Sasha Drysdale

BRITANNIA

PHARMACEUTICALS LTD
STADA GROUP

Received

06 SEP 2024

BRITANNIA PHARMACEUTICALS LIMITED

200 LONGWATER AVENUE
HM Coroner's Office GREEN PARK

READING, BERKSHIRE

RG2 6GP UK

T: +44 (0)118 920 9500
Chris Morris W: waw.britannia-pharm.com
Area Coroner
Coroner’s Court
1 Mount Tabor Street
Stockport
SK1 3AG

02-Sep-2024

Dear Mr Morris,

Thank you for your letter dated 18-Jul-2024, which was sent to the Britannia Managing Director - Robert Wood. The letter
was given to us — the Director Medical Affairs Corporate Pharmacovigilance/European Union Qualified Person for
Pharmacovigilance, STADA Arzneimittel AG and Senior Manager Pharmacovigilance, Britannia Pharmaceuticals, to provide
a response.

Clozapine is marketed under the brand name Denzapine on the United Kingdom market by Britannia Pharmaceuticals
Limited, who is also the Marketing Authorisation Holder (MAH) and a 100% affiliate of STADA Arzneimittel AG. Affiliates
of STADA Arzneimittel AG also hold licences for Clozapine in France, Germany, Ireland, The Netherlands, and Spain,
however, the product is marketed only in Ireland.

Clozapine is highly effective in the treatment of schizophrenia. The use of the substance is, however, limited by its severe,
potentially life-threatening risks (mainly of haematologic, but also cardiac and gastrointestinal nature), but nevertheless
Clozapine is the treatment of choice for patients where no other antipsychotic treatment has worked (last-line therapy).
Clinical experience with Clozapine covers more than 50 years, the benefit-risk profile is well-known, and the known risks
are adequately managed.

All available relevant information on the safety and efficacy of a medicinal product is described in the “Summary of
Medicinal Product Characteristics” (SmPC). The SmPC is an official document agreed with and approved by the Competent
Authority (in the United Kingdom - the Medicines and Healthcare products Regulatory Agency (MHRA)). It reflects the
current state of scientific knowledge. Similar information as in the SmPC is also provided in lay language in the Patient
Information Leaflet (PIL).

Marketing Authorisation Holders (such as Britannia) are obliged by law to continuously monitor the benefit-risk profile of
their products by collecting and systematically evaluating all reports on adverse reactions. This includes reports received
from Health Care Professionals, patients, and those published in the scientific literature.

Specifically for Clozapine, to minimise the known haematological risks, an additional system is in place. Patients are
required to undergo regular blood monitoring, an electronic system {at Britannia Pharmaceuticals Limited the so-called
‘Denzapine Monitoring System’, the other MAHs in the United Kingdom have similar systems in place) warrants in the
United Kingdom and in Ireland that pharmacies can only dispense the product if white blood cell count, and the absolute
neutrophil count of the patient are available and in the expected range. It should be noted that through this Monitoring
System all haematological deviations and most of the adverse events (sic! Not limited to adverse reactions with suspected
causality) are made available to the MAH, giving a quite reliable insight in the safety profile of the product.

Registered Office: 200 Longwater Avenue, Green Park, Reading, Berkshire RG2 6GP. Registered No. 01557088.
Britannia Phermaceuticals Ltd Is an affiliate of STADA Group.

A3

BRITANNIA

PHARMACEUTICALS LTD
STADA GROUP

BRITANNIA PHARMACEUTICALS LIMITED
200 LONGwaTER AVENUE

GREEN PARK

READING, BERKSHIRE

RG2 6GP UK

T: +44 (0)118 920 9500

W: www.britannia-pharm.com
All these activities are summarised as “Pharmacovigilance”. Should the data arising from Pharmacovigilance activities
show new risks or new aspects of known risks, this data would need to be submitted to the MHRA and potentially result
in an update of the SmPC and, if necessary, in additional Risk Minimisation Measures.

A causal relationship between Clozapine therapy and blood cancer (leukaemia) is at the current state of scientific
knowledge not established and therefore not referenced in the SmPC.

For generally rare events such as cancer methodological and ethical reasons make it impossible to conduct studies
according to the gold standard, i.e. randomised, double blind studies. Therefore, studies conducted are usually based on
available large databases.

