Table Of ContentMeyler’s Side Effects
of Drugs
The International Encyclopedia of
Adverse Drug Reactions and Interactions
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Meyler’s Side Effects
of Drugs
The International Encyclopedia of
Adverse Drug Reactions and Interactions
Sixteenth edition
Editor
J K Aronson MA, DPhil, MBChB, FRCP, HonFBPhS, HonFFPM
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Contents
Introduction vi
ThehistoryofMeyler’sSideEffectsofDrugsandtheSideEffectsofDrugsAnnuals,1951–2015 viii
Mechanisticandclinicaldescriptionsofadversedrugeffects,adversedrugreactions,anddruginteractions xxiii
Definitive(between-theeyes)adversedrugreactions xxvii
Classificationofimmunologicalreactions xxxii
Classificationofdrugteratogenicity xxxiii
Gradesofadversedrugreactions xxxiv
Howtousethisbook xxxv
Abbreviations xxxvii
Definitionsofterms xxxviii
Alphabeticalcontentslistofdrugmonographs xli
Drugmonographs 1:1–7:612
Indexofdrugnames 7:613
Indexofdrug-druginteractions 7:655
Indexofadverseeffectsandadversereactions 7:703
Introduction
Thisisacompletelyneweditionofwhathasbecomethe affectthepopulationbenefittoharmbalance,whilein
standardreferencetextinthefieldofadversedrugreac- theindividualasingleharmmayobviatetheuseofthe
tionsandinteractionssinceLeopoldMeylerpublishedhis drug;
firstreviewofthesubjectabout65yearsago.Althoughwe (cid:1) benefitsareidentifiableinadvance,whereasharmsare
haveretainedtheoldtitle,Meyler’sSideEffectsofDrugs, notornotalways;
thesubtitleofthisedition,TheInternationalEncyclopedia (cid:1) thelikelytime-courseofbenefitscangenerallybepre-
ofAdverseDrugReactionsandInteractions,reflectsboth dicted,whilethetime-courseofharmsoftencannotand
modern terminology and the scope of the review. The maybemuchdelayedbycomparisonwiththeduration
structureofthebookmayhavechanged,buttheEncyclo- ofatrial.
pedia remains the most comprehensive reference source
Forallthesereasons,largerandsometimeslongerstudies
onadversedrugeffects,adversedrugreactions,anddrug–
areneededtodetectharms.Inrecentyearsattemptshave
drug interactions, and is a major source of informed dis-
beenmadetoconductsystematicreviewsofadversereac-
cussionaboutthem.
tions,butthesehavealsobeenlimitedbyseveralproblems:
(cid:1) harmsareingeneralpoorlycollectedinrandomizedtri-
alsandtrialsmaynotlastlongenoughtodetectthemall;
(cid:1) even when they are well collected, as is increasingly
Scope
happening,theyareoftenpoorlyreported;
(cid:1) evenwhentheyarewellreportedinthebodyofareport,
ThescopeoftheEncyclopediaiswide.Itcoversnotonly
theymaynotbementionedintitlesandabstracts;
the vast majority of prescription drugs, old and new, but
alsonon-prescribedsubstances(suchasanesthetics,anti- (cid:1) even when they are well reported in the body of a
report,theymaybepoorlyindexedinlargedatabases.
septics, lifestyle compounds, and drugs of abuse), herbal
medicines, some devices (such as blood glucose meters), Allthismeansthatitisdifficulttocollectinformationon
andmethodsinalternativeandcomplementarymedicine. adversedrugreactionsfromrandomizedcontrolledtrials
It includes entries on some substances that may be forsystematicreview.Thiscanbeseenfromtheevidence
regarded as obsolete, such as smallpox vaccine, but still providedinTable1,whichshowstheproportionofdiffe-
havesomerelevanceorareatleastofhistoricalinterest. rent types of information that have been used in the
Others,suchasdiethylstilbestrolandThorotrast,although preparation of two volumes of the Side Effects of Drugs
no longer in use, continue to cast their shadow and are Annual, proportions that are likely be the same in this
included.Yetothers,currentlyregardedasobsolete,have Encyclopedia.
