warnings and precautions ——— ——— recent major … · agents (e.g., epinephrine,...

1

——— CONTRAINDICATIONS ———•Donotuseduringepisodesofhypoglycemia(4).•DonotuseinpatientswithhypersensitivitytoNovoLog®orone

ofitsexcipients.

——— WARNINGS AND PRECAUTIONS ———•Hypoglycemiaisthemostcommonadverseeffectofinsulin

therapy.Glucosemonitoringisrecommendedforallpatientswithdiabetes.Anychangeofinsulindoseshouldbemadecautiouslyandonlyundermedicalsupervision(5.1,5.2).

•Insulin,particularlywhengivenintravenouslyorinsettingsofpoorglycemiccontrol,cancausehypokalemia.Usecautioninpatientspredisposedtohypokalemia(5.3).

•Likeallinsulins,NovoLog®requirementsmaybereducedinpatientswithrenalimpairmentorhepaticimpairment(5.4,5.5).

•Severe,life-threatening,generalizedallergy,includinganaphylaxis,mayoccurwithinsulinproducts,includingNovoLog®(5.6).

——— ADVERSE REACTIONS ———AdversereactionsobservedwithNovoLog®includehypoglycemia,allergicreactions,localinjectionsitereactions,lipodystrophy,rashandpruritus(6).To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

——— DRUG INTERACTIONS ———•Thefollowingmayincreasetheblood-glucose-loweringeffect

andsusceptibilitytohypoglycemia:oralantidiabeticproducts,pramlintide,ACEinhibitors,disopyramide,fibrates,fluoxetine,monoamineoxidaseinhibitors,propoxyphene,salicylates,somatostatinanalogs,sulfonamideantibiotics(7).

•Thefollowingmayreducetheblood-glucose-loweringeffect:corticosteroids,niacin,danazol,diuretics,sympathomimeticagents(e.g.,epinephrine,salbutamol,terbutaline),isoniazid,phenothiazinederivatives,somatropin,thyroidhormones,estrogens,progestogens(e.g.,inoralcontraceptives),atypicalantipsychotics(7).

•Beta-blockers,clonidine,lithiumsalts,andalcoholmayeitherpotentiateorweakentheblood-glucose-loweringeffectofinsulin(7).

•Pentamidinemaycausehypoglycemia,whichmaysometimesbefollowedbyhyperglycemia(7).

•Thesignsofhypoglycemiamaybereducedorabsentinpatientstakingsympatholyticproductssuchasbeta-blockers,clonidine,guanethidine,andreserpine(7).

——— USE IN SPECIFIC POPULATIONS ———•Pediatric:Hasnotbeenstudiedinchildrenwithtype2diabetes.

Hasnotbeenstudiedinchildrenwithtype1diabetes<2yearsofage(8.4).

See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: 6/2011

FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 TreatmentofDiabetesMellitus2 DOSAGE AND ADMINISTRATION 2.1 Dosing 2.2 SubcutaneousInjection 2.3 ContinuousSubcutaneousInsulinInfusion(CSII)byExternalPump 2.4 IntravenousUse3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS 5.1 Administration 5.2 Hypoglycemia 5.3 Hypokalemia 5.4 RenalImpairment 5.5 HepaticImpairment 5.6 HypersensitivityandAllergicReactions 5.7 AntibodyProduction 5.8 MixingofInsulins 5.9 ContinuousSubcutaneousInsulinInfusionbyExternalPump6 ADVERSE REACTIONS7 DRUG INTERACTIONS8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy

8.3 NursingMothers 8.4 PediatricUse 8.5 GeriatricUse10 OVERDOSAGE11 DESCRIPTION12 CLINICAL PHARMACOLOGY 12.1 MechanismofAction 12.2 Pharmacodynamics 12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis,Mutagenesis,ImpairmentofFertility 13.2 AnimalToxicologyand/orPharmacology14 CLINICAL STUDIES 14.1 SubcutaneousDailyInjections 14.2 ContinuousSubcutaneousInsulinInfusion(CSII)byExternalPump 14.3 IntravenousAdministrationofNovoLog®16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 HowSupplied 16.2 RecommendedStorage17 PATIENT COUNSELING INFORMATION 17.1 PhysicianInstructions 17.2 PatientsUsingPumps 17.3 FDA-ApprovedPatientLabeling*Sectionsorsubsectionsomittedfromthefullprescribinginformationarenotlisted.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use NovoLog® safely and effectively. See full prescribing information for NovoLog®. NovoLog® (insulin aspart [rDNA origin] injection) solution for subcutaneous useInitial U.S. Approval: 2000

——— RECENT MAJOR CHANGES ———•DosageandAdministration(2.3) 7/2009•WarningsandPrecautions,Administration(5.1) 10/2009

——— INDICATIONS AND USAGE ———•NovoLog®isaninsulinanalogindicatedtoimproveglycemic

controlinadultsandchildrenwithdiabetesmellitus(1.1).

——— DOSAGE AND ADMINISTRATION ———•ThedosageofNovoLog®mustbeindividualized.•Subcutaneous injection:NovoLog®shouldgenerallybegiven

immediately(within5-10minutes)priortothestartofameal(2.2).

•Use in pumps:ChangetheNovoLog®inthereservoiratleastevery6days,changetheinfusionset,andtheinfusionsetinsertionsiteatleastevery3days.NovoLog®shouldnotbemixedwithotherinsulinsorwithadiluentwhenitisusedinthepump(2.3).

•Intravenous use:NovoLog®shouldbeusedatconcentrationsfrom0.05U/mLto1.0U/mLinsulinaspartininfusionsystemsusingpolypropyleneinfusionbags.NovoLog®hasbeenshowntobestableininfusionfluidssuchas0.9%sodiumchloride(2.4).

——— DOSAGE FORMS AND STRENGTHS ———Eachpresentationcontains100UnitsofinsulinaspartpermL(U-100)•10mLvials(3)•3mLPenFill®cartridgesforthe3mLPenFill®cartridgedevice(3)•3mLNovoLog®FlexPen®(3)

2NovoLog® (insulin aspart [rDNA origin] injection)

•Hypoglycemia Hypoglycemiaisthemostcommonlyobservedadversereactioninpatientsusinginsulin,

includingNovoLog®[see Warnings and Precautions (5)].• Insulin initiation and glucose control intensification Intensificationorrapidimprovementinglucosecontrolhasbeenassociatedwithatransitory,

reversibleophthalmologicrefractiondisorder,worseningofdiabeticretinopathy,andacutepainfulperipheralneuropathy.However,long-termglycemiccontroldecreasestheriskofdiabeticretinopathyandneuropathy.

•Lipodystrophy Long-termuseofinsulin,includingNovoLog®,cancauselipodystrophyatthesiteofrepeated

insulininjectionsorinfusion.Lipodystrophyincludeslipohypertrophy(thickeningofadiposetissue)andlipoatrophy(thinningofadiposetissue),andmayaffectinsulinabsorption.Rotateinsulininjectionorinfusionsiteswithinthesameregiontoreducetheriskoflipodystrophy.

•Weight gain Weightgaincanoccurwithsomeinsulintherapies,includingNovoLog®,andhasbeen

attributedtotheanaboliceffectsofinsulinandthedecreaseinglucosuria.•Peripheral Edema Insulinmaycausesodiumretentionandedema,particularlyifpreviouslypoormetabolic

controlisimprovedbyintensifiedinsulintherapy.•Frequencies of adverse drug reactions ThefrequenciesofadversedrugreactionsduringNovoLog®clinicaltrialsinpatientswithtype

1diabetesmellitusandtype2diabetesmellitusarelistedinthetablesbelow.Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 Diabetes Mellitus (Adverse events with frequency ≥ 5% and occurring more frequently with NovoLog® compared to human regular insulin are listed)

NovoLog® + NPH N= 596

Human Regular Insulin + NPH N= 286

Preferred Term N (%) N (%)Hypoglycemia* 448 75% 205 72%Headache 70 12% 28 10%Injuryaccidental 65 11% 29 10%Nausea 43 7% 13 5%Diarrhea 28 5% 9 3%

*Hypoglycemiaisdefinedasanepisodeofbloodglucoseconcentration<45mg/dL,withorwithoutsymptoms.SeeSection14fortheincidenceofserioushypoglycemiaintheindividualclinicaltrials.

Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 Diabetes Mellitus (except for hypoglycemia, adverse events with frequency ≥ 5% and occurring more frequently with NovoLog® compared to human regular insulin are listed)

NovoLog® + NPH N= 91

Human Regular Insulin + NPH N= 91

N (%) N (%)Hypoglycemia* 25 27% 33 36%Hyporeflexia 10 11% 6 7%Onychomycosis 9 10% 5 5%Sensorydisturbance 8 9% 6 7%Urinarytractinfection 7 8% 6 7%Chestpain 5 5% 3 3%Headache 5 5% 3 3%Skindisorder 5 5% 2 2%Abdominalpain 5 5% 1 1%Sinusitis 5 5% 1 1%

*Hypoglycemiaisdefinedasanepisodeofbloodglucoseconcentration<45mg/dL,withorwithoutsymptoms.SeeSection14fortheincidenceofserioushypoglycemiaintheindividualclinicaltrials.Postmarketing DataThe following additional adverse reactions have been identified during postapproval use ofNovoLog®.Becausetheseadversereactionsarereportedvoluntarilyfromapopulationofuncertainsize, it isgenerallynotpossible toreliablyestimate their frequency.Medicationerrors inwhichother insulins have been accidentally substituted for NovoLog® have been identified duringpostapprovaluse[see Patient Counseling Information (17)].7 DRUG INTERACTIONSAnumberofsubstancesaffectglucosemetabolismandmayrequireinsulindoseadjustmentandparticularlyclosemonitoring.•Thefollowingareexamplesofsubstancesthatmayincreasetheblood-glucose-loweringeffect

andsusceptibilitytohypoglycemia:oralantidiabeticproducts,pramlintide,ACEinhibitors,disopyramide,fibrates,fluoxetine,monoamineoxidase(MAO)inhibitors,propoxyphene,salicylates,somatostatinanalog(e.g.,octreotide),sulfonamideantibiotics.

