Changes

March 2022 — reviewed. A literature search was conducted in February 2022 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials (RCTs) published since the last revision of the topic. No major changes were made to the recommendations. 

Update

Goals

To support primary healthcare professionals to:

• Suspect adverse drug reactions (ADRs), when appropriate.
• Assess and manage suspected ADRs.
• Report suspected ADRs, if appropriate.

Outcome measures

Audit criteria

QOF indicators

QIPP - Options for local implementation

NICE quality standards

What is an adverse drug reaction?

• An adverse drug reaction (ADR):
  • Is a response to a medicinal product, or combination of medicinal products, which is noxious and unintended [MHRA, 2015a; EMeA, 2017].
  • May arise following the use of a medicinal product within or outside the terms of the marketing authorization, such as off-label therapeutic use, overdose, misuse, abuse or medication errors, or from occupational exposure [MHRA, 2015a; EMeA, 2017].
• An ADR may be a known effect of a drug, or a new and previously unrecognized effect [MHRA, 2015a; EMeA, 2017].
• There are other terms that should be distinguished:
  • The terms 'adverse reaction' and 'adverse effect' are interchangeable but reflect different points of view: a drug has an adverse effect, whereas a person experiences an adverse reaction [Edwards, 2000; Aronson, 2005].
  • These terms are preferred to other terms, such as 'toxic effect' or 'side effect', because they encompass all unwanted effects. They make no assumptions about mechanism, evoke no ambiguity, and avoid the risk of misclassification [Edwards, 2000; Aronson, 2005].

How are adverse drug reactions categorized?

• Adverse drug reactions (ADRs) are frequently categorized as Type A or Type B [Rawlins, 1977] [Pirmohamed, 1998] [Edwards, 2000] [MHRA, 2015a]:
  • Type A reactions (pharmacological/augmented reactions) result from an exaggeration of a drug’s normal pharmacological actions when given at the usual therapeutic dose (for example respiratory depression with opioids or bleeding with warfarin). They are dose dependent and are therefore readily reversible on reducing the dose of the drug or withdrawing treatment. Type A reactions also include those that are not directly related to the desired pharmacological action of the drug (for example, dry mouth with tricyclic antidepressants).
  • Type B reactions (idiosyncratic/bizarre reactions) cannot be predicted from the known pharmacology of the drug (for example, anaphylaxis with penicillin and skin rashes with antibiotics).
  • Type A adverse reactions are more common than Type B reactions and account for more than 80% of all reactions [Pirmohamed, 1998].
  • As Type B reactions can be rare, they are more likely to only be discovered after a drug is made available for general use.
• Other categories of ADRs include [MHRA, 2015a]:
  • Type C reactions (continuing reactions) — these persist for a relatively long time (for example, osteonecrosis of the jaw with bisphosphonates).
  • Type D reactions (delayed reactions) — these become apparent sometime after the use of a drug, thereby making them more difficult to detect (for example, leucopenia occurring up to 6 weeks following some chemotherapeutic drugs, for example, lomustine).
  • Type E reactions (end-of-use reactions) — these are associated with the withdrawal of a drug (for example, insomnia, anxiety, and perceptual disturbances following the withdrawal of benzodiazepines).
• Other classification schemes have been proposed to take into account properties of the reaction, the person, and other biological differences.
  • For example, the 'DoTS' system takes into account the dose-relatedness of the reaction, timing of the reaction, and individual susceptibility to the drug [Aronson, 2003; Aronson, 2005; Aronson, 2006; MHRA, 2015a; Coleman, 2016].
  • This classification system has been considered advantageous by some experts as the details of the reaction may offer prompts which could aid diagnosis and prevention of ADRs in clinical practice [Coleman, 2016]. 

What are the health and financial implications of adverse drug reactions?

