Dear Dr Harris Thank you for your letter dated 9th 2014 and bringing to attention the circumstances of the death of Miss Anokye-Boateng (Regulation 28 Report to Prevent Future Deaths) On reading your Prevent Future Deaths (PFD) report identified two distinct points for MHRA to address_ These are: a) the apparent lack of awareness amongst healthcare professionals that there is the potential for serious gastrointestinal toxicity to occur with short-term use of NSAIDs; and b) whether gastrointestinal protective agents should be routinely used alongside NSAIDs in children. The MHRA has sought the advice of its Pharmacovigilance Expert Advisory Group of the Commission on Human Medicines regarding any necessary actions to address these concerns_ set out below the actions_ a) Healthcare professional awareness of the potential for serious gastrointestinal toxicity to occur with short-term use of NSAIDs: Following a number of national and Europe-wide reviews of the gastrointestinal safety of NSAIDs, a set of elements was agreed for inclusion in the Summary of Product Characteristics (SPC) for all non- selective NSAIDs available as prescription only medicines (POM): These key elements include contraindications to use and extensive warnings in relation to the gastrointestinal side effects_ MHRA also formulated a set of elements for inclusion in the SPC for ibuprofen-containing products available in the UK without prescription as Pharmacy (P) or General Sales List (GSL) medicines_ attach a copy of the key elements for POM non-selective NSAIDs and also for P and GSL ibuprofen: These were implemented for all relevant products (including products authorised for use in children) in the UK in 2008_ CPRD NIBSC MHRA Your May my Akua key key

Medicines and Healthcare Products Regulatory Agency The SPCs for POM; P and GSL NSAIDs including ibuprofen state the following in section 4.4 (Special warnings and precautions for use): 'GI bleeding, ulceration or perforation; which can be fatal, has been reported with all NSAIDs at any time during treatment; with or without warning symptoms or a previous history of serious Gl events. The MHRA and its independent experts consider that this statement in the SPC is sufficient to alert readers to the possibility of serious gastrointestinal side effects occurring early in NSAID treatment: However we acknowledge that healthcare professionals do not always read the SPC before prescribing, particularly when prescribing commonly used medicines, and your report highlights that there are some healthcare professionals who are unaware of this fact Therefore we propose to inform and remind healthcare professionals about this through an article in the September 2014 issue of our monthly bulletin Safety Update'_ b) Should gastroprotective agents be routinely given alongside NSAIDs in children? The SPCs for all POM non-selective NSAIDs include a recommendation to use gastro-protective agents (proton pump inhibitors or misoprostol) when prescribing NSAIDs to those at high risk of gastrointestinal side-effects, as follows: 'The risk of GI bleeding, ulceration or perforation is higher with increasing NSAID doses, in patients with history of ulcer, particularly if complicated with haemorrhage or perforation (see section 4.3) , and in the elderly. These patients should commence treatment on the lowest dose available. Combination therapy with protective agents (e.g: misoprostol or proton pump inhibitors) should be considered for these patients, and also for patients requiring concomitant low dose aspirin, or other drugs likely to increase gastrointestinal risk (see below and 4.5). This recommendation is also included in the SPCs for POM non-selective NSAIDs authorised for use in children: For non-prescription use of ibuprofen in adults and children, a recommendation for the concurrent use of PPIs is not included in the SPC_ For those NSAIDs available over-the-counter; the authorised doses are lower than prescription-only products, and the indications only cover short term self-limiting conditions which do not require diagnosis & supervision by a medical practitioner_ Patients (or parents of patients) at high risk of gastrointestinal side effects who purchase ibuprofen as an over-the-counter product are advised in the package leaflet to discuss taking these products with their doctor s0 that can be properly advised about the need for gastro-protective medicines to be taken at the same time_ After careful consideration of the details of the case presented in your PFD report; the MHRA and its independent experts do not consider that this case changes the overall benefit-risk balance of ibuprofen in children or warrants a change to the current warnings about the need for gastro-protective agents for prescription only medicines_ However, for all NSAIDs we will be strengthening the information for patientslparents provided in the package leaflet on the risk and recognition of gastrointestinal side effects and the action should take_ In summary, in response to your report under Regulation 28 to Prevent Future Deaths, concerning the death of Miss Akua Anokye-Boateng, MHRA will take the following action to minimise risk from the gastrointestinal side-effects of NSAIDs: CPRD NIBSC MHRA 'Drug they they help

Medicines and Healthcare Products Regulatory Agency Proposed action Purpose of proposed action Timeline for action Drug Safety Update (DSU) To remind healthcare professionals of information Publication in the article already included in the SPCs for NSAIDs, that: September 2014 issue (wwmhragov ukldrugsafet the GI side-effects of NSAIDs can be serious and of DSU yupdate) life-threatening: Fatalities have been reported: serious Gl side-effects can occur with short-term use of NSAIDs serious Gl side-effects can occur in people who may be considered to be at low risk; including in children Strengthen the Patient To strengthen the NSAID product information Review and implement Information for all NSAIDs provided to patientslparents on the risk changes within 12 with regards to GI risk_ To aid patientlparent recognition of gastrointestinal months. side-effects and provide information on the action they should take if symptoms arise hope that this response addresses your concerns