Dear Mr Oliver,

We write in response to your letter to dated 15th February 2024 (CRAWFORD S B 18122020). We are sorry to hear the sad circumstances surrounding this case.

We have considered the matters of concern highlighted in your report, together with additional points raised during a discussion with one of Mr Crawford’s family members. We understand from that discussion that Mr Crawford was prescribed pregabalin in addition to clozapine; severe respiratory depression has been reported with the use of pregabalin, with a higher risk in those taking other CNS depressants. This warning is included in the important safety section of the BNF’s pregabalin monograph and reflects a safety alert from the MHRA issued in 2021.

The BNF includes information on pharmacodynamic interactions, that is interactions between drugs which have similar or antagonistic pharmacological effects or side-effects. This information is present within interaction messages of relevant drug monographs in online versions of the BNF and the BNF app. The same information is presented in tables in print editions of the BNF but, at the time of this death, these tables were not present in online versions of the BNF or in the BNF + BNFC app.

To address the concerns raised in your report, we plan to review the wording around the use of drugs that cause sedation (including clozapine and alcohol) and drugs with CNS depressant effects (including alcohol) within the pharmacodynamic interaction messages and in the tables. This will further highlight that concurrent use of two or more drugs that can cause sedation and / or CNS depression might increase the risk of CNS depressant effects, such as sedation, unconsciousness, coma, respiratory depression, and cardiovascular depression, and / or enhance the effects of drugs with CNS depressant effects. In addition, the pharmacodynamic interaction tables have now been added to the online versions of the BNF and BNFC ensuring this content is more accessible to users.

As alcohol is not a medicine, the BNF includes very limited information on alcohol, other than the information on its potential pharmacodynamic interactions. However, the BNF does include warnings on the use of medicines with alcohol where safety information is available. As mentioned in your report, where there are particular risks with the use of certain medicines with alcohol, such as with clozapine, the BNF recommends that cautionary and advisory labels should be added to dispensed medications. We acknowledge that these labels are concise, as is necessary for dispensing labels, however, the label provides information to the patient and should also prompt health professionals to counsel patients where appropriate.

We are aware that your report has also been sent to the MHRA. We have been in touch with the MHRA, and we will work together to ensure that any updates from the MHRA are reflected in the BNF where appropriate.

We trust that this addresses this important issue.

Dear Mr Oliver,

Regulation 28 Report concerning Sean Benjamin Crawford

Thank you for a copy of your report dated 15th February 2024, in which you asked the Medicines and Healthcare products Regulatory Agency (MHRA) to provide a response to the Regulation 28 Report to Prevent Future Deaths following the inquest into the sad death of Mr Sean Benjamin Crawford. We would like to extend our sincere sympathies to the family of Mr Crawford for their loss.

I understand from your report that Mr Crawford’s death resulted from the combined toxic effect of alcohol and clozapine, which were individually not at toxic levels, but acted together to suppress his central nervous system. Your report identified the following matters of concern relating to clozapine:

1. There is no guidance in any academic literature, the British National Formulary, or NICE or MHRA advice on the dangers of death when comparatively high, but not fatal, levels of both clozapine and ethanol in the blood result in central nervous system depression.

2. The patient information leaflet and wording on the outer label do not advise of the risk of death when clozapine and alcohol are taken together.

The MHRA is an executive agency of the Department of Health and Social Care (DHSC) with responsibility for the regulation of medicinal products in the UK. The MHRA ensures that medicines are efficacious and acceptably safe, and that any possible side effects which have been recognised to occur with use of a medicine are appropriately described in the authorised product information. This comprises the Summary of Product Characteristics (SmPC, intended for healthcare professionals), labelling, and Patient Information Leaflet (PIL, provided to patients in each medicine pack). The SmPC is a source of advice for healthcare professionals (HCPs) on the safe and effective use of a medicinal product.

Information regarding interactions is included in section 4.5 of the SmPC for every medicinal product. The current interactions section of the SmPC for clozapine states within the sub- section relating to contraindications of concomitant use that, “alcohol should not be used concomitantly with clozapine due to possible potentiation of sedation.” This section also includes a table noting the enhanced central effects of alcohol and that additive CNS depression and cognitive and motor performance interference may occur when it is used in combination with clozapine. This section also states that patients should be advised of the possible additive sedative effects and that they should be cautioned not to drive or operate machinery. As you have noted, the current PIL for clozapine includes the statement, “do not drink alcohol during treatment with clozapine.” Furthermore, when clozapine is dispensed it must also have a cautionary label which includes the warning “do not drink alcohol”. However, none of these materials specifically mention any risk of death because of the interaction with alcohol.

