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Pharmacovigilance Risk Assessment Committee (PRAC)

PRAC PSUR assessment report

Active substance(s): bendamustine hydrochloride
Procedure No.: PSUSA/00003162/202001

Data lock point: 06.01.2020

Status of this report and steps taken for the assessment!

Current Description Planned date Actual Date
U Start of procedure 8 May 2020 8 May 2020
Lead Member State preliminary 7 Jul 2020 7 Jul 2020
u assessment report (AR) " u
U MS/PRAC members and MAH comments 6 Aug 2020 6 Aug 2020
D Lead Member State updated assessment 21 Aug 2020 24 Aug 2020
report following comments
U Oral explanation N/A N/A
& PRAC recommendation 4 Sep 2020 4 Sep 2020

ı Tick the box corresponding to the applicable step - do not delete any of the steps. If not applicable,
add n/a instead of the date


Official address Domenico Scarlattilaan 6 e 1083 HS Amsterdam e The Netherlands
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Send us a question Go to Telephone +31 (0)88 781 6000 An agency of the European Union


© European Medicines Agency, 2020. Reproduction is authorised provided the source is acknowledged.

Procedure resources


Lead Member State DE
Lead Member State Contact person PSUR-Management
Email: psur@bfarm.de


Lead Member State Assessor Nam
PRAC Lead Name: Kerstin Löschcke

For benefit part

EMA Procedure Manager Name
EMA Procedure Assistant Name





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Table of contents

1. Background information on the procedure .....uuuunuaunnnonunnnnnnnanunnnnunnunnnnannnn 4
2. Assessment conclusions and actions ......uuuununununnnanunnnnnnnannununnnnunn ann nnnann nn 4
3. Recommendations ......unuauuuunnanunnnnnnnunnnnnnnnnanunnnnnnnanunnnnnnnanunnnnnnnunn nun nnnnnn nn 5
4. Issues to be addressed in the next PSUR: ....uuuuauuunnnununnunnnnununnunnunnnnanun mann 7
5. PSUR frequency ...unuuuuanunnnnnnnanunnnnnnnununnnnnn nun ann nn nn nun ann nn nun un un nun nn nun nnn an annannnn nn 7
6. Other considerations ........uuuauununnnnnnnununnnnnnnanunnnnnnnan nun nn nun an un nun nnnann an an nnnnnn nn 7


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1. Background information on the procedure

This is the assessment of PSUR(s) submitted in accordance with the requirements set out in the list of
Union reference dates (EURD list) for bendamustine hydrochloride.

For an overview of the nationally authorised products for which PSURs were submitted in the context of
this EU single assessment, please see the appendix to this assessment report.



2, Assessment conclusions and actions

This periodic safety update single assessment procedure (PSUSA) for bendamustine hydrochloride
includes the assessment of the PSURs for the products authorized by Astellas (Levact) and Dr. Reddy’s
Laboratories. It covers the period from 07 January 2018 to 06 January 2020. Bendamustine
hydrochloride was first approved in the former German Democratic Republic on 10 November 1971.

Bendamustine is an alkylating antitumor agent. It is indicated in the European Union for the first-line
treatment of chronic Iymphocytic leukaemia, indolent non-Hodgkin's Iymphomas and front line
treatment of multiple myeloma.

During the reporting period, approximately 101,683 patients have been exposed to Levact worldwide,
while the cumulative exposure is estimated to be 521,119. The global exposure for the products of Dr.
Reddy’s was 988 patients-years in the reporting period and 2227 patient-years cumulatively.

For Levact, 3,114 Serious Adverse Events (SAEs) were reported from clinical trials and 26,505 Adverse
Drug Reactions (ADRs) from post-marketing data sources cumulatively. In the reporting period, 5,294
ADRs were reported from post-marketing data sources.

The MAHSs discussed seven targeted medical events/signals: Encephalopathy/leukoencephalopathy
(incl. PML), opportunistic infections, interstitial lung disease, secondary malignancies, non-melanoma
skin cancer, hepatitis E, acute generalized exanthematous pustulosis (AGEP).

