Yellow Card Reports Research Articles

MHRA reviewing safety of asthma drug as Yellow Card reports increase

MHRA reviewing safety of asthma drug as Yellow Card reports increase

MHRA warns of dangers of fake weight loss pens after Yellow Card reports

MHRA warns of dangers of fake weight loss pens after Yellow Card reports

Dapagliflozin and euglycaemic diabetic ketoacidosis – ‘But doctor my sugars were normal!’

Dear Editor, A ‘Dear Doctor Letter’ was issued by the manufacturer of Forxiga (dapagliflozin) in November 2021; this followed reviews by the European Medicines Agency and the UK Medicines and Healthcare products Regulatory Agency. The letter stated that ‘The removal of the T1DM indication is not due to any safety concern for dapagliflozin in any indication, including T1DM’ but must be discontinued ‘in patients with T1DM by or in consultation with a physician specialised in diabetes care and be conducted as soon as clinically practical.’1 Dapagliflozin was previously approved in the treatment of diabetes for combination with insulin therapy in type 1 diabetes and with oral medications and insulin in type 2 patients. The pathogenesis of EuDKA occurs as a consequence of absolute insulin deficiency leading to reduced glucose utilisation and enhanced lipolysis; increased delivery of free fatty acids (FFAs) to the liver coupled with raised glucagon levels promotes FFA oxidation, and subsequent production of ketone bodies.2 Rosenstock and Ferrannini also reported that following a US FDA safety communication, the majority of reports of EuDKA between 2014 and 2015 in the US were actually in patients with type 2 diabetes.2 The UK Yellow Card report did not specify the type of diabetes. A review of the UK MHRA Yellow Card reporting system on dapagliflozin in October 20223 showed the following results: total number of adverse drug reactions (ADRs) reports, 2155; serious ADR reports, 1371; fatal ADR reports, 26 (cut-off 31 August 2022). Details of ADRs which could be related to EuDKA are shown in Table 1. The number of reports submitted had risen following the letter from the manufacturer. It is expected that a large number of these reports could be related to the concomitant use of dapagliflozin and insulin therapy in patients with type 2 diabetes. Appropriate monitoring and awareness on the part of health care professionals and patients are necessary to prevent potentially harmful and fatal consequences. The advice from both the manufacturer and the medicines regulatory agencies surrounding the actions required in patients with type 1 diabetes is clear and we may prevent problems by close monitoring of patients in diabetes specialist units. Such task is facilitated by the use of electronic medical records and access to the list of all medications used by these patients. Following the research findings on the occurrence of EuDKA in patients with type 2 diabetes, we may argue that these patients should also be included in a review for EuDKA. From personal and documented reports, patients with type 2 diabetes often react negatively to the introduction of insulin therapy to their medications.4 Part of the rationale to include insulin therapy usually includes improved glycaemic control. Following a period of improvement in their self-monitored blood glucose, some patients might react by stopping or reducing their use of insulin. The resulting ketonaemia in patients with insulin deficiency taking SGLT2 inhibitors is initially asymptomatic or clinically undetectable and could gradually lead to severe ketoacidosis. There are data which document the increased incidence of chronic heart failure, especially in people with type 2 diabetes;5 as this diagnosis is also included in the newer indications for dapagliflozin it will be important to communicate the association of EuDKA and dapagliflozin use to specialists who might not necessarily be expert in managing this complication of diabetes. Most patients with type 2 diabetes are managed in primary care and initiating a community-wide alert would take time to complete and require significant human resource, increased budget, and likely lead to increased patient anxiety. Blood tests to detect low endogenous insulin secretion would also take time and increased resources. A more rapid and simple approach is required. One option could be to request that all patients with long-standing type 2 diabetes who are treated with insulin in combination with dapagliflozin or any other SGLT2 inhibitors should be advised to use blood or urine ketone testing to detect EuDKA, particularly when insulin doses are being reduced or withdrawn. Awareness of these such parameters would help health professionals to quickly identify and treat patients at risk. The Association of British Clinical Diabetologists and Diabetes UK have produced joint guidance on communication and education requirements to be provided to patients who were prescribed an SGLT2 inhibitor for the first time.6 This provides useful and practical suggestions for minimising adverse reaction to the use of these medicines. Michael Stacey, MD, FRCP, Senior Lecturer, Royal Centre for Defence Medicine, UK There are no conflicts of interest declared.

Identifying and managing adverse drug reactions: Qualitative analysis of patient reports to the UK yellow card scheme.