We have considered the evidence provided and the circumstances leading to Mr Crawford’s death. We have also recently met with a member of Mr Crawford’s immediate family to discuss their concerns. Some of these relate to clinical discussions between a patient and their prescriber which we are not able to address, as it is not within our remit to comment on the clinical care in specific cases. However, because of the nature of some of the concerns raised, we intend to conduct a further assessment of the information provided within the clozapine product information regarding drug-drug interactions. As part of this assessment, we will be giving careful consideration to the information which is provided to healthcare professionals, patients and their families and carers, and whether this can be improved. We intend to engage with relevant stakeholders during this process to ensure that their concerns are addressed. This assessment will be considered as part of a wider review of clozapine which will be completed this year.

We are aware that you have also written to the BNF, and we will work with them as our assessment progresses. In the meantime, we will continue to closely monitor the safety of clozapine, including cases of drug-drug interactions. Should any updates to the product information be required we will issue an article in our bulletin to healthcare professionals “Drug Safety Update” accordingly.

Dear Mr Oliver,

Thank you for the Regulation 28 report to prevent future deaths of 15 February 2024 about the death of Sean Crawford. I am replying as Minister with responsibility for Medicines.

Firstly, I would like to say how saddened I was to read of the circumstances of Mr Crawford’s death, and I offer my sincere condolences to their family and loved ones. The circumstances your report describes are concerning and I am grateful to you for bringing these matters to my attention. Thank you for the additional time provided to the department to provide a response to the concern raised in the report.

The report raises concerns over the combined effects of clozapine with alcohol and the lack of guidance that provides advice on the dangers of death in this scenario.

In preparing this response, Departmental officials have made enquiries with National Institute for Health and Care Excellence (NICE). The National Institute for Health and Care Excellence (NICE) is the independent body responsible for developing authoritative, evidence-based guidance on best practice for the health and care system. NICE guidelines are developed by experts based on a thorough assessment of the available evidence and through extensive engagement with stakeholders. Healthcare professionals are expected to take them into full account in their decision making, although it is important to note that NICE guidelines are not mandatory and do not override a clinician’s responsibility to make decisions appropriate to individual patients.

NICE’s guideline on the prevention and management of psychosis and schizophrenia in adults was published in 2014. Recommendation 1.3.6.7 states that, when a patient starts antipsychotic medication (such as clozapine), the use of alcohol, tobacco, prescription and non-prescription medication, and illicit drugs, should be discussed. This includes the possible interference of these substances with the therapeutic effects of prescribed medication and psychological treatments. Furthermore, information provided by the British National Formulary on clozapine (which can be accessed on NICE’s website) states that alcoholic and toxic psychoses are contraindications, or conditions with which clozapine

should not be taken due to the potential harm to the patient. Departmental officials, however, have shared your report with NICE, so it can consider the impact of your findings on its published guidance.

I am aware that the Medicines & Healthcare products Regulatory Agency (MHRA) has provided a response in respect of the key concern you raise in the report. As you will be aware, MHRA is an executive agency of the Department of Health and Social Care (DHSC) with responsibility for the regulation of medicinal products in the UK. The MHRA ensures that medicines are efficacious and acceptably safe, and that any possible side effects which have been recognised to occur with use of a medicine are appropriately described in the authorised product information. However, MHRA has recognised in the response that none of the authorised product information specifically mention any risk of death because of the interaction with alcohol.

As I understand, MHRA has considered the concerns raised in your reports and intends to conduct a further assessment of the information provided within the clozapine product information regarding drug-drug interactions. As part of this assessment, MHRA will be giving careful consideration to the information which is provided to healthcare professionals, patients and their families and carers, and whether this can be improved. This will be part of a wider review of clozapine which will be completed this year. MHRA will engage with relevant stakeholders such as BNF during this process to ensure that their concerns are addressed. In the meantime, MHRA will continue to closely monitor the safety of clozapine, including cases of drug-drug interactions. Should any updates to the product information be required MHRA will issue an article in a bulletin to healthcare professionals, “Drug Safety Update” accordingly.

I hope this response is helpful. Thank you for bringing these concerns to my attention.