Encephalitis is a known adverse reaction of bendamustine. In addition, 25 cases of PML were reported
by the MAH Astellas for the reporting period and 42 cases have been identified in Eudravigilance. All
cases have been confounded by concomitant treatment, mostly rituximab and obinutuzumab.

However, bendamustine is known to cause prolonged Iymphocytopenia and low CD4-T-cell counts,
which may increase the risk for the development of PML. Low CD4-T-cell counts are a known risk factor
for the development of PML and thus a contribution of bendamustine to the development of PML cannot
be excluded. An update of the product information is warranted.

Opportunistic infections are known adverse reactions of bendamustine and the review did not reveal
further new information.

During the reporting period 22 cases of interstitial lung disease have been identified. Further analysis
of the cases revealed confounding with PI3K-inhibitors in 7 cases. The remaining cases have been
confounded by other substances also known to cause interstitial lung disease or related events (e.g.
rituximab (n=9), brentuximab (n=2), obiutuzumab (n=3) or ibrutinib (n=2)). A plausible mechanism,
how bendamustine could cause inflammation or eventually fibrosis of the lung interstitium is not
known. Therefore, a plausible causality with bendamustine could not be established.

Two studies showing an increased risk for non-melanoma skin cancer in patients treated with
bendamustine were published during the PSUR period [Flinn 2019, Hiddemann 2018]. In the BRIGHT
study 14 of 221 (6.3%) patients treated with BR and 5 of 215 (2.3%) patients treated with R-CHOP/R-
CVP developed a BCC or SCC. In the GALLIUM study 10 of 676 patients (1.5%) treated with a


EMA/462692/2020 Page 4/78

bendamustine containing regimen developed non-melanoma skin (grade 3-5) in comparison to 1 of
513 (0.2%) patients treated with a CHOP or CVP based therapy. The difference is even more
pronounced when the all malignancies occurring >6 month after first study drug intake are taken into
account. Basal cell carcinoma occurred in 16 of 676 patients (2.4%) receiving bendamustine vs. 1 of
513 patients receiving CHOP/CVP. Squamous cell carcinoma (without information on the localisation)
occurred in 11 of 676 patients receiving bendamustine, while no case was reported for patients
receiving CHOP/CVP. Squamous cell carcinoma of skin occurred in 3 of 676 patients tread with
bendamustine and in 1 of 513 patients treated with CHOP/CVP based therapy. In addition 3 patients
treated with bendamustine experienced Bowens’ disease compared to none with other chemotherapy
backbones. Patients treated with bendamustine have an already increased risk for non-melanoma skin
cancer due to disease and age, but the results of the two studies show that the risk might be further
increased by treatment with bendamustine. Thus, an update of the product information is warranted.

Six cases of Hepatitis E have been identified. The event is considered covered in the SmPC by the
current wording on infections and opportunistic infections in the SmPC.

Only 4 cases of AGEP were reported cumulatively. Allhave been confounded by concomitant
medication. Hence, the data is not considered sufficient to establish a causality between bendamustine
and AGEP.

Overall, the B/R remains unchanged provided that the Product Information is updated as

3. Recommendations

Based on the review of data on safety and efficacy by the Lead Member State and taking into account
any comments provided by the PRAC, the PRAC considers that the risk-benefit balance of medicinal
products containing the active substance bendamustine hydrochloride remains unchanged but
recommends that the terms of the marketing authorisation(s) should be varied.

Scientific conclusions and grounds for variation to the terms of the marketing authorisations

In view of available data on progressive multifocal encephalopathy (PML) in patients treated with
bendamustine in combination with other substances from clinical trials, including in some cases a close
temporal relationship and in view of a plausible mechanism of action, the PRAC considers a causal
relationship between bendamustine and PML is at least a reasonable possibility. The PRAC concluded
that the product information of products containing bendamustine should be amended accordingly

In view of the temporal relationship, the plausible mechanism of action and the severity of PML the
PRAC concluded that a warning should be included in section 4.4 of the SmPC. The product information
of products containing bendamustine hydrochloride should be amended accordingly.

