levemr

1

——— CONTRAINDICATIONS ———

•DonotuseinpatientswithhypersensitivitytoLEVEMIR®oranyofitsexcipients(4)

——— WARNINGS AND PRECAUTIONS ———•Doseadjustmentandmonitoring:Monitorbloodglucosein

allpatientstreatedwithinsulin.Insulinregimensshouldbemodifiedcautiouslyandonlyundermedicalsupervision(5.1)

•Administration:Donotdiluteormixwithanyotherinsulinorsolution.Donotadministersubcutaneouslyviaaninsulinpump,intramuscularly,orintravenouslybecauseseverehypoglycemiacanoccur(5.2)

•Hypoglycemiaisthemostcommonadversereactionofinsulintherapyandmaybelife-threatening(5.3,6.1)

•Allergicreactions:Severe,life-threatening,generalizedallergy,includinganaphylaxis,canoccur(5.4)

•Renalorhepaticimpairment:MayrequireadjustmentoftheLEVEMIR®dose(5.5,5.6)

——— ADVERSE REACTIONS ———

AdversereactionsassociatedwithLEVEMIR®includehypoglycemia,allergicreactions,injectionsitereactions,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 ———•Certaindrugsmayaffectglucosemetabolismrequiringinsulin

doseadjustmentandclosemonitoringofbloodglucose(7)•Thesignsofhypoglycemiamaybereducedorabsentinpatients

takinganti-adrenergicdrugs(e.g.,beta-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: 5/2012

FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION 2.1 Dosing 2.2 InitiationofLEVEMIR®Therapy 2.3 ConvertingtoLEVEMIR®fromOtherInsulin

Therapies3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS5 WARNINGS AND PRECAUTIONS 5.1 DosageAdjustmentandMonitoring 5.2 Administration 5.3 Hypoglycemia 5.4 HypersensitivityandAllergicReactions 5.5 RenalImpairment 5.6 HepaticImpairment 5.7 DrugInteractions6 ADVERSE REACTIONS 6.1 ClinicalTrialExperience 6.2 PostmarketingExperience7 DRUG INTERACTIONS8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 NursingMothers 8.4 PediatricUse 8.5 GeriatricUse10 OVERDOSAGE11 DESCRIPTION

12 CLINICAL PHARMACOLOGY 12.1 MechanismofAction 12.2 Pharmacodynamics 12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis,Mutagenesis,ImpairmentofFertility14 CLINICAL STUDIES16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 HowSupplied 16.2 Storage 16.3 PreparationandHandling17 PATIENT COUNSELING INFORMATION 17.1 InstructionsforPatients 17.2 NeverShareaLEVEMIR®FlexPen®BetweenPatients*Sectionsorsubsectionsomittedfromthefullprescribinginformationarenotlisted.

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use LEVEMIR® safely and effectively. See full prescribing information for LEVEMIR®.LEVEMIR® (insulin detemir [rDNA origin] injection) solution for subcutaneous injection Initial U.S. Approval: 2005

——— INDICATIONS AND USAGE ———LEVEMIR® is a long-acting human insulin analog indicated toimprove glycemic control in adults and children with diabetesmellitus.(1)ImportantLimitationsofUse:•Notrecommendedfortreatingdiabeticketoacidosis.Use

intravenous,rapid-actingorshort-actinginsulininstead.

——— DOSAGE AND ADMINISTRATION ———•Thestartingdoseshouldbeindividualizedbasedonthetypeof

diabetesandwhetherthepatientisinsulin-naïve(2.1,2.2,2.3)•Administersubcutaneouslyoncedailyorindivideddoses

twicedaily.Oncedailyadministrationshouldbegivenwiththeeveningmealoratbedtime(2.1)

•Rotateinjectionsiteswithinaninjectionarea(abdomen,thigh,ordeltoid)toreducetheriskoflipodystrophy(2.1)

•ConvertingfromotherinsulintherapiesmayrequireadjustmentoftiminganddoseofLEVEMIR®.CloselymonitorglucosesespeciallyuponconvertingtoLEVEMIR®andduringtheinitialweeksthereafter(2.3)

——— DOSAGE FORMS AND STRENGTHS ———Solutionforinjection100Units/mL(U-100)in•3mLLEVEMIR®FlexPen®

•10mLvial(3)

2LEVEMIR® (insulin detemir [rDNA origin] injection)

The frequencies of adverse reactions (excluding hypoglycemia)reported during LEVEMIR® clinical trials in patients with type 1diabetesmellitusandtype2diabetesmellitusarelistedinTables1-4below.SeeTables5and6forthehypoglycemiafindings.IntheLEVEMIR®add-ontoliraglutide+metformintrial,allpatientsreceived liraglutide 1.8 mg + metformin during a 12-week run-inperiod.Duringtherun-inperiod,167patients(17%ofenrolledtotal)withdrew from the trial:76 (46%ofwithdrawals)of thesepatientsdoingsobecauseofgastrointestinaladversereactionsand15(9%of withdrawals) doing so due to other adverse events. Only thosepatientswhocompletedtherun-inperiodwithinadequateglycemiccontrol were randomized to 26 weeks of add-on therapy withLEVEMIR® or continued, unchanged treatmentwith liraglutide1.8mg+metformin.Duringthisrandomized26-weekperiod,diarrheawas theonlyadverse reaction reported in≥5%ofpatients treatedwith liraglutide 1.8 mg + metformin (11.7%) and greater than inpatientstreatedwithliraglutide1.8mgandmetforminalone(6.9%).Intwopooledtrials,atotalof1155adultswithtype1diabeteswereexposed to individualized doses of LEVEMIR® (n=767) or NPH(n=388).ThemeandurationofexposuretoLEVEMIR®was153days,andthetotalexposuretoLEVEMIR®was321patient-years.ThemostcommonadversereactionsaresummarizedinTable1.Table 1: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 16 weeks and 24 weeks duration in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)

LEVEMIR®, % (n = 767)

NPH, % (n = 388)

Upperrespiratorytractinfection 26.1 21.4Headache 22.6 22.7Pharyngitis 9.5 8.0Influenza-likeillness 7.8 7.0AbdominalPain 6.0 2.6

A total of 320 adults with type 1 diabetes were exposed toindividualized doses of LEVEMIR® (n=161) or insulin glargine(n=159).ThemeandurationofexposuretoLEVEMIR®was176days,andthetotalexposuretoLEVEMIR®was78patient-years.ThemostcommonadversereactionsaresummarizedinTable2.Table 2: Adverse reactions (excluding hypoglycemia) in a 26-week trial comparing insulin aspart + LEVEMIR® to insulin aspart + insulin glargine in adults with type 1 diabetes (adverse reactions with incidence ≥ 5%)

LEVEMIR®, % (n = 161)

Glargine, % (n = 159)

Upperrespiratorytractinfection 26.7 32.1Headache 14.3 19.5Backpain 8.1 6.3Influenza-likeillness 6.2 8.2Gastroenteritis 5.6 4.4Bronchitis 5.0 1.9

Intwopooledtrials,atotalof869adultswithtype2diabeteswereexposed to individualized doses of LEVEMIR® (n=432) or NPH(n=437).ThemeandurationofexposuretoLEVEMIR®was157days,andthetotalexposuretoLEVEMIR®was186patient-years.ThemostcommonadversereactionsaresummarizedinTable3.Table 3: Adverse reactions (excluding hypoglycemia) in two pooled clinical trials of 22 weeks and 24 weeks duration in adults with type 2 diabetes (adverse reactions with incidence ≥ 5%)

LEVEMIR®, % (n = 432)

NPH, % (n = 437)

Upperrespiratorytractinfection 12.5 11.2Headache 6.5 5.3

A total of 347 children and adolescents (6-17 years) with type 1diabeteswereexposedtoindividualizeddosesofLEVEMIR®(n=232)orNPH(n=115).ThemeandurationofexposuretoLEVEMIR®was180 days, and the total exposure to LEVEMIR® was 114 patient-years.ThemostcommonadversereactionsaresummarizedinTable4.Table 4: Adverse reactions (excluding hypoglycemia) in one 26-week clinical trial of children and adolescents with type 1 diabetes (adverse reactions with incidence ≥ 5%)

LEVEMIR®, % (n = 232)

NPH, % (n = 115)

Upperrespiratorytractinfection 35.8 42.6Headache 31.0 32.2Pharyngitis 17.2 20.9Gastroenteritis 16.8 11.3Influenza-likeillness 13.8 20.9Abdominalpain 13.4 13.0Pyrexia 10.3 6.1Cough 8.2 4.3Viralinfection 7.3 7.8Nausea 6.5 7.0Rhinitis 6.5 3.5Vomiting 6.5 10.4

As with all insulin preparations, the time course of action forLEVEMIR®mayvaryindifferentindividualsoratdifferenttimesinthesameindividualandisdependentonmanyconditions,includingthelocalbloodsupply,localtemperature,andphysicalactivity.5.2 AdministrationLEVEMIR®shouldonlybeadministeredsubcutaneously.Do not administer LEVEMIR® intravenously or intramuscularly.The intended duration of activity of LEVEMIR® is dependent oninjection into subcutaneous tissue. Intravenous or intramuscularadministrationoftheusualsubcutaneousdosecouldresultinseverehypoglycemia[see Warnings and Precautions (5.3)].DonotuseLEVEMIR®ininsulininfusionpumps.Do not dilute or mix LEVEMIR® with any other insulin orsolution. IfLEVEMIR® isdilutedormixed, thepharmacokineticorpharmacodynamicprofile(e.g.,onsetofaction,timetopeakeffect)ofLEVEMIR®andthemixedinsulinmaybealteredinanunpredictablemanner.5.3 Hypoglycemia Hypoglycemia is the most common adverse reaction of insulintherapy, includingLEVEMIR®. The riskofhypoglycemia increaseswithintensiveglycemiccontrol.When a GLP-1 receptor agonist is used in combination withLEVEMIR®, theLEVEMIR® dosemayneed tobe loweredormoreconservatively titrated to minimize the risk of hypoglycemia [see Adverse Reactions (6.1)].All patients must be educated to recognize and managehypoglycemia.Severehypoglycemiacanleadtounconsciousnessorconvulsionsandmayresultintemporaryorpermanentimpairmentof brain function or death. Severe hypoglycemia requiring theassistance of another person or parenteral glucose infusion, orglucagon administration has been observed in clinical trials withinsulin,includingtrialswithLEVEMIR®.Thetimingofhypoglycemiausuallyreflectsthetime-actionprofileoftheadministeredinsulinformulations.Otherfactorssuchaschangesin food intake (e.g., amountof foodor timingofmeals), exercise,andconcomitantmedicationsmayalsoaltertheriskofhypoglycemia[see Drug Interactions (7)].TheprolongedeffectofsubcutaneousLEVEMIR®maydelayrecoveryfromhypoglycemia.As with all insulins, use caution in patients with hypoglycemiaunawareness and in patients who may be predisposed tohypoglycemia(e.g.,thepediatricpopulationandpatientswhofastorhaveerraticfoodintake).Thepatient’sabilitytoconcentrateandreactmaybeimpairedasaresultofhypoglycemia.Thismaypresentariskinsituationswheretheseabilitiesareespeciallyimportant,suchasdrivingoroperatingothermachinery.Earlywarningsymptomsofhypoglycemiamaybedifferentor lesspronouncedundercertainconditions,suchaslongstandingdiabetes,diabetic neuropathy, use of medications such as beta-blockers,or intensified glycemic control [see Drug Interactions (7)]. Thesesituations may result in severe hypoglycemia (and, possibly, lossofconsciousness)priortothepatient’sawarenessofhypoglycemia.5.4 Hypersensitivity and allergic reactionsSevere, life-threatening,generalizedallergy, includinganaphylaxis,canoccurwithinsulinproducts,includingLEVEMIR®.5.5 Renal ImpairmentNo difference was observed in the pharmacokinetics of insulindetemirbetweennon-diabeticindividualswithrenalimpairmentandhealthyvolunteers.However,somestudieswithhumaninsulinhaveshownincreasedcirculatinginsulinconcentrationsinpatientswithrenalimpairment.Carefulglucosemonitoringanddoseadjustmentsofinsulin,includingLEVEMIR®,maybenecessaryinpatientswithrenalimpairment[see Clinical Pharmacology (12.3)].5.6 Hepatic ImpairmentNon-diabetic individuals with severe hepatic impairment hadlower systemic exposures to insulin detemir compared to healthyvolunteers.However,somestudieswithhumaninsulinhaveshownincreased circulating insulin concentrations in patients with liverimpairment. Careful glucose monitoring and dose adjustments ofinsulin, including LEVEMIR®, may be necessary in patients withhepaticimpairment[see Clinical Pharmacology (12.3)].5.7 Drug interactionsSomemedicationsmayalterinsulinrequirementsandsubsequentlyincrease the risk for hypoglycemia or hyperglycemia [see Drug Interactions (7)].

