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Questions and answers about using NovoLog® What is NovoLog®? NovoLog® (insulin aspart [rDNA origin] injection) is a fast-acting insulin analog from Novo Nordisk — a world leader in diabetes care. It is absorbed quickly and starts working within minutes to lower your blood sugar. This way, you may take your insulin and eat within 5 to 10 minutes, unlike the 30-minute wait required with regular human insulin. What is NovoLog® FlexPen®? NovoLog® FlexPen® is a discreet insulin pen that goes with you almost anywhere.* FlexPen® comes prefilled with NovoLog® and is ready to use in just a few steps. Please refer to the attached instructions for use. NovoLog® FlexPen® requires low injection force, making it easy to press. NovoLog® FlexPen® fits in a pocket or purse, so you’ll have the insulin you need— right when you need it.† Does my health insurance plan cover NovoLog® FlexPen®? NovoLog® FlexPen® is available for the same co-pay as vial and syringe on most health insurance plans. What type of needles NovoFine® disposable needles† are recommended. NovoFine® needles are very thin and short. should I use with NovoLog® FlexPen®? How do I save money on NovoLog® FlexPen®? Regardless of your health insurance plan, you can save up to $50 off your first FlexPen® prescription and up to $25 off your next three prescriptions for a total savings of up to $125‡ with the Novo Nordisk Savings Card. Learn more about this offer from your health care provider or by visiting MyFlexPen.com. How do I get NovoLog® FlexPen®? NovoLog® FlexPen® is only available with a prescription. Ask your health care provider today if NovoLog® FlexPen® is right for you. Find out more about the benefits of FlexPen® at MyFlexPen.com or call 1-800-727-6500. Indications and Usage What is NovoLog® (insulin aspart [rDNA origin] injection)? •NovoLog® is a man-made insulin used to control high blood sugar in adults and children with diabetes mellitus. Important Safety Information Who should not use NovoLog®? •Do not use NovoLog® if your blood sugar is too low (hypoglycemia) or you are allergic to any of its ingredients. Please see additional Important Safety Information on the next page and accompanying Patient Information. *If NovoLog® FlexPen® is kept at room temperature below 86° F for up to 28 days. Needles are sold separately and may require a prescription in some states. Needles and FlexPen® must not be shared. Refer to the user manual for information on assembly and injection. † Eligible patients only. Discount is not to exceed patient’s out-of-pocket expenses. Please read terms & conditions for eligibility requirements at MyFlexPen.com. ‡ Important Safety Information (continued) What should I tell my healthcare provider before taking NovoLog® (insulin aspart [rDNA origin] injection)? •About all of your medical conditions, including liver or kidney problems. •If you are pregnant, breastfeeding, or plan to do either. •About all prescription and nonprescription medicines you take, including supplements, as your dose may need to change. How should I take NovoLog®? •Eat a meal within 5 to 10 minutes after using NovoLog® (insulin aspart [rDNA origin] injection), a fast-acting insulin, to avoid low blood sugar. Do not inject NovoLog® if you do not plan to eat right after your injection or bolus pump infusion. •Do not mix NovoLog® with any other insulin when used in a pump or with any insulin other than NPH when used with injections by syringe. •Do not change your dose or type of insulin unless you are told to by your healthcare provider. •Do not share needles, insulin pens, or syringes. •Check your blood sugar levels as directed by your healthcare provider. What should I consider while using NovoLog®? •Alcohol, including beer and wine, may affect your blood sugar. •Be careful when driving a car or operating machinery. You may have difficulty concentrating or reacting if you have low blood sugar. Talk to your healthcare provider if you often have low blood sugar or no warning signs of low blood sugar. What are the possible side effects of NovoLog®? •Low blood sugar, including when too much is taken. Some symptoms include sweating, shakiness, confusion, and headache. Severe low blood sugar can cause unconsciousness, seizures, and death. •Serious allergic reactions may occur. Get medical help right away, if you develop a rash over your whole body, have trouble breathing, a fast heartbeat, or sweating. •Other side effects include injection site reactions (like redness, swelling, and itching), skin thickening or pits at the injection site, swelling of your hands and feet, vision changes, low potassium in your blood, and weight gain. Please see accompanying Patient Information. Talk to your doctor about the importance of diet and exercise in your treatment plan. You can get additional help with your diabetes care at Cornerstones4Care.com. If you need assistance with prescription drug costs, help may be available. Visit pparx.org or call 1-888-4PPA-NOW. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch, or call 1-800-FDA-1088. FlexPen®, NovoFine®, and NovoLog® are registered trademarks and Cornerstones4Care™ is a trademark of Novo Nordisk A/S. © 2012 Novo Nordisk Printed in the U.S.A. 0912-00011436-1 December 2012 HIGHLIGHTS OF PRESCRIBING INFORMATION These 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 use Initial 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®inthereservoiratleast every6days,changetheinfusionset,andtheinfusionset insertionsiteatleastevery3days.NovoLog®shouldnotbe mixedwithotherinsulinsorwithadiluentwhenitisusedin thepump(2.3). •Intravenous use:NovoLog®shouldbeusedatconcentrations from0.05U/mLto1.0U/mLinsulinaspartininfusionsystems usingpolypropyleneinfusionbags.NovoLog®hasbeenshown tobestableininfusionfluidssuchas0.9%sodiumchloride (2.4). ——— DOSAGE FORMS AND STRENGTHS ——— Eachpresentationcontains100UnitsofinsulinaspartpermL (U-100) •10mLvials(3) •3mLPenFill®cartridgesforthe3mLPenFill®cartridgedevice(3) •3mLNovoLog®FlexPen®(3) FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 1.1 TreatmentofDiabetesMellitus 2 DOSAGE AND ADMINISTRATION 2.1 Dosing 2.2 SubcutaneousInjection 2.3 ContinuousSubcutaneousInsulinInfusion(CSII)byExternalPump 2.4 IntravenousUse 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 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 ContinuousSubcutaneousInsulinInfusionbyExternalPump 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy ——— CONTRAINDICATIONS ——— •Donotuseduringepisodesofhypoglycemia(4). •DonotuseinpatientswithhypersensitivitytoNovoLog®orone ofitsexcipients. •Beta-blockers,clonidine,lithiumsalts,andalcoholmayeither potentiateorweakentheblood-glucose-loweringeffectofinsulin (7). •Pentamidinemaycausehypoglycemia,whichmaysometimesbe followedbyhyperglycemia(7). •Thesignsofhypoglycemiamaybereducedorabsentinpatients takingsympatholyticproductssuchasbeta-blockers,clonidine, guanethidine,andreserpine(7). ——— WARNINGS AND PRECAUTIONS ——— •Hypoglycemiaisthemostcommonadverseeffectofinsulin therapy.Glucosemonitoringisrecommendedforallpatientswith diabetes.Anychangeofinsulindoseshouldbemadecautiously ——— USE IN SPECIFIC POPULATIONS ——— andonlyundermedicalsupervision(5.1,5.2). •Pediatric:Hasnotbeenstudiedinchildrenwithtype2diabetes. •Insulin,particularlywhengivenintravenouslyorinsettingsof Hasnotbeenstudiedinchildrenwithtype1diabetes<2yearsof poorglycemiccontrol,cancausehypokalemia.Usecautionin age(8.4). patientspredisposedtohypokalemia(5.3). •Likeallinsulins,NovoLog®requirementsmaybereducedin See 17 for PATIENT COUNSELING INFORMATION and patientswithrenalimpairmentorhepaticimpairment(5.4,5.5). FDA-approved patient labeling. •Severe,life-threatening,generalizedallergy,including Revised: 6/2011 anaphylaxis,mayoccurwithinsulinproducts,including NovoLog®(5.6). ——— ADVERSE REACTIONS ——— AdversereactionsobservedwithNovoLog®includehypoglycemia, allergicreactions,localinjectionsitereactions,lipodystrophy,rash andpruritus(6). To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Inc. at 1-800-727-6500 or FDA at 1-800FDA-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,sympathomimetic agents(e.g.,epinephrine,salbutamol,terbutaline),isoniazid, phenothiazinederivatives,somatropin,thyroidhormones, estrogens,progestogens(e.g.,inoralcontraceptives),atypical antipsychotics(7). 