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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection


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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection 1

Selected Adverse Events • Hypersensitivityreactions(HSR)canbe

fatal.HSRsusuallyoccurduringthefirstfewweeksofstartingtherapy.Symptomsmayincludefever,rash,nausea,vomiting,malaiseorfatigue,lossofappetite,andrespiratorysymptoms(e.g.,coughandshortnessofbreath).

• Severalobservationalcohortstudiessuggestincreasedriskofmyocardialinfarctioninadultswithrecentorcurrentuseofabacavir;however,otherstudieshavenotsubstantiatedthisfinding,andtherearenodatainchildren.

Special Instructions • TestpatientsfortheHLA-B*5701allele

beforestartingtherapytopredictriskofHSR.PatientspositivefortheHLA-B*5701alleleshouldnotbegivenabacavir.PatientswithnopriorHLA-B*5701testingwhoaretoleratingabacavirdonotneedtobetested.

• Warnpatientsandparentsaboutriskofserious,potentiallyfatalHSRs.OccurrenceofHSRsrequiresimmediate and permanent discontinuationofabacavir.Donotre-challenge.

• Abacavircanbegivenwithoutregardtofood.Oralsolutiondoesnotrequirerefrigeration.

Dosing RecommendationsNeonate/Infant Dose: • Notapprovedforinfantsaged<3months.

Pediatric DoseOral Solution (Aged ≥3 Months): • 8mg/kg(maximum300mgperdose)twice

dailyor16mg/kgoncedaily(maximum600mgperdose)(seetextbelow)

• Ininfantsandyoungchildrenbeingtreatedwithliquidformulationsofabacavir,initiationwithoncedailyabacavirisnotgenerallyrecommended.InclinicallystablepatientswithundetectableviralloadandstableCD4Tlymphocyte(CD4)cellcountsformorethan6months(24weeks)onabacavirtwicedaily,dosecanbechangedfromtwicedailytooncedaily(seetextbelow).

Weight (kg)

Scored 300-mg Tablet

Twice Daily AM Dose

Twice Daily PM Dose

Once Daily Dose

14to<20kg

½tablet(150mg)

½tablet(150mg)

1tablet(300mg)

≥20to<25kg

½tablet(150mg)

1tablet(300mg)

1½tablets(450mg)

≥25kg 1tablet(300mg)

1tablet(300mg)

2tablets(600mg)

Weight Band Dosing (Weighing ≥14 kg)

Abacavir (ABC, Ziagen) (Last updated April 27, 2017; last reviewed April 27,

2017)

ForadditionalinformationseeDrugs@FDA:http://www.accessdata.fda.gov/scripts/cder/daf/

FormulationsPediatric Oral Solution:20mg/mLTablets:300mg(scored)Fixed-Dose Combination Tablets: • [Epzicom]Abacavir600mgpluslamivudine300mg

• [Trizivir]Abacavir300mgpluslamivudine150mgpluszidovudine300mg

• [Triumeq]Abacavir600mgplusdolutegravir50mgpluslamivudine300mg

Generic Formulations: • Abacavirsulfate300mgtablets • Fixed-dosecombinationtabletsofabacavir300mgpluslamivudine150mgpluszidovudine300mg



• Inpatientswhocanbetreatedwithpillformulations,therapycanbeinitiatedwithonce-dailyadministration.Iftherapywasinitiatedwithtwice-dailyliquidabacavir,thenitcanbechangedfromtwicedailytooncedailyinclinicallystablepatientswithundetectableviralloadandstableCD4cellcounts(withoutdecline)formorethan6months(24weeks)(seetextbelow).

Adolescent (Weighing ≥25 kg) and Adult Dose: • 300mgtwicedailyor600mgoncedaily.

[Trizivir] Abacavir plus Lamivudine plus ZidovudineAdolescent (Weight ≥40 kg)/Adult Dose: • Onetablettwicedaily.

[Epzicom] Abacavir plus LamivudineAdolescent (Weight ≥25 kg) and Adult Dose: • Onetabletoncedaily.

[Triumeq] Abacavir plus Dolutegravir plus Lamivudine Adolescent (Weight ≥40 kg) and Adult Dose: • Onetabletoncedaily.

Metabolism/Elimination • Systemicallymetabolizedbyalcohol

dehydrogenaseandglucuronyltransferase.

• Intracellularlymetabolizedtocarbovirtriphosphate(CBV-TP).

• Activemetaboliteis82%renallyexcreted.

• Abacavirrequiresdosageadjustmentinhepaticinsufficiency.

• Donotusefixed-dosecombinationssuchasTrizivir,Epzicom,andTriumeq(orthefixed-dosecombination’sgenericequivalents),inpatientswithimpairedhepaticfunctionbecausethedoseofabacavircannotbeadjusted.

• DonotuseTrizivir,Epzicom,andTriumeq(orthefixed-dosecombination’sgenericequivalents)inpatientswithcreatinineclearance(CrCl)<50mL/minandpatientsondialysis(becauseofthefixeddoseoflamivudine).



Selected Adverse Events • Peripheralneuropathy • Diarrhea,abdominalpain,nausea,and

vomiting • Lacticacidosisandseverehepatomegaly

withsteatosis,includingfatalcases,havebeenreported(theriskisincreasedwhendidanosineisusedincombinationwithstavudine).

• Pancreatitis(lesscommoninchildrenthaninadults,morecommonwhendidanosineisusedincombinationwithTDForstavudine)

• Non-cirrhoticportalhypertension • Retinalchanges,opticneuritis • Insulinresistance/diabetesmellitus

Special Instructions • Administerdidanosineonanemptystomach

(30minutesbeforeor2hoursafterameal).Toimproveadherence,somepractitionersadministerdidanosinewithoutregardtotimingofmeals(seetextbelow).

• Didanosinepowderfororalsolutionandtabletsfororalsuspensioncontainantacidsthatmayinterferewiththeabsorptionofothermedications,includingproteaseinhibitors(PIs).SeeindividualPIforinstructionsontimingofadministration.

• Shakedidanosineoralsolutionwellbeforeuse.Keeprefrigerated;solutionisstablefor30days.

• Ifusingtabletsfororalsuspension:Tabletsarenottobeswallowedwhole.Forfull

Didanosine (ddl, Videx) (Last updated April 27, 2017; last reviewed April 27,

2017)


FormulationsVidex Pediatric Powder for Oral Solution:Reconstituted10mg/mLVidex Enteric-Coated (EC) Delayed-Release Capsules (EC Beadlets): 125mg,200mg,250mg,and400mgGeneric Didanosine Delayed-Release Capsules: 125mg,200mg,250mg,and400mgTablets for Oral Suspension:100mg,150mg,and200mg

Dosing RecommendationsNeonatal/Infant Dose (Aged 2 Weeks to <3 Months): • 50mg/m2ofbodysurfaceareaevery12

hours • Seedosingsectionbelowforjustificationof

thisdose.

Infant Dose (Aged ≥3 Months to 8 Months): • 100mg/m2bodysurfaceareaevery12hours

Pediatric Dose of Oral Solution (Age >8 Months): • 120mg/m2bodysurfaceareaevery12hours • Doserange:90–150mg/m2bodysurface

areaevery12hours.Donotexceedmaximumadultdose;seetablebelow.

• Intreatment-naivechildrenages3–21years,240mg/m2bodysurfaceareaoncedaily(oralsolutionorcapsules)haseffectivelyresultedinviralsuppression.

Body Weight (kg) Dose (mg)20kgto<25kg 200mgoncedaily

25kgto<60kg 250mgoncedaily

≥60kg 400mgoncedaily

Pediatric Dose of Videx EC or Generic Capsules (Aged 6–18 Years and Weighing ≥20 kg)

Body Weight (kg) Dose (mg)

<60kg 250mgoncedaily

≥60kg 400mgoncedaily

Adolescent and Adult Dose



therapeuticeffect,2tabletsmaybechewedordispersedinwaterbeforeadministration.Todispersetablets:add2tabletstoatleast1ounce(30mL)ofwater.Drinkentiredispersionimmediately.Forchildren1or2tabletsmaybechewedordispersedinwaterbeforeadministration.

Metabolism/Elimination • Renalexcretion50% • Decreasedosageinpatientswithimpaired

renalfunction.Consultmanufacturer’sprescribinginformationforadjustmentofdosageinaccordancewithcreatinineclearance.

Pediatric/Adolescent Dose of Didanosine when Combined with Tenofovir Disoproxil Fumarate (TDF): • Thiscombinationshouldbeavoidedbecause

ofenhanceddidanosinetoxicity,reportsofimmunologicnon-response,highratesofearlyvirologicfailureandrapidselectionofresistancemutations(GuidelinesfortheUseofAntiretroviralAgentsinHIV-1-InfectedAdultsandAdolescents).



Selected Adverse Events • Severeacuteexacerbationofhepatitiscan

occurinhepatitisBvirus(HBV)-coinfectedpatientswhodiscontinueemtricitabine.

• Hyperpigmentation/skindiscolorationonpalmsand/orsoles.

Special Instructions • Althoughemtricitabinecanbeadministered

withoutregardtofood,foodrequirementsvarydependingontheotherARVdrugscontainedinacombinationtablet.ForAtripla(administerwithoutfood)andComplera(administerwithamealofatleast500calories),refertoefavirenzorrilpivirinespecialinstructions.

• Emtricitabineoralsolutioncanbekeptatroomtemperatureupto77oF(25oC)ifusedwithin3months;refrigerateforlonger-termstorage.

• IfusingStribild,pleaseseetheelvitegravirsectionofthedrugappendixforadditionalinformation.

• Beforeusingemtricitabine,screenpatientsforHBV.

Metabolism/Elimination • Limitedmetabolism:NocytochromeP(CYP)

450interactions.

Dosing RecommendationsNeonatal/Infant Dose (Aged 0 to <3 Months)Oral Solution: • 3mg/kgoncedaily.

Note:PleaseseeSpecialConsiderationsforNeonatessection.

Pediatric Dose (Aged ≥3 Months to 17 Years)Oral Solution: • 6mg/kg(maximumdose240mg)once

daily;highermaximumdosebecausetheoralsolutionhas20%lowerplasmaexposureinpediatricpharmacokineticanalysis.

Capsules (Weight >33 kg): • 200mgoncedaily.

Adolescent (Aged ≥18 Years)/Adult DoseOral Solution for Those Unable to Swallow Capsules: • 240mg(24mL)oncedaily.

Capsules: • 200mgoncedaily.

Combination Tablets[Truvada tablet] Emtricitabine plus TDF

Emtricitabine (FTC, Emtriva) (Last updated July 10, 2017; last reviewed July 10, 2017)

ForadditionalinformationseeDrugs@FDA:http://www.accessdata.fda.gov/scripts/cder/daf

FormulationsPediatric Oral Solution:10mg/mLCapsules: 200mgGeneric Formulations:NoneavailableFixed-Dose Combination Tablets: • [Truvada low strength tablet] • Emtricitabine100mgplustenofovirdisoproxilfumarate(TDF)150mg • Emtricitabine133mgplusTDF200mg • Emtricitabine167mgplusTDF250mg • [Truvada tablet] Emtricitabine200mgplusTDF300mg • [Descovy] Emtricitabine200mgplustenofoviralafenamide(TAF)25mg • [Atripla]Efavirenz600mgplusemtricitabine200mgplusTDF300mg • [Complera]Emtricitabine200mgplusrilpivirine25mgplusTDF300mg • [Odefsey]Emtricitabine200mgplusrilpivirine25mgplusTAF25mg • [Stribild]Elvitegravir150mgpluscobicistat150mgplusemtricitabine200mgplusTDF300mg • [Genvoya]Elvitegravir150mgpluscobicistat150mgplusemtricitabine200mgplusTAF10mg



[Descovy] Emtricitabine plus TAF Adolescent (Weighing >35 kg) and Adult Dose: • 1tabletoncedaily

[Atripla] Efavirenz plus Emtricitabine plus TDF 300 mgAdolescent (Weighing ≥40 kg) and Adult Dose: • 1tabletoncedaily. • Administerwithoutfood. • Seeefavirenzsectionforpregnancywarning.

[Complera] Emtricitabine plus Rilpivirine plus TDFAdolescent (Weighing ≥35 kg) and Adult Dose: • 1tabletoncedailyintreatment-naivepatients

withbaselineplasmaRNA<100,000copies/mLorvirologicallysuppressedpatientswithnohistoryofvirologicfailure,resistancetorilpivirineandotherantiretroviral(ARV)drugs,andwhoarecurrentlyontheirfirstorsecondregimen.

• Administerwithamealofatleast500calories.

[Odefsey] Emtricitabine plus Rilpivirine plus (TAF)Adolescent (Weighing ≥35 kg) and Adult Dose: • 1tabletoncedailywithamealasinitialtherapy

inthosewithnoantiretroviraltreatment(ART)historywithHIV-1RNA≤100,000copiespermL;ortoreplaceastableARTregimeninthosewhoarevirologically-suppressed(HIV-1RNA<50copies/mL)foratleast6monthswithnohistoryoftreatmentfailureandnoknownsubstitutionsassociatedwithresistancetotheindividualcomponentsofOdefsey.


[Stribild] Elvitegravir plus Cobicistat plus Emtricitabine plus TDF Adult Dose (Aged ≥18 Years): • 1tabletoncedailyintreatment-naiveor

virologicallysuppressedadults. • Administerwithameal.

[Genvoya] Elvitegravir plus Cobicistat plus Emtricitabine plus TAF

• Renalexcretion86%:Potentialcompetitionwithothercompoundsthatundergorenalelimination.

• Dosingofemtricitabineinpatientswithrenalimpairment:Decreasedosageinpatientswithimpairedrenalfunction.Consultmanufacturer’sprescribinginformation.

• DonotuseAtripla(fixed-dosecombination)inpatientswithcreatinineclearance(CrCl)<50mL/minorinpatientsrequiringdialysis.

• DonotuseTruvada(fixed-dosecombination)inpatientswithCrCl<30mL/minorinpatientsrequiringdialysis.

• UseComplerawithcautioninpatientswithsevererenalimpairmentorend-stagerenaldisease.Increasemonitoringforadverseeventsbecauserilpivirineconcentrationsmaybeincreasedinpatientswithsevererenalimpairmentorend-stagerenaldisease.

• StribildshouldnotbeinitiatedinpatientswithestimatedCrCl<70mL/minandshouldbediscontinuedinpatientswithestimatedCrCl<50mL/min.

• TAF-containingformulationsarenotrecommendedinpatientswithestimatedCrClbelow30mLperminute.

