Minutes Prac Meeting 26 29 October 2020 - en
Minutes Prac Meeting 26 29 October 2020 - en
Minutes Prac Meeting 26 29 October 2020 - en
EMA/PRAC/12790/2021
Human Medicines Division
Disclaimers
Some of the information contained in the minutes is considered commercially confidential or sensitive
and therefore not disclosed. With regard to intended therapeutic indications or procedure scope 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, the minutes are a working document primarily designed for PRAC members and the work the
Committee undertakes.
Some documents mentioned in the minutes 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).
© European Medicines Agency, 2021. Reproduction is authorised provided the source is acknowledged.
Table of contents
1. Introduction 11
1.1. Welcome and declarations of interest of members, alternates and experts .......... 11
6.1.1. Alogliptin - VIPIDIA (CAP); alogliptin, metformin - VIPDOMET (CAP); alogliptin, pioglitazone
- INCRESYNC (CAP) - PSUSA/00010061/202004 ......................................................... 24
7.5. Interim results of imposed and non-imposed PASS submitted before the entry into
force of the revised variation regulation ............................................................... 40
7.9. Final Scientific Advice (Reports and Scientific Advice letters) .............................. 41
10. Other safety issues for discussion requested by the CHMP or EMA 42
10.1. Safety related variations of the marketing authorisation ...................................... 42
10.2. Timing and message content in relation to Member States’ safety announcements
............................................................................................................................. 42
11. Other safety issues for discussion requested by the Member States
42
11.1. Safety related variations of the marketing authorisation ...................................... 42
11.2. Other requests ...................................................................................................... 42
12.6. Contacts of the PRAC with external parties and interaction with the Interested
Parties to the Committee ...................................................................................... 43
12.10. Periodic safety update reports (PSURs) & Union reference date (EURD) list ........ 44
12.10.4. Union reference date list – consultation on the draft list ............................................... 44
12.11.1. Signal management – feedback from Signal Management Review Technical (SMART)
Working Group ........................................................................................................ 45
12.12.3. List of products under additional monitoring – consultation on the draft list .................... 45
12.13.2. EudraVigilance – Expert Working Group (EV-EWG) - work programme 2021-2022 ........... 46
12.14.1. Coronavirus (COVID-19) pandemic - coreRMP19 guidance and requirements for COVID-19
vaccines ................................................................................................................. 46
12.14.3. Tools, educational materials and effectiveness measurement of risk minimisations .......... 46
12.20.1. Good Pharmacovigilance Practice (GVP) - update on GVP status overview – planning for
2021 ...................................................................................................................... 47
12.20.2. Strategy on measuring the impact of pharmacovigilance – PRAC interest group (IG) Impact
– Revised process for prioritising impact research topics ............................................... 47
16.1.30. Yttrium (90Y) chloride - YTRACIS (CAP); YTTRIGA (CAP) - PSUSA/00003137/202003 ....... 62
17.5. Interim results of imposed and non-imposed PASS submitted before the entry into
force of the revised variation regulation ............................................................... 68
17.9. Final Scientific Advice (Reports and Scientific Advice letters) .............................. 71
18.1.4. Smallpox vaccine (live modified vaccinia virus Ankara) - IMVANEX (CAP) -
EMEA/H/C/002596/S/0054 (without RMP) .................................................................. 72
The Chairperson opened the 26 - 29 October 2020 meeting by welcoming all participants.
Due to the current coronavirus (COVID-19 outbreak), and the associated EMA Business
Continuity Plan (BCP), the meeting was held remotely.
Based on the declarations of interest submitted by the Committee members, alternates and
experts and based on the topics in the agenda of the current meeting, the Committee
Secretariat announced the restricted involvement of some Committee members in upcoming
discussions; in accordance with the Agency’s policy on the handling of conflicts of interests,
participants in this meeting were asked to declare any changes, omissions or errors to their
declared interests concerning the matters for discussion (Annex II – List of participants). No
new or additional conflicts were declared.
Discussions, deliberations and voting took place in full respect of the restricted involvement
of Committee members and experts in line with the relevant provisions of revision 2 of the
Rules of Procedure (EMA/PRAC/567515/2012 Rev.2). All decisions taken at this meeting held
under the conditions of an emergency situation, the Agency’s BCP and in compliance with
internal guidelines were made in the presence of a quorum of members (i.e. 18 or more
members were present in the room). All decisions, recommendations and advice were agreed
unanimously, unless otherwise specified.
The PRAC Chair welcomed Nadine Petitpain as the new member for Luxembourg.
The agenda was adopted with some modifications upon request from the members of the
Committee and the EMA secretariat.
The minutes were adopted with some amendments received during the consultation phase
and will be published on the EMA website.
Post-meeting note: the PRAC minutes of the meeting held on 28 September – 01 October
2020 were published on the EMA website on 31 December 2020 (EMA/PRAC/708023/2020).
None
None
None
None
Applicant(s): various
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
Background
A referral procedure under Article 31 of Directive 2001/83/EC is ongoing for the review of
ifosfamide solution and concentrate for solution following epidemiological studies suggesting
an increased risk of ifosfamide-induced encephalopathy with ifosfamide EG (ifosfamide)
solution for infusion compared with ifosfamide powder. For further background, see PRAC
minutes March 2020 and PRAC minutes July 2020.
Summary of recommendation(s)/conclusions
• The PRAC discussed the joint assessment report issued by the Rapporteurs.
• The PRAC adopted a second list of outstanding issues (LoOI), to be addressed by the
MAHs in accordance with a revised timetable (EMA/PRAC/111338/2020 rev2).
None
None
None
Background
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
The exposure for Tecentriq (atezolizumab) is estimated to have been more than 106,316
patients worldwide, in the period from first authorisation in 2016 to 2020. The exposure for
Bavencio (avelumab) is estimated to have been more than 2,812 patient-years worldwide, in
the period from first authorisation in 2017 to 2020. The exposure for Imfinzi (durvalumab) is
estimated to have been more than 26,833 patient-years worldwide, in the period from first
authorisation in 2017 to 2020. The exposure for Yervoy (ipilimumab) is estimated to have
been more than 81,450 patients worldwide, in the period from first authorisation in 2011 to
2020. The exposure for Opdivo (nivolumab) is estimated to have been more than 429,000
patients worldwide, in the period from first authorisation in 2015 to 2019. The exposure for
Keytruda (pembrolizumab) is estimated to have been more than 99,173 patient-years
worldwide, in the period from first authorisation in 2015 to 2018.
During routine signal detection activities, a signal of immune-mediated cystitis was identified
by France, based on 21 cases retrieved from EudraVigilance for the preferred term cystitis
non-infective. The Netherlands confirmed that the signal needed initial analysis and
prioritisation by the PRAC.
Discussion
Having considered the available evidence from case reports in EudraVigilance, the literature
and clinical trials as well as the plausible mechanism of action, the PRAC agreed that further
evaluation of the signal on immune-mediated cystitis associated with ICIs is warranted.
The PRAC appointed Menno van der Elst as Rapporteur for the signal.
Summary of recommendation(s)
Applicant(s): Astellas Pharma Europe B.V. (Advagraf, Modigraf), Chiesi Farmaceutici S.p.A.
(Envarsus), GW Pharma (International) B.V. (Epidyolex), Teva B.V. (Tacforius), various
Scope: Signal of drug interaction with cannabidiol leading to tacrolimus serum level
increased and toxicity
Background
The exposure for Epidyolex (cannabidiol) is estimated to have been more than 16,544
patient-years worldwide, in the period from first authorisation in 2018 to 2019. The exposure
for Advagraf and Modigraf (tacrolimus), in the period from 2015 to 2018 is estimated to have
been more than 423,986 patient-years. The exposure for Envarsus (tacrolimus) is estimated
to have been more than 19,681 patients-years cumulatively in the period from the first
authorisation in 2014 to 2018. Cumulated with nationally authorised medicinal products
containing tacrolimus, the exposure is estimated to be above 1 million patient-years.
