: Submission of the final report from study MS1222-0003 (listed as a category 3 study
in the RMP) as assessment of anti-platelet factor 4 (PF4) antibodies prior to, and following,
vaccination with AZD1222: a study where sera of vaccinated individuals in study
D8110C00001 are tested to elucidate whether vaccination with Vaxzevria (COVID-19
31 In accordance with Article 61a (6) of Regulation (EC) No 726/2004, in line with the revised variations regulation for any
submission as of 4 August 2013
32

EMA/PRAC/76191/2022 Page 52/69
vaccine) leads to increased levels of circulating anti-PF4 antibodies, a key component of the
hypothesised mechanism underlying thrombosis with thrombocytopenia syndrome (TTS)
7.4.3. Edoxaban - LIXIANA (CAP) - EMEA/H/C/002629/WS2078/0034; ROTEAS (CAP) -

EMEA/H/C/004339/WS2078/0020
Applicant: Daiichi Sankyo Europe GmbH
Scope: Submission of the final report from study ETNA-VTE-EUROPE (DSE-EDO-05-14-EU),

(listed as a category 3 study in the RMP): a non-interventional study on edoxaban
treatment in routine clinical practice in patients with venous thromboembolism in Europe.
The RMP (version 12.0) is updated accordingly
7.4.4. Empagliflozin - JARDIANCE (CAP) - EMEA/H/C/002677/WS2196/0063;

empagliflozin, linagliptin - GLYXAMBI (CAP) - EMEA/H/C/003833/WS2196/0042;
empagliflozin, metformin - SYNJARDY (CAP) - EMEA/H/C/003770/WS2196/0060
Applicant: Boehringer Ingelheim International GmbH
Scope: Update of section 4.4 of the SmPC to delete the warning on lower limb amputations
based on the results from the final meta-analysis report of study 1245.171 (listed as
category 3 study in the RMP): a meta-analysis of amputation risk in empagliflozin studies,
namely: 1) study 1245.25 (EMPA-REG OUTCOME): a study in patients with type 2 diabetes
mellitus (T2DM) and increased cardiovascular risk; 2) study 1245.110 (EMPEROR- HFpEF):
a study in patients with chronic heart failure (HF) with preserved ejection fraction; 3) study
1245.121 (EMPEROR- HFrEF): a study in patients with chronic HF with reduced ejection
fraction. The package leaflet and the RMP (version 17 for Jardiance, version 11 for Synjardy
and version 6 for Glyxambi) are updated accordingly. The conduct of this meta-analysis was
requested to MAHs of all sodium-glucose co-transporter-2 (SGLT2)-containing products as
part of the outcome of the referral procedure (EMEA/H/A-20/1419) under Article 20 of
Regulation (EC) No 726/2004 finalised in 2016
7.4.5. Etanercept - ENBREL (CAP) - EMEA/H/C/000262/II/0244
Scope: Submission of the final report from study B1801310 (BIKER) (listed as a category 3
study in the RMP): an observational PASS of etanercept and methotrexate in the treatment
of juvenile idiopathic arthritis (JIA) using data obtained from participants in the German
Biologics JIA registry (BIKER) to monitor long-term safety and effectiveness of etanercept in
the treatment of JIA in regular clinical practice

EMA/PRAC/76191/2022 Page 53/69
7.4.6. Human papillomavirus vaccine [types 16, 18] (recombinant, adjuvanted, adsorbed)
– CERVARIX (CAP) - EMEA/H/C/000721/II/0114
Applicant: GlaxoSmithkline Biologicals SA
Scope: Submission of the final report from study EPI-HPV-048 (listed as a category 3 study
in the RMP): a surveillance study part of a two-phase national human papillomavirus
vaccine (HPV) surveillance programme initiated in the UK by the Health Protection Agency in
order to evaluate the impact of HPV vaccination on HPV type replacement and to assess the
prevalence of type-specific HPV deoxyribonucleic acid (DNA) in young women in England
since HPV immunisation using Cervarix (human papillomavirus vaccine) was introduced (in
fulfilment of MEA 094). In addition, the submission includes the protocol for study EPI-HPV-
099: an observational, retrospective database post-authorisation safety study (PASS) to
assess trends and changes over time in incidence of anal cancer and feasibility for a case-
control study in European countries that introduced Cervarix (human papillomavirus
vaccine) in their National Immunisation Programmes (NIP) in order to address the safety
concern of ‘impact and effectiveness against anal lesions and cancer’. The RMP (version 25)
is updated accordingly

