Robin E. Ferner

Joining the DoTS: new approach to classifying adverse drug reactions

A new classification system for adverse drug reactions based on time course and susceptibility as well as dose responsiveness should improve drug development and management of adverse reactions

Comparative Tolerability Profiles of Oral Antidiabetic Agents

SummaryThe sulphonylureas and the biguanides are widely used as adjuncts to dietary measures in the treatment of non-insulin-dependent (type 2) diabetes mellitus (NIDDM). Adverse effect profiles differ markedly between the sulphonylureas and biguanides, reflecting differences in chemical structure and mode of action. Sulphonylureas are generally well tolerated, although pharmacokinetic differences between these agents have important clinical implications. The main adverse effect associated with sulphonylureas is hypoglycaemia. This effect is a predictable consequence of the principal pharmacological effect of these drugs, i.e. sensitisation of the islet β-cell to glucose, resulting in enhanced endogenous insulin secretion. Sulphonylurea-induced suppression of hepatic glucose production may cause profound and protracted hypoglycaemia, especially in elderly patients, in individuals with intercurrent illnesses and reduced caloric intake, or when taken in combination with other compounds with hypoglycaemic potential, e.g. alcohol (ethanol). Sulphonylureas with a longer duration of action, notably chlorpropamide and glibenclamide (glyburide), are more liable to induce serious hypoglycaemia, particularly when drug elimination is reduced by renal impairment. Other drugs such as salicylates may potentiate the actions of sulphonylureas, thereby increasing the risk of hypoglycaemia.Biguanide therapy is associated with alterations in lactate homeostasis which under certain clinical circumstances may result in fatal lactic acidosis. Phen-formin is associated with a markedly greater risk of lactic acidosis than metformin. Phenformin has been withdrawn in many countries for this reason. All biguanides must be avoided in patients with renal impairment, hepatic dysfunction and cardiac failure — conditions where drug accumulation or disordered lactate metabolism may predispose to lactic acidosis. Phenformin should not be given to individuals who exhibit a severe, genetically conferred hepatic defect of hydroxylation which impedes metabolism of this drug. Less seriously, the biguanides are associated with a relatively high incidence of gastrointestinal adverse effects which limit compliance.Acarbose, a competitive inhibitor of intestinal α-glucosidases, has recently been introduced. In contrast to the sulphonylureas and biguanides, acarbose has not been associated with life-threatening adverse effects. This reflects the low systemic absorption of the drug and, predictably, its principal unwanted effects are gastrointestinal disturbances resulting from iatrogenic carbohydrate malabsorption.

Clarification of terminology in medication errors: definitions and classification.

We have previously described and analysed some terms that are used in drug safety and have proposed definitions. Here we discuss and define terms that are used in the field of medication errors, particularly terms that are sometimes misunderstood or misused. We also discuss the classification of medication errors. A medication error is a failure in the treatment process that leads to, or has the potential to lead to, harm to the patient. Errors can be classified according to whether they are mistakes, slips, or lapses. Mistakes are errors in the planning of an action. They can be knowledge based or rule based. Slips and lapses are errors in carrying out an action — a slip through an erroneous performance and a lapse through an erroneous memory. Classification of medication errors is important because the probabilities of errors of different classes are different, as are the potential remedies.

Clarification of Terminology in Drug Safety

Nomenclature surrounding drug safety needs to be clear and unambiguous, so that patients, prescribers, manufacturers, and regulators can all understand each other. In particular, it needs to make it clear how adverse events and drug therapy are related to one another, how they are best classified, and their frequency, intensity and seriousness.In this article, we therefore discuss and define terms used in the field of drug safety, particularly terms that are sometimes misunderstood or misused, including medicinal product, pharmaceutical formulation, excipient, adverse event (or experience) and adverse drug reaction (or effect). We also discuss terms used to define the seriousness, intensity, and risk of adverse reactions, and their classification.Instead of creating definitions from scratch, as is commonly done, we have taken the novel approach of critically examining definitions that have been proposed or widely used and have formulated new or modified definitions based on a logical appraisal of their merits and demerits. We hope that these definitions will lead to discussion that will allow a corpus of satisfactory definitions to be widely agreed.

Management of paracetamol poisoning

#### Summary points Paracetamol (acetaminophen) is an effective oral analgesic, with few adverse effects when used at the recommended dose. Nevertheless, paracetamol poisoning is common and potentially fatal.1 It is a leading cause of acute liver failure in the United Kingdom2 and the United States.3 Potential liver damage, predicted from blood paracetamol concentration and time from ingestion, can be prevented by prompt treatment with antidote. However, young and otherwise healthy patients still risk serious liver injury, especially if they present more than a few hours after overdose or take staggered overdoses over hours or days.4 #### Sources and selection criteria We based our review on a PubMed search for articles on paracetamol (or acetaminophen) and acetylcysteine or ( N- acetylcysteine) published between 1 January 1990 and 31 December 2010, without language limits. The search was limited to human clinical trials, meta-analyses, randomised controlled trials, reviews, and case reports. We also searched a newspaper database for reports published after 1988 of coroners’ inquests and procurators’ fiscal inquiries into fatal cases of paracetamol poisoning. In addition, we used a bibliography and our own collections of relevant references.5 The …

