Charles Rendell

LETTER TO THE BERKSHIRE CORONER RE CIPROFLOXACIN

SErreER IN Ue eee eee oom

FAO Mr P Bedford

HM Senior Coroner for Berkshire
Reading Town Hall,

Blagrave Street,

Reading RG1 1QH

8 March 2017
Dear Sir
Report to Prevent Further Deaths: Mr Charles Rendell

| refer to your letter of 11 January 2017 attaching a report to prevent further
deaths, under paragraph 7, schedule 5, of the Coroners and Justice Act
2009 and regulations 28 and 29 of the Coroners (Investigations)
Regulations 2013. In this letter | respond to your report on behalf of Bayer

ple.

As a preliminary matter, please be aware that patient safety is taken very
seriously by Bayer. After receiving notification of Mr Rendell's death and the
associated circumstances, we have carefully reviewed all reports of
psychiatric effects, specifically attempted and completed suicide associated
with use of ciprofloxacin. The review included all sources of information
available to us. We have considered these in the context of the information
currently provided to prescribers and to patients and the matters raised in
your report.

Additionally, while Bayer supplies ciprofloxacin in the UK under the brand
name Ciproxin, generic versions of ciprofloxacin are also supplied by other
manufacturers and the information provided below may not apply to those
products. It is unclear to us whether Mr Rendell took Ciproxin or
ciprofloxacin manufactured by another company.

We respond below, in relation to the specific matters of concern set out in
your report.

1. Apart from the fact that Mr Rendell had undergone a diagnostic
biopsy to test for the possibility of prostate cancer, the only change in his
daily routine was the prescription of ciprofloxacin medication.

Bayer was informed that it should not attend the inquest on 5 January 2017
and we therefore have only very limited information in relation to Mr
Rendell's medical history and personal circumstances.

We understand, from information received from your office that Mr Rendell
was a 76 year old man, who had been prescribed ciprofloxacin 500 mg

Bayer PLC
400 South Oak Way
Green Park

Reading

RG26AD

United Kingdom
pvuk@bayer.com

Tel. +44 118 206 3055

Bayer plcis registered
In England No.935048
Registered office:

400 South Oak Way
Green Park

Reading

RG26AD

twice daily on 19 September 2016, following a needle biopsy for possible
prostate cancer. On 24 September 2016 he was apparently found 8 miles
away from home and was said to be vacant and confused. He was later
found hanged in his garage.

While Bayer is not in a position to respond to your report in relation to Mr
Rendell's particular case, the causes of suicide and suicidality are complex
and may result from a range of factors including mental illness and negative
life events. If Mr Rendell believed that a diagnosis of prostate cancer would
be confirmed in his case, it is possible that this would constitute a negative
life event.

Data issued by the Office for National Statistics for 2015" (the most recent
year for which figures are available) showed that men are around 3 times as
likely to commit suicide as women across all broad age groups and that
hanging is the most common suicide method used in the UK. ;

2. Ciprofloxacin carries __warnings/precautions _ that, in rare cases,
depression _or psychosis can progress to suicidal ideations/thoughts
culminating in attempted suicide or completed suicide. However, it is
unclear how clearly this is made known to ciprofloxacin users.

Manufacturers of medicinal products principally provide information
regarding their medicines, to prescribers in the EU/ UK through the
Summary of Product Characteristics (SmPC) and to patients, through the
Patient Information Leaflet (PIL) supplied with every pack of the relevant
medicine. The SmPC and PIL are referred to collectively as product
information. The required form and content of SmPCs and PILs is specified
in EU Directive 2001/83/EC (implemented in the UK by the Human
Medicines Regulations 2012). The particular information included for each
medicinal product in the SmPC and PIL, including the relative prominence
given to each statement, must be approved by the competent regulatory
authority, as reflecting available scientific and technical knowledge, before it
is put into circulation. Warnings of potential adverse events or side effects,
associated with a medicinal product, are included in product information on
a precautionary basis. This means that prescribers and patients will be
alerted to the possibility that a particular side effect may occur, if there is
some evidence of an association, even if this falls short of establishing a
causal relationship.

The competent regulatory authority for the purposes of supply of Ciproxin in
the UK, is the Medicines and Healthcare products Regulatory Agency
(MHRA). The MHRA has therefore considered the available evidence for
ciprofloxacin and has approved the information included in the SmPC and
PIL for Ciproxin (including in relation to the risk of particular adverse effects)

1

https://www.ons.gov.uk/peoplepopulationandcommunity/birthsdeathsandmarriages/
deaths/bulletins/suicidesintheunitedkingdom/201 Sregistrations

as reflecting the current state of scientific and medical knowledge regarding
the product.

