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Adverse drug reactions

This chapter will provide an overview of the problem of ADRs and emphasise the pharmacists role in preventing drug-induced morbidity in babies and children. It will also review the function of the yellow card scheme.

After completion of the chapter you should be able to:

discuss the problem of ADRs in children list three medicines frequently implicated in such reactions assess the likelihood that an ADR has occurred be familiar with the Yellow Card Scheme, its main advantages and disadvantages and the criteria used for reporting.

Adverse drug reactions

1. Background
Primum non nocere. (First of all be sure you do no harm.) Hippocrates (460-370BC) The above principle is enshrined in the Hippocratic oath. Adverse drug reactions (ADRs) are one of the major causes of iatrogenic disease and are as old as medicine itself. Historically, there are a multitude of examples of patients having come to harm through the use of prescribed medicines. The thalidomide tragedy was one of the worst examples. In healthcare today the risk of ADRs inuences every decision to prescribe and, ultimately, take a medicine. Adults who accept drug treatment are generally aware of the possibility of adverse effects, even if they are uncertain of specic side effects and their likelihood. Children, however, are exposed to many of the same medications as adults, without having made the decision to be treated. Although parents give consent on their behalf, this has led to the concept of children as innocent bystanders. Children damaged by in utero exposure to thalidomide were innocent bystanders. This drug was rst marketed in 1956 and the promotional literature claimed it was outstandingly safe. It was withdrawn from the market in November 1961, following the announcement that it had harmed thousands of babies born to women who had taken it during pregnancy. In the short time it was on the market, at least 8000 children in 46 countries were born without arms, legs, ears, blind or partially sighted. Many others died at birth. The thalidomide tragedy led to the establishment of regulatory agencies concerned with drug safety in many countries. Thalidomide has recently become available again as a licensed product for use in multiple myeloma, with strict controls in place to avoid unintentional exposure in pregnancy.

Commission on Human Medicines

In the UK the Committee on Safety of Drugs was established in 1963, becoming the Committee on Safety of Medicines (CSM) in 1970 and subsequently the Commission on Human Medicines (CHM) in 2005. The Commission on Human Medicines was formed by the amalgamation of the CSM and the Medicines Commission. The CHM is supported by a number of expert advisory groups, including a Paediatric Medicines Expert Advisory Group. Since then the CHM has been responsible for:

advising the UK government on the safety, quality and efcacy of all substances to which the 1968 Medicines Act applies medicines safety monitoring (or pharmacovigilance). It is well recognised that the toxicity of medicines in children can be different from that in adults mainly because of differences in drug handling. To compound the problem, children are an atypical group with regard to rational drug therapy. This is due to the lack of adequate controlled clinical trials and the high frequency of off-label prescribing, as discussed in previous chapters.

What is an adverse drug reaction?

An ADR is an unwanted or harmful reaction following the administration of a medication or combination of medications, that is suspected to be related to the medication. The reaction may be a known side effect of the medicine or it may be a new previously unrecognised ADR. In general, these are the essential features of an ADR:

there is a suspicion that at least one medicine is responsible the effect is unintended it is harmful, or potentially harmful the reaction is seen at normal doses used clinically (to distinguish ADRs from toxicity which is used to describe the symptoms of overdose or poisoning). 165

Introduction to paediatric pharmaceutical care

1.1 Classication of adverse drug reactions

Adverse drug reactions (ADRs) are commonly classied into two main categories; type A and type B reactions. Both are explained below.

Type A reactions
Type A (augmented) reactions result from an exaggeration of a medicines normal pharmacological actions when given at the usual therapeutic dose. They are normally dose dependent. Examples include:

low blood pressure with antihypertensives haemorrhage with warfarin respiratory depression with opioids cushingoid reactions to corticosteroids hypoglycaemia with insulin. Type A reactions also include reactions that are not directly related to the desired pharmacological action of the drug (e.g. dry mouth associated with tricyclic antidepressants).

