Adverse drug reactions

Source:
Clinical Knowledge Summaries
Publication date:
01 March 2017

Abstract

Adverse drug reactions Last revised in March 2017 Next planned review by December 2022 Summary Back to topAdverse drug reactions: Summary An adverse drug reaction (ADR) is an unwanted or harmful reaction which occurs after administration of a drug or drugs and is suspected or known to be due to the drug(s).ADRs have traditionally been categorized as Type A and Type B:Type A reactions (pharmacological/augmented) result from an exaggeration of a drug's normal pharmacological actions when given at the usual therapeutic dose. They are dose dependent and are therefore readily reversible on reducing the dose of (or withdrawing treatment with) the drug.Type B reactions (idiosyncratic/bizarre) cannot be predicted from the known pharmacology of the drug.Type A adverse reactions are more common than Type B reactions and account for more than 80% of all reactions. The health and financial implications of ADRs are significant: about 6–7% of hospital admissions in the UK are due to ADRs.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, through the process of pharmacovigilance.Spontaneous ADR reporting schemes (such as the Yellow Card Scheme) are important information sources for pharmacovigilance.Data from the Yellow Card Scheme underpins the process of pharmacovigilance in the UK. Yellow Card reports should be made for all suspected ADRs in adults and children that are:Serious, medically significant, or result in harm.Associated with Black Triangle products, including suspected ADRs considered not to be serious.Yellow Card reports can be made for:Suspected ADRs to all medicines, including vaccines, blood factors and immunoglobulins, and complementary medicines. All medical devices available on the UK market.Defective medicines (those that are not of an acceptable quality).Fake or counterfeit medicines or medical devices.Nicotine-containing electronic cigarettes and refill containers (e-liquids).The MHRA are particularly interested in receiving Yellow Card reports of suspected ADRs:In children. In people aged over 65 years.To biological medicines and vaccines.Associated with delayed drug effects and interactions.On congenital abnormalities.To complementary remedies.It is not necessary to be certain that an ADR has occurred before submitting a report.A Yellow Card can be submitted:Via the MHRA Yellow Card website (www.mhra.gov.uk/yellowcard). Via a free Yellow Card mobile app.  By post. Paper copies of the Yellow Card can be obtained from several sources, for example by downloading the 'Healthcare Professional Yellow Card Reporting Form' from the MHRA website, by writing to FREEPOST YELLOW CARD, by emailing yellowcard@mhra.gsi.gov.uk, or by calling the Yellow Card Scheme helpline on 0808 100 3352 (10am to 2pm Monday–Friday).Members of the public can also report suspected ADRs (by using the Yellow Card Scheme) via the MHRA Yellow Card website, by telephone on 0808 100 3352, or by downloading the 'Member Of Public Yellow Card Reporting Form' from the MHRA website. Patient Yellow Cards are also available from pharmacies and GP surgeries. Have I got the right topic? Back to topHave I got the right topic? From birth onwards.This CKS topic covers the assessment, management, and reporting of suspected adverse drug reactions.There is a separate CKS topic on Poisoning or overdose.The target audience for this CKS topic is healthcare professionals working within the NHS in the UK, and providing first contact or primary healthcare. How up-to-date is this topic? Back to topHow up-to-date is this topic? Back to top Changes Changes March 2017 — reviewed. A literature search was conducted in March 2017 to identify evidence-based guidelines, UK policy, systematic reviews, and key randomized controlled trials (RCTs) published since the last revision of the topic. The Medicines and Healthcare Products Regulatory Agency (MHRA) no longer request that all suspected adverse drug reactions (ADRs) in children are reported; the advice on which suspected ADRs to report in children is now the same as for adults. This new guidance is as a result of feedback that the previous guidelines (asking all suspected ADRs in children to be reported) were impractical and deterred reporting (MHRA, 2015).  