6 ADVERSE REACTIONSThefollowingadversereactionsarediscussedelsewhere:•Hypoglycemia[see Warnings and Precautions (5.3)]•Hypersensitivityandallergicreactions[see Warnings and

Precautions (5.4)]6.1 Clinical trial experienceBecauseclinicaltrialsareconductedunderwidelyvaryingdesigns,theadverse reactionrates reported inoneclinical trialmaynotbeeasilycomparedtothoseratesreportedinanotherclinicaltrial,andmaynotreflecttheratesactuallyobservedinclinicalpractice.

FULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGELEVEMIR® is indicated to improveglycemiccontrol in adults andchildrenwithdiabetesmellitus.ImportantLimitationsofUse:•LEVEMIR®isnotrecommendedforthetreatmentofdiabetic

ketoacidosis.Intravenousrapid-actingorshort-actinginsulinisthepreferredtreatmentforthiscondition.

2 DOSAGE AND ADMINISTRATION2.1 DosingLEVEMIR® is a recombinant human insulin analog for once- ortwice-dailysubcutaneousadministration.Patients treated with LEVEMIR® once-daily should administer thedosewiththeeveningmealoratbedtime.Patientswhorequiretwice-dailydosingcanadministertheeveningdosewiththeeveningmeal,atbedtime,or12hoursafterthemorningdose.The dose of LEVEMIR® must be individualized based on clinicalresponse. Blood glucose monitoring is essential in all patientsreceivinginsulintherapy.Patientsadjustingtheamountor timingofdosingwithLEVEMIR®should only do so under medical supervision with appropriateglucosemonitoring[see Warnings and Precautions (5.1)].In patients with type 1 diabetes, LEVEMIR® must be used in aregimenwithrapid-actingorshort-actinginsulin.Aswithallinsulins,injectionsitesshouldberotatedwithinthesameregion(abdomen,thigh,ordeltoid)fromoneinjectiontothenexttoreducetheriskoflipodystrophy [see Adverse Reactions (6.1)].LEVEMIR®canbeinjectedsubcutaneouslyinthethigh,abdominalwall,orupperarm.Aswithallinsulins,therateofabsorption,andconsequently theonsetanddurationofaction,maybeaffectedbyexerciseandothervariables,suchasstress,intercurrentillness,orchangesinco-administeredmedicationsormealpatterns.When using LEVEMIR® with a glucagon-like peptide (GLP)-1receptoragonist,administerasseparateinjections.Nevermix.ItisacceptabletoinjectLEVEMIR®andaGLP-1receptoragonistinthesamebodyregionbuttheinjectionsshouldnotbeadjacenttoeachother.2.2 Initiation of LEVEMIR® TherapyTherecommendedstartingdoseofLEVEMIR®inpatientswithtype1diabetesshouldbeapproximatelyone-thirdofthetotaldailyinsulinrequirements.Rapid-actingorshort-acting,pre-mealinsulinshouldbeusedtosatisfytheremainderofthedailyinsulinrequirements.TherecommendedstartingdoseofLEVEMIR®inpatientswithtype2diabetesinadequatelycontrolledonoralantidiabeticmedicationsis10Units(or0.1-0.2Units/kg)givenoncedailyintheeveningordividedintoatwicedailyregimen.TherecommendedstartingdoseofLEVEMIR®inpatientswithtype2diabetesinadequatelycontrolledonaGLP-1receptoragonistis10Unitsgivenoncedailyintheevening.LEVEMIR®dosesshouldsubsequentlybeadjustedbasedonbloodglucose measurements. The dosages of LEVEMIR® should beindividualizedunderthesupervisionofahealthcareprovider.2.3 Converting to LEVEMIR® from other insulin

therapiesIfconvertingfrominsulinglarginetoLEVEMIR®,thechangecanbedoneonaunit-to-unitbasis.IfconvertingfromNPHinsulin,thechangecanbedoneonaunit-to-unitbasis.However,somepatientswithtype2diabetesmayrequiremore LEVEMIR® than NPH insulin, as observed in one trial [see Clinical Studies (14)].As with all insulins, close glucose monitoring is recommendedduring the transitionand in the initialweeks thereafter.Dosesandtimingof concurrent rapid-actingorshort-acting insulinsorotherconcomitantantidiabetictreatmentmayneedtobeadjusted.

3 DOSAGE FORMS AND STRENGTHSLEVEMIR®solutionforinjection100UnitpermLisavailableas:•3mLLEVEMIR®FlexPen®

•10mLvial

4 CONTRAINDICATIONSLEVEMIR® is contraindicated in patients with hypersensitivityto LEVEMIR® or any of its excipients. Reactions have includedanaphylaxis [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)].

5 WARNINGS AND PRECAUTIONS5.1 Dosage adjustment and monitoringGlucose monitoring is essential for all patients receiving insulintherapy.Changestoaninsulinregimenshouldbemadecautiouslyandonlyundermedicalsupervision.Changes in insulin strength, manufacturer, type, or method ofadministrationmayresultintheneedforachangeintheinsulindoseoranadjustmentofconcomitantanti-diabetictreatment.


Systemic AllergySevere, life-threatening,generalizedallergy, includinganaphylaxis,generalized skin reactions, angioedema, bronchospasm, hypoten-sion,andshockmayoccurwithanyinsulin,includingLEVEMIR®,andmaybelife-threatening[see Warnings and Precautions (5.4)].•Antibody ProductionAll insulin products can elicit the formation of insulin antibodies.These insulin antibodies may increase or decrease the efficacy ofinsulinandmayrequireadjustmentoftheinsulindose.Inphase3clinical trials of LEVEMIR®, antibody development has beenobservedwithnoapparentimpactonglycemiccontrol.6.2 Postmarketing experienceThe following adverse reactions have been identified during postapproval use of LEVEMIR®. Because these reactions are reportedvoluntarily from a population of uncertain size, it is not alwayspossible to reliably estimate their frequency or establish a causalrelationshiptodrugexposure.Medication errors have been reported during post-approval useof LEVEMIR® in which other insulins, particularly rapid-acting orshort-acting insulins, have been accidentally administered insteadof LEVEMIR® [see Patient Counseling Information (17)]. To avoidmedication errorsbetweenLEVEMIR® andother insulins, patientsshouldbe instructedalways toverify the insulin labelbeforeeachinjection.

7 DRUG INTERACTIONSAnumberofmedicationsaffectglucosemetabolismandmayrequireinsulindoseadjustmentandparticularlyclosemonitoring.The following are examples of medications that may increase theblood-glucose-lowering effect of insulins including LEVEMIR®and, therefore, increase the susceptibility to hypoglycemia: oralantidiabeticmedications,pramlintideacetate,angiotensinconvertingenzyme (ACE) inhibitors, disopyramide, fibrates, fluoxetine,monoamineoxidase(MAO)inhibitors,propoxyphene,pentoxifylline,salicylates,somatostatinanalogs,andsulfonamideantibiotics.The following are examples of medications that may reduce theblood-glucose-lowering effect of insulins including LEVEMIR®:corticosteroids,niacin,danazol,diuretics,sympathomimeticagents(e.g., epinephrine, albuterol, terbutaline), glucagon, isoniazid,phenothiazinederivatives,somatropin,thyroidhormones,estrogens,progestogens(e.g., inoralcontraceptives),proteaseinhibitorsandatypicalantipsychoticmedications(e.g.olanzapineandclozapine).Beta-blockers, clonidine, lithium salts, and alcohol may eitherincrease or decrease the blood-glucose-lowering effect of insulin.Pentamidine may cause hypoglycemia, which may sometimes befollowedbyhyperglycemia.The signs of hypoglycemia may be reduced or absent in patientstaking anti-adrenergic drugs such as beta-blockers, clonidine,guanethidine,andreserpine.

8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancyCategoryBRiskSummaryThebackgroundriskofbirthdefects,pregnancyloss,orotheradverseevents that exists for all pregnancies is increased in pregnanciescomplicatedbyhyperglycemia.Femalepatientsshouldbeadvisedto tell their physician if they intend to become, or if they becomepregnantwhiletakingLEVEMIR®.ArandomizedcontrolledclinicaltrialofpregnantwomenwithtypeIdiabetesusingLEVEMIR®duringpregnancydidnotshowanincreaseintheriskoffetalabnormalities.Reproductive toxicology studies in non-diabetic rats and rabbitsthat included concurrent human insulin control groups indicatedthatinsulindetemirandhumaninsulinhadsimilareffectsregardingembryotoxicity and teratogenicity that were attributed to maternalhypoglycemia.ClinicalConsiderationsTheincreasedriskofadverseeventsinpregnanciescomplicatedbyhyperglycemiamaybedecreasedwithgoodglucosecontrolbeforeconceptionandthroughoutpregnancy.Becauseinsulinrequirementsvary throughout pregnancy and in thepost-partumperiod, carefulmonitoringofglucosecontrolisessentialinpregnantwomen.HumanDataInan,open-label, clinical study,womenwith type1diabeteswhowere(betweenweeks8and12ofgestation)orintendedtobecomepregnantwere randomized1:1 toLEVEMIR® (onceor twicedaily)or NPH insulin (once, twice or thrice daily). Insulin aspart wasadministeredbeforeeachmeal.Atotalof152womenintheLEVEMIR®armand158womenintheNPHarmwereorbecamepregnantduringthestudy(Totalpregnantwomen=310).Approximatelyonehalfofthestudyparticipantsineacharmwererandomizedaspregnantandwereexposed toNPHor toother insulinsprior toconceptionandin the first 8 weeks of gestation. In the 310 pregnant women, themeanglycosylatedhemoglobin(HbA1c)was<7%at10,12,and24weeksofgestationinbotharms.Intheintent-to-treatpopulation,theadjustedmeanHbA1c (standard error) at gestationalweek36was6.27% (0.053) in LEVEMIR®-treated patient (n=138) and 6.33%(0.052) in NPH-treated patients (n=145); the difference was notclinicallysignificant.