During routine signal detection activities, a signal of interaction between cannabidiol and
systemic tacrolimus leading to tacrolimus serum level increased and toxicity was identified
Discussion
The PRAC discussed the evidence from the literature and EudraVigilance on the cases of drug
interaction with cannabidiol leading to tacrolimus serum level increased and toxicity. The
PRAC noted that this interaction is currently assessed as part of a separate procedure9 for
Epidyolex (cannabidiol). The PRAC concurred that there is sufficient evidence to warrant the
inclusion in the product information of tacrolimus10-containing medicinal products a
recommendation to consider monitoring the blood levels of tacrolimus in view of the potential
interaction with co-administration of cannabidiol that may lead to the increase of plasma
concentrations of tacrolimus. In addition, the PRAC agreed that the current evidence is
sufficient to also recommend the inclusion of the same information regarding the risk of
interaction with cannabidiol, which may lead to the increase of plasma concentrations of
calcineurin inhibitors and of mammalian target of rapamycin (mTOR) inhibitors, in the
product information of medicinal products for systemic use containing other calcineurin
inhibitor (ciclosporin) or mTOR inhibitors (everolimus, sirolimus, temsirolimus). Furthermore,
the PRAC agreed that the potential interaction between tacrolimus and dronabinol or
nabilone should be evaluated through an ongoing procedure for tacrolimus.
Summary of recommendation(s)
5 Leino A, Emoto C, Fukuda T, Privitera M, Vinks A, Alloway R. Evidence of a clinically significant drug‐drug interaction between
cannabidiol and tacrolimus. American Journal of Transplantation 2019;19: 2944–2948 doi: 10.1111/ajt.15398
6 DeFilippis EM, Givertz MM. Marijuana use and candidacy for heart transplantation. The Journal of Heart and Lung
10.1016/j.psym.2019.01.009
9 Variation II/0005: extension of indication for use as adjunctive therapy of seizures associated with tuberous sclerosis
Background
The MAHs replied to the request for information on the signal of drug reaction with
eosinophilia and systemic symptoms (DRESS) and the responses were assessed by the
Rapporteur.
Discussion
Based on the available evidence arising from the publication by Saper et al. 201911 and on
the cumulative reviews provided by the MAHs which suggest a possible association between
anakinra/canakinumab and DRESS, the PRAC concurred that further information is necessary
before a conclusion can be drawn.
The PRAC agreed on a further list of questions (LoQ) to request additional clarifications to the
authors Saper et al. Furthermore, the PRAC agreed to request additional information from
the MAHs.
Summary of recommendation(s)
• The authors of the publication Saper et al. 2019 are invited to submit to EMA, within 60
days, responses to the LoQ agreed by the PRAC.
• The MAHs for Kineret (anakinra) and Ilaris (canakinumab) should submit to EMA, within
60 days, a further analysis of all case reports with anakinra or canakinumab and DRESS,
including a causality assessment and a review of the recent literature. A proposal for
amending the product information and the RMP should be provided as appropriate.
Applicant(s): various
Scope: Signal of drug reaction with eosinophilia and systemic symptoms (DRESS)
Background
The MAH for the originator cefepime-containing product, Bristol-Myers Squibb, replied to the
request for information on the signal of drug reaction with eosinophilia and systemic
symptoms (DRESS) and the responses were assessed by the Rapporteur.
Discussion
Having considered the available evidence of DRESS from the literature, EudraVigilance and
the cumulative review provided by the MAH of the originator cefepime-containing product,
the PRAC considered that there is insufficient evidence to establish a causal relationship
11Saper VE, Chen G, Deutsch GH, et al. Emergent high fatality lung disease in systemic juvenile arthritis. Ann Rheum Dis.
2019;78(12):1722-1731
Summary of recommendation(s)
Applicant(s): various
Background
The MAH for the originator ceftriaxone-containing product, Roche, replied to the request for
information on the signal of encephalopathy and the responses were assessed by the
Rapporteur.
Discussion
Having considered the available evidence from the non-clinical data, post–marketing setting,
clinical trials and literature and taking into account the plausible biological mechanism, the
PRAC considered that the strength of the causal relationship of encephalopathy with the use
of ceftriaxone containing medicinal products is sufficient to warrant an update of the product
information to reflect ‘encephalopathy’ as a warning and as an undesirable effect.
Summary of recommendation(s)
The MAH for Tafinlar (dabrafenib) and Mekinist (trametinib) replied to the request for
information on the signal of sarcoidosis and the responses were assessed by the Rapporteur.
Discussion
Having considered the available evidence from reported cases of sarcoidosis and the
plausible potential mechanism, the PRAC agreed that the product information for dabrafenib-
and trametinib-containing products should be updated to include the risk of sarcoidosis when
the medicinal products are used in combination. Should more evidence become available in
the future, the MAH should consider whether further updates of the product information
regarding sarcoidosis are necessary when the medicinal products are used in monotherapy.
Summary of recommendation(s)
• The MAH for Tafinlar (dabrafenib) and Mekinist (trametinib) should submit to EMA,
within 60 days, a variation to amend14 the product information.
Background
The MAH replied to the request for information on the signal of hepatitis E and the responses
were assessed by the Rapporteur.
Discussion
Having considered the available evidence of cumulative review of cases of hepatitis E as well
as the biological plausibility, the PRAC agreed that the product information for Imbruvica
(ibrutinib) should be amended to reflect the potential risk of hepatitis E.
Summary of recommendation(s)
• The MAH for Imbruvica (ibrutinib) should submit to the EMA, within 60 days, a variation
to amend15 the product information.
• In the next PSUR16, the MAH for Imbruvica (ibrutinib) should discuss whether the
current risk minimisation measures (RMMs) regarding hepatotoxicity are sufficient or
whether these could be improved in order to prevent serious outcomes (e.g. hepatic
failure). The MAH should discuss whether a product information update is warranted in
14 Update of SmPC sections 4.4 and 4.8. The package leaflet is to be updated accordingly
15 Update of section 4.4 of the SmPC. The package leaflet is to be updated accordingly
16 Data lock point (DLP): 12/11/2020
Background
The MAHs replied to the request for information on the signal of eosinophilic fasciitis and the
responses were assessed by the Rapporteur.
Discussion
Having considered the available evidence from cumulative reviews and epidemiology, the
PRAC agreed that the number of cases of eosinophilic fasciitis with immune checkpoint
inhibitors (ICIs) is very low and insufficient to conclude on a causal relationship between
eosinophilic fasciitis and ICIs. Therefore, the PRAC concurred that no further action is
warranted at this stage.
Summary of recommendation(s)
Applicant(s): various
The MAH for the originator ceftriaxone-containing product, GlaxoSmithKline B.V., replied to
the request for information on the signal of photosensitivity and the responses were
assessed by the Rapporteur.
Discussion
Having considered the available evidence from the Dutch pharmacovigilance database,
EudraVigilance and literature as well as the mechanism of action of lamotrigine, the PRAC
agreed that there is sufficient evidence to confirm a causal relationship between lamotrigine
and photosensitivity reaction.
Summary of recommendation(s)
Scope: Update of sections 4.4 and 4.8 of the SmPC in order to add a new warning on
diverticulitis following the recommendation of signal procedure SDA/010 (EPITT 19496)
adopted in May 2020. The package leaflet is updated accordingly
Background
Based on the evaluation of a signal procedure concluded in May 2020 on the occurrence or
diverticulitis (EPITT 19496), the MAH for Olumiant (baricitinib) submitted to EMA a variation
to update the product information to add the undesirable effect of diverticulitis of uncommon
frequency as a well as a new warning about this undesirable effect. For background
information, see PRAC minutes May 2020. The PRAC is responsible for adopting an outcome
based on the assessment report from the PRAC Rapporteur, to be further considered at the
level of the CHMP, responsible for adopting an opinion on this variation.
17 Update of sections 4.4 and 4.8 of the SmPC. The package leaflet is to be updated accordingly
• Based on the available data and the Rapporteur’s assessment, the PRAC supported to
update the product information18 in order to add diverticulitis as a warning and as an
undesirable effect with a frequency ‘uncommon’.
The PRAC provided the CHMP with advice on the proposed RMPs for a number of products
(identified by active substance below) that are under evaluation for initial marketing
authorisation. Information on the PRAC advice will be available in the European Public
Assessment Reports (EPARs) to be published at the end of the evaluation procedure.
Scope (accelerated assessment): Treatment of large B-cell lymphoma, diffuse large B-cell
lymphoma (DLBCL), primary mediastinal large B-cell lymphoma (PMBCL) and follicular
lymphoma grade 3B (FL3B)
18 Update of SmPC sections 4.4 and 4.8. The package leaflet is updated accordingly
19 Advanced therapy medicinal product
Background
The CHMP is evaluating an extension of application for Tysabri, a centrally authorised product
containing natalizumab, consisting of the introduction of a new pharmaceutical form
associated with a new strength and a new route of administration. The PRAC is responsible
for providing advice to the CHMP on the necessary updates to the RMP to support this
variation. For further background, see PRAC minutes July 2020.