Back to top Previous changes Previous changes March 2012 — minor update. The Yellow Card website URL has been changed to www.mhra.gov.uk/yellowcard in line with government policy to reduce the number of government domains. Links to this website have been updated throughout this topic. Issued in April 2012.December 2011 — revised. A literature search was conducted in October 2011 to identify evidence-based guidelines, UK policy, systematic reviews, and key RCTs published since the last revision of the topic. No changes to clinical recommendations were made. However, information from several additional information nodes have been incorporated into the main nodes to improve clarity. Issued in January 2012.January 2011 — topic structure revised to ensure consistency across CKS topics. No changes to clinical recommendations have been made.February to June 2007 — converted from CKS guidance to CKS topic structure. The evidence base has been reviewed in detail, and recommendations are more clearly justified.October 2005 — minor technical update. Issued in November 2005.November 2003 — rewritten. Validated in March 2004 and issued in June 2004.November 2000 — reviewed. Validated in March 2001 and issued in June 2001.August 1997 — written. Back to top Update Update Back to top New evidence New evidence Evidence-based guidelinesNo new guidelines published since 1 March 2017.HTAs (Health Technology Assessments)No new HTAs since 1 March 2017.Economic appraisalsNo new economic appraisals relevant to England since 1 March 2017.Systematic reviews and meta-analysesNo new systematic reviews published since 1 March 2017.Primary evidenceNo new randomized controlled trials published in the major journals since 1 March 2017. Back to top New policies New policies No new national policies or guidelines since 1 March 2017. Back to top New safety alerts New safety alerts No new safety alerts since 1 March 2017. Back to top Changes in product availability Changes in product availability No changes in product availability since 1 March 2017. Goals and outcome measures Back to topGoals and outcome measures Back to top Goals Goals To support primary healthcare professionals to:Suspect adverse drug reactions (ADRs), when appropriate.Assess and manage suspected ADRs.Report suspected ADRs, if appropriate. Back to top Outcome measures Outcome measures No outcome measures were found during the review of this topic. Back to top Audit criteria Audit criteria No audit criteria were found during the review of this topic. Back to top QOF indicators QOF indicators No QOF indicators were found during the review of this topic. Back to top QIPP - Options for local implementation QIPP - Options for local implementation No QIPP indicators were found during the review of this topic. Back to top NICE quality standards NICE quality standards No NICE quality standards were found during the review of this topic. Background information Back to topBackground information Back to top Definition What is an adverse drug reaction? An adverse drug reaction (ADR) can be defined as:An unwanted or harmful reaction which occurs after administration of a drug or drugs and is suspected or known to be due to the drug(s) [MHRA, 2006]. A response to a drug that is noxious, unintended, and occurs at doses normally used for prophylaxis, diagnosis, or treatment of disease, or for modification of physiological function [Tan, 2014].An ADR may be a known effect of the drug, or a new and previously unrecognized effect [MHRA, 2006].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 and Aronson, 2000; Aronson and Ferner, 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 and Aronson, 2000; Aronson and Ferner, 2005]. Back to top Categorization of ADRs How are adverse drug reactions categorized? Adverse drug reactions (ADRs) are frequently categorized as Type A or Type B [Rawlins and Thompson, 1977; Pirmohamed et al, 1998; Edwards and Aronson, 2000; MCA and CSM, 2002; 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 (or withdrawing treatment with) the drug. 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 et al, 1998]. Type B reactions may only be discovered for the first time after a drug has already been 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 some time after the use of a drug, thereby making them more difficult to detect (for example, leucopoenia occurring up to six 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 classifications 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 and Ferner, 2003; Aronson and Ferner, 2005; Aronson, 2006; MHRA, 2015a]. Back to top Health and financial implications of ADRs What are the health and financial implications of adverse drug reactions? The health and financial implications of adverse drug reactions (ADRs) are significant.The precise numbers of ADRs that occur cannot be determined, given the difficulties in assessing causality and the low proportion of ADRs that are reported [BMA Board of Science, 2006].Most research has tried to quantify ADRs by evaluating hospitalized patients, and admissions in particular [BMA Board of Science, 2006]:The percentage of hospital admissions due to ADRs in the UK has been estimated to be 6–7% [Smith et al, 1996; Bandolier, 2002; Pirmohamed et al, 2004]. One systematic review found 3.73% (range 1.36–15.42) of hospital admissions to be preventable and drug-related [Howard et al, 2007].