A study published by Chrétien et al. (Haematologic malignancies associated with clozapine v. all other antipsychotic
agents: a pharmacovigilance study in  VigiBase’. Psychol Med. 2021  Jul;51(9):1459-1466. doi:
10,1017/50033291720000161. Epub 2020 Feb 10) used disproportionality analysis to assess the association between
haematologic malignancies and clozapine using Vigibase*, the WHO pharmacovigilance database. Of the 140 226
clozapine-associated reports, 493 were malignant lymphoma cases, and 275 were leukaemia cases. Clozapine was
significantly associated with malignant lymphoma (aROR 9.14, 95% Cl 7.75-10.77) and leukaemia (aROR 3.54, 95% Cl 2.97-
4,22). The authors concluded that “Clozapine was significantly associated with a pharmacovigilance signal of
haematologic malignancies. The risk-benefit balance of clozapine should be carefully assessed in patients with risk factors
of haematologic malignancies. Clozapine should be used at the lowest effective posology.”

Vigibase® is probably the most comprehensive database on adverse reactions to medicinal products. All serious ADR
reports that e.g. Britannia sends to any Competent Authority are forwarded by the authorities to that database. It has,
however, to be considered that results can be misleading by various confounders, for example reporting bias. Specifically
for Clozapine, due to the monitoring systems as described above, the number of reports {including those where a causality
is completely unclear or not suspected) is much higher as for other medicinal products, where such monitoring
mechanisms are not established.

Consequently, this study was harshly criticised in a response publication by de Leon et al. (The association of clozapine
and haematological malignancies needs to be replicated by other studies and more importantly by analyses of subsamples
from VigiBase. Psychol Med 51, 1405-1406. https://doi.org/10.1017/S0033291 720001233). Quote: “It is not clear
whether Chrétien et al. recommended clozapine discontinuation, or whether psychiatrists should just ‘scare them to death’
by describing the increased risk of developing haematological malignancies with clozapine use. [...] Finally, the prior
literature on clozapine and haematological malignancies, which is rather limited, was reviewed by Chrétien et al. and had
no prior clinical or pharmacoepidemiological study providing similar findings including three malignancies: lymphoma,
leukaemia and myelodysplastic syndrome. Therefore, until Chrétien et al. replicate their results in subsamples and other
independent studies providing replication, it may be safer to ignore their results in clinical practice. Chrétien et al. might
look back in regret by having contributed to clozaphobia (Cetin, 2014) and having created an additional barrier to the
prescription of clozapine (Verdoux, Quiles, Bachmann, & Siskind, 2018)”.

In 2022, Tiihonen et al (Long-term treatment with clozapine and other antipsychotic drugs and the risk of haematological
malignancies in people with schizophrenia: a nationwide case-control and cohort study in Finland. Lancet Psychiatry. 2022
May;9(5):353-362. doi: 10.1016/52215-0366(22)00044-X, Epub 2022 Mar 22.) did a nationwide case-control (and cohort)
study of people with schizophrenia, using prospectively gathered data from Finnish national registers. A nested case-
control study was constructed by individually matching cases of lymphoid and haematopoietic tissue malignancy with up
to ten controls without cancer by age, sex, and time since first schizophrenia diagnosis.

Registered Office: 200 Longwater Avenue, Green Park, Reading, Berkshire RG2 6GP. Registered No. 01557088.
Britannia Pharmaceuticals Ltd is an affiliate of STADA Group.

A4

BRITANNIA

PHARMACEUTICALS LTD
STADA GROUP

BRITANNIA PHARMACEUTICALS LIMITED
200 LONGWATER AVENUE

GREEN PARK

READING, BERKSHIRE

RG2 6GP UK

T: +44 (0)118 920 9500

W: www. britannia-pharm.com
Their results showed that unlike other antipsychotics, long-term clozapine use is associated with increased odds of
haematological malignancies. Long-term clozapine use has a higher effect on mortality due to lymphoma and leukaemia
than due to agranulocytosis. However, the absolute risk is small compared with the previously observed absolute risk
reduction in all-cause mortality.

