Treatment of insulin poisoning: A 100-year review.

BACKGROUND: Insulin poisoning, as opposed to hypoglycaemia induced by therapeutic doses of insulin, is rare, and guidelines on management differ. We have reviewed the evidence on treatment of insulin poisoning. METHODS: We searched PubMed, EMBASE and J-Stage with no restrictions of date or language for controlled studies on treatment of insulin poisoning, collected published cases of insulin poisoning from 1923, and used data from the UK National Poisons Information Service. RESULTS: We identified no controlled trials of treatment in insulin poisoning and few relevant experimental studies. Case reports described 315 admissions (301 patients) with insulin poisoning between 1923 and 2022. The insulin with the longest duration of action was long-acting in 83 cases, medium-acting in 116, short-acting in 36 and a rapid-acting analogue in 16. Decontamination by surgical excision of the injection site was reported in six cases. To restore and maintain euglycaemia, almost all cases were treated with glucose, infused for a median 51 hours, interquartile range 16-96 h in 179 cases; 14 patients received glucagon and nine octreotide; adrenaline was tried occasionally. Both corticosteroids and mannitol were occasionally given to mitigate hypoglycaemic brain damage. There were 29 deaths reported, 22/156 (86% survival) up to 1999 and 7/159 (96% survival) between 2000 and 2022 (p = 0.003). CONCLUSIONS: There is no randomized controlled trial to guide treatment of insulin poisoning. Treatment with glucose infusion, sometimes supplemented with glucagon, is almost always effective in restoring euglycaemia, but optimum treatments to maintain euglycaemia and restore cerebral function remain uncertain.

Medicines legislation and regulation in the United Kingdom 1500-2020.

The initial purposes of regulation of medicines in England, and latterly in the United Kingdom, were principally to raise government revenue, to discourage murder by poisoning and to regulate the activities of pharmacists. It was only much later that regulators sought to ensure that medicines were of good quality, reasonably safe, and at least somewhat effective, and to curtail misuse of drugs. Here we survey the history of the regulation of medicines and poisons in England from the perspective of clinicians with an interest in therapeutics.

Drug shortages. Part 1. Definitions and harms.

Drug shortages are repeatedly in the news. The earliest drug shortages were reported during the First World War, but the numbers of shortages have increased in recent years. In the first part of this two-part review, we discuss definitions of drug shortages and so-called stockouts, which are localized shortages, and the harms that they can cause. Drug shortages make it difficult or impossible to meet the therapeutic needs of individual patients or populations, but we lack an adequate definition. The problems are too complicated to be encompassed in a brief intensional dictionary-style definition, and that is reflected in the many different attempts at definition that have been proposed. We therefore propose an extensional operational definition that incorporates the processes by which products are manufactured, the causes of shortages and the contributory factors. A definition of this sort allows one to identify the main causes of a particular drug shortage and therefore the remedies that might prevent, mitigate or manage it. In the second part of the review we discuss the causes and solutions in more detail. Adverse drug reactions and medication errors attributable to shortages occur but are not often reported. Adverse reactions to substitute medicines are possible, and errors can occur because of unfamiliarity or unnecessary treatment with replacement medicines. Other harmful outcomes include withdrawal reactions, undertreatment, treatment delays and cancellations, failure of alternatives and disruption of clinical trials.

Drug shortages. Part 2: Trends, causes and solutions.

Drug shortages make it difficult or impossible to meet the therapeutic needs of individual patients or populations. In the first part of this review we proposed an operational definition that incorporates the processes by which products are manufactured, the causes of shortages and stock-outs (local shortages), and the contributory factors. Here we discuss causes and possible solutions. Drug shortages have complex causes, and a single cause cannot always be identified. Reasons include lack or shortage of raw materials, manufacturing difficulties, regulatory and political actions, voluntary recalls, just-in-time inventory systems, halts in production for financial or other business reasons, low demand (eg, orphan products, reduced usage), mergers, market shifts (eg, diversion to home markets) and unexpected increases in demand (eg, improved diagnosis, new trial information, epidemics and pandemics, inappropriate use, off-label use). Potential solutions are as diverse as the potential causes. Prevention is hard, because shortages are not easily predicted. Everyone in the supply chain is involved in anticipating and managing shortages, with responsibilities for preventing them or at least trying to mitigate their effects. This includes manufacturers and suppliers, particularly of generic formulations, pharmacists, prescribers, patients and governments. Solutions can therefore be linked to the causes and classified according to where the responsibility for implementing them lies.