•Thefollowingareexamplesofsubstancesthatmayreducetheblood-glucose-loweringeffect:corticosteroids,niacin,danazol,diuretics,sympathomimeticagents(e.g.,epinephrine,salbutamol,terbutaline),isoniazid,phenothiazinederivatives,somatropin,thyroidhormones,estrogens,progestogens(e.g.,inoralcontraceptives),atypicalantipsychotics.

•Beta-blockers,clonidine,lithiumsalts,andalcoholmayeitherpotentiateorweakentheblood-glucose-loweringeffectofinsulin.

•Pentamidinemaycausehypoglycemia,whichmaysometimesbefollowedbyhyperglycemia.•Thesignsofhypoglycemiamaybereducedorabsentinpatientstakingsympatholytic

productssuchasbeta-blockers,clonidine,guanethidine,andreserpine.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category B. All pregnancies have a background risk of birth defects, loss, or otheradverseoutcomeregardlessofdrugexposure.Thisbackgroundriskisincreasedinpregnanciescomplicatedbyhyperglycemiaandmaybedecreasedwithgoodmetaboliccontrol.Itisessentialforpatientswithdiabetesorhistoryofgestationaldiabetestomaintaingoodmetaboliccontrolbefore

Needles and NovoLog® FlexPen® must not be shared.5.2 HypoglycemiaHypoglycemia is themostcommonadverseeffectofall insulin therapies, includingNovoLog®.Severe hypoglycemia may lead to unconsciousness and/or convulsions and may result intemporaryorpermanentimpairmentofbrainfunctionordeath.Severehypoglycemiarequiringtheassistanceofanotherpersonand/orparenteralglucoseinfusionorglucagonadministrationhasbeenobservedinclinicaltrialswithinsulin,includingtrialswithNovoLog®.The timing of hypoglycemia usually reflects the time-action profile of the administered insulinformulations[see Clinical Pharmacology (12)].Otherfactorssuchaschangesinfoodintake(e.g.,amountof foodor timingofmeals), injection site, exercise, andconcomitantmedicationsmayalsoaltertheriskofhypoglycemia[see Drug Interactions (7)].Aswithallinsulins,usecautioninpatientswithhypoglycemiaunawarenessandinpatientswhomaybepredisposedtohypoglycemia(e.g.,patientswhoarefastingorhaveerraticfoodintake).Thepatient’sabilitytoconcentrateandreactmaybeimpairedasaresultofhypoglycemia.Thismaypresentariskinsituationswheretheseabilitiesareespeciallyimportant,suchasdrivingoroperatingothermachinery.Rapidchangesinserumglucoselevelsmayinducesymptomsofhypoglycemiainpersonswithdiabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may bedifferent or less pronounced under certain conditions, such as longstanding diabetes, diabeticnerve disease, use of medications such as beta-blockers, or intensified diabetes control [see Drug Interactions (7)].Thesesituationsmay result inseverehypoglycemia (and,possibly, lossofconsciousness)prior to thepatient’sawarenessofhypoglycemia. Intravenouslyadministeredinsulinhasamorerapidonsetofactionthansubcutaneouslyadministeredinsulin,requiringmoreclosemonitoringforhypoglycemia.5.3 HypokalemiaAll insulin products, including NovoLog®, cause a shift in potassium from the extracellular tointracellular space, possibly leading to hypokalemia that, if left untreated, may cause respiratoryparalysis,ventriculararrhythmia,anddeath.Usecautioninpatientswhomaybeatriskforhypokalemia(e.g.,patientsusingpotassium-loweringmedications,patientstakingmedicationssensitivetoserumpotassiumconcentrations,andpatientsreceivingintravenouslyadministeredinsulin).5.4 Renal ImpairmentAswithotherinsulins,thedoserequirementsforNovoLog®maybereducedinpatientswithrenalimpairment[see Clinical Pharmacology (12.3)].5.5 Hepatic ImpairmentAs with other insulins, the dose requirements for NovoLog® may be reduced in patients withhepaticimpairment[see Clinical Pharmacology (12.3)].5.6 Hypersensitivity and Allergic ReactionsLocal Reactions - As with other insulin therapy, patients may experience redness, swelling, oritchingatthesiteofNovoLog®injection.Thesereactionsusuallyresolveinafewdaystoafewweeks,butinsomeoccasions,mayrequirediscontinuationofNovoLog®.Insomeinstances,thesereactionsmayberelatedtofactorsotherthaninsulin,suchasirritantsinaskincleansingagentorpoorinjectiontechnique.Localizedreactionsandgeneralizedmyalgiashavebeenreportedwithinjectedmetacresol,whichisanexcipientinNovoLog®.Systemic Reactions-Severe,life-threatening,generalizedallergy,includinganaphylaxis,mayoccurwithanyinsulinproduct,includingNovoLog®.AnaphylacticreactionswithNovoLog®havebeenreportedpost-approval.Generalizedallergytoinsulinmayalsocausewholebodyrash(includingpruritus),dyspnea,wheezing,hypotension,tachycardia,ordiaphoresis.Incontrolledclinicaltrials,allergicreactionswerereportedin3of735patients(0.4%)treatedwithregularhumaninsulinand10of1394patients(0.7%)treatedwithNovoLog®.Incontrolledanduncontrolledclinicaltrials,3of2341(0.1%)NovoLog®-treatedpatientsdiscontinuedduetoallergicreactions.5.7 Antibody ProductionIncreasesinanti-insulinantibodytitersthatreactwithbothhumaninsulinandinsulinasparthavebeenobservedinpatientstreatedwithNovoLog®.Increasesinanti-insulinantibodiesareobservedmorefrequentlywithNovoLog®thanwithregularhumaninsulin.Datafroma12-monthcontrolledtrialinpatientswithtype1diabetessuggestthattheincreaseintheseantibodiesistransient,andthedifferencesinantibodylevelsbetweentheregularhumaninsulinandinsulinasparttreatmentgroupsobservedat3and6monthswerenolongerevidentat12months.Theclinicalsignificanceoftheseantibodiesisnotknown.Theseantibodiesdonotappeartocausedeteriorationinglycemiccontrolornecessitateincreasesininsulindose.5.8 Mixing of Insulins•MixingNovoLog®withNPHhumaninsulinimmediatelybeforeinjectionattenuatesthepeak

concentrationofNovoLog®,withoutsignificantlyaffectingthetimetopeakconcentrationortotalbioavailabilityofNovoLog®.IfNovoLog®ismixedwithNPHhumaninsulin,NovoLog®shouldbedrawnintothesyringefirst,andthemixtureshouldbeinjectedimmediatelyaftermixing.

•TheefficacyandsafetyofmixingNovoLog®withinsulinpreparationsproducedbyothermanufacturershavenotbeenstudied.

•Insulinmixturesshouldnotbeadministeredintravenously.5.9 Continuous Subcutaneous Insulin Infusion by External PumpWhen used in an external subcutaneous insulin infusion pump, NovoLog® should not be mixed with any other insulin or diluent. When using NovoLog® in an externalinsulinpump,theNovoLog®-specificinformationshouldbefollowed(e.g.,in-usetime,frequencyofchanginginfusionsets)becauseNovoLog®-specificinformationmaydifferfromgeneralpumpmanualinstructions.Pump or infusion set malfunctions or insulin degradation can lead to a rapid onset ofhyperglycemiaandketosisbecauseofthesmallsubcutaneousdepotofinsulin.Thisisespeciallypertinentforrapid-actinginsulinanalogsthataremorerapidlyabsorbedthroughskinandhaveashorterdurationofaction.Promptidentificationandcorrectionofthecauseofhyperglycemiaorketosisisnecessary.Interimtherapywithsubcutaneousinjectionmayberequired[see Dosage and Administration (2.3), Warnings and Precautions (5.8, 5.9), How Supplied/Storage and Handling (16.2), and Patient Counseling Information (17.2)].NovoLog®shouldnotbeexposedtotemperaturesgreaterthan37°C(98.6°F).NovoLog®that will be used in a pump should not be mixed with other insulin or with a diluent[see Dosage and Administration (2.3), Warnings and Precautions (5.8, 5.9), How Supplied/Storage and Handling (16.2), and Patient Counseling Information (17.2)].6 ADVERSE REACTIONSClinical Trial ExperienceBecause clinical trials are conducted under widely varying designs, the adverse reaction ratesreportedinoneclinicaltrialmaynotbeeasilycomparedtothoseratesreportedinanotherclinicaltrial,andmaynotreflecttheratesactuallyobservedinclinicalpractice.

FULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGE1.1 Treatment of Diabetes MellitusNovoLog®isaninsulinanalogindicatedtoimproveglycemiccontrolinadultsandchildrenwithdiabetesmellitus.2 DOSAGE AND ADMINISTRATION2.1 DosingNovoLog® isan insulinanalogwithanearlieronsetof action than regularhuman insulin.Thedosage of NovoLog® must be individualized. NovoLog® given by subcutaneous injectionshouldgenerallybeusedinregimenswithanintermediateorlong-actinginsulin[see Warnings and Precautions (5), How Supplied/Storage and Handling (16.2)]. The total daily insulinrequirement may vary and is usually between 0.5 to 1.0 units/kg/day. When used in a meal-relatedsubcutaneous injection treatment regimen,50 to70%of total insulin requirementsmaybeprovidedbyNovoLog®andtheremainderprovidedbyanintermediate-actingor long-actinginsulin.BecauseofNovoLog®’scomparativelyrapidonsetandshortdurationofglucoseloweringactivity,somepatientsmayrequiremorebasalinsulinandmoretotalinsulintopreventpre-mealhyperglycemiawhenusingNovoLog®thanwhenusinghumanregularinsulin.DonotuseNovoLog®thatisviscous(thickened)orcloudy;useonlyifitisclearandcolorless.NovoLog®shouldnotbeusedaftertheprintedexpirationdate.2.2 Subcutaneous InjectionNovoLog®shouldbeadministeredbysubcutaneousinjectionintheabdominalregion,buttocks,thigh,orupperarm.BecauseNovoLog®hasamorerapidonsetandashorterdurationofactivitythanhumanregularinsulin,itshouldbeinjectedimmediately(within5-10minutes)beforeameal.Injectionsitesshouldberotatedwithinthesameregiontoreducetheriskoflipodystrophy.Aswithallinsulins,thedurationofactionofNovoLog®willvaryaccordingtothedose,injectionsite,bloodflow,temperature,andlevelofphysicalactivity.NovoLog® may be diluted with Insulin Diluting Medium for NovoLog® for subcutaneousinjection.DilutingonepartNovoLog® toninepartsdiluentwillyieldaconcentrationone-tenththatofNovoLog®(equivalenttoU-10).DilutingonepartNovoLog®toonepartdiluentwillyieldaconcentrationone-halfthatofNovoLog®(equivalenttoU-50). 2.3 Continuous Subcutaneous Insulin Infusion (CSII) by External Pump

NovoLog®canalsobeinfusedsubcutaneouslybyanexternalinsulinpump[see Warnings and Precautions (5.8, 5.9), How Supplied/Storage and Handling (16.2)].Dilutedinsulinshouldnotbeused inexternal insulinpumps.BecauseNovoLog®hasamore rapidonsetandashorterdurationofactivitythanhumanregularinsulin,pre-mealbolusesofNovoLog®shouldbeinfusedimmediately (within 5-10 minutes) before a meal. Infusion sites should be rotated within thesameregiontoreducetheriskoflipodystrophy.Theinitialprogrammingoftheexternalinsulininfusionpumpshouldbebasedonthetotaldailyinsulindoseofthepreviousregimen.Althoughthereissignificantinterpatientvariability,approximately50%ofthetotaldoseisusuallygivenasmeal-relatedbolusesofNovoLog®andtheremainderisgivenasabasalinfusion.Change the NovoLog® in the reservoir at least every 6 days, change the infusion sets and the infusion set insertion site at least every 3 days.Thefollowinginsulinpumps†havebeenusedinNovoLog®clinicalorin vitrostudiesconductedbyNovoNordisk,themanufacturerofNovoLog®:•MedtronicParadigm®512and712•MiniMed508•Disetronic®D-TRON®andH-TRON®

BeforeusingadifferentinsulinpumpwithNovoLog®,readthepumplabeltomakesurethepumphasbeenevaluatedwithNovoLog®.

2.4 Intravenous UseNovoLog®canbeadministeredintravenouslyundermedicalsupervisionforglycemiccontrolwithclosemonitoringofbloodglucoseandpotassiumlevelstoavoidhypoglycemiaandhypokalemia[see Warnings and Precautions (5), How Supplied/Storage and Handling (16.2)].Forintravenoususe,NovoLog®shouldbeusedatconcentrationsfrom0.05U/mLto1.0U/mLinsulinaspartininfusionsystemsusingpolypropyleneinfusionbags.NovoLog®hasbeenshowntobestableininfusionfluidssuchas0.9%sodiumchloride.InspectNovoLog®forparticulatematteranddiscolorationpriortoparenteraladministration.3 DOSAGE FORMS AND STRENGTHSNovoLog® is available in the following package sizes: each presentation contains 100 units ofinsulinaspartpermL(U-100).•10mLvials•3mLPenFillcartridgesforthe3mLPenFill®cartridgedeliverydevice(withorwithoutthe

additionofaNovoPen®3PenMate®)withNovoFine®disposableneedles•3mLNovoLog®FlexPen®

4 CONTRAINDICATIONSNovoLog®iscontraindicated•duringepisodesofhypoglycemia•inpatientswithhypersensitivitytoNovoLog®oroneofitsexcipients.

5 WARNINGS AND PRECAUTIONS5.1 AdministrationNovoLog®hasamorerapidonsetofactionandashorterdurationofactivitythanregularhumaninsulin.AninjectionofNovoLog®shouldimmediatelybefollowedbyamealwithin5-10minutes.BecauseofNovoLog®’sshortdurationofaction,a longeractinginsulinshouldalsobeusedinpatientswith type1diabetesandmayalsobeneededinpatientswith type2diabetes.Glucosemonitoringisrecommendedforallpatientswithdiabetesandisparticularlyimportantforpatientsusingexternalpumpinfusiontherapy.Any change of insulin dose should be made cautiously and only under medical supervision.Changingfromoneinsulinproducttoanotherorchangingtheinsulinstrengthmayresultintheneedforachangeindosage.Aswithallinsulinpreparations,thetimecourseofNovoLog®actionmayvaryindifferentindividualsoratdifferenttimesinthesameindividualandisdependentonmany conditions, including the site of injection, local blood supply, temperature, and physicalactivity.Patientswhochangetheirlevelofphysicalactivityormealplanmayrequireadjustmentof insulindosages. Insulin requirementsmaybealteredduring illness,emotionaldisturbances,orotherstresses.Patients using continuous subcutaneous insulin infusion pump therapy must be trained toadministerinsulinbyinjectionandhavealternateinsulintherapyavailableincaseofpumpfailure.


betweenNovoLog®andregularhumaninsulinweresimilartothoseinhealthyadultsubjectsandadultswithtype1diabetes.Gender-Inhealthyvolunteers,nodifferenceininsulinaspartlevelswasseenbetweenmenandwomenwhenbodyweightdifferencesweretakenintoaccount.Therewasnosignificantdifferenceinefficacynoted(asassessedbyHbA1c)betweengendersinatrialinpatientswithtype1diabetes.Obesity - A single subcutaneous dose of 0.1 U/kg NovoLog® was administered in a study of23patientswithtype1diabetesandawiderangeofbodymassindex(BMI,22-39kg/m2).Thepharmacokineticparameters,AUCandCmax,ofNovoLog®weregenerallyunaffectedbyBMIinthedifferentgroups–BMI19-23kg/m2(N=4);BMI23-27kg/m2(N=7);BMI27-32kg/m2(N=6)andBMI>32kg/m2(N=6).ClearanceofNovoLog®wasreducedby28%inpatientswithBMI>32kg/m2comparedtopatientswithBMI<23kg/m2.Renal Impairment - Some studies with human insulin have shown increased circulating levelsofinsulininpatientswithrenalfailure.Asinglesubcutaneousdoseof0.08U/kgNovoLog®wasadministeredinastudytosubjectswitheithernormal(N=6)creatinineclearance(CLcr)(>80ml/min)ormild(N=7;CLcr=50-80ml/min),moderate(N=3;CLcr=30-50ml/min)orsevere(butnotrequiringhemodialysis)(N=2;CLcr=<30ml/min)renalimpairment.Inthissmallstudy,therewasnoapparenteffectofcreatinineclearancevaluesonAUCandCmaxofNovoLog®.Carefulglucosemonitoringanddoseadjustmentsofinsulin,includingNovoLog®,maybenecessaryinpatientswithrenaldysfunction[see Warnings and Precautions (5.4)].Hepatic Impairment -Somestudieswithhumaninsulinhaveshownincreasedcirculatinglevelsofinsulininpatientswithliverfailure.Asinglesubcutaneousdoseof0.06U/kgNovoLog®wasadministeredinanopen-label,single-dosestudyof24subjects(N=6/group)withdifferentdegreeof hepatic impairment (mild, moderate and severe) having Child-Pugh Scores ranging from 0(healthyvolunteers)to12(severehepaticimpairment).Inthissmallstudy,therewasnocorrelationbetween the degree of hepatic failure and any NovoLog® pharmacokinetic parameter. Carefulglucosemonitoringanddoseadjustmentsofinsulin,includingNovoLog®,maybenecessaryinpatientswithhepaticdysfunction[see Warnings and Precautions (5.5)].The effect of age, ethnic origin, pregnancy and smoking on the pharmacokinetics andpharmacodynamicsofNovoLog®hasnotbeenstudied.13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of FertilityStandard 2-year carcinogenicity studies in animals have not been performed to evaluate thecarcinogenic potential of NovoLog®. In 52-week studies, Sprague-Dawley rats were dosedsubcutaneouslywithNovoLog®at10,50,and200U/kg/day(approximately2,8,and32timesthehumansubcutaneousdoseof1.0U/kg/day,basedonU/bodysurfacearea,respectively).Atadoseof200U/kg/day,NovoLog®increasedtheincidenceofmammaryglandtumorsinfemaleswhencomparedtountreatedcontrols.TheincidenceofmammarytumorsforNovoLog®wasnotsignificantlydifferentthanforregularhumaninsulin.Therelevanceofthesefindingstohumansisnotknown.NovoLog®wasnotgenotoxicinthefollowingtests:Amestest,mouselymphomacellforwardgenemutationtest,humanperipheralbloodlymphocytechromosomeaberrationtest,in vivomicronucleustestinmice,andinex vivoUDStestinratliverhepatocytes.Infertilitystudiesinmaleandfemalerats,atsubcutaneousdosesupto200U/kg/day(approximately32timesthehumansubcutaneousdose,basedonU/bodysurfacearea),nodirectadverseeffectsonmaleandfemalefertility,orgeneralreproductiveperformanceofanimalswasobserved.13.2 Animal Toxicology and/or PharmacologyInstandardbiologicalassaysinmiceandrabbits,oneunitofNovoLog®hasthesameglucose-loweringeffectasoneunitofregularhumaninsulin.Inhumans,theeffectofNovoLog®ismorerapid in onset and of shorter duration, compared to regular human insulin, due to its fasterabsorption after subcutaneous injection (see Section 12 CLINICAL PHARMACOLOGY Figure 2andFigure4).14 CLINICAL STUDIES14.1 Subcutaneous Daily InjectionsTwosix-month,open-label,active-controlledstudieswereconducted tocompare thesafetyandefficacyofNovoLog®toNovolin®Rinadultpatientswithtype1diabetes.Becausethetwostudydesignsandresultsweresimilar,dataareshownforonlyonestudy(seeTable3).NovoLog®wasadministeredbysubcutaneousinjectionimmediatelypriortomealsandregularhumaninsulinwasadministeredbysubcutaneousinjection30minutesbeforemeals.NPHinsulinwasadministeredasthebasalinsulinineithersingleordivideddailydoses.ChangesinHbA1candtheincidenceratesofseverehypoglycemia(asdeterminedfromthenumberofeventsrequiringinterventionfromathirdparty)werecomparableforthetwotreatmentregimensinthisstudy(Table3)aswellasintheotherclinicalstudiesthatarecitedinthissection.Diabeticketoacidosiswasnotreportedinanyoftheadultstudiesineithertreatmentgroup.Table 3. Subcutaneous NovoLog® Administration in Type 1 Diabetes(24weeks;n=882)