Type B reactions
Type B (bizarre) reactions represent a novel response not expected from the known pharmacological actions of the medicine. They are not normally dose dependent. Examples include:

anaphylaxis with penicillin skin rashes with antibiotics agranulocytosis with carbimazole. The table compares the characteristics usually associated with each type of reaction. Type A
Predictable Usually dose dependent High morbidity Low mortality Responds to dose reduction

Type B
Unpredictable Rarely dose dependent Low morbidity High mortality Responds to drug withdrawal

Activity 13.1 From your own experience, give an example of a type A reaction and a type B reaction. workbook page 28


Adverse drug reactions

2. Adverse drug reactions in children

Studies have shown that ADRs occur in about 10-20% of adult hospitalised inpatients and may be responsible for one in 1000 adult deaths on medical wards. A recent systematic review has shown that 7% of all hospital admissions are due to ADRs while they account for four out of 100 hospital bed days in the UK. The epidemiology in primary care is less well studied, but as many as 2% of GP consultations may be due to suspected ADRs. Although substantial research on the epidemiology of ADRs has been conducted in adult patients, little has been done in the paediatric population. In studies that have investigated the characteristics of ADRs specically in children, the reported incidence has varied considerably. This, in part, not only reects the limited amount of high quality research in children, but also the wide variations in study setting, patient group and denition of adverse reaction used.

2.1 Incidence in children

A meta-analysis of observational studies on the incidence of ADRs in children in different health care settings found that:

in hospitalised children the overall incidence of ADRs was 9.5% severe reactions accounted for 12.3% of the total the overall rate of paediatric hospital admissions due to ADRs was 2.1% and 39.3% of these were life-threatening reactions for children seen as outpatients, the overall incidence of ADRs was 1.5%. These rates are broadly similar to studies focusing on adults (although the rate of medicationinduced hospital admissions is somewhat lower than in adult studies). However, the high proportion of ADRs in the hospital setting that were severe in nature raises concern (these are higher than the corresponding gures in studies in adults). Some studies have suggested that the risk of ADRs associated with the use of unlicensed or off-label drugs may be greater than that for licensed medicines. This highlights the critical importance of reporting all suspected ADRs in children. As in adults, polypharmacy was found to be a consistent risk factor for ADRs. A more recent prospective study carried out over 8 months in a 10-bed childrens ward found that the incidence of ADRs caused by unlicensed or off-label drug use was not signicantly more than that caused by the licensed drug use. However, patients treated with unlicensed or off-label drugs were shown to be at signicantly increased risk of experiencing an ADR.

Fatal outcomes
There are few data on adverse drug reactions leading to a fatal outcome in children. A review was published in 2002 of all reports of suspected ADRs with a fatal outcome in children received by the CSM from 1964-2000. There were 331 deaths relating to 390 suspected medicines among children aged under 16. The main limitation of the study is that it is based on data from yellow card reports. The yellow card scheme depends on voluntary reporting and is, therefore, not a complete dataset of ADRs.


Introduction to paediatric pharmaceutical care

The data cannot be reliably used to assess causality (reports describe suspected reactions only) and there is no information on the numbers of patients exposed to the medicine in question. This review did not formally assess the potential causal relationship between medication exposure and the suspected ADR. Nevertheless, the study provides a useful insight into the drugs suspected of having caused deaths in children. The nature of the reported ADRs was diverse, with hepatic failure the most frequent. The classes of medicines most frequently associated with fatalities were:

anticonvulsants cytotoxic agents anaesthetic gases antibiotics. A recent 1 year study was carried out by the British Paediatric Surveillance Unit (BPSU) with the aim of quantifying the frequency of fatal ADRs in children under the age of 16 years in the UK and Ireland. The BPSU operates an active surveillance mechanism (the orange card scheme); approximately 2000 cards are sent out monthly to consultant paediatricians with a response rate of around 90%. The study involved the identication of all cases of suspected ADRs with a fatal outcome over a 1 year period. Cases were reviewed by an independent expert panel to assess causality using formal, published criteria. In total, seven reports meeting the study criteria were received. Five cases were thought to be unrelated to the index drug and in two the panel did not reach consensus. The results suggest that the true frequency of fatal ADRs in children appears to be low. This nding must be interpreted with caution, however, given the known issues with lack of recognition and reporting of adverse drug reactions.

Severity and preventability

Few studies have examined the severity and preventability of ADRs in children. A US study conducted in a 313-bed paediatric hospital over a 6-year period found a rate of ADRs of 0.85 per 100 admissions (based on 565 reported ADRs). Over 50% of the ADRs reported resulted in treatment intervention or temporary patient harm. Of the reported ADRs, 21% were categorised as preventable according to previously published criteria. The most frequently implicated drug classes were opioids, antiepileptics and antibiotics. The authors concluded that consideration should be given to strategies targeting patients prescribed these classes of medicine may be helpful in reducing the occurrence of ADRs.

2.2 Clinical presentation of ADRs in children

Adverse reactions in children typically occur at lower doses than in adults and symptoms may be atypical. Children are at particular risk from ADRs that affect growth and development. Examples of reactions of particular importance include: Hepatotoxicity associated with the use of sodium valproate. The major risk factors are:

age under three years concomitant use of other anti-epileptics developmental delay.