Are high-cost drug funding mechanisms fit for purpose? A retrospective study of individual funding requests in an NHS tertiary hospital.

AIMS: To report on a retrospective study of individual funding request (IFR) submissions from a large tertiary hospital and describe gaps in current mechanisms for funding of high-cost medicines in England. METHODS: Data on the number and outcome of IFR submissions submitted to commissioners between 2014/15 and 2018/19 was extracted from the electronic patient health record and a local high-cost drug database. RESULTS: In total, 230 IFRs were submitted: 112 to NHS England and 118 to a Clinical Commissioning Group (CCG). The decline rate for IFRs was 71% for NHS England and 34% for CCGs. Lack of exceptionality was the primary reason cited for declining IFRs submitted between 2016-18 (n = 42/45; 93%). Half of the patients whose IFR was declined received treatment funded through other routes, the majority (13/23; 57%) from internal hospital budget. This was governed via a local high-cost drug panel. Positive clinical outcomes were observed in 50% (4/8) of patients who received NHS England IFR-funded treatment, 54% (19/35) who received CCG IFR-funded treatment and 91% (21/23) who were funded via other routes. CONCLUSION: The high rate of IFR decline signals inefficient use of resource expended in the IFR process. Gaps in access to high-cost medicines remain for patients with rare and refractory disease requiring urgent treatment, largely due to the demand for exceptionality from NHS commissioners. Local mechanisms address this unmet need but have limitations. An outcomes-based evaluation approach to commissioning and greater transparency of previous funding decisions by commissioners may improve efficiency and equity in the IFR system.

Effectiveness of biosimilar adoption within a UK tertiary hospital: 6-year follow-up.

Health systems encourage switching from originators to biosimilars as biosimilars are more cost-effective. The speed and completeness of biosimilar adoption is a measure of efficiency. We describe the approach to biosimilar adoption at a single hospital Trust and compare its efficiency against the English average. We additionally follow up patients who reverted to a previously used biologic, having switched to a biosimilar, to establish whether they benefitted from re-establishing prior treatment. The approach we describe resulted in a faster and more complete switch to biosimilars, which saved an additional £380 000 on drug costs in 2021/2022. Of patients who reverted to their original biologic, 87% improved short-term, and a time on treatment analysis showed the benefit was retained long term. Our approach to biosimilar adoption outperformed the English average and permits patients to revert to their original biosimilar post-switch if appropriate.

How to assess pharmacogenomic tests for implementation in the NHS in England.

AIMS: Pharmacogenomic testing has the potential to target medicines more effectively towards those who will benefit and avoid use in individuals at risk of harm. Health economies are actively considering how pharmacogenomic tests can be integrated into health care systems to improve use of medicines. However, one of the barriers to effective implementation is evaluation of the evidence including clinical usefulness, cost-effectiveness, and operational requirements. We sought to develop a framework that could aid the implementation of pharmacogenomic testing. We take the view from the National Health Service (NHS) in England. METHODS: We used a literature review using EMBASE and Medline databases to identify prospective studies of pharmacogenomic testing, focusing on clinical outcomes and implementation of pharmacogenomics. Using this search, we identified key themes relating to the implementation of pharmacogenomic tests. We used a clinical advisory group with expertise in pharmacology, pharmacogenomics, formulary evaluation, and policy implementation to review data from our literature review and the interpretation of these data. With the clinical advisory group, we prioritized themes and developed a framework to evaluate proposals to implement pharmacogenomics tests. RESULTS: Themes that emerged from review of the literature and subsequent discussion were distilled into a 10-point checklist that is proposed as a tool to aid evidence-based implementation of pharmacogenomic testing into routine clinical care within the NHS. CONCLUSION: Our 10-point checklist outlines a standardized approach that could be used to evaluate proposals to implement pharmacogenomic tests. We propose a national approach, taking the view of the NHS in England. Using this approach could centralize commissioning of appropriate pharmacogenomic tests, reduce inequity and duplication using regional approaches, and provide a robust and evidence-based framework for adoption. Such an approach could also be applied to other health systems.