IntroductionAdverse drug reactions (ADRs) can have significant negative impact on peoples' daily lives, with physical, economic, social and/or psychological effects. Patient reporting of ADRs has been facilitated by pharmacovigilance systems across Europe. However, capturing data on patients' experiences of ADRs has proved challenging. Existing patient reports to the UK Yellow Card Scheme contain free‐text comments which could be useful sources of information.ObjectivesTo investigate patients' experiences of ADRs and their impact on patients as described in free‐text data within patient Yellow Card (YC) reports submitted to the Medicines and Healthcare products Regulatory Agency.MethodsA qualitative review of narrative texts was conducted on free‐text data from 2255 patient YC reports from July to December 2015.ResultsThree key narrative themes emerged from analysis of the free‐text data in 2255 reports: (1) identification of ADRs, (2) severity and impact of ADRs, and (3) management of ADRs. Temporal associations were the most common method of identification followed by differential diagnoses and confirmation with information sources such as healthcare professionals (HCPs). A combination of explicit and implicit impacts were described: physical, psychological, economic and social effects often persisted and caused serious disruption to many patients' lives. A range of strategies were used to manage ADRs, including consultation with HCPs, stopping/reducing the medicine or taking medicines to alleviate symptoms.ConclusionFree‐text data from YC reports has been an underutilised resource to date, but this research has confirmed its potential value to pharmacovigilance and medication safety research.

Spontaneous Reporting to Regulatory Authorities of Suspected Adverse Drug Reactions to COVID-19 Vaccines Over Time: The Effect of Publicity.

IntroductionThe UK Medicines and Healthcare products Regulatory Agency (MHRA) has published frequent summaries of spontaneous reports of suspected adverse drug reactions (ADRs) (Yellow Cards) to vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The EudraVigilance database has provided similar data for the European Economic Area.ObjectiveOur objective was to characterize the evolution over time of spontaneous reports of suspected ADRs to coronavirus disease 2019 (COVID-19) vaccines and to observe the effect of a publicized reaction (cerebral venous and sinus thrombosis [CVST]) on reporting rates.MethodsWe used publicly available data on reports of suspected ADRs and doses of vaccine administered, published by the MHRA, EudraVigilance, and the European Centre for Disease Prevention and Control to calculate reporting rates.ResultsApproximately 4814 Yellow Card reports (23 fatal) per million doses of ChAdOx1 nCoV-19 (AstraZeneca) and 2890 (13 fatal) per million doses of tozinameran (Pfizer/BioNTech) have been lodged. Between 15 March and 31 October 2021, cumulative European reports of CVST rose from 0 to 443 (183 with thrombocytopenia, 72 fatal) with ChAdOx1 nCoV-19 and from 2 to 315 (9 with thrombocytopenia, 28 fatal) with tozinameran. European cases of retinal vein occlusion and thrombosis rose from 0 to 168 with ChAdOx1 nCoV-19 and from 1 to 220 with tozinameran; four of the ChAdOx1 nCoV-19 cases were associated with thrombocytopenia.ConclusionReports of fatal adverse reactions to coronavirus vaccines are very rare. Reports of CVST have been made in relation to both vaccines. Most were submitted after the reaction had been publicized. Thrombocytopenia occurred in a minority of cases. Reports linked both vaccines to cases of retinal vein thrombosis, just four cases with thrombocytopenia. This suggests two different mechanisms of thrombosis associated with the vaccines.

MHRA receives Yellow Card reports of viral rebound in people treated with Paxlovid

MHRA receives Yellow Card reports of viral rebound in people treated with Paxlovid

Implementing a specialist paediatric clinical pharmacology service in a UK children's hospital.

AimsRoyal College of Paediatrics and Child Health subspecialist training in Paediatric Clinical Pharmacology and Therapeutics has been delivered in the UK for 20 years, but no specialist clinical services have been set up previously.MethodsProspective audit and service evaluation of paediatric clinical pharmacology service pilot phase and dedicated service at a UK children's hospital.ResultsPilot scheme (May–October 2019), then weekly service (established June 2020). Service covers the High Dependency Unit, and inpatients with polypharmacy. The pilot demonstrated high levels of acceptance, with 89% of suggested medication changes agreed by lead clinical team, and success, with 97.5% of suggested changes continued until discharge/pilot completion. Economic analysis estimated direct annualised cost savings on medications of up to £10 000. After 20 ward rounds of the established service, 270 potential medication changes were identified, 213 were carried out (78.9%). The most common were deprescribing (n = 143), prescribing (n = 47) and dose adjustment (n = 8). Seventy‐five different medications were deprescribed, most commonly chloral hydrate (n = 12), Lactulose, ibuprofen, Bio‐Kult and sodium alginate (all n = 4). The percentage of inpatients prescribed ≥10 medications decreased from 38.5 to 32.1%, while the subset prescribed ≥20 medications decreased from 11.0 to 5.67%. The mean number of medicines prescribed decreased from 9.0 to 8.0, while the median was unchanged at 7. Annual Yellow Card reports of suspected adverse drug reactions more than doubled (n = 66).ConclusionA UK model for subspecialist paediatric clinical pharmacology service delivery has demonstrated a positive clinical impact and could be replicated at other UK secondary/tertiary children's hospitals.

