Risk of next-morning impairment after use of insomnia drugs; FDA

Riskofnext‐morningimpairmentafteruseofinsomniadrugs;FDA

requireslowerrecommendeddosesforcertaindrugscontainingzolpidem

(Ambien,AmbienCR,Edluar,andZolpimist)



SafetyAnnouncement



[1‐10‐2013]TheU.S.FoodandDrugAdministration(FDA)isnotifyingthepublicofnew

informationaboutzolpidem,awidelyprescribedinsomniadrug.FDArecommendsthat

thebedtimedosebeloweredbecausenewdatashowthatbloodlevelsinsomepatients

maybehighenoughthemorningafterusetoimpairactivitiesthatrequirealertness,

includingdriving.Today’sannouncementfocusesonzolpidemproductsapprovedfor

bedtimeuse,whicharemarketedasgenericsandunderthebrandnamesAmbien,

AmbienCR,Edluar,andZolpimist.



FDAisalsoremindingthepublicthatalldrugstakenforinsomniacanimpairdrivingand

activitiesthatrequirealertnessthemorningafteruse.Drowsinessisalreadylistedasa

commonsideeffectinthedruglabelsofallinsomniadrugs,alongwithwarningsthat

patientsmaystillfeeldrowsythedayaftertakingtheseproducts.Patientswhotake

insomniadrugscanexperienceimpairmentofmentalalertnessthemorningafteruse,

eveniftheyfeelfullyawake.



FDAurgeshealthcareprofessionalstocautionallpatients(menandwomen)whouse

thesezolpidemproductsabouttherisksofnext‐morningimpairmentforactivitiesthat

requirecompletementalalertness,includingdriving.Forzolpidemproducts,datashow

theriskfornext‐mornin

gimpairmentishighestforpatientstakingtheextended‐release

formsofthesedrugs(AmbienCRandgenerics).Womenappeartobemoresusceptible

tothisriskbecausetheyeliminatezolpidemfromtheirbodiesmoreslowlythanmen

(seeDataSummarybelow).



Becauseuseoflowerdosesofzolpidemwillresultinlowerbloodlevelsinthemorning,

FDAisrequiringthemanufacturersofAmbien,AmbienCR,Edluar,andZolpimistto

lowertherecommendeddose.FDAhasinformedthemanufacturersthatthe

recommendeddoseofzolpidemforwomenshouldbeloweredfrom10mgto5mgfor

immediate‐releaseproducts(Ambien,Edluar,andZolpimist)andfrom12.5mgto6.25

mgforextended‐releaseproducts(AmbienCR).FDAalsoinformedthemanufacturers

that,formen,thelabelingshouldrecommendthathealthcareprofessionalsconsider

prescribingthelowerdoses―5mgforimmediate‐releaseproductsand6.25mgfor

extended‐releaseproducts(seeZolpidemDosingRecommendationsforAdults).



TherecommendeddosesofIntermezzo,alowerdosezolpidemproductapprovedfor

middle‐of‐the‐nightawakenings,arenotchanging.AtthetimeofIntermezzo’sapproval

inNovember2011,thelabelalreadyrecommendedalowerdosageforwomenthanfor

men.



FDAiscontinuingtoevaluatetheriskofimpairedmentalalertnesswithotherinsomnia

drugs,includingover‐the‐counter(OTC)drugsavailablewithoutaprescription.



Todecreasethepotentialriskofimpairmentwithallinsomniadrugs,healthcare

professionalsshouldprescribe,andpatientsshouldtake,thelowestdosecapableof

treatingthepatient’sinsomnia.Patientswhodriveorwhoseactivitiesrequirefull

alertnessthemorningafteruseofaninsomniadrugshoulddiscusstheappropriateness

oftheirmedicinewiththeirhealthcareprofessional(seeInsomniaMedicinesbelow).



FDAhaspreparedalistofquestionsandanswerstoprovideanadditionaloverviewof

thissafetyissue.



FactsaboutZolpidem



 Asedative‐hypnotic(sleep)medicineusedinadultsforthetreatmentofinsomnia

 Marketedasgenericsandunderthebrand‐namesAmbien,AmbienCR,Edluar,

Zolpimist,andIntermezzo

 In2011,about39millionprescriptionsforzolpidemproductsweredispensed,and

about9millionpatientsreceivedzolpidemproductsfromU.S.outpatientretail

pharmacies,ofwhich63%ofthepatientswerefemale.Extended‐releasezolpidem

products(AmbienCR

andgenerics)accountedfor11%(4.4millionprescriptions)of

thezolpidemmarket,immediate‐releaseproductsaccountedfor89%(35million

prescriptions)ofthemarketinY2011.





