promotion safe med childrens

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PROMOTING SAFETY

OF MEDICINES

FOR CHILDREN


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WHO LIBRARY CATALOGUING-IN-PUBLICATION DATA:

Promoting safety of medicines for children

1.Pharmaceutical preparations - administration and dosage.2.Child. 3.Infant. 4.Safety. 5.Drug monitoring. 6.Adverse drug reactionreporting systems. 7.Guidelines. I.World Health Organization.

ISBN 978-92-4-156343-7 (NLM classification: WS 366)

WORLD HEALTH ORGANIZATION 2007

All rights reserved. Publications of the World Health Organizationcan be obtained from WHO Press, World Health Organization,

20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264;fax: +41 22 791 4857; e-mail: [email protected]). Requests forpermission to reproduce or translate WHO publications whetherfor sale or for noncommercial distribution should be addressedto WHO Press, at the above address (fax: +41 22 791 4806; e-mail:[email protected]).

The designations employed and the presentation of the material inthis publication do not imply the expression of any opinionwhatsoever on the part of the World Health Organizationconcerning the legal status of any country, territory, city or area or

of its authorities, or concerning the delimitation of its frontiers orboundaries. Dotted lines on maps represent approximate borderlines for which there may not yet be full agreement.

The mention of specific companies or of certain manufacturersproducts does not imply that they are endorsed or recommendedby the World Health Organization in preference to others of asimilar nature that are not mentioned. Errors and omissionsexcepted, the names of proprietary products are distinguished byinitial capital letters.

All reasonable precautions have been taken by the World Health

Organization to verify the information contained in thispublication. However, the published material is being distributedwithout warranty of any kind, either expressed or implied. Theresponsibility for the interpretation and use of the material lies withthe reader. In no event shall the World Health Organization beliable for damages arising from its use.

Printed in France


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PROMOTING SAOF MEDICINEFOR CHILDRE


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Acknowledgements

This publication was developed following a recommendationAdvisory Committee for the Safety of Medicinal Products. Thhas been widely circulated and discussed at several consultatinternational experts in regulatory affairs and in paediatrics. Wparticularly grateful to Nilima A. Kshirsagar, India, Hansjrgen

Germany, and the Karolinska, Sweden for their initial input toSincere thanks are also due to the following persons for theirin evaluating this publication.

Niamh Arthur, Ireland, Jrgen Beckmann, Germany, Ulf BergmDavid Coulter, New Zealand, Gerald Dal Pan, USA, I. Ralph EdMurilo Freitas Dias, Brazil, Kenneth Hartigan-Go, Philippines,

Sten Olsson, Sweden, June Raine, UK, Anders Rane, SwedenForsberg, Sweden, Rachida Soulaymani-Bencheikh, Morocco.

Technical editing: Mary R. Couper, WHO and Susan KaplanArt direction: Guillaume Desbiolles, Calleo PortageAssistance in production of document: Caroline Scudamore,

WHO expresses its sincere appreciation to the Government oproviding financial support to finance the drafting of the man


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Promoting safety of medicines for childre

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 Current situation . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1 Problems with medicine treatment

in children and adolescents around th2.2 Consequences of present status of the

of medicines in children (environment2.3 General risk factors that predisposechildren to develop an adverse reactioto a medicine (medical aspects) . . . . . . . .

2.4 Differences between paediatric population2.5 The need for additional, independent

on the development of paediatric med

2.6 Current legal and regulatory framewo2.7 Consequences of the lack of studies

of medicines development in childrenand authorization of paediatric medic

3 The essential role of safety monitoringin the life-cycle of a medicine. . . . . . . . . . .

3.1 Pre-marketing assessment of medicine3.2 Post-marketing monitoring of medicin

safety for medicines already on the mincluding those used off-label . . . . . . .

3.3 Benefit-to-risk considerations in childr4 Medication errors . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Increased risk of medication errors in c

4.2 Incidence of medication errors . . . . . . . . .5 Primary responsibility of stakeholders .6 Guidance: measures to be taken . . . . . . .6.1 Improvement of awareness among sta6.2 Methods, approaches and infrastructu

f ff ti t f di i


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1. INTRODUCTION

Monitoring the safety of medicine use in children is of since, during the clinical development of medicines, onaspect are generated through clinical trials. Use of medspecifications described in the licence (e.g. in terms of contraindications or age) constitutes off-label and off-

a major area of concern.

These guidelines are intended to improve awareness oamong everyone who has an interest in the safety of mto provide guidance on effective systems for monitorinpaediatric populations. The document will be of intereprofessionals, medicine regulatory authorities, pharma

academia, the pharmaceutical industry and policy-mak

Systems for monitoring medicine safety are described in Anmethods and some examples of recent information onto marketed medicines are discussed in Annex 2.

Pharmacovigilance is the science and activities relatingassessment, understanding and prevention of adverse possible medicine-related problems (1). For the purposan adverse reaction to a medicine (ADR) includes not oduring normal use of medicines, but also reactions dueadministration, non-adherence, overdose, off-label useadverse effects due to the use of traditional and comp

It does not address the paediatric use of vaccines. Sepon safety monitoring of vaccine use in children will be


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2. CURRENT SITUATION

2.1 Problems with medicine treatment in adolescents around the world

The following problems occur with the use of medicinchildren and adolescents.

Often, medicines used are off-label and unlicenc Over-the-counter, traditional and herbal medicin

but their use is generally not evidence-based an Counterfeit and substandard medicines are wide Abuse by teenagers occurs with non-medical pr

medicines and illegal drugs. New and innovative medicines are available with a

with no evidence of long-term benefit and risk, e.gused as disease modifying antirheumatic medicine

Additionally, in resource-poor countries the following m

No treatment may be available, particularly during t

Medicines may be available through illegal stree Medicines are used in public health driven progtreatment of endemic infectious diseases such atuberculosis and for parasitic diseases.

In many low-income countries, much of the medicine official health care system. Consumers with limited bu

medicines from acquaintances, relatives and unregistelittle or no health-care training. In these countries, preoften be acquired without a prescription from marketsThe resulting self-medication, unsupervised by any heahaving a major effect on children. This situation is asso


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2.2 Consequences of the current status of the

medicines in children (environmental aspecThe consequences of the current status of the use of mchildren include the following:

Wrong dosage causes short-term toxicity or treatment example, a standard dose of phenobarbital of 15 mg/klikely be inappropriate for a newborn with seizures as

dose of more than 20 mg/kg is needed and a maintenmg/kg might already be more than enough.

Non-availability of appropriate paediatric formulations providers to resort to administering crushed tablets, disolvents or administering the powder contained insideConsequently, these formulations are administered with

regarding their bio-availability, efficacy and toxicity. Formulations of strengths suitable for administration toinfants and young children are not always available. Atherefore need to be diluted or administered in miniscperiod of time. This leads to administration errors (intrarunning fast, errors in dosage calculation and dilution)circumstances that require urgent action (as in emerge

premature units and paediatric and neonatal intensive Inappropriate packages and lack of awareness among

caregivers about the methods to be used for preventioaccidents and poisoning lead to accidental poisoning ismall children.

Adolescents may ingest medicines with suicidal intent health problems from illicit drug abuse.

Medicines can interact with traditional and herbal med Medicines may have long-term safety problems. For ex

may increase susceptibility to tuberculosis, or long-termcorticosteroids in early infancy may increase the risk ofretardation and/or osteoporosis


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2.3 General risk factors that predispose chan adverse reaction to a medicine (me

Risk factors that predispose children to develop an adv

medicine can be physiological, indirect or iatrogenic.

Physiological causes for increased risk:- young age, e.g. neonates and infants with the g

differences from adults;- continuous changes of medicine dispositional pa

maturation in all age classes.

Indirect causes for increased risk:- greater prevalence of polypharmacotherapy, e.g

intensive care unit;- greater length of hospital stay e g children with

Albendazole

Four children under 36 months died from chokingtablets during a deworming campaign in Ethiopia very small children to swallow large tablets may caasphyxiation. Recommendations for the administrare as follows: scored tablets should be broken incrushed for administration to young children; olde

encouraged to chew tablets of albendazole or mestrongly recommended that manufacturers of antpublic health programmes targeted at preschool cformulations that are appropriate for this age groshould be a safe single-dose formulation (e.g. granuse) to replace the tablets currently in use.


