11 May 2020 1
EMA/PRAC/201784/2020
Pharmacovigilance Risk Assessment Committee (PRAC)

PRAC recommendations on signals
Adopted at the 14-17 April 2020 PRAC meeting

This document provides an overview of the recommendations adopted by the Pharmacovigilance Risk
Assessment Committee (PRAC) on the signals discussed during the meeting of 14-17 April 2020
(including the signal European Pharmacovigilance Issues Tracking Tool [EPITT] 2 reference numbers).
PRAC recommendations to provide supplementary information are directly actionable by the concernedmarketing authorisation holders (MAHs). PRAC recommendations for regulatory action (e.g.
amendment of the product information) are submitted to the Committee for Medicinal Products for
Human Use (CHMP) for endorsement when the signal concerns Centrally Authorised Products (CAPs),and to the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh)
for information in the case of Nationally Authorised Products (NAPs). Thereafter, MAHs are expected totake action according to the PRAC recommendations.
When appropriate, the PRAC may also recommend the conduct of additional analyses by the Agency orMember States.
MAHs are reminded that in line with Article 16(3) of Regulation No (EU) 726/2004 and Article 23(3) of
Directive 2001/83/EC, they shall ensure that their product information is kept up to date with thecurrent scientific knowledge including the conclusions of the assessment and recommendations
published on the European Medicines Agency (EMA) website (currently acting as the EU medicines
webportal).
For CAPs, at the time of publication, PRAC recommendations for update of product information havebeen agreed by the CHMP at their plenary meeting (28-30 April 2020) and corresponding variations
will be assessed by the CHMP.
For nationally authorised medicinal products, it is the responsibility of the National Competent
Authorities (NCAs) of the Member States to oversee that PRAC recommendations on signals areadhered to.
Variations for CAPs are handled according to established EMA procedures. MAHs are referred to theavailable guidance. Variations for NAPs (including via mutual recognition and decentralised procedures)are handled at national level in accordance with the provisions of the Member States.
Expected publication date. The actual publication date can be checked on the webpage dedicated to PRAC
recommendations on safety signals.
2
The relevant EPITT reference number should be used in any communication related to a signal.
1

Official address Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands
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Send us a question Go to www.ema.europa.eu/contact

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An agency of the European Union© European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged.

The timeline recommended by PRAC for submission of variations following signal assessment isapplicable to both innovator and generic medicinal products, unless otherwise specified.
For procedural aspects related to the handling of PRAC recommendations on signals (e.g. submission
requirements, contact points, etc.) please refer to the Questions and Answers on signal management.

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1. Recommendations for update of the product information 3
1.1. Andexanet alfa – Erroneous assay results for levels of anti-factor Xa
activity
Authorisation procedure

Centralised

EPITT No19493

PRAC rapporteur(s)Menno van der Elst (NL)