•Peripheral EdemaInsulin, including LEVEMIR®, may cause sodium retention andedema,particularlyifpreviouslypoormetaboliccontrolisimprovedbyintensifiedinsulintherapy.•Allergic ReactionsLocal AllergyAs with any insulin therapy, patients taking LEVEMIR® mayexperience injection site reactions, including localized erythema,pain,pruritus,urticaria,edema,andinflammation.Inclinicalstudiesin adults, three patients treated with LEVEMIR® reported injectionsitepain(0.25%)comparedtoonepatienttreatedwithNPHinsulin(0.12%).The reportsofpain at the injectionsitedidnot result indiscontinuationoftherapy.Rotationoftheinjectionsitewithinagivenareafromoneinjectiontothenextmayhelptoreduceorpreventthesereactions.Insomeinstances, these reactions may be related to factors other thaninsulin,suchasirritantsinaskincleansingagentorpoorinjectiontechnique.Mostminorreactionstoinsulinusuallyresolveinafewdaystoafewweeks.

•Insulin Initiation and Intensification of Glucose ControlIntensification or rapid improvement in glucose control has beenassociated with a transitory, reversible ophthalmologic refractiondisorder, worsening of diabetic retinopathy, and acute painfulperipheral neuropathy. However, long-term glycemic controldecreasestheriskofdiabeticretinopathyandneuropathy.•LipodystrophyLong-term use of insulin, including LEVEMIR®, can causelipodystrophyatthesiteofrepeatedinsulininjections.Lipodystrophyincludes lipohypertrophy (thickening of adipose tissue) andlipoatrophy (thinning of adipose tissue), and may affect insulinabsorption.Rotateinsulininjectionsiteswithinthesameregiontoreduce the risk of lipodystrophy [see Dosage and Administration (2.1)].•Weight GainWeight gain can occur with insulin therapy, including LEVEMIR®,and has been attributed to the anabolic effects of insulin and thedecreaseinglucosuria[see Clinical Studies (14)].

PregnancyA randomized, open-label, controlled clinical trial has been conducted in pregnant women with type 1 diabetes. [see Use in Specific Populations (8.1)]•HypoglycemiaHypoglycemia is the most commonly observed adverse reaction in patients using insulin, including LEVEMIR® [see Warnings and Precautions (5.3)].Tables5and6summarizetheincidenceofsevereandnon-severehypoglycemiaintheLEVEMIR®clinicaltrials.Fortheadulttrialsandoneofthepediatrictrials(StudyD),severehypoglycemiawasdefinedasaneventwithsymptomsconsistentwithhypoglycemiarequiringassistanceofanotherpersonandassociatedwitheitheraplasmaglucosevaluebelow56mg/dL(bloodglucosebelow50mg/dL)orpromptrecoveryafteroralcarbohydrate,intravenousglucoseorglucagonadministration.Fortheotherpediatrictrial(StudyI),severehypoglycemiawasdefinedasaneventwithsemi-consciousness,unconsciousness,comaand/orconvulsionsinapatientwhocouldnotassistinthetreatmentandwhomayhaverequiredglucagonorintravenousglucose.For theadult trials andpediatricStudyD,non-severehypoglycemiawasdefinedasanasymptomaticor symptomaticplasmaglucose<56mg/dL(orequivalentlybloodglucose<50mg/dLasusedinStudyAandC)thatwasself-treatedbythepatient.ForpediatricStudyI,non-severehypoglycemiaincludedasymptomaticeventswithplasmaglucose<65mg/dLaswellassymptomaticeventsthatthepatientcouldself-treatortreatbytakingoraltherapyprovidedbythecaregiver.TheratesofhypoglycemiaintheLEVEMIR®clinicaltrials(seeSection14foradescriptionofthestudydesigns)werecomparablebetweenLEVEMIR®-treatedpatientsandnon-LEVEMIR®-treatedpatients(seeTables5and6).Table 5: Hypoglycemia in Patients with Type 1 Diabetes

SevereHypoglycemia Non-SevereHypoglycemiaPercentofpatientswithatleast1event

(n/totalN) Event/patient/year Percentofpatients(n/totalN) Event/patient/year

StudyAType1Diabetes

Adults16weeks

Incombinationwithinsulinaspart

Twice-DailyLEVEMIR®

8.7(24/276) 0.52 88.0

(243/276) 26.4

Twice-DailyNPH 10.6(14/132) 0.43 89.4

(118/132) 37.5

StudyBType1Diabetes

Adults26weeks


Twice-DailyLEVEMIR®

5.0(8/161) 0.13 82.0

(132/161) 20.2

Once-DailyGlargine 10.1(16/159) 0.31 77.4

(123/159) 21.8

StudyCType1Diabetes

Adults24weeks

Incombinationwithregularinsulin

Once-DailyLEVEMIR®

7.5(37/491) 0.35 88.4

(434/491) 31.1

Once-DailyNPH 10.2(26/256) 0.32 87.9

(225/256) 33.4

StudyDType1Diabetes

Pediatrics26weeks


Once-orTwiceDailyLEVEMIR®

15.9(37/232) 0.91 93.1

(216/232) 31.6

Once-orTwiceDailyNPH

20.0(23/115) 0.99 95.7

(110/115) 37.0

StudyIType1Diabetes

Pediatrics52weeks



1.7(3/177) 0.02 94.9

(168/177) 56.1


7.1(12/170) 0.09 97.6

(166/170) 70.7

Table 6: Hypoglycemia in Patients with Type 2 DiabetesStudyE

Type2DiabetesAdults

24weeksIncombinationwithoralagents

StudyFType2Diabetes

Adults22weeks


StudyHType2Diabetes

Adults26weeks

incombinationwithLiraglutideandMetforminTwice-DailyLEVEMIR®

Twice-DailyNPH



OnceDailyLEVEMIR®+Liraglutide+Metformin

Liraglutide+Metformin

Severehypoglycemia Percentofpatientswithatleast1event(n/totalN)

0.4(1/237)

2.5(6/238)

1.5(3/195)

4.0(8/199) 0 0

Event/patient/year 0.01 0.08 0.04 0.13 0 0Non-severehypoglycemia Percentofpatients

(n/totalN)40.5

(96/237)64.3

(153/238)32.3

(63/195)32.2

(64/199)9.2

(15/163)1.3

(2/158*)Event/patient/year 3.5 6.9 1.6 2.0 0.29 0.03

*Onesubjectisanoutlierandwasexcludeddueto25hypoglycemicepisodesthatthepatientwasabletoself-treat.Thispatienthadahistoryoffrequenthypoglycemiapriortothestudy


12 CLINICAL PHARMACOLOGY12.1 Mechanism of ActionTheprimaryactivityof insulindetemir is theregulationofglucosemetabolism.Insulins,includinginsulindetemir,exerttheirspecificactionthroughbindingtoinsulinreceptors.Receptor-boundinsulinlowersbloodglucosebyfacilitatingcellularuptakeofglucoseintoskeletalmuscleandadipose tissueandby inhibiting theoutputofglucose from the liver. Insulin inhibits lipolysis in the adipocyte,inhibitsproteolysis,andenhancesproteinsynthesis.12.2 PharmacodynamicsInsulindetemirisasoluble,long-actingbasalhumaninsulinanalogwith up to a 24-hour duration of action. The pharmacodynamicprofileofLEVEMIR®isrelativelyconstantwithnopronouncedpeak.ThedurationofactionofLEVEMIR®ismediatedbyslowedsystemicabsorptionofinsulindetemirmoleculesfromtheinjectionsiteduetoself-associationofthedrugmolecules.Inaddition,thedistributionofinsulindetemirtoperipheraltargettissuesisslowedbecauseofbindingtoalbumin.Figure2showsresultsfromastudyinpatientswithtype1diabetesconducted for a maximum of 24 hours after the subcutaneousinjection of LEVEMIR® or NPH insulin. The mean time betweeninjectionand theendofpharmacologicaleffect for insulindetemirrangedfrom7.6hoursto>24hours(24hourswastheendoftheobservationperiod).Figure 2: Activity Profiles in Patients with Type 1 Diabetes in a 24-hour Glucose Clamp Study

0 4 8 12 16 20 24

6.0

4.0

2.0

0.0

Pharmacodynamic Parameters for LEVEMIR® and NPH

AUCGIR (mg/kg)GIRmax (mg/kg/min)

LEVEMIR® NPH0.2 U/kg 0.4 U/kg 0.3 IU/kg

419 1184 7431.1 1.7 1.6

Gluc

ose I

nfusio

n Rate

(mg/k

g/min)

Time Since Insulin Injection (hours)LEVEMIR® 0.2 Units/kg LEVEMIR® 0.4 Units/kgNPH 0.3 International Units/kg

AUCGIR:AreaUnderCurveforGlucoseInfusionRateGIRmax:MaximumGlucoseInfusionRate

For doses in the interval of 0.2 to 0.4 Units/kg, insulin detemirexertsmorethan50%ofitsmaximumeffectfrom3to4hoursuptoapproximately14hoursafterdoseadministration.Figure3showsglucoseinfusionrateresultsfroma16-hourglucoseclampstudyinpatientswithtype2diabetes.Theclampstudywasterminatedat16hoursaccordingtoprotocol.Figure 3: Activity Profiles in Patients with Type 2 Diabetes in a 16-hour Glucose Clamp Study

0 2 4 6 8 10 12 14 16

6.05.55.04.54.03.53.02.52.01.51.00.50.0

Pharmacodynamic Parameters for LEVEMIR® and NPH

AUCGIR (mg/kg)GIRmax (mg/kg/min)

LEVEMIR® NPH0.6 U/kg 1.2 U/kg 0.6 IU/kg 1.2 IU/kg

1359 2333 1900 32202.3 3.7 3.2 4.8

Gluc

ose I

nfusio

n Rate

(mg/k

g/min)

Time since Insulin Injection (hours)

LEVEMIR® 0.6 Units/kg LEVEMIR® 1.2 Units/kgNPH 0.6 International Units/kg NPH 1.2 International Units/kg

AUCGIR:AreaUnderCurveforGlucoseInfusionRateGIRmax:MaximumGlucoseInfusionRate

12.3 PharmacokineticsAbsorption and BioavailabilityAftersubcutaneousinjectionofLEVEMIR® inhealthysubjectsandin patients with diabetes, insulin detemir serum concentrationshad a relatively constant concentration/time profile over 24 hourswith the maximum serum concentration (Cmax) reached between6-8 hours post-dose. Insulin detemir was more slowly absorbed

throughoutpregnancyatdosesup to300nmol/kg/day (3 timesahumandoseof0.5Units/kg/day,basedonplasmaareaunder thecurve (AUC) ratio). Doses of 150 and 300 nmol/kg/day producednumbersof litterswithvisceralanomalies.Dosesupto900nmol/kg/day(approximately135timesahumandoseof0.5Units/kg/daybased on AUC ratio) were given to rabbits during organogenesis.Drug and dose related increases in the incidence of fetuses withgallbladder abnormalities such as small, bilobed, bifurcated,and missing gallbladders were observed at a dose of 900 nmol/kg/day. The rat and rabbit embryofetal development studies thatincluded concurrent human insulin control groups indicated thatinsulin detemir and human insulin had similar effects regardingembryotoxicity and teratogenicity suggesting that the effects seenweretheresultofhypoglycemiaresultingfrominsulinexposureinnormalanimals.8.3 Nursing MothersItisunknownwhetherLEVEMIR®isexcretedinhumanmilk.Becausemanydrugs,includinghumaninsulin,areexcretedinhumanmilk,use caution when administering LEVEMIR® to a nursing woman.Womenwithdiabeteswhoarelactatingmayrequireadjustmentsoftheirinsulindoses.8.4 Pediatric UseThe pharmacokinetics, safety and effectiveness of subcutaneousinjectionsofLEVEMIR®havebeenestablishedinpediatricpatients(age2to17years)withtype1diabetes[see Clinical Pharmacology (12.3) and Clinical Studies (14)].LEVEMIR®hasnotbeenstudiedinpediatricpatientsyoungerthan2yearsofagewithtype1diabetes.LEVEMIR® has not been studied in pediatric patients with type 2diabetes.The dose recommendation when converting to LEVEMIR® is thesameas thatdescribed foradults [see Dosage and Administration (2) and Clinical Studies (14)].Asinadults,thedosageofLEVEMIR®must be individualized in pediatric patients based on metabolicneedsandfrequentmonitoringofbloodglucose.8.5 Geriatric UseIncontrolledclinicaltrialscomparingLEVEMIR®toNPHinsulinorinsulinglargine,64of1624patients(3.9%)inthetype1diabetestrialsand309of1082patients(28.6%)inthetype2diabetestrialswere≥65yearsofage.Atotalof52(7type1and45type2)patients(1.9%) were≥75 years of age. No overall differences in safety oreffectiveness were observed between these patients and youngerpatients,butsmallsamplesizes,particularlyforpatients≥65yearsofageinthetype1diabetestrialsandforpatients≥75yearsofagein all trials limits conclusions. Greater sensitivity of some olderindividualscannotberuledout.Inelderlypatientswithdiabetes,theinitialdosing,doseincrements,andmaintenancedosageshouldbeconservativetoavoidhypoglycemia.Hypoglycemiamaybedifficulttorecognizeintheelderly.