Body Weight kg

FTC/TDF Tablet OnceDaily

17to<22 One100mg/150mgtablet22to<28 One133mg/200mgtablet28to<35 One167mg/250mgtablet

Adolescent(Weighing≥35kg)andAdultDose

One200mg/300mgtablet

Truvada Tablets Dosing Table



Adolescent (Aged ≥12 Years and Weighing ≥35 kg) and Adult Dose: • 1tabletoncedailywithfoodinART-naive

patientsortoreplacethecurrentARTregimeninthosewhoarevirologicallysuppressed(i.e.,HIV-1RNA<50copies/mL)onastableARTregimenforatleast6monthswithnohistoryoftreatmentfailureandnoknownsubstitutionsassociatedwithresistancetotheindividualcomponentsofGenvoya.



Dosing RecommendationsNeonate and Infant Dose (Birth to <4 Weeks): • 2mg/kgtwicedaily

Note:PleaseseeInfantARVProphylaxisintheRecommendationsforUseofAntiretroviralDrugsinPregnantHIV-1-InfectedWomenforMaternalHealthandInterventionstoReducePerinatalHIVTransmissioninTheUnitedStatesfordosingusedtopreventperinataltransmission.

Pediatric Dose (Aged ≥4 Weeks): • 4mg/kg(upto150mg)twicedaily • Ininfantsandyoungchildrenbeingtreated

withliquidformulationsoflamivudine,initiationwithonce-dailylamivudineisnotgenerallyrecommended.Pleaserefertotextformoredetail.

Selected Adverse Events • Minimaltoxicity • Exacerbationofhepatitishasbeenreported

afterdiscontinuationoflamivudineinthesettingofchronichepatitisBvirus(HBV)infection.

Special Instructions • Lamivudinecanbegivenwithoutregardto

food. • Storelamivudineoralsolutionatroom

temperature. • ScreenpatientsforHBVinfectionbefore

administeringlamivudine.

Metabolism/Elimination • Renalexcretion:Dosageadjustmentrequired

inrenalinsufficiency. • Fixed-dosecombinationtabletsshouldnotbe

usedinpatientswithcreatinineclearance<50mL/min,ondialysis,orwithimpairedhepaticfunction.

WeightTwice-

Daily AM Dose

Twice- Daily PM

DoseOnce-Daily

Dose

14to<20kg ½tablet (75mg)

½tablet (75mg)

1tablet 150mg

≥20to<25kg ½tablet (75mg)

1tablet(150mg)

1½tablets 225mg

≥25kg 1tablet(150mg)

1tablet(150mg)

2tablets (300mg)

Weight-Band Dosing (Weighing ≥14 kg) Scored 150 mg tablet

Lamivudine (3TC, Epivir) (Last updated April 27, 2017; last reviewed April 27, 2017)

ForadditionalinformationseeDrugs@FDA:https://www.accessdata.fda.gov/scripts/cder/daf/

FormulationsPediatric Oral Solution:10mg/mL(Epivir),5mg/mL(EpivirHBVa)Tablets:150mg(scored)and300mg(generic);100mg(EpivirHBVa)Fixed-Dose Combination Tablets: • [Combivir and generic]Lamivudine150mgpluszidovudine300mg • [Epzicom]Abacavir600mgpluslamivudine300mg • [Trizivir]Abacavir300mgpluslamivudine150mgpluszidovudine300mg • [Triumeq]Abacavir600mgplusdolutegravir50mgpluslamivudine300mg

Generic Formulations Tablets: 100mg,150mg,and300mg



Note:ThePanelonAntiretroviralTherapyandMedicalManagementofChildrenLivingwithHIV(thePanel)supportsconsiderationofswitchingtoonce-dailydosingoflamivudinefromtwice-dailydosinginclinicallystablepatientsaged≥3 yearswithareasonableonce-dailyregimen,anundetectableviralload,andstableCD4Tlymphocytecount,atadoseof8to10mg/kg/dosetoamaximumof300mgoncedaily.

Adolescent and Adult Dose:Weighing <25 kg: • 4mg/kg(upto150mg)twicedaily

Weighing ≥25 kg: • 150mgtwicedailyor300mgoncedaily

[Combivir and Generic] Lamivudine/Zidovudine Adolescent (Weighing ≥30 kg)/Adult Dose: • 1tablettwicedaily

[Trizivir and Generic] Abacavir/Lamivudine/Zidovudine Adolescent (Weighing ≥40 kg)/Adult Dose: • 1tablettwicedaily

[Epzicom] Abacavir/Lamivudine Adolescent(Weighing≥25kg)/AdultDose: • 1tabletoncedaily

[Triumeq] Abacavir/Dolutegravir/Lamivudine Adolescent (Weighing ≥40 kg)/Adult Dose: • 1tabletoncedaily



Dosing RecommendationsNeonate/Infant Dose (Birth to 13 Days): • 0.5mg/kgperdosetwicedaily

Pediatric Dose (Aged ≥14 Days and Weighing <30 kg): • 1mg/kgperdosetwicedaily

Adolescent (≥30 kg)/Adult Dose: • 30mgperdosetwicedaily

Selected Adverse Events • Mitochondrialtoxicity,highestriskofallNRTI

drugs

• Peripheralneuropathyisdose-relatedandoccursmorefrequentlyinpatientswithadvancedHIVdisease,ahistoryofperipheralneuropathy,andinpatientsreceivingotherdrugsassociatedwithneuropathy.

• Facial/peripherallipoatrophy

• Pancreatitis

• Lacticacidosis/severehepatomegalywithhepaticsteatosis(higherincidencethanwithothernucleosidereversetranscriptaseinhibitors).Theriskisincreasedwhenusedincombinationwithdidanosine.

• Dyslipidemia

• Insulinresistance,asymptomatichyperglycemia

• Rapidlyprogressiveascendingneuromuscularweakness(rare)

Special Instructions • Stavudinecanbegivenwithoutregardtofood.

• Shakestavudineoralsolutionwellbeforeuse.Keeprefrigerated;thesolutionisstablefor30days.

Metabolism/Elimination • Renalexcretion50%.Decreasedoseinrenal

dysfunction.

• Stavudineisphosphorylatedintracellularlytotheactivemetabolitestavudinetriphosphate.

Stavudine (d4T, Zerit) (Last updated April 27, 2017; last reviewed April 27, 2017)


FormulationsPowder for Oral Solution:1mg/mLCapsules:15mg,20mg,30mg,and40mgGeneric Formulations: PowderforOralSolution:1mg/mL Capsules:15mg,20mg,30mg,40mg



Dosing RecommendationsCombination Tablets[Descovy] Emtricitabine 200 mg plus TAF 25 mg

Pediatric/Adolescent (Weighing ≥35 kg) and Adult Dose: • 1tabletoncedaily

[Genvoya] Elvitegravir plus Cobicistat plus Emtricitabine plus TAF

Pediatric/Adolescent (Weighing ≥35 kg) and Adult Dose: • 1tabletoncedailywithfoodinantiretroviral

(ARV)treatment-naivepatientsortoreplacethecurrentARVregimeninthosewhoarevirologicallysuppressed(i.e.,HIV-1RNA<50copies/mL)andonastableARVregimenforatleast6monthswithnohistoryoftreatmentfailureandnoknownsubstitutionsassociatedwithresistancetotheindividualcomponentsofGenvoya.

[Odefsey] Emtricitabine plus Rilpivirine plus TAF

Pediatric/Adolescent (Weighing ≥35 kg) and Adult Dose: • 1tabletoncedailywithamealasinitial

therapyinthosewithnoARVtreatmenthistorywithHIV-1RNAlessthanorequalto100,000copiespermL;ortoreplaceastableARVregimeninthosewhoarevirologically-suppressed(HIV-1RNAlessthan50copiespermL)foratleast6monthswithnohistoryoftreatmentfailureandnoknownsubstitutionsassociatedwithresistancetotheindividualcomponentsofOdefsey.

Tenofovir Alafenamide (TAF, Genvoya) (Last updated April 27, 2017; last reviewed April 27, 2017)


FormulationsFixed-Dose Combination Tablets • [Descovy]Emtricitabine200mgplustenofoviralafenamide(TAF)25mg • [Genvoya]Elvitegravir150mgpluscobicistat150mgplusemtricitabine200mgplusTAF10mg • [Odefsey]Emtricitabine200mgplusrilpivirine25mgplusTAF25mg

Selected Adverse Events • Asthenia,headache,diarrhea,nausea • Increasedserumlipids

Special Instructions • Measureserumcreatininebeforestartinga

TAF-containingregimen. • ScreenpatientsforhepatitisBvirus(HBV)

infectionbeforeuseofTAF.SevereacuteexacerbationofHBVinfectioncanoccurwhenTAFisdiscontinued;therefore,inpatientswithHBVinfectionmonitorhepaticfunctionforseveralmonthsaftertherapywithTAFisstopped.

• IfusingDescovypleaseseetheEmtricitabine sectionofthedrugappendix.

• IfusingGenvoyapleaseseetheElvitegravir,Emtricitabine,andCobicistatsectionsofthedrugappendixforadditionalinformation.

• UseofGenvoyaisnotrecommendedwithotherARVdrugs.

• DonotuseGenvoyawithelvitegravir,cobicistat,tenofovirdisoproxilfumarate,emtricitabine,lamivudine,orproteaseinhibitorsco-formulatedwithcobicistat.

• WhenusingOdefsey,refertotheEmtricitabine andRilpivirinesectionsofthedrugappendix.Patientsmustbeabletotakerilpivirinewithamealofatleast500caloriesonaregularschedule(aproteindrinkalonedoesnotconstituteameal).

Pharmacology • TAFundergoesrenalexcretion. • Dosinginpatientswithrenalinsufficiency:TAF-

containingformulationsarenotrecommendedinpatientswithestimatedcreatinineclearancebelow30mLperminute.



• TAF-containingformulationsdonotrequiredosageadjustmentinpatientswithmildormoderatehepaticimpairment,butshouldnotbeusedinpatientswithseverehepaticimpairmentbecausetheyhavenotbeenstudiedinthatgroup.



Dosing RecommendationsNeonate/Infant Dose: • NotFoodandDrugAdministration-approved

orrecommendedforuseinneonates/infantsaged<2years.

Pediatric Dose (Aged ≥2 Years to <12 Years)a: • 8mg/kg/doseoncedaily

TDF Oral Powder Dosing Table

Selected Adverse Events • Asthenia,headache,diarrhea,nausea,

vomiting,flatulence • Renalinsufficiency,proximalrenaltubular

dysfunctionthatmayincludeFanconisyndrome

• Decreasedbonemineraldensitya

Special Instructions • Donotcrushtablets;TDForalpowder

formulationisavailableforpatientsunabletoswallowtablets.

• TDForalpowdershouldbemeasuredonlywiththesupplieddosingscoop:1levelscoop=1gpowder=40mgTDF.

• MixTDForalpowderin2to4ozofsoftfoodthatdoesnotrequirechewing(e.g.,applesauce,yogurt).Administerimmediatelyaftermixingtoavoidthebittertaste.

• DonottrytomixtheTDForalpowderwithliquid.Thepowdermayfloatonthetopevenaftervigorousstirring.

• AlthoughTDFcanbeadministeredwithoutregardtofood,foodrequirementsvarydependingontheotherantiretroviral(ARV)drugscontainedinacombinationtablet.

Body Weight kg

TDF Oral Powder OnceDailyScoopsofPowder

10to<12 2scoops(80mg)

12to<14 2.5scoops(100mg)










≥35 7.5scoops(300mg)

Tenofovir Disoproxil Fumarate (TDF, Viread) (Last updated April 27,

2017; last reviewed April 27, 2017)


FormulationsOral Powder:40mgper1goforalpowder(1levelscoop=1goralpowder;suppliedwithdosingscoop)

Tablets:150mg,200mg,250mg,and300mg

Fixed-Dose Combination Tablets • [Truvada low strength tablet] • Emtricitabine100mgplustenofovirdisoproxilfumarate(TDF)150mg • Emtricitabine133mgplusTDF200mg • Emtricitabine167mgplusTDF250mg

• [Truvada tablet]Emtricitabine200mgplusTDF300mg • [Atripla]Efavirenz600mgplusemtricitabine200mgplusTDF300mg • [Complera]Emtricitabine200mgplusrilpivirine25mgplusTDF300mg • [Stribild]Elvitegravir150mgpluscobicistat150mgplusemtricitabine200mgplusTDF300mg



aSeetextforconcernsaboutdecreasedBMD,especiallyinpre-pubertalpatientsandthoseinearlypuberty(TannerStages1and2).

ForAtripla(administerwithoutfood)andComplera(administerwithamealofatleast400calories),refertoefavirenzorrilpivirinespecialinstructions,respectively. • Measureserumcreatinineandurinedipstick

forproteinandglucosebeforestartingaTDF-containingregimenandmonitorserumcreatinineandurinedipstickforproteinandglucoseatintervals(seeTable15i)duringcontinuedtherapy.Measureserumphosphateifclinicalsuspicionofhypophosphatemia.

• ScreenpatientsforhepatitisBvirus(HBV)infectionbeforeuseofTDF.SevereacuteexacerbationofHBVinfectioncanoccurwhenTDFisdiscontinued;therefore,inpatientswithHBVinfection,monitorhepaticfunctionforseveralmonthsaftertherapywithTDFisstopped.

• IfusingStribild,pleaseseetheelvitegravirandcobicistatsectionsofthedrugappendixforadditionalinformation.

Metabolism/Elimination • Renalexcretion

• DosingofTDFinpatientswithrenalinsufficiency:Decreaseddosageshouldbeusedinpatientswithimpairedrenalfunction(creatinineclearance<50mL/min).Consultmanufacturer’sprescribinginformationforadjustmentofdosageinaccordancewithcreatinineclearance(CrCl).

• AtriplaandComplera(fixed-dosecombinations)shouldnotbeusedinpatientswithCrCl<50mL/minorinpatientsrequiringdialysis.

• Truvada(fixed-dosecombination)shouldnotbeusedinpatientswithCrCl<30mL/minorinpatientsrequiringdialysis.

• StribildshouldnotbeinitiatedinpatientswithestimatedCrCl<70mL/minandshouldbediscontinuedinpatientswithestimatedCrCl<50mL/min.

• Stribildshouldnotbeusedinpatientswithseverehepaticimpairment.

Adolescent (Weighing ≥35 kg)a and Adult Dose: • TDF300mgoncedaily

Combination Tablets[Truvada] Emtricitabine plus TDF

[Atripla] Efavirenz plus Emtricitabine plus TDF Adolescent (Aged ≥12 years and Weighing ≥40 kg) and Adult Dose: • 1tabletoncedaily.

[Complera] Emtricitabine plus Rilpivirine plus TDFAdolescent (Weighing ≥35 kg) and Adult Dose: • 1tabletoncedailyintreatment-naiveadults

withbaselineviralload<100,000copies/mLorvirologicallysuppressedadults,withnohistoryofvirologicfailure,resistancetorilpivirineandotherARVdrugs,andwhoarecurrentlyontheirfirstorsecondregimen.