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 et al, 2004].A systematic review estimated that the overall impact of ADRs in England was four out of 100 hospital bed-days, or about fifteen to twenty 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 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. Back to top Monitoring adverse drug reactions Monitoring adverse drug reactions 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 health care 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 spontaneous ADR reporting scheme, called the Yellow Card Scheme, is run by the MHRA and the CHM.The Yellow Card Scheme receives voluntary reports of suspected ADRs from health professionals and members of the public [Independent Steering Committee, 2004].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/meno).The Health Improvement Network (THIN) in London (www.thin-uk.com).QResearch (www.qresearch.org).[MHRA, 2015c] Back to top How the Yellow Card reports are processed How is information from the Yellow Card reports processed and used?  All Yellow Card reports received are entered onto the Medicines and Healthcare products Regulatory Agency (MHRA)'s adverse drug reaction (ADR) database so that they are available for signal detection.Signal detection is the continual review of ADR reports to identify previously unrecognized concerns about medicines, vaccines, or blood products, which may warrant further action.Sometimes a signal can comprise a change in the pattern or frequency of ADRs already associated with a medicine — this may also warrant further action. The MHRA analyzes the data from the Yellow Card reports, alongside information from other sources, to quantify the risk and to decide on whether any actions need to be taken, including:Adding the new adverse effect to the existing list of adverse effect of the medicine.Restricting the uses of the medicine, revising the dosage recommendations, issuing advice on precautions (for example, by introducing special monitoring requirements), and/or contraindicating the medicine in certain circumstances.Changing the arrangements for supplying the medicine (for example, changing the classification of the medicine from an over-the-counter [OTC] medicine to a prescription only medicine [POM] or Pharmacy [P] medicine).Placing the medicine on a list of more intensively monitored medicines, thereby encouraging the reporting of all suspected adverse effects.Taking the medicine off the market (rare, considered if the risks of the medicine are thought to outweigh its benefits).For important medicines found to have serious adverse effects, introducing special measures, such as registering all people taking the medicine and supplying it only on the condition that the person undergoes specific screening.The MHRA publishes a Drug Safety Update, which is a monthly newsletter that contains information and clinical advice on the safe use of medicines. Healthcare professionals can register on the MHRA website (www.gov.uk/mhra) for an email alert subscription.The MHRA also provides information and feedback through:Updating patient information leaflets (PILs) and Summaries of Product Characteristics (SPCs) when new safety issues are identified.Letters sent to all doctors and pharmacists by post or electronic cascade highlighting urgent warnings about drug hazards.Fact sheets on major safety issues, which are produced for both healthcare professionals and patients.Safety alerts published on the MHRA website.A multi-disciplinary team at the MHRA is responsible for the operation of the General Practice Research Database (GPRD), which is the world's largest database of anonymized, longitudinal medical records from primary care.The MHRA acknowledges each Yellow Card report received and may ask for additional details if this will help during assessment of the report. All information provided to the MHRA is kept safe, secure, and confidential, and no details that could identify the reporter and/or the patient is passed on without prior permission.[MHRA, 2015a; MHRA, 2015b; MHRA, 2015c] Back to top Benefit of the Yellow Card Scheme How does the Yellow Card Scheme contribute to identifying drug safety issues? The Yellow Card Scheme has helped to identify numerous important drug safety issues, many of which were not recognized as being related to a particular medicine until the Medicines and Healthcare Products Regulatory Agency (MHRA) received information on Yellow Cards.Information on safety issues which the Yellow Card Scheme has helped identify is available on the MHRA website (www.gov.uk/mhra), and includes:Yasmin and hair loss.Amlodipine and grapefruit interaction.Warfarin and cranberry juice interaction.Vareniciline and sleep walking.Denosumab and osteonecrosis of the jaw.