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2.4 Differences between paediatric population

The paediatric population represents a spectrum of different children should not be treated as miniature men and womeJacobi, 1830-1919). The spectrum extends from the very smanewborn infant to the adolescent. The internationally agreedextent arbitrary, classification of the paediatric population is a

- preterm newborn infants- term newborn infants (0 to 28 days)- infants and toddlers (> 28 days to 23 months)- children (2 to 11 years)- adolescents (12 to 16 to 18 years, depending on the re

(Ages are defined in complete days, months and years.

Substantial changes in body proportions and composition accand development. This dynamic process of maturation is one between the paediatric and the adult populations. The develoin physiology and, consequently, in pharmacology, influence tand dosing regimens of medicines used in children. It is, therereview the relevant changes that take place from birth throug

The proportions of body fat, protein and extracellular water cchange significantly during early childhood. For example, thedecreases from about 80% in the newborn to 60% by five mThe percentage of body fat doubles by four to five months. Tcontinues throughout the second year of life until protein maa compensatory reduction in fat as the consequence of increa

activity of the child. Moreover, liver and kidney size, relative talso changes during growth and development. Both these ormaximum relative weight in the one- and two-year-old child of life when the capacity for drug metabolism and eliminatioLikewise, body surface area relative to body mass is greater in

hild th i ld hild d d lt I d


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gastric emptying. Thus during the neonatal period, acibenzylpenicillin and ampicillin are well-absorbed, while

medicines like phenytoin, phenobarbital and rifampicinof gastric contents retrograde into the oesophagus is vfirst year of life (3). Excessive gastro-oesophageal refluregurgitation of medication, particularly when associatemptying, which results in variable and unpredictable administered medicines. The gastric acid levels reach a

of age. Sustained-release preparations are not readily ato rapid intestinal transit times. Likewise, medicines wiclearance and first-pass metabolism such as propranolabsorption in children. In contrast, intact protein and hmedicines such as immunoglobulins, which are hardly children and adults, are more easily taken up in the gupermeable to large molecules (4, 5). The administratio

meals needs to be appropriately tailored, although momedicines like rifampicin, are best given with food to i

Medicine distribution: Newborn infants have a much hvolume than any other paediatric population or adultshigher extra-cellular fluid volume than full-term infantsTotal body water is also much greater in neonates. Oncontent is lower in premature babies than in full-term medicines are distributed between extracellular water their lipid/ water partition coefficient, these changes ininfluence the distribution of a medicine in various comFor water-soluble medicines such as aminoglycoside anantibiotics, larger initial doses, on a mg/kg body weigh

given to achieve plasma concentrations similar to thosHighly lipid-soluble compounds such as inhalation analipophilic sedative/hypnotic agents (see phenobarbital) distribution volumes in infants. This is related to the inbody fat that occurs during the first year of life. In adddi ib i f di i b i d l


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are generally more important than reductive or hydrolytic reasynthetic, metabolism involves conjugation of the substrate t

compounds such as glucuronic acid, sulfate or glycine. This upolar, water-soluble compound that is readily excreted. Theredifferences in the eliminating capacities of neonates, infants general, the more premature the infant the poorer the hepatand renal excreting capacity. For medicines that are cleared bleads to a longer plasma half-life and thus a longer time to re

Similarly, for medicines that are entirely eliminated renally, theprematurity, the less able are the kidneys to excrete them andlonger their half-life. Hence, compared to older children and require lower maintenance doses to avoid toxicity. Examples fdosage regimen are methylxanthines, phenobarbital, indomeaminoglycoside and furosemide. Maturation of the various hefunctions occurs with some variation during the first year of

In young children, the hepatic and renal elimination capacity may even exceed that in adults, which often makes administmaintenance dose necessary. The differentiation between loamaintenance dose is no longer appropriate.

Besides these quantitative differences in the disposition of mealso various qualitative differences in the metabolic pathwayschildren. For example, N7-methylation of theophylline to propharmacologically active caffeine is well developed in newbowhereas oxidative demethylation and inactivation is highly insimilar example is that of paracetamol (acetaminophen). In inchildren, the major pathway of paracetamol metabolism is su

whereas glucuronidation is the primary pathway in adolescen

Pharmacodynamics during development: Although a great deabout pharmacokinetic changes during development, informdevelopmental changes in pharmacodynamics (medicine actioli i d Th f l h id id f h


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Experimental studies have observed developmental chanfor prostanoids, angiotensin II, catecholamines including

GABA-A receptor complex with significant functional chorgan systems such as the cardiovascular, renal and neu

In genetic studies of patients with inherited salt-losing evidence was found that channels and transporters invelectrolyte transport are in a dynamic process during e

maturation, whichin contrast to that of loop diureticdiuretic response to thiazide diuretics in preterm and ter

There are several well-documented examples of increatoxicity in young children as well. For example, acute dseizures in young children have been reported after exdopamine 2-antagonists metoclopramide and prochlor

(14); hyperpyrexic reactions to anticholinergic drugs suscopolamine in infants and young children have been and an increased risk of sudden cardiac arrest has beesupraventricular tachyarrhythmias treated with verapam

Finally, it should be noted that specific diseases occur maturing organism, which are not seen in adults. Exam

the postnatal adaptation period of the newborn, such with respiratory stress and persistent fetal circulation whypertension or hormonal imbalances of the adolescen


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2.5 The need for additional, independent stud

development of paediatric medicinesIgnorance or lack of knowledge of these differences in paedipharmacotherapy has led to various medicine-related tragediMost of them occurred in early life, during the neonatal periosulfonamides causing kernicterus (severe brain damage relatehyperbilirubinaemia) and chloramphenicol causing grey baby

(cardiovascular collapse) in the newborn. Another well-knowof in utero exposure to thalidomide leading to the birth of codeformed infants (phocomelia).

As a consequence of these tragedies, the medicines agenciesmedicine manufactures for much more extensive and thoroumedicine investigations. Efficacy and safety of the medicine w

investigated in the population for which it is aimed and markmedicine development strategies for children are therefore nthere are a variety of obstacles to be overcome in this speciadevelopment:

- ethical hurdles, including the difficulties of obtaining in- need for non-invasiveness;- need for microassays, as volumes of samples (e.g. bloo

available are mostly smaller;- stratification of patient population into at least five cate

neonates, full-term neonates, infants and toddlers, oldadolescents;

- difficulty in predicting long-term effects during the mat

- rare diseases (making patient recruitment difficult and providing lower return on investment);

- necessity for training of paediatricians to assess protoco- high regulatory requirements.


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2.6 Current legal and regulatory framewo

European Union

Legislation came into force in January 2007, which is awith respect to medicinal products for paediatric use (1902/2006 of the European Parliament and of the CoRegulation (EC) 1901/2006 on medicinal products for legislation aims to enhance the safety of medicines for

research, development and authorization of medicinespaediatric experience, without subjecting the paediatrunnecessary clinical trials. In addition, this legislation cthe pharmaceutical industry regarding the developmenpaediatric use, as well as providing incentives to the insuch developments. A framework to manage the operincluding the development of a paediatric committee i

The EU has issued guidance relating to the above legisaddresses the conduct of pharmacovigilance for medicpaediatric population and is aimed at both the pharmanational competent authorities (19). A further draft guGuideline on the format and content of applications fo

modification of a paediatric investigation plan and reqdeferrals and concerning the operation of the compliacriteria for assessing significant studies) has been issueCommission for a period of consultation.

North America

In 2002, the Best Pharmaceuticals for Children Act (BPproviding an incentive of six months of marketing exclstudied in response to a written request for paediatric States Food and Drug Administration (US FDA). The BPsafety review for adverse events reported for the year areceived its paediatric exclusivity The adverse event rep


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use of antidepressants; cardiovascular and psychiatric events attention-deficit hyperactivity disorder (ADHD) medicines; and

neuropsychiatric adverse events (delirium, self-harm, confusiooseltamivir (Tamiflu). These reviews are in addition to the roupharmacovigilance activities for all products in all populationsto focus on safety issues that may present in paediatric patien

In Canada, paediatric associations take the initiative to report

from the use of off-label products, in order to make data on children available. These data are also shared with the nation

Other areas

There appears to be an absence of formal frameworks in othhighlighting the need for developments.


