Professional Documents
Culture Documents
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.
Objectives
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.
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 It was withdrawn from the market in November 1961, following the announcement that it had harmed thousands of babies born to women who had taken it during pregnancy.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.
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.
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
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
166
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.
167
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.
age under three years concomitant use of other anti-epileptics developmental delay.
168
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.
Activity 13.2 List three predisposing factors to the development of an ADR in children. workbook page 28
169
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.
170
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.
171
Timing
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.
172
Expression
Very common Common Uncommon Rare Very rare
Incidence
more than 10% 1-10% 0.1-1% 0.01-0.1% less than 0.01%
173
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.
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.
174
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 http://www.yellowcard.gov.uk 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. http://www.yccscotland.scot.nhs.uk/
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 http://www.mhra.gov.uk. 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
175
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
176