EMEA/H/C/003687/II/0054
Applicant: Orexigen Therapeutics Ireland Limited
Scope: Submission of the final report from study NB-542 (listed as a category 3 study in the
RMP): a cross-sectional survey aimed to evaluate the effectiveness of the Mysimba
(naltrexone hydrochloride/bupropion hydrochloride) physician prescribing checklist (PPC)
among physicians in the EU. The RMP (version 12.6) is updated accordingly
7.4.8. Romiplostim - NPLATE (CAP) - EMEA/H/C/000942/II/0083
Scope: Submission of the final report from study 20070797 (listed as a category 3 study in
the RMP): an observational study assessing the long-term safety of romiplostim treatment
in real-life clinical practice in three Nordic countries. The RMP (version 21.0) is updated
accordingly
7.4.9. Ustekinumab - STELARA (CAP) - EMEA/H/C/000958/II/0091

EMA/PRAC/76191/2022 Page 54/69
Scope: Submission of the final safety registry report from study CNTO1275PSO4007:
pregnancy research initiative - exposure to ustekinumab during pregnancy: a review and
analysis of birth outcomes from the Swedish, Danish, and Finnish medical birth registers (in
fulfilment of MEA 024). The RMP (version 22.1) is updated accordingly
7.5. Interim results of imposed and non-imposed PASS submitted before

the entry into force of the revised variation regulation
7.5.1. Adalimumab - HUMIRA (CAP) - EMEA/H/C/000481/MEA 075.10
Scope: Eighth annual interim study report for Humira ulcerative colitis registry P11-282: a
long-term non-interventional post-marketing study to assess safety and effectiveness of
Humira (adalimumab) in patients with moderately to severely active ulcerative colitis (UC)
7.5.2. Adalimumab - HUMIRA (CAP) - EMEA/H/C/000481/MEA 080.8
Scope: Sixth annual interim report for P11-292 registry: a long-term non-interventional
registry to assess safety and effectiveness of Humira (adalimumab) in paediatric patients
with moderately to severely active Crohn’s disease (CD) – CAPE
7.5.3. Dapagliflozin - EDISTRIDE (CAP) - EMEA/H/C/004161/MEA 009.3
Scope: Third interim report for study MB102-118 ST/D1690R00007 - (EUPAS12116): a

pharmacoepidemiology study assessing the risk of cancer [final clinical study report (CSR)
expected in 2024]
7.5.4. Dapagliflozin - FORXIGA (CAP) - EMEA/H/C/002322/MEA 004.8
Scope: Third interim report for study MB102-118 ST/D1690R00007 (EUPAS12116): a

pharmacoepidemiology study assessing the risk of cancer [final clinical study report (CSR)

EMA/PRAC/76191/2022 Page 55/69
due in 2024]
7.5.5. Filgrastim - NIVESTIM (CAP) - EMEA/H/C/001142/MEA 015.6
PRAC Rapporteur: Kirsti Villikka
Scope: Fifth annual report for study ZOB-NIV-1513 (C1121008): a multinational,

multicentre, prospective, non-interventional PASS in healthy donors (HDs) exposed to
Nivestim (biosimilar filgrastim) for haematopoietic stem cell (HSC) mobilisation (NEST)
[final clinical study report (CSR) expected in March 2023]
7.5.6. Pitolisant - WAKIX (CAP) - EMEA/H/C/002616/ANX 001.4
Applicant: Bioprojet Pharma
PRAC Rapporteur: Kirsti Villikka
Scope: Fourth annual interim study report for study P15-11: a 5-year multicentre,
observational PASS to document the utilisation of Wakix (pitolisant) in the treatment of
narcolepsy with or without cataplexy and to collect information on its long-term safety when
used in routine medical practice [final results expected in 2023]
7.5.7. Sebelipase alfa - KANUMA (CAP) - EMEA/H/C/004004/ANX 001.5
Applicant: Alexion Europe SAS
Scope: Sixth interim report for study ALX-LALD-501: a non-interventional, multicentre,