10 OVERDOSAGEAn excess of insulin relative to food intake, energy expenditure,or both may lead to severe and sometimes prolonged and life-threateninghypoglycemia.Mild episodesofhypoglycemiausuallycanbetreatedwithoralglucose.Adjustmentsindrugdosage,mealpatterns,orexercisemaybeneeded.More severe episodes with coma, seizure, or neurologic impair-mentmaybetreatedwithintramuscular/subcutaneousglucagonorconcentrated intravenous glucose. After apparent clinical recoveryfromhypoglycemia,continuedobservationandadditionalcarbohy-drateintakemaybenecessarytoavoidrecurrenceofhypoglycemia[see Warnings and Precautions (5.3)].

11 DESCRIPTIONLEVEMIR® (insulin detemir [rDNA origin] injection) is a sterilesolution of insulin detemir for use as a subcutaneous injection.Insulindetemir isa long-acting(upto24-hourdurationofaction)recombinant human insulin analog. LEVEMIR® is producedby a process that includes expression of recombinant DNA inSaccharomyces cerevisiaefollowedbychemicalmodification.Insulin detemir differs from human insulin in that the amino acidthreonine in position B30 has been omitted, and a C14 fatty acidchainhasbeenattachedtotheaminoacidB29.InsulindetemirhasamolecularformulaofC267H402O76N64S6andamolecularweightof5916.9.Ithasthefollowingstructure:Figure 1: Structural Formula of insulin detemir

LEVEMIR® is a clear, colorless, aqueous, neutral sterile solution.Each milliliter of LEVEMIR® contains 100 units (14.2 mg/mL)insulindetemir,65.4mcgzinc,2.06mgm-cresol,16.0mgglycerol,1.80mgphenol,0.89mgdisodiumphosphatedihydrate,1.17mgsodiumchloride,andwater for injection.Hydrochloricacidand/orsodiumhydroxidemaybeaddedtoadjustpH.LEVEMIR®hasapHofapproximately7.4.

Adversereactionsinpregnantpatientsoccurringatanincidenceof≥5%areshowninTable7.Thetwomostcommonadversereactionswere nasopharyngitis and headache. These are consistent withfindingsfromothertype1diabetestrials(seeTable1,Section6.1.),andarenotrepeatedinTable7.The incidence of adverse reactions of pre-eclampsia was 10.5%(16 cases) and 7.0% (11 cases) in the LEVEMIR® and NPHinsulin groups respectively. Out of the total number of cases ofpre-eclampsia,eight(8)casesintheLEVEMIR®groupand1casein the NPH insulin group required hospitalization. The rates ofpre-eclampsia observed in the study are within expected rates forpregnancy complicated by diabetes. Pre-eclampsia is a syndromedefinedby symptoms,hypertensionandproteinuria; thedefinitionofpre-eclampsiawasnotstandardizedinthetrialmakingitdifficulttoestablishalinkbetweenagiventreatmentandanincreasedriskofpre-eclampsia.Alleventswereconsideredunlikelyrelatedtotrialtreatment.Inallnine(9)casesrequiringhospitalizationthewomenhadhealthyinfants.Eventsofhypertension,proteinuriaandedemawere reported less frequently in the LEVEMIR® group than in theNPHinsulingroupasawhole.Therewasnodifferencebetweenthetreatment groups in mean blood pressure during pregnancy andtherewasnoindicationofageneralincreaseinbloodpressure.IntheNPHinsulingrouptherewere6seriousadversereactionsinfourmothersofthefollowingplacentaldisorders,‘Placentaprevia’,‘Placentapreviahemorrhage’,and‘Prematureseparationofplacenta’and1seriousadversereactionof‘Antepartumhaemorrhage’.TherewerenonereportedintheLEVEMIR®group.The incidence of early fetal death (abortions) was similar inLEVEMIR®andNPHtreatedpatients;6.6%and5.1%,respectively.The abortions were reported under the following terms: ‘Abortionspontaneous’, ‘Abortion missed’, ‘Blighted ovum’, ‘Cervicalincompetence’and‘Abortionincomplete’.Table 7: Adverse reactions during pregnancy in a trial comparing insulin aspart + LEVEMIR® to insulin aspart + NPH insulin in pregnant women with type 1 diabetes (adverse reactions with incidence ≥ 5%)*

LEVEMIR, % (n = 152)

NPH, % (n = 158)

Anemia 13.2 10.8Diarrhea 11.8 5.1Pre-eclampsia 10.5 7.0Urinarytractinfection 9.9 5.7Gastroenteritis 8.6 5.1Abdominalpainupper 5.9 3.8Vomiting 5.3 4.4Abortionspontaneous 5.3 2.5Abdominalpain 5.3 6.3Oropharyngealpain 5.3 6.3

*Becauseclinicaltrialsareconductedunderwidelyvaryingdesigns,theadversereactionratesreportedinoneclinicaltrialmaynotbeeasilycomparedtothoseratesreportedinanotherclinicaltrial,andmaynotreflecttheratesactuallyobservedinclinicalpractice.

The proportion of subjects experiencing severe hypoglycemiawas 16.4% and 20.9% in LEVEMIR® and NPH treated patientsrespectively. The rate of severe hypoglycemia was 1.1 and 1.2events per patient-year in LEVEMIR® and NPH treated patientsrespectively.Proportionandincidenceratesfornon-severeepisodesofhypoglycemiaweresimilarinbothtreatmentgroups(Table8).Table 8: Hypoglycemia in Pregnant Women with Type 1 Diabetes

StudyGType1Diabetes

PregnancyIncombinationwithinsulinaspartLEVEMIR® NPH

Severehypoglycemia*

Percentofpatientswithatleast1event(n/totalN)

16.4(25/152)

20.9(33/158)

Events/patient/year 1.1 1.2

Non-severehypoglycemia*

Percentofpatientswithatleast1event(n/totalN)

94.7(144/152)

92.4(146/158)

Events/patient/year 114.2 108.4*Fordefinitionregardingsevereandnon-severehypoglycemiaseesection6,Hypoglycemia.

In about a quarter of infants, LEVEMIR® was detected in theinfant cord blood at levels above the lower level of quantification(<25pmol/L).NodifferencesinpregnancyoutcomesorthehealthofthefetusandnewbornwereseenwithLEVEMIR®use.AnimalDataIn a fertility and embryonic development study, insulin detemirwasadministeredtofemaleratsbeforemating,duringmating,and


aftersubcutaneousadministrationtothethighwhereAUC0-5hwas30-40%lowerandAUC0-infwas10%lowerthanthecorrespondingAUCs with subcutaneous injections to the deltoid and abdominalregions.Theabsolutebioavailabilityofinsulindetemirisapproximately60%.Distribution and EliminationMore than98%of insulindetemir in thebloodstreamisbound toalbumin.Theresultsofin vitroandin vivoproteinbindingstudiesdemonstrate that there isnoclinically relevant interactionbetweeninsulindetemirandfattyacidsorotherprotein-bounddrugs.Insulin detemir has an apparent volume of distribution ofapproximately 0.1 L/kg. After subcutaneous administration inpatientswithtype1diabetes,insulindetemirhasaterminalhalf-lifeof5to7hoursdependingondose.Specific PopulationsChildren and Adolescents -ThepharmacokineticpropertiesofLEVEMIR®were investigated inchildren(6-12years),adolescents(13-17 years), and adults with type 1 diabetes. In children, theinsulindetemirplasmaareaunderthecurve(AUC)andCmaxwereincreased by 10% and 24%, respectively, as compared to adults.There was no difference in pharmacokinetics between adolescentsandadults.Geriatrics - In a clinical trial investigating differences inpharmacokinetics of a single subcutaneous dose of LEVEMIR®in young (20 to 35 years) versus elderly (≥68 years) healthysubjects, the insulin detemir AUC was up to 35% higher amongtheelderlysubjectsduetoreducedclearance.Aswithotherinsulinpreparations, LEVEMIR® should always be titrated according toindividualrequirements.Gender - No clinically relevant differences in pharmacokineticparametersofLEVEMIR®areobservedbetweenmalesandfemales.Race - In two clinical pharmacology studies conducted inhealthyJapaneseandCaucasiansubjects, therewerenoclinicallyrelevant differences seen in pharmacokinetic parameters. Thepharmacokinetics and pharmacodynamics of LEVEMIR® wereinvestigated in a clamp study comparing patients with type 2diabetesofCaucasian,African-American,andLatinoorigin.Dose-response relationships for LEVEMIR® were comparable in thesethreepopulations.Renal impairment-Asinglesubcutaneousdoseof0.2Units/kg(1.2 nmol/kg) of LEVEMIR® was administered to healthy subjectsandthosewithvaryingdegreesofrenalimpairment(mild,moderate,severe, andhemodialysis-dependent). In this study, therewerenodifferences in thepharmacokineticsofLEVEMIR®betweenhealthysubjects and those with renal impairment. However, some studieswith human insulin have shown increased circulating levels ofinsulininpatientswithrenalimpairment.Carefulglucosemonitoringand dose adjustments of insulin, including LEVEMIR®, may benecessary in patients with renal impairment [see Warnings and Precautions (5.5)].Hepatic impairment - A single subcutaneous dose of 0.2Units/kg (1.2nmol/kg) of LEVEMIR®was administered tohealthysubjects and those with varying degrees of hepatic impairment(mild, moderate and severe). LEVEMIR® exposure as estimatedby AUC decreased with increasing degrees of hepatic impairmentwith a corresponding increase in apparent clearance. However,somestudieswithhumaninsulinhaveshownincreasedcirculatinglevelsof insulin inpatientswith liver impairment.Carefulglucosemonitoringanddoseadjustmentsofinsulin,includingLEVEMIR®,maybenecessaryinpatientswithhepaticimpairment[see Warnings and Precautions (5.6)].Pregnancy-TheeffectofpregnancyonthepharmacokineticsandpharmacodynamicsofLEVEMIR®hasnotbeenstudied[see Use in Specific Populations (8.1)].Smoking - The effect of smoking on the pharmacokinetics andpharmacodynamicsofLEVEMIR®hasnotbeenstudied.Liraglutide-NopharmacokineticinteractionwasobservedbetweenliraglutideandLEVEMIR®whenseparatesubcutaneousinjectionsofLEVEMIR®0.5Unit/kg(single-dose)andliraglutide1.8mg(steadystate)wereadministeredinpatientswithtype2diabetes.

