Adverse drug reactions in children and young people

This article aims to review adverse drug reactions in children and young people, highlighting important differences from the adult population and outlining steps that can be taken to manage reactions.
Understanding common adverse drug reactions in children
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Adverse drug reactions (ADRs) are defined by the World Health Organization (WHO) as “a response to a drug which is noxious, and unintended, and which occurs at doses normally used in man for prophylaxis, diagnosis or therapy of disease, or for the modification of physiological function”​[1]​. Children comprise around 20% of the UK population but use only 5% of the prescribed medications​[2,3]​. However, a Canadian study demonstrated that the proportion of children receiving prescribed medicines is not uniform, with 25% of children accounting for more than 70% of prescriptions​[4]​

This article aims to review ADRs in children and young people, highlighting the main differences from the adult population, focusing on important disease groups — such as asthma and infection — and steps that can be taken to appropriately manage ADRs. 

ADR risk in children

The British National Formulary for Children (BNFc) provides medicines guidance for children up to the day before their 18th birthday​[5]​. In UK paediatric practice, most centres will aim to transition a young person to adult services in line with this, although some of the most complex patients, for example those with complex neurodisabilities requiring multidisciplinary care, may remain in paediatric services for longer​[6,7]​.

Historically, children were believed to be at a lower risk of ADRs than adults​[8–10]​. However, studies now show that children are at an equal, if not greater, risk of ADRs compared with non-elderly adults​[8,11]​. A systematic review of paediatric ADRs identified 30 studies, detailing incidence rates of ADRs causing hospital admission; the rates ranged from 0.4–10.3%​[12]​. Prospective data from a secondary/tertiary centre in the UK determined that 2.9% of all acute paediatric admissions (n=8,345) were directly related to an ADR​[13]​. Internationally, studies have shown that 0.6–16.8% of paediatric inpatients experience an ADR, while prospective data for the UK shows that 17.7% experience at least one ADR​[12,14]​. In outpatient and community settings, a similar proportion of ADRs have been reported, ranging from 0.6–11.0%​[12]​. More recent studies have demonstrated no significant change in the rates of ADRs in children over the past decade​[15–17]​.

The known risk factors for ADRs in children are:

  • Polypharmacy​[14,17,18]​;
  • Previous adverse reaction to another drug​[8,17,18]​;
  • Female sex​[8,13,18]​;
  • Impaired liver or renal function​[8,18]​;
  • General anaesthetic use​[14,17,18]​;
  • Off-label and unlicensed drug use​[18,19]​;
  • Genetic polymorphisms​[8,18]​.

Pharmacists, as medicines experts, should counsel patients on potential ADRs, and also have a role in the identification, management and reporting of ADRs. Opportunities to perform these activities exist in both the inpatient setting (e.g. during ward rounds), and the outpatient setting (e.g. at the point of drug dispensing).

Identification of ADRs in children and young people can be particularly challenging. This, in part, relates to the population, as babies and young children have limited communication. This is reflected in the low rates of reporting of suspected ADRs in UK neonatal units, where despite more than 100,000 babies being cared for annually, less than 10 Yellow Card reports are received by the Medicines and Healthcare products Regulatory Agency (MHRA) per year​[20,21]​. However, even in neonatal units, where active surveillance is undertaken, it is possible to increase the reporting rate​[22]​. The presence of pharmacists — even in highly specialised areas, such as neonatal and paediatric intensive care units — is critical for improved recognition and reporting of ADRs.  

Why are ADRs different in children? 

One of the challenges of describing ADRs in children is the rapid development that alters their anatomy and physiology​[23]​. The diseases often experienced by children differ from adults, and manifestations of diseases that occur in both childhood and adulthood may also be different​[23]​. The most rapid changes in pharmacokinetics occur in the first year of life​[24]​. By the age of one year, body weight will have tripled and body surface area doubled​[5,23]​. The relative proportions of fat, water and protein also change rapidly during infancy. Total body water (TBW) between birth and one year decreases from 80% to 65%. As the proportion of TBW decreases, the percentage of body fat increases, almost tripling by one year of age​[25]​. In contrast, protein mass does not start to increase significantly until the second year of life, when infants become more ambulatory​[23]​. These changes, and their potential impact on drug pharmacokinetics, are summarised in Table 1.