While Ciproxin has been licensed since 1986 (The Phillipines) and used
widely since its marketing authorisation in Europe in 1987, during clinical
trials of ciprofloxacin, when usage of the product has been monitored
closely under controlled conditions, no cases of self-harm, suicidal ideation
and attempted or completed suicide were reported. However, post
marketing authorisation very rare cases of self-harming behaviour have
been reported in patients prescribed ciprofloxacin in standard clinical use.
In view of the nature of post marketing reports, the information provided is
sometimes limited or difficult to interpret for example evidence for onset
from first dose cannot be reliably assessed. In these cases causality often
cannot be attributed solely to ciprofloxacin. An epidemiological study (Jick
SS et al (1998)? using the UK General Practice Research Database
compared the risk of suicidal behaviours among users of quinolones
(including ciprofloxacin), other antibiotics and no antibiotics and concluded
that there is no material increased risk of suicidal behaviours for users of
quinolone antibiotics, compared with the other groups. Your report indicates
that you were referred, during the inquest, to a variety of published literature
relating to ciprofloxacin and quinolone antibiotics. We would caution the
weight placed on these as an objective systematic review of all scientific
literature has not been performed upon which to draw firm conclusions.
However, depression and psychiatric disorders are identified risks for
ciprofloxacin with some evidence that these effects may progress to suicidal
thoughts or self-injurious behaviour. .The product information. for Ciproxin,
approved by the MHRA reflects the current state of scientific and medical
information about the product and includes warnings regarding the
possibility of such effects on a precautionary basis to ensure that
prescribers and patients are fully informed of the potential risks associated
with use of the product.

e The SmPC for Ciproxin published electronically by Bayer and
through the electronic medicines compendium
https:/Awww.medicines.org.uk/emc/ includes the following
information to inform prescribers about the possibility of
psychiatric effects:

o Under “Special warnings and precautions for use”:

“Central nervous system ... psychiatric reactions may
occur even after first administration of Ciprofloxacin. In-
rare cases, depression or psychosis can progress to
suicidal ideations/thoughts culminating in attempted suicide
or completed suicide. In the occurrence of such cases,
Ciprofloxacin should be discontinued.”

2 Jick SS et al. A study of the relation of exposure to quinolones and suicidal
behaviour. BJCP 1998; 45(1): 77-81

o Under “Undesirable effects”:
Psychiatric disorders:

Rare > 1/10,000 to < 1/1000 “Confusion and disorientation.
Anxiety reaction. Abnormal dreams. Depression
(potentially culminating in suicidal ideations/thoughts or
suicide attempts and completed suicide) ... Hallucinations.”

Very rare < 1/10,000 “Psychotic reactions (potentially
culminating in suicidal ideations/thoughts or suicide
attempts and completed suicide) ...”

Frequency not known (but cannot be estimated from the
available data) mania and hypomania.

e The PIL for Ciproxin, a copy of which is provided in each pack
of the product, starts by advising patients:

“Read all of this leaflet carefully before you start taking
this medicine because it contains important
information for you” [emboldened in original].

The PIL then includes the following information to inform
patients about the possibility of psychiatric effects:

o Under “While taking Ciproxin”:

“Tell your doctor immediately if any of the following occurs
while taking Ciproxin. Your doctor will decide whether
treatment with Ciproxin needs to be stopped ...

> You may experience psychiatric reactions the first
time you take Ciproxin. If you suffer from
depression or psychosis your symptoms may
become worse under treatment with Ciproxin. In
rare cases, depression or psychosis can progress to
thoughts of suicide, suicide attempts or completed
suicide. If this happens, contact your doctor
immediately.”

o Under “Possible side effects”

“Other side effects which had been observed during
treatment with Ciproxin are listed below by how likely they
are: .

Rare (may affect up to 1 in 1,000 people)

Confusion, disorientation, anxiety reaction, strange
dreams, depression (potentially leading to thoughts of
suicide, suicide attempts, or completed suicide) (see
Section 2: Warnings and Precautions), or hallucinations.

Very rare (may affect up to 1 in 10,000 people).

Mental disturbances (psychotic reactions potentially
leading to thoughts of suicide, suicide attempts or
completed suicide) (see Section 2: Warnings and
Precautions)...”

Ciprofloxicin is categorised as a prescription only medicine, which means
that it may only be made available following assessment by a healthcare
professional and the provision of information to the patient regarding use of
the medicine, tailored to their particular medical condition and
circumstances, prior to issue of-a prescription. Guidance on prescribing
issued by the UK General Medical Council emphasises that doctors must
keep their knowledge and skills up-to-date and should make use of
electronic and other systems that can improve the safety of prescribing.
Specific reference is made to the Electronic Medicines Compendium, which
lists SmPCs and PILs for medicinal products, including Ciproxin.