Preventable deaths involving opioids in England and Wales, 2013-2022: a systematic case series of coroners' reports.

BACKGROUND: Opioid deaths have increased in England and Wales. Coroners' Prevention of Future Deaths reports (PFDs) provide important insights that may enable safer use and avert harms, yet reports implicating opioids have not been synthesized. We aimed to identify opioid-related PFDs and explore coroners' concerns to prevent future deaths. METHODS: In this systematic case series, we screened 3897 coronial PFDs dated between 01 July 2013 and 23 February 2022, obtained by web scraping the UK's Courts and Tribunals Judiciary website. PFDs were included when an opioid was implicated in the death. Included PFDs were descriptively analysed, and content analysis was used to assess concerns reported by coroners. RESULTS: Opioids were involved in 219 deaths reported in PFDs (5·6% of PFDs), equating to 4418 years of life lost (median 33 years/person). Morphine (29%), methadone (23%) and diamorphine (16%) were the most common implicated opioids. Coroners most frequently raised concerns regarding systems and protocols (52%) or safety issues (15%). These concerns were most often addressed to National Health Service (NHS) organizations (51%), but response rates were low overall (47%). CONCLUSIONS: Opioids could be used more safely if coroners' concerns in PFDs were addressed by national organizations such as NHS bodies, government agencies and policymakers, as well as individual prescribing clinicians.

Prescribing direct-acting oral anticoagulants - Mind the evidence gap.

Direct-acting oral anticoagulants (DOACs) are licensed for the prevention of thromboembolism in non-valvular atrial fibrillation, amongst other indications. Prescribers use information derived from the summary of product characteristics which is based on the key trials supporting the DOAC's market authorisation. However, prescribers may not be aware of the limitations within these trials regarding underrepresentation of patient populations commonly encountered in clinical practice and how this may adversely impact them. This review highlights the gaps in the licensing evidence using four clinical vignettes that explore prescribing challenges in older adults, female patients, patients with obesity and patients from non-Europid ethnic backgrounds.

Free-of-charge medicine schemes in the NHS: A local and regional drug and therapeutic committee's experience.

INTRODUCTION: Free-of-charge (FoC) medicine schemes are increasingly available and allow access to investigational treatments outside clinical trials or in advance of licensing or NHS commissioning. METHODS: We retrospectively reviewed FoC medicine schemes evaluated between 2013 and 2019 by a single NHS trust and a regional drug and therapeutics committee (DTC). The details of each locally reviewed FoC scheme, and any nationally available Medicines and Healthcare products Regulatory Agency Early Access to Medicines Scheme (MHRA EAMS) in the same period, were recorded and categorised. RESULTS: Most FoC schemes (95%) allowed access to medicines intended to address an unmet clinical need. Over 7 years, 90% were company-FoC schemes and 10% were MHRA EAMS that were locally reviewed. Phase 3 clinical trial data were available for 44% of FoC schemes, 37% had phase 2 data and 19% were supported only by phase 1 data, retrospective observational studies or preclinical data. Utilisation of company-FoC schemes increased on average by 50% per year, while MHRA EAMS schemes showed little growth. CONCLUSION: Company-FoC medicine schemes are increasingly common. This may indicate a preference for pharmaceutical companies to independently co-ordinate schemes. Motivations for company-FoC schemes remain unclear and many provide access to treatments that are yet to be evaluated in appropriately conducted clinical trials, and whose efficacy and risk of harm remain uncertain. There is no standardisation of this practice and there is no regulatory oversight. Moreover, no standardised data collection framework is in place that could demonstrate the utility of such programmes in addressing unmet clinical need or to allow generation of further evidence.