In view of the available data on non-melanoma skin cancer in patients treated with bendamustine
containing regimens from two clinical studies, including in some cases a close temporal relationship,
and in view of a plausible mechanism of action, the PRAC considers a causal relationship between
bendamustine hydrochloride and non-melanoma skin cancers is at least a reasonable possibility. The
PRAC concluded that the product information of products containing bendamustine hydrochloride
should be amended accordingly.

Update of section 4.4 of the SmPC to add a warning on PML and non-melanoma skin cancer. The
Package leaflet is updated accordingly.


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The following changes to the product information of medicinal products containing the active substance
bendamustine hydrochloride are recommended (new text underlined and in bold, deleted text strike


Summary of Product Characteristics
. Section 4.4

A warning should be amended as follows:

Serious and fatal infections have occurred with bendamustine hydrochloride, including bacterial
(sepsis, pneumonia) and opportunistic infections such as Pneumocystis jirovecii pneumonia (PJP),
varicella zoster virus (VZV) and cytomegalovirus (CMV). Cases of progressive multifocal
leukoencephalopathy (PML) including fatal ones have been reported following the use of
bendamustine mainly in combination with rituximab or obinutuzumab. Treatment with
bendamustine hydrochloride may cause prolonged Iymphocytopenia (< 600/ul) and low CD4-positive
T-cell (T-helper cell) counts (< 200/ul) for at least 7-9 months after the completion of treatment.
Lymphocytopenia and CD4-positive T-cell depletion are more pronounced when bendamustine is
combined with rituximab, Patients with Iymphopenia and low CD4-positive T-cell count following
treatment with bendamustine hydrochloride are more susceptible to (opportunistic) infections. In case
of low CD4-positive T-cell counts (< 200/ul) Pneumocystis jirovecii pneumonia (PJP) prophylaxis
should be considered. All patients should be monitored for respiratory signs and symptoms throughout
treatment. Patients should be advised to report new signs of infection, including fever or respiratory
symptoms promptly. Discontinuation of bendamustine hydrochloride should be considered if there are
signs of (opportunistic) infections.

Consider PML in the differential diagnosis in patients with new or worsening neurological,
cognitive or behavioural signs or symptoms. If PML is suspected then appropriate diagnostic
evaluations should be undertaken and treatment suspended until PML is excluded.

A warning should be added as follows:

Non-melanoma skin cancer

In clinical studies, an increased risk for non-melanoma skin cancers (basal cell carcinoma


and squamous cell carcinoma) has been observed in patients treated with bendamustine

containing therapies. Periodic skin examination is recommended for all patients, particularly
those with risk factors for skin cancer.

Package Leaflet
2. What you need to know before you take [Product Name]

Warnings and precautions

At any time during or after your treatment, tell your doctor immediately if you notice or


these may be due to a very rare but serious brain infection which can be fatal (progressive
multifocal leukoencephalopathy or PML).

Contact your doctor if you _ notice any suspicious skin changes because there may be an




EMA/462692/2020 Page 6/78

4. Issues to be addressed in the next PSUR:

The safety concerns to be discussed in the next PSUR are:

Important identified risk:

. severe cutaneous adverse reactions (SCARs)
. opportunistic infections
. progressive multifocal leukoencephalopathy

Important potential risk:
Missing information:


5. PSUR frequency

Kl The current frequency for submission of 2 years PSURs should remain unchanged.

6. Other considerations




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Annex: Lead Member State assessment comments on PSUR


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1. PSUR Data

1.1. Introduction

This PSUSA procedure includes the PSURS for the bendamustine-containing prodcuts of Astellas and its
license partners Janssen, Mundipharma, SymBio and Teva (further referred to as Astellas), and of Dr.
Reddy’s Laboratories Ltd. (DRL), betapharm Arzneimittel GmbH (betapharm) and Altan
Pharmaceuticals S.A. (Altan) (further referred to as DRL).

Bendamustine is an alkylating antitumour agent. It is indicated in the European Union for

- first-line treatment of chronic Iymphocytic leukaemia (Binet stage B or C) in patients for whom
fludarabine combination chemotherapy is not appropriate

-  indolent non-Hodgkin's Iymphomas as monotherapy in patients who have progressed during or
within 6 months following treatment with rituximab or a rituximab containing regime

- front line treatment of multiple myeloma (Durie-Salmon stage II with progress or stage III) in
combination with prednisone for patients older than 65 years who are not eligible for
autologous stem cell transplantation and who have clinical neuropathy at time of diagnosis
precluding the use of thalidomide or bortezomib containing treatment.