8.3 NursingMothers 8.4 PediatricUse 8.5 GeriatricUse 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 MechanismofAction 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis,Mutagenesis,ImpairmentofFertility 13.2 AnimalToxicologyand/orPharmacology 14 CLINICAL STUDIES 14.1 SubcutaneousDailyInjections 14.2 ContinuousSubcutaneousInsulinInfusion(CSII)byExternalPump 14.3 IntravenousAdministrationofNovoLog® 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 HowSupplied 16.2 RecommendedStorage 17 PATIENT COUNSELING INFORMATION 17.1 PhysicianInstructions 17.2 PatientsUsingPumps 17.3 FDA-ApprovedPatientLabeling *Sectionsorsubsectionsomittedfromthefullprescribinginformationarenotlisted. 1 NovoLog® (insulin aspart [rDNA origin] injection) FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE 1.1 Treatment of Diabetes Mellitus NovoLog®isaninsulinanalogindicatedtoimproveglycemiccontrolinadultsandchildrenwith diabetesmellitus. 2 DOSAGE AND ADMINISTRATION 2.1 Dosing NovoLog®isaninsulinanalogwithanearlieronsetofactionthanregularhumaninsulin.The dosage of NovoLog® must be individualized. NovoLog® given by subcutaneous injection shouldgenerallybeusedinregimenswithanintermediateorlong-actinginsulin[see Warnings and Precautions (5), How Supplied/Storage and Handling (16.2)]. The total daily insulin requirement may vary and is usually between 0.5 to 1.0 units/kg/day. When used in a mealrelatedsubcutaneousinjectiontreatmentregimen,50to70%oftotalinsulinrequirementsmay beprovidedbyNovoLog®andtheremainderprovidedbyanintermediate-actingorlong-acting insulin.BecauseofNovoLog®’scomparativelyrapidonsetandshortdurationofglucoselowering activity,somepatientsmayrequiremorebasalinsulinandmoretotalinsulintopreventpre-meal hyperglycemiawhenusingNovoLog®thanwhenusinghumanregularinsulin. DonotuseNovoLog®thatisviscous(thickened)orcloudy;useonlyifitisclearandcolorless. NovoLog®shouldnotbeusedaftertheprintedexpirationdate. 2.2 Subcutaneous Injection NovoLog®shouldbeadministeredbysubcutaneousinjectionintheabdominalregion,buttocks, thigh,orupperarm.BecauseNovoLog®hasamorerapidonsetandashorterdurationofactivity thanhumanregularinsulin,itshouldbeinjectedimmediately(within5-10minutes)beforeameal. Injectionsitesshouldberotatedwithinthesameregiontoreducetheriskoflipodystrophy.Aswith allinsulins,thedurationofactionofNovoLog®willvaryaccordingtothedose,injectionsite,blood flow,temperature,andlevelofphysicalactivity. NovoLog® may be diluted with Insulin Diluting Medium for NovoLog® for subcutaneous injection.DilutingonepartNovoLog®toninepartsdiluentwillyieldaconcentrationone-tenth thatofNovoLog®(equivalenttoU-10).DilutingonepartNovoLog®toonepartdiluentwillyielda concentrationone-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)].Dilutedinsulinshouldnot beusedinexternalinsulinpumps.BecauseNovoLog®hasamorerapidonsetandashorter durationofactivitythanhumanregularinsulin,pre-mealbolusesofNovoLog®shouldbeinfused immediately(within5-10minutes)beforeameal.Infusionsitesshouldberotatedwithinthe sameregiontoreducetheriskoflipodystrophy.Theinitialprogrammingoftheexternalinsulin infusionpumpshouldbebasedonthetotaldailyinsulindoseofthepreviousregimen.Although thereissignificantinterpatientvariability,approximately50%ofthetotaldoseisusuallygivenas meal-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 vitrostudiesconducted byNovoNordisk,themanufacturerofNovoLog®: •MedtronicParadigm®512and712 •MiniMed508 •Disetronic®D-TRON®andH-TRON® BeforeusingadifferentinsulinpumpwithNovoLog®,readthepumplabeltomakesurethepump hasbeenevaluatedwithNovoLog®. 2.4 Intravenous Use NovoLog®canbeadministeredintravenouslyundermedicalsupervisionforglycemiccontrolwith closemonitoringofbloodglucoseandpotassiumlevelstoavoidhypoglycemiaandhypokalemia [see Warnings and Precautions (5), How Supplied/Storage and Handling (16.2)].Forintravenous use,NovoLog®shouldbeusedatconcentrationsfrom0.05U/mLto1.0U/mLinsulinaspartin infusionsystemsusingpolypropyleneinfusionbags.NovoLog®hasbeenshowntobestablein infusionfluidssuchas0.9%sodiumchloride. InspectNovoLog®forparticulatematteranddiscolorationpriortoparenteraladministration. 3 DOSAGE FORMS AND STRENGTHS NovoLog®isavailableinthefollowingpackagesizes:eachpresentationcontains100unitsof insulinaspartpermL(U-100). •10mLvials •3mLPenFillcartridgesforthe3mLPenFill®cartridgedeliverydevice(withorwithoutthe additionofaNovoPen®3PenMate®)withNovoFine®disposableneedles •3mLNovoLog®FlexPen® 4 CONTRAINDICATIONS NovoLog®iscontraindicated •duringepisodesofhypoglycemia •inpatientswithhypersensitivitytoNovoLog®oroneofitsexcipients. 5 WARNINGS AND PRECAUTIONS 5.1 Administration NovoLog®hasamorerapidonsetofactionandashorterdurationofactivitythanregularhuman insulin.AninjectionofNovoLog®shouldimmediatelybefollowedbyamealwithin5-10minutes. BecauseofNovoLog®’sshortdurationofaction,alongeractinginsulinshouldalsobeusedin patientswithtype1diabetesandmayalsobeneededinpatientswithtype2diabetes.Glucose monitoringisrecommendedforallpatientswithdiabetesandisparticularlyimportantforpatients usingexternalpumpinfusiontherapy. Any change of insulin dose should be made cautiously and only under medical supervision. Changingfromoneinsulinproducttoanotherorchangingtheinsulinstrengthmayresultinthe needforachangeindosage.Aswithallinsulinpreparations,thetimecourseofNovoLog®action mayvaryindifferentindividualsoratdifferenttimesinthesameindividualandisdependenton manyconditions,includingthesiteofinjection,localbloodsupply,temperature,andphysical activity.Patientswhochangetheirlevelofphysicalactivityormealplanmayrequireadjustment ofinsulindosages.Insulinrequirementsmaybealteredduringillness,emotionaldisturbances, orotherstresses. Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administerinsulinbyinjectionandhavealternateinsulintherapyavailableincaseofpumpfailure. Needles and NovoLog® FlexPen® must not be shared. 5.2 Hypoglycemia Hypoglycemiaisthemostcommonadverseeffectofallinsulintherapies,includingNovoLog®. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may result in temporaryorpermanentimpairmentofbrainfunctionordeath.Severehypoglycemiarequiringthe assistanceofanotherpersonand/orparenteralglucoseinfusionorglucagonadministrationhas beenobservedinclinicaltrialswithinsulin,includingtrialswithNovoLog®. Thetimingofhypoglycemiausuallyreflectsthetime-actionprofileoftheadministeredinsulin formulations[see Clinical Pharmacology (12)].Otherfactorssuchaschangesinfoodintake(e.g., amountoffoodortimingofmeals),injectionsite,exercise,andconcomitantmedicationsmay alsoaltertheriskofhypoglycemia[see Drug Interactions (7)].Aswithallinsulins,usecautionin patientswithhypoglycemiaunawarenessandinpatientswhomaybepredisposedtohypoglycemia (e.g.,patientswhoarefastingorhaveerraticfoodintake).Thepatient’sabilitytoconcentrateand reactmaybeimpairedasaresultofhypoglycemia.Thismaypresentariskinsituationswherethese abilitiesareespeciallyimportant,suchasdrivingoroperatingothermachinery. Rapidchangesinserumglucoselevelsmayinducesymptomsofhypoglycemiainpersonswith diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be differentorlesspronouncedundercertainconditions,suchaslongstandingdiabetes,diabetic nerve disease, use of medications such as beta-blockers, or intensified diabetes control [see Drug Interactions (7)].Thesesituationsmayresultinseverehypoglycemia(and,possibly,loss ofconsciousness)priortothepatient’sawarenessofhypoglycemia.Intravenouslyadministered insulinhasamorerapidonsetofactionthansubcutaneouslyadministeredinsulin,requiringmore closemonitoringforhypoglycemia. 5.3 Hypokalemia All insulin products, including NovoLog®, cause a shift in potassium from the extracellular to intracellularspace,possiblyleadingtohypokalemiathat,ifleftuntreated,maycauserespiratory paralysis,ventriculararrhythmia,anddeath.Usecautioninpatientswhomaybeatriskforhypokalemia (e.g.,patientsusingpotassium-loweringmedications,patientstakingmedicationssensitivetoserum potassiumconcentrations,andpatientsreceivingintravenouslyadministeredinsulin). 