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenicity, Mutagenicity, Impairment of

FertilityStandard 2-year carcinogenicity studies in animals have not beenperformed. Insulin detemir tested negative for genotoxic potentialinthein vitroreversemutationstudyinbacteria,humanperipheralblood lymphocyte chromosome aberration test, and the in vivo mousemicronucleustest.In a fertility and embryonic development study, insulin detemirwasadministeredtofemaleratsbeforemating,duringmating,andthroughoutpregnancyatdosesup to300nmol/kg/day (3 timesahumandoseof0.5Units/kg/day,basedonplasmaAUCratio).Therewerenoeffectsonfertilityintherat.

14 CLINICAL STUDIESThe efficacy and safety of LEVEMIR® given once-daily at bedtimeortwice-daily(beforebreakfastandatbedtime,beforebreakfastand

withtheeveningmeal,orat12-hourintervals)wascomparedtothatofonce-dailyortwice-dailyNPHinsulininopen-label,randomized,parallel studiesof1155adultswith type1diabetesmellitus,347pediatricpatientswith type1diabetesmellitus, and869adultswithtype2diabetesmellitus.TheefficacyandsafetyofLEVEMIR®giventwice-dailywascomparedtoonce-dailyinsulinglargineinanopen-label,randomized,parallelstudyof320patientswithtype1diabetes.TheeveningLEVEMIR®dosewastitratedinalltrialsaccordingtopre-definedtargetsforfastingbloodglucose.Thepre-dinnerbloodglucosewasusedtotitratethemorningLEVEMIR®doseinthosetrialsthatalsoadministeredLEVEMIR®inthemorning.Ingeneral,thereductioninglycosylatedhemoglobin(HbA1c)withLEVEMIR®wassimilartothatwithNPHinsulinorinsulinglargine.Type 1 Diabetes – AdultIna16-weekopen-labelclinicalstudy(StudyA,n=409),adultswithtype1diabeteswererandomizedtotreatmentwitheitherLEVEMIR®at12-hourintervals,LEVEMIR®administeredinthemorningandbedtimeorNPHinsulinadministeredinthemorningandbedtime.Insulinaspartwasalsoadministeredbeforeeachmeal.At16weeksoftreatment,thecombinedLEVEMIR®-treatedpatientshadsimilarHbA1candfastingplasmaglucose(FPG)reductionscomparedtotheNPH-treatedpatients(Table9).DifferencesintimingofLEVEMIR®administrationhadnoeffectonHbA1c,fastingplasmaglucose(FPG),orbodyweight.Ina26-week,open-labelclinicalstudy(StudyB,n=320),adultswithtype1diabeteswererandomizedtotwice-dailyLEVEMIR®(administeredinthemorningandbedtime)oronce-dailyinsulinglargine(administeredatbedtime).Insulinaspartwasadministeredbeforeeachmeal.LEVEMIR®-treatedpatientshadadecreaseinHbA1csimilartothatofinsulinglargine-treatedpatients.Ina24-week,open-labelclinicalstudy(StudyC,n=749),adultswithtype1diabeteswererandomizedtoonce-dailyLEVEMIR®oronce-dailyNPHinsulin,bothadministeredatbedtimeandincombinationwithregularhumaninsulinbeforeeachmeal.LEVEMIR®andNPHinsulinhadasimilareffectonHbA1c.Table 9: Type 1 Diabetes Mellitus – Adult

StudyA StudyB StudyCTreatmentduration 16weeks 26weeks 24weeksTreatmentincombinationwith NovoLog®(insulinaspart) NovoLog®(insulinaspart) HumanSolubleInsulin(regularinsulin)

Twice-dailyLEVEMIR®

Twice-dailyNPH


Once-dailyinsulinglargine Once-dailyLEVEMIR® Once-daily

NPHNumberofpatientstreated 276 133 161 159 492 257HbA1c(%) BaselineHbA1c 8.6 8.5 8.9 8.8 8.4 8.3 Adj.meanchangefrombaseline -0.8* -0.7* -0.6** -0.5** -0.1* 0.0* LEVEMIR®–NPH 95%CIforTreatmentdifference

-0.2(-0.3,-0.0)

-0.0(-0.2,0.2)

-0.1(-0.3,0.0)

Basalinsulindose(units/day) Baselinemean 21 24 27 23 12 24 Meanchangefrombaseline 16 10 10 4 9 2Totalinsulindose(units/day) Baselinemean 48 54 56 51 46 57 Meanchangefrombaseline 17 10 9 6 11 3Fastingbloodglucose(mg/dL) Baselinemean 209 220 153 150 213 206 Adj.meanchangefrombaseline -44* -9* -38** -41** -30* -9*Bodyweight(kg) Baselinemean 74.6 75.5 77.5 75.1 76.5 76.9 Adj.meanchangefrombaseline 0.2* 0.8* 0.5** 1.0** -0.3* 0.3**FromanANCOVAmodeladjustedforbaselinevalueandcountry.**FromanANCOVAmodeladjustedforbaselinevalueandstudysite.

Type 1 Diabetes – PediatricTwoopen-label,randomized,controlledclinicalstudieshavebeenconductedinpediatricpatientswithtype1diabetes.Onestudywas26weeksindurationandenrolledpatients6-17yearsofage.Theotherstudywas52weeksindurationandenrolledpatients2-16yearsofage.Inbothstudies,LEVEMIR®andNPHinsulinwereadministeredonce-ortwice-daily.Bolusinsulinaspartwasadministeredbeforeeachmeal.Inthe26-weekstudy,LEVEMIR®-treatedpatientshadameandecreaseinHbA1csimilartothatofNPHinsulin(Table10).Inthe52-weekstudy,therandomizationwasstratifiedbyage(2-5years,n=82,and6-16years,n=265)andthemeanHbA1cincreasedinbothtreatmentarms,withsimilarfindingsinthe2-5year-oldagegroup(n=80)andthe6-16year-oldagegroup(n=258)(Table10).Table 10: Type 1 Diabetes Mellitus – Pediatric

StudyD StudyITreatmentduration 26weeks 52weeksTreatmentincombinationwith NovoLog®(insulinaspart) NovoLog®(insulinaspart)

Once-orTwiceDailyLEVEMIR® Once-orTwiceDailyNPH Once-orTwiceDailyLEVEMIR® Once-orTwiceDailyNPHNumberofsubjectstreated 232 115 177 170HbA1c(%) BaselineHbA1c 8.8 8.8 8.4 8.4 Adj.meanchangefrombaseline -0.7* -0.8* 0.3** 0.2** LEVEMIR®–NPH 95%CIforTreatmentdifference

0.1-0.1;0.3

0.1-0.1;0.4

Basalinsulindose(units/day) Baselinemean 24 26 17 17 Meanchangefrombaseline 8 6 8 7Totalinsulindose(units/day) Baselinemean 48 50 35 34 Meanchangefrombaseline 9 7 10 8Fastingbloodglucose(mg/dL) Baselinemean 181 181 135 141 Adj.meanchangefrombaseline -39 -21 -10** 0**Bodyweight(kg) Baselinemean 46.3 46.2 37.4 36.5 Adj.meanchangefrombaseline 1.6* 2.7* 2.7** 3.6***FromanANCOVAmodeladjustedforbaselinevalue,geographicalregion,genderandage(covariate).**FromanANCOVAmodeladjustedforbaselinevalue,country,pubertalstatusatbaselineandage(stratificationfactor).


Table 12: Results of a 26-week open-label trial of LEVEMIR® as add on to liraglutide + metformin compared to continued treatment with liraglutide + metformin alone in patients not achieving HbA1c < 7% after 12 weeks of Metformin and Liraglutide

StudyHLEVEMIR®+Liraglutide+Metformin

Liraglutide+Metformin

Intent-to-Treat Population (N)a 162 157HbA1c (%) (Mean) Baseline(week0) 7.6 7.6 Adjustedmeanchangefrombaseline -0.5* 0* Differencefromliraglutide+metformin

arm(LSmean)b

95%ConfidenceInterval

-0.5***

(-0.7,-0.4)PercentageofpatientsachievingA1c<7% 43** 17**Fasting Plasma Glucose (mg/dL) (Mean) Baseline(week0) 166 159 Adjustedmeanchangefrombaseline -38* -7* Differencefromliraglutide+metformin

arm(LSmean)b

95%ConfidenceInterval

-31***

(-39,-23)aIntent-to-treatpopulationusinglastobservationonstudybLeastsquaresmeanadjustedforbaselinevalue*FromanANCOVAmodeladjustedforbaselinevalue,countryandpreviousoralantidiabetictreatmentcategory.

**FromalogisticregressionmodeladjustedforbaselineHbA1c.***p-value<0.0001

PregnancyA randomized, open-label, controlled clinical trial has beenconducted in pregnant women with type 1 diabetes. [see Use in Specific Populations (8.1)]

16 HOW SUPPLIED/STORAGE AND HANDLING16.1 How SuppliedLEVEMIR® is available in the following package sizes: eachpresentationcontaining100UnitsofinsulindetemirpermL(U-100).3mLLEVEMIR®FlexPen® NDC0169-6439-1010mLvial NDC0169-3687-12FlexPen® is for use with NovoFine® disposable needles. EachFlexPen®isforusebyasinglepatient.LEVEMIR®FlexPen®shouldneverbesharedbetweenpatients,eveniftheneedleischanged.16.2 Storage: Unused(unopened)LEVEMIR®shouldbestoredintherefrigeratorbetween2°and8°C (36° to46°F).Donot store in the freezerordirectlyadjacent to therefrigeratorcoolingelement.Donot freeze.DonotuseLEVEMIR®ifithasbeenfrozen.Unused (unopened) LEVEMIR® can be kept until the expirationdateprintedonthelabelifitisstoredinarefrigerator.KeepunusedLEVEMIR® in the carton so that it stays clean andprotected fromlight.If refrigeration isnotpossible,unused(unopened)LEVEMIR®canbekeptunrefrigeratedat roomtemperature,below30°C(86°F)aslongasitiskeptascoolaspossibleandawayfromdirectheatandlight.UnrefrigeratedLEVEMIR®shouldbediscarded42daysafteritisfirstkeptoutoftherefrigerator,evenif theFlexPen®orvialstillcontainsinsulin.Vials:After initialuse,vialsshouldbestored inarefrigerator,never inafreezer. If refrigeration is not possible, the in-use vial canbe keptunrefrigeratedatroomtemperature,below30°C(86°F)as longasit iskeptascoolaspossibleandaway fromdirectheatand light.Refrigerated LEVEMIR® vials should be discarded 42 days afterinitialuse.UnrefrigeratedLEVEMIR®vialsshouldbediscarded42daysaftertheyarefirstkeptoutoftherefrigerator.LEVEMIR® FlexPen®:Afterinitialuse,theLEVEMIR®FlexPen®mustNOTbestoredinarefrigeratorandmustNOTbestoredwiththeneedleinplace.Keepthe opened (in use) LEVEMIR® FlexPen® away from direct heatand light at room temperature, below30°C (86°F).UnrefrigeratedLEVEMIR®FlexPensshouldbediscarded42daysaftertheyarefirstkeptoutoftherefrigerator.ThestorageconditionsaresummarizedinTable13:

Type 2 Diabetes – AdultIn a 24-week, open-label, randomized, clinical study (Study E,n=476), LEVEMIR® administered twice-daily (before breakfastand evening) was compared to NPH insulin administered twice-daily (beforebreakfastandevening)aspartofa regimenofstablecombinationtherapywithoneortwoofthefollowingoralantidiabeticmedications: metformin, an insulin secretagogue, or an alpha–glucosidase inhibitor.Allpatientswere insulin-naïveat the timeofrandomization.LEVEMIR®andNPHinsulinsimilarlyloweredHbA1cfrombaseline(Table11).In a 22-week, open-label, randomized, clinical study (Study F,n=395)inadultswithtype2diabetes,LEVEMIR®andNPHinsulinwere given once- or twice-daily as part of a basal-bolus regimenwithinsulinaspart.AsmeasuredbyHbA1corFPG,LEVEMIR®hadefficacysimilartothatofNPHinsulin.