The antineoplastic and cytocidal effects of bendamustine is based essentially on cross-linking of
deoxyribonucleic acid (DNA) single and double strands by alkylation. As a result, DNA matrix functions,
and DNA synthesis and repair are impaired.

The bendamustine-containing products authorized to Astellas are available as powder for concentrate
for solution for infusion in vials containing 25 mg bendamustine hydrochloride and 100 mg
bendamustine hydrochloride. Products authorized to DRL are available as concentrate for solution for
infusion in vials containing 45 mg bendamustine hydrochloride and 180 mg bendamustine

The EU reference date for bendamustine is 07 Jul 2010. This PSUSA covers the period 07 Jan 2018- 06
Jan 2020. The cumulative period is 10 Nov 1971-06 Jan 2020.

The MAHs proposed no changes to the product information as part of this submission.

1.2. Worldwide marketing authorisation status

Bendamustine was first authorised in the former German Democratic Republic on 10 Nov 1971 and in
the EU (decentralized procedure) on 07 Jul 2010 (European Union Reference Date, EURD).


Bendamustine was first approved in EU on 07 Jul 2010. In the EU, bendamustine is authorized in
Germany, France, Spain, Denmark, Austria, Belgium, Poland, Finland, Ireland, Slovakia, Slovenia,
Spain, Greece, Cyprus, Czech Republic, Netherlands, Bulgaria, Sweden, Luxembourg, Portugal,
Romania and Italy. In addition, bendamustine is also authorized in Iceland, Norway and United
Kingdom. It is approved in a total of 93 countries and marketed in more than 75 countries.


DRL/betapharm/Altan bendamustine was first approved on 19 May 2009. To date,
DRL/betapharm/Altan bendamustine has been registered in seven countries worldwide. In EU the


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products are authorized in Spain, France, Italy, Germany, and Portugal. In addition the product is
authorized in United Kingdom.

1.3. Overview of exposure and safety data

1.3.1. Actions taken in the reporting interval for safety reasons


On 24 Jan 2018, LP Janssen received a request from the Therapeutic Goods Administration (Australia)
to distribute Direct Healthcare Professional Communication (DHPC) referring to Section 4.4 ‘Special
warnings and precautions for use’ and Section 4.8 ‘Undesirable effects’ of the updated EU Summary of
Product Characteristics (SmPC) dated 14 Jan 2018.

Furthermore, it was requested to submit a safety-related request application to update the Australia
Product Information in line with the EU SmPC.

In the same reporting period, in New Zealand, Medsafe also requested a DHPC letter on 05 Mar 2018.

No action has been taken for safety reasons.


Lead Member State assessment comment:

During the reporting period DHPCs have been disseminated in Australia and in New Zealand. The
Australian DHPC communicated information recently included in the EU SmPC.

The MAH Astellas is requested to clarify the topics of the DHPCs. (RSI)


1.3.2. Changes to reference safety information


The reference safety information (RSI) in effect is Sections 4.3 to 4.9 of the CCDS, version 3.0, dated
04 Oct 2017, which contains company core safety information. No changes were made to the company
core safety information during this reporting interval.


The decentralised procedure (DCP)-approved (DE/H/4539) Summary of Product Characteristics (SmPC)
of bendamustine (concentrate for solution for infusion) dated November 2017 was used as the
Reference Safety Information (RST) for this PSUR.

No changes were made to the safety relevant parts of the RSI during the reporting interval ofthe

The RSI has been compared against the SmPC for the innovator’s product, Levact, Astellas) dated
October 2017. The RSI is not harmonised to that to that of the innovator’s product. Some minor
differences have been identified. Refer Appendix 6 for the proposed changes. A variation to update the
DRL/betapharm/Altan SmPCs and PL is currently in preparation.



Lead Member State assessment comment:

The RSI of Astellas was not updated during the reporting period. DRL is preparing a variation to
harmonize the SmPC of their products with the SmPC of the reference product.



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