• The health and financial implications of adverse drug reactions (ADRs) are significant.
  • Estimates as to the incidence of ADRs vary, and appear dependent on both study data collection methods and the demographics of the study population:
    • A 2021 systematic review and meta-analysis identified a pooled estimate of ADRs among patients receiving primary care of approximately 8%. The pooled percentage of preventable ADRs was estimated as approximately 23% [Insani, 2021].
    • An analysis of Hospital Episodes Statistics data from 2008 to 2015 identified an increasing incidence of emergency admissions due to ADRs, rising from 1.2% in 2008 to 1.6% in 2014 [Veeren, 2017].
    • The percentage of hospital admissions due to ADRs in the UK has been previously estimated to be as high as 6–7% [Smith, 1996; Bandolier, 2002; Pirmohamed, 2004]. One systematic review found 3.73% (range 1.36–15.42) of hospital admissions to be preventable and drug-related [Howard, 2007].
    • The incidence of ADR hospitalization in children has been estimated at approximately 3% [Smyth, 2012].
    • The incidence of ADR hospitalization in the elderly has been estimated at 8.7% [Oscanoa, 2017].
    • ADRs are thought to occur in 10–20% of hospital in-patients. In one study, over 2% of people admitted with an ADR (approximately 0.15% of all people admitted) died [Pirmohamed, 2004].
    • A systematic review estimated that the overall impact of ADRs in England was four out of 100 hospital bed-days, or about 15–20 400-bed hospital equivalents at a cost of about £380 million a year to the NHS in England [Bandolier, 2002].
    • A meta-analysis assessed the percentage of patients with preventable ADRs as well as the preventability of ADRs [Hakkarainen, 2012]. For outpatients (n = 48,797 emergency visits/hospital admissions), the evidence showed that 2% had preventable ADRs, and 52% of ADRs present at the time of hospitalization/emergency visit were assessed as preventable. For inpatients (n = 24,128 inpatients), the results showed that 1.6% had preventable ADRs during hospital stay, and 45% of ADRs were assessed as preventable.
• According to The Medicines and Healthcare products Regulatory Agency (MHRA), ADRs [MHRA, 2015a]:
  • Adversely affect patients’ quality of life and can also cause patients to lose confidence in the healthcare system.
  • Contribute to increased costs of patient care and can lengthen hospital stays.
  • May mimic disease, resulting in unnecessary investigations and delays in treatment.

How are adverse drug reactions prevented?

• Most adverse drug reactions (ADRs) are difficult to predict.
  • Epidemiological studies have consistently shown that between one third and a half of all ADRs may be potentially preventable [Coleman, 2016].
  • Susceptibility to ADRs can be influenced by age, gender, disease states, pregnancy, ethnicity, and polypharmacy [Kaufman, 2016].
  • Commonly implicated drugs include antiplatelets, anticoagulants, cytotoxics, immunosuppressants, diuretics, antidiabetic medications, and antibiotics [Coleman, 2016].
• Vigilant prescribing practices may help to decrease the risk of ADRs.
  • Prevention strategies can include risk identification processes and risk mitigation procedures [Coleman, 2016].
  • Risk identification processes should involve [Yellow Card Centre Scotland, 2013; BNF, 2022]:
    • Assessing the risk of drug–drug interactions as polypharmacy and multiple comorbidities are risk factors for ADRs. Review the patient's current medication, including over-the-counter, herbal or traditional medicines, and supplements.
    • Asking if the patient has ever previously experienced an ADR. Patients who have previously experienced an ADR, particularly an allergic reaction, may have a similar reaction to other drugs in the same class. 
    • Assessing the risk of drug–food interactions, and the potential for other lifestyle choices (alcohol or smoking) to interact with medication.
    • Being aware of demographic and clinical factors which can increase the risk of ADRs, including age, pregnancy, ethnicity, and renal or hepatic conditions which may alter drug metabolism.
  • Risk mitigation procedures can involve [Yellow Card Centre Scotland, 2013; BNF, 2022]:
    • Providing clear instructions for use for all newly prescribed medication.
    • Informing the person, or their carer(s), about any known ADRs when prescribing new medication.
    • Ensuring the person complies with any required monitoring of clinical or biochemical parameters as recommended in prescribing guidelines or medicinal product literature (electronic Medicines Compendium — www.medicines.org.uk).
    • Providing regular medication reviews for elderly persons with multiple comorbidities using multiple medications.
    • Exercising cautious vigilance when prescribing an unfamiliar medication, or black triangle medicines.

How are adverse drug reactions monitored?