5.4 Renal Impairment Aswithotherinsulins,thedoserequirementsforNovoLog®maybereducedinpatientswithrenal impairment[see Clinical Pharmacology (12.3)]. 5.5 Hepatic Impairment Aswithotherinsulins,thedoserequirementsforNovoLog®maybereducedinpatientswith hepaticimpairment[see Clinical Pharmacology (12.3)]. 5.6 Hypersensitivity and Allergic Reactions Local Reactions-Aswithotherinsulintherapy,patientsmayexperienceredness,swelling,or itchingatthesiteofNovoLog®injection.Thesereactionsusuallyresolveinafewdaystoafew weeks,butinsomeoccasions,mayrequirediscontinuationofNovoLog®.Insomeinstances,these reactionsmayberelatedtofactorsotherthaninsulin,suchasirritantsinaskincleansingagent orpoorinjectiontechnique.Localizedreactionsandgeneralizedmyalgiashavebeenreportedwith injectedmetacresol,whichisanexcipientinNovoLog®. Systemic Reactions-Severe,life-threatening,generalizedallergy,includinganaphylaxis,mayoccur withanyinsulinproduct,includingNovoLog®.AnaphylacticreactionswithNovoLog®havebeen reportedpost-approval.Generalizedallergytoinsulinmayalsocausewholebodyrash(including pruritus),dyspnea,wheezing,hypotension,tachycardia,ordiaphoresis.Incontrolledclinicaltrials, allergicreactionswerereportedin3of735patients(0.4%)treatedwithregularhumaninsulinand 10of1394patients(0.7%)treatedwithNovoLog®.Incontrolledanduncontrolledclinicaltrials,3 of2341(0.1%)NovoLog®-treatedpatientsdiscontinuedduetoallergicreactions. 5.7 Antibody Production Increasesinanti-insulinantibodytitersthatreactwithbothhumaninsulinandinsulinasparthave beenobservedinpatientstreatedwithNovoLog®.Increasesinanti-insulinantibodiesareobserved morefrequentlywithNovoLog®thanwithregularhumaninsulin.Datafroma12-monthcontrolled trialinpatientswithtype1diabetessuggestthattheincreaseintheseantibodiesistransient,and thedifferencesinantibodylevelsbetweentheregularhumaninsulinandinsulinasparttreatment groupsobservedat3and6monthswerenolongerevidentat12months.Theclinicalsignificance oftheseantibodiesisnotknown.Theseantibodiesdonotappeartocausedeteriorationinglycemic controlornecessitateincreasesininsulindose. 5.8 Mixing of Insulins •MixingNovoLog®withNPHhumaninsulinimmediatelybeforeinjectionattenuatesthepeak concentrationofNovoLog®,withoutsignificantlyaffectingthetimetopeakconcentrationortotal bioavailabilityofNovoLog®.IfNovoLog®ismixedwithNPHhumaninsulin,NovoLog®should bedrawnintothesyringefirst,andthemixtureshouldbeinjectedimmediatelyaftermixing. •TheefficacyandsafetyofmixingNovoLog®withinsulinpreparationsproducedbyother manufacturershavenotbeenstudied. •Insulinmixturesshouldnotbeadministeredintravenously. 5.9 Continuous Subcutaneous Insulin Infusion by External Pump When used in an external subcutaneous insulin infusion pump, NovoLog® should not be mixed with any other insulin or diluent.WhenusingNovoLog®inanexternal insulinpump,theNovoLog®-specificinformationshouldbefollowed(e.g.,in-usetime,frequency ofchanginginfusionsets)becauseNovoLog®-specificinformationmaydifferfromgeneralpump manualinstructions. Pump or infusion set malfunctions or insulin degradation can lead to a rapid onset of hyperglycemiaandketosisbecauseofthesmallsubcutaneousdepotofinsulin.Thisisespecially pertinentforrapid-actinginsulinanalogsthataremorerapidlyabsorbedthroughskinandhavea shorterdurationofaction.Promptidentificationandcorrectionofthecauseofhyperglycemiaor ketosisisnecessary.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 REACTIONS Clinical Trial Experience Becauseclinicaltrialsareconductedunderwidelyvaryingdesigns,theadversereactionrates reportedinoneclinicaltrialmaynotbeeasilycomparedtothoseratesreportedinanotherclinical trial,andmaynotreflecttheratesactuallyobservedinclinicalpractice. 2 •Hypoglycemia Hypoglycemiaisthemostcommonlyobservedadversereactioninpatientsusinginsulin, includingNovoLog®[see Warnings and Precautions (5)]. •Insulin initiation and glucose control intensification Intensificationorrapidimprovementinglucosecontrolhasbeenassociatedwithatransitory, reversibleophthalmologicrefractiondisorder,worseningofdiabeticretinopathy,andacute painfulperipheralneuropathy.However,long-termglycemiccontroldecreasestheriskof diabeticretinopathyandneuropathy. •Lipodystrophy Long-termuseofinsulin,includingNovoLog®,cancauselipodystrophyatthesiteofrepeated insulininjectionsorinfusion.Lipodystrophyincludeslipohypertrophy(thickeningofadipose tissue)andlipoatrophy(thinningofadiposetissue),andmayaffectinsulinabsorption.Rotate insulininjectionorinfusionsiteswithinthesameregiontoreducetheriskoflipodystrophy. •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 Human Regular Insulin + NPH N= 596 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,withorwithout symptoms.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 Human Regular Insulin + NPH N= 91 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,withorwithout symptoms.SeeSection14fortheincidenceofserioushypoglycemiaintheindividualclinicaltrials. Postmarketing Data The following additional adverse reactions have been identified during postapproval use of NovoLog®.Becausetheseadversereactionsarereportedvoluntarilyfromapopulationofuncertain size,itisgenerallynotpossibletoreliablyestimatetheirfrequency.Medicationerrorsinwhich other insulins have been accidentally substituted for NovoLog® have been identified during postapprovaluse[see Patient Counseling Information (17)]. 7 DRUG INTERACTIONS Anumberofsubstancesaffectglucosemetabolismandmayrequireinsulindoseadjustmentand particularlyclosemonitoring. •Thefollowingareexamplesofsubstancesthatmayincreasetheblood-glucose-loweringeffect andsusceptibilitytohypoglycemia:oralantidiabeticproducts,pramlintide,ACEinhibitors, disopyramide,fibrates,fluoxetine,monoamineoxidase(MAO)inhibitors,propoxyphene, salicylates,somatostatinanalog(e.g.,octreotide),sulfonamideantibiotics. •Thefollowingareexamplesofsubstancesthatmayreducetheblood-glucose-lowering effect:corticosteroids,niacin,danazol,diuretics,sympathomimeticagents(e.g.,epinephrine, salbutamol,terbutaline),isoniazid,phenothiazinederivatives,somatropin,thyroidhormones, estrogens,progestogens(e.g.,inoralcontraceptives),atypicalantipsychotics. •Beta-blockers,clonidine,lithiumsalts,andalcoholmayeitherpotentiateorweakenthebloodglucose-loweringeffectofinsulin. •Pentamidinemaycausehypoglycemia,whichmaysometimesbefollowedbyhyperglycemia. •Thesignsofhypoglycemiamaybereducedorabsentinpatientstakingsympatholytic productssuchasbeta-blockers,clonidine,guanethidine,andreserpine. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy PregnancyCategoryB.Allpregnancieshaveabackgroundriskofbirthdefects,loss,orother adverseoutcomeregardlessofdrugexposure.Thisbackgroundriskisincreasedinpregnancies complicatedbyhyperglycemiaandmaybedecreasedwithgoodmetaboliccontrol.Itisessentialfor patientswithdiabetesorhistoryofgestationaldiabetestomaintaingoodmetaboliccontrolbefore NovoLog® (insulin aspart [rDNA origin] injection) Serum glucose (mg/dL) 300 250 200 150 100 50 0 0 1 2 3 4 5 6 Time (h) 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 diabetes demonstrated that intravenous infusion of NovoLog® resulted in a blood glucose profile that wassimilartothatafterintravenousinfusionwithregularhumaninsulin.NovoLog®orhuman insulinwasinfuseduntilthepatient’sbloodglucosedecreasedto36mg/dL,oruntilthepatient demonstratedsignsofhypoglycemia(riseinheartrateandonsetofsweating),definedasthetime ofautonomicreaction(R)(seeFigure3). Mean Blood Glucose (mg/dL) 180 162 144 126 108 90 72 54 36 18 0 0 10 R–20 R–10 R R+10 R+20 R+30 R+40 R+50 R+60 Time (min) 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 Pharmacokinetics ThesinglesubstitutionoftheaminoacidprolinewithasparticacidatpositionB28inNovoLog® reduces the molecule’s tendency to form hexamers as observed with regular human insulin. NovoLog®is,therefore,morerapidlyabsorbedaftersubcutaneousinjectioncomparedtoregular humaninsulin. Inarandomized,double-blind,crossoverstudy17healthyCaucasianmalesubjectsbetween18 and40yearsofagereceivedanintravenousinfusionofeitherNovoLog®orregularhumaninsulin at1.5mU/kg/minfor120minutes.Themeaninsulinclearancewassimilarforthetwogroups withmeanvaluesof1.2l/h/kgfortheNovoLog®groupand1.2l/h/kgfortheregularhuman insulingroup. Bioavailability and Absorption-NovoLog®hasafasterabsorption,afasteronsetofaction,anda shorterdurationofactionthanregularhumaninsulinaftersubcutaneousinjection(seeFigure2and Figure4).TherelativebioavailabilityofNovoLog®comparedtoregularhumaninsulinindicates thatthetwoinsulinsareabsorbedtoasimilarextent. 