[MHRA, 2015d] Management Back to topManagement Scenario: Adverse drug reactions: covers the assessment, management, and reporting of suspected adverse drug reactions. Back to top Scenario: Adverse drug reactions Scenario: Adverse drug reactions  From birth onwards. Back to top Assessment How should I assess a person with a suspected adverse drug reaction? Assess the nature and severity of the reaction.This will determine whether urgent action is required or whether the person can be managed in primary care. For example, a cough due to an angiotensin-converting enzyme inhibitor can be troublesome but not life threatening, but an anaphylactic reaction is a medical emergency.The nature of the presenting condition may strongly suggest that it is an adverse drug reaction (ADR). For example, the following conditions are often ADRs:Acute dystoniasBlood dyscrasiasSkin reactions, such as Stevens–Johnson syndrome and toxic epidermal necrolysisNeuroleptic malignant syndromeTake a history of the presenting symptoms, including:When it started:The time from when use of the drug was started to when the reaction develops may be characteristic of the reaction (for example anaphylaxis usually develops within a few minutes of parenteral drug administration).If the drug was stopped, the time it took for the reaction to abate will often be related to the known duration of action of the drug.Relationship to dose:ADRs are often dose related and may be minimized by reducing the dose of the drug.If the symptoms resolve when the drug is withdrawn, they may have been associated with the drug, although it could still have been coincidental.If a drug is reintroduced and symptoms recur, the drug is most probably responsible for the adverse reaction. However, deliberate re-challenge is only very rarely justified (clinically and ethically) after serious ADRs, because of the risks involved.Other possible causes:The symptoms may be a manifestation of the person's underlying illness or another disease.Other medications (including self-medication and herbal remedies) could be responsible.Consider the possibility of drug interactions (including with food and drinks).Consider the drug history, and review any history of allergy or previous ADRs.Take a complete drug history, including when the drug was started, what dose is being taken, what other drugs are being taken, and whether the person is also taking over-the-counter (OTC) or herbal medicines.Check whether the person has ever had similar symptoms or presentation in the past with other drugs (from the same or a different drug class) or has a history of atopy or of ADRs with different presentation(s).Be aware that even if a drug was stopped some time before the ADR, it may have been responsible if it has a very long duration of action (for example amiodarone).Review the adverse effect profile of the drug and consider:Whether the signs and symptoms are in keeping with the documented adverse effect profile of the drug.Whether the ADR been reported before. This can be checked in the readily available sources of information, including: The British National Formulary (BNF).The electronic Medicines Compendium (www.medicines.org.uk).Interactive Drug Analysis Profiles (iDAPs) — a complete listing of suspected ADRs for individual drugs that have been reported to the Medicines and Healthcare products Regulatory Agency (MHRA) through the Yellow Card scheme by health care professionals, members of the public, and pharmaceutical companies. Regional and district medicine information services. Details of regional centres and other useful contacts can be found in the front of the BNF and BNF for Children (or online). Local services can found by contacting the medicines information department or the hospital pharmacy in major hospitals.How common the suspected adverse reaction is.Consider the need for further examination and investigations, if necessary. These may include:Specific investigations and laboratory tests, for example liver or renal function tests.Assessing for further complications of the ADR, such as gastrointestinal bleeding.Drug monitoring, for example checking serum digoxin concentrations in a person with suspected toxicity. Back to top Basis for recommendation Basis for recommendation These recommendations are based on advice in the Medicines and Healthcare products Regulatory Agency (MHRA) guideline Healthcare professional reporting of suspected adverse drug reactions [MHRA, 2006] and on what CKS considers to be good clinical practice. Back to top Managing a suspected reaction How should I manage a person with a suspected adverse drug reaction? Following an initial assessment:Arrange emergency hospital admission if the adverse drug reaction (ADR) is serious or life threatening.Assess whether the ADR can be managed in primary care.Consider seeking specialist advice.If the ADR can be managed in primary care:Review and discuss treatment options with the person. These may include:Stopping the suspected drug if the ADR is serious, or at the request of the individual, and avoiding its use in future.Considering alternative drug treatment if treatment of the original condition is still required.Considering altering the dose or temporarily stopping drug treatment if the benefit-to-harm balance of drug treatment is favourable.Considering the effects of concurrent treatments (drug interactions).Considering the possibility of withdrawal effects if drug treatment is stopped suddenly.Manage symptoms of the ADR as appropriate:Explain the benefits and harms if another drug is prescribed to treat the ADR.Record the ADR in the person's health record.Consider submission of an ADR report (Yellow Card), if appropriate.  