• The Medicines and Healthcare products Regulatory Agency (MHRA) and the Commission on Human Medicines (CHM) are responsible for monitoring the safety of all medicines marketed in the UK.
  • Despite extensive research for specific medicines, some adverse drug reactions (ADRs) may not be seen until a very large number of people have used the medicine. It is therefore vital that the safety of all medicines is monitored throughout their marketed life, through a process known as pharmacovigilance.
  • Pharmacovigilance is the process of [MHRA, 2015c]:
    • Monitoring the use of medicines in everyday practice to identify previously unrecognized adverse effects or changes in the patterns of adverse effects.
    • Assessing the risks and benefits of medicines to determine what action, if any, is necessary or needed to improve their safe use.
    • Providing information to healthcare professionals and patients to optimize safe and effective use of medicines.
    • Monitoring the effect of any action taken.
• Spontaneous ADR reporting schemes are important information sources for pharmacovigilance.
  • The UK's ADR reporting scheme, the Yellow Card Scheme, is provided by the MHRA and the CHM [MHRA, 2015c].
    • The Yellow Card Scheme receives voluntary reports of suspected ADRs from health professionals and members of the public.
    • The scheme assists in alerting the MHRA and CHM to new signals (or potential safety concerns), such as previously unrecognized ADRs or ADRs related to a specific drug. It also helps to confirm a signal of an ADR with limited information from an alternative data source, such as the literature or post-marketing studies, and also in evaluating comparative risks of related drugs.
    • Information collected through the Yellow Card Scheme is vital in helping the MHRA and CHM monitor medicine safety. See the section on Benefits of the Yellow Card Scheme for more information.
    • Yellow Card reports are evaluated, alongside other information and evidence on medicine safety, to determine whether any regulatory action is required to allow medicines to be used more safely and effectively. See the section on How the Yellow Card reports are processed for more information.
    • The MHRA works closely with other European regulatory authorities on pharmacovigilance matters.
  • Data from the Yellow Card Scheme underpins the process of pharmacovigilance in the UK. However, the UK pharmacovigilance system does not rely solely on ADR reporting. Other data sources regularly used in the monitoring of drug safety in the UK include clinical and epidemiological studies, worldwide published medical literature, pharmaceutical companies, worldwide regulatory authorities, and morbidity and mortality databases.
• Pharmacovigilance and reporting of ADRs are important because the information collected during the pre-marketing phase of drug development is inevitably incomplete with regard to possible ADRs.
  • This is because [WHO, 2002; MHRA, 2007]:
    • Tests in animals are insufficient to predict human safety.
    • Participants in clinical trials are selected and limited in number; the conditions of actual use differ from those in clinical trials, and trials have limited duration.
    • Exposure of fewer than 5000 human subjects to a drug allows only the more common ADRs to be detected before the drug is licensed.
    • At least 30,000 people need to be treated with a drug to be sure that at least 1 person with an ADR that has an incidence of 1 in 10,000 exposed persons is not missed.
    • Information about rare but serious adverse reactions, long-term effects, use in special groups (such as children, elderly people, or pregnant women), or drug interactions is often incomplete or not available.
  • Consequently, pharmacovigilance and reporting of ADRs are important to permit detection of less common but sometimes very serious ADRs.
• Additional monitoring of ADRs is undertaken in the UK by other research organizations independent of the MHRA, such as:
  • The Drug Safety Research Unit (DSRU) in Southampton (www.dsru.org).
  • The Tayside Medicines Monitoring Unit (MEMO) (www.dundee.ac.uk/memo).
  • The Health Improvement Network (THIN) in London (www.the-health-improvement-network.co.uk).
  • QResearch (www.qresearch.org).

[MHRA, 2015c]

Scenario: Adverse drug reactions 

From birth onwards.

Search strategy

Scope of search

A literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of adverse drug reactions.

Search dates

March 2017 - February 2022

Key search terms

Various combinations of searches were carried out. The terms listed below are the core search terms that were used for Medline.

• exp Drug Toxicity/, adverse drug reaction.tw.
• Drug-Related Side Effects and Adverse Reactions /
• Adverse Drug Reaction Reporting Systems / standards*
• (adverse drug reaction$ or drug‐drug interaction$).ti,ab.