[Stribild] Elvitegravir plus Cobicistat plus Emtricitabine plus TDFAdolescent (Weighing >35 kg) and Adult Dose: • 1tabletoncedailyintreatment-naiveadultsor

toreplacethecurrentARVregimeninthosewhoarevirologicallysuppressed(HIV-1RNA<50copies/mL)onastableARVregimenforatleast6monthswithnohistoryoftreatmentfailureandnoknownsubstitutionsassociatedwithresistancetotheindividualcomponentsofStribild.

• Administerwithfood.

Body Weight kg

TDF Tablet OnceDaily

17to<22 150mg22to<28 200mg28to<35 250mg

≥35 300mg

TDF Tablet Dosing Table (Aged ≥2 Years and Weighing ≥17 kg)

Body Weight kg

FTC/TDF Tablet OnceDaily

17to<22 OneFTC100mg/TDF150mgtablet22to<28 OneFTC133mg/TDF200mgtablet28to<35 OneFTC167mg/TDF250mgtablet

≥35(AdolescentandAdult)

OneFTC200mg/TDF300mgtablet

Truvada Tablets Dosing Table



Selected Adverse Events • Bonemarrowsuppression:macrocytosiswith

orwithoutanemia,neutropenia

• Nausea,vomiting,headache,insomnia,asthenia

• Lacticacidosis/severehepatomegalywithhepaticsteatosis

• Lipodystrophyandlipoatrophy

• Myopathy(associatedwithprolongeduse)andmyositis

Special Instructions • Givezidovudinewithoutregardtofood.

• Ifsubstantialgranulocytopeniaoranemiadevelopsinpatientsreceivingzidovudine,itmaybenecessarytodiscontinuetherapyuntilbonemarrowrecoveryisobserved.Inthissetting,somepatientsmayrequireerythropoietinorfilgrastiminjectionsortransfusionsofredbloodcells.

Metabolism/Elimination • Metabolizedprimarilyintheliverto

zidovudineglucuronide,whichisrenallyexcreted.

• Zidovudineisphosphorylatedintracellularlytoactivezidovudine-triphosphate.

• Dosinginpatientswithrenalimpairment:Dosageadjustmentisrequiredinrenal

Dosing RecommendationsRecommended Neonatal Dose for

Treatment of HIVa

Weeks’ Gestation at Birth

Zidovudine Oral Dosing: •Twice-DailyDosing

Note:Forinfantsunabletotolerateoralagents,theIVdoseshouldbe75%oftheoraldosewhilemaintainingthesamedosinginterval.

≥35 Weeks’ Gestation at Birth

Birth to Age 4 Weeks: •4mg/kgorallytwicedailyoralternativesimplifiedweightbanddosing

Simplified Weight Band Dosing for Infants Aged ≥35 Weeks:

Note:Providesapproximately4mg/kgorallytwicedailyfrombirthto4weeksofage

Aged >4 Weeks: •12mg/kgorallytwicedaily

≥30 to <35 Weeks’ Gestation at Birth

Birth to Age 2 Weeks: •2mg/kgorallytwicedaily

Aged 2 Weeks to 6 to 8 Weeks: •3mg/kgorallytwicedaily

Aged >6 to 8 Weeks: •12mg/kgorallytwicedaily

Weight Band (kg)

Volume (mL) ZDV 10 mg/mL Oral Syrup Twice Daily

2to<3kg 1mL

3to<4kg 1.5mL

4to<5kg 2mL

Zidovudine (ZDV, AZT, Retrovir) (Last updated April 27, 2017; last reviewed April 27, 2017)


FormulationsCapsules:100mg

Tablets:300mg

Syrup:10mg/mL

Concentrate for Injection or Intravenous (IV) Infusion:10mg/mL

Generic Formulations:Zidovudinecapsules,tablets,syrup,andinjectionareapprovedbytheFoodandDrugAdministrationformanufactureanddistributionintheUnitedStates.

Fixed-Dose Combination Tablets: • [Combivir and Generic]Lamivudine150mgpluszidovudine300mg

• [Trizivir]Abacavir300mgpluslamivudine150mgpluszidovudine300mg



Infant/Child Dose (Age ≥35 Weeks Post-Conception and ≥4 Weeks Post-Delivery with Body Weight ≥4 kg):Weight-Based Dosing

Alternative Body Surface Area Dosing: • Oral:180–240mg/m2bodysurfaceareaevery

12hours

Adolescent (Aged ≥18 Years) and Adult Dose: • 300mgtwicedaily

[Combivir and Generic] Lamivudine plus Zidovudine Adolescent (Weight ≥30 kg) and Adult Dose: • 1tablettwicedaily

[Trizivir] Abacavir plus Lamivudine plus ZidovudineAdolescent (Weight ≥40 kg) and Adult Dose: • 1tablettwicedaily

Body Weight Twice-Daily Dosing4kgto<9kg 12mg/kg9kgto<30kg 9mg/kg≥30kg 300mg

insufficiency.

• Dosinginpatientswithhepaticimpairment:Decreaseddosingmayberequiredinpatientswithhepaticimpairment.

• Donotusefixed-dosecombinationproducts(e.g.,Combivir,Trizivir)inpatientswithcreatinineclearance<50mL/min,ondialysis,orwhohaveimpairedhepaticfunction.

Recommended Neonatal Dosing for Treatment of HIVa

<30 Weeks’ Gestation at Birth

Birth to Age 4 Weeks: •2mg/kgorallytwicedaily

Aged 4 Weeks to 8 to 10 Weeks:•3mg/kgorallytwicedaily

Aged >8 to 10 Weeks:•12mg/kgorallytwicedaily

aForpreventionofperinataltransmissionseeRecommendationsforUseofAntiretroviralDrugsinPregnantHIV-1-InfectedWomenforMaternalHealthandInterventionstoReducePerinatalHIVTransmissionintheUnitedStates.



Selected Adverse Events • Rash,whichisgenerallymildandtransient,

andappearstobemorecommoninchildrenthaninadults

• Centralnervoussystemsymptomssuchasfatigue,poorsleepingpatterns,vividdreams,impairedconcentration,agitation,seizures,depression,suicidalideation

• False-positivewithsomecannabinoidandbenzodiazepinetests

• Gynecomastia • Hepatotoxicity • QTcprolongationhasbeenobservedwith

theuseofefavirenz.Consideralternativestoefavirenzwhenco-administeredwithadrugwithknownriskofTorsades de PointesorwhenadministeredtopatientsathigherriskofTorsades de Pointes

Special Instructions • Efavirenzcanbeswallowedasawhole

capsuleortabletoradministeredbysprinklingthecontentsofanopenedcapsuleonfoodasdescribedbelow.

• AdministerwholecapsuleortabletofAtriplaonanemptystomach.Avoidadministrationwithahigh-fatmealbecauseofpotentialforincreasedabsorption.

• Bedtimedosingisrecommended,particularlyduringthefirst2to4weeksoftherapy,toimprovetolerabilityofcentralnervoussystemsideeffects.

• Efavirenzshouldbeusedwithcautioninfemaleadolescentsandadultswithreproductivepotentialbecauseofthepotentialriskofteratogenicity.

Dosing RecommendationsNeonatal Dose: • Efavirenzisnotapprovedforuseinneonates.

Pediatric Dose:Infants and Children Aged 3 Months to <3 Years and Weighing ≥3 kg: • ThePanelonAntiretroviralTherapyandMedical

ManagementofChildrenLivingwithHIV(thePanel)recommendsthatefavirenzgenerallynotbeusedinchildrenaged3monthsto<3years.Ifuseofefavirenzisunavoidableduetotheclinicalsituation,thePanelsuggeststheuseofinvestigationaldosesofefavirenzinthisagegroup.Seetextforinvestigationaldosingtables;evaluationofCYP2B6genotypeisrequiredpriortouse.Therapeuticdrugmonitoringshouldbeconsideredwithanefavirenzplasmaconcentrationmeasured2weeksafterinitiation;someexpertswouldalsomeasureatage3yearsaftermakingthetransitiontothenewdose(seetextundertherapeuticdrugmonitoringatthebottomofthissection).Fordoseadjustmentbasedonefavirenzconcentrations,consultationwithanexpertisrecommended.

Children Aged ≥3 Years and Weighing ≥10 kg:

Note:SeeTables1aand1bintextforrecommendeddosingifEFVmustbeusedinchildrenaged<3years

Efavirenz (EFV, Sustiva) (Last updated April 27, 2017; last reviewed April 27,

2017)


FormulationsCapsules:50mg,200mgTablets:600mgFixed-Dose Combination Tablets: • [Atripla]Efavirenz600mgplusemtricitabine200mgplustenofovirdisoproxilfumarate(TDF)300mg



Instructions for Use of Capsule as a Sprinkle Preparation with Food or Formula: • Holdcapsulehorizontallyoverasmallcontainer

andcarefullytwisttoopentoavoidspillage. • Gentlymixcapsulecontentswith1–2

teaspoonsofanage-appropriatesoftfood(e.g.,applesauce,grapejelly,yogurt),orreconstitutedinfantformulaatroomtemperature.

• Administerinfantformulamixtureusinga10-mLsyringe.

• Afteradministration,anadditional2teaspoonsoffoodorinfantformulamustbeaddedtothecontainer,stirred,anddispensedtothepatient.

• Administerwithin30minutesofmixinganddonotconsumeadditionalfoodorformulafor2hoursafteradministration.

Metabolism/Elimination • CytochromeP4503A(CYP3A)andCYP2B6

inducerin vivoandCYP2C9,2C19,and3A4isozymeinhibitorin vitro.

• Dosingofefavirenzinpatientswithhepaticimpairment:Norecommendationiscurrentlyavailable;usewithcautioninpatientswithhepaticimpairment.

• AdultdoseofAtriplainpatientswithrenalimpairment:BecauseAtriplaisafixed-dosecombinationproductandTDFandemtricitabinerequiredoseadjustmentbasedonrenalfunction,Atriplashouldnotbeusedinpatientswithcreatinineclearance<50mL/minuteorinpatientsondialysis.

• InterpatientvariabilityinefavirenzexposurecanbeexplainedinpartbypolymorphismsinCYP450withslowermetabolizersathigherriskoftoxicity(seetextforinformationabouttherapeuticdrugmonitoringformanagementofmildormoderatetoxicity).

Adolescent (Weighing ≥40 kg) and Adult Dose: • 600mgoncedaily

[Atripla] Efavirenz plus Emtricitabine plus TDF • Atriplashouldnotbeusedinpediatric

patients<40kgastheefavirenzdoseof600mgwouldbeexcessive.

Adult Dose: • Onetabletoncedaily

Weight (kg) Efavirenz Dose (mg)a,b

10kgto<15kg 200mg15kgto<20kg 250mg20kgto<25kg 300mg25kgto<32.5kg 350mg32.5kgto<40kg 400mg

≥40kg 600mg

Administer Efavirenz Once Daily

aThedoseinmgcanbedispensedinanycombinationofcapsulestrengths.bSomeexpertsrecommendadoseof367mg/m2bodysurfacearea(maximumdose600mg)becauseofconcernforunder-dosing,especiallyattheupperendofeachweightband(seePediatricUsefordetails).



Dosing RecommendationsNeonate/Infant Dose: • Notapprovedforuseinneonates/infants.

Pediatric Dose: • Notapprovedforuseinchildrenaged

<6years.Studiesininfantsandchildrenaged2monthsto6yearsareunderway.

Adult Dose (Antiretroviral-Experienced Patients): • 200mgtwicedailyfollowingameal

Antiretroviral-Experienced Children and Adolescents Aged 6–18 Years (and Weighing ≥16 kg)

Body Weight Kilogram (kg) Dose

16kgto<20kg 100mgtwicedaily



≥30kg 200mgtwice

Selected Adverse Events • Nausea • Diarrhea • Rash,includingStevens-Johnsonsyndrome • Hypersensitivitywithrash,constitutional

findings,andsometimesorgandysfunction,includinghepaticfailure.

Special Instructions • Alwaysadministeretravirinefollowinga

meal.Areaunderthecurveofetravirineisdecreasedbyabout50%whenthedrugistakenonanemptystomach.Thetypeoffooddoesnotaffecttheexposuretoetravirine.

• Etravirinetabletsaresensitivetomoisture;storeatroomtemperatureinoriginalcontainerwithdesiccant.

• Patientsunabletoswallowetravirinetabletsmaydispersethetabletsinliquid,asfollows:Placethetablet(s)in5mL(1teaspoon)ofwater,orenoughliquidtocoverthemedication,andstirwelluntilthewaterlooksmilky.Ifdesired,addmorewateroralternativelyorangejuiceormilk.Note: Patientsshouldnotplacethetabletsinorangejuiceormilkwithoutfirstaddingwater.Theuseofgrapefruitjuice,warm(>40°C)drinks,orcarbonatedbeveragesshouldbeavoided.Drinkimmediately,thenrinsetheglassseveraltimeswithwater,orangejuice,ormilkandcompletelyswallowtherinseeachtimetomakesuretheentiredoseisconsumed.

• Dosingofetravirineinpatientswithhepaticimpairment:Nodosageadjustmentisnecessaryforpatientswithmild-to-moderatehepaticinsufficiency.Nodosinginformationisavailableforpatientswithseverehepaticimpairment.

Etravirine (ETR, Intelence, TMC 125) (Last updated April 27, 2017; last

reviewed April 27, 2017)


FormulationsTablets:25mg,100mg,and200mg



• Dosingofetravirineinpatientswithrenalimpairment:Doseadjustmentisnotrequiredinpatientswithrenalimpairment.

Metabolism/Elimination • EtravirineisaninducerofcytochromeP450

3A4(CYP3A4)andaninhibitorofCYP2C9,CYP2C19,andP-glycoprotein.ItisasubstrateforCYP3A4,2C9,and2C19.

• Multipleinteractionswithantiretroviralagentsandotherdrugs(seetextbelow)



Selected Adverse Events • Rash,includingStevens-Johnsonsyndrome • Symptomatichepatitis,includingfatalhepatic

necrosis • Severesystemichypersensitivitysyndrome

withpotentialformultisystemorganinvolvementandshock

Special Instructions • Shakesuspensionwellbeforeadministering

andstoreatroomtemperature. • Canbegivenwithoutregardtofood. • Nevirapine-associatedskinrashusually

occurswithinthefirst6weeksoftherapy.Ifrashoccursduringtheinitial14daylead-inperiod,donotincreasedoseuntilrashresolves(seeMajorToxicitiessection).

• Nevirapineextended-releasetabletsmustbeswallowedwhole.Theycannotbecrushed,chewed,ordivided.