beenretained,bothforhistoricalreasonsandbecauseone Wherever possible, emphasis in this Encyclopedia has
canneverbesurewhenanoldcompoundmayoncemore beenplacedoninformationthathascomefromsystematic
becomerelevantorprovideusefulinformationinrelation reviews and clinical trials of all kinds; this is reflected in
to another compound; for example, in the 15th edition headingsunderwhichtrialresultsarereported(observa-
thalidomide was restored after it had re-entered clinical tional studies, comparative studies, placebo-controlled
practice.Somedrugshavebeenwithdrawnfromthemar- studies, systematic reviews). However, because many
ketinsomecountriessincethelasteditionofMeylerwas reports of adverse drug reactions (about 30%) are anec-
published; rofecoxib, rosiglitazone, and rimonabant are dotal, with evidence from one or just a few cases, many
examples.Nevertheless,monographshavebeenincluded individual case studies (see below) have also been
on these substances because of the lessons that they can included. In some cases the only information about an
teach usand in some cases becauseof theirrelevance to adverse effect, adverse reaction, or drug interaction is
othercompoundsintheirclassesthatarestillavailable;it containedinananecdotalreport;inothercasesthereport
is also not possible to predict whether these compounds illustrates a variant form of the reaction. A case report
will eventually reappear in some otherform or for some alsogivesmoreimmediacytoanadversereaction,allow-
newindication. ing the reader to appreciate more precisely the exact
Inthelast25yearstherehasbeenincreasingemphasis nature of the reported event. Furthermore, when drugs
ontheuseofhigh-qualityevidenceintherapeuticpractice, arewithdrawnfromthemarketbecauseofadverseevents
principallyasobtainedfromlargerandomizedclinicaltri- or adverse reactions, withdrawal decisions are based on
alsandfromsystematicreviewsoftheresultsofmanysuch anecdotalreportsinabout75%ofcases.Weneedbetter
trials.However,whileithasbeenpossibletoobtainuseful methods to make use of the information that this large
informationaboutthebeneficialeffectsofinterventionsin bodyofanecdotesprovides.
this way, evidence about harms, including adverse drug
reactions, has been more difficult to obtain. Even trials
thatyieldgoodestimatesofbenefitsarepooratproviding
Structure
evidenceaboutharms,forseveralreasons:
(cid:1) benefits are usually single, whereas harms are usually Asinthepreviousedition,thechapterstructureofearlier
multiple; editions (and of the Side Effects of Drugs Annual series
(cid:1) thechanceofanysingleformofharmisusuallysmaller of volumes) has given way to a monographic structure.
thanthechanceofbenefitandthereforemoredifficult Thatisbecausesomeoftheinformationaboutindividual
todetect;however,multipleharmscanaccumulateand drugs has previously been scattered over different
Introduction vii
Table1 Typesofarticlesonadversedrugreactionspublished included, complete with citations. This has resulted in
in 6576 papers in the world literature during 1999 and 2003 the inclusion of nearly 65 000 references in this edition.
(asreviewedinSEDA-24andSEDA-28) Readerswillstilloccasionallyhavetorefertoeditionsof
the Annual (SEDA) and occasionally to earlier editions
Typeofarticle Number* %
of Meyler’s Side Effects of Drugs for more detailed
descriptions;allpreviousvolumesofSEDAarenowavail-
Ananecdoteorsetofanecdotes(i.e. 2084 29.9
reportedcasehistories) ableelectronicallythroughScienceDirect.
Amajorrandomizedcontrolledtrialor 1956 28.1
observationalstudy
Aminorrandomizedcontrolledtrialor 1099 15.8
Acknowledgements
observationalstudyoranon-randomized
study(includingcaseseries)
AswithpreviouseditionsofMeyler’sSideEffectsofDrugs
Amajorreview,includingnon-systematic 951 13.7
I am grateful to all those at Elsevier who have helped
statisticalanalysesofpublishedstudies
in the production of this edition, particularly Kate
Abriefcommentary(e.g.aneditorialora 362 5.19
letter) Miklaszewska-GorczycaandRadhakrishnanLakshmanan.