Table 1. Effects of age on pharmacokinetics in children​​​[23,24,26]​

Types of ADRs 

The Rawlins and Thompson classification of ADRs include two principal types: type A reactions, which are dose-dependent and predictable (e.g. bleeding and anticoagulants); and type B reactions, which are non-dose-dependent and not predictable (e.g. penicillin hypersensitivity)​[27]​. Over time, this classification system has been extended to include: type C, dose- and time-dependent (chronic) reactions (e.g. corticosteroids and adrenal insufficiency); type D, delayed reactions (e.g. thalidomide and phocomelia); type E, withdrawal reactions (e.g. withdrawal seizures on discontinuation of anticonvulsants) and type F, failure of therapy​[28]​

Common mechanisms of ADRs include:

  • Synergistic effects between drug combinations (e.g. use of analgesic combinations post-operatively, specifically the combination of opioids and other analgesics such as non-steroidal anti-inflammatories [NSAIDs] or paracetamol)​[29]​
  • Antagonistic effects between drug combinations (e.g. concurrent use of antiepileptic drugs lamotrigine and carbamazepine can result in reduced levels of lamotrigine)​[5,30]​.
  • Abnormal pharmacokinetics from genetic polymorphisms in drug-metabolizing enzymes (e.g. phase I enzyme cytochrome P450 2D6 [CYP2D6] has 141 different alleles described to date, representing one of the most well understood examples of how pharmacogenetic variation can influence drug metabolism)​[31,32]​

Recognising ADRs in children 

In the paediatric population, availability of high-quality data about the harms of medicines used can be an issue. For more established medicines, there may be limited clinical trial data supporting their use in children and young people, making recognition of potential ADRs more difficult. The lack of paediatric-specific drugs also means that off-label and unlicensed use of medicines is common in paediatrics; this type of medication use is also associated with increased ADR risk​[19,33]​. Following the introduction of the Paediatric Regulation in the EU in 2007, the situation has improved, with 238 new medicines for use in children authorised between 2007 and 2015​[34]​

Unrecognised ADRs that appear in the post-marketing surveillance stage of drug development may compound the issue of limited information on paediatric drugs. Across a 25-year period examining 548 drugs newly approved for use in adults and children by the United States Food and Drug Administration, 45 (8.2%) acquired new black box warnings and 16 (2.9%) were withdrawn from the market​[35]​. Half of these occurred more than seven years after the drug was introduced to the market​[35]​. In the UK, this data is captured by spontaneous reporting of suspected ADRs through the MHRA’s Yellow Card scheme​[36]​. The majority of reports are submitted by healthcare professionals, although the proportion of reports submitted by patients, parents and carers has been steadily increasing as a result of several public health campaigns​[37–39]​. While spontaneous reporting systems have their advantages, and are one of WHO’s five minimum requirements for a functional national pharmacovigilance system, they have their drawbacks, the principal of which is enormous under-reporting, up to 98%, of ADRs​[20,40–42]​. Reasons given for under-reporting are numerous and include indifference, fear of litigation and ignorance on how to report ADRs​[43–45]​.

Initial observation of ADRs

In the UK, the routine immunisation schedule begins from the age of eight weeks​[46]​. Therefore, vaccinations represent one of the most commonly used medicinal products in those aged under one year​[20,47]​. As such, it is also this age group that generates large numbers of reports for suspected ADRs for vaccinations, dwarfing the number reported for medicines​[20,47,48]​.