NovoLog® + NPH Novolin® R + NPHN 596 286BaselineHbA1c(%)* 7.9±1.1 8.0±1.2ChangefromBaselineHbA1c(%) -0.1±0.8 0.0±0.8TreatmentDifferenceinHbA1c,Mean(95%confidenceinterval) -0.2(-0.3,-0.1)

Baselineinsulindose(IU/kg/24hours)* 0.7±0.2 0.7±0.2End-of-Studyinsulindose(IU/kg/24hours)* 0.7±0.2 0.7±0.2Patientswithseverehypoglycemia(n,%)** 104(17%) 54(19%)Baselinebodyweight(kg)*WeightChangefrombaseline(kg)*

75.3±14.50.5±3.3

75.9±13.10.9±2.9

*ValuesareMean±SD**Severehypoglycemiareferstohypoglycemiaassociatedwithcentralnervoussystemsymptomsandrequiringtheinterventionofanotherpersonorhospitalization.A24-week,parallel-groupstudyofchildrenandadolescentswithtype1diabetes(n=283)aged6to18yearscomparedtwosubcutaneousmultiple-dosetreatmentregimens:NovoLog®(n=187)orNovolin®R(n=96).NPHinsulinwasadministeredasthebasalinsulin.NovoLog®achievedglycemiccontrolcomparabletoNovolin®R,asmeasuredbychangeinHbA1c(Table4)andbothtreatmentgroupshadacomparableincidenceofhypoglycemia.SubcutaneousadministrationofNovoLog®andregularhumaninsulinhavealsobeencomparedinchildrenwithtype1diabetes(n=26)aged2to6yearswithsimilareffectsonHbA1candhypoglycemia.

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/dL) 250

150

Figure 2. Serial mean serum glucose collected up to 6 hours following a single pre-meal dose of NovoLog® (solid curve) or regular human insulin (hatched curve) injected immediately before a meal in 22 patients with type 1 diabetes.A double-blind, randomized, two-way cross-over study in 16 patients with type 1 diabetesdemonstrated that intravenous infusion of NovoLog® resulted in a blood glucose profile thatwassimilar to that after intravenous infusionwith regularhuman insulin.NovoLog® orhumaninsulinwasinfuseduntilthepatient’sbloodglucosedecreasedto36mg/dL,oruntilthepatientdemonstratedsignsofhypoglycemia(riseinheartrateandonsetofsweating),definedasthetimeofautonomicreaction(R)(seeFigure3).

180

162

144

126

108

90

72

54

36

18

00 10 R–20 R R+40 R+50 R+60

Time (min)

Mean Blood Glucose (mg/dL)

R–10 R+10 R+20 R+30

Note: The slashes on the mean profile indicate a jump on the time axis

Figure 3. Mean blood glucose profiles following intravenous infusion of NovoLog® (hatched curve) and regular human insulin (solid curve) in 16 patients with type 1 diabetes. R represents the time of autonomic reaction.12.3 PharmacokineticsThesinglesubstitutionoftheaminoacidprolinewithasparticacidatpositionB28inNovoLog®reduces the molecule’s tendency to form hexamers as observed with regular human insulin.NovoLog®is,therefore,morerapidlyabsorbedaftersubcutaneousinjectioncomparedtoregularhumaninsulin.Inarandomized,double-blind,crossoverstudy17healthyCaucasianmalesubjectsbetween18and40yearsofagereceivedanintravenousinfusionofeitherNovoLog®orregularhumaninsulinat1.5mU/kg/min for120minutes.Themean insulinclearancewassimilar for the twogroupswith mean values of 1.2 l/h/kg for the NovoLog® group and 1.2 l/h/kg for the regular humaninsulingroup.Bioavailability and Absorption-NovoLog®hasafasterabsorption,afasteronsetofaction,andashorterdurationofactionthanregularhumaninsulinaftersubcutaneousinjection(seeFigure2andFigure4).TherelativebioavailabilityofNovoLog®comparedtoregularhumaninsulinindicatesthatthetwoinsulinsareabsorbedtoasimilarextent.

80

60

40

20

00 1 2 3 4 5 6

Time (h)

Free

ser

um

insu

lin (

mU

/L)

Figure 4. Serial mean serum free insulin concentration collected up to 6 hours following a single pre-meal dose of NovoLog® (solid curve) or regular human insulin (hatched curve) injected immediately before a meal in 22 patients with type 1 diabetes.In studies in healthy volunteers (total n=107) and patients with type 1 diabetes (total n=40),NovoLog®consistentlyreachedpeakserumconcentrationsapproximatelytwiceasfastasregularhumaninsulin.Themediantimetomaximumconcentrationinthesetrialswas40to50minutesforNovoLog®versus80to120minutesforregularhumaninsulin.Inaclinicaltrialinpatientswithtype1diabetes,NovoLog®andregularhumaninsulin,bothadministeredsubcutaneouslyatadoseof0.15U/kgbodyweight,reachedmeanmaximumconcentrationsof82and36mU/L,respectively.Pharmacokinetic/pharmacodynamiccharacteristicsofinsulinasparthavenotbeenestablishedinpatientswithtype2diabetes.Theintra-individualvariabilityintimetomaximumseruminsulinconcentrationforhealthymalevolunteers was significantly less for NovoLog® than for regular human insulin. The clinicalsignificanceofthisobservationhasnotbeenestablished.In a clinical study in healthy non-obese subjects, the pharmacokinetic differences betweenNovoLog®andregularhumaninsulindescribedabove,wereobservedindependentofthesiteofinjection(abdomen,thigh,orupperarm).Distribution and Elimination-NovoLog®haslowbindingtoplasmaproteins(<10%),similartothatseenwithregularhumaninsulin.Aftersubcutaneousadministrationinnormalmalevolunteers(n=24), NovoLog® was more rapidly eliminated than regular human insulin with an averageapparenthalf-lifeof81minutescomparedto141minutesforregularhumaninsulin.Specific PopulationsChildren and Adolescents-ThepharmacokineticandpharmacodynamicpropertiesofNovoLog®andregularhumaninsulinwereevaluatedinasingledosestudyin18children(6-12years,n=9)andadolescents(13-17years[Tannergrade≥2],n=9)withtype1diabetes.Therelativedifferencesin pharmacokinetics and pharmacodynamics in children and adolescents with type 1 diabetes

conceptionandthroughoutpregnancy.Insulinrequirementsmaydecreaseduringthefirsttrimester,generallyincreaseduringthesecondandthirdtrimesters,andrapidlydeclineafterdelivery.Carefulmonitoringofglucosecontrolisessentialinthesepatients.Therefore,femalepatientsshouldbeadvisedtotell theirphysicianif theyintendtobecome,orif theybecomepregnantwhiletakingNovoLog®.Anopen-label,randomizedstudycomparedthesafetyandefficacyofNovoLog®(n=157)versusregularhuman insulin (n=165) in322pregnantwomenwith type1diabetes.Two-thirdsof theenrolledpatientswerealreadypregnantwhen theyentered thestudy.Becauseonlyone-thirdofthepatients enrolledbefore conception, the studywasnot large enough to evaluate the riskofcongenitalmalformations.BothgroupsachievedameanHbA1cof~6%duringpregnancy,andtherewasnosignificantdifferenceintheincidenceofmaternalhypoglycemia.Subcutaneous reproduction and teratology studies have been performed with NovoLog® andregularhumaninsulin inratsandrabbits. In thesestudies,NovoLog®wasgiven to femaleratsbeforemating,duringmating,and throughoutpregnancy,and to rabbitsduringorganogenesis.The effects ofNovoLog® didnot differ from thoseobservedwith subcutaneous regular humaninsulin.NovoLog®, likehuman insulin,causedpre-andpost-implantation lossesandvisceral/skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32 times the humansubcutaneousdoseof1.0U/kg/day,basedonU/bodysurfacearea)andinrabbitsatadoseof10U/kg/day(approximatelythreetimesthehumansubcutaneousdoseof1.0U/kg/day,basedonU/bodysurfacearea).Theeffectsareprobablysecondarytomaternalhypoglycemiaathighdoses.Nosignificanteffectswereobservedinratsatadoseof50U/kg/dayandinrabbitsatadoseof3U/kg/day.Thesedosesareapproximately8timesthehumansubcutaneousdoseof1.0U/kg/dayforratsandequaltothehumansubcutaneousdoseof1.0U/kg/dayforrabbits,basedonU/bodysurfacearea.8.3 Nursing MothersItisunknownwhetherinsulinaspartisexcretedinhumanmilk.UseofNovoLog®iscompatiblewithbreastfeeding,butwomenwithdiabeteswhoare lactatingmayrequireadjustmentsof theirinsulindoses.8.4 Pediatric UseNovoLog®isapprovedforuseinchildrenforsubcutaneousdailyinjectionsandforsubcutaneouscontinuousinfusionbyexternalinsulinpump.NovoLog®hasnotbeenstudiedinpediatricpatientsyounger than2 yearsof age.NovoLog® hasnot been studied inpediatricpatientswith type2diabetes.PleaseseeSection 14 CLINICAL STUDIESforsummariesofclinicalstudies.8.5 Geriatric UseOfthetotalnumberofpatients(n=1,375)treatedwithNovoLog®in3controlledclinicalstudies,2.6%(n=36)were65yearsofageorover.One-halfofthesepatientshadtype1diabetes(18/1285)andtheotherhalfhadtype2diabetes(18/90).TheHbA1cresponsetoNovoLog®,ascomparedtohuman insulin,didnotdifferbyage,particularly inpatientswith type2diabetes.Additionalstudiesinlargerpopulationsofpatients65yearsofageoroverareneededtopermitconclusionsregarding the safety of NovoLog® in elderly compared to younger patients. Pharmacokinetic/pharmacodynamicstudiestoassesstheeffectofageontheonsetofNovoLog®actionhavenotbeenperformed.10 OVERDOSAGEExcessinsulinadministrationmaycausehypoglycemiaand,particularlywhengivenintravenously,hypokalemia.Mildepisodesofhypoglycemiausuallycanbetreatedwithoralglucose.Adjustmentsin drug dosage, meal patterns, or exercise, may be needed. More severe episodes with coma,seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagonor concentrated intravenous glucose. Sustained carbohydrate intake and observation may benecessarybecausehypoglycemiamay recur after apparent clinical recovery.Hypokalemiamustbecorrectedappropriately.11 DESCRIPTIONNovoLog®(insulinaspart[rDNAorigin]injection)isarapid-actinghumaninsulinanalogusedtolowerbloodglucose.NovoLog®ishomologouswithregularhumaninsulinwiththeexceptionofasinglesubstitutionoftheaminoacidprolinebyasparticacidinpositionB28,andisproducedbyrecombinantDNAtechnologyutilizingSaccharomyces cerevisiae(baker’syeast).InsulinasparthastheempiricalformulaC256H381N65079S6andamolecularweightof5825.8.

