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TDM JOURNAL CLUB ScaryScience:OndansetronSafetyinPregnancyTwoOpposingResultsFromtheSameDanishRegistryA critical review of several recentpapers published on ondansetron usein pregnancyAbstract:While perceived safe in preg-nancy, several recent studies raise concernsabout both fetal and maternal safety ofondansetron. Until more data are available,it should not be arst-line medication formorning sickness.InFebruary2013,theNewEnglandJournal of Medicinepublished an articlebyPasternaketalreportingthatondanse-tronisnotassociatedwithincreasedmal-formation rates when used for morningsickness. This was based on retrospec-1tive analysis of data from the DanishBirth Registry collected between 2004and2011,andlinkedtotheNationalPre-scriptionRegistertoidentifyprescriptionsof the drug. Each woman exposed toondansetron (n = 1970) was matched to4unexposedcontrolcases.Ofnote,themeanageofexposurewas 10 gestational weeks, which meansthat half of the cases were exposed toondansetron at later than 10 gestationalweeks,whenmalformationscouldnotbeproducedanymore.Thiscancauseabiastowardthenull,thatis,diluteanexistingrisk because of inclusion of cases thatwerenotexposedduringembryogenesis.On August 27, 2013, this study byPasternak was presented again at theInternationalSocietyofPharmacoepi-demiologyinMontreal.Back-to-backwith this study, Andersen et al2fromDenmarkpresentedastudyusingthesameregistries. This study covered more years(19972010)and more pregnant women(897,018 versus 608,835) using the samenationalregistriesasinPasternaksstudy.Ofmajorconcern, Andersensstudydetecteda2-foldincreasedriskofcardiacmalformations with ondansetron {oddsratio = 2.0 (95% condence interval[CI], 1.33.1)} leading to an overallincreased risk of major malformations of30%.To rule out confounding by indica-tion, Andersen et al also examined meto-clopramide taken for morning sickness,nding noincreased teratogenic risk.Thefactthatthesamelargeregis-try can be manipulated to yield suchopposingresultsisveryconcerning.Wearewitnessingexponentialriseinuseofprescription database linkage to birthregistries. None of these were designedspecically to address fetal drug safety,andtheremaybeawsinthequalityandcompleteness of the data. The exampleoftheDanishdatashowsthatinadditiontothesepotentialaws,humandecisionscan shape the results in any direction.This is scary.Ondansetron, a potent antiemeticagent, is a 5-HT3 receptor antagonistblocking the effect of serotonin, whichwasdesignedoriginallyforcancerchemotherapy-induced nausea andvomit-ing. The drug is labeled also for use fornausea and vomiting associated withradiationtherapy,anesthesia,andsurgery.However,becauseof30yearswithoutanFDA-approveddrugformorningsicknessin the United States, increasing numbersof American women suffering from nau-sea and vomiting of pregnancy (NVP)havebeenmanagedwithondansetron.AsofApril2013,thedoxylaminepyridoxinecombination(Diclegis)hasbeenapprovedby theregulatoryagency.FETAL SAFETYThefetalsafetyofthedrughasbeenrst addressed by Einarson et al in 20043through a prospective controlled cohortstudy of 176 women, mostly American,inwhomwecouldnotdetectanincreasedteratogenicrisk.However,thissamplesizecouldruleoutonlya5-foldincreasedriskof major malformations and not any spe-cicmalformation.InFebruary2013,Pas-ternak et al1published the article citedabove, further suggesting that the drugmay be safe. However, the opposing re-sultsofanalysisofthesameDanishdata-base by a different group of researcherscall forcaution.Of potential importance, a recentlarge control study by the Sloan epide-miologyunitandtheCentersofDiseaseControlandPreventionhasdetecteda2-fold increased risk for cleft palate asso-ciated with ondansetron taken for NVPin therst trimester of pregnancy [oddsratio = 2.37 (95% CI, 1.284.76)].4MATERNAL SAFETYIn June 2012, the FDA issueda warning of possible serious QT pro-longation andTorsade the Pointeamongpeoplereceivingondansetron. Asaresult,5the FDA requires strict follow-up ofpatients receiving ondansetron, to ruleout long QT, electrolyte imbalance, con-gestiveheartfailure,ortakingconcomitantmedicationsthatprolongtheQTinterval.5InthecontextofNVP,quiteafewwomenwith severe NVP may have electrolyteabnormalities (hypokalemia or hypomag-nesemia).Presently,counselingofwomenwho receive ondansetron for morningsickness reveals that these FDA precau-tions are not being followed.SEROTONIN SYNDROMESerotonin syndrome islife-threaten-ing disorder of excessive serotonergicactivity typically occurring when 2 ormore serotonin-modifyingagentsare usedsimultaneously,althoughitmayalsooccurwithasingleagent. FromJanuary1,19986to December 30, 2002, Health Canadareceived53 reports of suspected serotoninsyndrome. Serotonin syndrome was mostoftenreportedwiththe use ofselectiveserotonin reuptake inhibitors, monoamineoxidase inhibitors, andvenlafaxine.Theclinicalpresentationischarac-terized by the triad of cognitive orbehavioralchanges(confusion,agitation,lethargy, coma), autonomic instability(hyperthermia, tachycardia, diaphoresis,nausea, vomiting, diarrhea, dilated pu-pils),andneuromuscularchanges(myoc-lonus,hyperreexia,tremor).6Critically,serotoninsyndromehas also been reported with the con-comitantuseof5-HT3 receptorantag-onists (eg, ondansetron, dolasetron,granisetron).7,8Because a large num-berofpregnantwomenareonselectiveserotoninreuptakeinhibitorsandupto The author was the PI on the US doxylaminepyridoxine study and is consultant for Duch-esnay Inc, Quebec.Correspondence: Gideon Koren, MD, UniversityofToronto,DepartmentofPediatrics,Toronto,Ontario,Canada(e-mail:gkoren@sickkids.ca).Copyright2014byLippincottWilliams&WilkinsTher Drug MonitVolume 36, Number 1, February 20141

90%experiencemorningsickness,apossibleinteractionwithondansetronleadingtoserotoninsyndromemustbeconsidered. Because the paramountchallenge of treating pregnant womenwithmedicationsisfetal,andmaternalsafetyondansetronshouldbeusedcau-tiously only after drugs with bettersafetyrecord,whichhavebeenlabeledto use in pregnancy (eg doxylaminepyridoxine) have been tried.Gideon Koren, MDUniversity of Toronto, Department ofPediatrics, Toronto, Ontario, Canada.REFERENCES1.Pasternak B, Svanstrm H, Hviid A. Ondanse-troninpregnancyandriskofadversefetalout-comes.N Engl J Med.2013;368:814823.2.Andersen JT, Jimenez-Solem E, Andersen NL,et al.Ondansetron Use in Early Pregnancyand the Risk of Congenital MalformationsA Register Based Nationwide Control Study.InternationalSocietyofPharmaco-epidemiology.Montreal, Canada; 2013. Abstract 25, Pregnancysession 1.3.Einarson A, Maltepe C, Navioz Y, et al. Thesafety of ondansetron for nausea and vomitingofpregnancy:aprospectivecomparativestudy.BJOG.2004;111:940943.4.AnderkaM,MitchellAA,LouikC,etal.Med-ications used to treat nausea and vomiting ofpregnancyandtheriskofselectedbirthdefects.BirthDefectsResAClinMolTeratol.2012;94:2230.5.FDA Drug Safety communication: Abnormalheart rhythms may be associated with use ofZofran (ondansetron). Available at: http://www.fda.gov/Drugs/DrugSafety/ucm271913.htm.6.Mason PJ, Morris VA, Balcezak TJ. Serotoninsyndromepresentationof2casesandreviewofthe literature.Medicine (Baltimore).2000;79:201209.7.Turkel SB, Nadala JG, Wincor MZ. Possibleserotonin syndrome in association with 5-HT3antagonist agents.Psychosomatics.2001;42:258260.8.SorscherSM.Probableserotoninsyndromevar-iant in a patient receiving a selective serotoninreuptake inhibitor and a 5-HT receptor antag-3onist.J Psychopharmacol.2002;16:191. TDM Journal ClubTher Drug MonitVolume 36, Number 1, February 201422014Lippincott Williams & Wilkins