2.3. with type 1 diabetes <3 years of age. (8.4)

Transcription

1 1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use HUMALOG sfely nd effectively. See full prescribing informtion for HUMALOG. HUMALOG (insulin lispro injection), for subcutneous or intrvenous use Initil U.S. Approvl: INDICATIONS AND USAGE HUMALOG is rpid cting humn insulin nlog indicted to improve glycemic control in dults nd children with dibetes mellitus. (1) DOSAGE AND ADMINISTRATION See Full Prescribing Informtion for importnt dministrtion instructions. (2.1, 2.2, 2.3, 2.4) Subcutneous injection: Administer HUMALOG U-100 or U-200 by subcutneous injection within 15 minutes before mel or immeditely fter mel. (2.2) Continuous subcutneous infusion (Insulin Pump): Administer HUMALOG U-100 by continuous subcutneous infusion using n insulin pump. DO NOT dminister HUMALOG U-200 by continuous subcutneous infusion. (2.2) Intrvenous Infusion: Administer HUMALOG U-100 by intrvenous infusion ONLY fter dilution nd under medicl supervision. DO NOT dminister HUMALOG U-200 by intrvenous infusion. (2.2) The dosge of HUMALOG must be individulized bsed on the route of dministrtion nd the individul's metbolic needs, blood glucose monitoring results nd glycemic control gol. (2.3) Do not perform dose conversion when using the HUMALOG U-100 or U-200 KwikPens. The dose window shows the number of insulin units to be delivered nd no conversion is needed. (2.1, 2.3) Do not mix HUMALOG U-200 with ny other insulin. (2.4) DOSAGE FORMS AND STRENGTHS HUMALOG 100 units/ml (U-100) is vilble s: (3) 10 ml vils 3 ml vils 3 ml Humlog KwikPen (prefilled) 3 ml Humlog Junior KwikPen (prefilled) 3 ml crtridges HUMALOG 200 units/ml (U-200) is vilble s: (3) 3 ml Humlog KwikPen (prefilled) CONTRAINDICATIONS Do not use during episodes of hypoglycemi. (4) Do not use in ptients with hypersensitivity to HUMALOG or ny of its excipients. (4) Never shre HUMALOG KwikPen, crtridge, reusble pen comptible with Lilly 3 ml crtridges, or syringe between ptients, even if the needle is chnged. (5.1) Hyper- or Hypoglycemi with Chnges in Insulin Regimen: Crry out under close medicl supervision nd increse frequency of blood glucose monitoring. (5.2) Hypoglycemi: My be life-thretening. Monitor blood glucose nd increse monitoring frequency with chnges to insulin dosge, use of glucose lowering medictions, mel pttern, physicl ctivity; in ptients with renl or heptic impirment; nd in ptients with hypoglycemi unwreness. (5.3, 7, 8.6, 8.7) Hypoglycemi Due to Mediction Errors: Accidentl mix-ups between insulin products cn occur. Instruct ptients to check insulin lbels before injection. Do not trnsfer HUMALOG U-200 from the HUMALOG KwikPen to syringe s overdosge nd severe hypoglycemi cn result. (5.4) Hypersensitivity Rections: My be life-thretening. Discontinue HUMALOG, monitor nd tret if indicted. (5.5) Hypoklemi: My be life-thretening. Monitor potssium levels in ptients t risk of hypoklemi nd tret if indicted. (5.6) Fluid Retention nd Hert Filure with Concomitnt Use of Thizolidinediones (TZDs): Observe for signs nd symptoms of hert filure; consider dosge reduction or discontinution if hert filure occurs. (5.7) Hyperglycemi nd Ketocidosis Due to Insulin Pump Device Mlfunction: Monitor glucose nd dminister HUMALOG U-100 by subcutneous injection if pump mlfunction occurs. (5.8) ADVERSE REACTIONS Adverse rections ssocited with HUMALOG include hypoglycemi, llergic rections, injection site rections, lipodystrophy, pruritus, nd rsh. (6.1) To report SUSPECTED ADVERSE REACTIONS, contct Eli Lilly nd Compny t LillyRx ( ) or FDA t 1-800FDA-1088 or DRUG INTERACTIONS Drugs tht Affect Glucose Metbolism: Adjustment of insulin dosge my be needed. (7.1, 7.2, 7.3) Anti-Adrenergic Drugs (e.g., bet-blockers, clonidine, gunethidine, nd reserpine): Signs nd symptoms of hypoglycemi my be reduced or bsent. (5.3, 7.4) USE IN SPECIFIC POPULATIONS Peditrics: Not studied in children with type 2 dibetes or in children with type 1 dibetes <3 yers of ge. (8.4) See 17 for PATIENT COUNSELING INFORMATION nd FDApproved ptient lbeling Revised: 08/ WARNINGS AND PRECAUTIONS FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Importnt Administrtion Instructions 2.2 Route of Administrtion 2.3 Dosge Informtion 2.4 Dosge Adjustment Due to Drug Interctions 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Never Shre HUMALOG KwikPen, Crtridge, Reusble 1 Pen Comptible with Lilly 3 ml Crtridges, or Syringe Between Ptients 5.2 Hyper- or Hypoglycemi with Chnges in Insulin Regimen 5.3 Hypoglycemi 5.4 Hypoglycemi Due to Mediction Errors 5.5 Hypersensitivity Rections 5.6 Hypoklemi 5.7 Fluid Retention nd Hert Filure with Concomitnt Use of PPAR-gmm Agonists 5.8 Hyperglycemi nd Ketocidosis Due to Insulin Pump Device Mlfunction 6 ADVERSE REACTIONS 6.1 Clinicl Tril Experience 6.2 Postmrketing Experience 7 DRUG INTERACTIONS 7.1 Drugs Tht My Increse the Risk of Hypoglycemi 7.2 Drugs Tht My Decrese the Blood Glucose Lowering Effect of HUMALOG 7.3 Drugs Tht My Increse or Decrese the Blood Glucose Lowering Effect of HUMALOG 7.4 Drugs Tht My Blunt Signs nd Symptoms of Hypoglycemi 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.3 Nursing Mothers 8.4 Peditric Use 8.5 Geritric Use 8.6 Renl Impirment 8.7 Heptic Impirment