Adverse drug reactions

Increased risk of Reyes syndrome with the use of salicylates in children with viral infection. Reyes syndrome is a life-threatening illness associated with drowsiness, coma, hypoglycaemia, seizures and liver failure. The mechanism of this toxicity remains unknown but the use of aspirin as an analgesic is generally avoided in children under 16 (except in Kawasaki disease). From April 2009 the Commission on Human Medicines (CHM) has recommended that topical oral pain relief products containing salicylate salts should be contraindicated in children and young people under the age of 16 years. This affects the use of several teething gels and Pyralvex (an oral paint indicated for denture pain and the relief of pain associated with mouth ulcers). Tooth discolouration and enamel hypoplasia with tetracyclines in children aged up to eight and after exposure in utero. Lamotrigine and serious skin reactions. Serious skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis (rarely with fatalities) have developed, especially in children. Factors associated with increased risk are concomitant valproate use, initial lamotrigine dose higher than recommended and more rapid dose escalation than recommended. Growth suppression/effects on adrenal function with long-term corticosteroids. The risk of serious reactions with propofol infusion for sedation in intensive care, including metabolic acidosis, hyperlipidaemia and hepatomegaly. The CSM subsequently advised that propofol should be contra indicated for sedation in children aged 16 and under. Grey baby syndrome with chloramphenicol in neonates. Some ADRs occur less frequently in children. These include

cholestatic jaundice due to erythromycin gastrointestinal bleeds with NSAIDs hepatoxicity with ucloxacillin severe skin reactions with trimethoprim/sulfamethoxazole.

Over the counter cough and cold medicines

The CHM has recently advised that the balance of risks and benets associated with the use of cough and cold medicines for children younger than 2 years of age is no longer favourable. The advice was based on a safety assessment carried out following recent safety advice from the US Food and Drug Administration. Cough and cold medicines containing antihistamines (e.g. chorphenamine and diphenhydramine), antitussives (e.g. dextromethorphan and pholcodine), expectorants (e.g. guaifenesin and ipecacuanha) and decongestants (e.g. ephedrine, phenylephrine and xylometazoline) should no longer be used in children younger than 2 years of age. For children older than 2 years, cough and cold medicines are considered safe at the recommended doses.

Activity 13.2 List three predisposing factors to the development of an ADR in children. workbook page 28


Introduction to paediatric pharmaceutical care

2.3 Pharmacovigilance
Pharmacovigilance is the process of:

monitoring the use of medicines to identify previously unrecognised adverse effects or changes in the pattern of such effects assessing the risks and benets of medicines providing information to optimise safe and effective use of medicines monitoring the impact of any action taken. Most new medicines have been studied in a relatively small number of people (1,500 on average) in clinical trials before licensing. This precludes identifying adverse effects with an incidence of less than one in 100 or one in 1000. Children are often excluded from these trials and the lack of evidence to support licensing applications for paediatric drug use is a well-recognised problem. However, millions of patients, including children, may take these medicines. In addition, clinical trials are conducted under very strict conditions. This contrasts with use of medicines in every day practice, when they are used in a less controlled environment, for example, in patients taking other medications, and with varying metabolism, distribution and excretion. Although clinical trials will identify the more common and predictable side effects of medicines, rarer side effects will only be seen once the medicine is used in larger numbers of patients, under the conditions of every day use. This is why post-marketing surveillance of licensed medicines is so important. Vigilance for suspected medicine side effects in children is vital because:

the action of a medicine and its disposition in children (especially in the very young) may be different from that in adults medicines are less intensively tested in children many medicines are not specically licensed for use in children and are used off-label suitable formulations may not be available to allow precise dosing for children the nature and course of illnesses and ADRs may differ between adults and children.