Figure 1. Structural formula of insulin aspart.NovoLog® is a sterile, aqueous, clear, and colorless solution, that contains insulin aspart 100Units/mL,glycerin16mg/mL,phenol1.50mg/mL,metacresol1.72mg/mL,zinc19.6mcg/mL,disodiumhydrogenphosphatedihydrate1.25mg/mL,sodiumchloride0.58mg/mLandwaterforinjection.NovoLog®hasapHof7.2-7.6.Hydrochloricacid10%and/orsodiumhydroxide10%maybeaddedtoadjustpH.12 CLINICAL PHARMACOLOGY12.1 Mechanism of ActionThe primary activity of NovoLog® is the regulation of glucose metabolism. Insulins, includingNovoLog®, bind to the insulin receptors on muscle and fat cells and lower blood glucose byfacilitatingthecellularuptakeofglucoseandsimultaneouslyinhibitingtheoutputofglucosefromtheliver.12.2 PharmacodynamicsStudies in normal volunteers and patients with diabetes demonstrated that subcutaneousadministrationofNovoLog®hasamorerapidonsetofactionthanregularhumaninsulin.In a study in patients with type 1 diabetes (n=22), the maximum glucose-lowering effectof NovoLog® occurred between 1 and 3 hours after subcutaneous injection (see Figure 2).Thedurationof action forNovoLog® is3 to5hours.The timecourseof actionof insulinandinsulinanalogssuchasNovoLog®mayvaryconsiderably indifferent individualsorwithin thesame individual. The parameters of NovoLog® activity (time of onset, peak time and duration)asdesignated inFigure2shouldbeconsideredonlyasgeneralguidelines.The rateof insulinabsorptionandonsetofactivityisaffectedbythesiteofinjection,exercise,andothervariables[see Warnings and Precautions (5.1)].


*ValuesareMean±SD**Severehypoglycemiareferstohypoglycemiaassociatedwithcentralnervoussystemsymptomsandrequiringtheinterventionofanotherpersonorhospitalization.An open-label, 16-week parallel design trial compared pre-prandial NovoLog® injection inconjunctionwithNPHinjectionstoNovoLog®administeredbycontinuoussubcutaneousinfusionin127adultswithtype2diabetes.ThetwotreatmentgroupshadsimilarreductionsinHbA1candratesofseverehypoglycemia(Table8)[see Indications and Usage (1), Dosage and Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling (16.2)].Table 8. Pump Therapy in Type 2 Diabetes (16weeks;n=127)

NovoLog® pump NovoLog® + NPHN 66 61BaselineHbA1c(%)* 8.2±1.4 8.0±1.1ChangefromBaselineHbA1c(%) -0.6±1.1 -0.5±0.9TreatmentDifferenceinHbA1c,Mean(95%confidenceinterval) 0.1(0.4,0.3)

Baselineinsulindose(IU/kg/24hours)* 0.7±0.3 0.8±0.5End-of-Studyinsulindose(IU/kg/24hours)* 0.9±0.4 0.9±0.5Baselinebodyweight(kg)*WeightChangefrombaseline(kg)*

96.4±17.01.7±3.7

96.9±17.90.7±4.1

*ValuesareMean±SD14.3 Intravenous Administration of NovoLog®

See Section 12.2 CLINICAL PHARMACOLOGY/Pharmacodynamics.16 HOW SUPPLIED/STORAGE AND HANDLING16.1 How SuppliedNovoLog®isavailableinthefollowingpackagesizes:eachpresentationcontaining100UnitsofinsulinaspartpermL(U-100). 10mLvials NDC0169-7501-11 3mLPenFill®cartridges* NDC0169-3303-12 3mLNovoLog®FlexPen® NDC0169-6339-10*NovoLog®PenFill®cartridgesaredesignedforusewithNovoNordisk3mLPenFill®cartridgecompatibleinsulindeliverydevices(withorwithouttheadditionofaNovoPen®3PenMate®)withNovoFine®disposableneedles.16.2 Recommended StorageUnused NovoLog® should be stored in a refrigerator between 2° and 8°C (36° to 46°F). Donot store in the freezerordirectly adjacent to the refrigerator coolingelement.Do not freeze NovoLog® and do not use NovoLog® if it has been frozen.NovoLog®shouldnotbedrawnintoasyringeandstoredforlateruse.Vials:Afterinitialuseavialmaybekeptattemperaturesbelow30°C(86°F)forupto28days,butshouldnotbeexposedtoexcessiveheatorsunlight.Openedvialsmayberefrigerated.Unpuncturedvialscanbeuseduntiltheexpirationdateprintedonthelabeliftheyarestoredinarefrigerator.Keepunusedvialsinthecartonsotheywillstaycleanandprotectedfromlight.PenFill® cartridges or NovoLog® FlexPen®:OnceacartridgeoraNovoLog®FlexPen®ispunctured,itshouldbekeptattemperaturesbelow30°C (86°F) for up to 28 days, but should not be exposed to excessive heat or sunlight. ANovoLog®FlexPen®orcartridgeinusemustNOTbestoredintherefrigerator.KeeptheNovoLog®FlexPen®andallPenFill®cartridgesawayfromdirectheatandsunlight.UnpuncturedNovoLog®FlexPen®andPenFill®cartridgescanbeuseduntiltheexpirationdateprintedonthelabeliftheyarestoredinarefrigerator.KeepunusedNovoLog®FlexPen®andPenFill®cartridgesinthecartonsotheywillstaycleanandprotectedfromlight.Always remove the needle after each injection and store the 3 mL PenFill® cartridge delivery device or NovoLog® FlexPen® without a needle attached. This prevents contamination and/or infection, or leakage of insulin, and will ensure accurate dosing. Always use a new needle for each injection to prevent contamination.Pump:NovoLog® in thepumpreservoirshouldbediscardedafterat leastevery6daysofuseorafterexposuretotemperaturesthatexceed37°C(98.6°F).Theinfusionsetandtheinfusionsetinsertionsiteshouldbechangedatleastevery3days.Summary of Storage Conditions:Thestorageconditionsaresummarizedinthefollowingtable:Table 9. Storage conditions for vial, PenFill® cartridges and NovoLog® FlexPen® NovoLog®presentation

Not in-use (unopened)RoomTemperature(below30°C)

Not in-use (unopened) Refrigerated

In-use (opened)RoomTemperature(below30°C)

10mLvial 28days Untilexpirationdate

28days(refrigerated/roomtemperature)

3mLPenFill®cartridges

28days Untilexpirationdate

28days(Donotrefrigerate)

3mLNovoLog®FlexPen®

28days Untilexpirationdate

28days(Donotrefrigerate)

Storage of Diluted NovoLog®

NovoLog®dilutedwith InsulinDilutingMedium forNovoLog® toaconcentrationequivalent toU-10 or equivalent to U-50 may remain in patient use at temperatures below 30°C (86°F) for28days.Storage of NovoLog® in Infusion FluidsInfusion bags prepared as indicated under Dosage and Administration (2) are stable at roomtemperaturefor24hours.Someinsulinwillbeinitiallyadsorbedtothematerialoftheinfusionbag.

