Prevention of Future Deaths reports · 2023
Regulation 28 report to prevent future deaths, reference 2023-0318, written 4 Sep 2023. A coroner writes one of these when an inquest reveals a risk that could cause further deaths unless something changes.
| Date of report | 4 Sep 2023 |
|---|---|
| Reference | 2023-0318 |
| Deceased | Talia Phillips |
| Coroner | Stephen Covell |
| Coroner area | Cornwall and the Isles of Scilly |
| Category | Road (Highways Safety) related deaths · Alcohol, drug and medication related deaths |
| Source | judiciary.uk record · original PDF |
| Responses published | 2 |
Text extracted from the PDF text layer. Reproduced verbatim, including the scan's own layout.
H.M. Coroner's Service for Cornwall & the Isles of Scilly H.M. Coroner's Office, Pydar House, Pydar Street, Truro, Cornwall TR1 1XU REGULATION 28 REPORT TO PREVENT FUTURE DEATHS 2 September 2023 THIS REPORT IS BEING SENT TO: The National Institute for Health and Care Excellence and the British National Formulary, Level 1A, City Tower, Piccadilly Plaza, Manchester, Mi 4BT CORONER 1 I am Stephen Covell, Assistant Coroner for Cornwall & the Isles of Scilly Truro Coroner's Court, Pydar House, Pydar Street, Truro TR1 1XU CORONER'S LEGAL POWERS 2 3 I make this report under paragraph 7, Schedule 5, of the Coroners and Justice Act 2009 and regulations 28 and 29 of the Coroners (Investigations) Regulations 2013. INVESTIGATION and INQUEST On 4 August 2022 I commenced an investigation into the death of Talia Evania Phillips. The investigation concluded at the end of the inquest on 9 March 2023. The conclusion of the inquest was a narrative conclusion; "Talia Evania Phillips died at 19.55 on 6 March 2022 on the B3266 opposite the main entrance to the Colquite Estate near Washaway Bodmin as a result of catastrophic head and neck injuries sustained when the vehicle she was driving was in head on collision with an oncoming vehicle. The Deceased had been driving in the direction of Washaway when it crossed over the white line into the Camelford bound lane. It is likely that the Deceased lost control of her vehicle when she suffered a cardiac event caused by a significantly elevated level of the drug Fluoxetine in her blood which had been prescribed to her. There is insufficient evidence evidence to establish why the drug was at such a high level . There is no evidence that the Deceased had any intention to harm herself" The medical cause of death was 1a Head and neck injuries 1b Fluoxetine toxicity. Cornwall and Isles of Scilly Coroner's Service CIRCUMSTANCES OF THE DEAT Talia Phillips died as a result of injuries sustained in a head on road traffic collision with an oncoming vehicle. It is likely that she lost control of her vehicle having suffered a cardiac event caused by a significantly elevated level of Fluoxetine in her blood. 4 Evidence from a toxicologist indicated that a chronically high level of fluoxetine may have led to arrhythmia in life and contributed to a collapse at the wheel. Talia was prescribed Fluoxetine by her general practitioner on 22 December 2021 for anxiety. On 31 January 2022 Talia experienced an episode of palpitations and contacted her general practitioner who organised routine blood tests and an ECG. The tests and the ECG were reported as normal, save for slightly low iron levels. The routine tests did not test Fluoxetine levels. CORONER'S CONCERNS During the course of the inquest, the evidence revealed matters giving rise to concern. in my opinion, there is a risk that future deaths will occur unless action is taken. In the circumstances, it is my statutory duty to report to you. The MATTERS OF CONCERN are as follows - During the course of the inquest I heard that guidance around the prescribing of Fluoxetine did not indicate that fluoxetine levels would should be routinely tested in a patient prescribed Fluoxetine in the event of an episode of palpitations. Such a test may have identified chronically high levels of Fluoxetine. It is requested that guidance in relation to the prescribing of Fluoxetine and management of patients on Fluoxetine should be reviewed to consider in what circumstances a blood test to establish the level of Fluoxetine in the patient's blood would be advisable. ACTION SHOULD BE TAKEN In my opinion action should be taken to prevent future deaths and I believe your