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2.7 Consequences of the lack of studies of mein children and authorization of paediat

Medicines of major clinical importance, even essential mtested and not officially approved for use, especially in Harry Shirkey in 1963 to state that children constitute t

Among the 340 medicines in the WHO Model List of Essthose that have relevance for paediatric populations shou

documenting paediatric experiences, wherever these med

However, children have therapeutic needs which probamedicines representing major therapeutic advances in and labelled for paediatric use. Once a medicine becommarket for adults, it is possible to use it in children in ause of unlicenced and off-label medicines for children

practice for decades; this does not offer children the saefficacy of medicines as adults. This situation is not coConvention on the Rights of the Child (22).

From the practical point of view this means that for th

No information is available on effective and safe

range, frequency of administration and duration An ethical dilemma exists as to the choice betwe

medications when little or no information is avaand efficacy or depriving the child of a possibly because it happens to be off-label.

It may be necessary to deal with parents and gureading the prescribing information, are appreh

not tested in children, or not cleared for use in ctreat their child.

It is necessary to take greater responsibility for uoff-label or unlicenced in case something goes wupon professional bodies, guidelines issued and


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3. THE ESSENTIAL ROLE OF SAFETY M

IN THE LIFE-CYCLE OF A MEDICINEThe benefit-risk assessment of any kind of medicine treassessment of the treatment is, however, possible withknowledge. The trial and error principle is not accepvulnerable population.

3.1 Pre-marketing assessment of medicineThe two major stakeholders responsible for medicine sauthorization are:

- marketing authorization holder (MAH/medicine - competent authorities/medicine regulatory agen

Preclinical investigations on reproductive toxicology, mcarcinogenicity are mandatory. Special consideration mlong-term follow-up on skeletal, neural, behavioural, smaturation and development in toxicology studies in jupredictive value of such studies in relation to effects inpopulation is however uncertain.

Clinical investigations include pharmacodynamic, pharstudies. Safety studies in the target population are reqbe performed using different methodological approachdependent on the type of safety parameters, and the economic circumstances.

A new conceptual model has been developed, which cpharmacovigilance processes to be involved earlier in tmedicine (24). The European Medicines Agency (EMEAthe policies for risk management strategies (proposed measures and if necessary risk minimization) to be app


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3.2 Post-marketing monitoring of medicine safetyalready on the market including those used

Paediatric pharmacovigilance assessment may be rather limiteauthorization due to difficulties and deficiencies in pre-authotrials of medicines for paediatric use. Sample sizes in phase I usually small and, even in phase III trials, sample size is nearlyend-points for efficacy. Thus the sample size limits the ability

than-common reactions. Serious adverse events are often rargenerally not observed in a paediatric clinical trial programmethere is a lag period before onset or a trigger such as changedevelopment. ADRs in children cannot be predicted on the bobserved in adults. Given these limitations every opportunity to increase the information available from ADR monitoring aand communicate this information to the medical community

Additional reasons for monitoring post-marketing medicine sinclude the following:

The use of unlicenced and off-label medicines is highlychildren (see above).

Children may not voice complaints and ADRs may rem

Long-term follow-up is essential in a population with aexpectancy and medicines may have a specific impact and maturation of the skeletal, neural, behavioural, sesystems.

Accidental ingestion in small children and suicidal ingeadolescents are not uncommon.

Routinely available safety data may not adequately caparising in the paediatric population and only in excepticircumstances can safety data in the paediatric populatextrapolated from data obtained in adults. This is becamay only be seen in the paediatric population, irrespec


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Benzyl alcohol

Benzyl alcohol is commonly used as the preservatiinjectable pharmaceutical preparations. For this puconcentrations in the range of 0.5-2% are used abenzyl alcohol injected is generally very well toleraof 0.9% are used in bacteriostatic sodium chloridebacteriostatic water for intravenous use (USP). It m

of water for hydration of medications (28). Benzylused as a preservative in allergenic extracts for scrintracutaneous testing, and can lead to false-posit

The content of benzyl alcohol in many injectable ppreparations should be considered carefully. Unfocountries still take the view that the identity of th

excipients in medicines is a trade secret, and this adeplored. The duty to declare the additives and exrealized in some countries.

Deaths in neonates have been associated with ad234 mg/kg/day benzyl alcohol in large-volume paendotracheal solutions. The toxic effects of benzyinclude respiratory vasodilatation, hypertension, coparalysis, have been known for years. However, litthe toxic effects or levels of benzyl alcohol and thcaused by accumulation of the metabolite, benzoespecially in sick premature infants. Its effect is maexcessive body burden relative to body weight, so

this metabolite may exceed the detoxification capimmature liver and kidneys.

The FDA has recommended that neither intramuscsolutions containing benzyl alcohol nor dilutions w


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4. MEDICATION ERRORS

Medical errors have received a great deal of attention phrase medical error is an umbrella term covering athe health-care system. Medication errors are probablycommon types of medical error, as medication is the mintervention. In the USA, it is estimated that medicatiopatients (both adults and children) per year (30). In UK

and consequences of medication errors appear similar USAwith prescribing errors occurring in 1.5% of prethe majority of all errors (61%) originated in medicatioserious errors (58%) originated in the prescribing decis

Several published reports confirm that medication erropaediatrics; one significant study has shown that pote

medication errors may be three times more common inpopulation than in adults (32). This in turn indicates thcharacteristics of medication errors may differ between

4.1 Increased risk of medication errors in

Paediatrics pose a unique set of risks of medication errors because of the need to make dosage calculations, which athe patients weight, age or body surface area, and their cthe likelihood of errors, particularly dosing errors (34). For a small fraction of the adult dose is required for children, icause dosing errors of 10-fold or greater because of misca

of the decimal point. For example, Selbst et al. (35) reportold baby who had received 10 times the correct dose of ina result of miscalculation of the drug dosage. Furthermorepatients weights and the difficulties health-care professionarithmetical calculations could also contribute to incorrect


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Furthermore, the lack of standardization has caused confusioresulting in serious medication errors. An example is the case

received his regular supplies of diazoxide suspension made asextemporaneously prepared suspension at 10 mg/ml, from a pharmacy. He was given a 50 mg/ml solution on his visit to ahospital. His parents did not read the label and gave the samsuspension resulting in a five times overdose. Consequently, thospitalization (37).

4.2 Incidence of medication errors

The following tables contain information on the epidemiologerrors in children and the stage in medication use at which th

Table 1: Epidemiology of medication errors in children

Author Study design PatientsADE per1000 pt-

day

ADE per100

admits

Near-miss

1000 pt-

daya

Nearmiss 10

admit

Kaushal,2001

Prospectivechart review

Ward,NICUPICU

6.6 2.3 29 10

Holdsworth,

2003

Prospective

chart review

Ward,

NICU

7.5 6 9.3 8

Proctor, 2003Prospectivechart reviewPaediatric

surgicalservice


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Author SettingMD ordering

(%)Transcribing

(%) d

Kaushal, 2001NICU, PICUwards

79 11

Ross, 2000

NICU, PICU

wards 20

Raju, 1989 PICU 3

Vincer, 1989 NICU 16 8

Table 2: Stage in medication use at which error o

NICU, neonatal intensive care unit; PICU, paediatric int

Source (38).


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5. PRIMARY RESPONSIBILITY OF STAK

When a medicine is marketed, the health professionalsother health-care workers and in part the parents/careresponsibility for the assessment of medicine safety. Thlabel use, which ranges between 50 and 90% in the pmost countries, as demonstrated by hospital-based surregulatory agencies and the medicine manufacturers m

responsibility whenever they receive feedback from theThese professionalsif they are trained adequatelyaable to observe reactions and events associated with amarket, when it is introduced into a quite heterogeneodifferent ages, sex, co-morbidity and polypharmacotheenvironmental, nutritional and social conditions are imthe ADRs experienced.

It has been recognized that the current system of medwestern countries does have some serious drawbacks regulatory agency has been responsible for the authorbeginning of the medicine life-cycle, there is a need foto reduce the influence of conflict of interest in the evmarketing events. It is important that drug manufactu

adverse reactions to their products once they are well-market. A Guideline on conduct of pharmacovigilancemedicines used by the paediatric population has been

Spontaneously reported ADRs remain one of the mostdetecting safety signals or other issues in the post-auth

However, spontaneous reporting is expected to be of osafety monitoring of paediatric medicines, unless the namong health professionals including paediatricians cabeen estimated that less than 10% of all serious, and ADRs are reported (40).