Sources of guidelines

• National Institute for Health and Care Excellence (NICE)
• Scottish Intercollegiate Guidelines Network (SIGN)
• Royal College of Physicians
• Royal College of General Practitioners
• Royal College of Nursing
• NICE Evidence
• World Health Organization
• Guidelines International Network
• TRIP database
• Agency for Healthcare Research and Quality
• Institute for Clinical Systems Improvement
• National Health and Medical Research Council (Australia)
• Royal Australian College of General Practitioners
• British Columbia Medical Association
• Canadian Medical Association
• Alberta Medical Association
• Michigan Quality Improvement Consortium
• Singapore Ministry of Health
• National Resource for Infection Control
• RefHELP NHS Lothian Referral Guidelines
• Medline (with guideline filter)
• Driver and Vehicle Licensing Agency
• NHS Health at Work (occupational health practice)

Sources of systematic reviews and meta-analyses

• The Cochrane Library:
  • Systematic reviews
  • Protocols
  • Database of Abstracts of Reviews of Effects
• Medline (with systematic review filter)
• EMBASE (with systematic review filter)

Sources of health technology assessments and economic appraisals

• NIHR Health Technology Assessment programme
• The Cochrane Library:
  • NHS Economic Evaluations
  • Health Technology Assessments
• Canadian Agency for Drugs and Technologies in Health
• International Network of Agencies for Health Technology Assessment

Sources of randomized controlled trials

• The Cochrane Library:
  • Central Register of Controlled Trials
• Medline (with randomized controlled trial filter)
• EMBASE (with randomized controlled trial filter)

Sources of evidence based reviews and evidence summaries

• Bandolier
• Drug and Therapeutics Bulletin
• TRIP database
• Central Services Agency COMPASS Therapeutic Notes

Sources of national policy

• Department of Health
• Health Management Information Consortium (HMIC)

Patient experiences

• Healthtalk
• BMJ - Patient Journeys

Sources of medicines information

The following sources are used by CKS pharmacists and are not necessarily searched by CKS information specialists for all topics. Some of these resources are not freely available and require subscriptions to access content.

• British National Formulary (BNF)
• electronic Medicines Compendium (eMC)
• European Medicines Agency (EMEA)
• LactMed
• Medicines and Healthcare products Regulatory Agency (MHRA)
• REPROTOX
• Scottish Medicines Consortium
• Stockley's Drug Interactions
• TERIS
• TOXBASE
• Micromedex
• UK Medicines Information

Stakeholder engagement

Our policy

The external review process is an essential part of CKS topic development. Consultation with a wide range of stakeholders provides quality assurance of the topic in terms of:

• Clinical accuracy.
• Consistency with other providers of clinical knowledge for primary care.
• Accuracy of implementation of national guidance (in particular NICE guidelines).
• Usability.

Principles of the consultation process

• The process is inclusive and any individual may participate.
• To participate, an individual must declare whether they have any competing interests or not. If they do not declare whether or not they have competing interests, their comments will not be considered.
• Comments received after the deadline will be considered, but they may not be acted upon before the clinical topic is issued onto the website.
• Comments are accepted in any format that is convenient to the reviewer, although an electronic format is encouraged.
• External reviewers are not paid for commenting on the draft topics.
• Discussion with an individual or an organization about the CKS response to their comments is only undertaken in exceptional circumstances (at the discretion of the Clinical Editor or Editorial Steering Group).
• All reviewers are thanked and offered a letter acknowledging their contribution for the purposes of appraisal/revalidation.
• All reviewers are invited to be acknowledged on the website. All reviewers are given the opportunity to feedback about the external review process, enabling improvements to be made where appropriate.

Stakeholders

• Key stakeholders identified by the CKS team are invited to comment on draft CKS topics. Individuals and organizations can also register an interest to feedback on a specific topic, or topics in a particular clinical area, through the Getting involved section of the Clarity Informatics website.
• Stakeholders identified from the following groups are invited to review draft topics:
  • Experts in the topic area.
  • Professional organizations and societies (for example, Royal Colleges).
  • Patient organizations, Clarity has established close links with groups such as Age UK and the Alzheimer’s Society specifically for their input into new topic development, review of current topic content and advice on relevant areas of expert knowledge.
  • Guideline development groups where the topic is an implementation of a guideline.
  • The British National Formulary team.
  • The editorial team that develop MeReC Publications.
• Reviewers are provided with clear instructions about what to review, what comments are particularly helpful, how to submit comments, and declaring interests.