Analysis of reports of unintended pregnancies associated with the combined use of non-enzyme-inducing antibiotics and hormonal contraceptives

BackgroundEnzyme-inducing antibacterial drugs can impair the efficacy of hormonal contraceptives. Suspicion that other antibiotics might do likewise led to advice that extra contraceptive precautions should be taken during a course...

MHRA Yellow Card reports on COVID-19 vaccine adverse reactions

MHRA Yellow Card reports on COVID-19 vaccine adverse reactions

Regulator recommends thyroid function tests for patients on levothyroxine with persistent symptoms

Patients with hypothyroidism, who report persistent symptoms after switching between different tablet formulations of the thyroid hormone levothyroxine, should be considered for a thyroid function test, the Medicines and Healthcare products Regulatory Agency (MHRA) has said. In guidance issued on 19 May 2021, the MHRA said it had received 335 Yellow Card reports between 1 […]

P137 Growing up on biologics: a case report of development of NMDAr encephalitis in a young person with JIA on abatacept

Abstract Background A 12-year-old female with JIA on biologic medication (IV abatacept every three weeks) presented with a first generalised tonic-clonic seizure on background of preceding headache and fatigue. The seizure self-terminated but disorientation and encephalopathy ensued. MRI brain demonstrated lesions with high signal intensity in the left periventricular and right occipital regions. The clinical picture and radiological imaging suggested a broad differential diagnosis including CNS infection, JC virus associated progressive multifocal leucoencephalomalacia (PML), acute disseminated encephalomyelitis (ADEM) and Anti-N-methyl-d-aspartate receptor (NMDAr) encephalitis. She was commenced on IV ceftriaxone, acyclovir and clarithromycin. All bloods including inflammatory markers and infection serology were unremarkable. CSF was acellular and JC virus PCR negative. NMDAr encephalitis was initially considered unlikely (pre-existing immunosuppression, abnormal MRI brain and no evidence of ovarian teratoma on abdominal MRI pelvis). However more classical clinical features developed including further seizures, significant movement disorder, cognitive dysfunction, sleep and speech dysfunction. Anti-NMDAr antibodies in both serum and CSF were positive. She made a good recovery following IV steroids, plasmapheresis and rituximab and was discharged home after a 10-week admission. NMDAr encephalitis developed three years after commencing abatacept treatment. Previous immune modulating treatment included methotrexate (since age 2 years), Etanercept (age 5-8 years) and Tocilizumab (aged 8-10 years). Flares of disease following a period of control necessitated the changes in therapy. Methods A literature review was conducted to explore the relationship between NMDAr encephalitis and biologic medication. A yellow card report and information request to abatacept manufacturer were also submitted. Results No previous cases of NMDAr encephalitis in patients on abatacept or paediatric cases related to biologic therapy are described. There are reports of adults developing NMDAr encephalitis on Adalumimab for Crohn’s disease and etanercept for rheumatoid arthritis. NMDAr encephalitis has also been described in patients on immune checkpoint inhibitors for malignant melanoma (nivolumab and ipilimumab). Known triggers of production of anti-NMDA receptor antibodies include tumours (ovarian teratoma; rarely associated in patients under 12 years) and viral infections. Developing autoimmune disorders on biologic medication is well reported, most notably psoriasis and inflammatory bowel disease. In relation to abatacept specifically, the development of anti-nuclear antibodies (ANA) and psoriasis have been described. However, patients with autoimmune disorders are known to be of increased risk for additional immune disease. A new cohort of patients are emerging who have received multiple biologic medications and the development of autoimmune conditions despite immunosuppression needs to be considered. Conclusion We describe the first case of NMDAr encephalitis occurring in a child on abatacept therapy, and the first case in JIA. We are unable to determine what contribution a history of autoimmune disease or immunomodulating therapy has made on its development in this case. Disclosures R. Close: None. P. Bale: None. K. Gallagher: None. G. Ambegaonkar: None. T. Rossor: None. N. Abbassi: None. K. Armon: None.