80 Free serum insulin (mU/L) conceptionandthroughoutpregnancy.Insulinrequirementsmaydecreaseduringthefirsttrimester, generallyincreaseduringthesecondandthirdtrimesters,andrapidlydeclineafterdelivery.Careful monitoringofglucosecontrolisessentialinthesepatients.Therefore,femalepatientsshouldbe advisedtotelltheirphysicianiftheyintendtobecome,oriftheybecomepregnantwhiletaking NovoLog®. Anopen-label,randomizedstudycomparedthesafetyandefficacyofNovoLog®(n=157)versus regularhumaninsulin(n=165)in322pregnantwomenwithtype1diabetes.Two-thirdsofthe enrolledpatientswerealreadypregnantwhentheyenteredthestudy.Becauseonlyone-thirdof thepatientsenrolledbeforeconception,thestudywasnotlargeenoughtoevaluatetheriskof congenitalmalformations.BothgroupsachievedameanHbA1cof~6%duringpregnancy,and therewasnosignificantdifferenceintheincidenceofmaternalhypoglycemia. Subcutaneous reproduction and teratology studies have been performed with NovoLog® and regularhumaninsulininratsandrabbits.Inthesestudies,NovoLog®wasgiventofemalerats beforemating,duringmating,andthroughoutpregnancy,andtorabbitsduringorganogenesis. TheeffectsofNovoLog®didnotdifferfromthoseobservedwithsubcutaneousregularhuman insulin.NovoLog®,likehumaninsulin,causedpre-andpost-implantationlossesandvisceral/ skeletal abnormalities in rats at a dose of 200 U/kg/day (approximately 32 times the human subcutaneousdoseof1.0U/kg/day,basedonU/bodysurfacearea)andinrabbitsatadoseof10 U/kg/day(approximatelythreetimesthehumansubcutaneousdoseof1.0U/kg/day,basedonU/ bodysurfacearea).Theeffectsareprobablysecondarytomaternalhypoglycemiaathighdoses. Nosignificanteffectswereobservedinratsatadoseof50U/kg/dayandinrabbitsatadoseof 3U/kg/day.Thesedosesareapproximately8timesthehumansubcutaneousdoseof1.0U/kg/ dayforratsandequaltothehumansubcutaneousdoseof1.0U/kg/dayforrabbits,basedonU/ bodysurfacearea. 8.3 Nursing Mothers Itisunknownwhetherinsulinaspartisexcretedinhumanmilk.UseofNovoLog®iscompatible withbreastfeeding,butwomenwithdiabeteswhoarelactatingmayrequireadjustmentsoftheir insulindoses. 8.4 Pediatric Use NovoLog®isapprovedforuseinchildrenforsubcutaneousdailyinjectionsandforsubcutaneous continuousinfusionbyexternalinsulinpump.NovoLog®hasnotbeenstudiedinpediatricpatients youngerthan2yearsofage.NovoLog®hasnotbeenstudiedinpediatricpatientswithtype2 diabetes.PleaseseeSection 14 CLINICAL STUDIESforsummariesofclinicalstudies. 8.5 Geriatric Use Ofthetotalnumberofpatients(n=1,375)treatedwithNovoLog®in3controlledclinicalstudies, 2.6%(n=36)were65yearsofageorover.One-halfofthesepatientshadtype1diabetes(18/1285) andtheotherhalfhadtype2diabetes(18/90).TheHbA1cresponsetoNovoLog®,ascompared tohumaninsulin,didnotdifferbyage,particularlyinpatientswithtype2diabetes.Additional studiesinlargerpopulationsofpatients65yearsofageoroverareneededtopermitconclusions regarding the safety of NovoLog® in elderly compared to younger patients. Pharmacokinetic/ pharmacodynamicstudiestoassesstheeffectofageontheonsetofNovoLog®actionhavenot beenperformed. 10 OVERDOSAGE Excessinsulinadministrationmaycausehypoglycemiaand,particularlywhengivenintravenously, hypokalemia.Mildepisodesofhypoglycemiausuallycanbetreatedwithoralglucose.Adjustments indrugdosage,mealpatterns,orexercise,maybeneeded.Moresevereepisodeswithcoma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessarybecausehypoglycemiamayrecurafterapparentclinicalrecovery.Hypokalemiamust becorrectedappropriately. 11 DESCRIPTION NovoLog®(insulinaspart[rDNAorigin]injection)isarapid-actinghumaninsulinanalogusedto lowerbloodglucose.NovoLog®ishomologouswithregularhumaninsulinwiththeexceptionofa singlesubstitutionoftheaminoacidprolinebyasparticacidinpositionB28,andisproducedby recombinantDNAtechnologyutilizingSaccharomyces cerevisiae(baker’syeast).Insulinasparthas theempiricalformulaC256H381N65079S6andamolecularweightof5825.8. 60 40 20 0 0 1 2 3 4 5 6 Time (h) Figure 1. Structural formula of insulin aspart. NovoLog®isasterile,aqueous,clear,andcolorlesssolution,thatcontainsinsulinaspart100 Units/mL,glycerin16mg/mL,phenol1.50mg/mL,metacresol1.72mg/mL,zinc19.6mcg/mL, disodiumhydrogenphosphatedihydrate1.25mg/mL,sodiumchloride0.58mg/mLandwaterfor injection.NovoLog®hasapHof7.2-7.6.Hydrochloricacid10%and/orsodiumhydroxide10% maybeaddedtoadjustpH. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action TheprimaryactivityofNovoLog®istheregulationofglucosemetabolism.Insulins,including NovoLog®,bindtotheinsulinreceptorsonmuscleandfatcellsandlowerbloodglucoseby facilitatingthecellularuptakeofglucoseandsimultaneouslyinhibitingtheoutputofglucosefrom theliver. 12.2 Pharmacodynamics Studies in normal volunteers and patients with diabetes demonstrated that subcutaneous administrationofNovoLog®hasamorerapidonsetofactionthanregularhumaninsulin. In a study in patients with type 1 diabetes (n=22), the maximum glucose-lowering effect of NovoLog® occurred between 1 and 3 hours after subcutaneous injection (see Figure 2). ThedurationofactionforNovoLog®is3to5hours.Thetimecourseofactionofinsulinand insulinanalogssuchasNovoLog®mayvaryconsiderablyindifferentindividualsorwithinthe sameindividual.TheparametersofNovoLog®activity(timeofonset,peaktimeandduration) asdesignatedinFigure2shouldbeconsideredonlyasgeneralguidelines.Therateofinsulin absorptionandonsetofactivityisaffectedbythesiteofinjection,exercise,andothervariables[see Warnings and Precautions (5.1)]. 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®consistentlyreachedpeakserumconcentrationsapproximatelytwiceasfastasregular humaninsulin.Themediantimetomaximumconcentrationinthesetrialswas40to50minutes forNovoLog®versus80to120minutesforregularhumaninsulin.Inaclinicaltrialinpatientswith type1diabetes,NovoLog®andregularhumaninsulin,bothadministeredsubcutaneouslyatadose of0.15U/kgbodyweight,reachedmeanmaximumconcentrationsof82and36mU/L,respectively. Pharmacokinetic/pharmacodynamiccharacteristicsofinsulinasparthavenotbeenestablishedin patientswithtype2diabetes. Theintra-individualvariabilityintimetomaximumseruminsulinconcentrationforhealthymale volunteers was significantly less for NovoLog® than for regular human insulin. The clinical significanceofthisobservationhasnotbeenestablished. In a clinical study in healthy non-obese subjects, the pharmacokinetic differences between NovoLog®andregularhumaninsulindescribedabove,wereobservedindependentofthesiteof injection(abdomen,thigh,orupperarm). Distribution and Elimination-NovoLog®haslowbindingtoplasmaproteins(<10%),similarto thatseenwithregularhumaninsulin.Aftersubcutaneousadministrationinnormalmalevolunteers (n=24), NovoLog® was more rapidly eliminated than regular human insulin with an average apparenthalf-lifeof81minutescomparedto141minutesforregularhumaninsulin. Specific Populations Children and Adolescents-ThepharmacokineticandpharmacodynamicpropertiesofNovoLog® andregularhumaninsulinwereevaluatedinasingledosestudyin18children(6-12years,n=9) andadolescents(13-17years[Tannergrade≥2],n=9)withtype1diabetes.Therelativedifferences in pharmacokinetics and pharmacodynamics in children and adolescents with type 1 diabetes 3 betweenNovoLog®andregularhumaninsulinweresimilartothoseinhealthyadultsubjectsand adultswithtype1diabetes. Gender-Inhealthyvolunteers,nodifferenceininsulinaspartlevelswasseenbetweenmenand womenwhenbodyweightdifferencesweretakenintoaccount.Therewasnosignificantdifference inefficacynoted(asassessedbyHbA1c)betweengendersinatrialinpatientswithtype1diabetes. Obesity-Asinglesubcutaneousdoseof0.1U/kgNovoLog®wasadministeredinastudyof 23patientswithtype1diabetesandawiderangeofbodymassindex(BMI,22-39kg/m2).The