Coping with COVID: Preparing prescribers during the pandemic.

In response to the COVID-19 pandemic, Health Education England (HEE) and the University of Birmingham provided National Health Service (NHS) staff free access to SCRIPT, a national eLearning programme for safer prescribing and therapeutics. The eLearning was particularly for those returning to work or being redeployed. In the year March 2020-21, 3412 users registered to access portfolios and opened an aggregate of 17 198 modules. Each user completed a median of 2 (range 1-50, interquartile range [IQR] 1-7) assessed learning modules. Marks improved from pre-test to post-test by a median of 2 (IQR 0-3) marks out of 10. The most frequently selected modules were Adherence and Concordance (1109 users), Fluids (981 users) and Diabetic Emergencies (818 users). A total of 878 users accessed the unassessed COVID-19 module. The SCRIPT modules provided standardised education in core principles relating to prescribing and therapeutics, and were used by professionals from many healthcare disciplines.

A novel approach to support implementation of biosimilars within a UK tertiary hospital.

Aims To assess the transfer of patients treated with originator biological therapies to biosimilar products in a large UK tertiary referral hospital reflecting practice within the National Health Service (NHS) using prospectively collected data by a hospital-based registry administered by the Biologics Steering Group (BSG). METHODS: We analysed data collected prospectively in a hospital-based registry in a large NHS tertiary referral hospital in the UK. The registry was administered by the hospital's BSG, which considered requests for patients to remain on or revert to originator products. The registry contained prospectively collected data on patients switching therapy from an originator to a biosimilar. The data included clinical circumstances or rationale for each request, whether it was granted, and the results of clinical reviews at 3-6 months. RESULTS: In a 12-month period, we identified 1299 patients who could switch to the respective biosimilar and, of these, 1196 (92%) did so. Of the 260 patients taking infliximab, 250 (96%) switched to infliximab biosimilar; of the 390 patients taking etanercept 50 mg, 298 (76%) switched to etanercept 50 mg biosimilar; and of the 649 patients taking rituximab, 648 (99%) switched to rituximab biosimilar. The BSG received 39 applications: 12 (out of 39) applications were to remain on the originator and 27 (out of 39) were to switch back to the originator. Of the applications to remain on the originator 10 (out of 12) were approved. At 3-6 month review, 2 of these approvals reported continued efficacy, 3 switched to the biosimilar, 3 switched to an alternative therapy and 2 stopped treatment. Two (out of 10) applications were not approved, both applicants reported efficacy with the biosimilar at follow up. Of the 27 applications to switch back to the originator, 16 (out of 27) applications were approved. At 3-6 months, 9 (out of 16) applicants reported regain of efficacy, 6 (out of 16) reported cessation of reported adverse effects and 1 (out of 16) switched to alternative therapy. Eight (out of 27) applications were not approved, and, at point of follow up, 50% reported efficacy with the biosimilar and 50% had switched to an alternative therapy. Three (out of 27) applications were withdrawn by the clinical team as efficacy was achieved with the biosimilar. CONCLUSION: We have set up a system within a busy NHS clinical practice to successfully switch patients to biosimilars, and established a mechanism to guide decisions on continuing with or reverting back to the originator. Such a system could be of use more broadly within the NHS and other health care systems.

Antithrombotic dose: Some observations from published clinical trials.

The clinical doses of antithrombotics-antiplatelet and anticoagulant agents-need to balance efficacy and safety. It is not clear from the published literature how the doses currently used in clinical practice have been derived from preclinical and clinical data. There are few large randomised controlled trials (RCTs) that compare outcomes with different doses vs placebo. For newer antithrombotics, RCT doses appear to have been chosen to maximise the probability of demonstrating noninferiority when compared to established agents such as warfarin or clopidogrel. Data from RCTs show that aspirin is an effective antithrombotic at doses below 75 mg daily, and that direct oral anticoagulants reduce the risk of stroke in patients with coronary disease at doses 1/4 of those recommended in atrial fibrillation. Lower doses than those currently recommended are safer and still maintain substantial efficacy.