• Ifnevirapinedosingisinterruptedformorethan14days,nevirapinedosingshouldberestartedwithonce-dailydosingfor14days,followedbyescalationtothefull,twice-dailyregimen(seeDosingConsiderations:Lead-InRequirement).

• Mostcasesofnevirapine-associatedhepatictoxicityoccurduringthefirst12weeksoftherapy;frequentclinicalandlaboratorymonitoring,includingliverfunctiontests,isimportantduringthisperiod(seeMajorToxicities).

Metabolism/Elimination • MetabolizedbycytochromeP450(3A

inducer);80%excretedinurine

Nevirapine (NVP, Viramune) (Last updated April 27, 2017; last reviewed April 27,

2017)


FormulationsTablets:Immediate-release200mg,extended-release(XR)100mgand400mgSuspension: 10mg/mL

Generic Formulations Tablets:Immediate-release200mg,extended-release(XR)400mgonlySuspension:NolongeravailableintheUnitedStates

Dosing RecommendationsNeonate/Infant Dose (≤14 Days) for Prevention: • SeeInfantAntiretroviralProphylaxisand

NeonatalAntiretroviralDrugDosingofthePerinatalGuidelinesfordosing.

Treatment of HIV Infection:Pediatric Dose: Immediate Release and Suspension Formulations • Inmostsituations,nevirapineisgivenonce

dailyfor2weekstoallowforautoinductionofenzymesinvolvedinitsmetabolism.Thismaynotbenecessaryinchildrenaged<2years.Seetextandfootnote.a

Aged <1 Month (Investigational dose not Food and Drug Administration approved): • 34–37weeksgestationalage(noleadin;

pleaseseetextandfootnotea):4mg/kg/dosetwicedailyforthefirstweekincreasingto6mg/kg/dosetwicedailythereafter

• �≥37weeksgestationalageto<1month:6mg/kg/dosetwicedaily(noleadin;pleaseseetextandfootnotea)

• SeeDosing:SpecialConsiderations:Neonates≤14DaysandPrematureInfants

Aged ≥1 Month to <8 Years:

• 200mg/m2ofbodysurfacearea(BSA)/dosetwicedailyafterlead-indosing.aInchildrenaged≤2years,someexpertsinitiatenevirapinewithoutalead-in(maximumdoseofimmediate-releasetabletsis200mgtwicedaily).

Aged ≥8 Years:

• 120–150mg/m2BSA/dosetwicedailyafterlead-indosinga(maximumdoseofimmediate-releasetabletsis200mgtwicedaily.)

• Whenadjustingthedoseforagrowingchild,



(glucuronidatedmetabolites). • Dosingofnevirapineinpatientswithrenal

failurereceivinghemodialysis:Anadditionaldoseofnevirapineshouldbegivenfollowingdialysis.

• Dosingofnevirapineinpatientswithhepaticimpairment:Nevirapineshouldnotbeadministeredtopatientswithmoderateorseverehepaticimpairment.

aNevirapineisusuallyinitiatedatalowerdoseandincreasedinastepwisefashiontoallowinductionofcytochromeP450metabolizingenzymes,whichresultsinincreaseddrugclearance.Theoccurrenceofrashisdiminishedbythisstepwiseincreaseindose.Initiatetherapywiththeage-appropriatedoseoftheimmediate-releaseformulationoncedaily(half-dailydose)forthefirst14daysoftherapy.Ifthereisnorashoruntowardeffect,at14daysoftherapy,increasetotheage-appropriatefulldose,administeredtwicedaily,oftheimmediate-releasepreparation.However,inchildrenaged≤2years,someexpertsinitiatenevirapinewithoutalead-in(seeDosingConsiderations:Lead-InRequirementandDosing:SpecialConsiderations:Neonates≤14DaysandPrematureInfants).Inpatientsalreadyreceivingfull-doseimmediate-releasenevirapine,extended-releasetabletscanbeusedwithoutthe200-mglead-inperiod.Patientsmustswallownevirapineextended-releasetabletswhole.Theymustnotbechewed,crushed,ordivided.Patientsmustnevertakemorethan1formofnevirapineatthesametime.Doseshouldnotexceed400mgdaily.

themgdoseneednotbedecreasedasthechildreachesage8years;rather,themgdoseisleftstatictoachievetheappropriatemg-per-m2dosageasthechildgrows,aslongastherearenountowardeffects.

Pediatric Dose Extended-Release Formulation (≥6 Years): • Patients≥6yearswhoarealreadytaking

immediate-releasenevirapinetwicedailycanbeswitchedtonevirapineextendedreleasewithoutlead-indosing.Pleaseseefootnote.a

Adolescent and Adult Dose: • 200mgtwicedailyor400mgextendedrelease

oncedaily.

Nevirapine in Combination with Lopinavir/ Ritonavir:Ahigherdoseofritonavir-boostedlopinavirmaybeneeded(seeRitonavir-BoostedLopinavirsection).

BSA Range (m2) NVP XR (mg)0.58–0.83 200mgoncedaily(2x100mg)

0.84–1.16 300mgoncedaily(3x100mg)

≥1.17 400mgoncedaily(1x400mg)

Key to Abbreviations:BSA=bodysurfacearea;NVPXR=nevirapineextendedrelease



Selected Adverse Events • Depression • Insomnia • Headache • Rash(canbesevereandincludeDrug

ReactionwithEosinophiliaandSystemicSymptoms[DRESS])

• Hepatotoxicity • AlteredACTHstimulationtestofuncertain

clinicalsignificance

Special Instructions • Patientsmustbeabletotakerilpivirinewith

amealofatleast500caloriesonaregularschedule(aproteindrinkalonedoesnotconstituteameal).

• Donotuserilpivirinewithothernon-nucleosidereversetranscriptaseinhibitors.

• Donotuserilpivirinewithprotonpumpinhibitors.

• Antacidsshouldonlybetakeneitheratleast2hoursbeforeoratleast4hoursafterrilpivirine.

• Userilpivirinewithcautionwhenco-administeredwithadrugwithaknownriskofTorsades de Pointes(seehttps://www.crediblemeds.org/).

• DonotstartrilpivirineinpatientswithHIVRNA>100,000copies/mLbecauseofincreasedriskofvirologicfailure.

Metabolism/Elimination • CytochromeP450(CYP)3Asubstrate • Dosinginpatientswithhepaticimpairment:

Nodoseadjustmentisnecessaryinpatients


Children Aged <12 Years: • NotFoodandDrugAdministration-approved

foruseinchildrenaged<12years.Formoreinformationregardingconsiderationforuseinchildrenaged<12yearsandweighing≥35kg,seethePharmocokineticssectionbelow.

Adolescent (Weighing ≥35 kg) and Adult Dose: Antiretroviral-Naive Patients with HIV RNA ≤100,000 copies/mL or Virologically-Suppressed (HIV RNA <50 copies/mL) Patients with No History of Virologic Failure or Resistance to Rilpivirine and Other Antiretroviral (ARV) Drugs and Currently on Their First or Second Regimen: • 25mgoncedaily

Combination Tablet[Complera] Emtricitabine plus Rilpivirine plus TDF Adolescent (Weighing ≥35 kg) and Adult Dose: • 1tabletoncedailyintreatment-naivepatients

withbaselineviralload<100,000copies/mLortoreplaceastableARVregimeninthosewhoarevirologically-suppressed(HIV-1RNAlessthan50copiespermL)foratleast6monthswithnohistoryoftreatmentfailureandhavenoknowncurrentorpastsubstitutionsassociatedwithresistancetotheindividualcomponentsofComplera,andcurrentlyontheirfirstorsecondregimen.

[Odefsey] Emtricitabine plus Rilpivirine plus TAF

Adolescent (Weighing ≥35 kg) and Adult Dose: • 1tabletoncedailywithamealasinitial

therapyinthosewithnoantiretroviraltreatmenthistorywithHIV-1RNAlessthan

Rilpivirine (RPV, Edurant) (Last updated April 27, 2017; last reviewed April 27,

2017)


FormulationsTablet:25mgFixed-Dose Combination Tablet: • [Complera]Emtricitabine200mgplusrilpivirine25mgplustenofovirdisoproxilfumarate(TDF)300mg • [Odefsey]Emtricitabine200mgplusrilpivirine25mgplustenofoviralafenamide(TAF)25mg



orequalto100,000copiespermL;ortoreplaceastableARTregimeninthosewhoarevirologically-suppressed(HIV-1RNA<50copiespermL)foratleast6monthswithnohistoryoftreatmentfailureandhavenoknowncurrentorpastsubstitutionsassociatedwithresistancetotheindividualcomponentsofOdefsey.

withmildormoderatehepaticimpairment. • Rilpivirinedecreasestubularsecretionof

creatinineandslightlyincreasesmeasuredserumcreatinine,butdoesnotaffectglomerularfiltration.

• Dosinginpatientswithrenalimpairment:Nodoseadjustmentisrequiredinpatientswithmildormoderaterenalimpairment.

• Complera(fixed-dosecombinations)shouldnotbeusedinpatientswithCrCl<50mL/minorinpatientsrequiringdialysis.

• Userilpivirinewithcautioninpatientswithsevererenalimpairmentorend-stagerenaldisease.Increasemonitoringforadverseeffectsbecauserilpivirineconcentrationsmaybeincreasedinpatientswithsevererenalimpairmentorend-stagerenaldisease.

• WhenusingCompleraseethetenofovirdisoproxilfumaratesection;whenusingOdefseyseethetenofoviralafenamidesection.



Selected Adverse Events • Indirecthyperbilirubinemia • ProlongedelectrocardiogramPRinterval,

first-degreesymptomaticatrioventricularblockinsomepatients

• Nephrolithiasis • Increasedserumtransaminases • Hyperlipidemia(primarilywithritonavir

boosting)

Special Instructions • Administeratazanavirwithfoodtoenhance

absorption. • Capsulesandpowderpacketsarenot

interchangeable. • Donotopencapsules. • PowderAdministration: • Mixatazanaviroralpowderwithatleast1

tablespoonoffoodsuchasapplesauceoryogurt.Oralpowdermixedwithabeverage(atleast30mLofmilkorwater)maybeusedforolderinfantswhocandrinkfromacup.Foryounginfants(<6months)whocannoteatsolidfoodordrinkfromacup,oralpowdershouldbemixedwithatleast10mLofinfantformulaandgivenusinganoraldosingsyringe.

• Administerritonavirimmediatelyfollowingpowderadministration.

• Administertheentiredosageoforalpowderwithin1hourofpreparation.

• BecauseatazanavircanprolongtheECG

Dosing RecommendationsNeonate Dose: • Notapprovedforuseinneonatesandinfants

youngerthan3months.Atazanavirshouldnotbeadministeredtoneonatesbecauseofrisksassociatedwithhyperbilirubinemia(kernicterus).

Pediatric DosePowder Formulation:a

• Powderformulationmustbeadministeredwithritonavir.

• Notapprovedforuseininfantsaged<3monthsorweighinglessthan5kg.

Infants and Children (Aged ≥3 Months; Weighing ≥5 kg): Atazanavir Powdera

Capsule Formulation:a

• Notapprovedforuseinchildren<6yearsor<15kg

Weight (kg) Once-Daily Dose

5to<15kg Atazanavir200mg(4packets)plusritonavir80mg(1mLoralsolution),bothoncedailywithfood

15to<25kgb Atazanavir250mg(5packets)plusritonavir80mg(1mLoralsolution),bothoncedailywithfood

Atazanavir (ATV, Reyataz) (Last updated April 27, 2017; last reviewed April 27,

2017)


FormulationsPowder Packet:50mg/packetCapsules:150mg,200mg,and300mgFixed-Dose Combination Tablets • [Evotaz] Atazanavir300mgpluscobicistat150mg

Capsules and powder packets are not interchangeable.



PRinterval,useatazanavirwithcautioninpatientswithpre-existingcardiacconductionsystemdiseaseorwithotherdrugsknowntoprolongthePRinterval(e.g.,calciumchannelblockers,beta-blockers,digoxin,verapamil). • Atazanavirabsorptionisdependentonlow

gastricpH;therefore,whenatazanavirisadministeredwithmedicationsthataltergastricpH,specialdosinginformationisindicated(seeDrugInteractionsusingtheatazanavirpackageinsert).Whenadministeredwithbuffereddidanosineformulationsorantacids,giveatazanaviratleast2hoursbeforeor1hourafterantacidordidanosineadministration.

• Theplasmaconcentration,andthereforetherapeuticeffect,ofatazanavircanbeexpectedtodecreasesubstantiallywhenatazanavirisco-administeredwithproton-pumpinhibitors.Antiretroviraltherapy-naivepatientsreceivingproton-pumpinhibitors(PPIs)shouldreceivenomorethana20-mgdoseequivalentofomeprazole,whichshouldbetakenapproximately12hoursbeforeboostedatazanavir.Co-administrationofatazanavirwithPPIsisnotrecommendedintreatment-experiencedpatients.

• PatientswithhepatitisBvirusorhepatitisCvirusinfectionsandpatientswithmarkedelevationsintransaminasesbeforetreatmentmaybeatincreasedriskoffurtherelevationsintransaminasesorhepaticdecompensation.

• Atazanaviroralpowdercontainsphenylalanine,whichcanbeharmfultopatientswithphenylketonuria.Eachpacketcontains35mgofphenylalanine.

Metabolism/Elimination • Atazanavirisasubstrateandinhibitorof

cytochromeP(CYP)3A4andaninhibitorofCYP1A2,CYP2C9,anduridinediphosphateglucuronosyltransferase(UGT1A1).

• Dosingofatazanavirinpatientswithhepaticimpairment:Atazanavirshouldbeusedwithcautioninpatientswithmild-to-moderatehepaticimpairment;consultmanufacturer’sprescribinginformationfordosageadjustmentinpatientswithmoderateimpairment.Atazanavirshouldnotbeusedinpatientswithseverehepaticimpairment.

• Dosingofatazanavirinpatientswithrenal

Children (Aged ≥6 Years; Weighing ≥15 kg):

Atazanavir Capsulesa

For Treatment-Naive Pediatric Patients who do not Tolerate Ritonavir: • Atazanavirpowdermustbeadministeredwith

ritonavir. • Forcapsuleformulation,atazanavir/

ritonavir(ATV/r)ispreferredforchildrenandadolescents.CurrentFood-and-Drug-Administration-approvedprescribinginformationdoesnotrecommendunboostedatazanavirinchildrenaged<13years.Ifunboostedatazanavirisusedinadolescents,higherdosesthanthoseusedinadultsmayberequiredtoachievetargetdrugconcentrations(seePediatricUse).

• OnlyATV/rshouldbeusedincombinationwithtenofovirdisoproxilfumarate(TDF)becauseTDFdecreasesatazanavirexposure.