Date of adoption

17 April 2020

Recommendation [see also section 3]
Having considered the available evidence, following the assessment of the Eudravigilance, literatureand data obtained from the Marketing Authorisation Holder (MAH) of Ondexxya (Portola Netherlands
B.V.), the PRAC has agreed the following recommendation:
1. The product information for Ondexxya (andexanet alfa) should be updated to reflect the risk oferroneous assay results for levels of anti-factor Xa activity with use of andexanet alfa. The MAH of
Ondexxya should submit a variation within two months to amend the product information as described
below (new text underlined/text to be removed with strikethrough).
[…]
Summary of product characteristics
4.4. Special warnings and precautions for use
Limitations of use
Clinical efficacy is based upon reversal of anti-FXa-activity in healthy volunteers dosed with apixaban
or rivaroxaban. Andexanet alfa is not suitable for pre-treatment of urgent surgery. Use for edoxabanor enoxaparin-reversal is not recommended due to lack of data. Andexanet alfa will not reverse theeffects of non-FXa inhibitors (see section 5.1).
Although determination of anti-FXa-activity in emergency situations is increasingly recommended, norecommendation for adapted andexanet alfa dosage is available. Therefore, Ttreatment monitoringshould be based mainly on clinical parameters indicative of appropriate response (i.e., achievement of
haemostasis), lack of efficacy (i.e., re-bleeding), and adverse events (i.e., thromboembolic events).
Treatment monitoring of andexanet alfa should not be based on anti-FXa-activity. Commercial antiFXa-activity assays are unsuitable for measuring anti-FXa activity following administration ofandexanet alfa as these assays result in erroneously elevated anti-FXa activity levels, thereby causing
a substantial underestimation of the reversal activity of andexanet alfa.
Dosage recommendation is based upon data-modelling in healthy volunteers. Validation has not beensuccessful, yet. Data from bleeding patients are limited. Preliminary data suggest higher risk ofthrombosis for patients receiving the higher dose of andexanet, previous lower dose of the anti-FXa
inhibitor, and patients on rivaroxaban.
In ANNEXA-4, intracranial haemorrhage (ICH) patients (GCS > 7 and haematoma volume < 60 mL)
have been included. Treatment of patients with more severe ICH with andexanet alfa has not beenstudied.

Translations in all official EU languages of the new product information adopted by PRAC are also available to MAHs on the
EMA website.

3

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5.1. Pharmacodynamic properties[…]
Pharmacodynamic effects
The effects of andexanet alfa can be measured through pharmacodynamic markers, including anti-FXa
activity, and free fraction of available FXa inhibitor as well as through restoration of thrombin
generation.
Anti-FXa activity correlates poorly to clinical efficacy and safety, making it unsuitable for dosing
guidance (see section 4.4 and 5.1) Commercial anti-FXa-activity assays are unsuitable for measuringanti-FXa activity following administration of andexanet alfa. Due to the reversible binding of andexanet
alfa to the FXa inhibitor, the high sample dilution currently used in these assays leads to dissociation of
the inhibitor from andexanet alfa, resulting in detection of erroneously elevated anti-FXa activity levels,
thereby causing a substantial underestimation of the reversal activity of andexanet alfa.
In prospective, randomized, placebo-controlled, dose-ranging studies in healthy subjects, the dose anddose regimen of andexanet alfa required to reverse anti-FXa activity and restore thrombin generation
for FXa inhibitors (apixaban or rivaroxaban) were determined with modified assays that are notcommercially available.

1.2. Ibuprofen; ketoprofen; and fixed-dose combinations – Serious
exacerbation of infections
Authorisation procedure

Centralised and non-centralised

EPITT No

19415

PRAC rapporteur(s)Anette Kirstine Stark (DK)

Date of adoption

17 April 2020

Recommendation [see also section 3 for Pedea]
Based on the available data, the PRAC concluded that the risk of complications due to masking ofsymptoms of infection associated to the use of ibuprofen and ketoprofen containing products, cannot
be excluded. Therefore, a product information update is deemed necessary.
Masking of signs and symptoms of an infection is a well-known risk of NSAIDs, and data from several
studies indicates that the risk is clinically relevant mainly in the setting of bacterial community
acquired pneumonia (CAP) and complications to varicella. Therefore, there is a need to update thecurrent warnings on this risk.
The MAH(s) of ibuprofen and ketoprofen-containing medicinal product(s) should submit a variation
within 6 months, to amend the product information of systemic products as described below (new text
to be added underlined):
This text is to be adapted, at a national level, to the existing wordings in the product information of theibuprofen and ketoprofen-containing medicinal product(s).

Summary of product characteristics
4.2. Posology and methods of administration

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The lowest effective dose should be used for the shortest duration necessary to relieve symptoms (seesection 4.4).
4.4. Special warnings and precautions for use
Masking of symptoms of underlying infections[Product name] can mask symptoms of infection, which may lead to delayed initiation of appropriate
treatment and thereby worsening the outcome of the infection. This has been observed in bacterial
community acquired pneumonia and bacterial complications to varicella. When [product name] isadministered for fever or pain relief in relation to infection, monitoring of infection is advised. In nonhospital settings, the patient should consult a doctor if symptoms persist or worsen.