Efficacy and toxicity of antihypertensive pharmacotherapy relative to effective dose 50.

Antihypertensive drugs have usually been approved at doses near the top of their respective dose-response curves. Efficacy plateaus but adverse drug reactions (ADRs), such as falls, cerebral or renal ischaemia, increase as dose is increased, especially in older patients with comorbidities. ADRs reduce adherence and may be difficult to ascertain reliably. Higher doses have generally not been shown to reduce total mortality, which provides a summary of efficacy and safety. Weight loss and other lifestyle measures are essential and may be sufficient treatment in many young and low risk patients. Most antihypertensive drug lower systolic blood pressure by around 10 mmHg, which reduces stroke and heart failure by about a quarter. Clinical trials have not been designed to demonstrate specific blood pressure treatment thresholds and targets, which are mostly extrapolated from epidemiology. Mean population oral effective dose 50 may be the most appropriate dose at which to commence antihypertensive drugs. The dose can then be titrated up if greater efficacy is demonstrated, or lowered if ADRs develop. Lower dose combination therapy may best balance benefit and harms with fewer ADRs and additive, potentially synergistic, efficacy.

Unlicensed and off-label uses of medicines: definitions and clarification of terminology.

The terms 'licensed', 'unlicensed', and 'off-label', often used in relation to marketing and prescribing medicinal products, may confuse UK prescribers. To market a medicinal product in the UK requires a Marketing Authorization ('product licence') for specified indications under specified conditions, regulated by the Medicines and Healthcare products Regulatory Agency (MHRA). The Marketing Authorization includes the product's agreed terms of use (the 'label'), described in the Summary of Product Characteristics (SmPC). Prescribing a licensed product outside those terms is called 'off-label' prescribing. Products for which no-one holds a UK Marketing Authorization are unlicensed. Prescribers can prescribe authorized products according to the conditions described in the SmPC ('on-label') or outside those conditions ('off-label'). They can also prescribe unauthorized products, even if they are unlicensed in the UK, if they are licensed elsewhere or if they have been manufactured in the UK by a licensed manufacturer as a 'special'. The complexities of this system can be understood by considering the status of the manufacturer of the product, the company that markets it (which may or may not be the same), the product itself, and its modes of use, and by emphasizing the word 'authorized'. If a Marketing Authorization is granted to the supplier of a product, it will specify the authorized modes of use; the product will be prescribable as authorized (i.e. 'on-label') or in other modes of use, which will all be off-label. Unlicensed products with no authorized modes of use can be regarded as 'unauthorized products'. All 'specials' can be regarded as authorized products lacking authorized modes of use.

Cato Guldberg and Peter Waage, the history of the Law of Mass Action, and its relevance to clinical pharmacology.

We have traced the historical link between the Law of Mass Action and clinical pharmacology. The Law evolved from the work of the French chemist Claude Louis Berthollet, was first formulated by Cato Guldberg and Peter Waage in 1864 and later clarified by the Dutch chemist Jacobus van 't Hoff in 1877. It has profoundly influenced our qualitative and quantitative understanding of a number of physiological and pharmacological phenomena. According to the Law of Mass Action, the velocity of a chemical reaction depends on the concentrations of the reactants. At equilibrium the concentrations of the chemicals involved bear a constant relation to each other, described by the equilibrium constant, K. The Law of Mass Action is relevant to various physiological and pharmacological concepts, including concentration-effect curves, dose-response curves, and ligand-receptor binding curves, all of which are important in describing the pharmacological actions of medications, the Langmuir adsorption isotherm, which describes the binding of medications to proteins, activation curves for transmembrane ion transport, enzyme inhibition and the Henderson-Hasselbalch equation, which describes the relation between pH, as a measure of acidity and the concentrations of the contributory acids and bases. Guldberg and Waage recognized the importance of dynamic equilibrium, while others failed to do so. Their ideas, over 150 years old, are embedded in and still relevant to clinical pharmacology. Here we explain the ideas and in a subsequent paper show how they are relevant to understanding adverse drug reactions.