2 2 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechnism of Action 12.2 Phrmcodynmics 12.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 13.2 Animl Toxicology nd/or Phrmcology 14 CLINICAL STUDIES 14.1 Type 1 Dibetes Adults nd Adolescents 14.2 Type 2 Dibetes Adults 14.3 Type 1 Dibetes Peditric nd Adolescents 14.4 Type 1 Dibetes Adults Continuous Subcutneous Insulin Infusion 14.5 Type 1 Dibetes Peditric Continuous Subcutneous Insulin Infusion How Supplied Storge nd Hndling Preprtion nd Hndling Admixture for Intrvenous Administrtion PATIENT COUNSELING INFORMATION 17.1 Never Shre HUMALOG KwikPen, Crtridge, Reusble Pen Comptible with Lilly 3 ml Crtridges, or Syringe Between Ptients 17.2 Hypoglycemi 17.3 Hypersensitivity Rections 17.4 Mediction Errors 17.5 Administrtion Instruction for HUMALOG U Women of Reproductive Potentil 17.7 Instructions For Ptients Using Continuous Subcutneous Insulin Pumps * Sections or subsections omitted from the full prescribing informtion re not listed. HOW SUPPLIED/STORAGE AND HANDLING FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE HUMALOG is rpid cting humn insulin nlog indicted to improve glycemic control in dults nd children with dibetes mellitus DOSAGE AND ADMINISTRATION Importnt Administrtion Instructions Alwys check insulin lbels before dministrtion [see Wrnings nd Precutions (5.4)]. Inspect HUMALOG visully before use. It should pper cler nd colorless. Do not use HUMALOG if prticulte mtter or colortion is seen. Do NOT mix HUMALOG U-100 with other insulins when dministering using continuous subcutneous infusion pump. Do NOT trnsfer HUMALOG U-200 from the KwikPen to syringe for dministrtion [see Wrnings nd Precutions (5.4)]. Do NOT perform dose conversion when using ny HUMALOG U-100 or U-200 KwikPens. The dose window shows the number of insulin units to be delivered nd no conversion is needed. HUMALOG U-100 nd U-200 KwikPens re designed to dil doses in increments of 1 unit. HUMALOG Junior KwikPen is designed to dil doses in 0.5 (1/2) unit increments. Do NOT mix HUMALOG U-200 with ny other insulins. Do NOT dminister HUMALOG U-200 using continuous subcutneous infusion pump (i.e., insulin pump). Do NOT dminister HUMALOG U-200 intrvenously. Route of Administrtion Subcutneous Injection: HUMALOG U-100 or U-200 Administer the dose of HUMALOG U-100 or HUMALOG U-200 within fifteen minutes before mel or immeditely fter mel by injection into the subcutneous tissue of the bdominl wll, thigh, upper rm, or buttocks. To reduce the risk of lipodystrophy, rotte the injection site within the sme region from one injection to the next [see Adverse Rections (6)]. HUMALOG dministered by subcutneous injection should generlly be used in regimens with n intermedite- or long-cting insulin. Continuous Subcutneous Infusion (Insulin Pump): HUMALOG U-100 ONLY Do NOT dminister HUMALOG U-200 using continuous subcutneous infusion pump. Administer HUMALOG U-100 by continuous subcutneous infusion into the subcutneous tissue of the bdominl wll. Rotte infusion sites within the sme region to reduce the risk of lipodystrophy [see Adverse Rections (6.1)]. Follow helthcre professionl recommendtions when setting bsl nd mel time infusion rte. Do NOT dilute or mix HUMALOG U-100 when dministering by continuous subcutneous infusion. Chnge HUMALOG U-100 in the pump reservoir t lest every 7 dys. Chnge the infusion sets nd the infusion set insertion site t lest every 3 dys. Do NOT expose HUMALOG U-100 in the pump reservoir to tempertures greter thn 98.6 F (37 C). Use HUMALOG U-100 in pump systems suitble for insulin infusion [see Ptient Counseling Informtion (17.7)]. Intrvenous Administrtion: HUMALOG U-100 ONLY Do NOT dminister HUMALOG U-200 intrvenously.

3 Dilute HUMALOG U-100 to concentrtions from 0.1 unit/ml to 1.0 unit/ml using 0.9% sodium chloride. Administer HUMALOG U-100 intrvenously ONLY under medicl supervision with close monitoring of blood glucose nd potssium levels to void hypoglycemi nd hypoklemi [see Wrnings nd Precutions (5.3, 5.6) nd How Supplied/Storge nd Hndling (16.4)]. Dosge Informtion Individulize nd djust the dosge of HUMALOG bsed on route of dministrtion, the individul's metbolic needs, blood glucose monitoring results nd glycemic control gol. Dosge djustments my be needed with chnges in physicl ctivity, chnges in mel ptterns (i.e., mcronutrient content or timing of food intke), chnges in renl or heptic function or during cute illness [see Wrnings nd Precutions (5.2, 5.3) nd Use in Specific Popultions (8.6, 8.7)]. Do NOT perform dose conversion when using ny HUMALOG U-100 or U-200 KwikPens. The dose window shows the number of insulin units to be delivered nd no conversion is needed. Dosge Adjustment Due to Drug Interctions Dosge djustment my be needed when HUMALOG is codministered with certin drugs [see Drug Interctions (7)]. Dosge djustment my be needed when switching from nother insulin to HUMALOG [see Wrnings nd Precutions (5.2)]. Instructions for Mixing with Other Insulins HUMALOG U-100 subcutneous injection route HUMALOG U-100 continuous subcutneous infusion route (Insulin Pump) HUMALOG U-200 subcutneous injection route HUMALOG U-100 my be mixed with NPH insulin preprtions ONLY. If HUMALOG U-100 is mixed with NPH insulin, HUMALOG U-100 should be drwn into the syringe first. Injection should occur immeditely fter mixing. Do NOT mix HUMALOG U-100 with ny other insulin. Do NOT mix with ny other insulin. 3 DOSAGE FORMS AND STRENGTHS HUMALOG 100 units per ml (U-100) is vilble s: 10 ml vils 3 ml vils 3 ml Humlog KwikPen (prefilled) 3 ml Humlog Junior KwikPen (prefilled) 3 ml crtridges HUMALOG 200 units per ml (U-200) is vilble s: 3 ml Humlog KwikPen (prefilled) 4 CONTRAINDICATIONS HUMALOG is contrindicted: during episodes of hypoglycemi in ptients who re hypersensitive to HUMALOG or to ny of its excipients. 5 WARNINGS AND PRECAUTIONS 5.1 Never Shre HUMALOG KwikPen, Crtridge, Reusble Pen Comptible with Lilly 3 ml Crtridges1, or Syringe Between Ptients HUMALOG KwikPens, crtridges, nd reusble pens comptible with Lilly 3 ml crtridges must never be shred between ptients, even if the needle is chnged. Ptients using HUMALOG vils must never shre needles or syringes with nother person. Shring poses risk for trnsmission of blood-borne pthogens. 5.2 Hyper- or Hypoglycemi with Chnges in Insulin Regimen Chnges in insulin strength, mnufcturer, type, or method of dministrtion my ffect glycemic control nd predispose to hypoglycemi [see Wrnings nd Precutions (5.3)] or hyperglycemi. These chnges should be mde cutiously nd under close medicl supervision nd the frequency of blood glucose monitoring should be incresed. 5.3 Hypoglycemi Hypoglycemi is the most common dverse rection ssocited with insulins, including HUMALOG. Severe hypoglycemi cn cuse seizures, my be life-thretening, or cuse deth. Hypoglycemi cn impir concentrtion bility nd rection time; this my plce n individul nd others t risk in situtions where these bilities re importnt (e.g., driving or operting other mchinery).