Adolescent and Adult DoseAntiretroviral-Naive Patients: • Atazanavir300mgplusritonavir100mgonce

dailywithfood.e • Atazanavir300mgpluscobicistatf150mg,

bothoncedailywithfoodorasco-formulatedEvotazoncedailywithfood.Cobicistatiscurrentlynotrecommendedforuseinchildrenaged<18years,butisunderinvestigationforchildrenandyouthaged3monthsto18years.

• Atazanavir400mgoncedailywithfood(ifunboostedatazanavirisusedinadolescents,higherdosesthanthoseusedinadultsmayberequiredtoachievetargetdrugconcentrations[seePediatricUse]).

Antiretroviral-Experienced Patients: • Atazanavir300mgplusritonavir100mg,

bothoncedailywithfood.e

• Atazanavir300mgpluscobicistatf150mg,

Weight (kg) Once-Daily Dose<15kg Capsulesnotrecommended

15to<20kg Atazanavir150mgplusritonavirc 100mg,bothoncedailywithfood

20to<40kgd Atazanavir200mgplusritonavirc 100mg,bothoncedailywithfood

≥40kg Atazanavir300mgplusritonavirc 100mg,bothoncedailywithfood



impairment:Nodoseadjustmentisrequiredforpatientswithrenalimpairment.However,atazanavirshouldnotbegiventotreatment-experiencedpatientswithend-stagerenaldiseaseonhemodialysis.

amg/kgdosingishigherforthepowderpacketsthanforthecapsules.Bioavailabilityishigherforthecapsulesthanforthepowderwhenstudiedinadults.

bForachildwhocannotswallowatazanavircapsulesandwhoweighs≥25kg,300mg(6packets)atazanavirpowderplusritonaviroralsolution100mg,bothoncedailywithfood,maybeused.

cEitherritonavircapsulesorritonaviroralsolutioncanbeused.dSomeexpertswouldincreaseatazanavirto300mgat≥35kgtoavoidunder-dosing,especiallywhenadministeredwithTDF(seetextfordiscussion).

eForadultpatientswhocannotswallowcapsules,atazanaviroralpowderistakenoncedailywithfoodatthesameadultdosageasthecapsulesalongwithritonavir.

fSeeCobicistatsectionforimportantinformationabouttoxicity,druginteractions,andmonitoringofpatientswhoreceivecobicistatandthecombinationofcobicistatandTDF.

bothoncedailywithfoodorasco-formulatedEvotazoncedailywithfood.Cobicistatiscurrentlynotrecommendedforuseinchildrenaged<18years,butisunderinvestigationforchildrenandyouthaged3monthsto18years.

Atazanavir in Combination with Efavirenz (Adults) in Treatment-Naive Patients Only: • Atazanavir400mgplusritonavir100mgplus

efavirenz600mg,alloncedailyatseparatetimes.e

• AlthoughATV/rshouldbetakenwithfood,efavirenzshouldbetakenonanemptystomach,preferablyatbedtime.Efavirenzshouldnotbeco-administeredwithatazanavir(withorwithoutritonavir)intreatment-experiencedpatientsbecauseefavirenzdecreasesatazanavirexposure.

Atazanavir in Combination with TDF (Adults): • Atazanavir300mgplusritonavir100mgplus

TDF300mg,alloncedailywithfood.e

• Atazanavir300mgpluscobicistatf150mgplusTDF300mg,alloncedailywithfood.Cobicistatiscurrentlynotrecommendedforuseinchildrenaged<18years,butisunderinvestigationforchildrenandyouthaged3monthsto18years.

• OnlyboostedatazanavirshouldbeusedincombinationwithTDFbecauseTDFdecreasesatazanavirexposure.



Dosing RecommendationsNote:Darunavirshouldnotbeusedwithoutapharma-cokinetic(PK)enhancer(boostingagent):ritonavir(childrenandadults)orcobicistat(adultsonly).

Neonate/Infant Dose: • Notapprovedforuseinneonates/infants.

Pediatric DoseAged <3 years: • Do not use darunavir in children aged

<3 years or weighing ≤10 kgbecauseoftoxicityconcernsbasedonseizuresanddeathobservedininfantratsandattributedtoimmaturityoftheblood-brainbarrierandlivermetabolicpathways.

Aged ≥3 years: • Seetablebelowforchildrenaged≥3years

whoareantiretroviraltreatment-naive and treatment-experiencedwithorwithoutoneormoredarunavirresistance-associatedmutations.

Weight (kg)

Dose (Twicedailywithfood)

10to<11kgb Darunavir200mg(2.0mL)plusritonavir 32mg(0.4mL)

11to<12kgb Darunavir220mg(2.2mL)plusritonavir 32mg(0.4mLc)



14to<15kg Darunavir280mg(2.8mL)plusritonavir 48mg(0.6mLc)

15to<30kg Darunavir375mg(combinationoftabletsor3.8mLd)plusritonavir48mg(0.6mLd)

30to<40kg Darunavir450mg(combinationoftabletsor4.6mLd)plusritonavir100mg(tabletor1.25mLb)

≥40kg Darunavir600mg(tabletor6mL)plusritonavir100mg(tabletor1.25mL)

Aged 3 to <12 Years and Weighing ≥10 kg

Selected Adverse Events • Skinrash,includingStevens-Johnson

syndromeanderythemamultiforme • Hepatotoxicity • Diarrhea,nausea • Headache • Hyperlipidemia,transaminaseelevation,

hyperglycemia • Fatmaldistribution

Special Instructions • Inpatientswithoneormoredarunavir-

associatedmutations,darunavirshouldonlybeusedtwicedaily.Darunavir resistance-associated mutations are:V11I,V32I,L33F,I47V,I50V,I54L,I54M,T74P,L76V,I84V,andL89V.

• Darunavirmustbeadministeredwithfood,whichincreasesplasmaconcentrationsby30%.

• Darunavircontainsasulfonamidemoiety.Usedarunavirwithcautioninpatientswithknownsulfonamideallergy.

• Pediatricdosingrequiresco-administrationoftabletswithdifferentstrengthstoachievetherecommendeddosesdependingonweightband.Carefulinstructionstocaregiverswhenrecommendingacombinationofdifferent-strengthtabletsisveryimportant.

• Storedarunavirtabletsandoralsuspensionatroomtemperature(25ºCor77ºF).Suspensionmustbeshakenwellbeforedosing.

Metabolism/Elimination • Cytochrome(CYP)P4503A4inhibitorand

substrate.

Darunavir (DRV, Prezista) (Last updated April 27, 2017; last reviewed April 27,

2017)


FormulationsOral suspension:100mg/mLTablets [Prezista]:75mg,150mg,600mg,and800mgFixed-Dose Combination Tablets • [Prezcobix]Darunavir800mgplusCobicistat150mg



Boostingdarunavirwithcobicistatiscurrentlynotrecommendedinchildrenaged<18years;PK,efficacy,andsafetyofdarunavir/cobicistatiscurrentlyunderinvestigationinchildrenaged12to18years.

Adolescent (Weighing ≥40 kg)e and Adult Dose (Treatment-Naive or Treatment-Experienced with No Darunavir Resistance-Associated Mutations) • Darunavir800mg(tabletorcombinationof

tablets)plusritonavir100mgonce daily

Adult Dose (Treatment-Naive or Treatment-Experienced with No Darunavir Resistance-Associated Mutations): • Darunavir800mg(tablet)pluscobicistatf150

mg(tablet)orcoformulatedasPrezcobixonce daily with food

Adolescent (Weight ≥30 to <40 kg; Treatment-Experienced with at Least 1 Darunavir Resistance-Associated Mutation): • Darunavir450mg(combinationoftablets)

plusritonavir100mgbothtwice daily with food

Adolescent (Weight ≥40 kg) and Adult Dose (Treatment-Experienced With at least 1 Darunavir Resistance-Associated Mutation): • Darunavir600mgplusritonavir100mg,both

twice daily with food • Theuseofcobicistatis not recommendedwith

darunavir600mgtwicedaily.

DosinginPatientswithHepaticImpairment: • Darunavirisprimarilymetabolizedbytheliver.

Cautionshouldbeusedwhenadministeringdarunavirtopatientswithhepaticimpairment.Darunavirisnotrecommendedinpatientswithseverehepaticimpairment.

DosinginPatientswithRenalImpairment: • Nodoseadjustmentisrequiredinpatients

withmoderaterenalimpairment(creatinineclearance[CrCl]30–60mL/min).

aOnce-dailydosingisFoodandDrugAdministration-approvedbutthePanelonAntiretroviralTherapyandMedicalManagementofChildrenLivingwithHIVdoesnotrecommenditforchildren(seetextunderFrequencyofAdministration).

bNotethatthedoseinchildrenweighing10to15kgis20mg/kgdarunavirand3mg/kgritonavirperkgbodyweightperdose,whichishigherthantheweight-adjusteddoseinchildrenwithhigherweight.

cRitonavir80g/mLoralsolutiondThe375-mgand450-mgdarunavirdosesareroundedforsuspension-doseconvenience.eSomePanelmembersrecommendoncedailydarunavir675mg(combinationoftablets)plusritonavir100mgoncedailyforadolescentswithbodyweight≥30to<40kg,especiallythose≥12yearsofage.

fSeecobicistatsectionforimportantinformationabouttoxicity,druginteractions,andmonitoringpatientswhoreceivecobicistat.



Dosing RecommendationsPediatric Dose (Aged >6 Months to 18 Years): • Unboostedfosamprenavir(without

ritonavir)isFoodandDrugAdministration(FDA)-approvedforantiretroviral(ARV)-naivechildrenaged2to5years,butnotrecommendedbyThePanelonAntiretroviralTherapyandMedicalManagementofHIV-InfectedChildren(thePanel)becauseoflowexposures(seetextbelow).

• Boostedfosamprenavir(withritonavir)isFDA-approvedforARV-naiveinfants≥4weeksandfortreatment-experiencedinfants≥6months;however,thePaneldoesnotrecommenduseininfantsyoungerthan6monthsbecauseofsimilarlylowexposures(seetextbelow).Ifusedininfantsasyoungas4weeks,itshouldonlybeadministeredtoinfantsbornat38weeks’gestationorgreater.

Once-daily dosing is not recommended for any pediatric patient.

Aged ≥6 Months to 18 Years:Twice-Daily Dosage Regimens by Weight for Pediatric Patients ≥6 Months Using Lexiva Oral Suspension with Ritonavir

aNottoexceedtheadultdoseoffosamprenavir700mgplusritonavir100mgtwicedaily.

WeightDose

Fosamprenavir Plus Ritonavir Bothtwicedailyawithfood

<11kg fosamprenavir45mg/kg/doseplusritonavir 7mg/kg/dose

11kgto<15kg

fosamprenavir30mg/kg/doseplusritonavir 3mg/kg/dose

15kgto<20kg

fosamprenavir23mg/kg/doseplusritonavir 3mg/kg/dose

≥20kg fosamprenavir18mg/kg/doseplusritonavir 3mg/kg/dose

Selected Adverse Events • Diarrhea,nausea,vomiting • Skinrash(Fosamprenavirhasasulfonamide

moiety.Stevens-Johnsonsyndromeanderythemamultiformehavebeenreported.)

• Headache • Hyperlipidemia,hyperglycemia • Nephrolithiasis • Transaminaseelevation • Fatmaldistribution • Possibleincreasedbleedingepisodesin

patientswithhemophilia

Special Instructions • Fosamprenavirtabletswithritonavirshould

betakenwithfood.Childrenshouldtakethesuspensionwithfood.

• Patientstakingantacidsorbufferedformulationsofdidanosineshouldtakefosamprenaviratleast1hourbeforeorafterantacidordidanosineuse.

• Fosamprenavircontainsasulfonamidemoiety.Thepotentialforcrosssensitivitybetweenfosamprenavirandotherdrugsinthesulfonamideclassisunknown.Fosamprenavirshouldbeusedwithcautioninpatientswithsulfonamideallergy.

• Shakeoralsuspensionwellbeforeuse.Refrigerationisnotrequired.

Metabolism/Elimination • Theprodrugfosamprenavirisrapidlyand

almostcompletelyhydrolyzedtoamprenavirbycellularphosphatasesinthegutasitisabsorbed.

• AmprenavirisacytochromeP4503A4(CYP3A4)inhibitor,inducer,andsubstrate.

Fosamprenavir (FPV, Lexiva) (Last updated April 27, 2017; last reviewed

April 27, 2017)


FormulationsTablets:700mgOral Suspension:50mg/mL



• Dosinginpatientswithhepaticimpairment:Dosageadjustmentisrecommended.Pleaserefertothepackageinsert.

Note:Whenadministeredwithritonavir,theadultregimenof700mgfosamprenavirtabletsplus100mgritonavir,bothgiventwicedaily,canbeusedinpatientsweighing≥39kg.Ritonavirtabletscanbeusedinpatientsweighing≥33kg.

Adolescent and Adult (Aged >18 Years) Dose: • Dosingregimendependsonwhetherthe

patientisARVnaiveorARVexperienced.

ARV-Naive PatientsBoostedwithRitonavir,Twice-DailyRegimen: • Fosamprenavir700mgplusritonavir100mg,

bothtwicedaily.

BoostedwithRitonavir,Once-DailyRegimen: • Fosamprenavir1400mgplusritonavir100–

200mg,bothoncedaily.

Protease Inhibitor (PI)-Experienced Patients: • Fosamprenavir700mgplusritonavir100mg,

bothtwicedaily.

• Note:Once-dailyadministrationoffosamprenavirplusritonavirisnotrecommended.

Fosamprenavir in Combination with Efavirenz (Adult): • Onlyfosamprenavirboostedwithritonavir

shouldbeusedincombinationwithefavirenz.

Twice-DailyRegimen: • Fosamprenavir700mgplusritonavir100mg,

bothtwicedailyplusefavirenz600mgoncedaily.

PI-NaivePatientsOnly,Once-DailyRegimen: • Fosamprenavir1400mgplusritonavir

300mgplusefavirenz600mg,alloncedaily.



Dosing RecommendationsNeonate and Infant Dose: • Notapprovedforuseinneonates/infants. • Shouldnotbeadministeredtoneonates

becauseoftherisksassociatedwithhyperbilirubinemia(kernicterus).

Pediatric Dose: • Notapprovedforuseinchildren. • Arangeofindinavirdoses(234–500mg/m2

bodysurfacearea)boostedwithlow-doseritonavirhasbeenstudiedinchildren(seetextbelow).

Adolescent and Adult Dose: • 800mgindinavirplus100or200mgritonavir

every12hours

Selected Adverse Events • Nephrolithiasis • Gastrointestinalintolerance,nausea • Hepatitis • Indirecthyperbilirubinemia • Hyperlipidemia • Hyperglycemia • Fatmaldistribution • Possibleincreasedbleedingepisodesin


Special Instructions • Whengivenincombinationwithritonavir,

mealrestrictionsarenotnecessary. • Adequatehydrationisrequiredtominimize

riskofnephrolithiasis(≥48ozoffluiddailyinadultpatients).

