TDM JOURNAL CLUB

detecteda2-foldincreasedriskofcardiac Of potential importance, a recent

ScaryScience:Ondansetron
malformations with ondansetron {odds
large control study by the Sloan epideSafetyinPregnancyTwo ratio = 2.0 (95% condence intervalmiologyunitandtheCentersofDisease
OpposingResultsFromthe[CI], 1.33.1)} leading to an overall ControlandPreventionhasdetecteda2increased risk of major malformations
fold
ofincreased risk for cleft palate assoSameDanishRegistry
30%. To rule out confounding by indicaciated with ondansetron taken for NVP

tion, Andersen et al also examined metoin therst trimester of pregnancy [odds

4
ratio = 2.37 (95% CI, 1.28
4.76)].
A critical review of several recent clopramide taken for morning sickness,
nding noincreased teratogenic risk.
papers published on ondansetron use
Thefactthatthesamelargeregisin pregnancy
MATERNAL SAFETY
try
can
be manipulated to yield such
Abstract:While perceived safe in pregopposingresultsisveryconcerning.We In June 2012, the FDA issued
nancy, several recent studies raise concerns
a warning of possible serious QT proabout both fetal and maternal safety ofarewitnessingexponentialriseinuseof
prescription database linkage to birth
longation and
Torsade the Pointe
among
ondansetron. Until more data are available,
5
registries. None of these were designed
it should not be a
rst-line medication for
peoplereceivingondansetron. Asaresult,
morning sickness.
speci
cally to address fetal drug safety,
the FDA requires strict follow-up of
andtheremaybe
awsinthequalityandpatients receiving ondansetron, to rule
InFebruary2013,the
NewEngland completeness of the data. The example
out long QT, electrolyte imbalance, conJournal of Medicine
published an article
oftheDanishdatashowsthatinaddition
gestiveheartfailure,ortakingconcomitant
byPasternaketalreportingthatondanse5
tothesepotential
aws,humandecisions
medicationsthatprolongtheQTinterval.
tronisnotassociatedwithincreasedmalcan shape the results in any direction.
InthecontextofNVP,quiteafewwomen
formation rates when used for morning
This is scary.
1
with severe NVP may have electrolyte
sickness. This was based on retrospec- Ondansetron, a potent antiemetic
abnormalities
(hypokalemia or hypomagtive analysis of data from the Danish
agent, is a 5-HT3 receptor antagonist
nesemia).Presently,counselingofwomen
Birth Registry collected between 2004
blocking the effect of serotonin, which
who receive ondansetron for morning
and2011,andlinkedtotheNationalPrewas designedoriginally for cancer sickness reveals that these FDA precauscriptionRegistertoidentifyprescriptions
chemotherapy-induced nausea andvomitare not being followed.
of the drug. Each woman exposed ing.
to The drug is labeled also for usetions
for
ondansetron (n = 1970) was matched
to and vomiting associated with
nausea
4 unexposedcontrolcases.
radiationtherapy,anesthesia,andsurgery.
SEROTONIN SYNDROME
Ofnote,themeanageofexposure
However,becauseof30yearswithoutan Serotonin syndrome islife-threatenwas 10 gestational weeks, which means
FDA-approveddrugformorningsickness
ing disorder of excessive serotonergic
that half of the cases were exposed
into
the United States, increasing numbers
activity typically occurring when 2 or
ondansetron at later than 10 gestational
of American women suffering from more
nau- serotonin-modifyingagentsare used
weeks,whenmalformationscouldnotbe
sea and vomiting of pregnancy (NVP)
simultaneously,althoughitmayalsooccur
producedanymore.Thiscancauseabias
6
havebeenmanagedwithondansetron.As
withasingleagent. FromJanuary1,1998
towardthenull,thatis,diluteanexisting
ofApril2013,thedoxylamine
pyridoxine to December 30, 2002, Health Canada
risk because of inclusion of cases that
combination(Diclegis)hasbeenapproved
received53 reports of suspected serotonin
werenotexposedduringembryogenesis.
by theregulatoryagency.
syndrome. Serotonin syndrome was most
On August 27, 2013, this study by
oftenreportedwiththe
use ofselective
Pasternak was presented again at the
serotonin reuptake inhibitors, monoamine
International
Societyof PharmacoepiFETAL SAFETY
oxidase inhibitors, andvenlafaxine.
demiologyin Montreal.Back-to-back
2
Thefetalsafetyofthedrughasbeen
Theclinicalpresentationischaracwith this study, Andersen et al
from
3
rst
addressed
by
Einarson
et
al
in
2004
terized
by the triad of cognitive or
Denmarkpresentedastudyusingthesame
behavioralchanges(confusion,agitation,
registries. This study covered more through
years a prospective controlled cohort
study of 176 women, mostly American,
lethargy, coma), autonomic instability
(1997
2010)and more pregnant women
inwhomwecouldnotdetectanincreased
(hyperthermia,
tachycardia, diaphoresis,
(897,018 versus 608,835) using the same
teratogenicrisk.However,thissamplesize
nausea,
vomiting,
diarrhea, dilated punationalregistriesasinPasternak
sstudy.
pils),andneuromuscularchanges(myocOf major concern, Andersen
sstudy couldruleoutonlya5-foldincreasedrisk
6
of major malformations and not anylonus,hyperre
speexia,tremor).
cicmalformation.InFebruary2013,Pas- Critically, serotoninsyndrome
1
ternak et alpublished the article cited
has also been reported with the conThe author was the PI on the US doxylamine
pyridoxine study and is consultant for Duchabove, further suggesting that the drug
comitantuseof5-HT3 receptorantagesnay Inc, Quebec.
may be safe. However, the opposing
onists
re- (eg, ondansetron, dolasetron,
Correspondence: Gideon Koren, MD, University
7,8
sultsofanalysisofthesameDanishdatagranisetron).
Because a large numofToronto,DepartmentofPediatrics,Toronto,
base by a different group of researchers
berofpregnantwomenareonselective
Ontario,Canada(e-mail:gkoren@sickkids.ca).
Copyright2014byLippincottWilliams&Wilkins
call forcaution.
serotoninreuptakeinhibitorsandupto
Ther Drug Monit Volume 36, Number 1, February 2014

Ther Drug Monit Volume 36, Number 1, February 2014

TDM Journal Club

BirthDefectsResAClinMolTeratol.
2012;94:
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90% experiencemorning sickness,
2230.
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comes.
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823.
considered. Because the paramount
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to use in pregnancy (eg doxylamine
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Gideon Koren, MD

2014Lippincott Williams & Wilkins