Package leaflet
2. Warnings and precautions
Talk to your pharmacist or doctor if:[…] you have an infection - please see heading “Infections” below.
[…]
Infections[Product name] may hide signs of infections such as fever and pain. It is therefore possible that[product name] may delay appropriate treatment of infection, which may lead to an increased risk ofcomplications. This has been observed in pneumonia caused by bacteria and bacterial skin infections
related to chickenpox. If you take this medicine while you have an infection and your symptoms of theinfection persist or worsen, consult a doctor without delay.
3. How to use [product name]
The lowest effective dose should be used for the shortest duration necessary to relieve symptoms. If
you have an infection, consult a doctor without delay if symptoms (such as fever and pain) persist or
worsen (see section 2).

1.3. Idelalisib – Drug reaction with eosinophilia and systemic symptoms(DRESS)
Authorisation procedure

Centralised

EPITT No

19500

PRAC rapporteur(s)Martin Huber (DE)Date of adoption

17 April 2020

Recommendation [see also section 3]
Based on the available data, the PRAC concluded that the risk of drug reaction with eosinophilia andsystemic symptoms (DRESS) associated to the use of idelalisib containing products cannot be excluded.
Therefore, the MAH(s) of idelalisib-containing medicinal product(s) should submit a variation within 2months, to amend the product information as described below (new text to be added underlined, text
to be removed strike-through):

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Summary of product characteristics
4.4. Special warnings and precautions for use
Severe cutaneous reactions Stevens-Johnson syndrome and toxic epidermal necrolysis
Cases of Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) and drug reaction
with eosinophilia and systemic symptoms (DRESS) with fatal outcomes have been reported when haveoccurred with idelalisib. Cases of SJS and TEN with fatal outcomes have been reported when idelalisib
was administered concomitantly with other medicinal products associated with these syndromes. If
SJS, or TEN or DRESS is suspected, idelalisib should be immediately discontinued interrupted and thepatient treated accordingly.

4.8. Undesirable effects
Table 2: Adverse drug reactions reported in clinical studies in subjects with haematologic malignancies
receiving idelalisib and from post-marketing
Reaction

Any grade

Grade ≥ 3

Skin and subcutaneous tissue disorders
Drug reaction with

Not known

Not applicableeosinophilia and systemic
symptoms (DRESS)******** observed in post-marketing data
Severe cutaneous reactions Stevens-Johnson syndrome and toxic epidermal necrolysis (see section
4.4)
Rarely, c Cases of SJS, and TEN and DRESS have occurred when idelalisib was administeredconcomitantly with other medicinal products associated with these syndromes (bendamustine,
rituximab, allopurinol, and amoxicillin, and sulfamethoxazole/trimethoprim). SJS or TEN occurred
within one month of the medicinal combination and fatal outcomes have resulted.

Package leaflet
2. What you need to know before you take [product name]Warnings and precautions…Severe skin blistering conditions including Stevens-Johnson syndrome and toxic epidermal necrolysis,
and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported in association
with idelalisib treatment some people who have received Zydelig while also receiving other medicines
known to cause these potentially life-threatening conditions. Stop using idelalisib and seek medical
attention immediately if you notice any of the symptoms described in section 4. Blistering can also
involve the lining of the mouth genitals, and/or. Peeling away of the skin may lead to serious infection.
Tell your doctor right away:•

if you have redness and blistering of the skin•

if you have swelling and blistering of the lining of the mouth, throat, nose, genitals, and/or eyes