Table 4. Pediatric Subcutaneous Administration of NovoLog® in Type 1 Diabetes (24weeks;n=283)

NovoLog® + NPH Novolin® R + NPHN 187 96BaselineHbA1c(%)* 8.3±1.2 8.3±1.3ChangefromBaselineHbA1c(%) 0.1±1.0 0.1±1.1TreatmentDifferenceinHbA1c,Mean(95%confidenceinterval) 0.1(-0.5,0.1)

Baselineinsulindose(IU/kg/24hours)* 0.4±0.2 0.6±0.2End-of-Studyinsulindose(IU/kg/24hours)* 0.4±0.2 0.7±0.2Patientswithseverehypoglycemia(n,%)** 11(6%) 9(9%)Diabeticketoacidosis(n,%) 10(5%) 2(2%)Baselinebodyweight(kg)*WeightChangefrombaseline(kg)*

50.6±19.62.7±3.5

48.7±15.82.4±2.6

*ValuesareMean±SD**Severehypoglycemiareferstohypoglycemiaassociatedwithcentralnervoussystemsymptomsandrequiringtheinterventionofanotherpersonorhospitalization.One six-month, open-label, active-controlled study was conducted to compare the safety andefficacyofNovoLog® toNovolin®R inpatientswith type2diabetes (Table5).NovoLog®wasadministeredbysubcutaneousinjectionimmediatelypriortomealsandregularhumaninsulinwasadministeredbysubcutaneousinjection30minutesbeforemeals.NPHinsulinwasadministeredasthebasalinsulinineithersingleordivideddailydoses.ChangesinHbA1candtheratesofseverehypoglycemia(asdeterminedfromthenumberofeventsrequiringinterventionfromathirdparty)werecomparableforthetwotreatmentregimens.Table 5. Subcutaneous NovoLog® Administration in Type 2 Diabetes (6months;n=176)

NovoLog® + NPH Novolin® R + NPHN 90 86BaselineHbA1c(%)* 8.1±1.2 7.8±1.1ChangefromBaselineHbA1c(%) -0.3±1.0 -0.1±0.8TreatmentDifferenceinHbA1c,Mean(95%confidenceinterval) -0.1(-0.4,-0.1)


88.4±13.31.2±3.0

85.8±14.80.4±3.1

*ValuesareMean±SD**Severehypoglycemiareferstohypoglycemiaassociatedwithcentralnervoussystemsymptomsandrequiringtheinterventionofanotherpersonorhospitalization.14.2 Continuous Subcutaneous Insulin Infusion (CSII) by External PumpTwo open-label, parallel design studies (6 weeks [n=29] and 16 weeks [n=118]) comparedNovoLog®tobufferedregularhumaninsulin(Velosulin)inadultswithtype1diabetesreceivingasubcutaneousinfusionwithanexternalinsulinpump.ThetwotreatmentregimenshadcomparablechangesinHbA1candratesofseverehypoglycemia.Table 6. Adult Insulin Pump Study in Type 1 Diabetes(16weeks;n=118)

NovoLog® Buffered human insulinN 59 59BaselineHbA1c(%)* 7.3±0.7 7.5±0.8ChangefromBaselineHbA1c(%) 0.0±0.5 0.2±0.6TreatmentDifferenceinHbA1c,Mean(95%confidenceinterval) 0.3(-0.1,0.4)


77.4±16.10.1±3.5

74.8±13.8-0.0±1.7

*ValuesareMean±SD**Severehypoglycemiareferstohypoglycemiaassociatedwithcentralnervoussystemsymptomsandrequiringtheinterventionofanotherpersonorhospitalization.Arandomized,16-week,open-label,paralleldesignstudyofchildrenandadolescentswithtype1diabetes (n=298)aged4-18yearscompared twosubcutaneous infusionregimensadministeredviaanexternalinsulinpump:NovoLog®(n=198)orinsulinlispro(n=100).ThesetwotreatmentsresultedincomparablechangesfrombaselineinHbA1candcomparableratesofhypoglycemiaafter16weeksoftreatment(seeTable7).Table 7. Pediatric Insulin Pump Study in Type 1 Diabetes(16weeks;n=298)

NovoLog® LisproN 198 100BaselineHbA1c(%)* 8.0±0.9 8.2±0.8ChangefromBaselineHbA1c(%) -0.1±0.8 -0.1±0.7TreatmentDifferenceinHbA1c,Mean(95%confidenceinterval) -0.1(-0.3,0.1)

Baselineinsulindose(IU/kg/24hours)* 0.9±0.3 0.9±0.3End-of-Studyinsulindose(IU/kg/24hours)* 0.9±0.2 0.9±0.2Patientswithseverehypoglycemia(n,%)** 19(10%) 8(8%)Diabeticketoacidosis(n,%) 1(0.5%) 0(0)Baselinebodyweight(kg)*WeightChangefrombaseline(kg)*

54.1±19.71.8±2.1

55.5±19.01.6±2.1

Rx onlyDateofIssue:June2011Version:19Novo Nordisk®, NovoLog®, NovoPen® 3, PenFill®, Novolin®, FlexPen®, PenMate® and NovoFine® are registered trademarks of Novo Nordisk A/S.NovoLog®iscoveredbyUSPatentNos.5,618,913;5,866,538,andotherpatentspending.FlexPen®iscoveredbyUSPatentNos.6,582,404;6,004,297;6,235,004,andotherpatentspending.PenFill®iscoveredbyUSPatentNo.5,693,027.†ThebrandslistedaretheregisteredtrademarksoftheirrespectiveownersandarenottrademarksofNovoNordiskA/S.Manufacturedby:NovoNordiskA/SDK-2880Bagsvaerd,DenmarkForinformationaboutNovoLog®contact:NovoNordiskInc.Princeton,NewJersey085401-800-727-6500www.novonordisk-us.com©2002-2011NovoNordiskA/S143208-R17/11

17 PATIENT COUNSELING INFORMATION[See FDA-Approved Patient Labeling (17.3)]17.1 Physician InstructionsMaintenanceofnormalornear-normalglucosecontrol is a treatmentgoal indiabetesmellitusandhasbeenassociatedwithareductionindiabeticcomplications.PatientsshouldbeinformedaboutpotentialrisksandbenefitsofNovoLog®therapyincludingthepossibleadversereactions.Patients should also be offered continued education and advice on insulin therapies, injectiontechnique,life-stylemanagement,regularglucosemonitoring,periodicglycosylatedhemoglobintesting,recognitionandmanagementofhypo-andhyperglycemia,adherencetomealplanning,complicationsofinsulintherapy,timingofdose,instructionintheuseofinjectionorsubcutaneousinfusiondevices,andproperstorageofinsulin.Patientsshouldbeinformedthatfrequent,patient-performedbloodglucosemeasurementsareneededtoachieveoptimalglycemiccontrolandavoidbothhyper-andhypoglycemia.Thepatient’sability toconcentrateandreactmaybeimpairedasaresultofhypoglycemia.Thismaypresentariskinsituationswheretheseabilitiesareespeciallyimportant,suchasdrivingoroperatingothermachinery.Patientswhohavefrequenthypoglycemiaorreducedorabsentwarningsignsofhypoglycemiashouldbeadvisedtousecautionwhendrivingoroperatingmachinery.Accidental substitutions between NovoLog® and other insulin products have been reported.Patientsshouldbeinstructedtoalwayscarefullycheckthattheyareadministeringtheappropriateinsulin to avoid medication errors between NovoLog® and any other insulin. The written prescription for NovoLog® should be written clearly, to avoid confusion with other insulin products, for example, NovoLog® Mix 70/30.17.2 Patients Using PumpsPatientsusingexternalpumpinfusiontherapyshouldbetrainedinintensiveinsulintherapywithmultipleinjectionsandinthefunctionoftheirpumpandpumpaccessories.Thefollowinginsulinpumps†havebeenusedinNovoLog®clinicalorin vitrostudiesconductedbyNovoNordisk,themanufacturerofNovoLog®:•MedtronicParadigm®512and712•MiniMed508•Disetronic®D-TRON®andH-TRON®

BeforeusinganotherinsulinpumpwithNovoLog®,readthepumplabeltomakesurethepumphasbeenevaluatedwithNovoLog®.NovoLog® is recommended foruse inany reservoir and infusionsets that arecompatiblewithinsulinandthespecificpump.Pleaseseerecommendedreservoirandinfusionsetsinthepumpmanual.To avoid insulin degradation, infusion set occlusion, and loss of the preservative (metacresol), insulin in the reservoir should be replaced at least every 6 days; infusion sets and infusion set insertion sites should be changed at least every 3 days.Insulin exposed to temperatures higher than 37°C (98.6°F) should be discarded.Thetemperatureoftheinsulinmayexceedambienttemperaturewhenthepumphousing,cover,tubing,orsportcaseisexposedtosunlightorradiantheat.Infusionsitesthatareerythematous,pruritic,orthickenedshouldbereportedtomedicalpersonnel,andanewsiteselectedbecausecontinuedinfusionmayincreasetheskinreactionand/oraltertheabsorptionofNovoLog®.Pumpor infusionsetmalfunctionsor insulindegradationcan lead tohyperglycemiaandketosis in ashort timebecauseof the small subcutaneousdepot of insulin. This is especially pertinent forrapid-actinginsulinanalogsthataremorerapidlyabsorbedthroughskinandhaveshorterdurationof action. These differences are particularly relevant when patients are switched from multipleinjectiontherapy.Promptidentificationandcorrectionofthecauseofhyperglycemiaorketosisisnecessary.Problemsincludepumpmalfunction,infusionsetocclusion,leakage,disconnectionorkinking,anddegradedinsulin.Lesscommonly,hypoglycemiafrompumpmalfunctionmayoccur.Iftheseproblemscannotbepromptlycorrected,patientsshouldresumetherapywithsubcutaneousinsulin injectionandcontact theirphysician[see Dosage and Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling (16.2)].17.3 FDA Approved Patient LabelingSeeseparateleaflet.


Patient InformationNovoLog® (NŌ-vō-log) (insulin aspart [rDNA origin] Injection)Important:Know your insulin.Donotchangethetypeofinsulinyouuseunlesstoldtodosobyyourhealthcareprovider.Theamountofinsulinyoutakeaswellasthebesttimeforyoutotakeyourinsulinmayneedtochangeifyoutakeadifferenttypeofinsulin.Makesureyouknowthetypeandstrengthofinsulinprescribedforyou.ReadthePatientInformationthatcomeswithNovoLog®beforeyoustarttakingitandeachtimeyougetarefill.Theremaybenewinformation.Thisleafletdoesnottaketheplaceoftalkingwithyourhealthcareprovideraboutyourdiabetesoryourtreatment.Makesureyouknowhowtomanageyourdiabetes.Askyourhealthcareproviderifyouhaveanyquestionsaboutmanagingyourdiabetes.

What is NovoLog®?NovoLog®isaman-madeinsulinthatisusedtocontrolhighbloodsugarinadultsandchildrenwithdiabetesmellitus.

Who should not use NovoLog®?Do not take NovoLog® if:•Yourbloodsugaristoolow(hypoglycemia).•YouareallergictoanythinginNovoLog®.Seetheendofthis

leafletforacompletelistofingredientsinNovoLog®.Checkwithyourhealthcareproviderifyouarenotsure.