prospective disease and clinical outcome registry of patients with lysosomal acid lipase
deficiency (LAL-D) to further understand the disease, its progression and any associated
complication, and to evaluate the long-term efficacy and safety of Kanuma (sebelipase alfa)
7.5.8. Teriflunomide - AUBAGIO (CAP) - EMEA/H/C/002514/MEA 005.3
Scope: Annual progress reports 2021 for: 1) pregnancy registry OBS12751 (international):
an international pregnancy exposure registry of women with multiple sclerosis (MS) exposed
to Aubagio (teriflunomide) and; 2) pregnancy registry OBS13499 (US/CA): teriflunomide
pregnancy outcome exposure registry: a ‘teratology information specialists (OTIS)’
autoimmune diseases in pregnancy project

EMA/PRAC/76191/2022 Page 56/69
7.5.9. Turoctocog alfa pegol - ESPEROCT (CAP) - EMEA/H/C/004883/ANX 001.1
Scope: First annual progress report for study NN7088-4029: a multinational, prospective,
open labelled, non-controlled, non-interventional PASS of turoctocog alfa pegol (N8-GP)
during long-term routine prophylaxis and treatment of bleeding episodes in patients with
haemophilia A
7.6. Others
7.6.1. Acalabrutinib - CALQUENCE (CAP) - EMEA/H/C/005299/MEA 002.2
PRAC Rapporteur: Željana Margan Koletić
Scope: MAH’s response to MEA 002.1 [protocol for study D8220C00008 (listed as a category
3 study in the RMP): a phase 3b, multicentre, open-label, single-arm study in subjects with
chronic lymphocytic leukaemia (ASSURE) to address missing information around moderate
to severe cardiac impaired patients in subjects treated with Calquence (acalabrutinib)] as
per the request for supplementary information (RSI) adopted in October 2021

EMEA/H/C/005675/MEA 007.4
Scope: Statistical analysis plan (SAP) for study D8111R00006: a post-authorisation/post-

marketing observational study using existing secondary health data sources to evaluate the
association between exposure to Vaxzevria (AZD1222) and safety concerns
7.6.3. Eribulin - HALAVEN (CAP) - EMEA/H/C/002084/MEA 024.2
Scope: MAH’s justification to request an extension of the due date of the final study report
for study E7389-M044-504 (IRENE): an observational, post-authorisation, single-arm,
prospective, multicentre cohort study to characterise and determine the incidence of
eribulin-induced peripheral neuropathy (PN), and the frequency and time to resolution of
eribulin-induced PN in adult patients treated with eribulin in a real-life setting with locally
advanced or metastatic breast cancer who have progressed after at least one

EMA/PRAC/76191/2022 Page 57/69
chemotherapeutic regimen for advanced disease
7.6.4. Insulin detemir - LEVEMIR (CAP) - EMEA/H/C/000528/MEA 045.11
Scope: Submission of a statement to clinical overview addendum in order to correct some

discrepancies related to post-marketing data from non-interventional study NN304-4016
(listed as a category 3 study in the RMP): a diabetes pregnancy registry study conducted to
assess the long-term safety of insulin use in pregnant women (in fulfilment of MEA 045)
7.7. New Scientific Advice
None
7.8. Ongoing Scientific Advice
None
7.9. Final Scientific Advice (Reports and Scientific Advice letters)
None
8. Renewals of the marketing authorisation, conditional renewal

and annual reassessments
8.1. Annual reassessments of the marketing authorisation
8.1.1. Defibrotide - DEFITELIO (CAP) - EMEA/H/C/002393/S/0057 (with RMP)
Applicant: Gentium S.r.l.
Scope: Annual reassessment of the marketing authorisation
8.1.2. Lomitapide - LOJUXTA (CAP) - EMEA/H/C/002578/S/0048 (without RMP)
Applicant: Amryt Pharmaceuticals DAC

EMA/PRAC/76191/2022 Page 58/69
8.1.3. Obiltoxaximab - OBILTOXAXIMAB SFL (CAP) - EMEA/H/C/005169/S/0004 (without