Summary of advice
• The RMP for Tysabri (natalizumab) in the context of the variation procedure under
evaluation by the CHMP could be considered acceptable provided that an update to RMP
version 26.2 is submitted.
Background
Based on the assessment of the PSUR(s), the PRAC reviewed the benefit-risk balance of
Vipidia, Vipdomet and Incresync, centrally authorised medicines containing alogliptin,
alogliptin/metformin and alogliptin/pioglitazone respectively and issued a recommendation
on their marketing authorisation(s).
• Based on the review of the data on safety and efficacy, the benefit-risk balance of
Vipidia (alogliptin), Vipdomet (alogliptin/metformin) and Incresync
(alogliptin/pioglitazone) in the approved indication(s) remains unchanged.
• In the next PSUR, the MAH should perform a detailed review of cases of severe
cutaneous adverse reactions (SCARs).
The next PSUR should be submitted in accordance with the requirements set out in the list
of Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC.
Background
20Update of SmPC sections 4.4 and 4.8. The package leaflet is updated accordingly. The PRAC AR and PRAC recommendation
are transmitted to the CHMP for adoption of an opinion
Based on the assessment of the PSUR(s), the PRAC reviewed the benefit-risk balance of
Invokana and Vokanamet, centrally authorised medicines containing canagliflozin and
canagliflozin/metformin respectively and issued a recommendation on their marketing
authorisation(s).
• Based on the review of the data on safety and efficacy, the benefit-risk balance of
Invokana (canagliflozin) and Vokanamet (canagliflozin/metformin) in the approved
indication(s) remains unchanged.
• The MAH should submit to EMA, within 60 days, a detailed review of cases of
pancreatitis with a positive dechallenge and those with a fatal outcome together with an
updated assessment. A proposal to update the product information should be provided
as warranted.
The frequency of PSUR submission should be revised from yearly to three-yearly and the
next PSUR should be submitted to the EMA within 90 days of the data lock point. The list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC
is updated accordingly.
Background
21Update of SmPC sections 4.4 and 4.8. The package leaflet is updated accordingly. The PRAC AR and PRAC recommendation
are transmitted to the CHMP for adoption of an opinion
Based on the assessment of the PSUR, the PRAC reviewed the benefit-risk balance of
Dupixent, a centrally authorised medicine containing dupilumab and issued a
recommendation on its marketing authorisation(s).
• Based on the review of the data on safety and efficacy, the benefit-risk balance of
Dupixent (dupilumab) in the approved indication(s) remains unchanged.
• In the next PSUR, the MAH should provide further cumulative reviews of inflammatory
arthritis and enthesitis, and of Stevens-Johnson syndrome (SJS). In addition, the MAH
should provide an updated cumulative review and discussion on the signal of lupus
erythematosus/lupus-like syndrome.
The next PSUR should be submitted in accordance with the requirements set out in the list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC. The frequency of submission of the subsequent PSURs should be changed from
6-monthly to yearly and the list of Union reference dates (EURD list) will be updated
accordingly.
Applicant(s): AstraZeneca AB
Background
Based on the assessment of the PSUR(s), the PRAC reviewed the benefit-risk balance of
Bydureon and Byetta, centrally authorised medicines containing exenatide and issued a
recommendation on their marketing authorisation(s).
22Update of SmPC sections 4.4 and 4.8. The package leaflet is updated accordingly. The PRAC AR and PRAC recommendation
are transmitted to the CHMP for adoption of an opinion
The next PSUR should be submitted in accordance with the requirements set out in the list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC.
Background
Based on the assessment of the PSUR, the PRAC reviewed the benefit-risk balance of Yervoy,
a centrally authorised medicine containing ipilimumab and issued a recommendation on its
marketing authorisation(s).
• Based on the review of the data on safety and efficacy, the benefit-risk balance of
Yervoy (ipilimumab) in the approved indication(s) remains unchanged.
23 Update of SmPC section 4.8. The package leaflet is updated accordingly. The PRAC AR and PRAC recommendation are
transmitted to the CHMP for adoption of an opinion
24 Update of SmPC sections 4.4 and 4.8 The package leaflet is updated accordingly. The PRAC AR and PRAC recommendation
The next PSUR should be submitted in accordance with the requirements set out in the list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC.
Background
Nintedanib is a tyrosine kinase inhibitor indicated, as Ofev, for the treatment of idiopathic
pulmonary fibrosis (IPF) and chronic fibrosing interstitial lung diseases (ILDs) with a
progressive phenotype.
Based on the assessment of the PSUR, the PRAC reviewed the benefit-risk balance of Ofev, a
centrally authorised medicine containing nintedanib and issued a recommendation on its
marketing authorisation(s).
• Based on the review of the data on safety and efficacy, the benefit-risk balance of Ofev
(nintedanib) in the approved indication(s) remains unchanged.
• In the next PSUR, the MAH should provide a detailed analysis of data from clinical trials
as well as post-marketing cases of renal thrombotic microangiopathy (TMA).
The next PSUR should be submitted in accordance with the requirements set out in the list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC.
Background
Based on the assessment of the PSUR, the PRAC reviewed the benefit-risk balance of
Ocrevus, a centrally authorised medicine containing ocrelizumab and issued a
recommendation on its marketing authorisation(s).
• Based on the review of the data on safety and efficacy, the benefit-risk balance of
Ocrevus (ocrelizumab) in the approved indication(s) remains unchanged.
• In the next PSUR, the MAH should provide a comparison of the frequency/reporting rate
of aseptic meningitis in the multiple sclerosis (MS) population.
• The MAH should submit to the EMA, within 60 days, a variation to include the
occurrence of a de-novo progressive multifocal leukoencephalopathy (PML) case
following ocrelizumab treatment in the product information.
The next PSUR should be submitted in accordance with the requirements set out in the list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC.
Background
Based on the assessment of the PSUR, the PRAC reviewed the benefit-risk balance of
Mayzent, a centrally authorised medicine containing siponimod and issued a recommendation
on its marketing authorisation(s).
• Based on the review of the data on safety and efficacy, the benefit-risk balance of
Mayzent (siponimod) in the approved indication(s) remains unchanged.
• Nevertheless, the product information should be updated to amend the existing warning
on cutaneous neoplasms with new information on the increased number of cases with
long-term exposure to siponimod. In addition, basal cell carcinoma should be added as
28Update of SmPC sections 4.4 and 4.8. The package leaflet is updated accordingly. The PRAC AR and PRAC recommendation
are transmitted to the CHMP for adoption of an opinion
• In the next PSUR, the MAH should provide detailed reviews of cases of depression and
suicide/self-injury, and of urinary tract infections. A discussion on the need to update
the product information should be provided as warranted. In addition, the MAH should
provide a detailed description of cases of medication error.
The next PSUR should be submitted in accordance with the requirements set out in the list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC.
Background
Based on the assessment of the PSUR, the PRAC reviewed the benefit-risk balance of
Lamzede, a centrally authorised medicine containing velmanase alfa and issued a
recommendation on its marketing authorisation(s).
• Based on the review of the data on safety and efficacy, the benefit-risk balance of
Lamzede (velmanase alfa) in the approved indication(s) remains unchanged.
• In the next PSUR, the MAH should provide a discussion on the need for a product
information update and for additional risk minimisation measures to ensure a safe
administration in a home-setting. In addition, the MAH should provide a root cause
analysis of medication errors including the setting where they occurred and discuss the
effectiveness of routine risk minimisation measures (instructions for reconstitution and
administration).
The next PSUR should be submitted in accordance with the requirements set out in the list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC.
29Update of SmPC sections 4.4, 4.8 and Annex II. The package leaflet is updated accordingly. The PRAC AR and PRAC
recommendation are transmitted to the CHMP for adoption of an opinion
Background
Based on the assessment of the PSUR(s), the PRAC reviewed the benefit-risk balance of
Inhixa, a centrally authorised medicine containing enoxaparin, and nationally authorised
medicine(s) containing enoxaparin and issued a recommendation on their marketing
authorisations.
• Based on the review of the data on safety and efficacy, the benefit-risk balance of
enoxaparin-containing medicinal products in the approved indication(s) remains
unchanged.
• In the next PSUR, all MAHs should include a detailed review of cases of acute
generalised exanthematous pustulosis (AGEP).
The next PSUR should be submitted in accordance with the requirements set out in the list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC.
Applicant(s): Gilead Sciences Ireland UC (Viread), Mylan S.A.S (Tenofovir disoproxil Mylan),
Zentiva k.s. (Tenofovir disoproxil Zentiva), various
Background
• Based on the review of the data on safety and efficacy, the benefit-risk balance of
tenofovir disoproxil-containing medicinal products in the approved indication(s) remains
unchanged.