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4. Possible side effects
STOP taking Zydelig and seek medical help immediately if you experience any of the following:
reddish patches on the trunk, small circumscribed changes in the colour of the skin, often with•central blisters, skin peeling, ulcers of mouth, throat, nose, genitals and eyes. These serious skinrashes can be preceded by fever and flu-like symptoms (Stevens-Johnson syndrome, toxic
epidermal necrolysis).
Widespread rash, high body temperature and enlarged lymph nodes (DRESS syndrome or drug•

hypersensitivity syndrome).
•

redness and blistering of the skin•

swelling and blistering of the lining of the mouth, genitals, and/or eyes

1.4. Insulin 4 – Cutaneous amyloidosis
Authorisation procedure

Centralised and non-centralised

EPITT No

19499

PRAC rapporteur(s)Hans Christian Siersted (DK)

Date of adoption

17 April 2020

Recommendation
Having considered the available evidence in EudraVigilance and in the literature with regards to therisk of cutaneous amyloidosis with insulins, the PRAC has agreed that the MAHs of insulin-containing
medicinal products should submit a variation within 2 months from the publication of the PRAC
recommendation, to amend the product information as described below (new text underlined, text tobe removed with strikethrough):
Summary of product characteristics
4.2. Posology and method of administration
Method of administration[…][Product name] is administered subcutaneously by injection in the abdominal wall, the thigh, the upper
arm, the deltoid region or the gluteal region. Injection sites should always be rotated within the same
region in order to reduce the risk of lipodystrophy and cutaneous amyloidosis (see section 4.4 and
4.8).
4.4. Special warnings and precautions for use
Patients must be instructed to perform continuous rotation of the injection site to reduce the risk ofdeveloping lipodystrophy and cutaneous amyloidosis. There is a potential risk of delayed insulin
absorption and worsened glycaemic control following insulin injections at sites with these reactions. A
sudden change in the injection site to an unaffected area has been reported to result in
hypoglycaemia. Blood glucose monitoring is recommended after the change in the injection site, anddose adjustment of antidiabetic medications may be considered.
4

All insulin-containing products are concerned.

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4.8. Undesirable effects
Skin and subcutaneous tissue disorders
Frequency ‘not known’: Cutaneous amyloidosis
Description of selected adverse reactions
Lipodystrophy Skin and subcutaneous tissue disorders:
Lipodystrophy and cutaneous amyloidosis may occur at the injection site and delay local insulin
absorption. Continuous rotation of the injection site within the given injection area may help to reduceor prevent these reactions (See section 4.4).

Package leaflet
2. What you need to know before you use [product name]
Skin changes at the injection site:
The injection site should be rotated to prevent skin changes such as lumps under the skin. The insulin
may not work very well if you inject into a lumpy area (see How to use [product name]). Contact yourdoctor if you are currently injecting into a lumpy area before you start injecting in a different area.
Your doctor may tell you to check your blood sugar more closely, and to adjust your insulin or yourother antidiabetic medications dose.

4. Possible side effects
Skin changes at the injection site:
If you inject insulin too often at the same place, the fatty tissue may either shrink (lipoatrophy) or
thicken (lipohypertrophy). Lumps under the skin may also be caused by build-up of a protein calledamyloid (cutaneous amyloidosis). The insulin may not work very well if you inject into a lumpy area.
Change the injection site with each injection to help prevent these skin changes.

If the risk of lipodystrophy in section 4 of the package leaflet is listed under a frequency that isdifferent from the above frequency for cutaneous amyloidosis the following update is proposed:
4. Possible side effects[…]
Other side effects include:[…]
Uncommon (may affect up to 1 in 100 people)
Changes under the skin where you use the injection (lipodystrophy):
Skin changes at the injection site:
If you inject insulin too often at the same place, the fatty tissue may shrink (lipoatrophy) or thicken(lipohypertrophy) (may affect up to 1 in 100 people). Lumps under the skin may also be caused bybuild-up of a protein called amyloid (cutaneous amyloidosis; how often this occurs is not known). The
insulin may not work very well if you inject into a lumpy area. Change the injection site with each
injection to help prevent these skin changes.