4 4 Hypoglycemi cn hppen suddenly nd symptoms my differ in ech individul nd chnge over time in the sme individul. Symptomtic wreness of hypoglycemi my be less pronounced in ptients with longstnding dibetes, in ptients with dibetic nerve disese, in ptients using medictions tht block the sympthetic nervous system (e.g., bet-blockers) [see Drug Interctions (7)], or in ptients who experience recurrent hypoglycemi. Risk Fctors for Hypoglycemi The risk of hypoglycemi fter n injection is relted to the durtion of ction of the insulin nd, in generl, is highest when the glucose lowering effect of the insulin is mximl. As with ll insulin preprtions, the glucose lowering effect time course of HUMALOG my vry in different individuls or t different times in the sme individul nd depends on mny conditions, including the re of injection s well s the injection site blood supply nd temperture [see Clinicl Phrmcology (12.2)]. Other fctors which my increse the risk of hypoglycemi include chnges in mel pttern (e.g., mcronutrient content or timing of mels), chnges in level of physicl ctivity, or chnges to co-dministered mediction [see Drug Interctions (7)]. Ptients with renl or heptic impirment my be t higher risk of hypoglycemi [see Use in Specific Popultions (8.6, 8.7)]. Risk Mitigtion Strtegies for Hypoglycemi Ptients nd cregivers must be educted to recognize nd mnge hypoglycemi. Self-monitoring of blood glucose plys n essentil role in the prevention nd mngement of hypoglycemi. In ptients t higher risk for hypoglycemi nd ptients who hve reduced symptomtic wreness of hypoglycemi, incresed frequency of blood glucose monitoring is recommended. 5.4 Hypoglycemi Due to Mediction Errors Accidentl mix-ups between bsl insulin products nd other insulins, prticulrly rpid-cting insulins, hve been reported. To void mediction errors between HUMALOG nd other insulins, instruct ptients to lwys check the insulin lbel before ech injection. Do not trnsfer HUMALOG U-200 from the HUMALOG KwikPen to syringe. The mrkings on the insulin syringe will not mesure the dose correctly nd cn result in overdosge nd severe hypoglycemi [see Dosge nd Administrtion (2.1) nd Wrnings nd Precutions (5.3)]. 5.5 Hypersensitivity Rections Severe, life-thretening, generlized llergy, including nphylxis, cn occur with insulin products, including HUMALOG. If hypersensitivity rections occur, discontinue HUMALOG; tret per stndrd of cre nd monitor until symptoms nd signs resolve [see Adverse Rections (6.1)]. HUMALOG is contrindicted in ptients who hve hd hypersensitivity rections to HUMALOG or ny of its excipients [see Contrindictions (4)]. 5.6 Hypoklemi All insulin products, including HUMALOG, cuse shift in potssium from the extrcellulr to intrcellulr spce, possibly leding to hypoklemi. Untreted hypoklemi my cuse respirtory prlysis, ventriculr rrhythmi, nd deth. Monitor potssium levels in ptients t risk for hypoklemi if indicted (e.g., ptients using potssium-lowering medictions, ptients tking medictions sensitive to serum potssium concentrtions). 5.7 Fluid Retention nd Hert Filure with Concomitnt Use of PPAR-gmm Agonists Thizolidinediones (TZDs), which re peroxisome prolifertor-ctivted receptor (PPAR)-gmm gonists, cn cuse dose-relted fluid retention, prticulrly when used in combintion with insulin. Fluid retention my led to or excerbte hert filure. Ptients treted with insulin, including HUMALOG, nd PPAR-gmm gonist should be observed for signs nd symptoms of hert filure. If hert filure develops, it should be mnged ccording to current stndrds of cre, nd discontinution or dose reduction of the PPAR-gmm gonist must be considered. 5.8 Hyperglycemi nd Ketocidosis Due to Insulin Pump Device Mlfunction Mlfunction of the insulin pump or insulin infusion set or insulin degrdtion cn rpidly led to hyperglycemi nd ketocidosis. Prompt identifiction nd correction of the cuse of hyperglycemi or ketosis is necessry. Interim subcutneous injections with HUMALOG my be required. Ptients using continuous subcutneous insulin infusion pump therpy must be trined to dminister insulin by injection nd hve lternte insulin therpy vilble in cse of pump filure [see How Supplied/Storge nd Hndling (16.2) nd Ptient Counseling Informtion (17.7)]. 6 ADVERSE REACTIONS Observed with HUMALOG U-100 The following dverse rections re discussed elsewhere: Hypoglycemi [see Wrnings nd Precutions (5.3)]. Hypoklemi [see Wrnings nd Precutions (5.6)]. 6.1 Clinicl Tril Experience Becuse clinicl trils re conducted under widely vrying designs, the dverse rection rtes reported in one clinicl tril my not be esily compred with those rtes reported in nother clinicl tril, nd my not reflect the rtes ctully observed in clinicl prctice. The frequencies of Tretment-Emergent Adverse Events during HUMALOG clinicl trils in ptients with type 1 dibetes mellitus nd type 2 dibetes mellitus re listed in the tbles below.