Referring to the Finnish study, a Dutch group of researchers (Schulte et al, Clozapine and the risk of haematological
malignancies. Lancet Psychiatry. 2022 Jul;9{7):538-539. doi: 10.1016/S2215-0366(22}00149-3.} representing the Dutch
Clozapine Collaboration Group (DCCG) emphasize that (Quote) “The lower all-cause mortality in clozapine users should be
stressed. If the topic of the small increase in the risk of haematological malignancies in clozapine users is raised, patients
and their caregivers should also be informed about the improved prognosis in clozapine users (32-9% mortality in patients
with ongoing clozapine use vs 50-7% in non-clozapine users in the investigated cohorts).”

We conclude that:

¢ Treatment with Clozapine is safe and effective, given that the indication and the precautions as defined in the
SmPC are observed.

* Acausal relationship between Clozapine and Blood Cancer has been investigated in large studies but has not been
confirmed.

© Astatistically calculated slightly increased risk of Blood Cancer in Clozapine patients is outweighed by the overall
reduction in mortality by Clozapine treatment.

* We as Marketing Authorisation Holders have no means and no power to prevent future deaths like that referred
to in your report. We have measures in place that prevent those deaths caused by Clozapine that are to the best
of our knowledge preventable.

Therefore, we currently do not propose any further action.

Kind Regards

02-Sep-2024

Director Medical Affairs Corporate Pharmacovigilance, EU QPPV
STADA Arzneimittel AG

02-Sep-2024

Senior Manager Pharmacovigilance
Britannia Pharmaceuticals Limited

Registered Office: 200 Longwater Avenue, Green Park, Reading, Berkshira RG2 BGP. Registered No. 01557088.
Britannia Pharmaceuticals Ltd Is an affiliate of STADA Group,

AS

Leyden Delta os
Leyden & Delta Un $ Chase Industrial Estate| Alton Road Zz
Ross-on-Wye | HR9-SWA | United Kingdom

Received
Att Chistopher Morris, Area Coroner
Coroner’s Court 11 SFP 2024
1 Mount Tabor Street

Stockport SK1 3AG HM Coroner's Office

Tuesday, September 10, 2024

RE: Leyden Delta’s response to your request related to the Regulation 28 Report into the death of
Sasha Drysdale

Dear Sir,

We are writing to you in response to your letter dated 18 July 2024, pertaining to your Regulation 28
Report in relation to the death of Ms Sasha Drysdale. In that letter you raised concerns about the
safety of clozapine and a potential link between clozapine and Acute Myeloid Leukaemia (AML). You
suggested that further research is needed and requested that Leyden Delta provide you with an
action plan which will address actions to prevent future deaths. Whilst we understand that
Zaponex® manufactured by Leyden Delta was not prescribed to Ms Drysdale, we respond below
accordingly.

As you are aware, medicines are licensed by the regulatory authority, the Medicines and Healthcare
products Regulatory Agency (MHRA) in the UK. The decision to grant a licence is based on evidence
from safety and efficacy studies and the therapeuticneed, in terms of clinical efficacy of the product
and/or lack of alternative treatment options. In cases where the benefits of a medicine are deemed
to outweigh the risks for individual patients and/or for the public health (a positive outcome of the
risk/ benefit assessment) a licence is granted.

The initial and continued licensing of clozapine reflects the MHRA's informed view of the
medication's safety and efficacy in this context. Details of the evidenced risks and benefits of
Zaponex® (clozapine) are provided in its product information.

Once a product is allowed to the market, pharmaceutical legislation also requires companies to
continuously monitor the safety profile of their products and to inform the Regulatory Authority and
to take action when changes to the benefit/risk profile become apparent.

Once a medicine is allowed to be placed on the market, the MHRA is principally responsible for
continuously monitoring the safety profile of the medicine. This is known as pharmacovigilance.
Patients, health professionals and pharmaceutical companies all contribute to pharmacovigilance
activities. The MHRA will take action when changes to the benefit/risk profile become apparent
based on its monitoring of multiple information sources, including spontaneous adverse drug
reaction reporting schemes, clinical and epidemiological studies and reviews of worldwide published
medical literature.

Leyden Delta, as the marketing authorisation holder for Zaponex, has a pharmacovigilance and risk
management system in place with processes for the continuous collection and evaluation of safety
information. Leyden Delta takes proactive steps in conjunction with the regulatory authority when
changes to the benefit/risk profile emerge.