AdditionalInformationforPatients



 Patientswhotakeinsomniamedicinescanexperiencedecreasedmental

alertnessthemorningafteruse,eveniftheyfeelfullyawake.

 Zolpidemextended‐release(AmbienCRandgenerics)productsmaynotbethe

rightmedicationchoiceforpatients(menorwomen)withinsomniawhoneedto

driveorperformactivitiesthatrequirefullalertn

essthenextmorning.

 Forwomen,FDAisrequiringthemanufacturersofzolpidem‐containingproducts

tolowertherecommendeddosesofAmbienandAmbienCR,Edluar,and

Zolpimistintheprofessionaldruglabelsthataccompanythemedications.FDAis

alsorequiringmanufacturerstorecommendthathealthcareprofessionals

considerprescribingthelowerdoseofthesedrugsinmen(seeZolpidemDosing

RecommendationsforAdults).

 Ifyouarecurrentlytakingthe10mgor12.5mgdoseofazolpidem‐containing

insomniamedicine,continuetakingyourprescribeddoseasdirecteduntilyou

havecontactedyourhealthcareprofessionaltoaskforinstructionsonhowto

safelycontinuetotakeyourmedicine.Eachpatientandsituationisunique,and

theappropriatedoseshouldbediscussedwithyourhealthcareprofessional.

 Thelowerzolpidemdosewillbeeffectiveinmostwomenandmanymen.

 ReadtheMedicationGuidethatcomesalongwithyourzolpidemprescriptionfor

additionalinformation.

 Forotherinsomniamedicines,talktoyourhealthcareprofessionalaboutways

totakethelowestdosethattreatsyoursymptoms.

 Takeyourinsomniamedicineexactlyasprescribed.

 Over‐the‐counter(OTC)insomniamedicinesthatareavailablewithouta

prescriptionshouldnotbeconsideredsaferthanprescriptioninsomnia

medicinesfornext‐morningalertnessanddriving.

 Contactyourhealthcareprofessionalifyouhaveanyquestionsorconcerns

aboutzolpidemorotherinsomniamedicines.

 Reportsideeffectsfromtheuseofzolpidemorotherinsomniamedicinesto

FDA’sMedWatchprogram,usingtheinformationinthe"ContactFDA"boxatthe

bottomofthispage.



AdditionalInformationforHealthCareProfessionals



 Immediate‐releaseproducts:FDAisrequiringthemanufacturersofcertain

immediate‐releasezolpidemproducts(Ambien,Edluar,andZolpimist)tolower

therecommendeddose.FDAhasinformedmanufacturersthat:

o Therecommendedinitialdoseforwomenshouldbeloweredfrom10mg

to5mg,immediatelybeforebedtime.

o Thedruglabelingshouldrecommendthathealthcareprofessionals

considerprescribingalowerdoseof5mgformen.Inmanymen,the5

mgdoseprovidessufficientefficacy.

o Thedruglabelingshouldincludeastatementthat,forbothmenand

women,the5mgdosecouldbeincreasedto10mgifneeded,butthe

higherdoseismorelikelytoimpairnext‐mornin

gdrivingandother

activitiesthatrequirefullalertness.

 Extended‐releaseproducts:FDAisalsorequiringthemanufacturerofextended‐

releasezolpidem(AmbienCR)tolowertherecommendeddose.FDAhas

informedthemanufacturerthat:

o Therecommendedinitialdoseforwomenshouldbeloweredfrom12.5

mgto6.25mg,immediatelybeforebedtime.

o Thedruglabelingshouldrecommendthathealthcareprofessionals

considerprescribingalowerdoseof6.25mginmen.Inmanymen,the

6.25mgdoseprovidessufficientefficacy.

o Thedruglabelingshouldincludeastatementthat,forbothmenand

women,the6.25mgdosecanbeincreasedto12.5mgifneeded,butthe

higherdoseismorelikelytoimpairnext‐morningdrivingandother

activitiesthatrequirefullalertness.

 FDAhasinformedthemanufacturersthattherecommendedzolpidemdosesfor

womenandmenshouldbedifferentbecausewomeneliminatezolpidemfrom

theirbodiesataslowerratethanmen.

 Forzolpidemandotherinsomniadrugs,prescribethelowestdosethattreatsthe

patient’ssymptoms.

