See 17 for PATIENT COUNSELING INFORMATION and FDAapproved patient labeling. Revised: 6/2016 FULL PRESCRIBING INFORMATION: CONTENTS*

Transcription

1 1 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include ll the informtion needed to use BASAGLAR sfely nd effectively. See full prescribing informtion for BASAGLAR BASAGLAR (insulin glrgine injection), for subcutneous use Initil U.S. Approvl: RECENT MAJOR CHANGES Dosge nd Administrtion (.1) 06/ INDICATIONS AND USAGE BASAGLAR is long-cting humn insulin nlog indicted to improve glycemic control in dults nd peditric ptients with type 1 dibetes mellitus nd in dults with type dibetes mellitus. (1) Limittions of Use: Not recommended for treting dibetic ketocidosis. (1) DOSAGE AND ADMINISTRATION Individulize dosge bsed on metbolic needs, blood glucose monitoring, glycemic control, type of dibetes, prior insulin use. (.,.3,.4) Administer subcutneously once dily t ny time of dy, but t the sme time every dy. (.) Rotte injection sites to reduce the risk of lipodystrophy. (.1) Closely monitor glucose when converting to BASAGLAR nd during initil weeks therefter. (.) Do not dilute or mix with ny other insulin or solution. (.1) DOSAGE FORMS AND STRENGTHS Injection: 100 units/ml (U-100) in 3 ml prefilled BASAGLAR KwikPen delivery device. (3) CONTRAINDICATIONS During episodes of hypoglycemi. (4) Hypersensitivity to BASAGLAR or one of its excipients. (4) WARNINGS AND PRECAUTIONS Never shre BASAGLAR KwikPen between ptients, even if the needle is chnged. (5.1) Hyper- or hypoglycemi with chnges in insulin regimen: Crry out under close medicl supervision. (5.) Hypoglycemi: My be life-thretening. Increse frequency of glucose monitoring with chnges to: insulin dosge, co-dministered glucose lowering medictions, mel pttern, physicl ctivity; nd in ptients with renl or heptic impirment nd hypoglycemi unwreness. (5.3, 6.1) Mediction Errors: Accidentl mix-ups between insulin products cn occur. Instruct ptients to check insulin lbels before injection. (5.4) Hypersensitivity rections: Severe, life-thretening, generlized llergy, including nphylxis, cn occur. Discontinue BASAGLAR, monitor nd tret if indicted. (5.5, 6.1) 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) ADVERSE REACTIONS Adverse rections commonly ssocited with insulin glrgine products (5% or greter incidence) re: Hypoglycemi, llergic rections, injection site rection, lipodystrophy, pruritus, rsh, edem, nd weight gin. (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 ffect glucose metbolism: Adjustment of insulin dosge my be needed; closely monitor blood glucose. (7) Anti-Adrenergic Drugs (e.g., bet-blockers, clonidine, gunethidine, nd reserpine): Signs nd symptoms of hypoglycemi my be reduced or bsent. (7) USE IN SPECIFIC POPULATIONS Pregnncy: Use during pregnncy only if the potentil benefit justifies the potentil risk to the fetus. (8.1) See 17 for PATIENT COUNSELING INFORMATION nd FDApproved ptient lbeling. Revised: 6/016 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE DOSAGE AND ADMINISTRATION.1 Importnt Administrtion Instructions. Generl Dosing Instructions.3 Initition of BASAGLAR Therpy.4 Chnging to BASAGLAR from Other Therpies 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Never Shre BASAGLAR KwikPen Between Ptients 5. Hyperglycemi or Hypoglycemi with Chnges in Regimen 5.3 Hypoglycemi 5.4 Mediction Errors 5.5 Hypersensitivity nd Allergic Rections 5.6 Hypoklemi 5.7 Fluid Retention nd Hert Filure with Concomitnt Use of PPAR-gmm Agonists 6 ADVERSE REACTIONS 6.1 Clinicl Tril Experience 6. Immunogenicity 6.3 Postmrketing Experience 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnncy 8.3 Nursing Mothers 8.4 Peditric Use Geritric Use Renl Impirment Heptic Impirment Obesity 10 OVERDOSAGE 11 DESCRIPTION 1 CLINICAL PHARMACOLOGY 1.1 Mechnism of Action 1. Phrmcodynmics 1.3 Phrmcokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Crcinogenesis, Mutgenesis, Impirment of Fertility 14 CLINICAL STUDIES 14.1 Overview of Clinicl Studies 14. Clinicl Studies in Adult nd Peditric Ptients with Type 1 Dibetes 14.3 Clinicl Studies in Adults with Type Dibetes 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16. Storge nd Hndling 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing informtion re not listed.