5 Tble 1: Tretment-Emergent Adverse Events in Ptients with Type 1 Dibetes Mellitus (dverse events with frequency 5%) Events, n (%) Lispro Regulr humn insulin (n=81) (n=86) Flu syndrome 28 (34.6) 28 (32.6) Phryngitis 27 (33.3) 29 (33.7) Rhinitis 20 (24.7) 25 (29.1) Hedche 24 (29.6) 19 (22.1) Pin 16 (19.8) 14 (16.3) Cough incresed 14 (17.3) 15 (17.4) Infection 11 (13.6) 18 (20.9) Nuse 5 (6.2) 13 (15.1) Accidentl injury 7 (8.6) 10 (11.6) Surgicl procedure 5 (6.2) 12 (14.0) Fever 5 (6.2) 10 (11.6) Abdominl pin 6 (7.4) 7 (8.1) Astheni 6 (7.4) 7 (8.1) Bronchitis 6 (7.4) 6 (7.0) Dirrhe 7 (8.6) 5 (5.8) Dysmenorrhe 5 (6.2) 6 (7.0) Mylgi 6 (7.4) 5 (5.8) Urinry trct infection 5 (6.2) 4 (4.7) 5 Tble 2: Tretment-Emergent Adverse Events in Ptients with Type 2 Dibetes Mellitus (dverse events with frequency 5%) Events, n (%) Lispro Regulr humn insulin (n=714) (n=709) Hedche 63 (11.6) 66 (9.3) Pin 77 (10.8) 71 (10.0) Infection 72 (10.1) 54 (7.6) Phryngitis 47 (6.6) 58 (8.2) Rhinitis 58 (8.1) 47 (6.6) Flu syndrome 44 (6.2) 58 (8.2) Surgicl procedure 53 (7.4) 48 (6.8) Insulin initition nd intensifiction of glucose control Intensifiction or rpid improvement in glucose control hs been ssocited with trnsitory, reversible ophthlmologic refrction disorder, worsening of dibetic retinopthy, nd cute pinful peripherl neuropthy. However, long-term glycemic control decreses the risk of dibetic retinopthy nd neuropthy. Lipodystrophy Long-term use of insulin, including HUMALOG, cn cuse lipodystrophy t the site of repeted insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of dipose tissue) nd lipotrophy (thinning of dipose tissue), nd my ffect insulin bsorption. Rotte insulin injection or infusion sites within the sme region to reduce the risk of lipodystrophy [see Dosge nd Administrtion (2.2)]. Weight gin Weight gin cn occur with insulin therpy, including HUMALOG, nd hs been ttributed to the nbolic effects of insulin nd the decrese in glucosuri. Peripherl Edem Insulin, including HUMALOG, my cuse sodium retention nd edem, prticulrly if previously poor metbolic control is improved by intensified insulin therpy. Adverse Rections with Continuous Subcutneous Insulin Infusion (CSII) HUMALOG U-100 In 12-week, rndomized, crossover study in dult ptients with type 1 dibetes (n=39), the rtes of ctheter occlusions nd infusion site rections were similr for HUMALOG U-100 nd regulr humn insulin treted ptients (see Tble 3). Ctheter occlusions/month Tble 3: Ctheter Occlusions nd Infusion Site Rections HUMALOG U-100 Regulr humn insulin (n=38) (n=39)

6 6 Infusion site rections 2.6% (1/38) 2.6% (1/39) In rndomized, 16-week, open-lbel, prllel design study of children nd dolescents with type 1 dibetes, dverse event reports relted to infusion-site rections were similr for insulin lispro nd insulin sprt (21% of 100 ptients versus 17% of 198 ptients, respectively). In both groups, the most frequently reported infusion site dverse events were infusion site erythem nd infusion site rection. Allergic Rections Locl Allergy As with ny insulin therpy, ptients tking HUMALOG my experience redness, swelling, or itching t the site of the injection. These minor rections usully resolve in few dys to few weeks, but in some occsions, my require discontinution of HUMALOG. In some instnces, these rections my be relted to fctors other thn insulin, such s irritnts in skin clensing gent or poor injection technique. Systemic Allergy Severe, life-thretening, generlized llergy, including nphylxis, my occur with ny insulin, including HUMALOG. Generlized llergy to insulin my cuse whole body rsh (including pruritus), dyspne, wheezing, hypotension, tchycrdi, or diphoresis. In controlled clinicl trils, pruritus (with or without rsh) ws seen in 17 ptients receiving regulr humn insulin (n=2969) nd 30 ptients receiving HUMALOG (n=2944). Loclized rections nd generlized mylgis hve been reported with injected metcresol, which is n excipient in HUMALOG [see Contrindictions (4)]. Antibody Production In lrge clinicl trils with ptients with type 1 (n=509) nd type 2 (n=262) dibetes mellitus, nti-insulin ntibody (insulin lispro-specific ntibodies, insulin-specific ntibodies, cross-rective ntibodies) formtion ws evluted in ptients receiving both regulr humn insulin nd HUMALOG (including ptients previously treted with humn insulin nd nive ptients). As expected, the lrgest increse in the ntibody levels occurred in ptients new to insulin therpy. The ntibody levels peked by 12 months nd declined over the remining yers of the study. These ntibodies do not pper to cuse deteriortion in glycemic control or necessitte n increse in insulin dose. There ws no sttisticlly significnt reltionship between the chnge in the totl dily insulin dose nd the chnge in percent ntibody binding for ny of the ntibody types. 6.2 Postmrketing Experience HUMALOG U-100 The following dditionl dverse rections hve been identified during post-pprovl use of HUMALOG. Becuse these rections re reported voluntrily from popultion of uncertin size, it is not lwys possible to relibly estimte their frequency or estblish cusl reltionship to drug exposure. Mediction errors in which other insulins hve been ccidentlly substituted for HUMALOG hve been identified during postpprovl use [see Ptient Counseling Informtion (17.4)] DRUG INTERACTIONS Drugs Tht My Increse the Risk of Hypoglycemi The risk of hypoglycemi ssocited with HUMALOG use my be incresed when co-dministered with ntidibetic gents, slicyltes, sulfonmide ntibiotics, monomine oxidse inhibitors, fluoxetine, prmlintide, disopyrmide, fibrtes, propoxyphene, pentoxifylline, ACE inhibitors, ngiotensin II receptor blocking gents, nd somtosttin nlogs (e.g., octreotide). Dose djustment nd incresed frequency of glucose monitoring my be required when HUMALOG is co-dministered with these drugs. 7.2 Drugs Tht My Decrese the Blood Glucose Lowering Effect of HUMALOG The glucose lowering effect of HUMALOG my be decresed when co-dministered with corticosteroids, isonizid, nicin, estrogens, orl contrceptives, phenothizines, dnzol, diuretics, sympthomimetic gents (e.g., epinephrine, lbuterol, terbutline), somtropin, typicl ntipsychotics, glucgon, protese inhibitors, nd thyroid hormones. Dose djustment nd incresed frequency of glucose monitoring my be required when HUMALOG is co-dministered with these drugs. 7.3 Drugs Tht My Increse or Decrese the Blood Glucose Lowering Effect of HUMALOG The glucose lowering effect of HUMALOG my be incresed or decresed with co-dministered with betblockers, clonidine, lithium slts, nd lcohol. Pentmidine my cuse hypoglycemi, which my sometimes be followed by hyperglycemi. Dose djustment nd incresed frequency of glucose monitoring my be required when HUMALOG is co-dministered with these drugs. 7.4 Drugs Tht My Blunt Signs nd Symptoms of Hypoglycemi The signs nd symptoms of hypoglycemi [see Wrnings nd Precutions (5.3)] my be blunted when betblockers, clonidine, gunethidine, nd reserpine re co-dministered with HUMALOG USE IN SPECIFIC POPULATIONS Pregnncy