Tell your healthcare provider:•about all of your medical conditions.Medicalconditions

canaffectyourinsulinneedsandyourdoseofNovoLog®.•if you are pregnant or breastfeeding.Youandyour

healthcareprovidershouldtalkaboutthebestwaytomanageyourdiabeteswhileyouarepregnantorbreastfeeding.NovoLog®hasnotbeenstudiedinnursingwomen.

•about all medicines you take,includingprescriptionsandnon-prescriptionmedicines,vitaminsandherbalsupplements.YourNovoLog®dosemaychangeifyoutakeothermedicines.

Know the medicines you take.Keepalistofyourmedicineswithyoutoshowyourhealthcareproviderswhenyougetanewmedicine.

How should I take NovoLog®?OnlyuseNovoLog®ifitappearsclearandcolorless.Theremaybeairbubbles.Thisisnormal.Ifitlookscloudy,thickened,orcolored,orifitcontainssolidparticlesdonotuseitandcallNovoNordiskat1-800-727-6500.NovoLog®comesin:•10mLvials(smallbottles)forusewithsyringe•3mLPenFill®cartridgesforusewiththeNovoNordisk3mL

PenFill®cartridgecompatibleinsulindeliverydevicesandNovoFine®disposableneedles.ThecartridgedeliverydevicecanbeusedwithaNovoPen®3PenMate®

•3mLNovoLog®FlexPen®

Read the instructions for use that come with your NovoLog® product.Talktoyourhealthcareproviderifyouhaveanyquestions.YourhealthcareprovidershouldshowyouhowtoinjectNovoLog®beforeyoustarttakingit.•Take NovoLog® exactly as prescribed.Youshouldeata

mealwithin5to10minutesafterusingNovoLog®toavoidlowbloodsugar.

•NovoLog® is a fast-acting insulin.TheeffectsofNovoLog®startworking10to20minutesafterinjectionorboluspumpinfusion.

•Do not inject NovoLog® if you do not plan to eat right after your injection or bolus pump infusion.

•Thegreatestbloodsugarloweringeffectisbetween1and3hoursaftertheinjectionorinfusion.Thisbloodsugarloweringlastsfor3to5hours.

•While using NovoLog® you may have to changeyourtotaldoseofinsulin,yourdoseoflonger-actinginsulin,orthenumberofinjectionsoflonger-actinginsulinyouuse.PumpusersgivenNovoLog®mayneedtochangetheamountoftotalinsulingivenasabasalinfusion.

•Do not mix NovoLog®:•withanyotherinsulinswhenusedinapump•withanyinsulinsotherthanNPHwhenusedwithinjections

bysyringeIfyourhealthcareproviderrecommendsdilutingNovoLog®,followyourhealthcareprovider’sinstructionsexactlysothatyouknow:•HowtomakeNovoLog®moredilute(thatis,asmallernumberof

unitsofNovoLog®foragivenamountofliquid)and•HowtousethismorediluteformofNovoLog®.Do not use

dilute insulin in a pump.

•Inject NovoLog® into the skin of your stomach area, upper arms, buttocks or upper legs.NovoLog®mayaffectyourbloodsugarlevelssoonerifyouinjectitintotheskinofyourstomacharea.Never inject NovoLog® into a vein or into a muscle.

•Change (rotate) your injection site within the chosen area (for example, stomach or upper arm) with each dose. Do not inject into the exact same spot for each injection.

•If you take too much NovoLog®, your blood sugar may fall low (hypoglycemia).Youcantreatmildlowbloodsugar(hypoglycemia)bydrinkingoreatingsomethingsugaryrightaway(fruitjuice,sugarcandies,orglucosetablets).Itisimportanttotreatlowbloodsugar(hypoglycemia)rightawaybecauseitcouldgetworseandyoucouldpassout(becomeunconscious).Ifyoupassoutyouwillneedhelpfromanotherpersonoremergencymedicalservicesrightaway,andwillneedtreatmentwithaglucagoninjectionortreatmentatahospital.See“WhatarethepossiblesideeffectsofNovoLog®?”formoreinformationonlowbloodsugar(hypoglycemia).

•If you forget to take your dose of NovoLog®, your blood sugar may go too high (hyperglycemia).Ifhighbloodsugar(hyperglycemia)isnottreateditcanleadtoseriousproblems,likelossofconsciousness(passingout),comaorevendeath.Followyourhealthcareprovider’sinstructionsfortreatinghighbloodsugar.Knowyoursymptomsofhighbloodsugarwhichmayinclude:

•increasedthirst •fruitysmellonthebreath•frequenturination •drowsiness•lossofappetite •ahardtimebreathing•highamountsofsugarandketonesinyoururine•nausea,vomiting(throwingup)orstomachpain

•Check your blood sugar levels.Askyourhealthcareproviderwhatyourbloodsugarsshouldbeandwhenyoushouldcheckyourbloodsugarlevels.

Your insulin dosage may need to change because of:•illness •changeindiet•stress •othermedicinesyoutake•changeinphysicalactivityorexercise

What should I avoid while using NovoLog®?•Alcohol.Alcohol,includingbeerandwine,mayaffectyour

bloodsugarwhenyoutakeNovoLog®.•Driving and operating machinery.Youmayhave

difficultyconcentratingorreactingifyouhavelowbloodsugar(hypoglycemia).Becarefulwhenyoudriveacaroroperatemachinery.Askyourhealthcareproviderifitisalrighttodriveifyouoftenhave:

•lowbloodsugar•decreasedornowarningsignsoflowbloodsugar

What are the possible side effects of NovoLog®?•Low blood sugar (hypoglycemia).Symptomsoflowblood

sugarmayinclude:•sweating • blurredvision•troubleconcentratingorconfusion•dizzinessorlightheadedness• hunger•shakiness • slurredspeech•fastheartbeat • tinglingoflipsandtongue•anxiety,irritabilityormoodchanges•headache

Severelowbloodsugarcancauseunconsciousness(passingout),seizures,anddeath.Knowyoursymptomsoflowbloodsugar.Followyourhealthcareprovider’sinstructionsfortreatinglowbloodsugar.Talktoyourhealthcareprovideriflowbloodsugarisaproblemforyou.

•Serious allergic reaction (whole body reaction).Get medical help right away, if you developarashoveryourwholebody,havetroublebreathing,afastheartbeat,orsweating.

•Reactions at the injection site (local allergic reaction).Youmaygetredness,swelling,anditchingattheinjectionsite.Ifyoukeephavingskinreactionsortheyareserioustalktoyourhealthcareprovider.YoumayneedtostopusingNovoLog®anduseadifferentinsulin.Donotinjectinsulinintoskinthatisred,swollen,oritchy.

•Skin thickens or pits at the injection site (lipodystrophy).Change(rotate)whereyouinjectyourinsulintohelptopreventtheseskinchangesfromhappening.Donotinjectinsulinintothistypeofskin.

•Swelling of your hands and feet•Visionchanges•Lowpotassiuminyourblood(hypokalemia)•WeightgainThesearenotallofthepossiblesideeffectsfromNovoLog®.

Askyourhealthcareproviderorpharmacistformoreinformation.Callyourhealthcareproviderformedicaladviceaboutsideeffects.YoumayreportsideeffectstoFDAat1-800-FDA-1088.

How should I store NovoLog®?All Unopened NovoLog®:•Keep all unopened NovoLog® in the refrigerator

between 36° to 46°F (2° to 8°C).•Donotfreeze.DonotuseNovoLog®ifithasbeenfrozen.•KeepunopenedNovoLog®inthecartontoprotectfromlight.NovoLog® in use:•Vials

•Keepintherefrigeratororatroomtemperaturebelow86°F(30°C)forupto28days.

•Keepvialsawayfromdirectheatorlight.•Throwawayanopenedvialafter28daysofuse,evenifthere

isinsulinleftinthevial.•DonotdrawupNovoLog®intoasyringeandstorefor

lateruse.•Unopenedvialscanbeuseduntiltheexpirationdateon

theNovoLog®label,ifthemedicinehasbeenstoredinarefrigerator.

•PenFill® Cartridges or NovoLog® FlexPen® •Keepatroomtemperaturebelow86°F(30°C)forupto

28days.•DonotstoreaPenFill®cartridgeorNovoLog®FlexPen®that

youareusingintherefrigerator.•KeepPenFill®cartridgesandNovoLog®FlexPen®awayfrom

directheatorlight.•ThrowawayausedPenFill®cartridgeorNovoLog®

FlexPen®after28days,evenifthereisinsulinleftinthecartridgeorsyringe.

•NovoLog® in the pump reservoir and the complete external pump infusion set

•Theinfusionsetandtheinfusionsiteshouldbechangedat least every 3 days.Theinsulininthereservoirshouldbechangedat least every 6 daysevenifyouhavenotusedalloftheinsulin.Changetheinfusionsetandtheinfusionsitemoreoftenthanevery3daysifyouhavehighbloodsugar(hyperglycemia),thepumpalarmsounds,ortheinsulinflowisblocked(occlusion).