• Nevertheless, the product information should be updated to amend the existing warning
on bone effects and the information regarding breastfeeding for medicinal products
indicated in treatment of hepatitis B virus (HBV) infections. Therefore, the current terms
of the marketing authorisations should be varied30.
• In the next PSUR, the MAHs should provide detailed information on cases of
osteoporosis/osteopenia reported in subjects <35 years old, together with a causality
assessment.
• The MAH for Viread (tenofovir disoproxil) should submit to EMA, within 365 days, a
detailed analysis of cases of neural tube defects, including information on concomitant
treatment.
Additionally, the PRAC considered that the information on bone effects as amended should be
implemented in the product information of other medicinal products containing tenofovir in
combination, unless the wording is already in place. Further consideration should be given at
the level of CHMP and CMDh.
The frequency of PSUR submission should be revised from yearly to three-yearly and the
next PSUR should be submitted to the EMA within 90 days of the data lock point. The list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC
is updated accordingly. Submission of PSURs for products referred to in Articles 10(1), 10a,
14, 16a of Directive 2001/83/EC is not required any longer and the EURD list should be
updated accordingly.
Background
Based on the assessment of the PSUR(s), the PRAC reviewed the benefit-risk balance of
Zonegran, a centrally authorised medicine containing zonisamide, and nationally authorised
medicine(s) containing zonisamide and issued a recommendation on their marketing
authorisations.
30Update of SmPC sections 4.4 and 4.6. The package leaflet is updated accordingly. The PRAC AR and PRAC recommendation
are transmitted to the CHMP for adoption of an opinion
• Based on the review of the data on safety and efficacy, the benefit-risk balance of
zonisamide-containing medicinal products in the approved indication(s) remains
unchanged.
The frequency of PSUR submission should be revised from yearly to two-yearly and the next
PSUR should be submitted to the EMA within 90 days of the data lock point. The list of Union
reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC is
updated accordingly.
Applicant(s): various
Background
Based on the assessment of the PSUR(s), the PRAC reviewed the benefit-risk balance of
nationally authorised medicine(s) containing ethosuximide and issued a recommendation on
their marketing authorisation(s).
• Based on the review of the data on safety and efficacy, the benefit-risk balance of
ethosuximide-containing medicinal product(s) in the approved indication(s) remains
unchanged.
• In the next PSUR, the MAHs should provide cumulative reviews of cases of abnormal
liver function and of cases of extrapyramidal undesirable effects with a proposal for
updating the product information, as appropriate. In addition, the MAHs should include
31 Update of SmPC section 4.4. The package leaflet is updated accordingly. The PRAC AR and PRAC recommendation are
transmitted to the CHMP for adoption of an opinion
32 Update of SmPC sections 4.4 and 4.8. The package leaflet is updated accordingly. The PRAC AR and PRAC recommendation
The frequency of PSUR submission should be revised from eight-yearly to three-yearly and
the next PSUR should be submitted to the EMA within 90 days of the data lock point. The list
of Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC is updated accordingly.
Applicant(s): various
Background
Based on the assessment of the PSUR(s), the PRAC reviewed the benefit-risk balance of
nationally authorised medicine(s) containing flucloxacillin and issued a recommendation on
their marketing authorisation(s).
• Based on the review of the data on safety and efficacy, the benefit-risk balance of
flucloxacillin-containing medicinal product(s) in the approved indication(s) remains
unchanged.
• In the next PSUR, the MAHs should carefully monitor the safety topics of cardiac
disorders, abdominal pain and upper abdominal pain, dyspepsia, chromaturia and
headache with a proposal for updating the product information, as appropriate. The
MAHs should also provide a cumulative review of cases of acute interstitial nephritis with
a causality assessment. Based on the article by Muilwijk et al34, the MAHs should
provide a discussion on all available information regarding the interaction between
flucloxacillin and voriconazole with a proposal for updating the product information, as
appropriate. In addition, based on the article by Gellatly et al35, the MAHs should
33 Update of SmPC sections 4.4 and 4.8 for all formulations of flucloxacillin-containing medicinal products, and sections 4.2
and 4.8 for oral formulations of flucloxacillin-containing medicinal products. The package leaflet is updated accordingly. The
PRAC AR and PRAC recommendation are transmitted to the CMDh for adoption of a position
34 Muilwijk EW et al. Flucloxacillin results in suboptimal plasma voriconazole concentrations. Antimicrob Agents Chemother.
transplant recipients. Journal of Pharmacy Practice and Research. 2019; 49: 466-70
The next PSUR should be submitted in accordance with the requirements set out in the list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC.
Applicant(s): various
Background
Based on the assessment of the PSUR(s), the PRAC reviewed the benefit-risk balance of
nationally authorised medicine(s) containing fluconazole and issued a recommendation on
their marketing authorisation(s).
• Based on the review of the data on safety and efficacy, the benefit-risk balance of
fluconazole-containing medicinal product(s) in the approved indication(s) remains
unchanged.
• Nevertheless, the product information should be updated to include drug reaction with
eosinophilia and systemic symptoms (DRESS) as a warning and as an undesirable effect
with a frequency ‘not known’. In addition, a warning on the risk of increased resistance
due to a rise in less susceptible Candida species should be added. Furthermore,
information on reports of congenital malformations with low-dose fluconazole use during
the first trimester of pregnancy should be added. Therefore, the current terms of the
marketing authorisation(s) should be varied36.
• In the next PSUR, the MAHs should provide a cumulative review of cases of pregnancy
outcomes, including in the literature, with a cumulative dose of fluconazole >150 mg
anytime during pregnancy with a proposal for updating the product information, as
appropriate.
The next PSUR should be submitted in accordance with the requirements set out in the list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC.
Applicant(s): various
36Update of SmPC sections 4.4, 4.6, 4.8 and 5.1. The package leaflet is updated accordingly. The PRAC AR and PRAC
recommendation are transmitted to the CMDh for adoption of a position
Background
Based on the assessment of the PSUR(s), the PRAC reviewed the benefit-risk balance of
nationally authorised medicine(s) containing galantamine and issued a recommendation on
their marketing authorisation(s).
• Based on the review of the data on safety and efficacy, the benefit-risk balance of
galantamine-containing medicinal product(s) in the approved indication(s) remains
unchanged.
• Nevertheless, the product information should be updated to amend the existing warning
on cardiac disorders to include information on QTc prolongation/Torsade de pointes.
Therefore, the current terms of the marketing authorisation(s) should be varied 37.
• In the next PSUR, the MAH should provide a detailed cumulative review of cases of QTc
prolongation/Torsade de pointes with a proposal for further updating the product
information, as appropriate. The MAH should also provide a follow-up discussion on the
risk of hypersensitivity/anaphylactic shock.
The next PSUR should be submitted in accordance with the requirements set out in the list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC.
Applicant(s): various
Background
Hydroxyethyl starch (HES) is a synthetic colloid indicated for intravenous use for infusion for
the treatment of hypovolemia due to acute blood loss when crystalloids alone are not
considered sufficient.
In the context of the ongoing assessment of the submitted PSUR(s), the PRAC discussed the
list of participants (LoP) for the upcoming ad-hoc expert group (AHEG) meeting.
Summary of conclusion(s)
• The PRAC endorsed the LoP for the AHEG meeting on 11 November 2020.
37 Update of SmPC section 4.4. The package leaflet is updated accordingly. The PRAC AR and PRAC recommendation are
transmitted to the CMDh for adoption of a position
38 Scheduled on 23-26 November 2020
Applicant(s): various
Background
Based on the assessment of the PSUR(s), the PRAC reviewed the benefit-risk balance of
nationally authorised medicine(s) containing lanthanum and issued a recommendation on
their marketing authorisation(s).
• Based on the review of the data on safety and efficacy, the benefit-risk balance of
lanthanum-containing medicinal product(s) in the approved indication(s) remains
unchanged.
• In the next PSUR, the MAH should provide an analysis and a detailed discussion on the
significant difference observed regarding the distribution of fatal cases by
pharmaceutical form, cumulatively and in the reporting interval, and an assessment on
the benefit-risk balance of lanthanum carbonate for each formulation. The MAH should
also provide a cumulative review of cases of lanthanum deposition in human tissues with
a detailed analysis of the long-term clinical effects, from all sources available including
literature, with a proposal for updating the product information and additional risk
minimisation measure, as appropriate.
The frequency of PSUR submission should be revised from three-yearly to yearly and the
next PSUR should be submitted to the EMA within 90 days of the data lock point. The list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC
is updated accordingly.