The most common ADRs reported for vaccinations include pyrexia, injection site reactions and headache​[48]​. As the vast majority of children and young people receiving a vaccination are healthy, any symptom exhibited may be considered a suspected ADR. The vaccines with the most reported ADRs in children and young people, submitted via the UK Yellow Card scheme, include the human papilloma virus (HPV) vaccines (Cervarix [GlaxoSmithKline UK], Gardasil and Gardasil 9 [Merck Sharp & Dohme Limited]), the measles, mumps and rubella (MMR) vaccine and the meningococcal B vaccine (Bexsero [GlaxoSmithKline UK]), with estimated reporting rates of 48.2, 36.6 and 19.3 per 100,000 doses respectively in 2017/2018​[48]​

In the UK, the categorisation and management of suspected ADRs related to vaccines is detailed in ‘Immunisation against infectious disease, popularly known as The Green Book​[49]​. For common adverse events following immunisations (AEFI), such as fever and local site reactions, simple self-care advice is recommended​[49–51]​. Rare AEFIs are typically neurologically or immune-mediated and include seizures, idiopathic thrombocytopaenic purpura and anaphylaxis; incidence rates are typically less than 1 per 100,000 doses​[52–54]​. In these cases, the appropriate emergency guidelines should be followed and referral to an allergist is usually indicated before deciding whether additional doses of the same vaccine or vaccines containing the same components should be used (for more on management of anaphylaxis, see here)​[49,55]​

Common childhood conditions and associated ADRs

Asthma 

Asthma is the most common, non-infective, chronic disease of childhood, affecting one in 11 children and young people in the UK​[56]​. Mainly managed in primary care, the management of asthma is guided by national and international evidence-based guidelines​[57–59]​. Commonly used medications include beta-agonists, inhaled corticosteroids (ICS), leukotriene receptor antagonists, xanthine derivatives and, more recently, monoclonal antibodies​[5]​. Each group of medications has its own adverse effect profile (see Table 2).

Table 2. Reported ADRs in asthma medications​[5,60,61]​

A systematic review of ADRs associated with asthma medications commonly used in children found that, of the ADRs reviewed, 43% (n=174) were associated with ICS, with serious ADRs ranging from 1–7% per drug across all medication classes​[62]​. Use of corticosteroids is common in asthma treatment​[58,63]​. Children and young people typically receive lower doses of ICS, meaning that some systemic ADRs to corticosteroids, such as striae and fat redistribution, are rarely seen in children and young people with asthma​[64]​. However, there are still concerns about ADRs caused by ICS in children and young people, particularly adrenal suppression​[65–67]​. Adrenal suppression can be difficult to identify, as the presentation can be asymptomatic; subtle (e.g. loss of growth velocity, increased lethargy, weight loss); or florid (e.g. symptomatic adrenal crisis)​[66]​. Owing to the insidious nature of adrenal suppression, a high level of vigilance is required, to ensure that it is considered in children and young people using corticosteroids (inhaled and oral), and that asthma medications are actively managed so children and young people are on the lowest dose that allows for symptom control​[66,67]​

Infection 

After vaccines, anti-infective agents are the most commonly reported group of medicines for ADRs in children and young people (all age groups), with antibacterials accounting for around half of the ADR burden in children​[12,68–70]​. The most common ADRs reported are nausea, vomiting, diarrhoea and skin rashes​[12]​. Beta-lactams are reportedly responsible for causing up to 40% of these ADRs​[69]​

Up to 6% of children are now labelled as allergic to beta-lactam antibiotics, with three-quarters of these children being labelled before their third birthday​[71,72]​. If these labels are then carried forward into adulthood, it can perpetuate the use of non-beta-lactam antibacterials, resulting in increased costs, reduced efficacy, increased antibacterial resistance and potentially increased mortality​[73–75]​. Indeed in a large programme of research on ADRs in children and young people, parental anxiety about the potential future implications of ADRs in their child(ren) was well highlighted​[76]​. Nevertheless, in studies where children have been tested for drug allergy or undergone drug challenges, more than 90% of children were able to tolerate the antibacterial they had previously been deemed allergic to​[71,77,78]​.

