Dear Ms. Schofield; Telephone +44 (0) 134L 742534 E-Mail Re: Inquest into the death of George Benjamin RIMMER Ellesfield Avenue Thank you for your letter of 16"h August 2019 (received 21" August 2019) in Bracknell, Berkshire RG12 8YS Telephone +44 (0) 1344 424600 relation to the above inquest: We are very sorry to hear about the death of Telefax +44 (0) 1344 741444 this gentleman and thank you for the opportunity to review the provision of WWW] boehringer-ingelheimco.uk Oramorph" Oral Solution 10 ml (Oramorph") to ensure optimal information is provided to patients: Boehringer Ingelheim Limited (BIL) takes the safety of our medicines extremely seriously and ensures compliance with all regulations with respect to the monitoring of safety, packaging; labelling and provision of information to healthcare professionals (via the Summary of Product Characteristics [SmPC] and patients (via the Patient Information Leaflet [PIL]). Changes have recently been made to the Oramorph" SmPc (ref 1) and PIL as a result of the European Medicine Agency (EMA) review of the Periodic Benefit Risk Evaluation Report (PBRER) for Oramorph" submitted by BIL in 2018. It Directors: should be noted that the EMA reviewed the PBRER's for all medicines Mr U Bose containing the active ingredient morphine at this time; with many of their (Managing) Mr B Moynihan recommendations intended to provide consistency in warnings associated (Finance & Administration) with the active ingredient (morphine) across all these medicines. BIL complied with all EMA recommendations and submitted them to the United Registered Office Kingdom (UK) Regulatory Agency, the Medicines and Healthcare products Ellesfield Avenue Bracknell, Berkshire RGI2 BYS Regulatory Agency (MHRA), who granted approval for the updated text on 1gth December 2018. The PIL version for this update was dated November Registered in England and Wales No. 711858
2018. There has been a subsequent update to the November 2018 PIL mg/5

2 reflecting an administrative change only in preparation for BREXIT: The current PIL date is therefore March 2019 (ref 2). In addition, following a request by the MHRA to the manufacturers of opioid containing medicines in a letter dated 7th May 2019,the outer carton (ref 3) (ref 4) labelling and bottle label have been updated to contain the following boxed statement: Can causo addiclion Contains opioid These changes were approved by MHRA for Oramorph" Oral Solution on 18th June 2019 and are the only recent non-administrative change to the carton and bottle labelling: In responding to your letter of 16t August 2019,we have, as requested_ addressed the 7 "matters of concern" describing already completed or proposed actions with associated timeline or explained why we have taken no action. We have referred to the current versions of the PIL (March 2019),outer carton (May 2019) and bottle labelling (May 2019) and also the versions supplied with the Oramorph@ product that we believe would have been dispensed to Mr Rimmer_ The PIL provided to Mr Rimmer inside the Oramorph" pack we assume to be the June 2015 PIL (ref 5) version: For your convenience, we have also included with this letter the June 2015 PIL, marked with annotations of the changes made in the update to the November 2018 PIL version (ref6) , which is identical in wording to the current (March 2019) PIL except for the name of the Marketing Authorisation Holder: These changes in the PIL from June 2015 can be summarised as follows: Changes from June 2015 to November 2018 PIL: Addition of a warning to check the suitability of taking Oramorph" if previously addicted to or alcohol: Addition of 'increased sensitivity to pain' as a side effect and in general a re-ordering of the side effects section: Addition of wording on the risk of pneumonia from an overdose and symptoms this may cause: Revised wording in the warnings and precautions regarding low cortisol, changes in sex hormone levels, dependency and withdrawal symptoms. Page drugs

Page 3 Revised wording of the risk of taking Oramorph@ with other sedative medicines_ Revised wording in the risk of newborn withdrawal if Oramorph" in pregnancy Revised wording warning of withdrawal and associated symptoms Updated adverse event reporting details. Changes from November 2018 to March 2019 PIL: Change in Marketing Authorisation Holder in light of preparations for BREXIT . You will see in our responses to the 7 "matters of concern" that whilst we do consider the PIL, outer carton and bottle labelling versions both now and as supplied with the Oramorph@ Mr Rimmer received, provide sufficient information to address your concerns, we have proposed one additional change to each of these documents. These changes are outlined below and also summarised on page 9. Mr Rimmer was known to swig out of the bottle rather than take a measured dose as most patients do. We view this matter of concern as more pertinent to Mr Rimmer's prescribing clinician and other healthcare professionals. As per Good Medical Practice (2013) (ref 7) and Good practice in prescribing (ref 8) and managing medicines and devices (2013) it is the responsibility of the prescribing clinician to ensure that helshe provides an explanation to the patient of how and when to take the medicine and how to adjust the dose if necessary. It is also the expectation that the prescribing clinician describes the likely benefits, risks and burdens, including serious and common side effects of any treatment provided Our view is that guidance provided in Good Medical Practice and Good practice in prescribing and managing medicines and devices is particularly relevant when also considering matters of concern 2,3 and 4 as listed in your report: The PIL is provided to supplement the instructions given by the prescribing clinician: The Oramorph@ PIL (both current and the presumed June 2015 version that Mr Rimmer received) provides clear instruction to the patient that the dose of Oramorph@ should be measured a Sml spoon (see also the response to matters of concerns numbers 2 and 6). taking using