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Reasons for underreporting in general medicine are as follow

- lack of information and awareness among most stakehpresent health system (most likely a consequence of nopharmacovigilance as an important issue in the undergpharmacy and nursing) curriculum;

- lack of training programmes for health-care profession- absence of formal pharmacovigilance systems in many

present, limited efforts made to inform health-care proregarding the systems in place in a given country or reg

- problems with diagnosis of ADRs;- problems with the clinical workload for most health-ca

especially in developing countries (i.e. no time to make- problems with the reporting procedure (too bureaucrat- problems related to potential conflicts (legal liability) an

consequences including unfavourable media coverage;- absence of a feedback system.

In addition, there are even more obstacles related to the repopaediatric patients (44, 45):

Children, particularly small children, may be unable to

sensations and complaints. A high proportion medicines used are off-label and unlic Many poorly evaluated phytotherapeutic, ayurvedic, an

traditional and homeopathic medications are popular bperceived as soft and less toxic medicines by many pand even health professionals.

There is irrational use of medicines, e.g. antibiotics. Clinical trials are lacking and experience and skills in re

AEs are insufficient. A paediatric essential medicine list (pEML) has yet to b Appropriate medicine formulations and administration

hild l ki


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Systematic and targeted local monitoring (if possible cmedical records may soon become another important safety signals (47). The advantages of this approach ar

One has the ability to focus on specific areas of life assessment of medicine safety, e.g. in a neo

The chances of detecting unrecognized medicatdose-related ADRs are much better; this is impofrequent and theoretically more preventable tha

The direct feedback at the local level is much meducational for all responsible health professioneffect on quality of medicine use and patient ca

From various pharmacoepidemiological studies in paedthat the risk of ADRs increases with the length of the the number of medicines she or he is receiving; the exthe dynamics of physiological changes during early liferetrospective and prospective monitoring from computrequiring a more or less passive role of the health prof

efficient compared with other intensive surveillance sysimprove spontaneous reporting of pharmacological, undose-related reactions and the much more common, adose-related reactions to a medicine.

Diethylene glycol

Diethylene glycol is a highly toxic organic solvent thatrenal failure and death when ingested. There have bereports of fatalities caused by accidental contaminatiowith this substance, most commonly in cough syrupschildren (46).


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6. GUIDANCE: MEASURES TO BE TAKE

Some developed countries have well-established systems fand analysing medicine safety data. Such systems are alsofew developing countries. However, the health administracountries cannot depend solely upon data generated in wpredicting ADRs and assessing medicine safety in their own

Children in developing countries belong to a difhence their genetic composition is unlike that ocountries. This could mean differences in medicvariability in the frequency and severity of ADRs

Children in developing countries have different from a dissimilar spectrum of disease. Malnutritworm infestations and infectious diseases are re

morbidity and mortality. Country-specific medicine handling circumstanc

from prescribing all the way to the patient receibe considered.

A large proportion of the population, particularcountries, concomitantly uses traditional medicinremedies to treat illnesses. These medicines are

treatment of upper respiratory tract infections, aasthma, conditions with a high prevalence in chthese medicines could have hitherto unnoticed

In the past, newer medicines were introduced intoyears after their launch in developed countries. Thgenerated in developed countries was, therefore,

medical professionals and consumers in developinmedicines were introduced to their local markets. globalization, newer medicines are sometimes lausimultaneously in developed and developing counpreliminary post-marketing data from developed c


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6.1 Improvement of awareness among stak

Improvement of awareness of the medicine safety issue and oof post-marketing surveillance in children, among health profwhole public health system appears to be an essential first st

Identification of the responsible stakeholders: They needmotivation and support. However, in addition, the spectrum stakeholders needs to be enlarged.

The stakeholders in post-marketing surveillance are:

- physicians, who are directly involved in treatment with medicines, e.g. general practitioners, paediatricians, chanaesthesiologists, dentists and medical students;

- pharmacists, particularly those working at a children's hresponsible for the medicine dispensary;- nurses, e.g. those working on a neonatology ward, stu

in the paediatric networks and particularly nurses speciassurance and risk management;

- other health workers, particularly programme managerprogrammes;

- regional and national pharmacovigilance centres in a cothe key institution in organizing and conducting local sthe clinical quality work in the rational and safe use of

- clinical pharmacology departments, even if there is nopharmacovigilance unit;

- patients, parents and caretakers: they can be very helpfwith special forms together with the patient informatio

encourage detailed recording as a supplement to the p- government agencies who formulate the laws, regulati

precautions and rules of reporting;- poison and medicine information centres, which can p

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identify and validate adequate biomarkers particpharmacodynamic and pharmacogenomic studie

- editors of scientific journals;- health administrators and health department off- programme directors of public media;- politicians;- civil society and nongovernmental organizations

6.2 Methods, approaches and infrastructusystem for medicine safety monitoring at

Post-marketing medicine surveillance is particularly impmedicines as they have often not been vigorously testephase of medicine development (see above).

The spectrum of conventional methodological approacmonitoring is presented in annex 1. They are also descGuideline E2E pharmacovigilance planning (25). Howeassessment of effectiveness and benefit of medicine trdiseases, less conventional approaches might be requievaluate potential medicine toxicity and to identify AD

patients available to analyse. The pharmacovigilance sicomplex when one considers the frequent use of off-lachildren, which is often associated with less standardizmedicine formulations and a less harmonized dosage rcircumstances add to the sum of avoidable bio-noise, detection of relevant signals.

Three approaches to paediatric safety monitoring mighin this context:

A detailed knowledge of the pathophysiology opharmacological profile and the toxic potential o


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Infrastructure

A suitable infrastructure would include the following: A full-time commissioner for medicine safety affairs sh

or employed in children's hospitals and departments omedical schools, as suggested by the Canadian Paediaspecial programme for reporting on use and safety of children.

Regional pharmacovigilance centres should be set up w

functions:- making access and contact easier for health profes- definition of priorities for spontaneous reporting;- providing information and support activities for re- feedback on pharmacovigilance activities;- and, last but not least, development of a local mo

that uses medical charts for the detection of serio

medication errors (see above). A national pharmacovigilance programme (NPP) with a

structure should be developed, paying attention to thecharacteristics of culture, climate, resources, equipmencomorbidity and genetics.

A single address for reporting ADRs and AEs is essentiaprocedure must be kept as simple and clear as possible

6.3 Implementation of methods and structuraleffective monitoring of medicine safety at the

Legal measures

Desirable legal measures include:

prevention of liability being a concern for practitionersADRs, for example through the anonymity of professio

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Regulatory measures

The regulatory measures to be taken are as follows:

reinforcement of conduct of more clinical trials through incentives and requests (see USA and Euro

acceptance of reports about ADRs not only fromfrom other stakeholders in the health systems, spharmacists;

pharmacovigilance measures for a product in thas suggested by the EMEA to include:- complete safety specification derived from t

medicine development phase;- an active postmarketing surveillance progra- periodic safety update reports (PSURs);- risk management plan;

- standardized safety evaluations in clinical trassessment of rare AEs and ADRs;

- data management should allow reproduciblanalysis by indication and by exact age in thsubpopulations and, if possible, data presensales statistics;

- up-to-date information about paediatric effbe included and explained in the summary ocharacteristics (SPC) and in the patients/par

6.4 Impact measurement and audit

All safety monitoring activities, and benefit versus risk subject to follow-up, audit and review for their impacthealth. It is essential to check that knowledge gained paediatrics is successfully communicated to and used bprofessionals. This is more important even than in adu


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7. MEASURES TO BE TAKEN BY WHO

Awareness

Methods to promote awareness include:

- workshops and training for health workers throuprogrammes;

- publication of guidelines and lists, e.g. a paediat

(pEML);- information about the need for pharmacovigilan

governments and appropriate governmental age- a paediatric list of laboratory values giving rise to

signal of a possible ADR.

Methods of monitoring

WHO should develop simple, standardized and internaprotocols for collecting data on ADRs from institutionsregional pharmacovigilance centres.

Infrastructure

The infrastructure should include the following:

electronic networks; IT-based reporting and communication systems for p development of simple protocols for regional monito

from medical records; central coordination, e.g. the WHO Collaborating Ce

Drug Monitoring (UMC) in Uppsala; harmonization of the national pharmacovigilance pro

regular conferences; joint venture with the Global Consortium of Paediatr formation of regional collaborations and partnership


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Charts with points of interest for local surveillance

Establishment of a national network between these centres a

with a relevant governmental agency would be desirable.