pharmacokineticparameters,AUCandCmax,ofNovoLog®weregenerallyunaffectedbyBMIinthe differentgroups–BMI19-23kg/m2(N=4);BMI23-27kg/m2(N=7);BMI27-32kg/m2(N=6)and BMI>32kg/m2(N=6).ClearanceofNovoLog®wasreducedby28%inpatientswithBMI>32kg/ m2comparedtopatientswithBMI<23kg/m2. Renal Impairment-Somestudieswithhumaninsulinhaveshownincreasedcirculatinglevels ofinsulininpatientswithrenalfailure.Asinglesubcutaneousdoseof0.08U/kgNovoLog®was administeredinastudytosubjectswitheithernormal(N=6)creatinineclearance(CLcr)(>80ml/ min)ormild(N=7;CLcr=50-80ml/min),moderate(N=3;CLcr=30-50ml/min)orsevere(butnot requiringhemodialysis)(N=2;CLcr=<30ml/min)renalimpairment.Inthissmallstudy,therewas noapparenteffectofcreatinineclearancevaluesonAUCandCmaxofNovoLog®.Carefulglucose monitoringanddoseadjustmentsofinsulin,includingNovoLog®,maybenecessaryinpatients withrenaldysfunction[see Warnings and Precautions (5.4)]. Hepatic Impairment -Somestudieswithhumaninsulinhaveshownincreasedcirculatinglevels ofinsulininpatientswithliverfailure.Asinglesubcutaneousdoseof0.06U/kgNovoLog®was administeredinanopen-label,single-dosestudyof24subjects(N=6/group)withdifferentdegree ofhepaticimpairment(mild,moderateandsevere)havingChild-PughScoresrangingfrom0 (healthyvolunteers)to12(severehepaticimpairment).Inthissmallstudy,therewasnocorrelation between the degree of hepatic failure and any NovoLog® pharmacokinetic parameter. Careful glucosemonitoringanddoseadjustmentsofinsulin,includingNovoLog®,maybenecessaryin patientswithhepaticdysfunction[see Warnings and Precautions (5.5)]. The effect of age, ethnic origin, pregnancy and smoking on the pharmacokinetics and pharmacodynamicsofNovoLog®hasnotbeenstudied. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of NovoLog®. In 52-week studies, Sprague-Dawley rats were dosed subcutaneouslywithNovoLog®at10,50,and200U/kg/day(approximately2,8,and32times thehumansubcutaneousdoseof1.0U/kg/day,basedonU/bodysurfacearea,respectively).Ata doseof200U/kg/day,NovoLog®increasedtheincidenceofmammaryglandtumorsinfemales whencomparedtountreatedcontrols.TheincidenceofmammarytumorsforNovoLog®wasnot significantlydifferentthanforregularhumaninsulin.Therelevanceofthesefindingstohumansis notknown.NovoLog®wasnotgenotoxicinthefollowingtests:Amestest,mouselymphomacell forwardgenemutationtest,humanperipheralbloodlymphocytechromosomeaberrationtest,in vivomicronucleustestinmice,andinex vivoUDStestinratliverhepatocytes.Infertilitystudies inmaleandfemalerats,atsubcutaneousdosesupto200U/kg/day(approximately32timesthe humansubcutaneousdose,basedonU/bodysurfacearea),nodirectadverseeffectsonmaleand femalefertility,orgeneralreproductiveperformanceofanimalswasobserved. 13.2 Animal Toxicology and/or Pharmacology Instandardbiologicalassaysinmiceandrabbits,oneunitofNovoLog®hasthesameglucoseloweringeffectasoneunitofregularhumaninsulin.Inhumans,theeffectofNovoLog®ismore rapid in onset and of shorter duration, compared to regular human insulin, due to its faster absorptionaftersubcutaneousinjection(seeSection 12 CLINICAL PHARMACOLOGYFigure2 andFigure4). 14 CLINICAL STUDIES 14.1 Subcutaneous Daily Injections Twosix-month,open-label,active-controlledstudieswereconductedtocomparethesafetyand efficacyofNovoLog®toNovolin®Rinadultpatientswithtype1diabetes.Becausethetwostudy designsandresultsweresimilar,dataareshownforonlyonestudy(seeTable3).NovoLog®was administeredbysubcutaneousinjectionimmediatelypriortomealsandregularhumaninsulinwas administeredbysubcutaneousinjection30minutesbeforemeals.NPHinsulinwasadministered asthebasalinsulinineithersingleordivideddailydoses.ChangesinHbA1candtheincidence ratesofseverehypoglycemia(asdeterminedfromthenumberofeventsrequiringinterventionfrom athirdparty)werecomparableforthetwotreatmentregimensinthisstudy(Table3)aswellasin theotherclinicalstudiesthatarecitedinthissection.Diabeticketoacidosiswasnotreportedinany oftheadultstudiesineithertreatmentgroup. Table 3. Subcutaneous NovoLog® Administration in Type 1 Diabetes(24weeks; n=882) NovoLog® + NPH Novolin® R + NPH N 596 286 7.9±1.1 8.0±1.2 BaselineHbA1c(%)* -0.1±0.8 0.0±0.8 ChangefromBaselineHbA1c(%) TreatmentDifferenceinHbA1c,Mean -0.2(-0.3,-0.1) (95%confidenceinterval) Baselineinsulindose(IU/kg/24hours)* 0.7±0.2 0.7±0.2 End-of-Studyinsulindose(IU/kg/24hours)* 0.7±0.2 0.7±0.2 Patientswithseverehypoglycemia(n,%)** 104(17%) 54(19%) Baselinebodyweight(kg)* 75.3±14.5 75.9±13.1 WeightChangefrombaseline(kg)* 0.5±3.3 0.9±2.9 *ValuesareMean±SD **Severehypoglycemiareferstohypoglycemiaassociatedwithcentralnervoussystemsymptomsand requiringtheinterventionofanotherpersonorhospitalization. A24-week,parallel-groupstudyofchildrenandadolescentswithtype1diabetes(n=283)aged6 to18yearscomparedtwosubcutaneousmultiple-dosetreatmentregimens:NovoLog®(n=187) orNovolin®R(n=96).NPHinsulinwasadministeredasthebasalinsulin.NovoLog®achieved glycemiccontrolcomparabletoNovolin®R,asmeasuredbychangeinHbA1c(Table4)andboth treatmentgroupshadacomparableincidenceofhypoglycemia.Subcutaneousadministrationof NovoLog®andregularhumaninsulinhavealsobeencomparedinchildrenwithtype1diabetes (n=26)aged2to6yearswithsimilareffectsonHbA1candhypoglycemia. NovoLog® (insulin aspart [rDNA origin] injection) Table 4. Pediatric Subcutaneous Administration of NovoLog® in Type 1 Diabetes (24weeks;n=283) NovoLog® + NPH Novolin® R + NPH N 187 96 8.3±1.2 8.3±1.3 BaselineHbA1c(%)* 0.1±1.0 0.1±1.1 ChangefromBaselineHbA1c(%) TreatmentDifferenceinHbA1c,Mean 0.1(-0.5,0.1) (95%confidenceinterval) Baselineinsulindose(IU/kg/24hours)* 0.4±0.2 0.6±0.2 End-of-Studyinsulindose(IU/kg/24hours)* 0.4±0.2 0.7±0.2 Patientswithseverehypoglycemia(n,%)** 11(6%) 9(9%) Diabeticketoacidosis(n,%) 10(5%) 2(2%) Baselinebodyweight(kg)* 50.6±19.6 48.7±15.8 WeightChangefrombaseline(kg)* 2.7±3.5 2.4±2.6 *ValuesareMean±SD **Severehypoglycemiareferstohypoglycemiaassociatedwithcentralnervoussystemsymptomsand requiringtheinterventionofanotherpersonorhospitalization. An open-label, 16-week parallel design trial compared pre-prandial NovoLog® injection in conjunctionwithNPHinjectionstoNovoLog®administeredbycontinuoussubcutaneousinfusion in127adultswithtype2diabetes.ThetwotreatmentgroupshadsimilarreductionsinHbA1cand ratesofseverehypoglycemia(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® + NPH N 66 61 8.2±1.4 8.0±1.1 BaselineHbA1c(%)* -0.6±1.1 -0.5±0.9 ChangefromBaselineHbA1c(%) TreatmentDifferenceinHbA1c,Mean 0.1(0.4,0.3) (95%confidenceinterval) *ValuesareMean±SD Baselineinsulindose(IU/kg/24hours)* 0.7±0.3 0.8±0.5 **Severehypoglycemiareferstohypoglycemiaassociatedwithcentralnervoussystemsymptomsand requiringtheinterventionofanotherpersonorhospitalization. End-of-Studyinsulindose(IU/kg/24hours)* 0.9±0.4 0.9±0.5 One six-month, open-label, active-controlled study was conducted to compare the safety and Baselinebodyweight(kg)* 96.4±17.0 96.9±17.9 efficacyofNovoLog®toNovolin®Rinpatientswithtype2diabetes(Table5).NovoLog®was 1.7±3.7 0.7±4.1 administeredbysubcutaneousinjectionimmediatelypriortomealsandregularhumaninsulinwas WeightChangefrombaseline(kg)* administeredbysubcutaneousinjection30minutesbeforemeals.NPHinsulinwasadministeredas *ValuesareMean±SD thebasalinsulinineithersingleordivideddailydoses.ChangesinHbA1candtheratesofsevere 14.3 Intravenous Administration of NovoLog® hypoglycemia(asdeterminedfromthenumberofeventsrequiringinterventionfromathirdparty) See Section 12.2 CLINICAL PHARMACOLOGY/Pharmacodynamics. werecomparableforthetwotreatmentregimens. ® 16 HOW SUPPLIED/STORAGE AND HANDLING Table 5. Subcutaneous NovoLog Administration in Type 2 Diabetes (6months; n=176) 16.1 How Supplied NovoLog® + NPH Novolin® R + NPH NovoLog®isavailableinthefollowingpackagesizes:eachpresentationcontaining100Unitsof insulinaspartpermL(U-100). N 90 86 10mLvials NDC0169-7501-11 8.1±1.2 7.8±1.1 BaselineHbA1c(%)* 3mLPenFill®cartridges* NDC0169-3303-12 -0.3±1.0 -0.1±0.8 ChangefromBaselineHbA1c(%) ®FlexPen® 3mLNovoLog NDC0169-6339-10 TreatmentDifferenceinHbA1c,Mean -0.1(-0.4,-0.1) (95%confidenceinterval) *NovoLog®PenFill®cartridgesaredesignedforusewithNovoNordisk3mLPenFill®cartridge compatibleinsulindeliverydevices(withorwithouttheadditionofaNovoPen®3PenMate®)with Baselineinsulindose(IU/kg/24hours)* 0.6±0.3 0.6±0.3 NovoFine®disposableneedles. End-of-Studyinsulindose(IU/kg/24hours)* 0.7±0.3 0.7±0.3 16.2 Recommended Storage Patientswithseverehypoglycemia(n,%)** 9(10%) 5(8%) Unused NovoLog® should be stored in a refrigerator between 2° and 8°C (36° to 46°F). Do Baselinebodyweight(kg)* 88.4±13.3 85.8±14.8 notstoreinthefreezerordirectlyadjacenttotherefrigeratorcoolingelement.Do not freeze WeightChangefrombaseline(kg)* 1.2±3.0 0.4±3.1 NovoLog® and do not use NovoLog® if it has been frozen.NovoLog®shouldnotbedrawn *ValuesareMean±SD intoasyringeandstoredforlateruse. **Severehypoglycemiareferstohypoglycemiaassociatedwithcentralnervoussystemsymptomsand Vials:Afterinitialuseavialmaybekeptattemperaturesbelow30°C(86°F)forupto28days,but requiringtheinterventionofanotherpersonorhospitalization. shouldnotbeexposedtoexcessiveheatorsunlight.Openedvialsmayberefrigerated. 