Conclusion 1) We took no specific action in response to this particular matter of concern: However please see our response to matter of concern 6,which is closely related. 2 Mr Rimmer self medicated as required. As mentioned in point 1 above, in relation to Good Medical Practice; we view this as a matter of concern more pertinent to Mr Rimmer's prescribing clinician and other healthcare professionals involved in his care rather than BIL. We have carefully reviewed the current and June 2015 version of the PIL and consider both versions provide clear instruction on the intended dosing (amount and frequency) in the section entitled 'HOW MUCH TO TAKE' by the reminding the patient: to take this exactly as the doctor has told the maximum dose is 5 to 1Omls (one to two teaspoons) to check with their doctor or pharmacist if they are not sure:
3. HOW TO TAKE ORAMORPH ORAL SOLUTION Always take this medicine exactly as your doctor has told you should check WIth your doctor or pharmacist ifyou are not sure Taking this medicine Take this medicine by mouth only Use a 5 ml plastic spoon to measure your dose are avallable from your pharmacist How much to take Your doctor WIll decide the amount of medicine to give you Adults The most that should be taken is 5 to 10 ml (one to two teaspoons) every four hours This section also included a statement not to take more than is prescribed and to discuss with a doctor if the prescribed dose is no longer effective. Your body may get used to the medicine (tolerance) Do not take more than your doctor has prescribed If you have been taking your medicine for some time You may find that it does not seem to be working as well as it did Ifthis happens_ talk to your doctor Page you" You They

5 Conclusion 2) Given the clear instructions in the current PIL (unchanged from the June 2015 version) to take the recommended dose and to seek advice if the prescribed dose is no longer effective, we took no specific action in response to this matter of concern_ 3 Mr Rimmer's GP did not recall advising him of the possible consequences of exceeding the prescribed dose: We view this point to be directed to Mr Rimmer's prescribing clinician and other healthcare professionals involved in his care rather than However; as discussed in relation to matters of concern 4 and 5,we do have clear warnings in the PIL of the consequences (symptoms, signs and risks) if more than the prescribed dose is taken: Conclusion 3) We took no specific action in response to this matter of concern: There was no evidence to show that anyone had counselled Mr Rimmer with regards to the use of this Whilst similarly we view this matter of concern as relevant to Mr Rimmer's prescribing clinician and other healthcare professionals involved in his care, we would like to point out that both the current (and also June 2015) PIL contain clear wording regarding: advice to seek medical help in case the patient took "more ORAMORPH than you should" specific guidance warning as to symptoms and signs may notice the risk of taking too much including in severe cases, unconsciousness and death_ Page BIL. drug: they

Page 6 If you take more ORAMORPH thanyou should Ifyou take more of this medicine than you should, talk to a doctor or g0 to a hospital straight away Take the medicine pack WIth you This is so the doctor knows what you have taken Ifyou take more than you should, the following effects may happen; The black circle In the centre of your eyes (pupIl) gets smaller You breathe more slowly You have low blood pressure People who have taken an overdose may also get pneumonia from Inhaling vomit or foreign matter; symptoms of this may include breathlessness, cough and fever In more severe cases, very high doses could cause your blood circulation and breathing to slow down and cause unconsciousness for a long time, or even death In children a high dose may cause fits (convulsions) Please note: In the extract of the wording ofthe current PIL (March
2019) shown in the screenshot above; the identical wording was used in the June 2015 PIL, save that the third paragraph People who__cough and fever" was added in this later version. Conclusion 4 We feel the wording of the PIL (both current and June 2015 version) is sufficient to warn the patient of the need to take only the dose the doctor has prescribed, to seek medical iftoo much is taken and the warning signs/symptoms and associated risks of taking too much and therefore we took no further action to this matter of concern.
5. The leaflet that comes with the bottle does not provide a sufficient warning of the dangers of taking an excess dose: We would like to refer to our answer to matter of concern 4). The section of the PIL entitled 'If you take more ORAMORPH than you should' , provides warnings and a clear instruction on what to do in the event of taking more than the doctor prescribed: This section also provides explicit information about the dangers of taking an excess dose including the risk of death Conclusion 5 Having reviewed the current and June 2015 version wording in light of your letter, we feel the PIL sufficiently warns ofthe dangers of taking an excess dose. Therefore, we took no further action in response to this matter of concern; help =