7 7 Pregnncy Ctegory B. All pregnncies hve bckground risk of birth defects, loss, or other dverse outcome regrdless of drug exposure. This bckground risk is incresed in pregnncies complicted by hyperglycemi nd my be decresed with good metbolic control. It is essentil for ptients with dibetes or history of gesttionl dibetes to mintin good metbolic control before conception nd throughout pregnncy. In ptients with dibetes or gesttionl dibetes insulin requirements my decrese during the first trimester, generlly increse during the second nd third trimesters, nd rpidly decline fter delivery. Creful monitoring of glucose control is essentil in these ptients. Therefore, femle ptients should be dvised to tell their physicins if they intend to become, or if they become pregnnt while tking HUMALOG. Although there re limited clinicl studies of the use of HUMALOG in pregnncy, published studies with humn insulins suggest tht optimizing overll glycemic control, including postprndil control, before conception nd during pregnncy improves fetl outcome. In combined fertility nd embryo-fetl development study, femle rts were given subcutneous insulin lispro injections of 5 nd 20 units/kg/dy (0.8 nd 3 times the humn subcutneous dose of 1 unit/kg/dy, bsed on units/body surfce re, respectively) from 2 weeks prior to cohbittion through Gesttion Dy 19. There were no dverse effects on femle fertility, implnttion, or fetl vibility nd morphology. However, fetl growth retrdtion ws produced t the 20 units/kg/dy-dose s indicted by decresed fetl weight nd n incresed incidence of fetl runts/litter. In n embryo-fetl development study in pregnnt rbbits, insulin lispro doses of 0.1, 0.25, nd 0.75 unit/kg/dy (0.03, 0.08, nd 0.24 times the humn subcutneous dose of 1 unit/kg/dy, bsed on units/body surfce re, respectively) were injected subcutneously on Gesttion dys 7 through 19. There were no dverse effects on fetl vibility, weight, nd morphology t ny dose. 8.3 Nursing Mothers It is unknown whether insulin lispro is excreted in humn milk. Becuse mny drugs re excreted in humn milk, cution should be exercised when HUMALOG is dministered to nursing womn. Use of HUMALOG is comptible with brestfeeding, but women with dibetes who re lctting my require djustments of their insulin doses. 8.4 Peditric Use HUMALOG is pproved for use in children for subcutneous dily injections [see Clinicl Studies (14)]. Only the U-100 formultion of HUMALOG is pproved for use in children by continuous subcutneous infusion in insulin pumps. HUMALOG hs not been studied in peditric ptients younger thn 3 yers of ge. HUMALOG hs not been studied in peditric ptients with type 2 dibetes. As in dults, the dosge of HUMALOG must be individulized in peditric ptients bsed on metbolic needs nd results of frequent monitoring of blood glucose. 8.5 Geritric Use Of the totl number of subjects (n=2834) in eight clinicl studies of HUMALOG, twelve percent (n=338) were 65 yers of ge or over. The mjority of these hd type 2 dibetes. HbA1c vlues nd hypoglycemi rtes did not differ by ge. Phrmcokinetic/phrmcodynmic studies to ssess the effect of ge on the onset of HUMALOG ction hve not been performed. 8.6 Renl Impirment Ptients with renl impirment my be t incresed risk of hypoglycemi nd my require more frequent HUMALOG dose djustment nd more frequent blood glucose monitoring [see Clinicl Phrmcology (12.3)]. 8.7 Heptic Impirment Ptients with heptic impirment my be t incresed risk of hypoglycemi nd my require more frequent HUMALOG dose djustment nd more frequent blood glucose monitoring [see Clinicl Phrmcology (12.3)]. 10 OVERDOSAGE Excess insulin dministrtion my cuse hypoglycemi nd hypoklemi. Mild episodes of hypoglycemi usully cn be treted with orl glucose. Adjustments in drug dosge, mel ptterns, or exercise my be needed. More severe episodes with com, seizure, or neurologic impirment my be treted with intrmusculr/subcutneous glucgon or concentrted intrvenous glucose. Sustined crbohydrte intke nd observtion my be necessry becuse hypoglycemi my recur fter pprent clinicl recovery. Hypoklemi must be corrected ppropritely. 11 DESCRIPTION HUMALOG (insulin lispro injection) is rpid-cting humn insulin nlog used to lower blood glucose. Insulin lispro is produced by recombinnt DNA technology utilizing non-pthogenic lbortory strin of Escherichi coli. Insulin lispro differs from humn insulin in tht the mino cid proline t position B28 is replced by lysine nd the lysine in position B29 is replced by proline. Chemiclly, it is Lys(B28), Pro(B29) humn insulin nlog nd hs the empiricl formul C257H383N65O77S6 nd moleculr weight of 5808, both identicl to tht of humn insulin.

8 8 HUMALOG hs the following primry structure: HUMALOG is sterile, queous, cler, nd colorless solution. Ech milliliter of HUMALOG U-100 contins insulin lispro 100 units, 16 mg glycerin, 1.88 mg dibsic sodium phosphte, 3.15 mg Metcresol, zinc oxide content djusted to provide mg zinc ion, trce mounts of phenol, nd Wter for Injection. Insulin lispro hs ph of 7.0 to 7.8. The ph is djusted by ddition of queous solutions of hydrochloric cid 10% nd/or sodium hydroxide 10%. Ech milliliter of HUMALOG U-200 contins insulin lispro 200 units, 16 mg glycerin, 5 mg tromethmine, 3.15 mg Metcresol, zinc oxide content djusted to provide mg zinc ion, trce mounts of phenol, nd Wter for Injection. Insulin lispro hs ph of 7.0 to 7.8. The ph is djusted by ddition of queous solutions of hydrochloric cid 10% nd/or sodium hydroxide 10% CLINICAL PHARMACOLOGY Mechnism of Action Regultion of glucose metbolism is the primry ctivity of insulins nd insulin nlogs, including insulin lispro. Insulins lower blood glucose by stimulting peripherl glucose uptke by skeletl muscle nd ft, nd by inhibiting heptic glucose production. Insulins inhibit lipolysis nd proteolysis, nd enhnce protein synthesis Phrmcodynmics HUMALOG hs been shown to be equipotent to humn insulin on molr bsis. One unit of HUMALOG hs the sme glucose-lowering effect s one unit of regulr humn insulin. Studies in norml volunteers nd ptients with dibetes demonstrted tht HUMALOG hs more rpid onset of ction nd shorter durtion of ctivity thn regulr humn insulin when given subcutneously. The time course of ction of insulin nd insulin nlogs, such s HUMALOG, my vry considerbly in different individuls or within the sme individul. The prmeters of HUMALOG ctivity (time of onset, pek time, nd durtion) s designted in Figure 1 should be considered only s generl guidelines. The rte of insulin bsorption, nd consequently the onset of ctivity re known to be ffected by the site of injection, exercise, nd other vribles [see Wrnings nd Precutions (5.2)]. Figure 1: Blood Glucose Levels After Subcutneous Injection of Regulr Humn Insulin or HUMALOG (0.2 unit/kg) Immeditely Before High Crbohydrte Mel in 10 Ptients with Type 1 Dibetes. Bseline insulin concentrtion ws mintined by infusion of 0.2 mu/min/kg humn insulin. Intrvenous Administrtion of HUMALOG U-100 The glucose lowering effect of intrvenously dministered HUMALOG ws tested in 21 ptients with type 1 dibetes. For the study, the ptients usul doses of insulin were held nd blood glucose concentrtions were llowed to rech stble rnge of 200 to 260 mg/dl during one to three hours run-in phse. The run-in phse ws followed by 6-hour ssessment phse. During the ssessment phse, ptients received intrvenous HUMALOG t n initil infusion rte of 0.5 units/hour. The infusion rte of HUMALOG could be djusted t regulr timed intervls to chieve nd mintin blood glucose concentrtions between 100 to 160 mg/dl.