Table 11: Type 2 Diabetes Mellitus – AdultStudyE StudyF

Treatmentduration 24weeks 22weeksTreatmentincombinationwith oralagents insulinaspart


Twice-dailyNPH


Once-orTwiceDaily

NPHNumberofsubjectstreated 237 239 195 200HbA1c(%) BaselineHbA1c 8.6 8.5 8.2 8.1 Adj.meanchangefrombaseline -2.0* -2.1* -0.6** -0.6** LEVEMIR®–NPH 95%CIforTreatmentdifference

0.1(-0.0,0.3)

-0.1(-0.2,0.1)

Basalinsulindose(units/day) Baselinemean 18 17 22 22 Meanchangefrombaseline 48 28 26 15Totalinsulindose1(units/day) Baselinemean - - 22 22 Meanchangefrombaseline - - 57 42Fastingbloodglucose2(mg/dL) Baselinemean 179 173 - - Adj.meanchangefrombaseline -69* -74* - -Bodyweight(kg) Baselinemean 82.5 82.3 82.0 79.6 Adj.meanchangefrombaseline 1.2* 2.8* 0.5** 1.2**

1StudyE–Conductedininsulin-naïvepatients2StudyF-Fastingbloodglucosedatanotcollected*FromanANCOVAmodeladjustedforbaselinevalue,countryandoralantidiabetictreatmentcategory.

**FromanANCOVAmodeladjustedforbaselinevalueandcountry.

Combination Therapy with Metformin and LiraglutideThis26-weekopen-labeltrialenrolled988patientswithinadequateglycemic control (HbA1c 7-10%) on metformin (≥1500 mg/day)aloneorinadequateglycemiccontrol(HbA1c7-8.5%)onmetformin(≥1500mg/day)andasulfonylurea.Patientswhowereonmetforminand a sulfonylurea discontinued the sulfonylurea then all patientsentereda12-weekrun-inperiodduringwhichtheyreceivedadd-ontherapywith liraglutidetitratedto1.8mgonce-daily.At theendofthe run-in period, 498 patients (50%) achieved HbA1c <7% withliraglutide 1.8 mg and metformin and continued treatment in anon-randomized, observational arm. Another 167 patients (17%)withdrewfromthetrialduringtherun-inperiodwithapproximatelyone-halfofthesepatientsdoingsobecauseofgastrointestinaladversereactions[see Adverse Reactions (6.1)].Theremaining323patientswithHbA1c≥7%(33%ofthosewhoenteredtherun-inperiod)wererandomized to26weeksofonce-dailyLEVEMIR® administered intheeveningasadd-ontherapy(N=162)ortocontinued,unchangedtreatment with liraglutide 1.8 mg and metformin (N=161). Thestarting dose of LEVEMIR® was 10 units/day and the mean doseat the end of the 26-week randomized period was 39 units/day.Duringthe26-weekrandomizedtreatmentperiod,thepercentageofpatientswhodiscontinuedduetoineffectivetherapywas11.2%inthegrouprandomizedtocontinuedtreatmentwithliraglutide1.8mgandmetforminand1.2%inthegrouprandomizedtoadd-ontherapywithLEVEMIR®.TreatmentwithLEVEMIR®asadd-ontoliraglutide1.8mg+metforminresulted in statistically significant reductions in HbA1c and FPGcomparedtocontinued,unchangedtreatmentwithliraglutide1.8mg+metforminalone (Table12).Fromameanbaselinebodyweightof96kgafterrandomization,therewasameanreductionof0.3kgin thepatientswho receivedLEVEMIR® add-on therapycomparedto a mean reduction of 1.1 kg in the patients who continued onunchangedtreatmentwithliraglutide1.8mg+metforminalone.

Novo Nordisk®, Levemir®, NovoLog®, FlexPen®, and NovoFine® areregisteredtrademarksofNovoNordiskA/S.LEVEMIR®iscoveredbyUSPatentNos.5,750,497,5,866,538,6,011,007,6,869,930andotherpatentspending.FlexPen®iscoveredbyUSPatentNos.6,582,404,6,004,297,6,235,400andotherpatentspending.Manufacturedby:NovoNordiskA/SDK-2880Bagsvaerd,DenmarkForinformationaboutLEVEMIR®contact:NovoNordiskInc.100CollegeRoadWestPrinceton,NJ085401-800-727-6500www.novonordisk-us.com©2005-2012NovoNordisk0512-00009441-16/12

Table 13: Storage Conditions for LEVEMIR® FlexPen® and vial

Not in-use (unopened) Refrigerated

Not in-use (unopened)

Room Temperature (below 30°C)

In-use (opened)

3mLLEVEMIR®FlexPen®

Untilexpirationdate 42days*

42days*RoomTemperature

(below30°C)(Do not refrigerate)

10mLvial Untilexpirationdate 42days*

42days*Refrigeratedor

RoomTemperature(below30°C)

*Thetotaltimeallowedatroomtemperature(below30°C)is42daysregardlessofwhethertheproductisin-useornotin-use.

16.3 Preparation and handlingParenteraldrugproductsshouldbeinspectedvisuallyforparticulatematteranddiscolorationpriortoadministration,wheneversolutionandcontainerpermit.LEVEMIR®shouldbeinspectedvisuallypriorto administrationandshouldonlybeused if thesolutionappearsclearandcolorless.Mixinganddiluting:LEVEMIR®mustNOTbemixedordilutedwithanyotherinsulinorsolution[See Warnings and Precautions (5.2)].

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling (Patient Information andInstructionsforUse)17.1 Instructions for PatientsPatientsshouldbeinformedthatchangestoinsulinregimensmustbe made cautiously and only under medical supervision. Patientsshouldbeinformedaboutthepotentialsideeffectsofinsulintherapy,includinghypoglycemia,weightgain, lipodystrophy (and theneedto rotate injectionsiteswithin thesamebody region),andallergicreactions.Patientsshouldbeinformedthattheabilitytoconcentrateand reactmaybe impairedasa resultofhypoglycemia.Thismaypresent a risk in situations where these abilities are especiallyimportant, such as driving or operating other machinery. Patientswhohavefrequenthypoglycemiaorreducedorabsentwarningsignsofhypoglycemiashouldbeadvisedtousecautionwhendrivingoroperatingmachinery.Accidental mix-ups between LEVEMIR® and other insulins,particularly short-acting insulins, have been reported. To avoidmedication errorsbetweenLEVEMIR® andother insulins, patientsshouldbe instructed toalwayscheck the insulin labelbeforeeachinjection.LEVEMIR®mustonlybeusedifthesolutionisclearandcolorlesswithnoparticlesvisible.Patientsmustbeadvised thatLEVEMIR®mustNOTbedilutedormixedwithanyotherinsulinorsolution.Patients should be instructed on self-management proceduresincluding glucose monitoring, proper injection technique, andmanagementofhypoglycemiaandhyperglycemia.Patients shouldbeinstructedonhandlingofspecialsituationssuchasintercurrentconditions(illness,stress,oremotionaldisturbances),aninadequateorskippedinsulindose,inadvertentadministrationofanincreasedinsulindose,inadequatefoodintake,andskippedmeals.Patientswithdiabetesshouldbeadvisedtoinformtheirhealthcareprofessional if they are pregnant or are contemplating pregnancy.ReferpatientstotheLEVEMIR®“PatientInformation”foradditionalinformation.17.2 Never Share a LEVEMIR® FlexPen® Between

PatientsCounselpatientsthattheyshouldnevershareaLEVEMIR®FlexPen®withanotherperson,even if theneedle ischanged.Sharingof theFlexPen® between patients may pose a risk of transmission ofinfection.


Itisimportanttotreatlowbloodsugar(hypoglycemia)rightawaybecauseitcouldgetworseandyoucouldpassout(loseconsciousness).

If you pass out you will need help from another person or emergency medical services right away. See “What are the possible side effects of LEVEMIR®?” for more information on low blood sugar (hypoglycemia).

• If you forget to take your dose of LEVEMIR®, your blood sugar may go too high (hyperglycemia).Ifhighbloodsugar(hyperglycemia)isnottreateditcanleadtoseriousproblems,likelossofconsciousness(passingout),comaorevendeath.

Followyourhealthcareprovider’sinstructionsfortreatinghighbloodsugar.

Knowyoursymptomsofhighbloodsugar,whichmayinclude:•increasedthirst•frequenturination•drowsiness•lossofappetite•ahardtimebreathing

•fruitysmellonthebreath•highamountsofsugarand

ketonesinyoururine•nausea,vomiting(throwing

up)orstomachpain•Donotshareneedles,insulinpensorsyringeswithothers.•Check your blood sugar levels.Askyourhealthcare

providerwhatyourbloodsugarsshouldbeandwhenyoushouldcheckyourbloodsugarlevels.

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

•changeindiet•changeinphysicalactivity

orexercise

What should I avoid while taking LEVEMIR®?• Alcohol. Drinkingalcoholmayaffectyourbloodsugarwhen

youuseLEVEMIR®.•Driving and operating machinery.Youmayhavetrouble

payingattentionorreactingifyouhavelowbloodsugar(hypoglycemia).Becarefulwhenyoudriveacaroroperatemachinery.Askyourhealthcareproviderifitisalrightforyoutodriveifyouoftenhave:

•lowbloodsugar(hypoglycemia)•decreasedornowarningsignsoflowbloodsugar

What are the possible side effects of LEVEMIR®?LEVEMIR® can cause serious side effects, including:•Low blood sugar (hypoglycemia).Signsandsymptomsof

lowbloodsugarmayinclude:•dizzinessor

lightheadedness•shakiness•hunger•fastheartbeat•tinglinginyourhands,

feet,lipsortongue

•troubleconcentratingorconfusion

•blurredvision•slurredspeech•anxietyormoodchanges•headache•sweating

Verylowbloodsugar(hypoglycemia)cancauselossofconsciousness(passingout),seizures,anddeath.Insomepeopletheirbloodsugarmaygetsolowthattheyneedanotherpersontohelpthem.TalktoyourhealthcareproviderabouthowtotellifyouhavelowbloodsugarandwhattodoifthishappenswhiletakingLEVEMIR®.Knowyoursymptomsoflowbloodsugar.Followyourhealthcareprovider’sinstructionsfortreatinglowbloodsugar.IfyouareusingLEVEMIR®withanotherdiabetesmedicine,yourLEVEMIR®dosemayneedtobechangedtoreduceyourchanceofgettinglowbloodsugar.Talktoyourhealthcareprovideriflowbloodsugarisaproblemforyou.YourdoseofLEVEMIR®mayneedtobechanged.•Skin thickening or pits at the injection site

(lipodystrophy).Change(rotate)theareawhereyouinjectyourinsulintohelppreventtheseskinchangesfromhappening.Donotinjectinsulinintoareasofskinthathavethickeningorpits.