• Ifco-administeredwithdidanosine,giveindinaviranddidanosine≥1hourapartonanemptystomach.

• Indinavircapsulesaresensitivetomoisture;storeatroomtemperature(59–86ºF)inoriginalcontainerwithdesiccant.

Metabolism/Elimination • CytochromeP4503A4(CYP3A4)inhibitorand

substrate • Dosinginpatientswithhepaticimpairment:

Decreaseddosageshouldbeusedinpatientswithmild-to-moderatehepaticimpairment(recommendeddoseforadultsis600mgindinavirevery8hours).Nodosinginformationisavailableforchildrenwithanydegreeofhepaticimpairmentorforadultswithseverehepaticimpairment.

Indinavir (IDV, Crixivan) (Last updated April 27, 2017; last reviewed April 27,

2017)


FormulationsCapsules:100mg,200mg,and400mg



Selected Adverse Events • Gastrointestinal(GI)intolerance,nausea,

vomiting,diarrhea,tastealteration • Hyperlipidemia,especiallyhypertriglyceridemia • Elevatedtransaminases • Hyperglycemia • PRintervalprolongation • QTintervalprolongationandtorsadesde

pointes • Riskoftoxicity—includinglife-threatening

cardiotoxicity—isincreasedinprematureinfants(seeMajorToxicitiesbelow).

Special Instructions • Lopinavir/ritonavirtabletscanbeadministered

withoutregardtofood;administrationwithoraftermealsmayenhanceGItolerability.

• Lopinavir/ritonavirtabletsmustbeswallowedwhole.Donotcrushorsplittablets.

• Lopinavir/ritonaviroralsolutionshouldbeadministeredwithfoodbecauseahigh-fatmealincreasesabsorption.

• Thepoorpalatabilityoflopinavir/ritonaviroralsolutionisdifficulttomaskwithflavoringsorfoods(seePediatricUse).

• Lopinavir/ritonaviroralsolutioncanbekeptatroomtemperatureupto77ºF(25ºC)ifusedwithin2months.Ifkeptrefrigerated(2ºto8ºCor36ºto46ºF)lopinavir/ritonaviroralsolutionremainsstableuntiltheexpirationdateprintedonthelabel.

• Once-dailydosingisnotrecommendedbecauseofconsiderablevariabilityinplasmaconcentrationsinchildrenaged<18yearsandhigherincidenceofdiarrhea.

• Useoflopinavir/ritonavironcedailyisspecificallycontraindicatedifthreeormoreof

Lopinavir/Ritonavir (LPV/r, Kaletra) (Last updated April 27, 2017; last

reviewed April 27, 2017)

ForadditionalinformationseeDrugs@FDA:

FormulationsPediatric Oral Solution:80mg/20mgLPV/rpermL(contains42.4%alcoholbyvolumeand15.3%propyleneglycolbyweight/volume)Film-Coated Tablets:100mg/25mgLPV/r,200mg/50mgLPV/r

Dosing RecommendationsNeonatal Dose (<14 Days): • Nodataonappropriatedoseorsafetyinthis

agegroup.Donotadministertoneonatesbeforeapost-menstrualageof42weeksandapostnatalageofatleast14daysbecauseofpotentialtoxicities.

Dosing for Individuals not Receiving Concomitant Nevirapine, Efavirenz, Fosamprenavir, or NelfinavirInfant Dose (14 Days–12 Months): • Once-dailydosingis not recommended.

• 300mg/75mglopinavir/ritonavirperm2ofbodysurfaceareatwicedaily(approximates16mg/4mglopinavir/ritonavirperkgbodyweighttwicedaily).Note:Thisdoseininfantsaged<12monthsisassociatedwithlowerlopinavirtroughlevelsthanthosefoundinadults;lopinavirdosingshouldbeadjustedforgrowthatfrequentintervals(seetextbelow).Alsoseetextfortransitioninginfantstolowermgperm2dose).

Pediatric Dose (>12 Months to 18 Years): • Once-dailydosingis not recommended.

• 300mg/75mglopinavir/ritonavirperm2 ofbodysurfaceareaperdosetwicedaily(maximumdose400mg/100mglopinavir/ritonavirtwicedailyexceptasnotedbelow).Forpatientswithbodyweight<15kg,thisapproximates13mg/3.25mglopinavir/ritonavirperkgbodyweighttwicedaily;andforpatientswithbodyweight≥15to45kgthisdoseapproximates11mg/2.75mglopinavir/ritonavirperkgbodyweighttwicedaily.Thisdoseisroutinelyusedbymanycliniciansandisthepreferreddosefortreatment-experiencedpatientswhocouldharborviruswithdecreasedlopinavirsusceptibility(seetextbelow).

http://www.accessdata.fda.gov/scripts/cder/daf/



• 230mg/57.5mglopinavir/ritonavirperm2 ofbodysurfaceareaperdosetwicedailycanbeusedinantiretroviral(ARV)-naivepatientsaged>1year.Forpatients<15kg,thisdoseapproximates12mg/3mglopinavir/ritonavirperkgbodyweightgiventwicedailyandforpatients≥15kgto40kg,thisdoseapproximates10mg/2.5mglopinavir/ritonavirperkgbodyweightgiventwicedaily.Thisdoseshould not be usedintreatment-experiencedpatientswhocouldharborviruswithdecreasedlopinavirsusceptibility.

Adult Dose (>18 Years): • 800mg/200mglopinavir/ritonavironcedaily,

or

• 400mg/100mglopinavir/ritonavirtwicedaily.

• Donotuseonce-dailydosinginchildrenoradolescents,orinpatientsreceivingconcomitanttherapywithnevirapine,efavirenz,fosamprenavir,ornelfinavir,orinpatientswiththreeormorelopinavir-associatedmutations(seeSpecialInstructionsforlist).

Recommended Number of 100-mg/ 25-mg Lopinavir/Ritonavir Tablets Given Twice Daily

Dosing Target300mg/m2/dosegiventwicedaily

230mg/m2/dosegiventwicedaily

Body Weight (kg)

15 to 20 kg 2 2>20 to 25 kg 3 2>25 to 30 kg 3 3>30 to 35 kg 4a 3>35 to 45 kg 4a 4a

>45 kg 4a or5b 4a

Weight-Band Dosing for 100 mg/25 mg Lopinavir/ Ritonavir Pediatric Tablets for Children/Adolescents

aFourofthe100mg/25mglopinavir/ritonavirtabletscanbesubstitutedwith2tabletseachcontaining200mg/50mglopinavir/ritonavirinchildrencapableofswallowingalargertablet.

bInpatientsreceivingconcomitantnevirapine,efavirenz,fosamprenavir,ornelfinavir,forbodyweight>45kg,theFoodandDrugAdministration(FDA)-approvedadultdoseis500mg/125mglopinavir/ritonavirtwicedaily,givenasacombinationof2tabletsof200/50mglopinavir/ritonavirand1tabletof100mg/25mglopinavir/ritonavir.Alternatively,3tabletsof200/50mglopinavir/ritonavircanbeusedforeaseofdosing.

thefollowinglopinavirresistance-associatedsubstitutionsarepresent—L10F/I/R/V,K20M/N/R,L24I,L33F,M36I,I47V,G48V,I54L/T/V,V82A/C/F/S/T,andI84V—becausehigherlopinavirtroughconcentrationsmayberequiredtosuppressresistantvirus.

Metabolism/Elimination • CytochromeP(CYP)3A4inhibitorand

substrate. • Dosingoflopinavir/ritonavirinpatientswith

hepaticimpairment:Lopinavir/ritonavirisprimarilymetabolizedbytheliver.Cautionshouldbeusedwhenadministeringlopinavirtopatientswithhepaticimpairment.Nodosinginformationiscurrentlyavailableforchildrenoradultswithhepaticinsufficiency.

• Intheco-formulationoflopinavir/ritonavir,theritonaviractsasapharmacokineticenhancer,notasanARVagent.Itdoesthisbyinhibitingthemetabolismoflopinavirandincreasinglopinavirplasmaconcentrations.



In Patients with Three or more Lopinavir-Associated Mutations (see Special Instructions for list): • 400mg/100mglopinavir/ritonavirtwicedaily.

Dosing for Individuals Receiving Concomitant Nevirapine, Efavirenz, Fosamprenavir, or Nelfinavir: Note:Thesedrugsinducelopinavirmetabolismandreducelopinavirplasmalevels;increasedlopinavir/ritonavirdosingisrequiredwithconcomitantadministrationofthesedrugs.

• Once-dailydosingshouldnotbeused.

Pediatric Dose (>12 Months to 18 Years): • 300mg/75mglopinavir/ritonavirperm2ofbody

surfaceareaperdosetwicedaily.Seetableforweight-banddosingwhenusingtablets.

Adult Dose (>18 Years): • FDA-approveddoseis500mg/125mglopinavir/

ritonavirtwicedaily,givenasacombinationof2tabletsof200/50mglopinavir/ritonavirand1tabletof100mg/25mglopinavir/ritonavir.Alternatively,3tabletsof200/50mglopinavir/ritonavircanbeusedforeaseofdosing.Once-dailydosingshouldnotbeused.

Lopinavir/Ritonavir in Combination with Saquinavir Hard-Gel Capsules (Invirase) or in Combination with Maraviroc: • Saquinavirandmaravirocdosesmayneed

modification(seetheSaquinavirandMaravirocsectionsformoreinformation).



Dosing RecommendationsNeonate/Infant Dose: • Nelfinavirshouldnotbeusedfortreatmentin

childrenaged<2years.

Pediatric Dose (Aged 2–13 Years): • 45–55mg/kgtwicedaily

Adolescent and Adult Dose: • 1250mg(five250-mgtabletsortwo625-mg

tablets)twicedaily • Someadolescentsrequirehigherdosesthan

adultstoachieveequivalentdrugexposures.Considerusingtherapeuticdrugmonitoringtoguideappropriatedosing.

Nelfinavir (NFV, Viracept) (Last updated April 27, 2017; last reviewed April 27,

2017)

ForadditionalinformationseeDrugs@FDA:

FormulationsTablets:250mgand625mg

Selected Adverse Events • Diarrhea • Hyperlipidemia • Hyperglycemia • Fatmaldistribution • Possibleincreaseinbleedingepisodesin


Special Instructions • Administernelfinavirwithmealorlightsnack. • Ifco-administeredwithdidanosine,

administernelfinavir2hoursbeforeor1hourafterdidanosine.

• Patientsunabletoswallownelfinavirtabletscandissolvethetabletsinasmallamountofwater.Oncetabletsaredissolved,patientsshouldmixthecloudymixturewellandconsumeitimmediately.Theglassshouldberinsedwithwaterandtherinseswallowedtoensurethattheentiredoseisconsumed.Tabletscanalsobecrushedandadministeredwithpuddingorothernonacidicfoods.

Metabolism/Elimination • CYP2C19and3A4substrate • MetabolizedtoactiveM8metabolite • CYP3A4inhibitor

http://www.accessdata.fda.gov/scripts/cder/daf/



Dosing RecommendationsNeonate and Infant Dose: • Notapprovedforuseinneonates/infants.

Pediatric Dose: • Notapprovedforuseinchildrenand

adolescentsaged<16years.

Investigational Doses in Treatment-Experienced Children: • Saquinavirmustbeboostedwithritonavir.

Aged <2 Years: • Nodosehasbeendetermined.

Adolescent (Aged ≥16 years) and Adult Dose: • Saquinavirshouldonlybeusedin

combinationwithritonavir. • Saquinavir1000mgplusritonavir100mg,

bothtwicedaily.

Aged ≥2 Years (Conditional Dosing Based on Limited Data; See Text):

Weight (kg)

Dose Saquinavir plus Ritonavir

5to<15kg Saquinavir50mg/kgplusritonavir3mg/kg,bothtwicedaily

15to<40kg

Saquinavir50mg/kgplusritonavir2.5mg/kg,bothtwicedaily

≥40kg Saquinavir50mg/kgplusritonavir100mg,bothtwicedaily

Selected Adverse Events • Gastrointestinalintolerance,nausea,and

diarrhea • Headache • Elevatedtransaminases • Hyperlipidemia • Hyperglycemia • Fatmaldistribution • Increasedbleedingepisodesinpatientswith

hemophilia • PRintervalprolongation,QTinterval

prolongation,andventriculartachycardia(Torsades de Pointes)havebeenreported.

Special Instructions • Administerwithin2hoursafterafullmeal. • Sunexposurecancausephotosensitivity

reactions;advisepatientstousesunscreenorprotectiveclothing.

• Pre-therapyelectrocardiogramisrecommendedandsaquinaviriscontraindicatedinpatientswithaprolongedQTinterval.

Metabolism/Elimination • CytochromeP(CYP)4503A4andinhibitor,

90%metabolizedintheliver. • Useinpatientswithhepaticimpairment:use

withcaution.

Saquinavir (SQV, Invirase) (Last updated April 27, 2017; last reviewed April 27,

2017)


FormulationsCapsules:200mgTablets:500mg



Dosing RecommendationsNote:Tipranavirmustbeusedwithritonavirboosting.Theritonavirboostingdoseusedfortipranavirishigherthanthatusedforotherproteaseinhibitors.

Pediatric Dose (Aged <2 Years): • Notapprovedforuseinchildrenaged

<2years.

Pediatric Dose (Aged 2–18 Years):Note:Notrecommendedfortreatment-naivepatients

Body Surface Area Dosing: • Tipranavir375mg/m2plusritonavir150mg/

m2,bothtwicedaily(maximumtipranavir500mgplusritonavir200mg,bothtwicedaily)

Weight-Based Dosing: • Tipranavir14mg/kgplusritonavir6mg/kg,

bothtwicedaily(maximumtipranavir500mgplusritonavir200mg,bothtwicedaily)

Adult Dose:Note:Notrecommendedfortreatment-naivepatients

• Tipranavir500mg(two250-mgcapsules)plusritonavir200mg,bothtwicedaily

Tipranavir (TPV, APTIVUS) (Last updated April 27, 2017; last reviewed April

27, 2017)


FormulationsOral Solution:100mgtipranavir/mL,with116InternationalUnits(IU)vitaminE/mLCapsules:250mg

Selected Adverse Events • Rarecasesoffatalandnon-fatalintracranial

hemorrhage

• Skinrash(morecommoninchildrenthanadults)

• Nausea,vomiting,diarrhea

• Hepatotoxicity:elevatedtransaminases;clinicalhepatitis

• Hyperlipidemia

• Hyperglycemia

• Elevatedcreatinephosphokinase

Special Instructions • Administertipranavirandritonavirtogether

withfood.