In respect of the concern raised, concerning a potential for clozapine to cause AML, it is the
considered position of Leyden Delta that there is no causal link between clozapine and AML. Neither
we, nor the MRHA have identified such a link through pharmacovigilance. Upon receipt of your
letter, Leyden Deita has additionally sought the expert opinion of their Consultant Haematologist,

Phone +44 (0)207 3655842 Fax +44 (0)207 3655843 —_ E-mail info@ztas.co.uk
IBAN NL93 RABO 0112225926 BIC no. RABONL2U = VAT no. UK 208498484 = VAT no. NL 81 .81,28.148.801 Commercial Register no. 09172190

v
Leyden Delta F y 7
Leyden ‘a Delta Unit 5 Chase industrial Estate Alton Road Or
Ross-on-Wye | HR9-SWA | United Kingdom

Professor Dr T.J.M. de Witte of Radboud Medical University, Nijmegen. Prof. de Witte has advised
that based on his assessment of the clinical information of case reports from Leyden Delta's safety
database and a review of scientific literature, he could not see convincing evidence for a causal
relation between clozapine and AML.

Leyden Delta will continue to comply with its pharmacovigilance obligations and operating
procedures for monitoring the safety profile of Zaponex. In particular we encourage, and will
carefully review, any further research into clozapine (and indeed, AML) and we will not hesitate to
take appropriate action should changes to the medicine's safety profile emerge.

We trust that this response is of assistance, and we would be happy to respond to any questions you
may have.

Yougs-faithfull

Medical

Phone +44 (0)207 3655842 Fax +44 (0)207 365 5843 E-mail info@ztas.co.uk
IBAN NL93 RABO 0112 225926 BIC no, RABONL2U = VAT no. UK 208498484 = VAT no. NL 81.81.28.148.801 Commercial Register no. 09172190

A7

2nd Floor 
2 Redman Place 
London 
E20 1JQ 
United Kingdom 

+44 (0)300 323 0140 

30 August 2024 

Mr Chris Morris 
Area Coroner for Manchester South 

Sent via email: 

Our reference: 

Dear Mr Morris,    

Re: Regulation 28 Prevention of Future Deaths Report – Sasha Esther Moira Drysdale 
(ref: 30303936) 

I write in response to your regulation 28 report dated 18 July 2024 regarding the sad death of 
Miss Drysdale. I would like to express my sincere condolences to Miss Drysdale’s family.   

We have reflected on the circumstances surrounding Miss Drysdale’s death and the concerns 
raised  in  your  report.  We  note  your  concerns  that  further  research  is  needed  to  refute  or 
confirm whether or not taking clozapine materially increases the risk of a patient developing 
certain blood cancers.  

For context, you may find the following information that NICE holds on clozapine useful.   

There are strict monitoring requirements for Clozapine as listed in the BNF; Clozapine | Drugs 
| BNF | NICE 

These  are  also  reflected  in  the  CKS  summary  Scenario:  The  routine  schizophrenia  or 
psychosis review | Management | Psychosis and schizophrenia | CKS | NICE.   

The BNF is a joint publication of the British Medical Association and the Royal Pharmaceutical 
Society. Although we make the BNF accessible from the NICE website, we are not responsible 
for its content. 

The CKS are developed externally to NICE. We commission an external organisation (Agilio 
software)  to  compile  the  CKS.  They  are  designed  to  provide  a  summary  of  the  published 
evidence on the treatment of a range of health conditions that present in primary care. They 
use a variety of sources and may include NICE guidance, if there is any that is relevant, but 
they use many other sources too. We publish them on our website as a source of advice and 
information for health professionals working in primary care, but they do not constitute formal 
NICE guidance.    

A1 
 
 
 
 
 
 
 
 In relation to the main issue that you have asked us to respond to, you may be aware that 
NICE is not the regulator for medicines and medical devices in the UK; this is the role of the 
Medicines & Healthcare products Regulatory Agency (MHRA). The MHRA is responsible for 
issuing the marketing authorisation for medicines (also known as the licence) and has ongoing 
responsibility for monitoring their safety. 

Following receipt of your report, senior clinical advisors within the patient safety team at NICE 
have reviewed the concerns raised. They have advised that these concerns would be best 
investigated by the MHRA as the responsible body for the regulatory approval of medicines. 
The  safety  of  Clozapine  and  risk  of  developing  haematological  malignancy  requires 
surveillance which should be led by the MHRA, however NICE would welcome any findings 
that may impact our current recommendations and advice on this treatment.    