Back to top Basis for recommendation Basis for recommendation These recommendations are based on what CKS considers to be good clinical practice.  Back to top Which reactions to report Which kind of suspected adverse drug reactions should I report? Report to the Medicines and Healthcare products Regulatory Agency (MHRA), using the Yellow Card Scheme, all suspected adverse drug reactions (ADRs) in adults and children that are:Serious, medically significant, or result in harm.Serious reactions include those that are fatal, life-threatening, a congenital abnormality, disabling or incapacitating, or result in or prolong hospitalization.For established medicines and vaccines you should report all serious suspected ADRs, even if the effect is well recognized.Associated with Black Triangle products, including suspected ADRs considered not to be serious.Black Triangle products are new drugs and vaccines that are being intensively monitored by the MHRA to confirm their risk/benefit profile. Black Triangle products are marked with an inverted Black Triangle in the British National Formulary (BNF), the British National Formulary for Children (BNFC), the Monthly Index of Medical Specialties (MIMS), the Association of the British Pharmaceutical Industry (ABPI) Medicines Compendium, the MHRA Drug Safety Updates, Summaries of Product Characteristics (SPCs) and Patient Information Leaflets (PILs), and on advertising materials.Products usually retain a Black Triangle status for 5 years, but this can be extended if required.The list of Black Triangle products are updated monthly and can found on the European Medicines Agency (EMA) website (www.ema.europa.eu). The MHRA are particularly interested in receiving Yellow Card reports of suspected ADRs:In childrenIn people aged over 65 years.To biological medicines and vaccines.Associated with delayed drug effects and interactions.Congenital abnormalities.To complementary remedies, such as homeopathic and herbal products.See the section on Additional information on which adverse drug reactions to report for more information.Yellow Card reports can be made for:Suspected ADRs to all medicines, including vaccines, blood factors and immunoglobulins, and complementary medicines (such as herbal and homeopathic remedies), whether self-medicated or prescribed. This includes suspected ADRs associated with misuse, overdose, or medication errors, or from use of unlicensed and off-label medicines.  All medical devices available on the UK market.Defective medicines (those that are not of an acceptable quality).Fake or counterfeit medicines or medical devices.Nicotine-containing electronic cigarettes and refill containers (e-liquids).ADRs that occur as a result of a medication error are also reportable as a Yellow Card or through the local risk management systems into the National Reporting and Learning System (NRLS).If reported to the NRLS, these will be shared with the MHRA.If the NRLS is not available and harm occurs, report using a Yellow Card.It is not necessary to be certain that an ADR has occurred before submitting a Yellow Card report.If in doubt, it is best to submit a report. Back to top Additional information on which ADRs to report Additional information on which adverse drug reactions to report Although the Medicines and Healthcare products Regulatory Agency (MHRA) monitors suspected adverse drug reactions (ADRs) associated with all medicines on the UK market, they are particularly interested in receiving reports on suspected ADRs involving:Children, because:They react differently to medicines (the pharmacodynamics and pharmacokinetics of a medicine may be very different in a child compared with an adult). For example, the liver and kidneys in a child may not have fully developed and may affect how the child metabolizes and excretes the medicine compared with an adult.Many drugs that are routinely used to treat children have not been extensively tested in children; many are not licensed for use in children and are used off-label. Medicines may affect the way a child grows and develops or may cause delayed adverse reactions which do not occur in adults.Available formulations may not allow precise dosing in children or they may contain excipients that should not be used in children, such as alcohol.The nature and course of illnesses and suspected ADRs may differ between adults and children, for example otitis media and treatment of chronic cough in children.People aged over 65 years of age, because:Elderly people may be more susceptible to developing ADRs as they may metabolize or excrete drugs less effectively and may be more sensitive to their effects.For both pharmacokinetic and pharmacodynamic reasons, they may be more susceptible to developing reactions.Biological medicines (such as blood products, antibodies and advanced therapies [such as gene and tissue therapy]) and vaccines, because:A variety of biological medicines and vaccines are fundamentally different from standard chemical medicines in terms of their complexity, and the characteristics