• Tipranaviroralsolutioncontains116IUvitaminE/mL,whichissignificantlyhigherthanthereferencedailyintakeforvitaminE.PatientstakingtheoralsolutionshouldavoidtakinganyformofsupplementalvitaminEthatcontainsmorevitaminEthanfoundinastandardmultivitamin.

• Tipranavircontainsasulfonamidemoietyandshouldbeusedwithcautioninpatientswithsulfonamideallergy.

• Storetipranaviroralsolutionatroomtemperature,25°C(77°F);donotrefrigerateorfreeze.Oralsolutionmustbeusedwithin60daysafterthebottleisfirstopened.

• Storeunopenedbottlesoforaltipranavircapsulesinarefrigeratorat2°Cto8°C(36°Fto46°F).Oncebottleisopened,capsulescanbekeptatroomtemperature(maximumof77°For25°C)ifusedwithin60days.

• Usetipranavirwithcautioninpatientswhomaybeatincreasedriskofintracranial



hemorrhage,includingindividualswithbrainlesion,headtrauma,recentneurosurgery,coagulopathy,hypertension,oralcoholism,orwhouseanticoagulantorantiplateletagents(includingvitaminE).

• Useoftipranaviriscontraindicatedinpatientswithmoderateorseverehepaticimpairment.

Metabolism/Elimination • CytochromeP4503A4(CYP3A4)inducerand

substrate;P-glycoproteinsubstrate;

• Dosinginpatientswithrenalimpairment:Nodoseadjustmentrequired

• Dosinginpatientswithhepaticimpairment:Nodoseadjustmentrequiredformildhepaticimpairment;usecontraindicatedformoderate-to-severehepaticimpairment.



Dosing RecommendationsPediatric and Adolescent Dose (Aged 6–16 Years)Children Aged <6 Years: • Notapprovedforuseinchildrenaged<6

yearsChildren Aged ≥6 Years: • 2mg/kg(maximumdose90mg[1mL])

twicedailyinjectedsubcutaneously(SQ)intotheupperarm,anteriorthigh,orabdomen

Adolescent (Aged >16 Years) and Adult Dose: • 90mg(1mL)twicedailyinjectedSQintothe

upperarm,anteriorthigh,orabdomen

Selected Adverse Events • Localinjectionsitereactions(e.g.,pain,

erythema,induration,nodulesandcysts,pruritus,ecchymosis)inupto98%ofpatients.

• Increasedrateofbacterialpneumonia(unclearassociation).

• Hypersensitivityreaction(HSR)—symptomsmayincluderash,fever,nausea,vomiting,chills,rigors,hypotension,orelevatedserumtransaminases.Rechallengeisnotrecommended.

Special Instructions • Carefullyinstructpatientorcaregiverin

propertechniquefordrugreconstitutionandadministrationofSQinjections.Enfuvirtideinjectioninstructionsareprovidedwithconveniencekits.

• Allowreconstitutedvialtostanduntilthepowdergoescompletelyintosolution,whichcouldtakeupto45minutes.Donotshake.

• Oncereconstituted,injectenfuvirtideimmediatelyorkeeprefrigeratedintheoriginalvialuntiluse.Reconstitutedenfuvirtidemustbeusedwithin24hours.

• EnfuvirtidemustbegivenSQ;severityofreactionsincreasesifgivenintramuscularly.

• Giveeachinjectionatasitedifferentfromtheprecedinginjectionsite;donotinjectintomoles,scartissue,bruises,orthenavel.Boththepatient/caregiverandhealthcareprovidershouldcarefullymonitorforsignsandsymptomsoflocalinfectionorcellulitis.

• Tominimizelocalreactions,applyiceorheatafterinjectionorgentlymassageinjection

Enfuvirtide (T-20, Fuzeon) (Last updated April 27, 2017; last reviewed

April 27, 2017)


FormulationsLyophilized Powder for Injection: • 108-mgvialofenfuvirtide.Reconstitutionwith1.1mLsterilewaterwilldeliver90mg/mL.Convenience Kit: • 60single-usevialsofenfuvirtide(108-mgvialreconstitutedas90mg/mL),60vialsofsterilewaterfor

injection,60reconstitutionsyringes(3mL),60administrationsyringes(1mL),alcoholwipes.



sitetobetterdispersethedose.Therearereportsofinjection-associatedneuralgiaandparesthesiawhenalternativedeliverysystems,suchasneedle-freeinjectiondevices,areused. • Advisepatients/caregiversofthepossibilityof

aHSR;instructthemtodiscontinuetreatmentandseekimmediatemedicalattentionifapatientdevelopssignsandsymptomsconsistentwithaHSR.

Metabolism/Elimination • Catabolismtoconstituentaminoacids.




Pediatric Dose: • Approvedforusebychildrenaged≥2years

andweighing≥10kg

Recommended Dosage in Antiretroviral Experienced Children Aged ≥2 Years and Weighing ≥10 kg: Tablets or Oral SuspensionWhengivenwithpotentcytochromeP(CYP)3Ainhibitors(withorwithoutapotentCYP3Ainducer)includingelvitegravir/ritonavir(EVG/r)andproteaseinhibitors(PIs)(excepttipranavir/ritonavir[TPV/r]):

10kgto<20kg 50mg 2.5mL 225-mg20kgto<30kg 75mg 4mL 175-mg30kgto<40kg 100mg 5mL 125-mg&

175-mg>40kg 150mg 7.5mL 1150-mg

Weight BandTwice-Daily

Dosing

Liquid 20 mg/

mLTablets

Whengivenwithnucleosidereversetranscriptaseinhibitors(NRTIs),enfuvirtide,TPV/r,nevirapine,raltegravir,andotherdrugsthatarenotpotentCYP3Ainhibitorsorinducers:

10kgto<20kg Notrecommended20kgto<30kg Notrecommended30kgto<40kg 300mg 15mL 1300-mg>40kg 300mg 15mL 1300-mg

Weight BandTwice-Daily

Dosing

Liquid 20 mg/

mLTablets

WhengivenwithpotentCYP3Ainducersincludingefavirenzandetravirine(withoutapotentCYP3Ainhibitor):

Notrecommended

Selected Adverse Events • Vomiting,diarrhea • Cough • Upperrespiratorytractinfections • Dizziness • Fever • Rash • Hepatotoxicity(whichmaybeprecededby

severerashand/orothersignsofsystemicallergicreaction)

• Posturalhypotension(generallyinpatientswithsevererenalinsufficiency)

Special Instructions • Maravirocisrecommendedforpatientswith

onlyCCR5-tropicHIV-1.ConducttestingwithHIVtropismassay(seeAntiretroviralDrug-ResistanceTestinginAdultandAdolescentAntiretroviralGuidelines)beforeusingMVCtoexcludethepresenceofCXCR4-usingormixed/dual-tropicHIV.DonotuseifCXCR4ormixed/dual-tropicHIVispresent.

• Maraviroccanbegivenwithoutregardtofood. • Instructpatientsonhowtorecognizesymptoms

ofallergicreactionsorhepatitis. • Usecautionwhenadministeringmaravirocto

patientswithunderlyingcardiacdisease.

Metabolism/Elimination • CytochromeP4503A4(CYP3A4)substrate • Dosingofmaravirocinpatientswithhepatic

impairment:Usecautionwhenadministeringmaraviroctopatientswithhepaticimpairment.Becausemaravirocismetabolizedbytheliver,concentrationsmaybeincreasedinpatientswithhepaticimpairment.

• Dosingofmaravirocinadultsandadolescentswithrenalimpairment:refertothe

Maraviroc (MVC, Selzentry) (Last updated April 27, 2017; last reviewed April

27, 2017)


FormulationsTablets: 25mg,75mg,150mgand300mgOral Solution:20mg/mL



Adult Dose

WhengivenwithpotentCYP3Ainhibitors(withorwithoutapotentCYP3Ainducer)includingPIs(exceptTPV/r)andEVG/r

150mgtwicedaily

WhengivenwithNRTIs,enfuvirtide,TPV/r,nevirapine,raltegravir,andotherdrugsthatarenotpotentCYP3Ainhibitorsorinducers

300mgtwicedaily

WhengivenwithpotentCYP3Ainducersincludingefavirenzandetravirine(withoutapotentCYP3Ainhibitor)

600mgtwicedaily

manufacturer’sprescribinginformation. • Dataareinsufficienttomakedosing

recommendationsforuseofmaravirocinchildrenconcomitantlyreceivingnon-interactingmedicationsandweighinglessthan30kgorinallchildrenconcomitantlyreceivingpotentCYP3AinducerswithoutapotentCYP3Ainhibitor.



Dolutegravir (DTG, Tivicay) (Last updated April 27, 2017; last reviewed April

27, 2017)

ForadditionalinformationseeDrugs@FDA:https://www.accessdata.fda.gov/scripts/cder/daf/

FormulationsTablet:10mg,25mg,and50mgFixed-Dose Combination Tablet: • [Triumeq]Abacavir600mgplusdolutegravir50mgpluslamivudine300mg

Dosing RecommendationsNeonate/Infant Dose: • Notapprovedforuseinneonates/infants

Children Weighing ≥30 to <40 kg: • NotFoodandDrugAdministration-approved

foruseinchildrenweighing<30kg. • Aclinicaltrialinantiretroviral(ARV)

treatment-experienced(butintegrasestrandinhibitor[INSTI]-naivechildren)weighing <30kgisunderway(seetext).

aThesedosesareforchildrenwhoareARV-naiveorARV-experienced(butINSTI-naive)andwhoarenotbeingtreatedwithUGT1A1/CYP3Ainducers

Note:Dolutegravir10-mgand25-mgtabletsmaybeavailableintheretailpharmacy.Ifnotavailable,whenorderingdolutegravir10-mgor25-mgtablets,havethepharmacycontacttheirdrugwholesalerandtellthedrugwholesalertoorderdirectlyfromtheGSKdistributioncenter.TheGSKdistributioncenterwillshiptheformulationdirectlytothepharmacy.

Body weight (kg)

Dosea (mg/day)

Dosing Frequency

Tablet Size (mg)

30to<40 35 Oncedaily One10-mgtabletplusone25-mgtablet

Selected Adverse Events • Insomnia • Headache • Hypersensitivityreactionsincludingrash,

constitutionalsymptoms,andorgandysfunction(includingliverinjury)havebeenreportedrarely.

Special Instructions • Maybetakenwithoutregardtomeals • Shouldbetaken2hoursbeforeor6hours

aftertakingcation-containingantacidsorlaxatives,sucralfate,oralironsupplements,oralcalciumsupplements,orbufferedmedications

• Inpatientswhohavedifficultyswallowingtabletswhole,10-,25-,and50-mgtabletsmaybeeithersplitintohalvesfollowedbyimmediateingestionofboth halvesofthetablet,orcrushedandaddedtoasmallamountofsemi-solidfoodorliquid,allofwhichshouldbeconsumedimmediately.1

• Theefficacyof50-mgdolutegravirtwicedailyisreducedinpatientswithcertaincombinationsofINSTI-resistancemutations(seeResistancesectionbelow).

Metabolism/Elimination • UGT1A1andcytochromeP450(CYP)3A

substrate • Dosinginpatientswithhepaticimpairment:

Nodoseadjustmentisnecessaryinpatientswithmildormoderatehepaticimpairment.Becauseoflackofdata,dolutegravirisnotrecommendedinpatientswithseverehepaticimpairment.

• Dolutegravirdecreasestubularsecretionofcreatinineandslightlyincreasesmeasured



serumcreatinine,butdoesnotaffectglomerularfiltration. • Dosinginpatientswithrenalimpairment:No

doseadjustmentisrequiredinINSTI-naivepatientswithmild,moderate,orsevererenalimpairmentorinINSTI-experiencedpatientswithmildormoderaterenalimpairment.

• UsedolutegravirwithcautioninINSTI-experiencedpatientswithsevererenalimpairment(creatinineclearance<30mL/min)becausedolutegravirconcentrationswillbedecreased(thecauseofthisdecreaseisunknown).

Combination Tablet[Triumeq] Abacavir plus Dolutegravir plus Lamivudine: Adolescent (Weighing ≥40 kg) and Adult Dose: • 1tabletoncedaily • ForuseinpatientswhoareARVtreatment-

naiveortreatment-experienced(butINSTI-naive)andnotbeingtreatedwithUGT1A1/CYP3Ainducers

Population Recommended Dose

Treatment-naiveortreatment-experienced/INSTI-naive

50mgoncedaily

Treatment-naiveortreatment-experienced/INSTI-naivewhenco-administeredwiththefollowingpotentUGT1A/CYP3Ainducers:efavirenz,fosamprenavir/ritonavir,tipranavir/ritonavir,orrifampin

50mgtwicedaily

INSTI-experiencedwithanyINSTI-associatedresistancesubstitutionsorclinicallysuspectedINSTIresistancea

50mgtwicedaily

aCombinationsthatdonotincludemetabolicinducersshouldbeconsideredwherepossible.

Children and Adolescents (Weighing ≥40 kg) and Adult Dose:



Selected Adverse Events • Diarrhea(elvitegravir)

• Stribild-associatedadverseevents:Nausea,diarrhea,fatigue,headache.TDF—renalinsufficiency,decreasedbonemineraldensity,flatulence;cobicistat—alterationintubularsecretionofcreatinine.

• Genvoya-associatedadverseevents:Nausea,diarrhea,fatigue,headache.

• TAF-associatedadverseevents:Increasedlow-densitylipoprotein-cholesterolandtotalcholesterol.

• Cobicistat-associatedadverseevents:Alterationintubularsecretionofcreatinine.

Special Instructions • Administerwithfood.

• WhenusedincombinationwithTDF,monitorestimatedcreatinineclearance(CrCl),urineglucose,andurineproteinatbaselineandevery3to6monthswhileontherapy;inpatientsatriskofrenalimpairment,alsomonitorserumphosphate.Patientswithincreaseinserumcreatinine>0.4mg/dLshouldbecloselymonitoredforrenalsafety.

• ScreenpatientsforhepatitisBvirus(HBV)infectionbeforeuseofemtricitabine,TDF,orTAF.SevereacuteexacerbationofHBVcanoccurwhenemtricitabine,TDF,orTAFisdiscontinued;therefore,monitorhepaticfunctionforseveralmonthsaftertherapywithemtricitabine,TDF,orTAFisstopped.

• NeitherStribildnorGenvoyaisrecommendedforusewithotherARVdrugs.

Dosing RecommendationsNote:Elvitegravirisonlyavailableinfixed-dosecombinationtabletswiththepharmacokinetic(PK)enhancer(boostingagent)cobicistat(i.e.,StribildorGenvoya).

Pediatric Dose (Weighing <35 kg): • Nodataonappropriatedoseofelvitegravirin

Stribildinchildrenweighing<35kg.

• StudiesongoingfordosingofGenvoyainchildrenaged6to<12yearsweighing25to<35kg.