Anexperimentalstudy(animalorinvitro) 263 3.77 I am grateful to all the authors of chapters in previous
Ameta-analysisorotherformofsystematic 172 2.47 editions andAnnualsfor their hard workand for making
review their expertise available; they are listed in the section
Officialstatements(e.g.byGovernmental 75 1.07 below on the history of the project. I am also grateful to
organizations,theWHO,or IghoOnakpoyaforexcellenteditorialassistance.
manufacturers)
Totalnumberofdescriptions* 6962 100
Totalnumberofarticles 6576
Envoi
*Somearticlesaredescribedinmorethanoneway.
The history of Meyler’s Side Effects of Drugs goes back
chaptersinthebook;forexample,ciclosporinwasprevi-
over60years.WhenLeopoldMeyler,aphysician,experi-
ously covered in Chapter 37 and in scattered sections
encedunwantedeffectsofdrugsthatwereusedtotreathis
throughout Chapter 45; it is now dealt with in a single
tuberculosis,hediscoveredthattherewasnosingletextto
monograph.Themonographsarearrangedinalphabetical
which medical practitioners could turn for information
order,withcross-referencingasrequired.Forexample,if
about the adverse effects of drug therapy; Louis Lewin’s
you turn to the monograph on cetirizine, you will be
text Die Nebenwirkungen der Arzneimittel (“The Unto-
referred to the complementary general monograph on
ward Effects of Drugs”) of 1881 had long been out of
antihistamines, where much information that is relevant
print(SEDA-27,pp.xxv–xxix).Meylerthereforesurveyed
to cetirizine is given; the monograph on cetirizine itself
the current literature, initially in Dutch as Schadelijke
containsinformationthatisrelevantonlytocetirizineand
Nevenwerkingen van Geneesmiddelen (Van Gorcum,
not to other antihistamines. Within each monograph the
1951),andtheninEnglishasSideEffectsofDrugs(Elsevier,
materialisarrangedinthesamewayasintheSideEffects 1952). He followed up with what he called surveys of
ofDrugsAnnuals(see“Howtousethisbook”). unwanted effects of drugs. Each survey covered a period
of2–4yearsandculminatedinVolumeVIII(1976),edited
by Graham Dukes (SEDA-23, pp. xxiii–xxvi), Meyler
Definitions of Terms and having died in1973. By then the published literature was
tooextensivetobecomfortablyencompassedina4-yearly
Classifications of Adverse Drug
cycle, and an annual cycle was started instead. The first
Reactions
SideEffectsofDrugsAnnual(SEDA-1)waspublishedin
1977.The4-yearlyreviewwasreplacedbyacomplementary
Thesearecoveredinseparatearticles.
critical encyclopedic survey of the entire field; the first
encyclopedic edition of Meyler’s Side Effects of Drugs,
which appeared in 1980, was labelled the ninth edition.
Cross-References After that, Meyler’s Side Effects of Drugs was published
every 4 years, providing an encyclopaedic survey of the
Previous editions of the Encyclopedia contained many entire field up to the year 2000, and the 15th editionwas
unreferenced statements and cross-references to the publishedin2006.
Annuals, on the assumption that all the information We have come a long way since Meyler published his
would be readily available to the reader, although that firstaccountinabookof192pages.Ithinkthathewould
may not always be the case. In the 15th edition much of have approved of this latest edition of the Encyclopedia
the reference material on which previous editions of the thatproudlybearshisname.
Encyclopedia were based was restored. This process has
beencontinuedinthisedition,andthereisnowhardlya JKAronson
statementthatisnotbackedupbyatleastonereference Oxford,September2015
totheprimaryliterature.Inaddition,muchofthematerial
that was published in Annuals 28 onwards has been
The history of Meyler’s Side Effects of Drugs and the Side Effects of
Drugs Annuals, 1951–2015
LeopoldMeylerwasapioneerinthecollectionandcriti- instead. The 4-yearly volume could then concentrate on
cal analysis of descriptions of adverse drug reactions [1], providingacomplementarycriticalencyclopaedic survey
preceded only by Louis Lewin, whose work had been oftheentirefield.ThefirstSideEffectsofDrugsAnnual
forgotten by the time Meyler came to be interested in was published in 1977 (Table 2). The first encyclopaedic
thesubject[2]. editionofMeyler’sSideEffectsofDrugs,whichappeared
Meyler was a Dutch physician who underwent treat- in1980,waslabelledtheninthedition,afterwhichanew
ment for tuberculosis during the late 1940s, and experi- encyclopaedic edition appeared every 4 years (Table 2)
encedadversedrugreactions.AccordingtoProfessorWim until2000,whichsawthepublicationofthe14thedition.