2 FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE BASAGLAR is indicted to improve glycemic control in dults nd peditric ptients with type 1 dibetes mellitus nd in dults with type dibetes mellitus. Limittions of Use BASAGLAR is not recommended for the tretment of dibetic ketocidosis DOSAGE AND ADMINISTRATION Importnt Administrtion Instructions Alwys check insulin lbels before dministrtion [see Wrnings nd Precutions (5.4)]. Trin ptients on proper use nd injection technique before inititing BASAGLAR. Visully inspect BASAGLAR KwikPen for prticulte mtter nd discolortion prior to dministrtion. Only use if the solution is cler nd colorless with no visible prticles. Inject between 1 nd 80 units per injection. Administer BASAGLAR subcutneously into the bdominl re, thigh, or deltoid, nd rotte injection sites within the sme region from one injection to the next to reduce the risk of lipodystrophy [see Adverse Rections (6.1)]. Do not dilute or mix BASAGLAR with ny other insulin or solution s the onset of ction or time to pek effect of BASAGLAR nd the mixed insulin my be ltered in n unpredictble mnner. Do not dminister intrvenously or vi n insulin pump becuse this could result in severe hypoglycemi. Generl Dosing Instructions In ptients with type 1 dibetes, BASAGLAR must be used concomitntly with short-cting insulin. Inject BASAGLAR subcutneously once dily t ny time of dy but t the sme time every dy. Individulize nd titrte the dosge of BASAGLAR bsed on 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), during cute illness, or chnges in renl or heptic function nd should be mde under medicl supervision with pproprite glucose monitoring [see Wrnings nd Precutions (5.)]. Initition of BASAGLAR Therpy The recommended strting dose of BASAGLAR in ptients with type 1 dibetes should be pproximtely onethird of the totl dily insulin requirements. Short- or rpid-cting, pre-mel insulin should be used to stisfy the reminder of the dily insulin requirements. The recommended strting dose of BASAGLAR in ptients with type dibetes is 0. units/kg or up to 10 units once dily. One my need to djust the mount nd timing of short- or rpid-cting insulins nd dosges of ny nti-dibetic drugs. Chnging to BASAGLAR from Other Therpies If chnging ptients from nother insulin glrgine product, 100 units/ml, to BASAGLAR, the dose of BASAGLAR should be the sme s the other insulin glrgine product, 100 units/ml, nd the time of dy for dministrtion should be determined by the physicin. If chnging ptients from once-dily insulin glrgine product, 300 units/ml, to once-dily BASAGLAR, the recommended initil BASAGLAR dosge is 80% of the insulin glrgine product, 300 units/ml, dose tht is being discontinued. This dosge reduction will lower the likelihood of hypoglycemi [see Wrnings nd Precutions (5.)]. If chnging from tretment regimen with n intermedite- or long-cting insulin (other thn n insulin glrgine product, 100 units/ml) to regimen with BASAGLAR, chnge in the dose of the bsl insulin my be required nd the mount nd timing of shorter-cting insulins nd doses of ny nti-dibetic drugs my need to be djusted. If chnging ptients from twice-dily NPH insulin to once-dily BASAGLAR, the recommended initil BASAGLAR dosge is 80% of the totl NPH dosge tht is being discontinued. This dosge reduction will lower the likelihood of hypoglycemi [see Wrnings nd Precutions (5.)]. 3 DOSAGE FORMS AND STRENGTHS Avilble s cler, colorless, sterile solution for injection: 100 units per ml (U-100) in 3 ml prefilled delivery device (BASAGLAR KwikPen ) 4 CONTRAINDICATIONS BASAGLAR is contrindicted:

3 5 5.1 During episodes of hypoglycemi [see Wrnings nd Precutions (5.3)]. In ptients with hypersensitivity to insulin glrgine or one of its excipients [see Wrnings nd Precutions (5.5)]. 3 WARNINGS AND PRECAUTIONS Never Shre BASAGLAR KwikPen Between Ptients BASAGLAR KwikPens must never be shred between ptients, even if the needle is chnged. Shring poses risk for trnsmission of blood-borne pthogens. 5. Hyperglycemi or Hypoglycemi with Chnges in 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 only under close medicl supervision, nd the frequency of blood glucose monitoring should be incresed. For ptients with type dibetes, dosge djustments of concomitnt nti-dibetic products my be needed. 5.3 Hypoglycemi Hypoglycemi is the most common dverse rection ssocited with insulins, including BASAGLAR [see Adverse Rections (6.1)]. 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). BASAGLAR, or ny insulin, should not be used during episodes of hypoglycemi [see Contrindictions (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 BASAGLAR 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 (1.)]. The risk of hypoglycemi generlly increses with intensity of glycemic control. 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. The long-cting effect of BASAGLAR my dely recovery from hypoglycemi. 5.4 Mediction Errors Accidentl mix-ups between insulin glrgine product, 100 units/ml, nd other insulins, prticulrly rpid-cting insulins, hve been reported. To void mediction errors between BASAGLAR nd other insulins, instruct ptients to lwys check the insulin lbel before ech injection. 5.5 Hypersensitivity nd Allergic Rections Severe, life-thretening, generlized llergy, including nphylxis, cn occur with insulin products, including BASAGLAR. If hypersensitivity rections occur, discontinue BASAGLAR; tret per stndrd of cre nd monitor until symptoms nd signs resolve [see Adverse Rections (6.1)]. BASAGLAR is contrindicted in ptients who hve hd hypersensitivity rections to insulin glrgine or one of the excipients [see Contrindictions (4)]. 5.6 Hypoklemi All insulin products, including BASAGLAR, 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 BASAGLAR, 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.

4 4 6 ADVERSE REACTIONS The following dverse rections re discussed elsewhere: Hypoglycemi [see Wrnings nd Precutions (5.3)]. Hypersensitivity nd llergic rections [see Wrnings nd Precutions (5.5)]. Hypoklemi [see Wrnings nd Precutions (5.6)]. 6.1 Clinicl Tril Experience Becuse clinicl trils re conducted under widely vrying conditions, dverse rection rtes observed in the clinicl trils of drug cnnot be directly compred to rtes in the clinicl trils of nother drug nd my not reflect the rtes observed in prctice. Two clinicl trils with BASAGLAR were conducted: one in type 1 dibetes nd one in type dibetes. The type 1 dibetes popultion hd the following chrcteristics: Men ge ws 41 yers nd men durtion of dibetes ws 16 yers. 58% were mle. 75% were Cucsin, % Blck or Africn Americn nd 4% Americn Indin or Alskn ntive. 4% were Hispnic. At bseline, men egfr ws 109 ml/min/1.73m percent of ptients hd egfr>90 ml/min/1.73m. The men BMI ws pproximtely 6 kg/m. HbA1c t bseline ws 7.8%. The dt in Tble 1 reflect exposure of 68 ptients to BASAGLAR with men exposure durtion of 49 weeks. The type dibetes popultion hd the following chrcteristics: Men ge ws 59 yers nd men durtion of dibetes ws 11 yers. 50% were mle. 78% were Cucsin, 8% Blck or Africn Americn nd 5% Americn Indin or Alskn ntive. 