1. Establishment of national pharmacovigilance centrelarger health-care units

Admission/emergency room/outpatient clinics/intcare unit/general wards

Electronic medical records

Reviewing team including the commissioner for medi

affairs in the hospital for all reported serious A

Reassurance by nurses/doctors specialized in quand risk management

Report to the regional pharmacovigilance cen

Discussion at a local conference including the local p

Report to the national pharmacovigilance centand feedback to the house staff

2. Establishment of pharmacovigilance centres at minocentres/hospitals


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References

1. The importance of pharmacovigilance; safety monitoring of med

World Health Organization, 2002.2. ICH E 11 Clinical investigation of medicinal products in the paed

the UK in: EU: Note for guidance on clinical investigation of mepaediatric population (CPMP/ICH/2711/99). London, 2000; and Conference on Harmonisation. Guidance on E 11 clinical investipediatric population; Notice. Federal Register, 2000, 65:78493-

3. Sondheimer J. Gastroesophageal reflux: update on pathogenesiClinics of North America, 1988, 35:103-116.

4. Weaver LT, Austin S, Cole TJ. Small intestinal length: a factor es1991, 32:1321-1323.5. Heimann G. Enteral absorption and bioavailability in children in

Journal of Clinical Pharmacology, 1980, 18:43-50.6. Brazier JL, Salle B. Conversion of theophylline to caffeine by the

Perinatology, 1981, 5:315-320.7. Miller RP, Roberts RJ, Fischer LJ. Acetaminophen elimination kin

adults. Clinical Pharmacology and Therapeutics, 1976, 19:284-8. Freye E. Development of sensory information processingthe o

sites in nociceptive afferents and their significance in the clinicaAnaesthesiologica Scandinavica (Suppl.), 1996, 109:98-101.

9. Olkkola KT, Maunuksela EL, Korpela R, Rosenberg PH. Kinetics aintravenous morphine in children. Clinical Pharmacology and Th

10. Marshall JD, Kearns GL. Developmental pharmacodynamics of cPharmacology and Therapeutics, 1999, 66:66-75.

11. Bouayad A, et al. Characterization of PGE2 receptors in fetal anin the pig. Seminars in Perinatology, 2001, 25:70-75.

12. Kaufman RE. Drug action and therapy in the infant and child. InNeonatal and pediatric pharmacology: therapeutic principles in pMD, Lippincott Williams & Wilkins, 2005:20-31. Review.

13. Reinalter SC, Jeck N, Peters M, Seyberth HW. Pharmacotyping otubular disorders.Acta Physiologica Scandinavica, 2004, 181:51

14. Wong DF, et al. Effects of age on dopamine and serotonin receptomography in the living human brain. Science, 1984, 226:1393

15. Garson A Jr. Medicolegal problems in the management of cardia

Pediatrics, 1987, 79:84-88.16. International ethical guidelines for biomedical research involving

International Organizations of Medical Sciences (CIOMS), 2002.17. Regulation (EC) No. 1901/2006 of the European Parliament and

December 2006 on medicinal products for paediatric use and a1768/92 Directive 2001/20/EC Directive 2001/83/EC and Regu


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23. Kaushal R, et al. Medication errors and adverse drug events in pediatric the American Medical Association, 2001, 285:2114-2120.

24. Waller PC, Evans SJ. A model for the future conduct of pharmacovigilan

Pharmacoepidemiology and Drug Safety, 2003, 12:17-29.25. ICH Guideline E2E pharmacovigilance planning. International Conference o26. Gershanik J, et al. The gasping syndrome and benzyl alcohol poisoning.

of Medicine, 1982, 307:1384-1388.27. Nissen E. ADHD drugs and cardiovascular risk. New England Journal of M

354:1445-1448.28. Reynolds P, Wilton N. Inadvertent benzyl alcohol administration in neona

contribute? Anesthesia and Analgesia, 1989, 69:855-856.

29. Fisher A.A. Allergic paraben and benzyl alcohol hypersensitivity relationsand "immediate" varieties. Contact Dermatitis, 1975, 1:281-284.

30. Kohn LT, Corrigan JM, Donaldson MS. To err is human: building a safer Washington, DC, Institute of Medicine National Academy Press, 1999.

31. Dean B, et al. Prescribing errors in hospital inpatientstheir incidence aQuality and Safety in Health Care, 2002, 11:340-344.

32. Kaushal R, et al. Medication errors and adverse drug events in pediatric the American Medical Association, 2001, 285:2114-2120.

33. Ghaleb MA, Wong ICK. Medication errors in paediatric patients.ArchiveChildhood - Education and Practice, 2006;91:ep20;doi:1136/adc.2005.034. Wong ICK, et al. Incidence and nature of dosing errors in paediatric med

review. Drug Safety, 2004, 27:661-670.35. Selbst SM, et al. Medication errors in a pediatric emergency department

Care, 1999, 15:1-4.36. Conroy S, et al. Survey of unlicensed and off label drug use in paediatric

countries. British Medical Journal, 2000, 320:79-82.37. Yeung YW, Tuleu CL, Wong ICK. National study of extemporaneous pre

paediatric hospital pharmacies. Paediatric and Perinatal Drug Therapy, 238. Walsh K E, Kaushal R, Chessare J B. How to avoid paediatric medication

to the literature.Archives of Disease in Childhood, 2005, 90:698-702.39. Ray WA, Stein CM. Reform of drug regulationbeyond an independent

New England Journal of Medicine, 2006, 354:194-201.40. Pirmohamed M, Breckenridge AM, Kitteringham NR, Park BK. Adverse d

Medical Journal, 1998, 316:1295-1298.41. Vallano A, et al. Obstacles and solutions for spontaneous reporting of a

in the hospital. British Journal of Clinical Pharmacology, 2005, 60:653-642. Eland IA, Belton KJ, van Grootheest AC, Meiners AP, Rawlins MD, Strick

survey of voluntary reporting of adverse drug reactions. British Journal oPharmacology, 1999, 48:623-627.

43. Ball D, Tisocki T. Adverse drug reaction reporting by general medical prapharmacists in Harare a pilot study Central African Journal of Medicine


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ANNEX 1 - PHARMACOVIGILANCE ME

Passive surveillance

Spontaneous reports

A spontaneous report is an unsolicited communicationprofessionals or consumers to a company, regulatory aorganization (e.g., WHO, a regional centre or a poisondescribes one or more adverse drug reactions (ADRs) i

given one or more medicinal products and that does nor any organized data collection scheme (1).

Spontaneous reports play a major role in the identificaonce a medicine is marketed. In many instances, sponta company to rare adverse events that were not detectrials or other pre-marketing studies. Spontaneous repimportant information on at-risk groups, risk factors aknown serious ADRs. Caution should, however, be exespontaneous reports, especially when comparing mediaccompanying spontaneous reports are often incomplwhich cases are reported is dependent on many factorsince the launch of the medicine, pharmacovigilance-r

media attention and the indication(s) for use of the me

Systematic methods for the evaluation of sponta

More recently, systematic methods for the detection of spontaneous reports have begun to be used. Many of tin development and their usefulness for identifying safe

evaluated. These methods include the calculation of theratio, as well as the use of Bayesian and other technique8). Data mining techniques have also been used to examinteractions (9), but these techniques should always be and not in place of, analyses of single case-reports. Dat


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Case series

Series of case-reports can provide evidence of an association

medicine and an adverse event, but they are generally more generating hypotheses than for verifying an association betwexposure and outcome. There are certain distinct adverse eveassociated more frequently with medicine therapy, such as ananaemia, toxic epidermal necrolysis and Stevens-Johnson SynTherefore, when events such as these are spontaneously reposhould place more emphasis on these reports for detailed an

Stimulated reporting

Several methods have been used to encourage and facilitate health professionals in specific situations (e.g., in hospital setproducts or for limited time periods (12). Such methods inclureporting of adverse events and systematic stimulation of rep

events based on a pre-designed method. Although these meshown to improve reporting, they are not immune to the limsurveillance, especially selective reporting and incomplete info

During the early post-marketing phase, companies might acthealth professionals with safety information and, at the same

cautious use of new products and the submission of spontanwhen an adverse event is identified. A plan can be developedproduct is launched (e.g., through site visits by company reprdirect mailings or faxes). Stimulated adverse event reporting postmarketing phase can lead companies to notify health carnew therapies and provide safety information early on in thegeneral population (e.g., Early Post-marketing Phase Vigilanc

This should be regarded as a form of spontaneous event repodata obtained from stimulated reporting cannot be used to gincidence rates, but reporting rates can be estimated.