organisation the power to take such action. YOUR RESPONSE You are under a duty to respond to this report within 56 days of the date of this report, Cornwall and Isles of Scilly Coroner's Service 5 6 7 namely by 30 October 2023. I, the coroner, may extend the period. Your response must contain details of action taken or proposed to be taken, setting out the timetable for action. Otherwise you must explain why no action is proposed. COPIES and PUBLICATION I have sent a copy of my report to the following; Talia's Family Wadebridge & Camel Estuary Practice 8 I am also under a duty to send the Chief Coroner a copy of your response. The Chief Coroner may publish either or both in a complete or redacted or summary form. He may send a copy of this report to any person who he believes may find it useful or of interest. You may make representations to me, the coroner, at the time of your response, about the release or the publication of your response by the Chief Coroner. 4 September 2023 9 Signature Stephen Covell Assistant Coroner for Cornwall and the Isles of Scilly Cornwall and Isles of Scilly Coroner's Service
2 responses published against this report on judiciary.uk. A response is a body's written reply to the coroner's concerns; publication is at the discretion of the Chief Coroner's office, so an absent response does not mean nobody replied.
10 South Colonnade Canary Wharf London E14 4PU United Kingdom gov.uk/mhra Mr Stephen H G Covell Assistant Coroner Coroner for Cornwall & the Isles of Scilly H.M Coroner’s Office 28 May 2024 Dear Mr Covell, Regulation 28 Report concerning Talia Evania Phillips, DOB 18/08/2000 Thank you for your Regulation 28 Report relating to the death of Talia Evania Phillips. I would like to offer my sincere condolences to Ms Phillip’s’ family on their tragic loss. In the Matters of Concern section of the report relating to the tragic death of Talia Evania Phillips you request that guidance in relation to the prescribing of fluoxetine and management of patients on fluoxetine should be reviewed to consider in what circumstances a blood test to establish the level of fluoxetine in the patient's blood would be advisable. We have reviewed the available evidence from the fluoxetine Summary of Product Characteristics (SmPC), data from the UK Yellow Card Scheme, literature1-8 as well as the advice of our Expert Advisory Group (EAG) of the Commission on Human Medicines on the monitoring of blood levels of antidepressants in patients on fluoxetine treatment which was sought in May 2020 in response to a fatal case report and a Regulation 28 request. The EAG previously advised that the evidence from the analyses of Yellow Card data and published information on antidepressant drug level monitoring was not sufficiently robust to advise clinicians to routinely monitor blood levels of antidepressants for all patients on treatment. The Group recommended however that blood level monitoring of antidepressants may be helpful in certain circumstances, for example in the event of symptoms suggestive of toxicity or when concomitant medicines may interact to increase antidepressant drug levels. Circumstances which can have an impact on fluoxetine levels are described in the SmPC and the medications which are known to alter plasma levels of fluoxetine are detailed in the fluoxetine SmPC section 4.5 on Interactions with other medicinal products and other forms of interactions. The use of fluoxetine concomitantly with a number of medicines requires caution, and these are listed in the attached Annex. When fluoxetine drug level testing was previously discussed, the EAG commented that fluoxetine has a good safety margin in overdose with even a 10-fold increase in dose causing only low toxicity. The EAG acknowledged that fluoxetine has a wide therapeutic range and that currently there is no robust data regarding therapeutic plasma levels to support guidance. Overall, the EAG concluded that routine therapeutic drug level monitoring for fluoxetine would not be recommended unless clinically indicated based on risk factors for toxicity and QT prolongation in the patient. In addition, the fluoxetine SmPC describes that steady state plasma concentrations are dependent on body weight. Fluoxetine is extensively metabolised by the liver and excreted by the kidneys. A lower dose, e.g., alternate day dosing, is