The Royal College of Paediatrics and Child Health has produced a care pathway for drug allergy and describes a set of competencies required to diagnose, treat and optimally manage drug allergy​[79]​. In the context of suspected drug allergy with only mild reactions, where no additional treatment is required, drug provocation testing is gold standard and has become routine among large centres in the UK and elsewhere​[80]​

Allergy

Systemic antihistamines are commonly used in children for symptomatic relief in a variety of allergic diseases, including allergic rhinitis, allergic conjunctivitis, food allergy, chronic spontaneous urticaria and atopic eczema​[5,81]​. Studies have shown that, of the major drug classes, antihistamines are responsible for around 1–3% of reported ADRs​[82–84]​

Historically, although highly effective, first-generation antihistamines (e.g. chlorphenamine and promethazine), were associated with a greater incidence of ADRs than second-generation antihistamines, such as loratadine and cetirizine​[85]​. de Vries and van Hunsel examined reports of ADRs from systemic antihistamines in the Netherlands and found 228 reports over a 13-year period, 5 of which were deemed serious​[81]​. This included one death, which was attributed to malignant neuroleptic malignancy syndrome after alimemazine was prescribed for sedative purposes. Interestingly, the remaining four serious ADRs were seen in second-generation antihistamines. One report included a boy aged 14 years who had an atrioventricular re-entry tachycardia after co-administration of azithromycin and fexofenadine; and three children who had convulsions after receiving loratadine/desloratadine​[81]​. A similar report reviewing ADRs from antihistamines used in children and young people found that, of 8,918 reports, 57% involved second-generation antihistamines​[86]​. Of the serious ADRs, classified as causing death, hospitalisation, life-threatening, permanent disability and birth defects, there was no significant difference between first- and second-generation antihistamines. 

Other more commonly reported ADRs attributed to antihistamines include skin reactions, headache, somnolence and aggressive behaviour​[61,81,87]​

Pain

Pain is often undertreated in children and young people, and its management varies globally​[88–90]​. Three groups of analgesics are commonly used in children and young people: paracetamol, NSAIDs and opioids. These account for around 10% of ADRs reported in children​[12,91]​. A systematic review examined ADRs involving these analgesics in children presenting with acute pain​[92]​. Twenty-three studies involving 2,300 children were included. Opioids were associated with markedly more adverse events than paracetamol or NSAIDs, particularly in the central nervous system (CNS), and dual therapy with a non-opioid/opioid combination conferred a protective effect for ADRs compared with opioids alone​[92]​. Codeine raised particular concerns about harms in children after the deaths/serious harms reported in children given ‘standard’ doses of codeine, whom were later found to be ultra-rapid metabolisers at the CYP2D6 locus​[93,94]​. Codeine is now contraindicated in children and young people aged under 18 years who undergo procedures for obstructive sleep apnoea, and is not routinely prescribed in children​[5,95]​. With the known implications of CYP2D6 polymorphisms on codeine use — in conjunction with the improved access to and reduced costs of genotyping — it is possible that the evolving field of pharmacogenomics will allow safer use of codeine and other opioids in perioperative pain control in children and young people​[96]​.

Epilepsy

Epilepsy is a common neurological condition affecting both adults and children. The majority of patients will depend on antiepileptic drugs (AEDs) to achieve seizure control​[97–99]​. AEDs are the second most frequently reported therapeutic class associated with ADRs in children and young people and up to 25% of AED treatment failure has been attributed to ADRs​[12,97,100]​. The risk of ADRs from AEDs is almost tripled in patients prescribed more than one drug​[101]​Sodium valproate and carbamazepine account for the majority of AED ADRs; however, this is likely to be because of their widespread use among children and young people with epilepsy​[101–103]​. The most common ADRs reported involve the CNS and include behavioural disturbance, somnolence/fatigue and increased seizures​[12,97,101–103]​. While it is recognised that most AEDs increase the risk of harm to the foetus, valproate is of particular concern, with up to 40% of children exposed affected by neurodevelopmental disorders in later childhood​[104,105]​. As such, valproate is now only prescribed to female patients post puberty with a pregnancy prevention programme in place​[106]​. Pharmacists have an essential role in the identification of women and girls of childbearing potential and provision of information via this scheme in the UK (see here for more information)​[106]​

Diabetes

Insulin is the primary agent used to treat diabetes mellitus in children​[5]​. Various insulin products are available that vary in their time-action profiles: short-acting (including soluble insulin and rapid-acting insulin), intermediate-acting insulins and long-acting insulins​[5]​