Applicant(s): various
Background
• Based on the review of the data on safety and efficacy, the benefit-risk balance of
metamizole-containing medicinal product(s) in the approved indication(s) remains
unchanged.
• In the next PSUR, the MAH should continue to closely monitor cases of drug reaction
with eosinophilia and systemic symptoms (DRESS).
Additionally, the PRAC considered that information on the risk of DILI is relevant for other
fixed-drug combination products containing metamizole. The PRAC agreed that the product
information of these products should be updated accordingly. Further consideration should
be given at the level of CMDh.
The PRAC also agreed that the pharmacokinetic drug interaction between metamizole and
CYP2B6 and/or CYP3A4 substrates resulting in potentially decreased therapeutic levels of
such medicinal products and lack of efficacy should also be included in the product
information of fixed-drug combination products containing metamizole, as well as in the
product information of interacting medicinal products (i.e. tacrolimus, sertraline, valproate,
and methadone, as well as the sensitive CYP2B6 substrate efavirenz). Further consideration
should be given at the level of CHMP and CMDh.
The next PSUR should be submitted in accordance with the requirements set out in the list of
Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC.
Scope: Update of section 4.8 to add acute febrile neutrophilic dermatosis (Sweet’s
syndrome), Stevens-Johnson syndrome, transverse myelitis, posterior reversible
encephalopathy syndrome, tumour lysis syndrome as requested in the conclusions of the
latest periodic safety update report single assessment (PSUSA) procedure
(PSUSA/00010535/201911) adopted in June 2020. The package leaflet is updated
accordingly
Background
Following the evaluation of the most recently submitted PSUR(s) for the above mentioned
medicine(s), the PRAC requested the MAH to submit a variation to update the product
information in line with the conclusions of the PSUR single assessment. For background
information, see PRAC minutes June 2020. The PRAC is responsible for adopting an outcome
based on the assessment report from the PRAC Rapporteur, to be further considered at the
level of the CHMP, responsible for adopting an opinion on this variation.
Summary of recommendation(s)
• Based on the available data and the Rapporteur’s assessment, the PRAC agreed to
update the product information42 to include the undesirable effects of ‘tumour lysis
syndrome’, ‘posterior reversible encephalopathy disorders’, ‘transverse myelitis’,
‘Stevens-Johnson syndrome’ and ‘acute febrile neutrophilic dermatosis’ with a frequency
‘rare’ in the tabulated summary of adverse reactions in patients treated with ixazomib in
combination with lenalidomide and dexamethasone (all grades, grade 3 and grade 4). A
clarification is also added on the actual undesirable effect data sources.
Scope: Sixth expedited monthly summary safety report for remdesivir for October 2020
including spontaneously reported data and data from compassionate use and expanded
access programmes for the duration of the coronavirus disease (COVID-19) pandemic
Background
The PRAC assessed the sixth expedited summary safety report for Veklury (remdesivir) for
the safety monitoring of remdesivir.
Summary of advice/conclusion(s)
• The PRAC agreed that the data presented in the summary safety report are consistent
with the known safety profile of remdesivir, and no new signal was identified based on
the assessed data44.
• The MAH should provide, in the next pandemic report, or in the first PSUR, follow-up
information of reported cases where needed. In addition, more information is requested
on adverse events of special interest (AESI) including the assessment and critical
discussion on causality for reported cases.
None
44 A separate signal procedure (EPITT 19605) on remdesivir and acute kidney injury triggered by EMA based on cumulative
data from EudraVigilance is currently under evaluation
45 In accordance with Article 107n of Directive 2001/83/EC
46 In accordance with Article 107m of Directive 2001/83/EC, supervised by PRAC in accordance with Article 61a (6) of
None
None
None
None
None
9.3. Others
None
None
None
None
None
None
None
None
None
None
The EMA secretariat updated the PRAC on the activities of the COVID-19 EMA pandemic
Task Force (ETF), including an overview of ongoing clinical trials and epidemiological studies
and initiatives, as well as a summary of medicines in development and medicines
authorised for other indications, as potential treatments for COVID-19, and their safety
surveillance. In addition, the EMA Secretariat provided the PRAC with an update on COVID-
19–observational research initiatives.
According to its mandate the European Network of Centres for Pharmacoepidemiology and
Pharmacovigilance (ENCePP) steering group includes a number of representatives from
various Committees nominated for a period of three year that may be renewed. A call for
nomination of a PRAC representative to the ENCePP Steering Group for the period 2021-2023
was launched in advance of the current plenary meeting. The PRAC endorsed the nomination
of Daniel Morales as the PRAC representative to the ENCePP steering group.
None
12.6. Contacts of the PRAC with external parties and interaction with the
Interested Parties to the Committee
None
None
The EMA Secretariat presented to the PRAC an overview of the quarterly figures on the EMA
pharmacovigilance system-related workload and performance indicators. For previous
update, see PRAC minutes September 202049.
None
None
None
12.10. Periodic safety update reports (PSURs) & Union reference date
(EURD) list
None
None
None
The PRAC endorsed the draft revised EURD list, version November 2020, reflecting the
PRAC’s comments impacting on the data lock point (DLP) and PSUR submission frequencies
of the substances/combinations. The PRAC endorsed the newly allocated Rapporteurs for
upcoming PSUSAs in accordance with the principles previously endorsed by the PRAC (see
PRAC minutes April 2013).
Post-meeting note: following the PRAC meeting of November 2020, the updated EURD list
was adopted by the CHMP and CMDh at their November 2020 meetings and published on
The EMA Secretariat updated PRAC on the development of the EURD tool. Following a second
Member States survey on 50 EURD list entries, the EMA Secretariat worked on several
iterations of the tool to improve the correlation with the selected criteria. The model
developed using calibration curve from the last survey has been fine-tuned by reducing
signals/EudraVigilance data to the last 3 years improving the correlation. The EMA
Secretariat proposed to launch another Member States survey on 118 active substances with
a data lock point (DLP) in 2025 (‘parked’ entries) to test the model. The PRAC supported the
approach.
None
None
None
12.12.3. List of products under additional monitoring – consultation on the draft list
The PRAC was informed of the updates made to the list of products under additional
monitoring.
Post-meeting note: The updated additional monitoring list was published on the EMA website
on 25/11/2020, see: Home>Human Regulatory>Post-
authorisation>Pharmacovigilance>Medicines under additional monitoring>List of medicines
under additional monitoring
None
The EMA Secretariat presented to PRAC the draft EudraVigilance Expert Working Group (EV-
EWG) work programme reflecting the key activities to be performed for 2021-2022. Members
were invited to send comments on the work programme and to send expression of interest
to join the EV-EWG as a joint PRAC-EV EWG member by 15 November 2020. Follow-up
discussion is planned in December 2020.
Post-meeting note: On 13 November 2020, the EMA published on its website ‘Consideration
on core requirements for RMPs of COVID19 vaccines’ (EMA/544966/2020).
None
None
None
None
None
None
None
None
None
12.20. Others
12.20.1. Good Pharmacovigilance Practice (GVP) - update on GVP status overview – planning
for 2021
The PRAC was provided with an overview of the GVP module status, including an update on
the ongoing or planned work on new or revised GVP modules together with their scope,
proposed timelines for PRAC discussion and adoption. This work should be planned for 2021
according to priorities, also taking into account current constraints as well as needs due to
the Corona pandemic. The PRAC agreed with the proposal for 2021 and will be included in
the PRAC work plan 2021 due for discussion in December 2020.
12.20.2. Strategy on measuring the impact of pharmacovigilance – PRAC interest group (IG)
Impact – Revised process for prioritising impact research topics
As a follow-up to the September 2020 discussion (for background, see PRAC minutes
September 202050), the EMA Secretariat presented to PRAC on behalf of the PRAC interest
group Impact a revised proposal for prioritising impact research topics for selected
procedures, replacing the current monthly notification process. The PRAC endorsed the
revised proposal. The new process will start as of January 2021.
None
As per agreed criteria for new signal(s), the PRAC adopted without further plenary discussion
the recommendation of the Rapporteur to request MAH(s) to submit a cumulative review
following standard timetables52.
As per agreed criteria, the PRAC endorsed without further plenary discussion the conclusions
of the Rapporteur on the assessment of the RMP for the below mentioned medicines under
evaluation for initial marketing authorisation application. Information on the medicines
containing the below listed active substance(s) will be made available following the CHMP
opinion on their marketing authorisation(s).