9 9 The men blood glucose levels during the ssessment phse for ptients on HUMALOG therpy re summrized below in Tble 4. All ptients chieved the trgeted glucose rnge t some point during the 6-hour ssessment phse. At the endpoint, blood glucose ws within the trget rnge (100 to 160 mg/dl) for 17 of 20 ptients treted with HUMALOG. The verge time (±SE) required to ttin ner normoglycemi ws 129 ± 14 minutes for HUMALOG. Tble 4: Men Blood Glucose Concentrtions (mg/dl) During Intrvenous Infusions of HUMALOG U-100 Time from Strt of Infusion (minutes) Men Blood Glucose (mg/dl) Intrvenous ± ± ± ± ± ± ± ± 25 Results shown s men ± SD The phrmcodynmics of single 20 unit dose of HUMALOG U-200 dministered subcutneously were compred to the phrmcodynmics of single 20 unit dose of HUMALOG U-100 dministered subcutneously in euglycemic clmp study enrolling helthy subjects. In this study, the overll, mximum, nd time to mximum glucose lowering effect were similr between HUMALOG U-200 nd HUMALOG U-100. The men re under the glucose infusion rte curves (mesure of overll phrmcodynmic effect) were 125 g nd 126 g for HUMALOG U-200 nd HUMALOG U-100, respectively. The mximum glucose infusion rte ws 534 mg/min nd 559 mg/min nd the corresponding medin time (min, mx) to mximum effect were 2.8 h (0.5 h 6.3 h) nd 2.4 h (0.5 h 4.7 h) for HUMALOG U-200 nd HUMALOG U-100, respectively Phrmcokinetics Absorption nd Biovilbility Studies in helthy volunteers nd ptients with dibetes demonstrted tht HUMALOG is bsorbed more quickly thn regulr humn insulin. In helthy volunteers given subcutneous doses of HUMALOG rnging from 0.1 to 0.4 unit/kg, pek serum levels were seen 30 to 90 minutes fter dosing. When helthy volunteers received equivlent doses of regulr humn insulin, pek insulin levels occurred between 50 to 120 minutes fter dosing. Similr results were seen in ptients with type 1 dibetes (see Figure 2). Figure 2: Serum HUMALOG nd Insulin Levels After Subcutneous Injection of Regulr Humn Insulin or HUMALOG (0.2 unit/kg) Immeditely Before High Crbohydrte Mel in 10 Ptients with Type 1 Dibetes. Bseline insulin concentrtion ws mintined by infusion of 0.2 mu/min/kg humn insulin. HUMALOG U-100 ws bsorbed t consistently fster rte thn regulr humn insulin in helthy mle volunteers given 0.2 unit/kg t bdominl, deltoid, or femorl subcutneous sites. After HUMALOG ws dministered in the bdomen, serum drug levels were higher nd the durtion of ction ws slightly shorter thn fter deltoid or thigh dministrtion. Biovilbility of HUMALOG is similr to tht of regulr humn insulin. The bsolute biovilbility fter subcutneous injection rnges from 55% to 77% with doses between 0.1 to 0.2 unit/kg, inclusive.

10 10 The results of study in helthy subjects demonstrted tht HUMALOG U-200 is bioequivlent to HUMALOG U-100 following dministrtion of single 20 unit dose. The men observed re under the serum insulin concentrtion-time curve from time zero to infinity ws 2360 pmol hr/l nd 2390 pmol hr/l for HUMALOG U-200 nd HUMALOG U-100, respectively. The corresponding men pek serum insulin concentrtion ws 795 pmol/l nd 909 pmol/l for HUMALOG U-200 nd HUMALOG U-100, respectively. The medin time to mximum concentrtion ws 1.0 hour for both formultions. Distribution When dministered intrvenously s bolus injections of 0.1 nd 0.2 U/kg dose in two seprte groups of helthy subjects, the men volume of distribution of HUMALOG ppered to decrese with increse in dose (1.55 nd 0.72 L/kg, respectively) in contrst to tht of regulr humn insulin for which, the volume of distribution ws comprble cross the two dose groups (1.37 nd 1.12 L/kg for 0.1 nd 0.2 U/kg dose, respectively). Metbolism Humn metbolism studies hve not been conducted. However, niml studies indicte tht the metbolism of HUMALOG is identicl to tht of regulr humn insulin. Elimintion After subcutneous dministrtion of HUMALOG, the t1/2 is shorter thn tht of regulr humn insulin (1 versus 1.5 hours, respectively). When dministered intrvenously, HUMALOG nd regulr humn insulin demonstrted similr dose-dependent clernce, with men clernce of 21.0 ml/min/kg nd 21.4 ml/min/kg, respectively (0.1 unit/kg dose), nd 9.6 ml/min/kg nd 9.4 ml/min/kg, respectively (0.2 unit/kg dose). Accordingly, HUMALOG demonstrted men t1/2 of 0.85 hours (51 minutes) nd 0.92 hours (55 minutes), respectively for 0.1 unit/kg nd 0.2 unit/kg doses, nd regulr humn insulin men t1/2 ws 0.79 hours (47 minutes) nd 1.28 hours (77 minutes), respectively for 0.1 unit/kg nd 0.2 unit/kg doses. Specific Popultions The effects of ge, gender, rce, obesity, pregnncy, or smoking on the phrmcokinetics of HUMALOG hve not been studied. Renl Impirment Type 2 dibetic ptients with vrying degree of renl impirment showed no difference in phrmcokinetics of regulr insulin nd HUMALOG. However, the sensitivity of the ptients to insulin did chnge, with n incresed response to insulin s the renl function declined. Some studies with humn insulin hve shown incresed circulting levels of insulin in ptients with renl impirment. Creful glucose monitoring nd dose djustments of insulin, including HUMALOG, my be necessry in ptients with renl dysfunction. Heptic Impirment Type 2 dibetic ptients with impired heptic function showed no effect on the phrmcokinetics of HUMALOG s compred to ptients with no heptic dysfunction. However, some studies with humn insulin hve shown incresed circulting levels of insulin in ptients with liver filure. Creful glucose monitoring nd dose djustments of insulin, including HUMALOG, my be necessry in ptients with heptic dysfunction NONCLINICAL TOXICOLOGY Crcinogenesis, Mutgenesis, Impirment of Fertility Stndrd 2-yer crcinogenicity studies in nimls hve not been performed. In Fischer 344 rts, 12-month repet-dose toxicity study ws conducted with insulin lispro t subcutneous doses of 20 nd 200 units/kg/dy (pproximtely 3 nd 32 times the humn subcutneous dose of 1 unit/kg/dy, bsed on units/body surfce re). Insulin lispro did not produce importnt trget orgn toxicity including mmmry tumors t ny dose. Insulin lispro ws not mutgenic in the following genetic toxicity ssys: bcteril muttion, unscheduled DNA synthesis, mouse lymphom, chromosoml berrtion nd micronucleus ssys. Mle fertility ws not compromised when mle rts given subcutneous insulin lispro injections of 5 nd 20 units/kg/dy (0.8 nd 3 times the humn subcutneous dose of 1 unit/kg/dy, bsed on units/body surfce re) for 6 months were mted with untreted femle rts. In combined fertility, perintl, nd postntl study in mle nd femle rts given 1, 5, nd 20 units/kg/dy subcutneously (0.16, 0.8, nd 3 times the humn subcutneous dose of 1 unit/kg/dy, bsed on units/body surfce re), mting nd fertility were not dversely ffected in either gender t ny dose Animl Toxicology nd/or Phrmcology In stndrd biologicl ssys in fsted rbbits, 0.2 unit/kg of insulin lispro injected subcutneously hd the sme glucose-lowering effect nd hd more rpid onset of ction s 0.2 unit/kg of regulr humn insulin. 