•Serious allergic reactions. LEVEMIR® can cause life threatening symptoms.Getmedicalhelprightawayifyouhaveanyofthesesymptomsofanallergicreaction:

•arashalloveryourbody•itching•shortnessofbreath•troublebreathing(wheezing)

•fastheartbeat•sweating•feelfaint

Common side effects of LEVEMIR® include:•Low blood sugar (hypoglycemia). See “What are

the possible side effects of LEVEMIR®?” for more information on low blood sugar (hypoglycemia).

•Reactions at the injection site (local allergic reaction).Youmaygetredness,swelling,anditchingattheinjectionsite.Ifyoukeephavingskinreactionsortheyareserious,talktoyourhealthcareprovider.

•Weight gain.Thiscanoccurwithanyinsulintherapy.TalktoyourhealthcareproviderabouthowLEVEMIR®canaffectyourweight.

Tellyourhealthcareproviderifyouhaveanysideeffectthatbothersyouordoesnotgoaway.ThesearenotallofthepossiblesideeffectsfromLEVEMIR®.Askyourhealthcareproviderorpharmacistformoreinformation.Callyourdoctorformedicaladviceaboutsideeffects.YoumayreportsideeffectstoFDAat1-800-FDA-1088.

How should I store LEVEMIR®?Unopened LEVEMIR®:•KeepallunopenedLEVEMIR® in the refrigerator

between 36°F to 46°F (2°C to 8°C).•UnopenedLEVEMIR®canbekeptuntiltheexpirationdateonthe

labelifthemedicinehasbeenstoredinarefrigerator.•Ifrefrigerationisnotpossible,youcankeeptheunopened

LEVEMIR®atroomtemperaturebelow86°F(30°C).•ThrowawayLEVEMIR®42daysafteritisfirstkeptoutofthe

refrigerator.•Donotfreeze.DonotuseLEVEMIR®ifithasbeenfrozen.•KeepunopenedLEVEMIR®inthecartontoprotectitfromlight.LEVEMIR® in use:• Vials

•KeepopenedvialsofLEVEMIR®intherefrigeratororatroomtemperaturebelow86°F(30°C)awayfromdirectheatorlight.

•Throwawayavialthathasalwaysbeenkeptintherefrigeratorafter42daysofuse,evenifthereisinsulinleftinthevial.

•Throwawayavialthathasbeenkeptatroomtemperature42daysafteritisfirstkeptoutoftherefrigerator,evenifthereisinsulinleftinthevial.

• LEVEMIR® FlexPen®

•Keepatroomtemperaturebelow86°F(30°C)forupto42days.

•DonotstoreaLEVEMIR®FlexPen®thatyouareusingintherefrigerator.

•DonotstoreLEVEMIR®withtheneedleattached.•KeepLEVEMIR®FlexPen®awayfromdirectheatorlight.•ThrowawayusedLEVEMIR®FlexPens®after42days,even

ifthereisinsulinleftinthem.KeepLEVEMIR® and all medicines out of the reach of children.

General information about LEVEMIR®

Medicinesaresometimesprescribedforconditionsthatarenotmentionedinthepatientleaflet.DonotuseLEVEMIR®foraconditionforwhichitwasnotprescribed.DonotgiveLEVEMIR®tootherpeople,eveniftheyhavethesamesymptomsyouhave.Itmayharmthem.ThisleafletsummarizesthemostimportantinformationaboutLEVEMIR®.IfyouwouldlikemoreinformationaboutLEVEMIR®ordiabetes,talkwithyourhealthcareprovider.YoucanaskyourhealthcareproviderforinformationaboutLEVEMIR®thatiswrittenforhealthcareprofessionals.FormoreinformationaboutLEVEMIR®,call1-800-727-6500orgotowww.novonordisk-us.com.

What are the ingredients in LEVEMIR®?ActiveIngredient:InsulindetemirInactiveIngredients:zinc,m-cresol,glycerol,phenol,disodiumphosphatedihydrate,sodiumchlorideandwaterforinjection.Hydrochloricacidorsodiumhydroxidemaybeadded.ThisPatientInformationhasbeenapprovedbytheU.S.FoodandDrugAdministration.

Patient InformationLEVEMIR® (LEV–uh-mere)(insulindetemir[rDNAorigin]injection)solutionforsubcutaneousinjectionReadthePatientInformationthatcomeswithLEVEMIR®beforeyoustarttakingitandeachtimeyougetarefill.Theremaybenewinformation.Thisleafletdoesnottaketheplaceoftalkingwithyourhealthcareprovideraboutyourdiabetesoryourtreatment.Makesurethatyouknowhowtomanageyourdiabetes.Askyourhealthcareprovider,ifyouhaveanyquestionsaboutmanagingyourdiabetes.

What is LEVEMIR®?LEVEMIR®isaman-madelong-actinginsulinusedtocontrolhighbloodsugarinadultsandchildrenwithdiabetesmellitus.ItisnotrecommendedtouseLEVEMIR®totreatdiabeticketoacidosis.

Who should not use LEVEMIR®?Do not use LEVEMIR® if:•youareallergictoanyoftheingredientsinLEVEMIR®.Seethe

endofthisleafletforacompletelistofingredientsinLEVEMIR®.What should I tell my healthcare provider before using LEVEMIR®?Before you use LEVEMIR®, tell your healthcare provider if you:•haveliverorkidneyproblems•haveanyothermedicalconditions.Somemedicalconditionscan

affectyourinsulinneedsandyourdoseofLEVEMIR®.•arepregnantorplantobecomepregnant.Itisnotknown,if

LEVEMIR®wouldharmyourunbornbaby.Talktoyourhealthcareprovider,ifyouarepregnantorplantobecomepregnant.Youandyourhealthcareprovidershouldtalkaboutthebestwaytomanageyourdiabeteswhileyouarepregnant.

•arebreastfeedingorplantobreast-feed.ItisnotknownifLEVEMIR®passesintobreastmilk.YouandyourhealthcareprovidershoulddecideifyouwilltakeLEVEMIR®whileyoubreastfeed.

Tell your healthcare provider about all the medicines you take,includingprescriptionandnon-prescriptionmedicines,vitaminsandherbalsupplements.LEVEMIR®mayaffectthewayothermedicineswork,andothermedicinesmayaffecthowLEVEMIR®works.Knowthemedicinesyoutake.Keepalistofyourmedicineswithyoutoshowyourhealthcareproviderandpharmacistwhenyougetanewmedicine.

How should I use LEVEMIR®?•UseLEVEMIR®exactlyasyourhealthcareprovidertoldyouto

useit.•YourhealthcareproviderwilltellyouhowmuchLEVEMIR®to

useandwhentouseit.•Donotmakeanychangestoyourdoseortypeofinsulinunless

youaretoldtodosobyyourhealthcareprovider. Knowyourinsulin.Make sure you know:

•thetypeandstrengthofinsulinprescribedforyou.•theamountofinsulinyoutake.•thebesttimeforyoutotakeyourinsulin.Thismaychangeif

youtakeadifferenttypeofinsulin.•DonotdiluteormixLEVEMIR®withanyotherinsulinor

injectablediabetesmedicine.YourLEVEMIR®willnotworktherightwayandyoumaylosecontrolofyourbloodsugar,whichcanbeserious.Giveyourselfseparateinjections.Youmaygivetheseparateinjectionsinthesamebodyarea(forexample,yourstomacharea),butyoushouldnotgivetheinjectionsrightnexttoeachother.

•DonotuseLEVEMIR®inaninsulinpump.•InjectLEVEMIR®underyourskin(subcutaneously)inyourupper

arm,abdomen(stomacharea),orthigh.NeverinjectLEVEMIR®intoaveinormuscle.

•Changeinjectionsiteswithintheareayouchoosewitheachdose.Donotinjectintotheexactsamespotforeachinjection.

•Read the instructions for use that comes with your LEVEMIR®. Talktoyourhealthcareproviderifyouhaveanyquestions.YourhealthcareprovidershouldshowyouhowtoinjectLEVEMIR®beforeyoustarttakingit.

•YourhealthcareproviderwilldecidewhichtypeofLEVEMIR®toprescribeforyou.

LEVEMIR®comesin:•10mLvials(smallbottles)forusewithasyringe•3mLLEVEMIR®FlexPen®

AskyourhealthcareproviderhowyoushoulduseLEVEMIR®.•If you use too much LEVEMIR®, your blood sugar may

fall low (hypoglycemia).Youcantreatmildlowbloodsugar(hypoglycemia)bydrinkingoreatingsomethingsugaryrightaway(fruitjuice,sugarcandies,orglucosetablets).

Revised:April2012Novo Nordisk®, LEVEMIR®, and FlexPen® are registered trademarks of Novo Nordisk A/S.LEVEMIR®iscoveredbyUSPatentNos.5,750,497,5,866,538,6,011,007,6,869,930andotherpatentspending.FlexPen®iscoveredbyUSPatentNos.6,582,404,6,004,297,6,235,004andotherpatentspending.Manufacturedby:NovoNordiskA/SDK-2880Bagsvaerd,DenmarkForinformationaboutLEVEMIR®contact:NovoNordiskInc.100CollegeRoadWestPrinceton,NewJersey08540www.novonordisk-us.com1-800-727-6500©2005-2012NovoNordisk0512-00009441-16/12


10. Ifthereareairbubbles,tapthesyringegentlywithyourfingertoraisetheairbubblestothetopoftheneedle.Thenslowlypushtheplungertothecorrectunitmarkingforyourdose.

11.ChecktomakesureyouhavetherightdoseofLEVEMIR®inthesyringe.

12.Pullthesyringeoutofthevial.13. InjectyourLEVEMIR®rightawayasinstructedbyyour

healthcareprovider.

How should I inject LEVEMIR® with a syringe?

Ifyoucleanyourinjectionsitewithanalcoholswab,lettheinjectionsitedrybeforeyouinject.Talkwithyourhealthcareproviderabouthowtorotateinjectionsitesandhowtogiveaninjection.1. Pinchyourskinbetween

twofingers,pushtheneedleintotheskinfold,usingadart-likemotionandpushtheplungertoinjecttheinsulinunderyourskin.Theneedlewillbestraightin.

2. Keeptheneedleunderyourskinforatleast6secondstomakesureyouhaveinjectedalltheinsulin.AfteryoupulltheneedlefromyourskinyoumayseeadropofLEVEMIR®attheneedletip.Thisisnormalandhasnoeffectonthedoseyoujustreceived.

3. Ifbloodappearsafteryoupulltheneedlefromyourskin,presstheinjectionsitelightlywithanalcoholswab.Donotrubthearea.

4. Aftereachinjection,remove the needle without recappinganddisposeofitinapuncture-resistantcontainer.Usedsyringes,needles,andlancetsshouldbeplacedinsharpscontainers(suchasredbiohazardcontainers),hardplasticcontainers(suchasdetergentbottles),ormetalcontainers(suchasanemptycoffeecan).Suchcontainersshouldbesealedanddisposedofproperly.