Patients are advised to read the PIL relating to their medicine, which
supports the information provided by the prescribing healthcare
professional, before usage is commenced.

Relevant information about ciprofloxacin is therefore made available to
healthcare professionals and to patients through the SmPC and the PIL for
Ciproxin. These documents which provide information regarding the
potential risks of psychiatric symptoms including suicidal behaviour following
use of ciprofloxacin, are readily available to healthcare professionals
electronically and to patients in every pack of product.

3; The literature suggests that this type of side effect can occur even
soon after commencing ciprofloxicin at a comparatively low dose. As it is an
antibiotic, there is no compelling reason why patients should expect to have
this effect unless this fact, and potential symptoms, are brought clearly to
their attention by prescribing clinicians.

As indicated above, the reports of cases of suicidal behaviour following use
of ciprofloxicin, are derived from post marketing data only and are
sometimes very limited and difficult to interpret. Bayer is aware that some
individual reports suggest that patients prescribed ciprofloxicin may exhibit

signs of depression, very soon after treatment is commenced, although it is
difficult to exclude the potential influence of other factors in these cases.
Therefore, as a matter of caution, prescribers are warned in the SmPC for
Ciproxin:

“psychiatric reactions may occur even after first administration of
Ciprofloxacin”.

In summary therefore, prescribers and patients are warned of the risk of
suicidal behaviours following use of ciprofloxacin in the SmPC and PIL
supplied by Bayer in relation to Ciproxin. The warnings, as set out above,
are explicit and clearly stated. Professional standards require that doctors
are familiar with current information relating to the medicines they prescribe;
it is a matter for the prescriber to determine the information to be discussed
with the patient based on the medical history of the patient and his current
condition and personal circumstances. Patients are strongly advised to read
the PIL, provided in every pack of product, before use.

4. One of Mr Rendell’s family members is a general practitioner in New
Zealand. At the inquest, she advised that she had_no knowledge of the
potential effect of Ciprofloxicin and, in conversation with her colleague, nor
did they. | am therefore concerned that this potential risk has not been
given_sufficient_emphasis_and_that_consideration should be given to
prescribing clinicians highlighting the symptoms and suggesting to patients
that they are alert to the possibility and react appropriately.

The product information supplied by manufacturers of medicinal products in
New Zealand is subject to control by the New Zealand competent regulatory
authority, Medsafe. The New Zealand Data Sheet (the equivalent of the
EU/UK SmPC) and the New Zealand Consumer Medicines Information (the
equivalent of the EU/UK PIL) must both be approved by Medsafe before
they are put into circulation in New Zealand The fact that there is a different
approval process applicable in New Zealand and in the UK, may accordingly
result in some differences between the product information supplied with
ciprofloxacin products in New Zealand and those supplied in the UK.

Following receipt of your report however we have examined the New
Zealand Data Sheet and CMI for Ciproxin and can confirm that they both
contain warnings about the possible risk of suicidal behaviour, directed
towards prescribing healthcare professionals and patients respectively.

In contrast, the document which you provided and which was, seemingly,
supplied to you by the relative of Mr Rendell who is a general practitioner in
New Zealand, is a Data Sheet for a generic version of ciprofloxicin supplied
in New Zealand by Multichem NZ Limited (i.e. a formulation of ciprofloxacin
that is not manufactured or supplied by Bayer). Bayer does not control the
content of the information produced by Multichem. It is relevant that the
information contained in this document is less detailed than that in the
product information supplied by Bayer in relation to Ciproxin (whether in

New Zealand or the UK) and includes no explicit reference to the possibility
of suicidal behaviour following use of ciprofloxacin.

In summary, Bayer keeps the product information for its medicines under
constant review and, while the data relating to a risk of suicidal behaviour
following use of ciprofloxicin are very limited, the UK product information for
Ciproxin (both the SmPC and the PIL) includes an appropriate and
sufficiently prominent warning to advise prescribers and patients. We
recognise that this information is important, but do not believe greater
prominence is appropriate, based on the available data and our concern not
to detract from other information regarding use of. ciprofloxacin. For
completeness, we have carried out a review of the UK product information
issued by manufacturers of generic formulations of ciprofloxacin and believe
that all such information adequately warns prescribers and patients
regarding the risk of suicidal behaviour.