14 CLINICAL STUDIES The sfety nd efficcy of HUMALOG U-100 were studied in children, dolescent, nd dult ptients with type 1 dibetes (n=789) nd dult ptients with type 2 dibetes (n=722) Type 1 Dibetes Adults nd Adolescents A 12-month, rndomized, prllel, open-lbel, ctive-controlled study ws conducted in ptients with type 1 dibetes to ssess the sfety nd efficcy of HUMALOG (n=81) compred with Humulin R [REGULAR insulin humn injection, USP (rdna origin)] (n=86). HUMALOG ws dministered by subcutneous injection immeditely prior to mels nd Humulin R ws dministered 30 to 45 minutes before mels. Humulin U [ULTRALENTE humn insulin (rdna origin) extended zinc suspension] ws dministered once or twice dily s the bsl insulin. There ws 2- to 4-week run-in period with Humulin R nd Humulin U before rndomiztion. Most ptients were Cucsin (97%). Forty-seven percent of the ptients were mle. The men ge ws 31 yers (rnge 12 to 70 yers). Glycemic control, the totl dily

11 11 doses of HUMALOG nd Humulin R, nd the incidence of severe hypoglycemi (s determined by the number of events tht were not self-treted) were similr in the two tretment groups. There were no episodes of dibetic ketocidosis in either tretment group. Tble 5: Type 1 Dibetes Mellitus Adults nd Adolescents Tretment Durtion 12 months Tretment in Combintion with: Humulin U HUMALOG N 81 Bseline HbA1c (%) 8.2 ± 1.4 Chnge from bseline HbA1c (%) -0.1 ± 0.9 Tretment Difference in HbA1c Men (95% confidence intervl) 0.4 (0.0, 0.8) Bseline short-cting insulin dose (units/kg/dy) 0.3 ± 0.1 End-of-Study short-cting insulin dose (units/kg/dy) 0.3 ± 0.1 Chnge from bseline short-cting insulin dose (units/kg/dy) 0.0 ± 0.1 Bseline Body weight (kg) 72 ± 12.7 Weight chnge from bseline (kg) 1.4 ± 3.6 b Ptients with severe hypoglycemi (n, %) 14 (17%) Vlues re Men ± SD b Severe hypoglycemi refers to hypoglycemi for which ptients were not ble to self-tret. Humulin R ± ± ± ± ± ± ± (21%) 14.2 Type 2 Dibetes Adults A 6-month rndomized, crossover, open-lbel, ctive-controlled study ws conducted in insulin-treted ptients with type 2 dibetes (n=722) to ssess the sfety nd efficcy of HUMALOG for 3 months followed by Humulin R for 3 months or the reverse sequence. HUMALOG ws dministered by subcutneous injection immeditely before mels nd Humulin R ws dministered 30 to 45 minutes before mels. Humulin N [NPH humn insulin (rdna origin) isophne suspension] or Humulin U ws dministered once or twice dily s the bsl insulin. All ptients prticipted in 2- to 4week run-in period with Humulin R nd Humulin N or Humulin U. Most of the ptients were Cucsin (88%), nd the numbers of men nd women in ech group were pproximtely equl. The men ge ws 58.6 yers (rnge 23.8 to 85 yers). The verge body mss index (BMI) ws 28.2 kg/m2. During the study, the mjority of ptients used Humulin N (84%) compred with Humulin U (16%) s their bsl insulin. The reductions from bseline in HbA1c nd the incidence of severe hypoglycemi (s determined by the number of events tht were not self-treted) were similr between the two tretments from the combined groups (see Tble 6). Tble 6: Type 2 Dibetes Mellitus Adults Bseline HbA1c (%) 8.9 ± 1.7 Chnge from bseline HbA1c (%) Short-cting insulin dose (units/kg/dy) 0.3 ± 0.2 Chnge from bseline short-cting insulin dose (units/kg/dy) Body weight (kg) 80 ± 15 Weight chnge from bseline b Ptients with severe hypoglycemi (n, %) Vlues re Men ± SD b Severe hypoglycemi refers to hypoglycemi for which ptients were not ble to self-tret. End point HUMALOG Humulin R + + Bsl Bsl 8.2 ± ± ± ± ± ± ± ± ± ± ± ± (2%) 16 (2%) 14.3 Type 1 Dibetes Peditric nd Adolescents An 8-month, crossover study of dolescents with type 1 dibetes (n=463), ged 9 to 19 yers, compred two subcutneous multiple-dose tretment regimens: HUMALOG or Humulin R, both dministered with Humulin N (NPH humn insulin) s the bsl insulin. HUMALOG chieved glycemic control comprble to Humulin R, s mesured by HbA1c (see Tble 7), nd both tretment groups hd comprble incidence of hypoglycemi. In 9-month, crossover study of prepubescent children (n=60) with type 1 dibetes, ged 3 to 11 yers, HUMALOG dministered immeditely before mels, HUMALOG dministered immeditely fter mels nd Humulin R dministered 30 minutes before mels resulted in similr glycemic control, s mesured by HbA1c, nd incidence of hypoglycemi, regrdless of tretment group. Tble 7: Peditric Subcutneous Administrtion of HUMALOG in Type 1 Dibetes