We are aware that the MHRA currently have an ongoing safety review into Clozapine, so this 
may well be a good opportunity for them to capture the issues raised in this case as part of 
their review. 

Our clinical adviser added that the haematological risks of Clozapine need to be considered 
in the context of risks from mental illness that is responding poorly to treatment. It is used for 
patients who have not responded to 2 other antipsychotics.  

He  added  that  NICE  would normally  suggest that  when  balancing  risks, patient  consent  is 
important, but this would be almost impossible in the context of refractory psychosis.   

Finally,  NICE  does not have  a  direct  role  in  clinical  research  the  UK;  this  is  the  role of  the 
National Institute for Health and Care Research (NIHR) . You may wish to contact them directly 
regarding any upcoming research on this subject area.  

I hope this response has helped outline our role in relation to this specific area and I would 
like to reiterate my sincere condolences to Miss Drysdale’s family.   

Yours sincerely, 

Chief Executive     

                                                                                                                                 Page | 2 

A2

Viatris UK Healthcare Limited,  

Building 4, Trident Place,  

Mosquito Way,  

Hatfield,  

Hertfordshire,  

AL10 9UL 

13 September 2024 

HM Coroner Morris 
Manchester South Coroner's Court 
1 Mount Tabor Street 
Stockport 
SK1 3AG 

Dear Sir 

REGULATION  28  PREVENTION  OF  FUTURE  DEATHS  REPORT,  SASHA  DRYSDALE  (D.O.D.  28  MARCH 
2023) 

1.1 

1.2 

Viatris  UK  Healthcare  is  the  registered  U.K.  Marketing  Authorisation  Holder  (MAH)  for 
Clozaril®,  Viatris’  clozapine  product  (the  Product).  We  have  prepared  this  letter  in 
response to your “Regulation 28: Prevention of Future Deaths report” dated 18 July 2024 
(your PFD Report) made pursuant to paragraph 7, Schedule 5 of the Coroners and Justice 
Act  2009  and  regulations  28  and  29  of  the  Coroners  (Investigations)  Regulations  2023, 
following the inquest touching the death of Miss Sasha Drysdale.  

The  efficacy  and  safety  of  Viatris’  products  is  our  utmost  priority.  We  have  carefully 
reviewed  your  PFD  Report,  in  particular  the  matters  that  reference  clozapine.  We  are 
satisfied  that  the  Product  is suitable  for  its  intended  use  when  used  in  accordance  with 
current prescribing information, which has been approved by the Medicines and Healthcare 
Products Regulatory Agency (MHRA). We set out in detail below the steps that are taken 
by Viatris to monitor any change in the benefit risk profile of the Product. On this basis, and 
following Viatris’ review of your PFD Report, Viatris concludes that there is no change in 
the benefit risk profile, which remains positive as approved by the MHRA, and no action is 
proposed at this time, and it will continue its ongoing monitoring.  

2.  CLOZAPINE AND CLOZARIL® 

2.1 

Clozapine is a prescription-only anti-psychotic medicine.  

2.2 

There are three clozapine products available in the UK.  Each is marketed by a different 
company under a different brand name. These are:  

(a) 

Clozaril®; 

(b) 

Denzapine; and 

(c) 

Zaponex.  

Clozaril® is Viatris’ product.  

A8 
 
 
 
 As set out in paragraph 4.1 of the Summary of Product Characteristics (SmPC) (which is 
available  to  all  clinicians),  the  Product  is  licensed  for  use  with  patients  with  treatment-
resistant  schizophrenia  and  in  schizophrenic  patients  who  have  severe,  untreatable 
neurological  adverse  reactions 
including  atypical 
antipsychotics. The Product is also licensed to treat psychotic disorders occurring during 
the course of Parkinson's disease, in cases where standard treatment has failed.  

to  other  antipsychotic  agents, 

2.3 

As set out in a letter to The Times from the President of the Royal College of Psychiatrists1: 

“Clozapine is the most effective medication  available to relieve the symptoms of 
treatment resistant schizophrenia and this allows people to lead healthier and more 
fulfilling lives. It is proven to reduce mortality, both from suicide and natural causes, 
and has helped thousands of people return home from hospital.” 