 FDAurgeshealthcareprofessionalstocautionallpatients(menandwomen)

whousetheseproductsabouttherisksofnext‐morningimpairmentforactivities

thatrequirecompletementalalertness,includingdriving.

 Informpatientsthatimpairmentfromsleepdrugscanbepresentdespitefeeling

fullyawake.

 EncouragepatientstoreadtheMedicationGuidewhentheyreceivetheir

zolpidemprescription.

 ReportadverseeventsinvolvingzolpidemorotherinsomniadrugstoFDA’s

MedWatchprogram,usingtheinformationinthe"ContactFDA"boxatthe

bottomofthispage.



DataSummary



DrivingsimulationandlaboratorystudiesrecentlysubmittedtoFDAindicatethat

zolpidembloodlevelsaboveapproximately50ng/mLappearcapableofimpairing

drivingtoadegreethatincreasestheriskofamotorvehicleaccident.In

pharmacokinetictrialsof10mgAmbien(orbioequivalentzolpidemproducts)that

includedapproximately250menand250women,about15%ofwomenand3%ofmen

hadzolpidemconcentrationsthatexceeded50ng/mLapproximately8hourspost‐

dosing.Threemeasurementsinwomenandoneinmenwere≥90ng/mLatabout8

hoursafteruse.



Ahigherpercentageofbothmenandwomenexperiencepotentiallyimpairingmorning

zolpidemlevelsafteruseofextended‐releasezolpidemproducts(AmbienCRorgeneric

equivalents).Inpharmacokinetictrialsofzolpidemextend

ed‐release12.5mg,

approximately33%ofwomenand25%ofmenhadzolpidembloodconcentrations

exceeding50ng/mLapproximately8hourspost‐dosing.About5%ofpatientshadblood

levels≥100ng/mL.



Instudiesofzolpidemextended‐release6.25mg,at8hoursafterdosing,about15%of

adultwomenand5%ofadultmenhadazolpidemlevelof≥50ng/mL,whereasforboth

elderl

ymenandwomen,about10%hadsuchazolpidemlevel.



FDAiscontinuingtoevaluatetheriskofnext‐morningimpairmentwithotherinsomnia

drugs.



ZolpidemDosingRecommendationsforAdults(Non‐Elderly)



 Dosingrecommendationsin

currentdruglabelfor

zolpidem

FDA’sproposednewdosing

recommendationsfor

zolpidem

Ambien,Edluar,

Zolpimist

MenandWomen:

10mgoncedaily,immediately

beforebedtime

Women:

5mgoncedaily,immediately

beforebedtime



Men:

5or10mgoncedaily,

immediatelybeforebedtime

AmbienCR MenandWomen:

12.5mgoncedaily,

immediatelybeforebedtime

Women:

6.25mgoncedaily,

immediatelybeforebedtime



Men:

6.25or12.5mgoncedaily,

immediatelybeforebedtime



InsomniaMedicines

PrescriptionInsomniaMedicines

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Genericname Foundinbrandname(s)

zolpidemtartrate Ambien,AmbienCR,Edluar,Zolpimist,

Intermezzo

butabarbitalsodium Butisolsodium

pentobarbitaland

carbromal

Carbrital

flurazepamhydrochloride Dalmane

quazepam Doral

triazolam Halcion

eszopiclone Lunesta

ethchlorvynol Placidyl

estazolam Prosom

temazepam Restoril

ramelteon Rozerem

secobarbitalsodium Seconal

doxepinhydrochloride Silenor

zaleplon Sonata

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Over‐the‐counter(OTC)InsomniaMedicines

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Genericname Commonbrandname(s)

diphenhydramine Benadryl

Alsoinmanycoldandheadache

combinationproducts*

doxylamine Unisom

Alsoinmanycoldandheadache

combinationproducts*

*BesuretoalwaysreadtheDrugFactsboxonOTCmedicines.

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Reference

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1. IMS,VectorOne:National(VONA)andTotalPatientTracker(TPT).Year2011.

ExtractedJune2012.

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ContactFDA

1‐800‐332‐1088

1‐800‐FDA‐0178Fax

ReportaSeriousProblem

MedWatchOnline

RegularMail:Usepostage‐paidFDAForm3500

Mailto:MedWatch5600FishersLane

Rockville,MD20857

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RelatedInformation

 FDADrugSafetyCommunication:Riskofnext‐morningimpairmentafteruseof

insomniadrugs;FDArequireslowerrecommendeddosesforcertaindrugs

containingzolpidem(Ambien,AmbienCR,Edluar,andZolpimist)

 QuestionsandAnswers