12 12 Bseline End point HUMALOG Humulin R + + NPH NPH 8.7 ± ± ± ± ± ± ± ± ± ± ± ± (1.1%) 5 (1.1%) 11 (2.4%) 9 (1.9%) HbA1c (%) 8.6 ± 1.5 Chnge from bseline HbA1c (%) Short-cting insulin dose (units/kg/dy) 0.5 ± 0.2 Chnge from bseline short-cting insulin dose (units/kg/dy) Body weight (kg) 59.1 ± 13.1 Weight chnge from bseline (kg) Ptients with severe hypoglycemi (n, %)b Dibetic ketocidosis (n, %) Vlues re Men ± SD b Severe hypoglycemi refers to hypoglycemi tht required glucgon or glucose injection or resulted in com Type 1 Dibetes Adults Continuous Subcutneous Insulin Infusion To evlute the dministrtion of HUMALOG U-100 vi externl insulin pumps, two open-lbel, crossover design studies were performed in ptients with type 1 dibetes. One study involved 39 ptients, ges 19 to 58 yers, treted for 24 weeks with HUMALOG or regulr humn insulin. After 12 weeks of tretment, the men HbA1c vlues decresed from 7.8% to 7.2% in the HUMALOG-treted ptients nd from 7.8% to 7.5% in the regulr humn insulin-treted ptients. Another study involved 60 ptients (men ge 39, rnge 15 to 58 yers) treted for 24 weeks with either HUMALOG or buffered regulr humn insulin. After 12 weeks of tretment, the men HbA1c vlues decresed from 7.7% to 7.4% in the HUMALOG-treted ptients nd remined unchnged from 7.7% in the buffered regulr humn insulin-treted ptients. Rtes of hypoglycemi were comprble between tretment groups in both studies Type 1 Dibetes Peditric Continuous Subcutneous Insulin Infusion A rndomized, 16-week, open-lbel, prllel design, study of children nd dolescents with type 1 dibetes (n=298) ged 4 to 18 yers compred two subcutneous infusion regimens dministered vi n externl insulin pump: insulin sprt (n=198) or HUMALOG U-100 (n=100). These two tretments resulted in comprble chnges from bseline in HbA1c nd comprble rtes of hypoglycemi fter 16 weeks of tretment (see Tble 8). Infusion site rections were similr between groups. Tble 8: Peditric Insulin Pump Study in Type 1 Dibetes (16 weeks; n=298) HUMALOG Asprt N Bseline HbA1c (%) 8.2 ± ± 0.9 Chnge from Bseline HbA1c (%) -0.1 ± ± 0.8 Tretment Difference in HbA1c, Men (95% confidence intervl) 0.1 (-0.3, 0.1) Bseline insulin dose (units/kg/24 hours) 0.9 ± ± 0.3 End-of-Study insulin dose (units/kg/24 hours) 0.9 ± ± 0.2 b Ptients with severe hypoglycemi (n, %) 8 (8%) 19 (10%) Dibetic ketocidosis (n, %) 0 (0) 1 (0.5%) Bseline body weight (kg) 55.5 ± ± 19.7 Weight Chnge from bseline (kg) 1.6 ± ± 2.1 Vlues re Men ± SD b Severe hypoglycemi refers to hypoglycemi ssocited with centrl nervous system symptoms nd requiring the intervention of nother person or hospitliztion HOW SUPPLIED/STORAGE AND HANDLING How Supplied HUMALOG is vilble s: HUMALOG Totl Volume Concentrtion U-100 vil U-100 vil 1 U-100 crtridge U-100 KwikPen U-100 Junior KwikPen 10 ml 3 ml 3 ml 3 ml 3 ml 100 units/ml 100 units/ml 100 units/ml 100 units/ml 100 units/ml Totl Units Avilble in Presenttion 1000 units 300 units 300 units 300 units 300 units NDC Number Mx Dose per Injection Dose Increment Pckge Size n/ n/ n/ 60 units 30 units n/ n/ n/ 1 unit 0.5 units 1 vil 1 vil 5 crtridges 5 pens 5 pens

13 13 U-200 KwikPen 3 ml 200 units/ml 600 units units 1 unit 2 pens Ech prefilled KwikPen, crtridge, nd reusble pen comptible with Lilly 3 ml crtridges is for use by single ptient. HUMALOG KwikPens, crtridges, nd reusble pens comptible with Lilly 3 ml crtridges must never be shred between ptients, even if the needle is chnged. Ptients using HUMALOG vils must never shre needles or syringes with nother person Storge nd Hndling Do not use fter the expirtion dte. Unopened HUMALOG should be stored in refrigertor (36 to 46 F [2 to 8 C]), but not in the freezer. Do not use HUMALOG if it hs been frozen. In-use HUMALOG vils, crtridges, nd HUMALOG KwikPen should be stored t room temperture, below 86 F (30 C) nd must be used within 28 dys or be discrded, even if they still contin HUMALOG. Protect from direct het nd light. See tble below: 10 ml vil Not In-Use (Unopened) Not In-Use (Unopened) Room Temperture Refrigerted (Below 86 F [30 C]) HUMALOG U dys Until expirtion dte 3 ml vil 28 dys Until expirtion dte 3 ml crtridge 28 dys Until expirtion dte 3 ml Humlog KwikPen (prefilled) 3 ml Humlog Junior KwikPen (prefilled) 28 dys Until expirtion dte 28 dys Until expirtion dte 3 ml Humlog KwikPen (prefilled) 28 dys HUMALOG U-200 Until expirtion dte In-Use (Opened) Room Temperture, (Below 86 F [30 C]) 28 dys, refrigerted/room temperture. 28 dys, refrigerted/room temperture. 28 dys, Do not refrigerte. 28 dys, Do not refrigerte. 28 dys, Do not refrigerte. 28 dys, Do not refrigerte. Use in n Externl Insulin Pump Chnge the HUMALOG U-100 in the reservoir t lest every 7 dys, chnge the infusion sets nd the infusion set insertion site t lest every 3 dys or fter exposure to tempertures tht exceed 98.6 F (37 C). A HUMALOG 3 ml crtridge used in the D-Tron pumps should be discrded fter 7 dys, even if it still contins HUMALOG. However, s with other externl insulin pumps, the infusion set should be replced nd new infusion set insertion site should be selected t lest every 3 dys. Diluted HUMALOG U-100 for Subcutneous Injection Diluted HUMALOG my remin in ptient use for 28 dys when stored t 41 F (5 C) nd for 14 dys when stored t 86 F (30 C). Do not dilute HUMALOG contined in crtridge or HUMALOG used in n externl insulin pump Preprtion nd Hndling Diluted HUMALOG U-100 for Subcutneous Injection HUMALOG my be diluted with Sterile Diluent for HUMALOG for subcutneous injection. Diluting one prt HUMALOG to nine prts diluent will yield concentrtion onetenth tht of HUMALOG (equivlent to U-10). Diluting one prt HUMALOG to one prt diluent will yield concentrtion one-hlf tht of HUMALOG (equivlent to U-50) Admixture for Intrvenous Administrtion Infusion bgs prepred with HUMALOG U-100 re stble when stored in refrigertor (2 to 8 C [36 to 46 F]) for 48 hours nd then my be used t room temperture for up to n dditionl 48 hours [see Dosge nd Administrtion (2.2)]. 17 PATIENT COUNSELING INFORMATION Advise the ptient to red the FDA-pproved ptient lbeling (Ptient Informtion nd Instructions for Use) Never Shre HUMALOG KwikPen, Crtridge, Reusble Pen Comptible with Lilly 3 ml Crtridges, or Syringe Between Ptients Advise ptients tht they must never shre HUMALOG KwikPen, crtridge, or reusble pen comptible with Lilly 3 ml crtridges with nother person, even if the needle is chnged. Advise ptients using HUMALOG vils not to shre needles or syringes with nother person. Shring poses risk for trnsmission of blood-borne pthogens Hypoglycemi Instruct ptients on self-mngement procedures including glucose monitoring, proper injection technique, nd mngement of hypoglycemi nd hyperglycemi, especilly t initition of HUMALOG therpy. Instruct ptients on hndling of specil situtions such s intercurrent conditions (illness, stress, or emotionl disturbnces), n indequte or