2.4 

2.5 

2.6 

The Product was first approved for use in the UK by the Medicines Control Agency (the 
"MCA",  now  called  the  MHRA)  on  22 December  1989.  Viatris  (formerly  Mylan)  became 
MAH in November 2016 having acquired the Product from Novartis in March 2016.  

It is a mandatory licensing requirement of the MHRA for each manufacturer of a clozapine 
product to operate its own patient monitoring service to help clinicians manage the risk of 
agranulocytosis (see 3.6) associated with clozapine. The monitoring service for users of 
the Product is the Clozaril® Patient Monitoring Service (CPMS). 

The  Product  is  only  licensed  for  treating  patients  in  the  UK  who  are  registered  with  the 
CPMS.  In  addition  to  registering  their  patients,  prescribing  physicians  must  register 
themselves  and  a  nominated  pharmacist  with  the  CPMS.    All  Clozaril® treated  patients 
must be under the supervision of an appropriate healthcare specialist and supply of  the 
Product  is  restricted  to  hospital  and  retail  pharmacies  registered  with  the  CPMS.  The 
minimum frequency at which white blood cell count (WBC) monitoring must occur is stated 
in the SmPC. The SmPC states “Prescribing physicians must comply fully with the required 
safety measures.” (paragraph 4.4). 

3.  RESPONSE 

3.1 

In section 5 of your PFD Report, you indicate that during the course of the inquest touching 
the death of Miss Sasha Drysdale, evidence revealed matters giving rise to concern.  In 
section 6 of your PFD Report, you state the matters of concern are as follows. 

“The  court  heard  evidence  as  to  a  small  number  of  studies  conducted 
internationally  which,  whilst  having  small  sample  sizes,  could  be  read  as 
suggesting an increased incidence of certain forms of blood cancer amongst those 
taking Clozapine.  

I am concerned that further research is needed to either refute or confirm whether 
or not taking Clozapine materially increases the risk of a patient developing certain 
blood cancers.”   

1  

Letter to the Times from the President of the Royal College of Psychiatrists, dated 12 January 2024 

A9 
 
 
 Viatris’ processes for monitoring benefit risk profile of the Product 

Viatris  has  a  robust  pharmacovigilance  system  in place  in  respect  of  all  of  its  products, 
including Clozaril®. All reported suspected adverse reactions to the Product are evaluated 
by Viatris’ pharmacovigilance team (PV team). Viatris undertakes routine and continued 
monitoring of the benefit/risk balance of the Product. 

As with all medicinal products, adverse event data is collected for the Product. This data is 
submitted to the MHRA, in the same manner as adverse event data relating to the other 
clozapine products is. Given the length of time that clozapine products have been available, 
a substantial body of evidence has built up about the types of adverse effects that may be 
experienced  by  patients  taking  clozapine.  This  data  is  the  source  of  the  information 
provided to physicians in the Product’s SmPC and Patient Information Leaflet (PIL).  

routine  pharmacovigilance 

Viatris’ 
the  Guidance  on 
Pharmacovigilance  Procedures  published  by  the  MHRA  on  31  December  2020  and 
subsequent updates, and adheres to the relevant regulatory requirements and EU good 
pharmacovigilance  practices  (GVP)  modules.  In  respect  of  the  Product,  this  includes 
undertaking the following. 

the  Product 

follows 

for 

3.2 

3.3 

(a) 

Maintaining the CPMS, which is the mandatory patient monitoring service and a 
condition of marketing authorisation approval for clozapine. 

(b) 

Daily monitoring of individual case reports in the CPMS database. 

(c) 

Daily monitoring for any UK and non-UK Individual Case Safety Reports (ICSRs) 
in respect of the Product and patients being treated with clozapine. 

(d)  Weekly  review  of  worldwide  scientific  literature  to  identify  ICSRs  (please  see 

paragraph 0 below).   

(e)  Weekly review of worldwide scientific literature to identify articles of interest (not an 

ICSR) to be included in Periodic Safety Reports.  

(f) 

(g) 

(h) 

Reviewing any safety trigger events or reports from the MHRA or other regulators 
as and when published or provided to Viatris by the MHRA or other regulator.  

Routine  review,  assessment  and  validation  of  a  signal2  to  ensure  that  Viatris’ 
analysis of the Product’s safety profile remains up-to-date, the data is current and 
to check whether any changes to the profile may need to be made. Where no signal 
assessment  and  validation  trigger  event  has  occurred,  this  routine  review  is 
undertaken on an annual basis.  

