Isotretinoin and Pregnancy Prevention

It’snonews that isotretinoin,themosteffectivetreatmentforsevere or recalcitrant acne, is a potent teratogen. From its release asAccutanebyHoffman-LaRoche in1982, isotretinoinhadbeen classified as a pregnancy categoryXdrug,definedasadrug with positive evidence of humanfetal risk,where the risks involved inuseof thedrug inpregnantwomenclearlyoutweigh potentialbenefits.Riskmanagementatthetimeofinitialapproval was limited to labeling,whichdescribed the riskof teratogenicity in the package insert and the patient information brochure. In relatively short order, it was clear that such labelingwas not enough to reduce the risk of fetal exposure to isotretinoin. Ifonecombinestheteratogenicpotentialof isotretinoinand the fact that 50% of pregnancies in the United States are unplanned,1 preventing fetal exposure to isotretinoin becomes crucial.AccordingtotheUSFoodandDrugAdministration(FDA) DrugUseData,Accutaneuseinwomenincreasedmorethan200% from1992to1999.2Asof1998,therewereover1.4millionisotretinoin prescriptionswritten in the United States.3 Half of the patients taking isotretinoinwerewomen,and85%to90%of these womenwere of childbearing potential, ages 15 to 44 years. The first reports of birthdefects secondary to isotretinoin appeared in 1983.By the2000, therewere 1995 fetal exposures to isotretinoin,whichresultedin1446electiveorspontaneousterminations and383livebirths,ofwhichtherewere162infantswithcongenital anomalies.The futureofourbestweaponagainst adisease that hassuchphysicalandpsychologicalrepercussionswasprecarious. In 1988, a short article titled “The Needless Tragedies of Accutane” appeared in the New York Times Health Section.4 In it, the unnamed author claimed that 97% of those prescribedAccutane canbe treatedwith other drugs and that the FDA failed tomake sure that physicians do not overprescribe the drug. The authorwent on to say, “But the company (Hoffman-LaRoche), theFDA,andcarelessdermatologists share the blame for failing tominimize its side effects. FrankYoung, the FDA’s commissioner, now has a clear remedial task: Regulate Accutane so that allwhoneed it get it,withnobirth defects.”4 TheFDAregulationscame.Thefirst risk reductionprogram was theAccutanePregnancyPreventionProgram(PPP) in 1988, which proved to be unsuccessful in reducing pregnancy risk in patients prescribed Accutane, followed by the FDA’s System to ManageAccutane-RelatedTeratogenicity(SMART) in2002.Both the PPP and SMARTwere initiated byRoche, themanufacturer ofAccutane.Because theSMARTprogramdidnot substantially changepregnancyrates inpatientsprescribedAccutane,theFDA institutediPledge, itsmostrestrictiveriskreductionprogram,on March1, 2006.5OnJuly30,2007, theAssociatedPress6 reported that the number of pregnancies in the first year of iPledge was about the same as the numbers reported annually prior to FDA regulations. Unfortunately,what did decreasewas the number ofpatientstreatedwithisotretinoin.Astudyconductedtoevaluate the impactof iPledgeon isotretinoin fetalexposure ina large Californiamultispecialtymedical group showed that therewas anoverall29%decreaseintreatmentcoursesandpatientstreated with isotretinoin after the implementation of iPledge.7 It seems that more and more stringent regulations, which weregoingtosolvetheproblemoffetalexposureto isotretinoin, didnotwork.Where is thedisconnect?TheDrugSafetyandRisk ManagementAdvisoryCommittee’s iPledgeyear1updatestated that themostcommonreasons forpregnancyduring iPledge includecontraceptivefailureandnoncompliancewithbirthcontrol methods.8Similarly,underSMART,themostcommonlyreported reasons for pregnancyduring isotretinoin therapywere unsuccessfulattemptsatabstinence,useof ineffectivecontraception, inconsistentuseofcontraception,unexpectedsexualactivity,and contraceptive failure.9 Let’s look at these factorsmore closely. In 2003, Isaacs and Creinin10 examined the impact of prior healthcareprovidercounselingonprevioususeofcontraception inwomen seeking surgical abortion. The study concluded that miscommunicationbetweenpatientsandtheirhealthcareprovider negatively affected the use of a primary contraceptive methodin14%ofthepatients.AstudypublishedintheCanadian FamilyPhysician11 in2006lookedat theself-reportedreasonsfor women’snoncompliancewithpregnancypreventionrecommendationswhilereceivingisotretinointreatment.Thestudywasdesignedtoassesswhetherprescribingphysiciansadvised female patients receiving isotretinoin according to pregnancy prevention recommendations,whetherwomenunderstoodthose recommendations,andwhetherwomencompliedwithrecommendationstopreventpregnancy.Astandardizedquestionnairewas administeredbytelephoneto47eligiblefemalepatientswhowere 14yearsorolder,werefertileasfarastheyknew,andweretreated with isotretinoinat the timeof the interviewor in thepreceding 6months.Theauthorsfoundthattheassociationofwomen’suse of double contraceptionwith their recollection that physicians discussedpregnancypreventionduringtheinterviewwasstatistically significant. They concluded that women’s retention of knowledgeandtheirperceptionoftheprecautionstakenbyphysiciansareessential for their compliance.Oneadditionalpatient in3will complywithdoublecontraceptionwhenphysiciansdiscuss that issue. The absolute risk reductionwas 37%. Another study,12published in2010,examinedadherence to oralcontraceptionbywomentakingcategoryXmedications.