Hypoglycaemia is the most serious and potentially life threatening adverse effect of insulin and a major barrier to achieving adequate glycaemic control​[107]​. Risk factors for hypoglycaemia include longer duration of disease, renal impairment and impaired hypoglycaemia awareness​[108–110]​. For children and young people, older age is associated with a lower risk of severe hypoglycaemia​[111]​. Educational awareness should be improved in children and young people who have a higher risk of hypoglycaemic consequences. Additionally, a higher, more relaxed glycated haemoglobin (HbA1c) target can be recommended​[112–115]​. When comparing the different insulin preparations, rapid-acting insulin analogues and insulin glargine result in fewer hypoglycaemic events when compared with regular and neutral protamine Hagedorn insulins respectively​[107,116,117]​.

Insulin is an anabolic hormone involved in promoting the uptake of fatty acid into adipose tissue; unsurprisingly, with the exception of insulin detemir, weight gain is another commonly reported adverse effect of insulin​[61,118,119]​. Although the mechanisms are not entirely understood, detemir is associated with reduced food intake compared with other insulin preparations​[120,121]​. Weight gain can be a significant barrier to adherence to insulin, especially in a teenage population​[122,123]​

Several types of local injection site lesions from subcutaneous insulin have been reported. True hypersensitivity reactions are uncommon​[107]​. Other lesions include lipoatrophy, lipohypertrophy and cutaneous amyloidosis​[124]​. The latter two conditions can both appear as painless, slow-growing subcutaneous nodules at insulin injection sites​[124]​. Patients are advised to rotate their injection sites within the same body area to reduce the risk of nodule formation and reduced insulin absorption​[5]​

Attention deficient hyperactive disorder

Attention deficit hyperactivity disorder (ADHD) is now the most common neurodevelopmental disorder, with a global prevalence of 5%​[125]​. In the UK, methylphenidate and lisdexamfetamine are recommended in children aged over five years where ADHD symptoms persist despite environmental modifications​[126]​. Both agents can only be initiated by an appropriate specialist trained in the diagnosis, management and monitoring of ADHD​[5,126]​. Second-line medications include atomoxetine and guanfacine​[126]​.  

A review of 43 studies involving 7,244 children treated with amphetamine (n=1,076), methylphenidate (n=2,092), atomoxetine (n=3127) and modafinil (n=949) revealed ADRs as one of the most common reasons for non-completion of treatment in the trial setting​[127]​. For all four drugs, anorexia, gastrointestinal pain and headache were the most commonly reported ADRs​[127]​.

Reasons for discontinuation of ADHD medications have been reviewed among various age groups, identifying female sex and the presence of co-morbid psychiatric conditions as risk factors​[128]​

According to UK Yellow Card scheme reports for methylphenidate and lisdexamfetamine, the age group with the largest number of reported ADRs was 10–19 years, with a drop in the number of submitted reports in each subsequent age group​[61]​. It is not known if this reflects the peak years where medication is used for this condition, or increased susceptibility to ADRs in the teenage years.  

Corticosteroids

ICS have been discussed previously; however, systemic corticosteroids (e.g. prednisolone, methylprednisolone and dexamethasone) are also widely used in paediatrics for their anti‐inflammatory, immunomodulatory and immunosuppressive characteristics across a range of diseases​[129]​. Equally wide ranging are the potential adverse effects of corticosteroids on almost all organ systems​[130]​

Retrospective reviews have demonstrated that both dose and duration of therapy are independent predictors of ADRs secondary to use of corticosteroids​[131,132]​. Increasingly, genetic polymorphisms, such as the single nucleotide polymorphism rs591118 in the platelet-derived growth factor gene (PDGFD), are being implicated in the type and severity of ADRs experienced by patients requiring corticosteroids​[60,133]​.  

Prevention and monitoring are essential to reduce the incidence of serious ADRs in patients requiring corticosteroids. It is recommended that patients are routinely asked about ADRs related to corticosteroids throughout therapy and individual risk factors should also be taken into consideration. Particular focus should be given to avoid​[134]​:

  • Opportunistic infection; 
  • Loss of bone mineral density and osteoporosis;
  • Hyperglycaemia and steroid-induced diabetes mellitus; 
  • Adrenal insufficiency;
  • Growth suppression.