We are surprised that Mr Rendell's New Zealand relative was not aware of
the content of the New Zealand product information for Ciproxin (which also
notifies prescribers of the possibility of suicidal behaviour following
treatment with ciprofloxacin), as approved by the New Zealand regulatory
authority. This may however be due to the generic versions of ciprofloxacin
in New Zealand’s product information being less detailed than that of the
UK. However, as with the UK, the New Zealand medicines regulatory
authority has reviewed and approved the ciprofloxacin information available
to prescribers and patients and is entirely satisfied with the adequacy of
warnings.

We hope that this letter answers your matters of concern. Please feel free
to contact us should you require further information.

Yours-faithfully

Head of Pharmacovigilance, —_ of

dicines & Healthcare products oivefe MHRA

} . 2 e Requisting Medicines and Medical Deviess
' Regulatory Agency

Dr Peter J Bedford MHRA

Her Majesty's Senior Coroner for Berkshire 181 Buckingham Palace Road

Reading Town Hall London

Blagrave Street SWIW 982

Reading United Kingdom

RG11OH www.gov.uldmhra

4 October 2017

Dear Dr Bedford,

Reference: regulation 28: report to prevent future deaths - Charlies Hugh Rendell

The MHRA has been provided with a copy of the above Regulation 28 report sent to Bayer Pic,
whi geath of Mr. Charles Hugh Rendell. The report was brought to our attention by
who is a General Practitioner in New Zealand and is Mr Rendell's niece. The
as aise seen a copy of the letter from Bayer Plc in response to your report. has

also submitted to MHRA a Yellow Card report of Mr. Rendell’s suicide whilst taking ciprofloxacin.

We have considered the information provided from these documents on the circumstances leading
to Mr Rendell's death. We have focussed on the course of ciprofloxacin that was given to him to
take following his prostate biopsy procedure, and have considered whether the statutory information
currently provided by the MHRA to prescribers on the safe use of these medicines contains all
necessary information.

Looking at the events relevant to these considerations, it is reported that Mr Rendell was being
investigated with a needie biopsy of the prostate on 19 Sept 2016 for the possibility of prostate
cancer. After the procedure, he was given ciprofloxacin 500 mg tablets to take twice a day for a
period of 5 days. It is reported that Mr Rendell had no history of depression or other mental health
problems. However, on the fourth day of ciprofloxacin tablets, he became confused, agitated and
was found wandering 10 miles from home. Later the same day, he committed suicide by hanging in
his garage.

Information on the safe use of medicines is provided to healthcare professionals through the
Summary of Product Characteristics (SmPC) available from the electronic medicines compendium
(httos://www.medicines.org.uk/eme/) and to patients through the Patient Leaflet in every pack of
product. Full details of the SmPCs may also be found on the MHRA’s website
(http://www mhra.gov.uk/spe-pil/).

With respect to Mr Rendell's case, the following advice is provided in the Ciproxin SmPC:

e Psychiatric adverse reactions may occur even after first administration of Ciproxin.

e Depression or psychosis can progress in rare cases to suicidal ideations/thoughts
culminating in attempted suicide or compieied suicide, and that Ciproxin should be
discontinued if such psychiatric reactions occur.

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e The rare undesirable effects of agitation, confusion, disorientation, depression and very rare
psychotic reaction (potentially culminating in suicidal ideations/thoughts or suicide atlempis
and completed suicide) are also mentioned,

The Package Leaflets for Ciproxin (Bayer) provides the following advice:

* Patients taking Ciproxin may experience psychiatric reactions, even at the first dose.

* Patients suffering depression or psychosis may experience worsening of the symptoms of
these conditions under therapy with Ciproxin.

e Inrare cases, depression or psychosis can progress to thoughts of suicide, suicide atternpis,
or cornpieted suicide.

* Patients should contact their doctor immediately if any of the aforernentioned undesirable
effects occur while taking Ciproxin.

« Agitation, confusion, disorientation, anxiety, depression (potentially leading to thoughts of
suicide, suicide atternpts, or completed suicide) while taking Ciproxin are also mentioned as
possible side effects

in light of the above, we consider that the product information for Ciproxin provides comprehensive,
up-to-date information on the risk of mental disturbances including agitation, confusion, psychosis,
depression, suicidal ideation and the possibilily of completed suicide. in addition, there is clear
advice on the need for immediate contact with the prescribing doctor, should these undesirable
effects occur whilst taking Ciproxin.

We will review all the UK Package Leaflets for generic ciprofloxacin products to ensure that the
information mentioned above is consistently presented across these products.

Yours sincerely

—_

VRMM Division (Vigilance and Risk Management of Medicines)