14.2 Continuous Subcutaneous Insulin Infusion (CSII) by External Pump Unpuncturedvialscanbeuseduntiltheexpirationdateprintedonthelabeliftheyarestoredin Two open-label, parallel design studies (6 weeks [n=29] and 16 weeks [n=118]) compared arefrigerator.Keepunusedvialsinthecartonsotheywillstaycleanandprotectedfromlight. ® NovoLog tobufferedregularhumaninsulin(Velosulin)inadultswithtype1diabetesreceivinga PenFill® cartridges or NovoLog® FlexPen®: subcutaneousinfusionwithanexternalinsulinpump.Thetwotreatmentregimenshadcomparable OnceacartridgeoraNovoLog®FlexPen®ispunctured,itshouldbekeptattemperaturesbelow changesinHbA1candratesofseverehypoglycemia. 30°C (86°F) for up to 28 days, but should not be exposed to excessive heat or sunlight. A Table 6. Adult Insulin Pump Study in Type 1 Diabetes(16weeks;n=118) NovoLog®FlexPen®orcartridgeinusemustNOTbestoredintherefrigerator.KeeptheNovoLog® NovoLog® Buffered human insulin FlexPen®andallPenFill®cartridgesawayfromdirectheatandsunlight.UnpuncturedNovoLog® FlexPen®andPenFill®cartridgescanbeuseduntiltheexpirationdateprintedonthelabelifthey N 59 59 arestoredinarefrigerator.KeepunusedNovoLog®FlexPen®andPenFill®cartridgesinthecarton 7.3±0.7 7.5±0.8 BaselineHbA1c(%)* sotheywillstaycleanandprotectedfromlight. 0.0±0.5 0.2±0.6 ChangefromBaselineHbA1c(%) 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 TreatmentDifferenceinHbA1c,Mean 0.3(-0.1,0.4) contamination and/or infection, or leakage of insulin, and will ensure accurate (95%confidenceinterval) dosing. Always use a new needle for each injection to prevent contamination. Baselineinsulindose(IU/kg/24hours)* 0.7±0.8 0.6±0.2 Pump: End-of-Studyinsulindose(IU/kg/24hours)* 0.7±0.7 0.6±0.2 NovoLog®inthepumpreservoirshouldbediscardedafteratleastevery6daysofuseorafter Patientswithseverehypoglycemia(n,%)** 1(2%) 2(3%) exposuretotemperaturesthatexceed37°C(98.6°F).Theinfusionsetandtheinfusionsetinsertion Baselinebodyweight(kg)* 77.4±16.1 74.8±13.8 siteshouldbechangedatleastevery3days. WeightChangefrombaseline(kg)* 0.1±3.5 -0.0±1.7 Summary of Storage Conditions: *ValuesareMean±SD Thestorageconditionsaresummarizedinthefollowingtable: **Severehypoglycemiareferstohypoglycemiaassociatedwithcentralnervoussystemsymptomsand Table 9. Storage conditions for vial, PenFill® cartridges and NovoLog® FlexPen® requiringtheinterventionofanotherpersonorhospitalization. Not in-use (unopened) Not in-use In-use (opened) Arandomized,16-week,open-label,paralleldesignstudyofchildrenandadolescentswithtype1 NovoLog® RoomTemperature (unopened) RoomTemperature diabetes(n=298)aged4-18yearscomparedtwosubcutaneousinfusionregimensadministered presentation ® (below30°C) Refrigerated (below30°C) viaanexternalinsulinpump:NovoLog (n=198)orinsulinlispro(n=100).Thesetwotreatments resultedincomparablechangesfrombaselineinHbA1candcomparableratesofhypoglycemiaafter 10mLvial 28days Until 28days 16weeksoftreatment(seeTable7). expirationdate (refrigerated/room Table 7. Pediatric Insulin Pump Study in Type 1 Diabetes(16weeks;n=298) temperature) NovoLog® Lispro Until 28days 3mLPenFill® 28days N 198 100 cartridges expirationdate (Donotrefrigerate) 8.0±0.9 8.2±0.8 BaselineHbA1c(%)* 3mLNovoLog® 28days Until 28days -0.1±0.8 -0.1±0.7 ChangefromBaselineHbA1c(%) FlexPen® expirationdate (Donotrefrigerate) TreatmentDifferenceinHbA1c,Mean -0.1(-0.3,0.1) (95%confidenceinterval) Baselineinsulindose(IU/kg/24hours)* 0.9±0.3 0.9±0.3 Storage of Diluted NovoLog® NovoLog®dilutedwithInsulinDilutingMediumforNovoLog®toaconcentrationequivalentto End-of-Studyinsulindose(IU/kg/24hours)* 0.9±0.2 0.9±0.2 U-10orequivalenttoU-50mayremaininpatientuseattemperaturesbelow30°C(86°F)for Patientswithseverehypoglycemia(n,%)** 19(10%) 8(8%) 28days. Diabeticketoacidosis(n,%) 1(0.5%) 0(0) Storage of NovoLog® in Infusion Fluids Baselinebodyweight(kg)* 54.1±19.7 55.5±19.0 Infusion bags prepared as indicated under Dosage and Administration (2) are stable at room WeightChangefrombaseline(kg)* 1.8±2.1 1.6±2.1 temperaturefor24hours.Someinsulinwillbeinitiallyadsorbedtothematerialoftheinfusionbag. 4 17 PATIENT COUNSELING INFORMATION [See FDA-Approved Patient Labeling (17.3)] 17.1 Physician Instructions Maintenanceofnormalornear-normalglucosecontrolisatreatmentgoalindiabetesmellitus andhasbeenassociatedwithareductionindiabeticcomplications.Patientsshouldbeinformed aboutpotentialrisksandbenefitsofNovoLog®therapyincludingthepossibleadversereactions. Patientsshouldalsobeofferedcontinuededucationandadviceoninsulintherapies,injection technique,life-stylemanagement,regularglucosemonitoring,periodicglycosylatedhemoglobin testing,recognitionandmanagementofhypo-andhyperglycemia,adherencetomealplanning, complicationsofinsulintherapy,timingofdose,instructionintheuseofinjectionorsubcutaneous infusiondevices,andproperstorageofinsulin.Patientsshouldbeinformedthatfrequent,patientperformedbloodglucosemeasurementsareneededtoachieveoptimalglycemiccontrolandavoid bothhyper-andhypoglycemia. Thepatient’sabilitytoconcentrateandreactmaybeimpairedasaresultofhypoglycemia.This maypresentariskinsituationswheretheseabilitiesareespeciallyimportant,suchasdrivingor operatingothermachinery.Patientswhohavefrequenthypoglycemiaorreducedorabsentwarning signsofhypoglycemiashouldbeadvisedtousecautionwhendrivingoroperatingmachinery. Accidental substitutions between NovoLog® and other insulin products have been reported. Patientsshouldbeinstructedtoalwayscarefullycheckthattheyareadministeringtheappropriate insulin 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 Pumps Patientsusingexternalpumpinfusiontherapyshouldbetrainedinintensiveinsulintherapywith multipleinjectionsandinthefunctionoftheirpumpandpumpaccessories. Thefollowinginsulinpumps†havebeenusedinNovoLog®clinicalorin vitrostudiesconductedby NovoNordisk,themanufacturerofNovoLog®: •MedtronicParadigm®512and712 •MiniMed508 •Disetronic®D-TRON®andH-TRON® BeforeusinganotherinsulinpumpwithNovoLog®,readthepumplabeltomakesurethepump hasbeenevaluatedwithNovoLog®. NovoLog®isrecommendedforuseinanyreservoirandinfusionsetsthatarecompatiblewith insulinandthespecificpump.Pleaseseerecommendedreservoirandinfusionsetsinthepump manual. 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,andanewsiteselectedbecause continuedinfusionmayincreasetheskinreactionand/oraltertheabsorptionofNovoLog®.Pump orinfusionsetmalfunctionsorinsulindegradationcanleadtohyperglycemiaandketosisina shorttimebecauseofthesmallsubcutaneousdepotofinsulin.Thisisespeciallypertinentfor rapid-actinginsulinanalogsthataremorerapidlyabsorbedthroughskinandhaveshorterduration of action. These differences are particularly relevant when patients are switched from multiple injectiontherapy.Promptidentificationandcorrectionofthecauseofhyperglycemiaorketosisis necessary.Problemsincludepumpmalfunction,infusionsetocclusion,leakage,disconnectionor kinking,anddegradedinsulin.Lesscommonly,hypoglycemiafrompumpmalfunctionmayoccur. Iftheseproblemscannotbepromptlycorrected,patientsshouldresumetherapywithsubcutaneous insulininjectionandcontacttheirphysician[see Dosage and Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling (16.2)]. 