of such products won't be identical.It is therefore very important that surveillance is carried out on a brand/product-specific basis, which may vary from batch-to-batch.Drug interactions:Some precipitant drugs (the drug causing the interaction) can alter the pharmacokinteics of object drugs (the drug affected by the interaction) by altering the absorption, distribution metabolism, or excretion of the object drug.Some drugs have pharmacodynamic interactions and can change the response of one or multiple drugs, having an additive or antagonistic effect. Either type of drug interactions can result in ADRs in some people, and the frequency of drug-drug interactions can increase with the number of medications the person is taking.Rare or delayed drug effects, because:These reactions may appear months or years after exposure (for example cancers or retroperitoneal fibrosis).They are not likely to be identified in short-term clinical studies and may become apparent only after extensive and long-term use of the drug.Congenital anomalies, because:Information on these adverse reactions is very limited, given that clinical trials do not generally involve pregnant women.Herbal remedies, because:Although some herbal medicines are licensed for use, many unlicensed herbal remedies are available from outlets other than pharmacies (or are supplied by herbal practitioners).It is important for the MHRA to monitor all herbal products to ensure their safety. For example, Yellow Card reporting identified hepatotoxicity associated with Kava-Kava, resulting in its supply being prohibited in the UK in 2003 [Independent Steering Committee, 2004].[MHRA, 2015e] Back to top Basis for recommendation Basis for recommendation These recommendations are based on the Medicines and Healthcare products Regulatory Agency (MHRA) guidelines New guidance on reporting suspected adverse drug reactions in children [MHRA, 2014], Specific areas of interest for reporting suspected adverse drug reactions [MHRA, 2015e], The Yellow Card Scheme — Reporting Adverse Drug Reactions [MHRA, 2015b], and The Yellow Card Scheme: guidance for healthcare professionals [MHRA, 2017a], and on information in the British National formulary (BNF) [BNF 72, 2016]. Back to top How to report a suspected reaction How should I report a suspected adverse drug reaction? Report suspected adverse drug reactions (ADRs) through the Yellow Card Scheme using the electronic form at www.mhra.gov.uk/yellowcard. Healthcare professionals who use SystmOne and Vision software systems can report suspected ADRs to the Medicines and Healthcare Products Regulatory Agency (MHRA) through their clinical software. The MHRA are establishing timelines with other suppliers as to when this reporting functionality will be added into their systems.Alternatively, Yellow Cards can be submitted:Via a free Yellow Card mobile app from iTunes Yellow Card for iOS devices or PlayStore Yellow Card for Android devices. By post. Paper copies of the Yellow Card are available:By downloading the Healthcare Professional Yellow Card Reporting Form from the MHRA website.By writing to FREEPOST YELLOW CARD (no other address details necessary).By emailing yellowcard@mhra.gsi.gov.uk.By calling the National Yellow Card Information Service on 0808 100 3352 (10am to 2pm Monday–Friday).In the back cover of the British National Formulary (BNF) and British National Formulary for Children (BNFc). When filling out a Yellow card report, include the following pieces of information:The name and full address of the reporter so that MHRA can acknowledge receipt of the report and follow up for further information if necessary.If known, information about the suspect drug(s), including route of administration; daily dose, dose frequency, and schedule; dates of administration; and brand and batch number (if it is a vaccine).If known, information about the suspect reaction(s), including when the reaction occurred, seriousness of the reaction, any treatment given, and outcome of reaction.If the reaction has already been reported (for example by another healthcare professional or the person) but there is additional information to report, submit a Yellow Card as the MHRA can detect duplicate reports and link the information.At least one of the following pieces of patient information: sex, age at the time of the reaction, weight (if known), and the person's initials and a local identification number (for example the person's local practice or hospital number or any other reference number) that will identify the person to you (but not to the MHRA). Be aware that providing this information does not violate patient confidentiality.Also include (where possible):For congenital abnormalities, all other drugs taken during the pregnancy and the date of the last menstrual period.Relevant test results (include print-outs if necessary).Relevant medical history, including allergies.Relevant drug information:This should include any information on re-challenge with the suspect drug(s) and Information on the drug(s) taken in the