RMP)
Applicant: SFL Pharmaceuticals Deutschland GmbH
8.1.4. Susoctocog alfa - OBIZUR (CAP) - EMEA/H/C/002792/S/0044 (without RMP)
Applicant: Baxalta Innovations GmbH
8.1.5. Tafamidis - VYNDAQEL (CAP) - EMEA/H/C/002294/S/0076 (without RMP)
8.1.6. Tocofersolan - VEDROP (CAP) - EMEA/H/C/000920/S/0041 (without RMP)
Applicant: Recordati Rare Diseases
PRAC Rapporteur: Melinda Palfi
8.2. Conditional renewals of the marketing authorisation
8.2.1. Onasemnogene abeparvovec - ZOLGENSMA (CAP) - EMEA/H/C/004750/R/0021

(without RMP)
Applicant: Novartis Gene Therapies EU Limited, ATMP33
Scope: Conditional renewal of the marketing authorisation
33

EMA/PRAC/76191/2022 Page 59/69
Action: For adoption of advice to CAT and CHMP
8.2.2. Selumetinib - KOSELUGO (CAP) - EMEA/H/C/005244/R/0003 (without RMP)
Scope: Conditional renewal of the marketing authorisation
8.3. Renewals of the marketing authorisation
8.3.1. Adalimumab - IMRALDI (CAP) - EMEA/H/C/004279/R/0050 (without RMP)
Applicant: Samsung Bioepis NL B.V.
Scope: 5-year renewal of the marketing authorisation
8.3.2. Atezolizumab - TECENTRIQ (CAP) - EMEA/H/C/004143/R/0069 (without RMP)
8.3.3. Brodalumab - KYNTHEUM (CAP) - EMEA/H/C/003959/R/0019 (with RMP)
Applicant: LEO Pharma A/S
8.3.4. Cladribine - MAVENCLAD (CAP) - EMEA/H/C/004230/R/0022 (with RMP)
Applicant: Merck Europe B.V.

EMA/PRAC/76191/2022 Page 60/69
8.3.5. Fampridine - FAMPYRA (CAP) - EMEA/H/C/002097/R/0050 (without RMP)
Applicant: Biogen Netherlands B.V.
8.3.6. Ivacaftor - KALYDECO (CAP) - EMEA/H/C/002494/R/0106 (without RMP)
Applicant: Vertex Pharmaceuticals (Ireland) Limited
PRAC Rapporteur: Maria del Pilar Rayon
8.3.7. Meningococcal group b vaccine (recombinant, adsorbed) - TRUMENBA (CAP) -

EMEA/H/C/004051/R/0036 (with RMP)
8.3.8. Midostaurin - RYDAPT (CAP) - EMEA/H/C/004095/R/0023 (without RMP)
8.3.9. Rituximab - BLITZIMA (CAP) - EMEA/H/C/004723/R/0049 (without RMP)
Applicant: Celltrion Healthcare Hungary Kft.
8.3.10. Sarilumab - KEVZARA (CAP) - EMEA/H/C/004254/R/0029 (with RMP)

EMA/PRAC/76191/2022 Page 61/69
8.3.11. Sofosbuvir, velpatasvir, voxilaprevir - VOSEVI (CAP) - EMEA/H/C/004350/R/0053

(with RMP)

EMEA/H/C/002736/R/0024 (with RMP)
Applicant: CO.DON AG, ATMP34
Action: For adoption of advice to CAT and CHMP
8.3.13. Telotristat ethyl - XERMELO (CAP) - EMEA/H/C/003937/R/0032 (without RMP)
Applicant: Ipsen Pharma
9. Product related pharmacovigilance inspections
9.1. List of planned pharmacovigilance inspections
None
9.2. Ongoing or concluded pharmacovigilance inspections
Disclosure of information on results of pharmacovigilance inspections could undermine the

protection of the purpose of these inspections, investigations and audits. Therefore such
information is not reported in the agenda.
9.3. Others
None
34