Adverse drug reactions

3. Assessing adverse drug reactions

3.1 Sources of information
Some sources of information on adverse drug reactions provide more reliable evidence than others as outlined below. Randomised controlled trials should indicate the most common reactions and their incidence, but:

the small patient population involved means that rare reactions are unlikely to be discovered the patients involved in clinical trials are highly selective and not representative of the real patient population the procedures for ADR monitoring in clinical trials are variable and may not be sufciently robust. Case reports are simply reports of a single patient who was exposed to a medicine and experienced a particular adverse outcome. They are useful for raising hypotheses about the effects of medicines that can be tested with more rigorous study designs. They have been vital in alerting healthcare professionals to serious ADRs. In most cases, however, they are insufcient to establish a causal association for the following reasons:

they are prone to bias a single case report linking a reaction to a drug could be just coincidence or due to one of a large number of confounding inuences there is no comparison group not exposed to the drug to allow for a quantitative estimate of risk. Post-marketing epidemiological studies generally provide the best source of quantitative information on ADRs, given the limitations of clinical trials and case reports. They fall into two broad categories:

Cohort studies They identify subsets of a dened population and follow them over time, looking for differences in their outcome. Cohort studies are generally used to compare exposed patients to unexposed patients with subsequent events recorded and compared. For example, this technique has been used to investigate the potential link between the MMR vaccine and autism. The rate of autism in a vaccinated group was compared with the rate in an unvaccinated group and a gure for the relative risk of autism calculated. Case-control studies They compare patients with a disease to controls without a disease, looking for differences in previous medicine exposures. A signicant excess of exposures to the suspect drug in the case group suggests that there may be an association with the drug. Once the hypothesis had been raised that aspirin may be implicated with Reyes syndrome, the association was conrmed by several rigorous case-control studies.


Introduction to paediatric pharmaceutical care

3.2 Assessing causality

When an adverse reaction is suspected, it may be helpful to try and assess how likely it is that the symptom has occurred because of a medicine. Below are the main factors to take into account:

Nature of the reaction

Some clinical events are commonly caused by medicines including acute dystonias, blood dyscrasias, and skin reactions (for example Stevens-Johnson syndrome or toxic epidermal necrolysis). Such conditions should raise the possibility that they have been caused by a medicine.

The time from when the medicine was started until the reaction develops may be characteristic of the reaction. For example, anaphylaxis usually develops within a few minutes of parenteral drug administration. On the other hand, some reactions develop months or years later and may be related to a cumulative effect of the drug. They may even cause an effect on the next generation, for example, an increased risk of vaginal cancer in girls whose mothers had taken diethylstilbestrol.

Relationship with dose

Adverse reactions are often dose related and may be minimised by reducing the dose of the medicine being taken. If the symptoms resolve when the medicine is stopped, this suggests that the symptoms were associated with the medicine, although it could also be coincidental. In contrast, if a medicine is reintroduced and the symptoms recur, this strongly suggests that the medicine is responsible. However, following serious adverse reaction, deliberate re-challenge is seldom justiable.

Other possible causes

Pharmacists need to consider other possible causes for the symptoms being experienced. For instance, could the symptoms be manifestations of the patients underlying illness or another disease? Could any other medicines be responsible? Could the problem be due to a drug interaction?


Adverse drug reactions

4 The pharmacists role

4.1 Preventing and detecting adverse drug reactions
Ensuring that medicines are used safely is fundamental in pharmaceutical care. Pharmacists involvement in patient care should assist in prevention and early detection of ADRs. Studies have shown that pharmacist involvement has averted a large number of potential adverse reactions. Based on knowledge of relevant patient and medication factors, pharmacists can ensure that prescribing is as safe as reasonably possible. Be alert to the possibility of ADRs in all patients. Children or their parents may ask about symptoms experienced since taking a newly prescribed medicine and whether or not this is a side effect. Your observations in linking signs or symptoms to current or previous drug therapy are vital. Remember to consider the use of over the counter (OTC) medicines and herbal remedies. Pharmacists are also uniquely placed to identify ADRs occurring as a consequence of drug interactions. A new community pharmacy based system to identify paediatric ADRs is being piloted in Scotland. The study involves community pharmacists providing questionnaires to the parents or guardians of children taking medicines for epilepsy, depression or attention decit disorder. The aim is to develop a system to detect signals of ADRs in children at an early stage. The study is being carried out in collaboration with the MHRAs Yellow Card Centre Scotland.

4.2 Counselling on side effects

An increasing proportion of patients and their carers want to be involved in decisions about medication and the need to empower people accordingly is a component of Scotlands strategy for pharmaceutical care. Studies focusing on adults and patient surveys have shown that people believe they are not given enough information about the potential side effects of medicines. It seems reasonable to expect that providing such information could assist in preventing or minimising ADRs. There is very little published research on childrens needs for information about their medicines.