National and international agreement on how best to monitor and manage patients requiring long-term systemic corticosteroids is limited​[135]​. Nevertheless, evidence-based, practical recommendations on how best to manage the complications of systemic corticosteroid therapy exist for both adults and children​[136]​

Other specialist areas where ADRs are common

Biologic agents are increasingly used across most paediatric subspecialties​[137,138]​. While a detailed review of biologics lies outside the scope of this article, previous work has highlighted that despite being used routinely in paediatric practice for more than two decades, only 60% of biologics have a licensed paediatric indication​[139]​. This again highlights the difficulties in obtaining information about potential harms in children and young people.

Childhood cancers are rare, with one in 500 children developing cancer by the age of 14 years in the UK​[140]​. The majority of treatment regimens involve use of multiple drugs in varying combinations at high doses with broad toxicity profiles, resulting in a wide variety of complications​[141]​. As such, ADRs seen in paediatric cancers are beyond the scope of this article and have been previously dealt with in previous reviews, most recently by Conyers et al.​[141]​.

Actions pharmacists can take to manage ADRs

When managing ADRs in primary and secondary care, the WHO recommends three steps for evaluation​[142]​:

  1. Assess the nature and severity of the reaction;
  2. Establish the cause;
  3. Take corrective and follow-up action.

The first step in managing an ADR, even before assessing its nature and severity, is to suspect that one exists in the first place. This can be difficult in a population where communication skills may be limited by age or by conditions such as neurodevelopmental delay. The task of identification therefore often falls on the parents/guardians. However, this identification relies on the parent/guardian and/or child knowing what signs and symptoms to look for. Unfortunately, parents/guardians often feel that clinicians do not provide them with enough advice regarding ADRs​[76]​. The patient information leaflet (PIL) for Calpol (Johnson and Johnson) has more than 1,900 words and a Flesch Reading Ease of 58.2, making it “fairly difficult to read”​[143,144]​. Although certainly not suitable for children, some parents/guardians will also have difficulty reading PILs, which makes communication of potential ADRs to both the parents/guardians and the child vital. The Medicines for Children website can be a useful resource for parents/guardians wanting more accessible medicines information​[145]​. Other additional resources that can be helpful in finding information about known ADRs can be found in the Box.

Box: Additional resources for information about known adverse drug reactions

  • British National Formulary for Children​[5]​
  • MHRA Yellow Card scheme Interactive Drug Analysis Profiles​[61]​
  • Electronic medicines compendium​[146]​
  • The International Encylopedia of Adverse Drug Reactions and Interactions​[147]​

Medicines use reviews (MURs) are less frequently performed in children, with one study showing that 81% of pharmacists had not performed a MUR in patients aged under 18 years​[148]​. Given that the purpose of these reviews is to improve patients’ understanding of their medicines; highlight problematic side effects and propose solutions, where appropriate; improve adherence; and reduce medicines wastage, MURs would help identify and educate children taking multiple medicines on ADRs​[149]​.  

Assessing the nature and severity of the reaction and establishing the cause

Historically, none of the causality tools for assessing ADRs — such as the Naranjo probability scale — were designed for use in paediatrics​[150–152]​. The Adverse Drug Reactions in Children (ADRIC) programme highlighted the difficulties in applying these existing tools within paediatric populations and the need to develop paediatric-specific methodologies​[153]​. The ADRIC tools developed include the Liverpool Causality Assessment Tool (LCAT) and the Liverpool Avoidability Assessment Tool (LAAT), both based on existing tools but with more user-friendly flow diagrams​[153]​. The LCAT classifies ADRs as “unlikely”, “possible”, “probable” or “definite” and LAAT classifies them as “unassessable”, “not avoidable”, “possibly avoidable” and “definitely avoidable”​[152,154]​. Assessment of ADRs by healthcare professionals is often informal, which can lead to inconsistencies in practice. The LCAT and LAAT offer a systematic approach to assessment.