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Other side effects include:[…]
Uncommon (may affect up to 1 in 100 people)[…]

2. Recommendations for submission of supplementary
information
INN

Signal (EPITT No)

PRAC

Action for MAH

MAH

Updated cumulative
reviews of literatureand clinical studies tobe provided in next
PSURs (submission by
17 February 2023 fordutasteride; check
update of EURD list for
finasteride next PSUR
submission date)

MAHs of

Supplementary
information requested(submission by 2 July
2020)

Janssen-Cilag

Supplementary
information requested(submission by 2 July
2020)

Merck Serono

Supplementary
information requested(submission by 2 July
2020)

Roche

All MAHs withproducts
containing
paclitaxelauthorised in
the EEA andwith at least
one case
concerning PMLwith paclitaxel
as suspect drugin theirpharmacovigilan
ce databases

Rapporteur

5 alfa-reductase

Type 2 diabetes

Annikainhibitors

mellitus (19424)

Folin (SE)(5ARIs):finasteride;dutasterideAbiraterone

Anaphylactic reaction

Eva A.

(19535)

Segovia(ES)

Bisoprolol

Angioedema (19542)

Kirsti
Villikka (FI)Ceftriaxone

Encephalopathy

Zane(19492)

Neikena(LV)

Paclitaxel

Progressive multifocal

Menno vanSupplementaryleukoencephalopathy

der Elst

information requested(PML) (19553)(NL)(submission by 2 July
2020)

PRAC recommendations on signals
EMA/PRAC/201784/2020

finasteride anddutasteridecontaining
products with
PSURs
obligations

International NV

Ltd

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INN

Signal (EPITT No)

PRAC

Action for MAH

MAH

Rapporteur

Pomalidomide

Progressive multifocal

Eva A.

Supplementary

Celgene Europe

leukoencephalopathy

Segovia

information requested

BV(PML) (19546)(ES)(submission by 2 July
2020)

Tumour necrosis
factor alphainhibitors:
adalimumab;
certolizumab
pegol;
etanercept;
golimumab;
infliximab

Kaposi’s sarcoma

Ulla

Supplementary

AbbVie(19480)Wändelinformation requested

Deutschland

Liminga(submission by 8 May

GmbH & Co.,

(SE)

2020)

UCB Pharma

Vedolizumab

Evans’ syndrome,

Adam

Supplementary

Takeda Pharma

autoimmune haemolytic

Przybylkow

information requested

A/S

anaemia, immuneski (PL)(submission by 2 July

S.A., Pfizer
Europe MA
EEIG, Janssen
Biologics B.V.

thrombocytopenic

2020)

purpura (19547)

3. Other recommendations
INN

Signal (EPITT No)

PRAC

Action for MAH

MAH

Rapporteur

Adalimumab

Andexanet alfa

Autoimmune

Ulla

RoutineMAHs ofencephalitis (19483)

Wändelpharmacovigilanceadalimumab

Liminga

containing(SE)

products

Erroneous assay results

Menno vanfor levels of anti-factor

der Elst

Xa activity (19493)(NL)∙ See section 1.1∙ Monitor in upcoming
PSURs

PortolaNetherlands
B.V.

∙ Include key elements
defined by PRAC in the
Direct Healthcare
Professional
Communication (DHPC)
to be finalised anddistributed as per thetime schedule agreed
within the type IIvariation
EMEA/H/C/004108/II/0
011

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INN

Signal (EPITT No)

PRAC

Action for MAH

MAH

Rapporteur

Ibuprofen

Serious exacerbation ofAnetteRoutineRecordati Rare

infections (19415)

Kirstine

pharmacovigilance

Diseases (MAH

Stark (DK)
Idelalisib

Drug reaction with

Martineosinophilia andHuber (DE)systemic symptoms(DRESS) (19500)

of Pedea)∙ See section 1.4∙ Monitor serious
cutaneous adverse
reactions inforthcoming PSURs

PRAC recommendations on signals
EMA/PRAC/201784/2020

MAHs ofidelalisibcontaining
medicinal
products

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