EMA/PRAC/76191/2022 Page 62/69
10. Other safety issues for discussion requested by CHMP or EMA
10.1. Safety related variations of the marketing authorisation
10.1.1. Infliximab – REMICADE (CAP) - EMEA/H/C/000240/IB/0233
Applicant: Janssen Biologics B.V.
Scope: PRAC consultation on a variation updating sections 4.4, 4.5 and 4.6 of the SmPC,
the patient reminder card in Annex II with regards to the administration of live vaccines to
infants following in utero exposure to Remicade (infliximab) as per the outcome of post-
authorisation measure (LEG 159.2) adopted in November 2021. The package leaflet is
updated accordingly
10.2. Timing and message content in relation to Member States’ safety

announcements
None
10.3. Other requests
None
10.4. Scientific Advice
Information related to this section cannot be released at the present time as it is deemed to
contain commercially confidential information.
11. Other safety issues for discussion requested by the Member

States
11.1. Safety related variations of the marketing authorisation
None
11.2. Other requests
None

EMA/PRAC/76191/2022 Page 63/69
12. Organisational, regulatory and methodological matters
12.1. Mandate and organisation of the PRAC
12.1.1. PRAC membership
Action: For information
12.1.2. PRAC working group - Best practice guide on using PRAC plenary time efficiently
and effectively – update on the implementation of quantitative goals – Q4 2021
Action: For discussion
12.1.3. Vote by proxy
None
12.2. Coordination with EMA Scientific Committees or CMDh-v
None
12.3. Coordination with EMA Working Parties/Working Groups/Drafting

Groups
12.3.1. Classification of post-authorisation studies group (CPAS) - activities overview
12.4. Cooperation within the EU regulatory network
12.4.1. Coronavirus (COVID-19) pandemic - update
12.5. Cooperation with International Regulators
None
12.6. Contacts of the PRAC with external parties and interaction with the
Interested Parties to the Committee
None

EMA/PRAC/76191/2022 Page 64/69
12.7. PRAC work plan
None
12.8. Planning and reporting
12.8.1. EU Pharmacovigilance system - quarterly workload measures and performance

indicators – Q4 2021 and predictions
12.8.2. PRAC workload statistics – Q4 2021
12.9. Pharmacovigilance audits and inspections
12.9.1. Pharmacovigilance systems and their quality systems
None
12.9.2. Pharmacovigilance inspections
None
12.9.3. Pharmacovigilance audits
None
12.10. Periodic safety update reports (PSURs) & Union reference date
(EURD) list
12.10.1. Periodic safety update reports
None
12.10.2. Granularity and Periodicity Advisory Group (GPAG)
PRAC lead: Menno van der Elst, Maia Uusküla
12.10.3. PSURs repository
None

EMA/PRAC/76191/2022 Page 65/69
12.10.4. Union reference date list – consultation on the draft list
12.11. Signal management
12.11.1. Signal management – feedback from Signal Management Review Technical (SMART)
Working Group
PRAC lead: Menno van der Elst
12.12. Adverse drug reactions reporting and additional reporting
12.12.1. Management and reporting of adverse reactions to medicinal products
None
12.12.2. Additional monitoring
None
12.12.3. List of products under additional monitoring – consultation on the draft list
12.13. EudraVigilance database
12.13.1. Activities related to the confirmation of full functionality
None
12.14. Risk management plans and effectiveness of risk minimisations
12.14.1. Risk management systems
None
12.14.2. Tools, educational materials and effectiveness measurement of risk minimisations
None

EMA/PRAC/76191/2022 Page 66/69
12.14.3. Coronavirus (COVID-19) pandemic - coreRMP19: update
PRAC lead: Jean-Michel Dogné, Brigitte Keller-Stanislawski, Zane Neikena, Hans Christian
Siersted, Anette Kirstine Stark, Menno van der Elst, Ulla Wändel Liminga
12.15. Post-authorisation safety studies (PASS)
12.15.1. Post-authorisation Safety Studies – imposed PASS
None
12.15.2. Post-authorisation Safety Studies – non-imposed PASS
None
12.16. Community procedures
12.16.1. Referral procedures for safety reasons
None
12.17. Renewals, conditional renewals, annual reassessments
None
12.18. Risk communication and transparency
12.18.1. Public participation in pharmacovigilance
None
12.18.2. Safety communication
None
12.19. Continuous pharmacovigilance
12.19.1. Incident management
None

EMA/PRAC/76191/2022 Page 67/69
12.20. Impact of pharmacovigilance activities
None
12.21. Others
12.21.1. EU pharmaceutical legislation – revision of Directive 2001/83/EC and Regulation