Active surveillance


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Sentinel sites

Active surveillance can be achieved by reviewing medical r

patients and/or physicians in a sample of sentinel sites to eaccurate data on reported adverse events are collected froselected sites can provide information, such as data from sthat would not be available in a passive spontaneous repoinformation on the use of a medicine, such as abuse, can sentinel sites (14). The major weaknesses of sentinel sites selection bias, small numbers of patients and increased cowith sentinel sites is most efficient for those medicines usesettings such as hospitals, nursing homes and haemodialysettings may use certain medicinal products more frequeninfrastructure for dedicated reporting. In addition, automalaboratory values from computerized laboratory reports in can provide an efficient active surveillance system. Intensiv

sites can also be helpful in identifying risks among patientmedicines.

Medicine event monitoring

Medicine event monitoring is a method of active pharmStudies using this method are cohort-based and prospeFor medicine event monitoring, patients can be identifi

prescription data including electronic or automated heaprescription data might represent the total population ta region, depending on the source. A single prescriptiocollected over the period of monitoring. A follow-up qusent to each prescribing physician or patient at pre-speoutcome information. Requests for information on pat

indication for treatment, duration of therapy (includingclinical events, reasons for discontinuation and relevantincluded in the questionnaires (12, 15-19). The limitatiomonitoring can include poor physician and patient respthe New Zealand Intensive Medicines Monitoring Progr


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The data can be stratified to look for subpopulations at increwithin the cohort can be further investigated using nested ca

Further value might be gained by undertaking collaborative sinternationally.

Patient confidentiality is as secure as with spontaneous repor

The other forms of active surveillance, described below, are omedicine event monitoring e.g. cohort studies, comparator st

registries and drug utilization studies.

Registries

A registry is a list of patients presenting with the same characcharacteristic can be a disease (disease registry) or a specific eregistry). Both types of registry, which differ only by the type

interest, can collect a battery of information using standardizin a prospective fashion. Disease registries, such as registries dyscrasias, severe cutaneous reactions, or congenital malformto collect data on medicine exposure and other factors associclinical condition. A disease registry might also be used as a bcontrol study comparing the medicine exposure of cases idenregistry with controls selected either from patients with anot

within the registry, or from patients outside the registry.

Exposure (medicine) registries address populations exposed tointerest (e.g., a registry of rheumatoid arthritis patients expostherapies) to determine if a medicine has a special impact on patients. Some exposure (medicine) registries address drug expopulations, such as pregnant women. Patients can be followincluded in a cohort study to collect data on adverse events uquestionnaires. Single cohort studies can measure incidence, comparison group, cannot provide proof of association. Howuseful for signal amplification, particularly for rare outcomes.


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Cross-sectional study (survey)

Data collected on a population of patients at a single

specified interval of time) regardless of exposure or discross-sectional study. These types of study are primarilsurveys or for ecological analyses. The major drawbackstudies is that the temporal relationship between expocannot be directly addressed. These studies are best usprevalence of a disease at one time point or to examinwhen data for serial time points can be captured. Thes

used to examine the crude association between exposecological analyses. Cross-sectional studies are most usnot change over time.

Case-control study

In a case-control study, cases of disease (or events) are

patients in whom the disease or event of interest has nselected from the source population that gave rise to tshould be selected in such a way that the prevalence ocontrols represents the prevalence of exposure in the sexposure status of the two groups is then compared uwhich is an estimate of the relative risk of disease in thcan be identified from an existing database or using da

for the purpose of the study. If safety information is sopopulations, the cases and controls can be stratified acpopulation of interest (e.g. the elderly, children, pregnadverse events, existing large population-based databaefficient means of providing the necessary data on memedical outcome relatively quickly. Case-control studie

when the goal is to investigate whether there is an assmedicine (or medicines) and one specific rare adverse eidentify risk factors for adverse events. Risk factors cansuch as renal and hepatic dysfunction, which might mbetween the medicine exposure and the adverse event


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medicine use and followed over time. Cohort studies are usefneed to know the incidence rates of adverse events in additio

risks. Multiple adverse events can also be investigated using tsource in a cohort study. However, it can be difficult to recrunumbers of patients who are exposed to the medicine of inteorphan medicine) or to study very rare outcomes. Like case-copatients for cohort studies can be identified from large automor from data collected specifically for the study at hand. In adstudies can be used to examine safety issues in special popula

children, patients with comorbid conditions, pregnant womesampling of these patients or by stratifying the cohort if suffipatients are included.

There are several automated databases available for pharmacstudies (12, 15, 18). They include databases that contain autorecords or automated accounting/billing systems. Databases tfrom accounting/billing systems might be linked to pharmacymedical claims databases. These datasets may include millionSince they are created for administrative or billing purposes, thave all the detailed and accurate information needed for soas validated diagnostic information or laboratory data. Althourecords can be used to ascertain and validate test results and

diagnoses, one should be cognizant of the privacy and confidregulations that apply to patient medical records.

Targeted clinical investigations

When significant risks are identified from pre-approval clinical tclinical studies might be called for to evaluate the mechanism

adverse reaction. In some instances, pharmacodynamic and phstudies might be conducted to determine whether a particularcan put patients at an increased risk of adverse events. Geneticprovide clues about which group of patients might be at an inadverse reactions. Furthermore, based on the pharmacological


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To elucidate the benefit-risk profile of a medicine outsiclinical trial setting and/or to fully quantify the risk of a

rare adverse event, a large simplified trial might be conenrolled in a large simplified trial are usually randomizebias. In this type of trial, though, the event of interest ensure a convenient and practical study. One limitationthe outcome measure might be too simplified and thison the quality and ultimate usefulness of the results osimplified trials are also resource-intensive.

Descriptive studies

Descriptive studies are an important component of phalthough not for the detection or verification of adversmedicine exposures. These studies are primarily used torate of outcome events and/or to establish the prevale

medicines in specified populations.

Natural history of disease

The science of epidemiology originally focused on the disease, including the characteristics of diseased patienof disease in selected populations, as well as estimatinprevalence of potential outcomes of interest. These ouinclude a description of disease treatment patterns andthat examine specific aspects of adverse events, such aincidence rate of, or risk factors for, the adverse event putting spontaneous reports into perspective (15). For epidemiological study can be conducted using a diseasthe frequency at which the event of interest might occ

such as patients with concomitant illnesses.

Medicine utilization study

Medicine utilization studies (DUS) describe how a medib d d d i l ti d h th f


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References

1. ICH Guideline E2D; Post-approval safety data management: definitions a

expedited reporting, 3.1.1 Spontaneous reports 2004. International Confere2. Pinkston V, Swain EJ. Management of adverse drug reactions and advers

collection, storage, and retrieval. In: Stephens MDB, Talbot JCC, Routledof new adverse drug reactions. 4th ed. London, MacMillan Reference Lt

3. Faich GA, U.S. adverse drug reaction surveillance 1989-1994. PharmacoSafety, 1996, 393-398.

4. Goldman SA. Limitations and strengths of spontaneous reports data. Cli1998, 20 (Suppl C):C40-C44.

5. Hartmann K, Doser AK, Kuhn M. Postmarketing safety information: Howspontaneous reports. Pharmacoepidemiology and Drug Safety, 1999, 8:

6. Waller PC, Arlett PA. Responding to signals. In: Mann RD, Andrews E, edChichester, John Wiley and Sons Ltd, 2002:105-128.

7. DuMouchel W. Bayesian data mining in large frequency tables, with an Spontaneous Reporting system. The American Statistician, 1999, 53:177

8. Bate A, Lindquist M, Edwards IR. A Bayesian neural network method forsignal generation. European Journal of Clinical Pharmacology, 1998, 54

9. Van Puijenbroek E, Egberts ACG, Heerdink ER, Leufkens HGM. Detectin

interactions using a database for spontaneous adverse drug reactions: Adiuretics and non-steroidal anti-inflammatory drugs. European Journal oPharmacology, 2000, 56:733-738.

10. Venning GR. Identification of adverse reactions to new drugs. III: Alertinwarning systems. British Medical Journal, 1983, 286:458-460.

11. Edwards IR. The management of adverse drug reactions: from diagnosis2001, 56:727-733.

12. Strom BL (ed.) Pharmacoepidemiology, 3rd ed. New York, NY, John Wile

13. Mitchell AA, Van Bennekom CM, Louik C. A pregnancy-prevention progchildbearing age receiving isotretinoin. New England Journal of Medicin

14. Task Force on Risk Management. Report to the FDA Commissioner. Manmedical product use: Creating a risk management framework. Part 3. Hpostmarketing surveillance and risk assessment. May 1999.