51 51 Each 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
52 Either MA(s)’s submission within 60 days followed by a 60 day-timetable assessment or MAH’s submission cumulative
review within an ongoing or upcoming PSUR/PSUSA procedure (if the DLP is within 90 days), and no disagreement has been
raised before the meeting
Scope: Treatment of metastatic carcinoma of the colon or rectum, metastatic breast cancer
and metastatic or recurrent non-small cell lung cancer, advanced and/or metastatic renal
cell cancer, epithelial ovarian, fallopian tube, or primary peritoneal cancer and persistent,
recurrent, or metastatic carcinoma of the cervix. 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
As per agreed criteria, the PRAC endorsed without further plenary discussion the conclusions
of the Rapporteur on the assessment of the variation procedure for the below mentioned
medicine(s).
Scope: Submission of an updated RMP (version 23.1) in order to revise the list of safety
concerns, important identified and potential risks in line with revision 2 of GVP module V on
‘Risk management systems’. In addition, the completed studies have been deleted and, as
agreed in the conclusions of LEG 031 adopted in January 2019, the frequency of the
educational material distribution is updated to once yearly
Scope: Submission of an updated RMP (version 8.1) in order to include information about
the termination/finalisation of: 1) non-interventional study Ceplene-3290 (listed as a
category 3 study in the RMP): an open study designed to gain further knowledge on
Ceplene (histamine dihydrochloride) under day to day conditions with special emphasis on
tolerability, practicability, usage, and measurable minimal residual disease and course of
blast cells and; 2) post-authorisation efficacy study (PAES) Ceplene cohort study 3306: an
international, multicentre, observational, non-interventional, registry-based cohort study
aiming to describe and evaluate minimal residual disease (MRD) at baseline and follow-up
for the assessment of the anti-leukaemic activity of Ceplene (histamine
dihydrochloride)/interleukin-2 (IL-2) as remission maintenance therapy in adult patients
with acute myeloid leukaemia (AML) in first complete remission (CR1) compared to
matched control patients who did not receive Ceplene (histamine dihydrochloride)/IL-2. In
addition, the RMP is brought in line with revision 2.0.1 of the guidance on the format of RMP
in the EU (template). As a consequence, the list of safety concerns is amended in particular
‘drug effect decreased as a consequence of drug interaction’ is added as a new important
potential risk
Applicant: Bayer AG
Scope: Submission of an updated RMP (version 8.0) to introduce respiratory tract infection
as an important potential risk as requested in the conclusions of the periodic safety update
report single assessment (PSUSA) procedure (PSUSA/00001724/201709) adopted in May
2018. In addition, the MAH took the opportunity to update the RMP in line with revision 2 of
GVP module V on ‘Risk management systems’
Scope: Submission of an updated RMP (version 9.0) brought in line with revision 2.0.1 of
the guidance on the format of RMP in the EU (template). The MAH took the opportunity to
review the safety information and proposed to reclassify ‘cough’ from an important potential
risk to an important identified risk; to remove the important identified risks of
‘bronchospasm during and after the initiation dose assessment’ and ‘bronchospasm during
long term use’; to remove the important potential risk of ‘cough-related sequelae’, ‘off label
use in non-cystic fibrosis (CF) bronchiectasis’, ‘off label use in paediatric/adolescent CF
patients (aged 6-17 years)’, ‘administration of Bronchitol via the wrong inhaler device’ and
‘starting Bronchitol treatment without completing the full Bronchitol initiation dose
assessment (BIDA) dose’; to remove the missing information of ‘patients requiring home
oxygen or needing assisted ventilation’, ‘children <6 years of age’, ‘pregnancy and
lactation’, ‘risks associated with long-term use’ from the list of safety concerns; to add
‘increased risk of respiratory or systemic infection’ as an important potential risk replacing
‘pulmonary abscess on continued use’, ‘septicaemia on continued use’, ‘increased risk of
bacteria sputum identified or infections with extended use of Bronchitol’ and ‘microbial
infection via a contaminated inhaler device’ previously classified as important potential
risks. In addition, the pharmacovigilance plan is updated with completed studies. Finally,
the RMP is updated as requested in the conclusions of the periodic safety update report
single assessment (PSUSA) procedure (PSUSA/00009226/201904) adopted at the
November 2019 PRAC meeting
Scope: Submission of an updated RMP (version 12.0) as requested in the conclusions of the
PSUR single assessment (PSUSA) procedure (PSUSA/00002491/201904) adopted in
December 2019 in order to remove cardiac failure from the list of important identified risks
and to amend the information on dopamine agonist withdrawal syndrome (DAWS) as an
important identified risk
Scope: Submission of an updated RMP (version 14.4) to include dehydration and the
pregnancy prevention programme as additional risk minimisation measures (aRMM) in order
to align the RMP with Annex II-D on ‘Conditions or restrictions with regard to the safe and
effective use of the medicinal product’
Scope: Submission of an updated RMP (version 9.0) in order to reflect new available data
from completed studies, removal of safety concerns and removal of a target follow-up
questionnaire. The RMP is also brought in line with revision 2.0.1 of the guidance on the
format of RMP in the EU (template)
As per agreed criteria, the PRAC endorsed without further plenary discussion the conclusions
of the Rapporteur on the assessment of the updated versions of the RMP for the below
mentioned medicine(s).
Scope: Grouped variations consisting of: 1) extension of indication to include the treatment
of chronic immune thrombocytopenia (ITP) in adult patients who are refractory to other
treatments. As a consequence, sections 4.1, 4.2, 4.4, 4.5, 4.8, 5.1 and 5.2 of the SmPC are
updated. In addition, section 5.3 of the SmPC is updated with data from juvenile toxicity
studies; 2) addition of a pack size of 30 tablets with subsequent updates of sections 6.5 and
8 of the SmPC. The package leaflet, labelling and the RMP (version 2.1) are updated in
accordance. Furthermore, the product information is brought in line with the latest quality
review of documents (QRD) template (version 10.1)
Scope: Update of section 4.2 of the SmPC in order to introduce a new anti-Müllerian
hormone (AMH) assay to determine the dose of follitropin delta, following an agreed
recommendation. The RMP (version 5.0) is updated accordingly and in line with revision 2
of GVP module V on ‘Risk management systems’. The MAH took the opportunity to amend
section 4.4 of the SmPC to introduce traceability information. Finally, the product
information is brought in line with the latest quality review of documents (QRD) template
(version 10.1)
Scope: Extension of indication to include treatment of adult patients with mismatch repair
deficient (dMMR) or microsatellite instability-high (MSI-H) metastatic colorectal cancer
(CRC) for combination treatment with Opdivo (nivolumab) and 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 RMPs (Opdivo version 18.0, Yervoy version 29.0) are updated in accordance
Scope: Extension application to introduce a new pharmaceutical form (solution for infusion),
a new strength (10mg/mL) and a new route of administration (intravenous use). The RMP
(version 1.0) is updated accordingly
Scope: Grouped variations consisting of: 1) update of sections 4.5, 4.6 and 5.2 of the SmPC
to reflect the results of study 1199-0340 conducted in female patients with systemic
sclerosis associated interstitial lung disease (SSc-ILD) to investigate a potential interaction
between nintedanib and a combined oral contraceptive (COC) containing
ethinylestradiol/levonorgestrel; 2) update of sections 4.3 and 4.6 of the SmPC to introduce
a new contraindication of pregnancy. This follows the update for Ofev (nintedanib) on SSc-
ILD introduced in the context of variation II/0026 finalised in February 2020 and as
requested in the conclusions of the PSUR single assessment (PSUSA) procedure
(PSUSA/00010318/201910) adopted in May 2020. The package leaflet and the RMP
(version 7.0) are updated accordingly
Scope: Update of section 4.4 in order to include the term ‘anaphylaxis’ among the possible
symptoms of infusion-related reactions (IRRs), following an analysis of cases retrieved by
anaphylactic reaction MedDRA53 narrow standardised MedDRA queries (SMQ). The MAH took
the opportunity to update Annex II-C on ‘Other conditions and requirements of the
marketing authorisation’ and Annex II-D on ‘Conditions or restrictions with regard to the
safe and effective use of the medicinal product’ ’in line with the latest quality review of
documents (QRD) template (version 10.1). The RMP (version 6.0) is updated accordingly
Scope: Grouped variations consisting of: 1) update of section 4.4 of the SmPC to remove
the warning on growth hormone secreting tumours, consequential to the removal of
pituitary tumour growth as a potential risk from the RMP. The package leaflet is updated
accordingly; 2) update of the RMP (version 2.0) to reflect the evaluation of the final results
of study A6291010 (ACROSTUDY) (listed as a category 3 study in the RMP): an open-label,
global, multicentre, non-interventional PASS performed to monitor the long-term safety and
outcomes of pegvisomant treatment in clinical practice as per the conclusions of variation
II/0089 adopted in July 2019. The RMP is also brought in line with revision 2 of GVP module
V on ‘Risk management systems’
Scope: Submission of the final clinical study report (CSR) for study CT-P10 3.4: a phase 3,
Applicant: Bayer AG
Scope: Update of sections 4.2 and 5.2 of the SmPC in order to update the information on
the use of rucaparib in patients with hepatic impairment based on final results from part I of
study CO-338-078 (listed as a category 3 study in the RMP): a phase 1, open-label, parallel
group study to determine the pharmacokinetics, safety and tolerability of rucaparib in
patients with an advanced solid tumour and either moderate hepatic impairment or normal
hepatic function. The package leaflet and the RMP (version 4.0) are updated accordingly.