Preparing  Periodic  Safety  Update  Reports  (PSURs)  which  summarise  all  new 
safety data in respect of the Product and are submitted to the MHRA periodically. 
The PSURs includes data on the number of any type of adverse events and deaths 
of patients prescribed and treated with the Product.  

2  

Signal detection involves the systematic process of identifying potential safety concerns or new risks associated with 
a drug product. It involves the analysis of aggregated data from various sources to identify patterns or trends that may 
indicate a safety issue.  

A10 
 
 3.4 

3.5 

3.6 

3.7 

Reviewing  and  collaborating  on  any  safety  reporting  that  may  be  required  for  global 
regulators (e.g. the FDA or EMA) and on responses to any ad hoc requests that Viatris 
may receive from other health authorities in countries where the Product is authorised and 
Viatris is the MAH in that jurisdiction.  

Viatris  contracts  with  a  third  party  service  which  conducts  worldwide  scientific  literature 
searches and media screening in respect of the Product and clozapine on a weekly basis. 
This service provides Viatris access to a repository of those literature articles selected from 
weekly  runs.  However,  any  ICSR  identified  by  this  service  relating  to  the  Product  are 
immediately  notified  to  Viatris’  pharmacovigilance  team.  The  relevant  literature  for 
clozapine related ICSRs (i.e. ICSRs not specifically related to the Product) is reviewed by 
the member of the Viatris PV team on a weekly basis.    

Current scientific knowledge of Benefit Risk Profile as reflected in the Product’s SmPC 

Section  4.8  of  the  SmPC  gives  a  summary  of  the  Product’s  safety  profile,  including  its 
possible “undesirable effects”. These are also listed in the PIL, which is available to patients 
as package insert with the Product.  

The listed “undesirable effects” of clozapine include, inter alia, the most common which are 
drowsiness/sedation, dizziness, tachycardia, constipation and hypersalivation. The most 
serious adverse reactions experienced with clozapine are seizure, cardiovascular effects 
and fever, neutropenia (a type of granulocytopenia) and agranulocytosis. Neutropenia is a 
drop  in  the  number  of  neutrophils  (a  type  of  white  blood  cell)  and  occurs  when  the 
neutrophil count is less than 1.5x10⁹/l. These white blood cells help protect the body from 
infection.  If  the  number  of  neutrophils  continues  to  drop  to  below  0.5x109/l,  then 
agranulocytosis  may  develop  which  increases  a  patient’s  risk  of  infection  due  to  their 
suppressed immune system.  

Section 4.8 also contains a table (Table 4) in the SmPC, which provides a comprehensive 
summary  of  the  adverse  reactions  to  the  Product  accumulated  and  established  from 
reports  made  spontaneously  (during  use  of  the  Product  with  patients)  and  also  during 
clinical studies. The data is constantly reviewed to ensure that the information provided in 
the SmPC and PIL is up-to-date. In Table 4, adverse reactions are ranked under headings 
of frequency, using the following convention:  

•  Very common (≥ 1/10),  

•  common (≥ 1/100 to <1/10),  

•  uncommon (≥ 1/1,000 to <1/100),  

• 

rare (≥ 1/10,000 to <1/1,000),  

•  very rare (<1/10,000),  

•  not known (cannot be estimated from the available data).  

Viatris notes that the contents of Table 4, which represents treatment-emergent adverse 
experience frequency estimated from spontaneous and clinical trial reports, do not include 
any  reference  to  an  adverse  side  effect  for  acute  myeloid  leukaemia,  myelodysplastic  
syndrome or any other form of blood cancer. Based on Viatris’ current knowledge, there is 

A11 
 not  sufficient  data  to  support  any  relation  between  haematological  malignancies  and 
clozapine use to require inclusion of this in Table 4.  

3.8 

The wording in the PIL and SmPC is agreed and approved by the MHRA as part of the 
process of assessing the safety, efficacy and quality of the Product.  