6_ There is no mention of the dangers of drinking from the bottle and not measuring the dose: The 'HOW TO TAKE ORAMORPH ORAL SOLUTION' section of the PIL gives clear instructions on how to administer Oramorph@, by mouth, using a Sml spoon (available from a pharmacist) with the maximum dose one to two teaspoons every four hours: We also understand it to be good dispensing practice that a pharmacist ensures any solution has a measuring spoon (or alternative device) provided.
3. HOW TO TAKE ORAMORPH ORAL SOLUTION Always take this medicine exactly as your doctor has told you should check with your doctor or pharmacist Ifyou are not sure Taking this medicine Take this medicine by mouth only Use a 5 ml plastic spoon to measure your dose They are available from your pharmacist How much to take Your doctor will decide the amount of medicine to give you Adults The most that should be taken is 5t0 10 ml (one to two teaspoons) every four hours Whilst there is no explicit warning in the PIL not to drink directly from the bottle, the wording ofthe 'HOW TO TAKE ORAMORPH ORAL SOLUTION' is also consistent with other oral morphine solutions (ref 9, 10) available in the UK These also provide specific instructions about measuring the correct dose but, like Oramorph@, do not have an warning not to drink directly from the bottle_ The Oramorph@ PIL, the SmPC, bottle and carton labelling; has been approved by the relevant regulatory authority in the UK, the MHRA, and in our view, meets their requirements as to the information that must be provided to patients. However, we will propose to the MHRA that we include within the 'HOW TO TAKE ORAMORPH ORAL SOLUTION' section the following statement (or words to that effect to be agreed with the MHRA): 'Do not drink directly from the bottle as this may result in you taking the incorrect dose (too little or too much) Drinking from the bottle can result in an overdose with potential for harmful effects including, but not limited to, pneumonia, low blood pressure; unconsciousness and even death:' Page being You they ' explicit

8 Conclusion 6 We believe the PIL wording is clear and of note; is consistent with other providers of oral morphine solution (rer 9,10). However, we will request to the MHRA that we add to the PIL an explicit warning statement not to drink directly from the bottle, additionally with text highlighting the risks of doing so, S0 mirroring the points made in the text explaining the consequences of taking too much, as referred to in matter of concern 4. There is no warning on the bottle to act as a reminder of the dangers of 'taking an excess dose or of the cumulative effect of taking more than the prescribed amount_ Please be aware the space to include additional information on the bottle label is limited and guidance to the patient is covered in detail in the PIL (see response to matter of concern 4 confirming that the warning symptoms Isigns and risks of an excess dose, including death, are clearly stated). The bottle and outer carton labelling both currently has the following statement "To be taken as directed by the prescriber"_ We consider this statement to clearly instruct the patient to follow the advice of the clinician and is in line with statutory requirements for medicines on prescription_ As mentioned in our response to matter of concern 6,the SmPC, PIL and outer carton and bottle labelling for Oramorph? have been reviewed and approved by the MHRA, meeting required standards However, we propose to strengthen and emphasise the wording on both the bottle label and carton label: From To be taken as directed by the prescriber' To "Must only be taken as directed by the prescriber'_ emboldening the font in this revision, to ensure prominence of the wording to the patient: Conclusion Z We believe the current bottle and carton labelling wording is sufficiently clear: However, we will request to the MHRA that we amend the wording and embolden for emphasis the statement regarding taken as directed by the prescriber"_ Page supplied

Page 9 Summary of BIL proposed actions: We have proposed three new actions, as summarised below: Change to PIL We propose to add the following wording (or words to that effect) to the HOW TO TAKE ORAMORPH ORAL SOLUTION' section: 'Do not drink directly from the bottle as this may result in you taking the incorrect dose (too little or too much) Drinking from the bottle can result in an overdose with potential for harmful effects including, but not limited to, pneumonia, low blood pressure, unconsciousness and even death:'
2. Change tothe_bottle _label We propose to amend the bottle label (in case the patient misplaces the outer carton and/or PIL): From: 'To be taken as directed by the prescriber' To: 'Must only be taken as directed by the prescriber' We further propose the amended text will be emboldened for emphasis. 3 Changetoouter_carton labelling Similar to above, we propose to amend the statement on the outer carton: From: 'To be taken as directed by the prescriber' To: 'Must only be taken as directed by the prescriber' (text will be emboldened for emphasis). Please be advised that any proposed additions and amendments to the PIL, bottle and outer carton labelling will need to be reviewed and approved by both the MHRA (UK) and the Healthcare and Products Regulatory Agency (HPRA) in Ireland, since we maintain a joint pack for both countries_

10 We will, as part of the submission of these proposed changes to the regulatory authorities in both the UK and Ireland, provide the MHRA and HPRA with your letter (redacted for the patient's name) so are aware of the background for our proposed changes. We undertake to submit these changes to the MHRA and HPRA no later than the end of December 2019. We trust that we have adequately addressed the maters of concern that you have raised, but should there be anything further you require, please do not hesitate to let me know;