Patient Instructions For Use LEVEMIR® 10 mL vialPleasereadthefollowingInstructionsforusecarefullybeforeusingyourLEVEMIR®10mLvialandeachtimeyougetarefill.Youshouldreadtheinstructionsinthismanualevenifyouhaveusedaninsulin10mLvialbefore.

How should I use the LEVEMIR® 10 mL vial?Using the 10 mL vial:1. Checktomakesurethatyouhavethecorrecttypeofinsulin.

Thisisespeciallyimportantifyouusedifferenttypesofinsulin.

2. Lookatthevialandtheinsulin.TheLEVEMIR®insulinshouldbeclearandcolorless.Thetamper-resistantcapshouldbeinplacebeforethefirstuse.Ifthecaphasbeenremovedbeforeyourfirstuseofthevial,oriftheinsuliniscloudyorcolored,Do notusetheinsulinandreturnittoyourpharmacy.

3. Washyourhandswithsoapandwater.4. Ifyouareusinganew

vial,pulloffthetamper-resistantcap.

Beforeeachuse,wipetherubberstopperwithanalcoholwipe.

5. Donotrollorshakethevial.Shakingthevialrightbeforethedoseisdrawnintothesyringemaycausebubblesorfoam.Thiscancauseyoutodrawupthewrongdoseofinsulin.Theinsulinshouldbeusedonlyifitisclearandcolorless.

6. Pullbacktheplungeronyoursyringeuntiltheblacktipreachesthemarkingforthenumberofunitsyouwillinject.

7. Pushtheneedlethroughtherubberstopperintothevial.

8. Pushtheplungerallthewayin.Thisinsertsairintothevial.

9. Turnthevialandsyringeupsidedownandslowlypulltheplungerbacktoafewunitsbeyondthecorrectdosethatyouneed.

Revised:January2012Novo Nordisk® and LEVEMIR® are registered trademarks of Novo Nordisk A/S.LEVEMIR®iscoveredbyUSPatentNos.5,750,497;5,866,538;6,011,007;6,869,930,andotherpatentspending.Manufacturedby:NovoNordiskA/SDK-2880Bagsvaerd,DenmarkForinformationaboutLEVEMIR®contact:NovoNordiskInc.100CollegeRoadWest,Princeton,NewJersey08540©2005-2012NovoNordisk0512-00009441-16/12

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Injectthedosebypressingthepush-buttonallthewayinuntilthe0linesupwiththepointer(seediagramI).Becarefulonlytopushthebuttonaftertheneedleisintheskin.

Turningthedoseselectorwillnotinjectinsulin.J. Keeptheneedleintheskinforatleast6seconds,andkeepthepush-

buttonpressedallthewayinuntiltheneedlehasbeenpulledoutfromtheskin(seediagramJ).Thiswillmakesurethatthefulldosehasbeengiven.

YoumayseeadropofLEVEMIR®attheneedletip.Thisisnormalandhasnoeffectonthedoseyoujustreceived.Ifbloodappearsafteryoutaketheneedleoutofyourskin,presstheinjectionsitelightlywithanalcoholswab.Do not rub the area.

After the injectionCarefully remove the needle from the pen after each injection. Thishelpstopreventinfectionandleakageofinsulin.Youcancarefullyrecaptheneedlewiththebiggeroutercaptohelpmakeiteasiertoremovetheneedle.

Do not recap the needle with the small inner cap. Recappingwiththissmallpartcanincreaseyourchancesofhavinganeedlestickinjury.

Puttheneedleinasharpscontainerorsometypeofhardplasticormetalcontainerwithascrewtopsuchasadetergentbottleoremptycoffeecan.Thesecontainersshouldbesealedandthrownawaytherightway.Checkwithyourhealthcareproviderabouttherightwaytothrowawayusedsyringesandneedles.Theremaybelocalorstatelawsabouthowtothrowawayusedneedlesandsyringes.Donotthrowawayusedneedlesandsyringesinhouseholdtrashorrecyclingbins.

K.PutthepencapontheLEVEMIR®FlexPen®andstoretheLEVEMIR®FlexPen®withouttheneedleattached(seediagramK).

TheLEVEMIR®FlexPen®preventsthecartridgefrombeingcompletelyemptied.Itcandeliver300unitsthenyoushouldthrowitawayinasharpscontainerorsometypeofhardplasticormetalcontainerwithascrewtop,suchasadetergentbottleoremptycoffeecan.

FunctIonchEcKL. IfyourLEVEMIR®FlexPen®isnotworkingtherightway,followthe

stepsbelow: •AttachanewNovoFine®needle. •Removethebigouterneedlecapandtheinnerneedlecap. •Doanairshotasdescribedin“Givingtheairshotbeforeeach

injection”(seediagramEthroughG). •Putthebigouterneedlecapontotheneedle.Donotputontheinnerneedlecap. •Turnthedoseselectorsothedoseindicatorwindowshows20units. •HoldtheLEVEMIR®FlexPen®sotheneedleispointingdown. •Pressthepush-buttonallthewayin.Theinsulinshouldfillthelowerpartofthebigouterneedlecaptothemarker(seediagramL).IfLEVEMIR®FlexPen®hasreleasedtoomuchortoolittleinsulin,dothefunctioncheckagain.Ifthesameproblemhappensagain,donotuseyourLEVEMIR®FlexPen®andcontactNovoNordiskat1-800-727-6500.

MaintenanceYourFlexPen®isdesignedtoworkaccuratelyandsafely.Itmustbehandledwithcare.IfyoudropyourFlexPen®itcouldgetdamaged.IfyouareconcernedthatyourFlexPen®isdamaged,useanewone.YoucancleantheoutsideofyourFlexPen®bywipingitwithadampcloth.DonotsoakorwashyourFlexPen®.SoakingorwashingtheFlexPen®coulddamageit.DonotrefillyourFlexPen®.

RemovetheneedlefromtheLEVEMIR®FlexPen®aftereachinjection.Thishelpstocutdownyourchanceofinfection,preventleakageofinsulin.Becarefulwhenhandlingusedneedlestoavoidneedlesticksandtransferofinfections.

KeepyourLEVEMIR®FlexPen®andneedlesoutofthereachofchildren.UseLEVEMIR®FlexPen®asdirectedtotreatyourdiabetes.NeedlesandLEVEMIR®FlexPen®mustnotbeshared.

Alwaysuseanewneedleforeachinjection.NovoNordiskisnotresponsibleforharmduetousingthisinsulinpenwithproductsnotrecommendedbyNovoNordisk.

Asasafetymeasure,alwayscarryaspareinsulindeliverydeviceincaseyourLEVEMIR®FlexPen®islostordamaged.

RemembertokeepthedisposableLEVEMIR®FlexPen®withyou.Donotleaveitinacarorotherlocationwhereitcangettoohotortoocold.

Instructions For Use LEVEMIR® FlexPen®

PleasecarefullyreadthefollowingInstructionsforusebeforeusingyourLEVEMIR®FlexPen®andeachtimeyougetarefill.YoushouldreadtheinstructionsinthismanualevenifyouhaveusedaLEVEMIR®FlexPen®before.LEVEMIR®FlexPen®isadisposabledial-a-doseinsulinpen.Youcanselectdosesfrom1to60unitsinincrementsof1unit.LEVEMIR®FlexPen®isdesignedtobeusedwithNovoFine®needles.

LEVEMIR®FlexPen®shouldnotbeusedbypeoplewhoareblindorhavesevereeyesightproblemswithoutthehelpofapersonwhohasgoodeyesightandwhoistrainedtousetheLEVEMIR®FlexPen®therightway.

Getting readyMakesureyouhavethefollowingitems:•LEVEMIR®FlexPen®

•NovoFine®disposableneedles•AlcoholswabPREPARING YOUR LEVEMIR® FLEXPEN®

Washyourhandswithsoapandwater.Beforeyoustarttoprepareyourinjection,checkthelabeltomakesurethatyouaretakingtherighttypeofinsulin.Thisisespeciallyimportantifyoutakemorethan1typeofinsulin.LEVEMIR®shouldlookclearandcolorless.A.Pulloffthepencap(seediagramA). Wipetherubberstopperwithanalcoholswab.B.Attaching the needle Removetheprotectivetabfromanewdisposableneedle. AttachtheneedletightlyontoyourFlexPen®.Itisimportantthatthe

needleisputonstraight(seediagramB). NeverplaceadisposableneedleonyourLEVEMIR®FlexPen®until

youarereadytogiveyourinjection.C.Pulloffthebigouterneedlecap(seediagramC).D.Pullofftheinnerneedlecapandthrowitaway(seediagramD).

Alwaysuseanewneedleforeachinjectiontocutdownthechanceofinfectionandtopreventblockedneedles.

Becarefulnottobendordamagetheneedlebeforeuse.Toreducetheriskofneedlesticks,neverputtheinnerneedlecapbackontheneedle.

Giving the airshot before each injectionBeforeeachinjection,smallamountsofairmaycollectinthecartridgeduringnormaluse.Toavoidinjectingairandtoensureyoutaketherightdoseofinsulin:E.Turnthedoseselectortoselect2units(seediagramE).F. HoldyourLEVEMIR®FlexPen®withtheneedlepointingup.Tapthe

cartridgegentlywithyourfingerafewtimestomakeanyairbubblescollectatthetopofthecartridge(seediagramF).

G.Whileyoukeeptheneedlepointingupwards,pressthepush-buttonallthewayin(seediagramG).Thedoseselectorreturnsto0.

Adropofinsulinshouldappearattheneedletip.Ifnot,changetheneedleandrepeattheprocedurenomorethan6times.

Ifyoudonotseeadropofinsulinafter6times,donotusetheLEVEMIR®FlexPen®andcontactNovoNordiskat1-800-727-6500.

Asmallairbubblemayremainattheneedletip,butitwillnotbeinjected.

SELECTING YOUR DOSECheckandmakesurethatthedoseselectorissetat0.H.Turnthedoseselectortothenumberofunitsyouneedtoinject.The

pointershouldlineupwithyourdose. Thedosecanbecorrectedeitherupordownbyturningthedose

selectorineitherdirectionuntilthecorrectdoselinesupwiththepointer(seediagramH).Whenturningthedoseselector,becarefulnottopressthepush-buttonasinsulinwillcomeout.

Youcannotselectadoselargerthanthenumberofunitsleftinthecartridge.

Youwillhearaclickforeverysingleunitdialed.Donotsetthedosebycountingthenumberofclicksyouhear.

Donotusethecartridgescaleprintedonthecartridgetomeasureyourdoseofinsulin.

GIVING THE INJECTIONDotheinjectionexactlyasshowntoyoubyyourhealthcareprovider.Yourhealthcareprovidershouldtellyouifyouneedtopinchtheskinbeforeinjecting.Wipetheskinwithanalcoholswabandlettheareadry.I. Inserttheneedleintoyourskin.

Rubberstopper Cartridge

Cartridgescale

PointerDose

selector

Push-button

Revised:January2012Novo Nordisk®, LEVEMIR®, FlexPen®, NovoPen®, and NovoFine® are registered trademarks of Novo Nordisk A/S.LEVEMIR®iscoveredbyUSPatentNos.5,750,497;5,866,538;6,011,007;6,869,930,andotherpatentspending.FlexPen®iscoveredbyUSPatentNos.6,582,404;6,004,297;6,235,004,andotherpatentspending.Manufacturedby:NovoNordiskA/SDK-2880Bagsvaerd,DenmarkForinformationaboutLEVEMIR®contact:NovoNordiskInc.100CollegeRoadWestPrinceton,NewJersey08540©2005-2012NovoNordisk0512-00009441-16/12

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