last 3 months prior to the reaction, including over-the-counter (OTC) and herbal medicines.If the person was not taking any other drugs, or if no other information is available, this should be indicated on the form.Consider including a copy of the Yellow Card report in the person's notes for future reference.Members of the public can also report suspected ADRs through the Yellow Card scheme.Reports can be submitted directly to the MHRA using the electronic form at www.mhra.gov.uk/yellowcard, by telephone on 0808 100 3352 (10am to 2pm Monday–Friday), or by downloading the Member Of Public Yellow Card Reporting Form from the MHRA website. Alternatively, patient Yellow Cards (which are different from those used by healthcare professionals and are designed for use by the members of the public) are available from pharmacies and GP surgeries.Information on the Yellow Card Scheme is available in other languages at www.mhra.gov.uk/yellowcard.Members of the public who wish to remain anonymous or are unable to complete the form can ask a representative to complete it on their behalf. Correspondence from the MHRA can be directed to the representative. Back to top Basis for recommendation Basis for recommendation These recommendations are based on advice in the Medicines and Healthcare products Regulatory Agency (MHRA) guidelines What to include in your Yellow Card of an adverse drug reaction [MHRA, 2015f] and The Yellow Card Scheme — Reporting Adverse Drug Reactions [MHRA, 2015b], and the MHRA Drug Safety Update Yellow Card reporting added to second clinical software system [MHRA, 2017b]. Supporting evidence Back to topSupporting evidence The recommendations in this CKS topic are largely based on information on the Medicines and Healthcare products Regulatory Agency (MHRA) Yellow Card website (www.yellowcard.mhra.gov.uk). How this topic was developed Back to topHow this topic was developed This section briefly describes the processes used in developing and updating this topic. Further details on the full process can be found in the About Us section and on the Clarity Informatics website. Back to top Search strategy Search strategy Scope of searchA literature search was conducted for guidelines, systematic reviews and randomized controlled trials on primary care management of adverse drug reactions.Search datesOctober 2011 - March 2017.Key search termsVarious 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.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 Health Protection Agency World Health Organization National Guidelines Clearinghouse Guidelines International Network TRIP database GAIN NHS Scotland National Patient Pathways New Zealand Guidelines Group 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 University of Michigan Medical School Michigan Quality Improvement Consortium Singapore Ministry of Health National Resource for Infection Control Patient UK Guideline links UK Ambulance Service Clinical Practice Guidelines 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 AssessmentSources 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 & amp; Therapeutics Bulletin TRIP database Central Services Agency COMPASS Therapeutic NotesSources of national policy Department of Health Health Management Information Consortium(HMIC)Patient experiences Healthtalkonline BMJ - Patient Journeys Patient.co.uk - Patient Support GroupsSources of medicines informationThe 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 Back to top Stakeholder engagement Stakeholder engagement Our policyThe 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 processThe 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.StakeholdersKey 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 engagementClarity 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 selectionScoping of topicSelection of clinical scenariosFirst draft internal reviewSecond draft internal reviewExternal reviewFinal draft and pre-publicationOur lay and patient involvement includes membership on the editorial steering group, contacting expert patient groups, organizations and individuals. Back to top Evidence exclusion criteria Evidence exclusion criteria Our policyScoping 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 studiesOriginal research is not written in EnglishPossible exclusions for reviewed literature:Sample size too small or study underpoweredBias evident or promotional literaturePopulation not relevantIntervention/treatment not relevantOutcomes not relevantOutcomes have no clear evidence of clinical effectivenessSetting not relevantNot relevant to UKIncorrect study typeReview articleDuplicate reference Back to top Organizational, behavioural and financial barriers Organizational, behavioural and financial barriers Our policyThe CKS literature searches take into consideration the following concepts, which are discussed at the initial scoping of the topic.FeasibilityStudies 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 AnalysisStudies 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 populationCurrent interventionsLikely uptake of new intervention or recommendationCost of the current or new intervention mixImpact on other costsCondition-related costsIn-direct costs and service impactsTime dependenciesCost-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. Back to top Declarations of interest Declarations of interest Our policyClarity 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 interestsPersonal family interestPersonal non-financial interestNon-personal financial gain or benefitAlthough 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. References Back to topReferences Aronson,J.K. and Ferner,R.E. (2003) Joining the DoTS: new approach to classifying adverse drug reactions. British Medical Journal. 