17.3 FDA Approved Patient Labeling Seeseparateleaflet. Rx only DateofIssue:June2011 Version:19 Novo 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,andotherpatents pending.PenFill®iscoveredbyUSPatentNo.5,693,027. †Thebrandslistedaretheregisteredtrademarksoftheirrespectiveownersandarenottrademarks ofNovoNordiskA/S. Manufacturedby: NovoNordiskA/S DK-2880Bagsvaerd,Denmark ForinformationaboutNovoLog®contact: NovoNordiskInc. Princeton,NewJersey08540 1-800-727-6500 www.novonordisk-us.com ©2002-2011NovoNordiskA/S 143208-R17/11 NovoLog® (insulin aspart [rDNA origin] injection) Patient Information NovoLog® (NŌ-vō-log) (insulin aspart [rDNA origin] Injection) Important: Know your insulin.Donotchangethetypeofinsulinyouuse unlesstoldtodosobyyourhealthcareprovider.Theamountof insulinyoutakeaswellasthebesttimeforyoutotakeyourinsulin mayneedtochangeifyoutakeadifferenttypeofinsulin. Makesureyouknowthetypeandstrengthofinsulinprescribedforyou. ReadthePatientInformationthatcomeswithNovoLog®before youstarttakingitandeachtimeyougetarefill.Theremaybenew information.Thisleafletdoesnottaketheplaceoftalkingwithyour healthcareprovideraboutyourdiabetesoryourtreatment.Make sureyouknowhowtomanageyourdiabetes.Askyourhealthcare providerifyouhaveanyquestionsaboutmanagingyourdiabetes. What is NovoLog®? NovoLog®isaman-madeinsulinthatisusedtocontrolhighblood sugarinadultsandchildrenwithdiabetesmellitus. •Inject NovoLog® into the skin of your stomach area, upper arms, buttocks or upper legs.NovoLog®mayaffect yourbloodsugarlevelssoonerifyouinjectitintotheskinof yourstomacharea.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).Youcantreatmildlowblood sugar(hypoglycemia)bydrinkingoreatingsomethingsugary rightaway(fruitjuice,sugarcandies,orglucosetablets).Itis importanttotreatlowbloodsugar(hypoglycemia)rightaway becauseitcouldgetworseandyoucouldpassout(become unconscious).Ifyoupassoutyouwillneedhelpfromanother personoremergencymedicalservicesrightaway,andwillneed treatmentwithaglucagoninjectionortreatmentatahospital. See“WhatarethepossiblesideeffectsofNovoLog®?”formore informationonlowbloodsugar(hypoglycemia). •If you forget to take your dose of NovoLog®, your blood sugar may go too high (hyperglycemia).Ifhigh bloodsugar(hyperglycemia)isnottreateditcanleadtoserious problems,likelossofconsciousness(passingout),comaor evendeath.Followyourhealthcareprovider’sinstructionsfor treatinghighbloodsugar.Knowyoursymptomsofhighblood sugarwhichmayinclude: •increasedthirst •fruitysmellonthebreath •frequenturination •drowsiness •lossofappetite •ahardtimebreathing •highamountsofsugarandketonesinyoururine •nausea,vomiting(throwingup)orstomachpain •Check your blood sugar levels.Askyourhealthcare providerwhatyourbloodsugarsshouldbeandwhenyoushould checkyourbloodsugarlevels. Your insulin dosage may need to change because of: •illness •changeindiet •stress •othermedicinesyoutake •changeinphysicalactivityorexercise Who should not use NovoLog®? Do not take NovoLog® if: •Yourbloodsugaristoolow(hypoglycemia). •YouareallergictoanythinginNovoLog®.Seetheendofthis leafletforacompletelistofingredientsinNovoLog®.Checkwith yourhealthcareproviderifyouarenotsure. Tell your healthcare provider: •about all of your medical conditions.Medicalconditions canaffectyourinsulinneedsandyourdoseofNovoLog®. •if you are pregnant or breastfeeding.Youandyour healthcareprovidershouldtalkaboutthebestwaytomanage yourdiabeteswhileyouarepregnantorbreastfeeding. NovoLog®hasnotbeenstudiedinnursingwomen. •about all medicines you take,includingprescriptionsand non-prescriptionmedicines,vitaminsandherbalsupplements. YourNovoLog®dosemaychangeifyoutakeothermedicines. Know the medicines you take.Keepalistofyourmedicines withyoutoshowyourhealthcareproviderswhenyougetanew medicine. What should I avoid while using NovoLog®? •Alcohol.Alcohol,includingbeerandwine,mayaffectyour How should I take NovoLog®? bloodsugarwhenyoutakeNovoLog®. OnlyuseNovoLog®ifitappearsclearandcolorless.Theremaybe airbubbles.Thisisnormal.Ifitlookscloudy,thickened,orcolored, •Driving and operating machinery.Youmayhave difficultyconcentratingorreactingifyouhavelowbloodsugar orifitcontainssolidparticlesdonotuseitandcallNovoNordisk (hypoglycemia).Becarefulwhenyoudriveacaroroperate at1-800-727-6500. machinery.Askyourhealthcareproviderifitisalrighttodriveif NovoLog®comesin: youoftenhave: •10mLvials(smallbottles)forusewithsyringe •lowbloodsugar ® •3mLPenFill cartridgesforusewiththeNovoNordisk3mL •decreasedornowarningsignsoflowbloodsugar ® PenFill cartridgecompatibleinsulindeliverydevicesand ® What are the possible side effects of NovoLog®? NovoFine disposableneedles.Thecartridgedeliverydevicecan beusedwithaNovoPen®3PenMate® •Low blood sugar (hypoglycemia).Symptomsoflowblood sugarmayinclude: •3mLNovoLog®FlexPen® •sweating • blurredvision Read the instructions for use that come with your •troubleconcentratingorconfusion NovoLog® product.Talktoyourhealthcareproviderifyouhave •dizzinessorlightheadedness• hunger anyquestions.Yourhealthcareprovidershouldshowyouhowto injectNovoLog®beforeyoustarttakingit. •shakiness • slurredspeech •fastheartbeat • tinglingoflipsandtongue •Take NovoLog® exactly as prescribed.Youshouldeata •anxiety,irritabilityormoodchanges mealwithin5to10minutesafterusingNovoLog®toavoidlow bloodsugar. •headache •NovoLog® is a fast-acting insulin.TheeffectsofNovoLog® Severelowbloodsugarcancauseunconsciousness(passing startworking10to20minutesafterinjectionorboluspump out),seizures,anddeath.Knowyoursymptomsoflowblood infusion. sugar.Followyourhealthcareprovider’sinstructionsfortreating lowbloodsugar.Talktoyourhealthcareprovideriflowblood •Do not inject NovoLog® if you do not plan to eat right sugarisaproblemforyou. after your injection or bolus pump infusion. •Serious allergic reaction (whole body reaction).Get •Thegreatestbloodsugarloweringeffectisbetween1and3 medical help right away, if you developarashoveryour hoursaftertheinjectionorinfusion.Thisbloodsugarlowering wholebody,havetroublebreathing,afastheartbeat,orsweating. lastsfor3to5hours. •Reactions at the injection site (local allergic reaction). •While using NovoLog® you may have to changeyour Youmaygetredness,swelling,anditchingattheinjectionsite. totaldoseofinsulin,yourdoseoflonger-actinginsulin,orthe Ifyoukeephavingskinreactionsortheyareserioustalktoyour numberofinjectionsoflonger-actinginsulinyouuse.Pump healthcareprovider.YoumayneedtostopusingNovoLog®and usersgivenNovoLog®mayneedtochangetheamountoftotal useadifferentinsulin.Donotinjectinsulinintoskinthatisred, insulingivenasabasalinfusion. swollen,oritchy. •Do not mix NovoLog®: •Skin thickens or pits at the injection site •withanyotherinsulinswhenusedinapump (lipodystrophy).Change(rotate)whereyouinjectyourinsulin •withanyinsulinsotherthanNPHwhenusedwithinjections tohelptopreventtheseskinchangesfromhappening.Donot bysyringe injectinsulinintothistypeofskin. IfyourhealthcareproviderrecommendsdilutingNovoLog®,follow •Swelling of your hands and feet yourhealthcareprovider’sinstructionsexactlysothatyouknow: •Visionchanges •HowtomakeNovoLog®moredilute(thatis,asmallernumberof •Lowpotassiuminyourblood(hypokalemia) unitsofNovoLog®foragivenamountofliquid)and •Weightgain •HowtousethismorediluteformofNovoLog®.Do not use ThesearenotallofthepossiblesideeffectsfromNovoLog®. dilute insulin in a pump. 5 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,ifthemedicinehasbeenstoredina refrigerator. •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,evenifthereisinsulinleftinthe cartridgeorsyringe. •NovoLog® in the pump reservoir and the complete external pump infusion set •Theinfusionsetandtheinfusionsiteshouldbechangedat least every 3 days.Theinsulininthereservoirshould bechangedat least every 6 daysevenifyouhavenot usedalloftheinsulin.Changetheinfusionsetandthe infusionsitemoreoftenthanevery3daysifyouhavehigh bloodsugar(hyperglycemia),thepumpalarmsounds,orthe insulinflowisblocked(occlusion). General advice about NovoLog® Medicinesaresometimesprescribedforconditionsthatare notmentionedinthepatientleaflet.DonotuseNovoLog®fora conditionforwhichitwasnotprescribed.DonotgiveNovoLog® tootherpeople,eveniftheyhavethesamesymptomsyouhave. Itmayharmthem. Thisleafletsummarizesthemostimportantinformationabout NovoLog®.IfyouwouldlikemoreinformationaboutNovoLog® ordiabetes,talkwithyourhealthcareprovider.Youcanaskyour healthcareproviderorpharmacistforinformationaboutNovoLog® thatiswrittenforhealthcareprofessionals.Call1-800-727-6500or visitwww.novonordisk-us.comformoreinformation. Helpfulinformationforpeoplewithdiabetesispublishedby theAmericanDiabetesAssociation,1701NBeauregardStreet, Alexandria,VA22311andonwww.diabetes.org. NovoLog® ingredients include: •insulinaspart •zinc •glycerin •phenol •metacresol •sodiumchloride •disodiumhydrogenphosphatedihydrate •waterforinjection AllNovoLog®vials,PenFill®cartridgesandNovoLog®FlexPen® arelatexfree. DateofIssue:June2011 Version: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,andother patentspending. FlexPen®iscoveredbyUSPatentNos.6,582,404,6,004,297,6,235,004, andotherpatentspending. PenFill®iscoveredbyUSPatentNo.5,693,027. Manufacturedby: NovoNordiskA/S DK-2880Bagsvaerd,Denmark ForinformationaboutNovoLog®contact: NovoNordiskInc. 