When assessing causality, healthcare professionals should be mindful that the ADR may be secondary to the excipient and not necessarily the drug. Excipient toxicity is well recognised in the neonate​[155]​. Arthur and Burgess illustrate several examples of problem’ excipients​[156]​.

Severity assessments describe the clinical impact of ADRs. The Hartwig scale is commonly used; severity levels range from Level 1 (the ADR required no change in treatment with the suspected drug) to Level 7 (the ADR was fatal)​[157]​

Taking corrective and follow-up action

Once an ADR is suspected, management will depend on the severity of the ADR and how important that medicine is to the child’s treatment. A patient prescribed systemic anti-cancer therapy to treat a life-limiting condition will be prepared for more severe ADRs, and on balance of risk/benefit will likely proceed with treatment. This would not be the same for a patient prescribed a medicine for sleep, for example. Similarly, a pharmacist may not be confident in advising that a patient’s systemic anti-cancer medicine is paused, unless the ADR was an immediate threat to life. Whether a drug should be discontinued depends on several factors: is it dose-related; the severity of reaction; the consequences of stopping the medicine; satisfactory disease control with the offending drug; and the ability to treat the ADR​[158]​.

If the ADR is dose-related, the drug may be stopped or paused to allow concentrations to decrease before commencing a more appropriate dose or immediately switched to the most appropriate dose. If the ADR is not felt to be dose-related, then there are three options in paediatrics: to stop the drug; continue with the drug and add in a second medicine to manage the effects of the ADR; or switch the drug to another in class. The second option, although possibly the easiest, will increase polypharmacy burden and risk additional ADRs​[159]​. Regardless of the corrective action chosen, communication between multi-disciplinary team members, including the patient or parents/guardians themselves, is vital.

For hospital-based pharmacists, the management of ADRs is often easier, as they have direct access to the prescriber. This is especially true in paediatrics, where most long-term medicines in children are initiated by specialist paediatricians. For community pharmacists, the management of ADRs can be more difficult and the need to contact the GP or paediatrician will have to be decided on a case-by-case basis. Development of links to hospital pharmacists, prescribers and medication safety officers can help facilitate communication about potential ADRs​[153]​.

Consideration should always be given to reporting the ADR to the MHRA via the Yellow Card scheme. Parents involved in the ADRIC study described confusion and uncertainty about the roles and responsibilities for recording and reporting of suspected ADRs​[76]​. Most parents and children were unaware that such a system existed. Those that did report an ADR via the Yellow Card Scheme did so because they wanted to help prevent other children experiencing the same ADRs and realised that their report would not directly help their own child​[76]​

The role of children themselves should not be forgotten. They may want to report the ADR given that they are the ones affected, and children as young as 10 years have been known to submit their own Yellow Card​[86]​. Barriers to ADR reporting by children and young people are not well understood and represent an area of unmet need which must be addressed before development of new strategies aimed at improving reporting by children and young people​[86]​.

Conclusion

ADRs are common occurrences in everyday clinical practice and should be at the forefront of the minds of pharmacists working with children and young people. 

Actionable points that pharmacists can take into their everyday clinical practice include:

  • Suspect ADRs — ask your patients/parents/guardians about both positive and negative responses to medication. Consider whether requests for over-the-counter medicines could be owing to ADRs to their current treatment;
  • Assess whether an ADR is likely to have occurred (use LCAT or LAAT);
  • Take corrective action;
  • Report the ADR(s) — use the Yellow Card scheme; 
  • Educate your patients about possible ADRs. Use the medicines for children PILs to identify ADRs that are specifically relevant to children.

Financial and conflicts of interest disclosure

The authors have no relevant affiliations or financial involvement with any organisation or entity with a financial interest in or financial conflict with the subject matter or materials discussed in this manuscript. No writing assistance was used in the production of this manuscript.

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This article has been peer reviewed by relevant subject experts prior to acceptance for publication. The reviewers declared no relevant affiliations or financial involvement with any organisation or entity with a financial involvement with any organisation or entity with a financial interest in or in financial conflict with the subject matter or materials discussed in this article.
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The Pharmaceutical Journal, May 2021;Online:DOI:10.1211/PJ.2021.1.75935