327(7425), 1222-1225. Aronson, J.K. and Ferner, R.E. (2005) Clarification and terminology in drug safety. Drug Safety. 28(10), 851-870. [Abstract] Aronson,J.K. (Eds.) (2006) Meyler's side effects of drugs. The international encyclopedia of adverse drug reactions and interactions. Oxford: Elsevier.. Bandolier (2002) Adverse drug reactions in hospital patients. A systematic review of the prospective and retrospective studies. Bandolier.. www.medicine.ox.ac.uk/bandolier [Free Full-text] BMA Board of Science (2006) Reporting adverse drug reactions: a guide for healthcare professionals. BMA. . www.bma.org.uk BNF 72 (2016) British National Formulary. British Medical Association and Royal Pharmaceutical Society of Great Britain.. Edwards,I.R. and Aronson,J.K. (2000) Adverse drug reactions: definitions, diagnosis, and management. Lancet. 356(9237), 1255-1259. [Abstract] Hakkarainen, K.M., Hedna, K. and Petzold, M. et al. (2012) Percentage of patients with preventable adverse drug reactions and preventability of adverse drug reactions – a meta-analysis. PLoS One. 7(3), e33236. [Free Full-text] Howard,R.L., Avery,A.J., Slavenburg,S., et al. (2007) Which drugs cause preventable admissions to hospital? A systematic review. British Journal of Clinical Pharmacology. 63(2), 136-147. [Abstract] Independent Steering Committee (2004) Report of an independent review of access to the yellow card scheme. The Stationery Office.. www.mhra.gov.uk [Free Full-text] MCA, CSM (2002) Suspected adverse drug reaction (ADR) reporting and the yellow card scheme.. www.mhra.gov.uk MHRA (2006) Healthcare professional reporting of suspected adverse drug reactions. Medicines and Healthcare products Regulatory Agency.. www.mhra.gov.uk MHRA (2007) Pharmacovigilance - how we monitor the safety of medicines. Medicines and Healthcare products Regulatory Agency.. www.mhra.gov.uk [Free Full-text] MHRA (2014) New guidance on reporting suspected adverse drug reactions in children. Medicines and Healthcare products Regulatory Agency.. [Free Full-text] MHRA (2015a) Guidance on adverse drug reactions. Medicines and Healthcare products Regulatory Agency.. www.mhra.gov.uk MHRA (2015b) The Yellow Card Scheme - Reporting adverse drug reactions. Medicines and Healthcare products Regulatory Agency.. www.mhra.gov.uk [Free Full-text] MHRA (2015c) Pharmacovigilance – how the MHRA monitors the safety of medicines. Medicines and Healthcare products Regulatory Agency.. [Free Full-text] MHRA (2015d) Contribution of Yellow Cards to identifying safety issues. Medicines and Healthcare products Regulatory Agency.. www.mhra.gov.uk [Free Full-text] MHRA (2015e) Specific areas of interest for reporting suspected adverse drug reactions. Medicines and Healthcare products Regulatory Agency.. www.mhra.gov.uk [Free Full-text] MHRA (2015f) What to include in your Yellow Card of an adverse drug reaction. Medicines and Healthcare products Regulatory Agency.. www.mhra.gov.uk [Free Full-text] MHRA (2017a) The Yellow Card Scheme: guidance for healthcare professionals. Medicines and Healthcare products Regulatory Agency.. www.mhra.gov.uk [Free Full-text] MHRA (2017b) Yellow Card reporting added to second clinical software system. Drug Safety Update. 10(7), 2. [Free Full-text] Pirmohamed,M., Breckenridge,A.M., Kitteringham,N.R. and Park,B.K. (1998) Adverse drug reactions. 316(7140), 1295-1298. Pirmohamed,M., James,S., Meakin,S., et al. (2004) Adverse drug reactions as cause of admission to hospital: prospective analysis of 18820 patients. British Medical Journal. 329(7456), 15-19. [Abstract] Rawlins,M.D. and Thompson,J.W. (1977) Textbook of adverse drug reactions. In: Davies,D.M. (Eds.) Pathogenesis of adverse drug reactions.Oxford: Oxford University Press. Smith, C.C., Bennett,P.M., Pearce,H.M., et al. (1996) Adverse drug reactions in a hospital general medical unit meriting notification to the Committee on Safety of Medicines. British Journal of Clinical Pharmacology. 42(4), 423-429. [Abstract] Tan, K., Petrie, K.J., Faasse, K. et al. (2014) Unhelpful information about adverse drug reactions. British Medical Journal. 349(g5019). [Abstract] WHO (2002) Safety of medicines. A guide to detecting and reporting adverse drug reactions. Why health professionals need to take action. World Health Organization.. www.who.int [Free Full-text]