recommended in patients with significant hepatic dysfunction. When given fluoxetine 20mg/day for 2 months, patients with severe renal failure (GFR <10ml/min) requiring dialysis showed no difference in plasma levels of fluoxetine or norfluoxetine compared to controls with normal renal function. We note that the Deceased had a normal ECG during fluoxetine treatment in relation to an episode of palpitations. Palpitations at normal therapeutic doses are listed in the fluoxetine SmPC as commonly occurring in association with fluoxetine use and Electrocardiogram QT prolonged (QTcF≥450msec) is also listed as common. The fluoxetine SmPC describes that signs of toxicity in overdose of fluoxetine alone usually have a mild course. Symptoms of overdose have included nausea, vomiting, seizures, cardiovascular dysfunction ranging from asymptomatic arrhythmias (including nodal rhythm and ventricular arrhythmias) or ECG changes indicative of QTc prolongation to cardiac arrest (including very rare cases of Torsade de Pointes), pulmonary dysfunction, and signs of altered CNS status ranging from excitation to coma. Fatality attributed to overdose of fluoxetine alone has been extremely rare. The approved fluoxetine SmPC contains information reflecting the currently available data on known interactions and clinical circumstances which may predispose a person to fluoxetine toxicity and describes symptoms of toxicity in overdose. The fluoxetine SmPC does not make specific recommendations on when to perform blood tests to establish the level of fluoxetine as this is a clinical judgement depending on the unique individual patient circumstances and therefore would be a matter for clinical guidelines. In order to complete our assessment of the adequacy of the current fluoxetine product information, we have sought details of any other medical indications in addition to anxiety, any concomitant medications the Deceased was prescribed, any information about the prescribed dose and duration of fluoxetine use in addition to the blood levels found and information on previous tests performed and a copy of the postmortem report via a response for further information to the registered Yellow Card. If the follow up information indicates that additional guidance would be beneficial, a further review of the adequacy of the fluoxetine product information will be undertaken. Finally, I take this opportunity to confirm that this case report has been added to the Yellow Card database (reference number ADR 28344736), which is the UK’s system for collecting and monitoring information on suspected adverse drug reactions (ADRs) and medical device adverse incidents. Should you have any further questions, please do not hesitate to contact me. Yours sincerely, Chief Executive Medicines and Healthcare products Regulatory Agency E: Executive.Office@mhra.gov.uk Annex: The use of fluoxetine concomitantly with a number of medicines requires caution Phenytoin: Changes in blood levels have been observed when combined with fluoxetine. In some cases, manifestations of toxicity have occurred. Consideration should be given to using conservative titration schedules of the concomitant drug and to monitoring clinical status. Serotoninergic drugs (lithium, tramadol, triptans, tryptophan, selegiline (MAOI-B), St. John's Wort (Hypericum perforatum)): There have been reports of mild serotonin syndrome when SSRIs were given with drugs also having a serotoninergic effect. Therefore, the concomitant use of fluoxetine with these drugs should be undertaken with caution, with closer and more frequent clinical monitoring. QT interval prolongation: Pharmacokinetic and pharmacodynamic studies between fluoxetine and other medicinal products that prolong the QT interval have not been performed. An additive effect of fluoxetine and these medicinal products cannot be excluded. Therefore, co-administration of fluoxetine with medicinal products that prolong the QT interval, such as Class IA and III antiarrhythmics, antipsychotics (e.g. phenothiazine derivatives, pimozide, haloperidol), tricyclic antidepressants, certain antimicrobial agents (e.g. sparfloxacin, moxifloxacin, erythromycin IV, pentamidine), anti-malaria treatment particularly halofantrine, certain antihistamines (astemizole, mizolastine), should be used with caution. Buprenorphine-containing medicinal products