Researchers unable to identify batches of biologic drugs from 85% of Yellow Card reports

Researchers unable to identify batches of biologic drugs from 85% of Yellow Card reports

Making medicines safer: analysis of patient reports to the UK’s Yellow Card Scheme

ABSTRACTObjectives: No studies describing UK patient Yellow Card reports have been published since the evaluation of the first two years of direct patient reporting (2005–7), when 5,180 reports were analyzed.Methods: Patient Yellow Card reports submitted July-December 2015 for vaccines and other drugs were analyzed. Comparisons to the initial evaluation were made of: reporting method, number of suspect drugs, proportion classed as serious. Factors affecting seriousness of reports were examined.Results: There were 3,060 patient Yellow Card reports analyzed. Vaccine reports have increased from very few in 2005–7 to 25% of reports. The proportion of reports citing one drug (94.3%) and the proportion considered serious (70.3%) increased from the 84% and 58% respectively found in 2005–7. The main method of reporting had changed from paper (61%) to internet (88.5%). Serious reports were more common in females, for vaccines in young persons, but in adults for other drugs, and included more reaction terms than non-serious reports.Conclusion: Patient reporting, in particular to vaccines, has increased dramatically since 2005–7. Increases in the proportion of reports concerning one drug and the proportion considered serious could indicate that the usability of patient reports may have improved in comparison to early reporting.

MHRA seeks help in reversing decline in Yellow Card reports

MHRA seeks help in reversing decline in Yellow Card reports

Majority of Welsh community pharmacists have never submitted a Yellow Card report, study finds

Majority of Welsh community pharmacists have never submitted a Yellow Card report, study finds

Research roundup: June 2018

In brief Surveillance study of Yellow Card reports finds no significant safety concerns over the introduction of Bexsero Inappropriate medicines and prescription omissions compromise quality and longevity of life Community nurses' prescribing needs: expert consensus reached

PP-34 Adverse drug reactions in neonates: comparing retrospective spontaneous yellow card reports to prospectively collected reports

Background The UK Medicines and Healthcare prod-ucts Regulatory Agency (MHRA) encourages the report-ing of all adverse drug reactions (ADRs) in children that are ‘serious or result in harm’.1 The rate of under-report-ing of ADRs has been estimated to be approximately 94% and neonatal ADR reports are not influencing the clinical warnings issued by the MHRA.2,3 This study aims to compare reports of neonatal ADRs actively collected by a researcher from a tertiary neonatal unit to those reported to the UK yellow card system between 2001 and 2010. Methods An independent researcher collected data on ADRs in a tertiary neonatal care unit by daily ward round attendance, note reviewing and staff questioning. The results collected over four weeks were then compared to the yellow cards submitted to the MHRA between 2001 and 2010 by means of reviewing a recently published paper.3 Results Between 2001 and 2010 there were ninety seven yellow card reports of neonatal ADRs to the MHRA. Over a four week observational period thirty three neonatal ADR cases were suspected and reported by a researcher. The highest number of yellow card reports were for swine flu vaccinations (eight), whereas the researcher only collected one report relating to a vaccine, with the highest number of reports involving diuretics or antibiotics (six each). The yellow card reports most frequently reported rashes or erythema (twenty one) whereas the researcher most frequently reported electrolyte disturbances (seven), car-diac effects (five) or gastrointestinal effects (five). Conclusion There are a number of differences between neonatal ADRs reported to the MHRA and those occur-ring commonly. It is thought the predicted under-report-ing of ADRs and lack of knowledge or attention to neona-tal ADRs may be contributing to this.

Yellow Card reports associated with use of natural health products in children – An exploratory analysis

Abstract of a presentation given at the Research council for complementary medicine 2015 conference (RCCM): demonstrating the value of integrative medicine, 10 September, London, UK.

Completing a Yellow Card report following an adverse reaction

Even the most experienced practitioners can come across moderate or severe complications when treating patients with toxins and fillers. Any adverse reactions to a therapeutic agent should be reported using the Medicines and Healthcare Products Regulatory Agency's Yellow Card scheme. Rachel Goddard summarises the process of adverse incident reporting and addresses key questions

Completing a Yellow Card report following an adverse reaction to a medicine

Aesthetic nurses are more than aware that medicines have the potential for unwanted effects. Whereas some adverse effects are predictable and dose-related, others are less predictable and may bear little relationship to the dose in question. Any suspected adverse reactions to a therapeutic agent, including complementary and herbal products, should be reported as an incident and the online or paper Yellow Card sets out the information required. In this article, the author summarises the Medicines and Healthcare Products Regulatory Agency's guidelines on completing a Yellow Card report.