15. Shakir SAW. PEM in the UK. In: Mann RD, Andrews EB, eds. PharmacovJohn Wiley and Sons, 2002:333-344.

16. Coulter DM. PEM in New Zealand. In: Mann RD, Andrews EB, eds. Phar

Chichester, John Wiley & Sons, 2002:345-362.17. Coulter DM. The New Zealand intensive medicines monitoring programmsurveillance. Pharmacoepidemiology and Drug Safety, 2000, 9:273-280.

18. Mackay FJ. Post-marketing studies. The work of the Drug Safety Researc1998, 19:343-353.

19 Garcia Rodriguez LA Perez Gutthann S Use of the UK General Practice


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ANNEX 2

Recent information on adverse reactions to marketeMedicines used for treating attention-deficit hyperactiAttention deficit hyperactivity disorder (ADHD) is being intreated in children. A recommended medicine, methylphincreasingly used to treat this condition. Its side-effects inand include appetite suppression, insomnia, tachycard

headache (1); fixed medicine eruption induced by MPH iand a small minority of ADHD children on MPH therapy growth decrement (3). In addition, preliminary data sunocturnal dipping of blood pressure (BP) during sleepielevations in BP during waking hours (4). Paediatricians smonitor the dose-related side-effects and aim for the lowshould also monitor heart rate, BP and growth in child

Pemoline is another medicine used to treat ADHD. Theserious hepatotoxicity (hepatic enzyme abnormalities, jascribed to its use. Limitations in post-marketing survereporting in the United States of America, particularly accounted for delays in initiating an appropriate respohepatotoxicity (5).

Medicines used to treat nocturnal enuresisPrimary nocturnal enuresis is one of the most frequentpractice. Either imipramine or desmopressin are routinnocturnal enuresis in children. Although very rare, imipreported to cause sudden cardiac arrest. A number of

desmopressin use with hyponatraemic hypervolaemia aand seizures attributed to excess water intake before t

Inhaled corticosteroids for asthmaInhaled corticosteroids (ICS) are now the first-line thera

h ld l th t th hild i i th t d d i


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should also ensure that the child is using the metered-dose inWrong technique can result in increased swallowing of medic

availability of the medicine, defeating the purpose of inhaler asthmatic children with concomitant allergic conditions (allerdermatitis) that require multiple forms of topical corticosteroihigh doses is compounded. The use of ICS where tuberculospresent another risk. A report from India has documented th548 patients with asthma, including adults, developed activefollowing the use of ICS (12).

Anti-pyretic and anti-inflammatory medicinesNimesulide, a selective cyclo-oxygenase-2 inhibitor has becomroutine antipyretic and anti-inflammatory medicine in some cIndia, Italy and Turkey. Its routine use after day-care surgery, in pain relief, has been reported from India (13). Randomizedtrials carried out in Turkey (14) and in India (15) have documeantipyretic activity is better than that of paracetamol and ibuBetter in this case means that the antipyretic activity is greateHowever, as for any medicine, it is not only its efficacy that isalso its safety. Such small studies, with only about 100 childredetect the rare adverse effects. Only post-marketing surveillaspontaneous reporting can detect these effects. Nimesulide h

widely in children in Italy although there is no robust evidencbase its rational use (16). An analysis from Italy of its databasspontaneously reported adverse events has cautioned that uspatients at risk can be associated with hepatic and renal impaPaediatricians in India have also reported occurrence of grossorbital oedema and hypothermia associated with nimesulide response to the concern about hepatotoxicity, a pharmaceuti

manufactures the medicine in India has analysed 4097 case-rgathered from 430 paediatricians who had prescribed nimesuanalysis revealed that no child had developed hepatotoxicity aftHowever, it is believed that nimesulide is associated with rare

i d) b i d di bl h i

to lack of sufficient data There have been recent repo


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to lack of sufficient data. There have been recent repoibuprofen in children primarily as a result of its availab

counter preparation (23, 24). The predominant reactiourticaria, fixed medicine eruption), gastrointestinal andand even haematemesis.

Cisapride for gastro-oesophageal refluxGastro-oesophageal reflux (GOR) is an extremely commlimiting condition in infants. Cisapride, a pro-kinetic ag

prescribed for the symptomatic management of GOR ifeed intolerance in premature neonates. Adverse cardiventricular arrhythmias, QTc interval prolongation, synchave been reported in adult patients treated with cisapconcomitant ingestion of antifungal medicines (fluconmacrolides (clarithromycin). A study from the United Sreported that 15 (30%) of 50 infants receiving cisaprid

prolongation three days after starting to take the medthe QTc interval had normalized by day 14 of cisapridesuggested that documenting a prolongation of the QTfollowing initiation of cisapride administration, would adverse cardiac events. Such a finding would mandatehelp reduce cardiac morbidity in hospitalized infants re

However a Cochrane Review has recently stated that tthat cisapride reduces symptoms of GOR (26). Studies India have also found no benefit of cisapride in reducinpremature neonates (27, 28).

Anti-epileptic medicinesA recent survey in the UK looking for fatal suspected A

anticonvulsants were associated with the greatest numfatalities and hepatotoxicity in particular. The individuafrequently mentioned was sodium valproate (29).

A i il i di i h i i i d (AHS)

reported in a child treated with lamotrigine a nonaromatic a


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reported in a child treated with lamotrigine, a nonaromatic aAlso, cross-reactivity between aromatic antiepileptics and lam

documented by doing the in vitro lymphocyte toxicity assay ingirl who developed AHS following administration of phenoba

Newer antiepileptics (lamotrigine, oxcarbazepine and topirammarketed for paediatric use. There is a worldwide lack of syspharmacoepidemiological studies investigating ADRs to the nantiepileptics, making it difficult to assess their incidence accu

with the older antiepileptics, the majority of ADRs to the neware related to the central nervous system. The ADRs identifiedhypersensitivity reactions ranging from simple morbilliform raorgan failure; psychiatric ADRs and deterioration of seizure coto lamotrigine; hyponatraemia and skin rash in response to oand, cognitive deficits, word-finding difficulties, renal calculi response to topiramate (37). Vigabatrin, which is effective in

seizures in children with tuberous sclerosis, has been reportedencephalopathy, motor disturbances and late-onset visual field c

Cefaclor-induced serum sickness-like reactionCefaclor, an oral second-generation cefhalosporin, is commorespiratory and skin infections in children. Recently a unique

induced serum sickness-like reaction (SSLR), in which the chilurticaria, arthralgia and facial oedema on receiving a second cefaclor, has been identified. It occurs in 0.055% of children to develop is probably genetically (maternally) inherited (38). India described a four-year old boy who developed SSLR (39)received multiple courses of cefaclor (self-medication given bAfter his clinical condition improved with antihistamines and

parents were advised to ensure that the child never receives cef

Multiple antibiotic sensitivity syndrome (MASS)Multiple antibiotic sensitivity syndrome (MASS) is a rare but d

if i i i i ki h i k lik

Delhi moderate hypotension was reported in six (19%


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Delhi, moderate hypotension was reported in six (19%who received midazolam sedation during mechanical v

no increase in any adverse neurological event (44). Midreported to cause adverse effects (delayed time to becbehaviour) on withdrawal in critically ill children (45).

About 3.4% of children scheduled for elective surgerydevelop paradoxical reactions following premedicationmidazolam. These reactions may occur at variable time

and include restlessness, violent behaviour, physical assand need for restraints (46). Ketamine has been reportmedicine for the treatment of these paradoxical reactionof these reactions and how they are resolved by ketam

Intranasal midazolam is being increasingly used as a sebefore painful procedures in children. An acute allergic

been reported in a healthy 5-year-old boy, after receiviintranasal atomizer for sedation purposes in a dental cthe midazolam was given, the child developed urticariarapidly progressed to the lower extremities, stomach, bface. The periorbital skin also became oedematous. Thtreatment with intramuscular diphenylhydramine in the

Medicines for opportunistic infections and antiretroviraTrimethoprim-sulfamethoxazole (TMP-SMZ) is being roinfected children for the treatment and Pneumocystis clife-threatening and treatment-limiting adverse events delayed hypersensitivity are known to occur after 7-21SMZ (48, 49). These include cardiorespiratory arrest, se

necrolysis, hypotension, respiratory distress, liver functiazotaemia, neutropenia, anaemia and gastrointestinal di

Adverse effects associated with antiretroviral medicinei 30% f HIV i f d hild i

The lamivudine-zidovudine combination for the prevention of


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The lamivudine zidovudine combination for the prevention oftransmission of HIV has been reported to result in neutropen

the infants, which at times is severe enough to require bloodeven premature discontinuation of treatment (51). Reversiblehas been reported to occur in all infants between 1.5 and 3 mwho had received short-term antiretroviral prophylaxis with nin combination with zidovudine to prevent mother-to-child tr

Newer adverse reactions to medicines in neonates

With improved neonatal care, many preterm newborn infantroutinely surviving. This has resulted in an increasing occurrenof prematurity (ROP) which needs early specialized interventiovisual disability. Recently, a preterm newborn infant has beendeveloped renal failure after undergoing a mydriatic test withdrops, which were instilled several times. The blood concentrphenylephrine was elevated sufficiently to contract the renal

inducing renal failure (53).