Fluoxetine should be used cautiously when co-administered with Buprenorphine-containing medical products as the risk of serotonin syndrome, a potentially life-threatening condition, is increased. Drugs affecting haemostasis (oral anticoagulants, whatever their mechanism, platelet anti- aggregants including aspirin and NSAIDs): risk of increased bleeding. Clinical monitoring, and more frequent monitoring of INR with oral anticoagulants, should be made. A dose adjustment during the fluoxetine treatment and after its discontinuation may be suitable. Cyproheptadine: There are individual case reports of reduced antidepressant activity of fluoxetine when used in combination with cyproheptadine. Drugs inducing hyponatremia: Hyponatremia is an undesirable effect of fluoxetine. Use in combination with other agents associated with hyponatremia (e.g. diuretics, desmopressin, carbamazepine and oxcarbazepine) may lead to an increased risk. Drugs lowering the epileptogenic threshold: Seizures are an undesirable effect of fluoxetine. Use in combination with other agents which may lower the seizure threshold (for example, TCAs, other SSRIs, phenothiazines, butyrophenones, mefloquine, chloroquine, bupropion, tramadol) may lead to an increased risk. Other drugs metabolised by CYP2D6: Fluoxetine is a strong inhibitor of CYP2D6 enzyme, therefore concomitant therapy with drugs also metabolised by this enzyme system may lead to drug interactions, notably those having a narrow therapeutic index (such as flecainide, propafenone and nebivolol) and those that are titrated, but also with atomoxetine, carbamazepine, tricyclic antidepressants, and risperidone. They should be initiated at or adjusted to the low end of their dose range. This may also apply if fluoxetine has been taken in the previous 5 weeks. References 1. Fiaturi N. et al. Therapeutic Drug Monitoring of Antidepressants. Handb Exp Pharmacol. 2018 Sep 8. 2. Ostad Haji E1, Hiemke C, Pfuhlmann B. Therapeutic drug monitoring for antidepressant drug treatment. Curr Pharm Des. 2012;18(36):5818-27. 3. Barbey JT, Roose SP. SSRI Safety in Overdose.J Clin Psychiatry. 1998;59 Suppl 15:42-8 4. Pope S , Solomon Z. Serum fluoxetine and norfluoxetine levels support the safety of fluoxetine in overdose. Annals of General Psychiatry 15. 30 (2016) 5. Hiemke C et al. AGNP consensus guideline for therapeutic drug monitoring in psychiatry: update 2011.Pharmacopsychiatry,44, 195-235. 6. Task Force. Tricyclic antidepressants―blood level measurements and clinical outcome: an APATask Force report. Am J Psychiatry. 1985;142:155–162. 7. Orsulak PJ. Therapeutic monitoring of antidepressant drugs―guidelines updated. Ther Drug Monit. 1989;11:497–507. 8. Linder MW., Keck PE., Jr. Standards of laboratory practice: antidepressant drug monitoring. Clin Chem. 1998;44:1073–1084. ]
2nd Floor 2 Redmond Place London E20 1JQ United Kingdom 11 October 2023 Mr Stephen Covell Assistant Coroner - Cornwall & the Isles of Scilly H.M. Coroner’s Office Pydar House Pydar Street Truro TR1 1XU Dear Mr Covell, I write in response to your regulation 28 report, sent to NICE on 4 September 2023, regarding the very sad death of Ms Talia Phillips. I would like to offer my sincere condolences to Ms Phillips’ family. We have reflected on the circumstances surrounding Ms Phillips’ death and the concerns raised in your report regarding monitoring requirements for fluoxetine. We have made recommendations on the use of antidepressants in our guidelines on the treatment of anxiety and we have also published guidance on safe prescribing of antidepressants in our guideline on medicines associated with dependence or withdrawal symptoms. However, we consider that the Medicines and Healthcare products Regulatory Agency (MHRA), as the regulator or medicines, would be best placed to address concerns you have raised regarding monitoring requirements as these are covered by the summary of product characteristics (SmPC) for a drug, a document which is agreed by the MHRA. We would therefore suggest you send the regulation 28 report to the MHRA for their consideration. If the MHRA issues revised prescribing advice, we would consider whether any relevant NICE guidance needs to be amended. Please do let me know if you require any further information. Yours sincerely, Chief Executive
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