Patient engagement

Clarity Informatics has enlisted the support and involvement of patients and lay persons at all stages in the process of creating the content which include:

• Topic selection
• Scoping of topic
• Selection of clinical scenarios
• First draft internal review
• Second draft internal review
• External review
• Final draft and pre-publication

Our lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals.

Evidence exclusion criteria

Our policy

Scoping a literature search, and reviewing the evidence for CKS is a methodical and systematic process that is carried out by the lead clinical author for each topic. Relevant evidence is gathered in order that the clinical author can make fully informed decisions and recommendations. It is important to note that some evidence may be excluded for a variety of reasons. These reasons may be applied across all CKS topics or may be specific to a given topic.

Studies identified during literature searches are reviewed to identify the most appropriate information to author a CKS topic, ensuring any recommendations are based on the best evidence. We use the principles of the GRADE and PICOT approaches to assess the quality of published research. We use the principles of AGREE II to assess the quality of published guidelines.

Standard exclusions for scoping literature:

• Animal studies
• Original research is not written in English

Possible exclusions for reviewed literature:

• Sample size too small or study underpowered
• Bias evident or promotional literature
• Population not relevant
• Intervention/treatment not relevant
• Outcomes not relevant
• Outcomes have no clear evidence of clinical effectiveness
• Setting not relevant
• Not relevant to UK
• Incorrect study type
• Review article
• Duplicate reference

Organizational, behavioural and financial barriers

Our policy

The CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.

• Feasibility
  • Studies are selected depending on whether the intervention under investigation is available in the NHS and can be practically and safely undertaken in primary care.
• Organizational and Financial Impact Analysis
• Studies are selected and evaluated on whether the intervention under investigations may have an impact on local clinical service provision or national impact on cost for the NHS. The principles of clinical budget impact analysis are adhered to, evaluated and recorded by the author. The following factors are considered when making this assessment and analysis.
  • Eligible population
  • Current interventions
  • Likely uptake of new intervention or recommendation
  • Cost of the current or new intervention mix
  • Impact on other costs
  • Condition-related costs
  • In-direct costs and service impacts
  • Time dependencies
• Cost-effectiveness or cost-benefit analysis studies are identified where available. 

We also evaluate and include evidence from NICE accredited sources which provide economic evaluations of recommendations, such as NICE guidelines. When a recommended action may not be possible because of resource constraints, this is explicitly indicated to healthcare professionals by the wording of the CKS recommendation.

Declarations of interest

Our policy

Clarity Informatics requests that all those involved in the writing and reviewing of topics, and those involved in the external review process to declare any competing interests. Signed copies are securely held by Clarity Informatics and are available on request with the permission of the individual. A copy of the declaration of interest form which participants are asked to complete annually is also available on request. A brief outline of the declarations of interest policy is described here and full details of the policy is available on the Clarity Informatics website. Declarations of interests of the authors are not routinely published, however competing interests of all those involved in the topic update or development are listed below. Competing interests include:

• Personal financial interests
• Personal family interest
• Personal non-financial interest
• Non-personal financial gain or benefit

Although particular attention is given to interests that could result in financial gains or losses for the individual, competing interests may also arise from academic competition or for political, personal, religious, and reputational reasons. An individual is not obliged to seek out knowledge of work done for, or on behalf of, the healthcare industry within the departments for which they are responsible if they would not normally expect to be informed.

Who should declare competing interests?

Any individual (or organization) involved in developing, reviewing, or commenting on clinical content, particularly the recommendations should declare competing interests. This includes the authoring team members, expert advisers, external reviewers of draft topics, individuals providing feedback on published topics, and Editorial Steering Group members. Declarations of interest are completed annually for authoring team and editorial steering group members, and are completed at the start of the topic update and development process for external stakeholders.

Competing interests declared for this topic:

None.