Expressing the incidence of potential side effects

The EU classication for expressing the incidence of potential side effects is used in the manufacturers summary of product characteristics and patient information leaets as listed in the following table:

Very common Common Uncommon Rare Very rare

more than 10% 1-10% 0.1-1% 0.01-0.1% less than 0.01%

Side effect e.g. with carbamazepine

drowsiness uid retention diarrhoea depression arrhythmias


Introduction to paediatric pharmaceutical care

Whenever possible, the risks and benets of medicines should be fully explained to patients but, in reality, communication is difcult. Often the patients perception of a risk (the likelihood that something unpleasant will happen) does not correspond to the numerical value that has been assigned to it. Patients usually nd it difcult to interpret statistical relationships and prefer to have risk expressed in relative terms (compared, for example, with the risk of being struck by lightning). Health professionals should be aware that patients tend to grossly over-estimate the EU descriptions of risk shown.

4.3 Reporting suspected ADRs in children

For reasons previously discussed, it is particularly important to focus on the safety of medicines in children. The CHM requests that all suspected adverse reactions in children should be reported, even if it is an established drug and regardless of whether the medicine is licensed for use in children. (If a baby is born with a congenital abnormality, or if a pregnancy results in a malformed aborted fetus, the CHM asks health professionals to consider if this should be reported). Further information on how to report is included in the MHRA guidance notes on suspected ADR reporting and the yellow card scheme at: Reportingsuspectedadversedrugreactions/Healthcareprofessionalreporting/Howtoreport/index.htm

The Yellow Card Scheme

The MHRA Yellow Card Scheme is regarded as one of the worlds best spontaneous reporting schemes for suspected ADRs, acting as an early warning system for the identication of previously unrecognised reactions. It has helped to identify many safety issues including:

renal failure due to aristolochia in Chinese herbs severe oesophageal reactions with alendronate serious cardiovascular reactions with cisapride. About 20,000 yellow card reports are submitted each year by doctors, dentists, pharmacists, nurses, coroners and the pharmaceutical industry. About half that number represent serious ADRs, but it is generally accepted that there is under-reporting to the MHRA by a factor of 10. It follows from this that about 100,000 people in the UK suffer a serious ADR every year. The CHM has an expert working group on paediatric medicines. Its remit is to improve the availability of medicines for children within the regulatory framework and to advise on safety issues relating to specic medicines used in children.

Criteria for submitting Yellow card reports

In adults, the Medicines and Healthcare products Regulatory Agency (MHRA) ask for reports to be submitted on all serious suspected reactions to established drugs and all suspected reactions to new medicines (indicated by the Black Triangle symbol in prescribing information). In children, however, the reporting of all suspected reactions is strongly encouraged, even if the black triangle symbol has been removed, because experience in children may still be limited. Further details on what to report can be found in the BNF , the BNF for Children or on the MHRA website: - Medicines/index.htm


Adverse drug reactions

Further information on how to report is included in the CSM/MHRA guidance notes on suspected ADR reporting and the yellow card scheme. Yellow cards can be submitted electronically at Both healthcare professionals and patients are able to report via the Yellow Card Scheme. In Scotland, a regional monitoring centre of the MHRA for Scotland , Yellow Card Centre Scotland, was established in 2002. The remit of this centre is to provide education and training on ADRs and pharmacovigilance; and to promote the Yellow Card Scheme to improve ADR reporting in Scotland.

Current problems in pharmacovigilance

The CSM/MHRA updates health professionals about topical drug safety issues through its bulletin Current Problems in Pharmacovigilance. This is sent to all doctors, dentists, pharmacists and coroners in the United Kingdom, alerting them to problems with medicines and providing advice on the ways medicines may be used more safely. Copies of current and previous editions of Current Problems in Pharmacovigilance can be found on the CSM website (details above).

Activity 13.3 The CHM/MHRA updates health professionals about topical drug safety issues through its bulletin Drug Safety Update. This is issued monthly and can be accessed via the MHRA website. It alerts health professionals to problems with medicines and provides advice on the ways medicines may be used more safely. Copies of current and previous editions can be found on the MHRA website Take a look at this website now and nd the article on: Over-the-counter cough and cold medicines in children Note the main issues discussed in this article. workbook page 28


Introduction to paediatric pharmaceutical care

Activity 13.4 Consider each of the following suspect case scenarios. Should a yellow card be completed? a: Eczematous skin rash in a nine year old child after three weeks treatment with etanercept. b: 15 year old girl became pregnant despite taking using emergency contraceptive (Levonelle). c: Baby born at 36 weeks gestation to mother who had taken venlafaxine throughout pregnancy. Baby had signs of agitation and poor feeding. d: Child prescribed lacosamide for seizures complains of mood swings and irritability. e: Interstitial nephritis develops in a child shortly after completing a course of amoxicillin. workbook page 28