The law of mass action and the pharmacological concentration-effect curve: resolving the paradox of apparently non-dose-related adverse drug reactions.

BACKGROUND: Adverse drug reactions are sometimes described as being 'non-dose-related' because no relationship has been found between increasing doses and either the intensity of the response or the proportion of individuals in whom the response occurs; furthermore, hypersensitivity reactions are often regarded as being non-dose-related, even if different doses have not been studied. However, the law of mass action implies that all pharmacological effects are concentration related and should increase in intensity with increasing dose. We set out to explain this paradox. METHODS: We searched for published adverse drug reactions that have been described as non-dose-related and analysed them. RESULTS: We identified four categories of explanations that resolve the paradox: (i) the reaction is not real; it may have occurred by chance or there may be methodological problems, such as bias or confounding factors; (ii) the dose-response curve for the adverse effect reaches a maximum at doses lower than were studied (i.e. a hypersusceptibility reaction); this underpins the use of test doses to predict the possibility of an adverse reaction at therapeutic doses; (iii) susceptibility to the adverse reaction differs widely among individuals; and (iv) imprecision or inaccuracy in the measurement of either dose or effect obscures dose responsiveness. This last explanation encompasses: (a) reactions related to cumulative dose; (b) dissociation between dose and concentration through saturable pharmacokinetics; and (c) variability in the measurement of the effect. CONCLUSIONS AND IMPLICATIONS: If an adverse drug reaction appears to be non-dose-related, the reasons should be sought, having these mechanisms in mind.

A systematic review and meta-analysis of thiazide-induced hyponatraemia: time to reconsider electrolyte monitoring regimens after thiazide initiation?

AIMS: Hyponatraemia is one of the major adverse effects of thiazide and thiazide-like diuretics and the leading cause of drug-induced hyponatraemia requiring hospital admission. We sought to review and analyze all published cases of this important condition. METHODS: Ovid Medline, Embase, Web of Science and PubMed electronic databases were searched to identify all relevant articles published before October 2013. A proportions meta-analysis was undertaken. RESULTS: One hundred and two articles were identified of which 49 were single patient case reports. Meta-analysis showed that mean age was 75 (95% CI 73, 77) years, 79% were women (95% CI 74, 82) and mean body mass index was 25 (95% CI 20, 30) kg m(-2) . Presentation with thiazide-induced hyponatraemia occurred a mean of 19 (95% CI 8, 30) days after starting treatment, with mean trough serum sodium concentration of 116 (95% CI 113, 120) mm and serum potassium of 3.3 (95% CI 3.0, 3.5) mm. Mean urinary sodium concentration was 64 mm (95% CI 47, 81). The most frequently reported drugs were hydrochlorothiazide, indapamide and bendroflumethiazide. CONCLUSIONS: Patients with thiazide-induced hyponatraemia were characterized by advanced age, female gender, inappropriate saliuresis and mild hypokalaemia. Low BMI was not found to be a significant risk factor, despite previous suggestions. The time from thiazide initiation to presentation with hyponatraemia suggests that the recommended practice of performing a single investigation of serum biochemistry 7-14 days after thiazide initiation may be insufficient or suboptimal. Further larger and more systematic studies of thiazide-induced hyponatraemia are required.

Harms from medicines: inevitable, in error or intentional.

Rational therapeutics requires a balance between benefits and harms. (i) Harm may be inevitable. Some adverse drug reactions cannot be predicted or prevented. (ii) Some harm occurs in error when a medicine is wrongly formulated, prescribed, dispensed or administered. Adverse drug reactions that might have been prevented, for example, by monitoring, fall into this category. (iii) Rarely, harm is inflicted deliberately, for example, in murder by poisoning. Here I consider adverse drug reactions, errors and deliberate drug-induced harm from the perspective of a clinical pharmacologist.