(EC) No 726/2004
PRAC lead: Amelia Cupelli, Maria del Pilar Rayon, Liana Gross-Martirosyan, Martin Huber,
Eva Segovia, Sabine Straus, Menno van der Elst, Ulla Wändel Liminga
13. Any other business

EMA/PRAC/76191/2022 Page 68/69
14. Explanatory notes
The Notes give a brief explanation of relevant agenda items and should be read in conjunction with the
agenda.
EU Referral procedures for safety reasons: Urgent EU procedures and Other EU referral
procedures
(Items 2 and 3 of the PRAC agenda)
A referral is a procedure used to resolve issues such as concerns over the safety or benefit-risk balance of a
medicine or a class of medicines. In a referral, EMA is requested to conduct a scientific assessment of a
particular medicine or class of medicines on behalf of the European Union (EU). For further detailed
information on safety related referrals please see:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general content 000150.jsp&mid
=WC0b01ac05800240d0
Signals assessment and prioritisation

(Item 4 of the PRAC agenda)
A safety signal is information on a new or incompletely documented adverse event that is potentially caused
by a medicine and that warrants further investigation. Signals are generated from several sources such as
spontaneous reports, clinical studies and the scientific literature. The evaluation of safety signals is a routine
part of pharmacovigilance and is essential to ensuring that regulatory authorities have a comprehensive
knowledge of a medicine’s benefits and risks.
The presence of a safety signal does not mean that a medicine has caused the reported adverse event. The
adverse event could be a symptom of another illness or caused by another medicine taken by the patient.
The evaluation of safety signals is required to establish whether or not there is a causal relationship between
the medicine and the reported adverse event.
The evaluation of safety signals may not necessarily conclude that the medicine caused the adverse event in
question. In cases where a causal relationship is confirmed or considered likely, regulatory action may be
necessary and this usually takes the form of an update of the summary of product characteristics and the
package leaflet.
Risk Management Plans (RMPs)

The RMP describes what is known and not known about the side effects of a medicine and states how these
risks will be prevented or minimised in patients. It also includes plans for studies and other activities to gain
more knowledge about the safety of the medicine and risk factors for developing side effects.
RMPs are continually modified and updated throughout the lifetime of the medicine as new information
becomes available.
Assessment of Periodic Safety Update Reports (PSURs)

A PSUR is a report providing an evaluation of the benefit-risk balance of a medicine, which is submitted by
marketing authorisation holders at defined time points following a medicine’s authorisation.
PSURs summarises data on the benefits and risks of a medicine and includes the results of all studies carried
out with this medicine (in the authorised and unauthorised indications).
Post-authorisation Safety Studies (PASS)

A PASS is a study of an authorised medicinal product carried out to obtain further information on its safety,
or to measure the effectiveness of risk management measures. The results of a PASS help regulatory
agencies to evaluate the safety and benefit-risk profile of a medicine.
Product related pharmacovigilance inspections

Inspections carried out by regulatory agencies to ensure that marketing authorisation holders comply with
their pharmacovigilance obligations.
More detailed information on the above terms can be found on the EMA website:
https://www.ema.europa.eu/en

EMA/PRAC/76191/2022 Page 69/69

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07 February 2022

Pharmacovigilance Risk Assessment Committee (PRAC)

Chair: Sabine Straus – Vice-Chair: Martin Huber

07 February 2022, 10:30 – 19:30, via teleconference

08 February 2022, 08:30 – 19:30, via teleconference

09 February 2022, 08:30 – 19:30, via teleconference

10 February 2022, 08:30 – 16:00, via teleconference

Organisational, regulatory and methodological matters (ORGAM)

24 February 2022, 09:00 – 12:00, via teleconference

Note on access to documents

Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands

1.2. Agenda of the meeting on 07-10 February 2022 ................................................... 12

1.3. Minutes of the previous meeting on 10-13 January 2022 ..................................... 12

2. EU referral procedures for safety reasons: urgent EU procedures 12

2.2. Ongoing procedures ............................................................................................. 12

2.3. Procedures for finalisation.................................................................................... 12

3. EU referral procedures for safety reasons: other EU referral

3.2. Ongoing procedures ............................................................................................. 13

3.2.1. Chlormadinone (NAP); chlormadinone, ethinylestradiol (NAP); nomegestrol (NAP);

3.3. Procedures for finalisation.................................................................................... 13

3.4. Re-examination procedures .................................................................................. 13

3.5. Others .................................................................................................................. 13