The MAH took the opportunity to introduce minor corrections in the SmPC, to update the list
of local representatives in the package leaflet, and to bring the product information in line
with the latest quality review of documents (QRD) template (version 10.1).and in line with
the European Commission (EC) guideline on ‘excipients in the labelling and package leaflet
of medicinal products for human use’
Scope: Submission of the final report from study CLCZ696D2301 (PARAGON HF) (listed as a
category 3 study in the RMP): a multicentre, randomized, double-blind, parallel group,
active-controlled study to evaluate the efficacy and safety of LCZ696 (sacubitril/valsartan)
Scope: Extension application to introduce a new pharmaceutical form associated with a new
strength (350 mg/mL oral solution). The RMP (version 0.1) is updated in accordance
Scope: Extension application to introduce a new pharmaceutical form associated with a new
strength (500 mg film-coated tablets). The RMP (version 0.1) is updated in accordance
Applicant: Biocodex
Scope: Extension application to add a new strength (100 mg capsules). The RMP (version
2.0) is updated in accordance
Based on the assessment of the following PSURs, the PRAC concluded that the benefit-risk
balance of the below mentioned medicines remains favourable in the approved indication(s)
and adopted a recommendation to maintain the current terms of the marketing
authorisation(s) together with the assessment report. As per agreed criteria, the procedures
listed below were finalised at the PRAC level without further plenary discussion.
The next PSURs should be submitted in accordance with the requirements set out in the list
of Union reference dates (EURD list) provided for under Article 107c(7) of Directive
2001/83/EC and published on the European medicines web-portal, unless changes apply as
stated in the outcome of the relevant PSUR/PSUSA procedure(s).
Applicant(s): AstraZeneca AB
Applicant: AstraZeneca AB
Applicant(s): Cis Bio International (Ytracis), Eckert & Ziegler Radiopharma GmbH (Yttriga)
None
Applicant(s): various
Applicant(s): various
Scope: Detailed review of cases of B-cell acute lymphoblastic leukaemia as requested in the
conclusions of the PSUR single assessment (PSUSA) procedure (PSUSA/00001838/201912)
adopted in July 2020
Based on the assessment of the following PASS protocol(s), result(s), interim result(s) or
feasibility study(ies), and following endorsement of the comments received, the PRAC
adopted the conclusion of the Rapporteurs on their assessment for the medicines listed
below without further plenary discussion.
Scope: MAH’s response to MEA 092 [protocol for study 20190404: a retrospective cohort
study to assess the use of erythropoiesis stimulating agents (ESAs) in subjects receiving
myelosuppressive chemotherapy in Europe] as per the request for supplementary
information (RSI) adopted in May 2020
Scope: MAH’s response to MEA 088 [protocol for a joint PASS for study 2600153 (INFORM):
an observational study regarding interferon beta exposure in the second and third
trimesters of pregnancy - a register-based drug utilisation study (DUS) in Finland and
Sweden] as per the request for supplementary information (RSI) adopted in April 2020
Scope: MAH’s response to MEA 045 [protocol for a joint PASS for study 2600153 (INFORM):
an observational study regarding interferon beta exposure in the second and third
trimesters of pregnancy - a register-based drug utilisation study (DUS) in Finland and
Sweden] as per the request for supplementary information (RSI) adopted in April 2020
Applicant: Bayer AG
Scope: MAH’s response to MEA 025 [protocol for a joint PASS for study 2600153 (INFORM):
an observational study regarding interferon beta exposure in the second and third
trimesters of pregnancy - a register-based drug utilisation study (DUS) in Finland and
Sweden] as per the request for supplementary information (RSI) adopted in April 2020
Scope: MAH’s response to MEA 023 [protocol for a joint PASS for study 2600153 (INFORM):
59In accordance with Article 107m of Directive 2001/83/EC, supervised by PRAC in accordance with Article 61a (6) of
Regulation (EC) No 726/2004
Scope: MAH’s response to MEA 010 [protocol for a joint PASS for study 2600153 (INFORM):
an observational study regarding interferon beta exposure in the second and third
trimesters of pregnancy - a register-based drug utilisation study (DUS) in Finland and
Sweden] as per the request for supplementary information (RSI) adopted in April 2020
None
Applicant: AstraZeneca AB
Scope: Submission of the final report from study D6570R00002 (listed as a category 3
study in the RMP): a descriptive, non-interventional, multinational European cohort study of
new users of aclidinium, aclidinium/formoterol, and other selected chronic obstructive
pulmonary disease (COPD) medications to describe the characteristics and patterns of use.
As a consequence, the following safety concerns listed as missing information in the RMP
are removed: ‘safety in patients with hepatic or severe renal impairment’, ‘safety in patients
with benign hyperplasia or urinary retention’ and ‘use in pregnancy or lactation’. The RMP
(version 8.0) is updated accordingly
Applicant: AstraZeneca AB
Scope: Submission of the final report from study D6570R00002 (listed as a category 3
study in the RMP): a descriptive, non-interventional, multinational European cohort study of
new users of aclidinium, aclidinium/formoterol, and other selected chronic obstructive
pulmonary disease (COPD) medications to describe the characteristics and patterns of use.