Imidazole nasal drops are widely used as a nasal decongestanformulations with reduced drug concentration are available fmost preparations are available over-the-counter. Three casesreported of neonates who developed apnoea and coma, two

short-term mechanical ventilation (54). After the exclusion ofmetabolic causes of these episodes, there remained at least ato the treatment with oxymethazoline- and xylometazoline-basedthree infants. Similar cases have been reported previously (55, 56that these compounds can easily cross the blood-brain barriecause hypotensive and sedative effects by binding receptors of a the rostral ventrolateral medulla, to which clonidine also belo

Another more recently reported ADR in neonates is that the serotonin reuptake inhibitors (paroxetine, fluoxetine, sertralinin pregnant women being treated for depression has been do

l l i d l i hd l d

under conditions with a restricted effective circulatory


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under conditions with a restricted effective circulatory However, these problems are avoidable, if the infants hbalance (62, 63). Moreover, the transient vasoconstrictindomethacin on the cerebrovascular may even have abrain (64). The alternative to indomethacin, ibuprofenhave fewer adverse effects than indomethacin (65). Howas later found to be associated with an increased riskpulmonary hypertension (66) and kernicterus (67). Ibubilirubin-albumin and increases the unbound bilirubin

plasma. Besides these safety concerns, ibuprofen has bqualitative negative effects on renal function similar toother nonselective NSAID (68). Further well-controlled comparative studies with particular emphasis on short-aspects are needed to answer one of the most urgent phin neonatology, namely, whether ibuprofen is really suFor the time being indomethacin remains the medicine

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14:219-223. Review.2. Cohen HA, et al. Fixed drug eruption of the scrotum due to me

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3. Holtkamp K, et al. Methylphenidate-related growth impairmentAdolescent Psychopharmacology, 2002, 12:55-61.4. Stowe CD, et al. 24-hour ambulatory blood pressure monitoring

stimulant therapy.Annals of Pharmacotherapy, 2002, 36:1142-5. Safer DJ, Zito JM, Gardner JE. Pemoline hepatotoxicity and post

of American Academy of Child and Adolescent Psychiatry, 20016. Muller D, Roehr CC, Eggert P. Comparative tolerability of drug t

enuresis in children. Drug Safety, 2004, 27:717-727.7. Allen DB. Inhaled corticosteroid therapy for asthma in preschoo

Pediatrics, 2002, 109(2 Suppl):373-380. Review.8. Saha MT, Laippala P, Lenko HL. Growth of asthmatic children is

treatment with inhaled glucocorticoids.Acta Paediatrica, 1997, 9. Agerttoft L, Pedersen S. Effect of long-term treatment with inha

height in children with asthma. New England Journal of Medicin

19. Sharma S. Hypothermia with nimesulide. Indian Pediatrics, 2001, 38:799


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20. Srishyla MV, Sireesha K, Bhaduri J, Kumaresan S. A countrywide post-manimesulide suspension. Indian Pediatrics, 2002, 39:310-311.

21. Boelsterli UA. Mechanisms of NSAID-induced hepatotoxicity: focus on niDrug Safety, 2002, 25:633-648.22. Gupta P, Sachdev HP. Safety of oral use of nimesulide in children: system

randomized controlled trials. Indian Pediatrics, 2003, 40:518-531.23. Diaz Jara M, et al. Allergic reactions due to ibuprofen in children. Pediatr

18:66-67.24. Titchen T, Cranswick N, Beggs S. Adverse drug reactions to nonsteroidal

drugs, COX-2 inhibitors and paracetamol in a paediatric hospital. BritishPharmacology, 2005, 59:718-723.

25. Chhina S, et al. QTc interval in infants receiving cisapride. Journal of PeriJournal of the California Perinatal Association, 2002, 22:144-148.

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28. Barnett CP, et al. Effect of cisapride on gastric emptying in premature inf

intolerance.Journal of Paediatrics and Child Health, 2001, 37:559-563.29. Carkson A, Choonara I. Surveillance for fatal suspected adverse drug rea

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children.Annals of Pharmacotherapy, 2001, 35:533-538.32. Gogtay NJ, Bavdekar SB, Kshirsagar NA. Anticonvulsant hypersensitivity s

Expert Opinion on Drug Safety, 2005, 4:571-581. Review.33. Yigit S, Korkmaz A, Sekerel B. Drug-induced hypersensitivity syndrome inPediatric Dermatology, 2005, 22:71-74.

34. Brown TS, Appel JE, Kasteler JS, Callen JP. Hypersensitivity reaction in a clamotrigine. Pediatric Dermatology, 1999, 6:46-49.

35. Bavdekar SB, et al. Anticonvulsant hypersensitivity syndrome: lymphocyte toconfirmation of diagnosis and risk assessment.Annals of Pharmacotherapy

36. Wong IC, Lhatoo SD. Adverse reactions to new anticonvulsant drugs. Dr23:35-56. Review.

37. Lhatoo SD, Wong IC, Sander JW. Prognostic factors affecting long-term topiramate in patients with chronic epilepsy. Epilepsia, 2000, 41:338-34

38. Kearns GL, et al. Serum sickness-like reactions to cefaclor: role of hepatiindividual susceptibility.Journal of Pediatrics, 1994, 125:805-811.

39. Sanklecha MU. Cefaclor induced serum sickness like reaction. Indian Jou

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trimethoprim/sulfamethoxazole in pediatric human immunodeficPediatrics, 1994, 93:519-521.

49. Hughes WT, LaFon SW, Scott JD, Masur H. Adverse events assocsulfamethoxazole and atovaquone during the treatment of AIDSpneumonia.Journal of Infectious Diseases, 1995, 171:1295-130

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51. Mandelbrot L, et al. Agence Nationale de Recherches sur le SIDALamivudine-zidovudine combination for prevention of maternal-Journal of the American Medical Association, 2001, 285:2083-2

52. Taha TE, et al. Haematological changes in African children who with nevirapine and zidovudine at birth.Annals of Tropical Paedi

53. Shinomiya K, et al. Renal failure caused by eyedrops containingretinopathy of prematurity.Journal of Medical Investigation, 200

54. Meyburg J, Klker S, Hoffmann GF, Zilow E. Coma in neonates fdrops? Deutsches Arzteblatt, 2006, 103:A 3411-3413 ( the Engfound at: http://www.aerzteblatt.de/v4/archiv/artikel.asp?id=538

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57. Yamazato M, et al. Hypotensive and sedative effects of clonidineventrolateral medulla of conscious rats.American Journal of Phyand Comparative Physiology, 2001, 281:R1868-1876.

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63. Leonhardt A, Strehl R, Barth H, Seyberth HW. High efficacy and indomethacin treatment during individualized fluid intake in preductus arteriosus.Acta Paediatrica, 2004, 93:233-240.

64. Miller SP, et al. Prolonged indomethacin exposure is associated winjury detected with magnetic resonance imaging in premature gestation at birth Pediatrics 2006 117:1626 1631


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ISBN 978-92-4-156343-7

PROMOTING SAFETY OF MEDICINES FOR CHILDREN

Pharmacovigilance and medicine safety issues in children arerelevant to everyone who has an interest in and cares about thehealth of children. The purpose of this guideline is I) to present acase for the importance of the improving safety monitoring ofmedicines for children, II) to describe possible ways of achieving itand III) to provide an outline for national pharmacovigilance

programmes to make them more sensitive and open to adversereactions to medicines in children.

promotion safe med childrens

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