4. Signals assessment and prioritisation 13

4.2. New signals detected from other sources ............................................................. 14

4.2.1. Coronavirus (COVID-19) mRNA vaccine (nucleoside-modified) - SPIKEVAX (CAP) ............ 14

4.2.2. Coronavirus (COVID-19) mRNA vaccine (nucleoside-modified) - SPIKEVAX (CAP) ............ 14

4.2.3. Tozinameran - COMIRNATY (CAP) .............................................................................. 14

4.2.4. Tozinameran - COMIRNATY (CAP) .............................................................................. 14

4.3. Signals follow-up and prioritisation ...................................................................... 15

4.3.1. Enzalutamide - XTANDI (CAP) - EMEA/H/C/002639/SDA/015 ........................................ 15

4.3.2. Obinutuzumab - GAZYVARO (CAP) - EMEA/H/C/002799/SDA/012 .................................. 15

4.3.3. Sorafenib - NEXAVAR (CAP) - EMEA/H/C/000690/SDA/041 ........................................... 15

4.3.4. Tocilizumab – ROACTEMRA (CAP) .............................................................................. 15

4.4. Variation procedure(s) resulting from signal evaluation ...................................... 16

4.4.1. Coronavirus (COVID-19) mRNA vaccine (nucleoside-modified) - SPIKEVAX (CAP) -

Pharmacovigilance Risk Assessment Committee (PRAC)

5.1.1. Bevacizumab - EMEA/H/C/005574 ............................................................................. 16

5.1.2. Coronavirus (COVID-19) Vaccine (inactivated, adjuvanted, adsorbed) - EMEA/H/C/00601916

5.1.3. Dabigatran etexilate - EMEA/H/C/005639 ................................................................... 16

5.1.4. Fosdenopterin - EMEA/H/C/005378, Orphan................................................................ 17

5.1.5. Insulin human - EMEA/H/W/005779 ........................................................................... 17

5.1.6. Insulin human - EMEA/H/W/005780 ........................................................................... 17

5.1.7. Molnupiravir – LAGEVRIO (CAP MAA) - EMEA/H/C/005789 ............................................ 17

5.1.8. Olipudase alfa - EMEA/H/C/004850, PRIME, Orphan ..................................................... 17

5.1.9. Pirfenidone - EMEA/H/C/005873 ................................................................................ 17

5.1.10. Ranibizumab - EMEA/H/C/005610 .............................................................................. 17

5.2. Medicines in the post-authorisation phase – PRAC-led procedures ....................... 18

5.2.1. Alogliptin - VIPIDIA (CAP) - EMEA/H/C/002182/WS2191/0029; alogliptin, metformin -

5.2.2. Coronavirus (COVID-19) mRNA vaccine (nucleoside-modified) - SPIKEVAX (CAP) -

5.2.3. Nintedanib - VARGATEF (CAP) - EMEA/H/C/002569/II/0044.......................................... 18

5.3. Medicines in the post-authorisation phase – CHMP-led procedures ...................... 19

5.3.1. Acalabrutinib - CALQUENCE (CAP) - EMEA/H/C/005299/X/0009/G ................................. 19

5.3.2. Aflibercept - EYLEA (CAP) - EMEA/H/C/002392/II/0077/G ............................................ 19

5.3.3. Apalutamide - ERLEADA (CAP) - EMEA/H/C/004452/II/0017 ......................................... 19

5.3.4. Axicabtagene ciloleucel - YESCARTA (CAP) - EMEA/H/C/004480/II/0042, Orphan ............ 20

5.3.5. Axicabtagene ciloleucel - YESCARTA (CAP) - EMEA/H/C/004480/II/0046, Orphan ............ 20

5.3.6. Baloxavir marboxil - XOFLUZA (CAP) - EMEA/H/C/004974/X/0003/G ............................. 20

5.3.7. Brolucizumab - BEOVU (CAP) - EMEA/H/C/004913/II/0010 ........................................... 21

5.3.8. Buprenorphine - BUVIDAL (CAP) - EMEA/H/C/004651/II/0017 ...................................... 21