3.9 

Safety Analysis re: haematological malignancies 

As part of Viatris’ pharmacovigilance activities for the Product, if any new safety information 
(showing  potential  correlation  between  the  Product  and  a  potential  safety  issue)  is 
identified from any of the activities listed in paragraph 3.3, it triggers a process whereby 
Viatris will undertake a signal validation and assessment exercise in accordance with GVP 
module IX. This exercise involves a thorough analysis of ICSR data available in Viatris’ 
global safety database, data from clinical studies, worldwide scientific literature, review of 
major health authorities websites and their publicly available safety database globally to 
collect as much information to evaluate any potential evidence supporting any association 
between the Product and a potential safety issue. As a part of this exercise, consideration 
is  given  to  whether  or  not  the  topic  requires  the  regulator  to  be  notified,  if  further  close 
monitoring of the Product is required, whether or not the preparation of an additional PSUR 
or a standalone signal notification is required, or if an update is required to the Product 
information. For all products authorised in the UK, MAHs are obliged to notify the MHRA 
of  new  safety  information  arising  from  any  data  source  (save  for  the  MHRA’s  own 
database) which impacts on the benefit risk profile of the product.  

3.10  Viatris confirms  that  as  a  part  of  its  routine  pharmacovigilance  for  the  Product,  a  signal 
validation and assessment exercise was conducted in July 2022 following publication of 
the following literature article: Chrétien B, Lelong-Boulouard V, Chantepie S, Sassier M, 
Bertho M, Brazo P, et al. Haematologic malignancies associated with clozapine v. all other 
antipsychotic  agents:  a  pharmacovigilance  study  in  VigiBase®.  Psychol  Med.  2021 
Jul;51(9):1459-1466. During this exercise, a search for regulatory documents on this topic 
was  performed  (with  no  results  identified)  and  searches  for  additional  literature  from 
various databases including Medline, Embase and Pubmed were performed to obtain any 
other literature which addressed clozapine and any risk of haematological malignancies. 
The  following  additional  article  was  identified  and  also  analysed:  Tiihonen  J.  Long-term 
treatment  with  clozapine  and  other  antipsychotic  drugs  and  the  risk  of  haematological 
malignancies in people with schizophrenia: a nationwide case-control and cohort study in 
Finland. The Lancet Psychiatry 9: 353-362, No. 5, May 2022.   

3.11  As part of Viatris’ signal validation and assessment exercise, Viatris  reviewed  the literature 
and analysed  the safety data that was relied upon in these two articles, and concluded 
that  no  causal  relationship  between  haematologic  malignancies  and  clozapine  could  be 
established by either study. This is consistent with the conclusions reached by the authors 
in  both  studies.  When  assessed  holistically  against  the  adverse  event  and  safety 
information contained in Viatris’ safety database and the fact that there are no regulatory 
documents available on this topic, the signal was not validated (i.e. the “signal”: a potential 
link between an increased incidence of haematological malignancies and clozapine use, 
was not proven). Furthermore, Viatris’ confirms that there is no data in its safety database 
that confirms a link between the Product and any increased incidence of haematological 
malignancies in the Product’s patient population.  

A12 
 
 3.12  Viatris’  assessment  remains  unchanged  by  the  ongoing  pharmacovigilance  since  the 

signal validation and assessment exercise in 2022. Accordingly no action is proposed.  

4.  CONCLUSION 

The Product has been approved by regulatory authorities as an efficacious and valuable 
therapy for patients with treatment resistant schizophrenia, when used according to strict 
prescribing requirements and monitoring. The information Viatris supplies with the Product 
to  patients,  carers  and  healthcare  professionals,  clearly  identifies  the  potential  risks  of 
treatment with the Product . As a part of Viatris’ ongoing pharmacovigilance practices, as 
a  responsible  MAH  for  a  clozapine  product,  Viatris  undertakes  robust  review  and 
assessment of adverse event  and safety reports, data and literature on a routine basis. 
Monitoring  of  the  Product  and  continued  assessment  of  the  safety  profile  is  done  on  a 
continual basis by Viatris. As a result, we believe no additional actions are required. 

4.1  We trust that this letter addresses your matters of concern as they relate to us. Please feel 

free to contact us should you require further information.  

Yours faithfully 

Affiliate Safety Representative 
United Kingdom and Ireland 
Product Safety & Risk Management 

Viatris UK Healthcare Ltd. 
Building 4, Trident Place  
Mosquito Way  
Hatfield  
Hertfordshire AL10 9UL  
United Kingdom 

A13