Where errors occur in the preparation and administration of intravenous medicines: a systematic review and Bayesian analysis

Objective To investigate the overall probability of error in preparing and administering intravenous medicines; to identify at which stage of the process an error is most likely to occur; and to determine the impact of error correction on the error probability. Design Systematic review and random-effects Bayesian conditional independence modelling. Methods Medline and EMBASE were searched for studies on intravenous medicines. The error rates of each stage were extracted. These, expert estimates, and error rates from generic tasks, were used in a Bayesian conditional independence model to find error ‘hot-spots.’ The main outcome measure was the probability of at least one error occurring during intravenous therapy. Results Nine published studies were identified for inclusion in the systematic review and meta-analysis. The overall probability of making at least one error in intravenous therapy was 0.73 (95% credible interval (CrI) 0.54 to 0.90). If error-checking was introduced at each stage of the process, the overall rate fell to 0.22 (95% CrI 0.14 to 0.31). Errors were most likely in the reconstitution step. Removing the reconstitution step by providing preprepared injections would reduce the overall error rate to 0.17 (95% CrI 0.09 to 0.27). Conclusions Intravenous therapy is complex and error-prone. Error-checking at each stage could reduce the error probability. The use of preprepared injections may help by eliminating errors in the reconstitution of drug and diluent. However, it will be important to ensure that benefits are not outweighed by practical disadvantages such as an increase in selection errors.

Preventability of drug-related harms - part I: a systematic review.

Abstract‘Preventability’ is a crucial concept in the literature on adverse drug reactions (ADRs). We have carried out a systematic review in order to identify and analyse the approaches used to define ‘preventability’ in relation to ADRs. We have restricted this investigation to definitions of preventability and have not dealt with other aspects. We searched MEDLINE (1963–April 2009) and EMBASE (1980–April 2009), without language restriction, for papers in which preventability of ADRs was likely to be defined.We found 234 papers, of which we retrieved 231. Of these, 172 either contained original definitions of preventability or referred to other papers in which preventability was defined. Forty contained no definition, and 19 were not relevant. In the 172 papers selected, we identified eight different general approaches to defining the preventability of ADRs: (1) analysis without explicit criteria; (2) assessment by consensus; (3) preventability linked to error; (4) preventability linked to standards of care; (5) preventability linked to medication-related factors; (6) preventability linked to information technology; (7) categorization of harmful treatments in explicit lists; and (8) a combination of more than one approach.These approaches rely on two general methods: the judgement of one or more investigators or the use of pre-defined explicit criteria; neither is satisfactory. Specific problems include the weakness of consensus as a method (since experts can agree and yet be wrong), inadequacy of definition of standards of care, and circularity in several definitions of preventability. Furthermore, attempts to list all preventable effects are bound to be incomplete and will not always apply to an individual case.We conclude that an approach based on analysis of the mechanisms of adverse reactions and their clinical features could be preferable; such an approach is described in a companion paper (Part II) in this issue of Drug Safety.

Using drugs safely

The recent Audit Commission report A Spoonful of Sugar was grim reading.1 The report suggested that nearly 1100 people died last year in England and Wales as a result of medication errors or adverse reactions to medicines and that the number had increased fivefold in just 10 years. This alarming increase may be an overestimate inflated by changes in defining and reporting causes of death and cannot all be attributed to a true deterioration in prescribing. However, studies elsewhere also hint at high rates, 2 3 although the definitions and data have been questioned.3 The Audit Commission failed to distinguish clearly between medication errors, inevitable adverse reactions, and potentially preventable adverse reactions. Since strategies for minimising each are different, we need data that tell us where problems lie. There are several reasons why drug errors might have risen (see box). In addition, human error is most likely when inexperienced and overworked staff, in a stressful environment, struggle with unfamiliar …

Controversy over generic substitution

Substitution of branded medicine with a generic equivalent is already common. Robin Ferner, Warren Lenney, and John Marriott argue that concerns about UK plans to let pharmacists make the decision are unwarranted

The epidemiology of medication errors: the methodological difficulties

1. Medication errors should be amenable to epidemiological analysis, giving insights into the causes of error and the effects of interventions to prevent them or reduce harm from them. 2. There are formidable difficulties in establishing the rates of medication errors. 3. There is no agreement on a clear operational definition of the condition. 4. The methods used to enumerate cases so far have been unreliable or incomplete or both. 5. There is disagreement about whether cases of error that do not cause harm should be included in calculations of error rates. 6. When harm occurs in association with drug therapy, it is often unclear whether the harm might have been prevented, and its occurrence should therefore be considered to result from error. 7. The denominator for calculating the rate of error is both ill-defined and inconsistently measured. Better definitions, more complete evaluation, and more thorough impact assessment may improve matters.