As a consequence, the following safety concerns listed as missing information in the RMP
are removed ‘safety in patients with hepatic or severe renal impairment’, ‘safety in patients
with benign hyperplasia or urinary retention’ and ‘use in pregnancy or lactation’. The RMP
(version 5.0) is updated accordingly
Scope: Submission of the final report from study I4V-MC-B010 (listed as a category 3 study
in the RMP): an observational, multinational cross-sectional survey amongst
rheumatologists to assess the effectiveness of the risk minimisation measures (RMM) for
Olumiant (baricitinib). The RMP (version 9.2) is updated accordingly. The MAH took the
opportunity to remove from the RMP three safety concerns listed as missing information
namely ‘use in combination with biologic disease-modifying anti-rheumatic drugs
(bDMARDs) or with other Janus kinase (JAK) inhibitors’, ‘use in patients with severe hepatic
impairment’, ‘effect on fertility, on pregnancy and the foetus’, and ‘use in breastfeeding’ as
requested in the conclusions of variation II/006 finalised in July 2018
Scope: Submission of the final clinical study report (CSR) for study CRAD001MIC03
(TOSCA): an international disease registry collecting data on manifestations, interventions
and outcomes in patients with tuberous sclerosis complex (TSC). The RMP (version 15.0) is
updated accordingly and in line with the conclusions of variation WS1671 adopted in
October 2019
Scope: Submission of the final report from study GS-US-248-0123 (listed as a category 3
study in the RMP): a long-term observational follow-up registry of subjects who did not
achieve sustained virologic response in Gilead-sponsored trials in subjects with chronic
hepatitis C infection. The RMPs (Harvoni version 7.1, Epclusa version 6.1, Vosevi version
3.1) are updated accordingly
Scope: Submission of the final study report for study 178-CL-114: an evaluation of
cardiovascular events in users of mirabegron and other treatments for overactive bladder
Scope: Submission of the final report from study A3921205 (listed as a category 3 study in
the RMP): an observational PASS within the Consortium of Rheumatology Researchers of
North America (CORRONA) registry comparing rates of malignancy, cardiovascular and
serious infection outcomes among patients treated for moderately to severely active
rheumatoid arthritis. The RMP (version 10.1) is updated accordingly
Scope: Interim report of the safety surveillance programme using the Register for
Antirheumatic Therapies in Sweden (ARTIS): a national prospective, observational,
uncontrolled cohort study to evaluate the risk of selected adverse events (AEs) in
rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA) and other rheumatic disease
patients treated with adalimumab
Scope: Annual registry report of the safety surveillance programme using the Spanish
Registry for Adverse Events for Biological Therapy in Rheumatic Diseases (BIOBASASER)
Applicant: Bayer AG
Scope: MAH’s response to MEA 003 [tenth annual European Haemophilia Safety
Surveillance (EUHASS) report for study 14149 (listed as a category 3 study in the RMP):
evaluation of cases with adverse events (AEs) of special interest in the EUHASS registry
[final clinical study report (CSR) expected in December 2021]] as per the request for
supplementary information (RSI) adopted in May 2020
Scope: Second annual interim results for study M-41008-40 (listed as a category 3 study in
the RMP): an observational PASS in European psoriasis registers to evaluate the long-term
safety of Skilarence (dimethyl fumarate) used for the treatment of patients with moderate
to severe psoriasis [future due date(s): end of data collection: Q1 2027; final study report
expected within a year of availability of the final data set]
Scope: Fifth annual report for study CNTO148ART4001: a pregnancy research initiative to
study the exposure to golimumab during pregnancy in patients with rheumatoid arthritis,
psoriatic arthritis, and ankylosing spondylitis: a review and analysis of birth outcomes from
the Swedish, Danish, and Finnish medical birth registers; together with the study summary
results for the 2020 interval report for study CNTO148ART4001
Scope: Fifth progress report for study MK-8259-013, the ulcerative colitis (UC) Nordic
registry: a non-interventional observational longitudinal PASS of Simponi (golimumab) in
the treatment of UC using Nordic national health registries
Scope: MAH’s response to MEA 004.7 [third interim report for study CLCZ696B2015 (PASS
3) (listed as a category 3 study in the RMP): a non-interventional post-authorisation
European multi-database safety study to assess the risk of myotoxicity, hepatotoxicity and
Scope: MAH’s response to MEA 003.4 [third interim report for study CLCZ696B2015 (PASS
3) (listed as a category 3 study in the RMP): a non-interventional post-authorisation
European multi-database safety study to assess the risk of myotoxicity, hepatotoxicity and
acute pancreatitis in statin-exposed heart failure patients with or without concomitant use
of Entresto/Neparvis (sacubitril/valsartan) [final report expected in Q2/2020]] as per the
request for supplementary information (RSI) adopted in June 2020
Applicant: Octapharma AB
Scope: Yearly progress report for study GENA-99: a prospective, multinational, non-
interventional post-authorisation study to document the long-term immunogenicity, safety,
and efficacy of simoctocog alfa in patients with haemophilia A treated in routine clinical
practice [final report due date expected in 2020]
Applicant: Octapharma AB
Scope: Yearly progress report for study GENA-99: a prospective, multinational, non-
interventional post-authorisation study to document the long-term immunogenicity, safety,
and efficacy of simoctocog alfa in patients with haemophilia A treated in routine clinical
practice [final report due date expected in 2020]
Scope: MAH’s response to MEA 018.3 [fourth yearly progress report for study PGL14-001: a
prospective, multinational, multicentre, non-interventional study to evaluate the long-term
safety of Esmya (ulipristal acetate) in particular the endometrial safety and the current
prescription and management patterns of Esmya (ulipristal acetate) in a long-term
treatment setting [final clinical study report (CSR) expected in 2023]] as per the request for
supplementary information (RSI) adopted in June 2020
Scope: MAH’s response to MEA 001 [interim analysis report for study MLN-0002-401 (listed
as a category 3 study in the RMP): an international prospective, observational, cohort
safety study comparing vedolizumab to other biologic agents in patients with ulcerative
colitis or Crohn’s disease [final clinical study report (CSR) expected in June 2022]] as per
the request for supplementary information (RSI) adopted in July 2020
17.6. Others
None
Disclosure of information related to this section cannot be released at the present time as it
is deemed to contain commercially confidential information.
Information related to this section cannot be released at the present time as it is deemed to
contain commercially confidential information.
Information related to this section cannot be released at the present time as it is deemed to
contain commercially confidential information.
Based on the review of the available pharmacovigilance data for the medicines listed below
and the CHMP Rapporteur’s assessment report, the PRAC considered that either the renewal
of the marketing authorisation procedure could be concluded - and supported the renewal of
their marketing authorisations for an unlimited or additional period, as applicable - or no
amendments to the specific obligations of the marketing authorisation under exceptional
circumstances for the medicines listed below were recommended. As per agreed criteria, the
procedures were finalised at the PRAC level without further plenary discussion.
18.1.4. Smallpox vaccine (live modified vaccinia virus Ankara) - IMVANEX (CAP) -
EMEA/H/C/002596/S/0054 (without RMP)
15.3.16.
Rivaroxaban -
XARELTO (CAP)
17.2.4.
Interferon beta-
1b -
BETAFERON
(CAP)
17.5.4.
Damoctocog
alfa pegol - JIVI
(CAP)
Karen Pernille Harg Alternate Norway No interests Full involvement
declared
Adam Przybylkowski Member Poland No interests Full involvement
declared
Katarzyna Ziolkowska Alternate Poland No interests Full involvement
declared
Ana Diniz Martins Member Portugal No interests Full involvement
declared
Marcia Silva Alternate Portugal No interests Full involvement
declared
Roxana Stefania Stroe Member Romania No interests Full involvement
declared
Alexandra - Maria Alternate Romania No interests Full involvement
Spurni declared
Michal Radik Member Slovakia No interests Full involvement
declared
Marek Juracka Alternate Slovakia No interests Full involvement
declared
Jasmina Klopcic Alternate Slovenia No interests Full involvement
declared
Eva Segovia Member Spain No interests Full involvement
declared
Maria del Pilar Rayon Alternate Spain No interests Full involvement
declared
Ulla Wändel Liminga Member Sweden No interests Full involvement
declared
Annika Folin Alternate Sweden No interests Full involvement
declared
Milou Daniel Drici Member Independent No Full involvement
scientific expert restrictions
applicable to
this meeting
Birgitta Grundmark Member Independent No interests Full involvement
scientific expert declared
Daniel Morales Member Independent No interests Full involvement
scientific expert declared
Hedvig Nordeng Member Independent No interests Full involvement
scientific expert declared
Stefan Weiler Member Independent No 17.5.12.
scientific expert participation Ulipristal
in acetate - ESMYA
discussion, (CAP)
final
deliberations
and voting
on:
Raymond Anderson Member Healthcare No interests Full involvement
Professionals' declared
Representative
Roberto Frontini Alternate Healthcare No Full involvement
Professionals' restrictions
Representative applicable to
this meeting
Cathalijne van Doorne Member Patients’ No interests Full involvement
Organisation declared
Representative
Virginie Hivert Alternate Patients’ No Full involvement
Organisation restrictions
Representative applicable to
this meeting
Ivona Bahnik Biševac Expert - via Croatia No Full involvement
telephone* restrictions
applicable to
this meeting
Ivana Ljubičić Expert - via Croatia No Full involvement
telephone* restrictions
applicable to
this meeting
Katica Milčić Expert - via Croatia No Full involvement
telephone* restrictions
applicable to
this meeting
Maja Tabak Slošić Expert - via Croatia No Full involvement
telephone* restrictions
applicable to
this meeting
Karin Erneholm Expert - via Denmark No Full involvement
telephone* restrictions
applicable to
this meeting
Pernille Gammelgaard Expert - via Denmark No interests Full involvement
telephone* declared
Marian Hjortlund Allon Expert - via Denmark No interests Full involvement
telephone* declared
Moritz Sander Expert - via Denmark No interests Full involvement
telephone* declared
Caroline Marie Voss Expert - via Denmark No interests Full involvement
telephone* declared
Mette Juul Wikkelsø Expert - via Denmark No interests Full involvement
telephone* declared
Kroot Aab Expert - via Estonia No interests Full involvement
telephone* declared
Emiliano Gemma Expert - via France No interests Full involvement
telephone* declared
Faustine Vidil Expert - via France No interests Full involvement
telephone* declared
* Experts were only evaluated against the agenda topics or activities they participated in
For a list of acronyms and abbreviations used in the PRAC minutes, see:
Home>Committees>PRAC>Agendas, minutes and highlights
The Notes give a brief explanation of relevant minute’s items and should be read in conjunction with the
minutes.
EU Referral procedures for safety reasons: Urgent EU procedures and Other EU referral
procedures
(Items 2 and 3 of the PRAC minutes)
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, the 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
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
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)
(Item 6 of the PRAC minutes)
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)
(Item 7 of the PRAC minutes)
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
(Item 9 of the PRAC minutes)
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