100CollegeRoadWest Princeton,NewJersey08540 ©2002-2011NovoNordiskA/S 143208-R17/11 NovoLog® (insulin aspart [rDNA origin] injection) NovoLog® FlexPen® Introduction PleasereadthefollowinginstructionscarefullybeforeusingyourNovoLog®FlexPen®. NovoLog®FlexPen®isadisposabledial-a-doseinsulinpen.Youcanselectdosesfrom1to60units inincrementsof1unit.NovoLog®FlexPen®isdesignedtobeusedwithNovoFine®needles. NovoLog®FlexPen®shouldnotbeusedbypeoplewhoareblindorhaveseverevisualproblems withoutthehelpofapersonwhohasgoodeyesightandwhoistrainedtousetheNovoLog® FlexPen®therightway. NovoLog® FlexPen® NovoFine® needle Pen cap Big outer Inner needle Protective Getting ready needle cap cap Needle tab Makesureyouhavethe followingitems: • NovoLog®FlexPen® • NewNovoFine®needle • Alcoholswab Rubber stopper Cartridge Cartridge scale Preparing Your NovoLog® FlexPen® Washyourhandswithsoap andwater.Beforeyoustarttoprepareyour injection,checkthelabeltomakesurethatyouaretakingtheright typeofinsulin.Thisisespeciallyimportantifyoutakemorethan1type ofinsulin.NovoLog®shouldlookclear. A.Pulloffthepencap(seediagramA). Wipetherubberstopperwithanalcoholswab. B. Attaching the needle Removetheprotectivetabfromadisposableneedle. ScrewtheneedletightlyontoyourFlexPen®.Itisimportantthatthe needleisputonstraight(seediagramB). NeverplaceadisposableneedleonyourNovoLog®FlexPen®until youarereadytotakeyourinjection. Pointer PushDose button selector A B D Toreducetheriskofunexpectedneedlesticks,neverputtheinner needlecapbackontheneedle. E E.Turnthedoseselectortoselect2units(seediagramE). G.Keeptheneedlepointingupwards,pressthepush-buttonalltheway in(seediagramG).Thedoseselectorreturnsto0. Adropofinsulinshouldappearattheneedletip.Ifnot,changethe needleandrepeattheprocedurenomorethan6times. Ifyoudonotseeadropofinsulinafter6times,donotusethe NovoLog®FlexPen®andcontactNovoNordiskat1-800-727-6500. Asmallairbubblemayremainattheneedletip,butitwillnotbe injected. Donotusethecartridgescaleprintedonthecartridgetomeasure yourdoseofinsulin. Giving the injection Dotheinjectionexactlyasshowntoyoubyyourhealthcareprovider. Yourhealthcareprovidershouldtellyouifyouneedtopinchtheskin beforeinjecting. After the injection Do not recap the needle.Recappingcanleadtoaneedlestickinjury.Removetheneedlefromthe NovoLog®FlexPen®aftereachinjection.Thishelpstopreventinfection,leakageofinsulin,andwill helptomakesureyouinjecttherightdoseofinsulin. PuttheneedleandanyemptyNovoLog®FlexPen®oranyusedNovoLog®FlexPen®still containinginsulininasharpscontainerorsometypeofhardplasticormetalcontainerwitha screwtopsuchasadetergentbottleoremptycoffeecan.Thesecontainersshouldbesealed andthrownawaytherightway.Checkwithyourhealthcareproviderabouttherightwaytothrow awayusedsyringesandneedles.Theremaybelocalorstatelawsabouthowtothrowaway usedneedlesandsyringes.Donotthrowawayusedneedlesandsyringesinhouseholdtrashor recyclingbins. TheNovoLog®FlexPen®preventsthecartridgefrombeingcompletelyemptied.Itisdesignedto deliver300units. K K.PutthepencapontheNovoLog®FlexPen®andstorethe NovoLog®FlexPen®withouttheneedleattached(seediagramK). Maintenance YourFlexPen®isdesignedtoworkaccuratelyandsafely.Itmustbehandledwithcare.Avoiddropping yourFlexPen®asitmaydamageit.IfyouareconcernedthatyourFlexPen®isdamaged,useanew one.YoucancleantheoutsideofyourFlexPen®bywipingitwithadampcloth.Donotsoakorwash yourFlexPen®asitmaydamageit.DonotrefillyourFlexPen®. RemovetheneedlefromtheNovoLog®FlexPen®aftereachinjection.Thishelpstoensure sterility,preventleakageofinsulin,andwillhelptomakesureyouinjecttherightdoseofinsulin forfutureinjections. Becarefulwhenhandlingusedneedlestoavoidneedlesticksandtransferofinfectiousdiseases. KeepyourNovoLog®FlexPen®andneedlesoutofthereachofchildren. UseNovoLog®FlexPen®asdirectedtotreatyourdiabetes. NeedlesandNovoLog®FlexPen®mustnotbeshared.Alwaysuseanewneedleforeachinjection. NovoNordiskisnotresponsibleforharmduetousingthisinsulinpenwithproductsnot recommendedbyNovoNordisk. Asaprecautionarymeasure,alwayscarryaspareinsulindeliverydeviceincaseyourNovoLog® FlexPen®islostordamaged. RemembertokeepthedisposableNovoLog®FlexPen®withyou.Donotleaveitinacarorother locationwhereitcangettoohotortoocold. 2 units selected F G Selecting your dose Checkandmakesurethatthedoseselectorissetat0. H.Turnthedoseselectortothenumberofunitsyouneedtoinject. Thepointershouldlineupwithyourdose. Thedosecanbecorrectedeitherupordownbyturningthedose selectorineitherdirectionuntilthecorrectdoselinesupwiththe pointer(seediagramH).Whenturningthedoseselector,becarefulnot topressthepush-buttonasinsulinwillcomeout. Youcannotselectadoselargerthanthenumberofunitsleftinthe cartridge. Youwillhearaclickforeverysingleunitdialed.Donotsetthedose bycountingthenumberofclicksyouhear. J L •ScrewonanewNovoFine®needle. •Removethebigouterneedlecapandtheinnerneedlecap. •Doanairshotasdescribedin“Givingtheairshotbeforeeach 20 injection”. •Putthebigouterneedlecapontotheneedle.Donotputonthe innerneedlecap. •Turnthedoseselectorsothedoseindicatorwindowshows20units. •HoldtheNovoLog®FlexPen®sotheneedleispointingdown. •Pressthepush-buttonallthewayin. Theinsulinshouldfillthelowerpartofthebigouterneedlecap(seediagramL).Ifthe NovoLog®FlexPen®hasreleasedtoomuchortoolittleinsulin,dothefunctioncheckagain. Ifthesameproblemhappensagain,donotuseyourNovoLog®FlexPen®andcontact NovoNordiskat1-800-727-6500. C Becarefulnottobendordamagetheneedlebeforeuse. F. HoldyourNovoLog®FlexPen®withtheneedlepointingup. Tapthecartridgegentlywithyourfingerafewtimestomakeanyair bubblescollectatthetopofthecartridge(seediagramF). 0 L.IfyourNovoLog®FlexPen®isnotworkingtherightway,followthe stepsbelow: D.Pullofftheinnerneedlecapanddisposeofit(seediagramD). Giving the airshot before each injection Beforeeachinjectionsmallamountsofairmaycollectinthecartridge duringnormaluse.Toavoidinjectingairandtoensureproperdosing: J. Keeptheneedleintheskinforatleast6seconds,andkeepthepushbuttonpressedallthewayinuntiltheneedlehasbeenpulledoutfrom theskin(seediagramJ).Thiswillmakesurethatthefulldosehas beengiven. YoumayseeadropofNovoLog®attheneedletip.Thisisnormaland hasnoeffectonthedoseyoujustreceived.Ifbloodappearsafteryou taketheneedleoutofyourskin,presstheinjectionsitelightlywitha finger.Do not rub the area. I Function Check C.Pulloffthebigouterneedlecap(seediagramC). Alwaysuseanewneedleforeachinjectiontohelpensuresterility andpreventblockedneedles. I. Inserttheneedleintoyourskin. Injectthedosebypressingthepush-buttonallthewayinuntilthe0 linesupwiththepointer(seediagramI).Becarefulonlytopushthe buttonwheninjecting. Turningthedoseselectorwillnotinjectinsulin. 4 6 Patient Instructions for Use 6 H 5 units selected 4 6 24 units selected 24 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®iscoveredby USPatentNos.6,582,404,6,004,297,6,235,004,andotherpatentspending.PenFill®iscoveredbyUSPatentNo. 5,693,027. Manufacturedby: NovoNordiskA/S DK-2880Bagsvaerd,Denmark ForinformationaboutNovoLog®contact: NovoNordiskInc. 100CollegeRoadWest Princeton,NewJersey08540 ©2002-2011NovoNordiskA/S 143208-R17/11