General advice about NovoLog®

Medicinesaresometimesprescribedforconditionsthatarenotmentionedinthepatientleaflet.DonotuseNovoLog®foraconditionforwhichitwasnotprescribed.DonotgiveNovoLog®tootherpeople,eveniftheyhavethesamesymptomsyouhave.Itmayharmthem.ThisleafletsummarizesthemostimportantinformationaboutNovoLog®.IfyouwouldlikemoreinformationaboutNovoLog®ordiabetes,talkwithyourhealthcareprovider.YoucanaskyourhealthcareproviderorpharmacistforinformationaboutNovoLog®thatiswrittenforhealthcareprofessionals.Call1-800-727-6500orvisitwww.novonordisk-us.comformoreinformation.HelpfulinformationforpeoplewithdiabetesispublishedbytheAmericanDiabetesAssociation,1701NBeauregardStreet,Alexandria,VA22311andonwww.diabetes.org.NovoLog® ingredients include:

•insulinaspart •zinc•glycerin •phenol•metacresol •sodiumchloride•disodiumhydrogenphosphatedihydrate•waterforinjection

AllNovoLog®vials,PenFill®cartridgesandNovoLog®FlexPen®arelatexfree.DateofIssue:June2011Version:11

Novo Nordisk®, NovoLog®, PenFill®, FlexPen®, NovoPen®, NovoFine®, and PenMate® are registered trademarks of Novo Nordisk A/S.NovoLog®iscoveredbyUSPatentNos.5,618,913,5,866,538,andotherpatentspending.FlexPen®iscoveredbyUSPatentNos.6,582,404,6,004,297,6,235,004,andotherpatentspending.PenFill®iscoveredbyUSPatentNo.5,693,027.Manufacturedby:NovoNordiskA/SDK-2880Bagsvaerd,DenmarkForinformationaboutNovoLog®contact:NovoNordiskInc.100CollegeRoadWestPrinceton,NewJersey08540©2002-2011NovoNordiskA/S143208-R17/11


I. Inserttheneedleintoyourskin.Injectthedosebypressingthepush-buttonallthewayinuntilthe0linesupwiththepointer(seediagramI).Becarefulonlytopushthebuttonwheninjecting.Turningthedoseselectorwillnotinjectinsulin.

J. Keeptheneedleintheskinforatleast6seconds,andkeepthepush-buttonpressedallthewayinuntiltheneedlehasbeenpulledoutfromtheskin(seediagramJ).Thiswillmakesurethatthefulldosehasbeengiven.YoumayseeadropofNovoLog®attheneedletip.Thisisnormalandhasnoeffectonthedoseyoujustreceived.Ifbloodappearsafteryoutaketheneedleoutofyourskin,presstheinjectionsitelightlywithafinger.Do not rub the area.

After the injectionDo not recap the needle.Recappingcanleadtoaneedlestickinjury.RemovetheneedlefromtheNovoLog®FlexPen®aftereachinjection.Thishelpstopreventinfection,leakageofinsulin,andwillhelptomakesureyouinjecttherightdoseofinsulin.

PuttheneedleandanyemptyNovoLog®FlexPen®oranyusedNovoLog®FlexPen®stillcontaininginsulininasharpscontainerorsometypeofhardplasticormetalcontainerwithascrewtopsuchasadetergentbottleoremptycoffeecan.Thesecontainersshouldbesealedandthrownawaytherightway.Checkwithyourhealthcareproviderabouttherightwaytothrowawayusedsyringesandneedles.Theremaybelocalorstatelawsabouthowtothrowawayusedneedlesandsyringes.Donotthrowawayusedneedlesandsyringesinhouseholdtrashorrecyclingbins.TheNovoLog®FlexPen®preventsthecartridgefrombeingcompletelyemptied.Itisdesignedtodeliver300units.

K.PutthepencapontheNovoLog®FlexPen®andstoretheNovoLog®FlexPen®withouttheneedleattached(seediagramK).

Function CheckL. IfyourNovoLog®FlexPen®isnotworkingtherightway,followthe

stepsbelow:

•ScrewonanewNovoFine®needle. •Removethebigouterneedlecapandtheinnerneedlecap. •Doanairshotasdescribedin“Givingtheairshotbeforeeach

injection”. •Putthebigouterneedlecapontotheneedle.Donotputonthe

innerneedlecap. •Turnthedoseselectorsothedoseindicatorwindowshows20units. •HoldtheNovoLog®FlexPen®sotheneedleispointingdown. •Pressthepush-buttonallthewayin.

Theinsulinshouldfillthelowerpartofthebigouterneedlecap(seediagramL).IftheNovoLog®FlexPen®hasreleasedtoomuchortoolittleinsulin,dothefunctioncheckagain.Ifthesameproblemhappensagain,donotuseyourNovoLog®FlexPen®andcontactNovoNordiskat1-800-727-6500.

MaintenanceYourFlexPen®isdesignedtoworkaccuratelyandsafely.Itmustbehandledwithcare.AvoiddroppingyourFlexPen®asitmaydamageit.IfyouareconcernedthatyourFlexPen®isdamaged,useanewone.YoucancleantheoutsideofyourFlexPen®bywipingitwithadampcloth.DonotsoakorwashyourFlexPen®asitmaydamageit.DonotrefillyourFlexPen®.

RemovetheneedlefromtheNovoLog®FlexPen®aftereachinjection.Thishelpstoensuresterility,preventleakageofinsulin,andwillhelptomakesureyouinjecttherightdoseofinsulinforfutureinjections.

Becarefulwhenhandlingusedneedlestoavoidneedlesticksandtransferofinfectiousdiseases.KeepyourNovoLog®FlexPen®andneedlesoutofthereachofchildren.UseNovoLog®FlexPen®asdirectedtotreatyourdiabetes.NeedlesandNovoLog®FlexPen®mustnotbeshared.Alwaysuseanewneedleforeachinjection.NovoNordiskisnotresponsibleforharmduetousingthisinsulinpenwithproductsnotrecommendedbyNovoNordisk.

Asaprecautionarymeasure,alwayscarryaspareinsulindeliverydeviceincaseyourNovoLog®FlexPen®islostordamaged.

RemembertokeepthedisposableNovoLog®FlexPen®withyou.Donotleaveitinacarorotherlocationwhereitcangettoohotortoocold.

Patient Instructions for UseNovoLog® FlexPen®

IntroductionPleasereadthefollowinginstructionscarefullybeforeusingyourNovoLog®FlexPen®.NovoLog®FlexPen®isadisposabledial-a-doseinsulinpen.Youcanselectdosesfrom1to60unitsinincrementsof1unit.NovoLog®FlexPen®isdesignedtobeusedwithNovoFine®needles.

NovoLog®FlexPen®shouldnotbeusedbypeoplewhoareblindorhaveseverevisualproblemswithoutthehelpofapersonwhohasgoodeyesightandwhoistrainedtousetheNovoLog®FlexPen®therightway.

Getting readyMakesureyouhavethefollowingitems:

• NovoLog®FlexPen®

• NewNovoFine®needle• Alcoholswab

Preparing Your NovoLog® FlexPen®

Washyourhandswithsoapandwater.Beforeyoustarttoprepareyourinjection,checkthelabeltomakesurethatyouaretakingtherighttypeofinsulin.Thisisespeciallyimportantifyoutakemorethan1typeofinsulin.NovoLog®shouldlookclear.

A.Pulloffthepencap(seediagramA).Wipetherubberstopperwithanalcoholswab.

B. Attaching the needleRemovetheprotectivetabfromadisposableneedle.ScrewtheneedletightlyontoyourFlexPen®.Itisimportantthattheneedleisputonstraight(seediagramB).NeverplaceadisposableneedleonyourNovoLog®FlexPen®untilyouarereadytotakeyourinjection.

C.Pulloffthebigouterneedlecap(seediagramC).

D.Pullofftheinnerneedlecapanddisposeofit(seediagramD).

Alwaysuseanewneedleforeachinjectiontohelpensuresterilityandpreventblockedneedles.

Becarefulnottobendordamagetheneedlebeforeuse.

Toreducetheriskofunexpectedneedlesticks,neverputtheinnerneedlecapbackontheneedle.

Giving the airshot before each injectionBeforeeachinjectionsmallamountsofairmaycollectinthecartridgeduringnormaluse.Toavoidinjectingairandtoensureproperdosing:

E.Turnthedoseselectortoselect2units(seediagramE).

F. HoldyourNovoLog®FlexPen®withtheneedlepointingup.Tapthecartridgegentlywithyourfingerafewtimestomakeanyairbubblescollectatthetopofthecartridge(seediagramF).

G.Keeptheneedlepointingupwards,pressthepush-buttonallthewayin(seediagramG).Thedoseselectorreturnsto0.Adropofinsulinshouldappearattheneedletip.Ifnot,changetheneedleandrepeattheprocedurenomorethan6times.Ifyoudonotseeadropofinsulinafter6times,donotusetheNovoLog®FlexPen®andcontactNovoNordiskat1-800-727-6500.Asmallairbubblemayremainattheneedletip,butitwillnotbeinjected.

Selecting your doseCheckandmakesurethatthedoseselectorissetat0.

H.Turnthedoseselectortothenumberofunitsyouneedtoinject.Thepointershouldlineupwithyourdose.Thedosecanbecorrectedeitherupordownbyturningthedoseselectorineitherdirectionuntilthecorrectdoselinesupwiththepointer(seediagramH).Whenturningthedoseselector,becarefulnottopressthepush-buttonasinsulinwillcomeout.Youcannotselectadoselargerthanthenumberofunitsleftinthecartridge.Youwillhearaclickforeverysingleunitdialed.Donotsetthedosebycountingthenumberofclicksyouhear.

Donotusethecartridgescaleprintedonthecartridgetomeasureyourdoseofinsulin.

Giving the injectionDotheinjectionexactlyasshowntoyoubyyourhealthcareprovider.Yourhealthcareprovidershouldtellyouifyouneedtopinchtheskinbeforeinjecting.

4 6 0

I

J

K

20

L

Pen capNovoLog® FlexPen®

Big outerneedle cap

Inner needle cap Needle

Protective tab

NovoFine® needle

Rubberstopper Cartridge

Cartridgescale

PointerDose

selector

Push-button

A

24 unitsselected

24

5 unitsselected

46

H

B

C

D

2 unitsselected

E

F

G

Novo Nordisk®, NovoLog®, PenFill®, FlexPen®, NovoPen®, NovoFine®, and PenMate® are registered trademarks of Novo Nordisk A/S.NovoLog®iscoveredbyUSPatentNos.5,618,913,5,866,538,andotherpatentspending.FlexPen®iscoveredbyUSPatentNos.6,582,404,6,004,297,6,235,004,andotherpatentspending.PenFill®iscoveredbyUSPatentNo.5,693,027.Manufacturedby:NovoNordiskA/SDK-2880Bagsvaerd,DenmarkForinformationaboutNovoLog®contact:NovoNordiskInc.100CollegeRoadWestPrinceton,NewJersey08540©2002-2011NovoNordiskA/S143208-R17/11

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