Adolescent (Weighing >35 kg) and Adult Dose:Genvoya (Any Sexual Maturity Rating; Tanner Stage):a

• Onetabletoncedaily

Stribild (SMR 4 or 5)a: • Onetabletoncedaily

Elvitegravir (EVG, VITEKTA) (Last updated April 27, 2017; last reviewed April

27, 2017)


FormulationsTablet:Discontinuedbythemanufacturer.Onlyavailableinfixed-dosecombinationtablets.

Fixed-Dose Combination Tablets: • [Stribild]Elvitegravir150mgpluscobicistat150mgplusemtricitabine200mgplustenofovirdisoproxil

(TDF)300mg

• [Genvoya]Elvitegravir150mgpluscobicistat150mgplusemtricitabine200mgplustenofoviralafenamide(TAF)10mg



aStribildandGenvoyaareFoodandDrugAdministration-approvedforuseinantiretroviral(ARV)treatment-naiveadultsortoreplacethecurrentARVregimeninadultswhoarevirologicallysuppressed(HIV-1RNA<50copies/mL)onastableARVregimenforatleast6monthswithnohistoryoftreatmentfailureandnoknownsubstitutionsassociatedwithresistancetotheindividualcomponentsofStribildorGenvoya.

Metabolism/Elimination • ElvitegravirismetabolizedbycytochromeP

(CYP)4503A4andisamodestinducerofCYP2C9.

• ElvitegravirshouldonlybeusedwiththePKenhancer(boostingagent)cobicistatinStribildorGenvoya.RefertoTDFandTAFsectionsforfurtherdetails.

• StribildshouldnotbeinitiatedinpatientswithestimatedCrCl<70mL/minandshouldbediscontinuedinpatientswithestimatedCrCl<50mL/minbecausedoseadjustmentsrequiredforemtricitabineandTDFcannotbeachievedwithafixed-dosecombinationtablet.

• GenvoyashouldnotbeinitiatedinpatientswithestimatedCrCl<30mL/min.

• NeitherStribildnorGenvoyashouldbeusedinpatientswithseverehepaticimpairment.



Dosing RecommendationsNeonate Dose: • Notapprovedforuseinneonates. • Investigationaldoseforneonates≥37weeks

ofgestationandweighing≥2kgunderstudyinIMPAACTP1110:

• Birthtoage7days:1.5mg/kgoncedaily • Aged8–28days:3mg/kgtwicedaily • Aged≥4weeks:6mg/kgtwicedaily(see

belowforapprovedinfantandpediatricdose)

• Nodosinginformationisavailableforpretermorlowbirthweightinfants.

Note:Metabolismbyuridinediphosphateglucotransferase(UGT1A1)islowatbirthandincreasesrapidlyoverthenext4–6weeksoflife.

Infant and Pediatric Dose:

Body Weight (kg)

Volume (Dose) of Suspension to be Administered

3to<4 1mL(20mg)twicedaily

4to<6 1.5mL(30mg)twicedaily





Oral Suspension Dosing Tablea

Children Aged ≥4 Weeks and Weighing ≥3 kg to <20 kg:

aTheweight-baseddosingrecommendationfortheoralsuspensionisbasedonapproximately6mg/kg/dosetwicedaily.

Note:Maximumdoseoforalsuspensionis5mL(100mg)twicedaily.

Raltegravir (RAL, Isentress) (Last updated April 27, 2017; last reviewed April

27, 2017)


FormulationsTablets:400mg(film-coatedpoloxamertablet)Chewable Tablets:100mg(scored)and25mgGranules for Oral Suspension:Single-usepacketof100mgofraltegravir,suspendedin5mLofwaterforfinalconcentrationof20mg/mL.Note:Film-coatedtablets,chewabletablets,andoralsuspensionare not interchangeable.

Selected Adverse Events • Rash,includingStevens-Johnsonsyndrome,

hypersensitivityreaction,andtoxicepidermalnecrolysis

• Nausea,diarrhea • Headache,dizziness,fatigue • Insomnia • Fever • Creatinephosphokinaseelevation,muscle

weakness,andrhabdomyolysis

Special Instructions • Canbegivenwithoutregardtofood. • Avoidtakingaluminumand/ormagnesium

containingantacids. • Chewabletabletscanbechewed,crushed

(beforeadministration),orswallowedwhole. • Chewabletabletsandoralsuspensionhave

betterbioavailabilitythanthefilm-coatedtablets.Becausetheformulationsarenotinterchangeable,donotsubstitutechewabletabletsororalsuspensionforfilm-coatedtablets.Seespecificrecommendationsforproperdosingofdifferentpreparations.

• Chewabletabletsshouldbestoredintheoriginalpackagewithdesiccanttoprotectfrommoisture.

• Chewabletabletscontainphenylalanine.Therefore,patientswithphenylketonuriashouldmakethenecessarydietaryadjustments.

• Oralsuspensionisprovidedwithakitthatincludestwomixingcups,twodosingsyringes,and60foilpackets.Detailed



instructionsareprovidedintheInstructionsforUsedocument.Eachfoil,single-usepacketcontains100mgofraltegravir,whichwillbesuspendedin5mLofwaterforfinalconcentrationof20mg/mL.Doseshouldbeadministeredwithin30minutesofmixing;unusedsolutionshouldbediscardedasdirectedintheInstructionsforUsedocument.

Metabolism/Elimination • UGT1A1-mediatedglucuronidation • Dosingofraltegravirinpatientswithhepatic

impairment:Nodosageadjustmentisnecessaryforpatientswithmild-to-moderatehepaticinsufficiency.Nodosinginformationisavailableforpatientswithseverehepaticimpairment.

• Dosingofraltegravirinpatientswithrenalimpairment:Nodosageadjustmentnecessary.

Note:Forchildrenweighing11–20kg,eitheroralsuspensionorchewabletabletscanbeused.

Pediatric Dose for Chewable Tablets and Film-Coated Tablets:Children Weighing ≥11 kg: • <25kg:Chewabletablettwicedaily.Seetable

belowforchewabletabletdose. • �≥25kg:400-mgfilm-coatedtablettwicedaily

orchewabletabletstwicedaily.Seetablebelowforchewabletabletdose.

Film-Coated TabletsChild/Adolescent Weighing ≥25 kg and Adult Dose: • 400-mgfilm-coatedtablettwicedaily

Body Weight (kg) Dose Number of Chewable

Tablets

11to<14 75mgtwicedaily 3X25mgtwicedaily


20to<28 150mgtwicedaily 1.5X100mgbtwicedaily


≥40 300mgtwicedaily 3X100mgtwicedaily

aTheweight-baseddosingrecommendationforthechewabletabletisbasedonapproximately6mg/kg/dosetwicedaily.

bThe100-mgchewabletabletcanbedividedintoequalhalves.

Chewable Tablet Dosing Tablea

Note:Maximumdoseofchewabletabletsis300mgtwicedaily.



Selected Adverse Events • Whenco-administeredwithTDF,cobicistat

maybeassociatedwithhigherriskofrenaltubularadverseeventsthanritonavir.

Special Instructions • Cobicistatisnotinterchangeablewithritonavir. • Donotadministercobicistatwithritonaviror

withdrugscontainingcobicistat. • Notrecommendedforusewithmorethanone

ARVdrugthatrequiresPKenhancement(e.g.,elvitegravirincombinationwithaPI)becausenodataareavailable.

• UsewithPIsotherthanatazanavir300mgordarunavir800mgadministeredoncedailyisnotrecommendedbecausenodataareavailableonothercombinationsordoses.

• Patientswithaconfirmedincreaseinserumcreatinine>0.4mg/dLfrombaselineshouldbecloselymonitoredforrenalsafety.

• WhenusedincombinationswithTDF,monitorserumcreatinine,urineprotein,andurineglucoseatbaselineandevery3to6monthswhileontherapy(seeTable13i).Inpatientsatriskofrenalimpairment,alsomonitorserumphosphate.

• WhenusedincombinationwithotherARVdrugs,seethosespecificsectionsoftheappendix(atazanavir,darunavir,elvitegravir,TDF,TAF).

Metabolism/Elimination • CytochromeP(CYP)3A4andCYP2D6

inhibitor

Dosing RecommendationsCobicistat is a Pharmacokinetic (PK) Enhancer: • Theonlyuseofcobicistatisinadolescents

andadultsasaPKenhancer(boostingagent)ofselectedproteaseinhibitors(PIs)andtheintegraseinhibitorelvitegravir.Cobicistatisnotinterchangeablewithritonavir.SeedosinginformationforspecificPIsandelvitegravirthatrequirecobicistatforboosting.

Pediatric DosingNot Food and Drug Administration (FDA)-Approved for Use in Children Aged <18 years: • Cobicistatalone(asTybost) • Stribild • Evotaz • Prezcobix • SomePanelmembersconsiderthatthese

agentsmaybeappropriateinselectchildrenaged<18yearsandweighing≥35kg;anexpertinpediatricHIVinfectionshouldbeconsulted.

Not FDA-Approved for Use in Children Aged <12 Years or Weighing <35 kg: • Genvoya • Panelmembersconsiderthatitmaybe

appropriatetouseGenvoyainchildrenaged<12yearsandweighing≥35kg;anexpertinpediatricHIVinfectionshouldbeconsulted.

Child/Adolescent and Weighing ≥35 kg • Cobicistat150mgorallyoncedailyasa

componentofGenvoya

Adult (Aged ≥18 Years) Dose: • Cobicistatmustbeadministeredas • ThecombinationtabletStribildorGenvoya,

Cobicistat (COBI, TYBOST) (Last updated April 27, 2017; last reviewed April 27, 2017)


FormulationsTablets:150mgFixed-Dose Combination Tablets: • [Stribild]Elvitegravir150mgpluscobicistat150mgplusemtricitabine200mgplustenofovirdisoproxil

fumarate300mg • [Genvoya]Elvitegravir150mgpluscobicistat150mgplusemtricitabine200mgplustenofovir

alafenamide10mg • [Evotaz]Atazanavir300mgpluscobicistat150mg • [Prezcobix]Darunavir800mgpluscobicistat150mg



Cobicistat Dose

Co-administered Agent Dose Patient Population

150mgorallyoncedaily

AspartofStribildorGenvoya;nootherARVdrugsneeded

Treatment-naiveortreatment-experiencedwithvirussusceptibletoallARVdrugcomponentsofStribildorGenvoya


Atazanavir300mg(co-formulatedasEvotazorgivenasaseparatedrug)orallyoncedailyplusotherARVdrugs

Treatment-naiveortreatment-experienced


Darunavir800mg(co-formulatedasPrezcobixorgivenasaseparatedrug)orallyoncedailyplusotherARVdrugs

Treatment-naiveortreatment-experiencedwithnodarunavir-associatedresistancemutations

• Cobicistatinhibitsrenaltubularsecretionofcreatinine,increasingtheserumcreatinineconcentration(anddecreasingestimatedglomerularfiltrationrate)withoutdecreasingactualglomerularfunction.

DosingofCobicistatinPatientswithRenalImpairment: • Stribildshouldnotbeinitiatedinpatientswith

estimatedcreatinineclearance(CrCl)<70mL/minandshouldbediscontinuedinpatientswithestimatedCrCl<50mL/minbecausedoseadjustmentsrequiredforemtricitabineandTDFcannotbeachievedwithafixed-dosecombinationtablet.

• GenvoyashouldnotbeinitiatedinpatientswithestimatedCrCl<30mL/min.

• NeitherStribildnorGenvoyashouldbeusedinpatientswithseverehepaticimpairment.

inwhichcaseitwouldnotbedosedwithanyotherantiretroviral(ARV)drugs;or • ThetabletTybostco-administeredwith

atazanavirordarunaviratthedoseslistedinthetablebelowandatthesametime,incombinationwithotherARVdrugs;or

• Combinationtabletswithatazanavir(Evotaz)ordarunavir(Prezcobix),withfood,andincombinationwithotherARVdrugs.



Dosing RecommendationsRitonavir as a Pharmacokinetic (PK) Enhancer:a • RitonavirisusedasaPKenhancerofother

proteaseinhibitors(PIs).Therecommendeddoseofritonavirvariesandisspecifictothedrugcombinationselected.SeedosinginformationforspecificPIs.

aRitonavirhasantiviralactivitybutisnotusedasanantiviralagent(seetext).

Selected Adverse Events • Gastrointestinalintolerance,nausea,vomiting,

diarrhea • Paresthesia(circumoralandextremities) • Hyperlipidemia,especially

hypertriglyceridemia • Hepatitis • Asthenia • Tasteperversion • Hyperglycemia • Fatmaldistribution • Possibleincreasedbleedingepisodesin

patientswithhemophilia • ToxicepidermalnecrolysisandStevens-

Johnsonsyndrome

Special Instructions • Administerritonavirwithfoodtoincrease

absorptionandreducegastrointestinaladverseeffects.

• Donotadministerritonavirwithcobicistatordrugsthatcontaincobicistat(e.g.,Stribild,Genvoya,Prezcobix,Evotaz).

• Ifritonavirisprescribedwithdidanosine,administerthedrugs2hoursapart.

• Donotrefrigerateritonaviroralsolution;storeat68°Fto77°F(20°Cto25°C).Shakethesolutionwellbeforeuse.

• ToIncreaseTolerabilityofRitonavirOralSolutioninChildren:

• Mixsolutionwithmilk,chocolatemilk,orvanillaorchocolatepuddingoricecream.

• Beforeadministration,giveachildicechips,aPopsicle,orspoonfulsofpartiallyfrozenorangeorgrapejuiceconcentratetodullthetastebuds,orgivepeanutbuttertocoatthemouth.

Ritonavir (RTV, Norvir) (Last updated April 27, 2017; last reviewed April 27,

2017)


FormulationsOral Solution (Contains 43% Alcohol by Volume):80mg/mLTablets:100mg



• Afteradministration,giveachildstrong-tastingfoodssuchasmaplesyruporcheese.

• Checkfoodallergyhistorybeforemakingtheserecommendations.

• Counselparentsorpatientsthatthebadtastewillnotbecompletelymasked.

Metabolism/Elimination • CytochromeP(CYP)3A4andCYP2D6

inhibitor;CYP1A2,CYP2B6,CYP2C9,CYP2C19,andglucuronidationinducer.

• Dosingofritonavirinpatientswithhepaticimpairment:Ritonavirisprimarilymetabolizedbytheliver.Nodosageadjustmentisnecessaryinpatientswithmildormoderatehepaticimpairment.Dataareunavailableonritonavirdosingforadultorpediatricpatientswithseverehepaticimpairment.Usecautionwhenadministeringritonavirtopatientswithmoderate-to-severehepaticimpairment.

guidelines for the use of antiretroviral agents in ... · pdf filepediatric dose oral solution...

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