Lammers,writingatributeinVolumeVIII(1975),Meyler Forthenewmillennium,itwasdecidedthatthematerial
got a fever from para-aminosalicylic acid, but elsewhere hadtobedigitizedandsoforthe15theditionthearrange-
Graham Dukes has written, based on information from mentoftheencyclopaediawaschanged—insteadofbeing
Meyler’swidow,thatitwasdeafnessfromdihydrostrepto- organized in chapters (e.g. Antihypertensive drugs,
mycin; perhaps it was both. Meyler discovered that there Diuretics)itwasorganizedinmonographs,eachdevoted
was no single text to which medical practitioners could toasingledrugoragroupofdrugs(e.g.Spironolactone,
lookforinformationaboutunwantedeffectsofdrugther- Beta-adrenoceptorantagonists).Itwaspublishedinboth
apy. He therefore determined to make such information hardandelectronicversionsin2006.
available and persuaded the Netherlands publishing firm AnotherinnovationintroducedbyDukeswastheinclu-
of Van Gorcum to publish a book, in Dutch, entirely sionof alistoftheaddressesofall theNationalCentres
devoted to descriptions of the adverse effects that drugs participatingintheWHOdrugmonitoringschemeineach
could cause and the adverse reactions that could result. volume of SEDA and Meyler. The list of addresses first
HewentontoagreewiththeElsevierPublishingCompany, appearedinthenintheditionofMeylerandwasprefaced
as it was then called, to prepare and issue an English withanoteaboutinternationalpharmacovigilance,which
translation. The first edition of 192 pages (Schadelijke Dukeswrotehimself;laterhegaveoverauthorshipofthis
Nevenwerkingen van Geneesmiddelen) appeared in 1951 sectiontomembersoftheWHOCollaboratingCentrefor
andtheEnglishversion(SideEffectsofDrugs)ayearlater. InternationalDrugMonitoringinUppsala,Sweden,Kjell
The book was a great success, and a few years later Strandberginthe11theditionandRalphEdwardsandhis
Meyler started to publish what he called surveys of colleaguesinsubsequenteditions.Nowthatallthatinfor-
unwantedeffectsofdrugs.Eachsurveycoveredaperiod mationisavailableelectronicallyithasbeenomittedfrom
of 2–4 years (Table 1). They were labelled as volumes thebooks.
ratherthaneditions,andafterVolumeIVhadbeenpub- DukesalsointroducedintotheAnnualsthefeatureof
lished Meyler could no longer handle the task alone. special reviews—short articles, typographically distin-
For subsequent volumes he recruited collaborators, such guished from the rest of the text, and marked by the
as Andrew Herxheimer (Table 1). In September 1973 prescriptionsymboloftheeyeofHorus,dealingindepth
Meyler died unexpectedly, and Elsevier invited Graham with a specific topic of current interest. These continue
DukestotakeovertheeditingofVolumeVIII. today, as does the Side Effects of Drugs Essay, usually
HavingeditedVolumeVIII,Dukeswaspersuadedthat writtenbyaguestauthor(Table3).
the published literature was too large to be comfortably ThecontributorstoMeyler’sSideEffectsofDrugsand
encompassed in a 4-yearly cycle, and he suggested to the Side Effects of Drugs Annuals 1–35 are listed in
Elsevier that the volumes should be produced annually Tables 4 and 5. The volumes on the series are truly
Table1 ThepublishinghistoryoftheeditionsofSideEffectsofDrugsthatwerewrittenoreditedbyLeopoldMeyler
Volume DateofPublication Yearscovered Collaborators
Firstedition 1951(Dutch)* Upto1951
1952(English)
I 1957 1955–1956
II 1958 1956–1957
III 1960 1958–1960
IV 1963 1960–1962
V 1966 1963–1965 CDalderup,WvanDijl,HGDBouma
VI 1968 1965–1967 AHerxheimer
VII 1972 1968–1971 AHerxheimer
*SeveralupdatestotheDutchvolumeweresubsequentlypublished.