8% were Hispnic. At bseline, men egfr ws 109 ml/min/1.73m percent of ptients hd egfr>90 ml/min/1.73m. The men BMI ws pproximtely 3 kg/m. HbA1c t bseline ws 8.3%. The dt in Tble reflect exposure of 376 ptients to BASAGLAR with men exposure durtion of weeks. Common dverse rections were defined s rections occurring in 5% of the popultion studied. Common dverse rections during clinicl trils in ptients with type 1 dibetes mellitus nd type dibetes mellitus (other thn hypoglycemi) re listed in Tble 1 nd Tble, respectively. Tble 1: Adverse rections occurring in 5% of dult ptients with type 1 dibetes treted with BASAGLAR in 5-week tril BASAGLAR + Lispro, % (n=68) Infection 4 Nsophryngitis 16 Upper respirtory trct infection 8 Infections other thn nsophryngitis or upper respirtory trct infection. Tble : Adverse rections occurring in 5% of dult ptients with type dibetes treted with BASAGLAR in 4-week tril BASAGLAR + Orl Antidibetic Mediction, % (n=376) Infection 17 Nsophryngitis 6 Upper respirtory trct infection 5 Infections other thn nsophryngitis or upper respirtory trct infection. The frequencies of dverse rections during clinicl tril of 5 yers durtion with nother insulin glrgine product, 100 units/ml, in ptients with type dibetes mellitus re listed in Tble 3. Tble 3: Common dverse rections in 5-yer tril of dult ptients with type dibetes (dverse rections with incidence 10% nd higher with nother insulin glrgine product, 100 units/ml, thn comprtor), % NPH, % (n=514) (n=503) Hypertension 0 19 Sinusitis Ctrct Bronchitis Bck pin 13 1 Cough 1 7 Urinry trct infection Dirrhe 11 10

5 5 Depression Hedche The frequencies of dverse rections during clinicl trils with nother insulin glrgine product, 100 units/ml, in children nd dolescents with type 1 dibetes mellitus re listed in Tble 4. Tble 4: Adverse rections in 8-week clinicl tril of children nd dolescents with type 1 dibetes (dverse rections with frequency 5% nd the sme or higher with nother insulin glrgine product, 100 units/ml, thn comprtor), % NPH, % (n=174) (n=175) Rhinitis 5 5 Severe Hypoglycemi Hypoglycemi is the most commonly observed dverse rection in ptients using insulin, including BASAGLAR [see Wrnings nd Precutions (5.3)]. The rtes of reported hypoglycemi depend on the definition of hypoglycemi used, dibetes type, insulin dose, intensity of glucose control, bckground therpies, nd other intrinsic nd extrinsic ptient fctors. For these resons, compring rtes of hypoglycemi in clinicl trils for BASAGLAR with the incidence of hypoglycemi for other products my be misleding nd lso, my not be representtive of hypoglycemi rtes tht will occur in clinicl prctice. Severe symptomtic hypoglycemi ws defined s n event with symptoms consistent with hypoglycemi requiring the ssistnce of nother person nd ssocited with either blood glucose below 50 mg/dl ( 56 mg/dl in the 5-yer tril nd 36 mg/dl in the ORIGIN tril) or prompt recovery fter orl crbohydrte, intrvenous glucose or glucgon dministrtion. The incidence of severe symptomtic hypoglycemi in ptients receiving BASAGLAR with type 1 dibetes mellitus nd type dibetes mellitus [see Clinicl Studies (14)] ws 4% t 5 weeks nd 1% t 4 weeks, respectively. The incidence of severe symptomtic hypoglycemi in clinicl tril with nother insulin glrgine product, 100 units/ml, in children nd dolescents ge 6 to 15 yers with type 1 dibetes [see Clinicl Studies (14)] ws 3% t 6 weeks. Tble 5 displys the proportion of ptients experiencing severe symptomtic hypoglycemi in nother insulin glrgine product, 100 units/ml, nd Stndrd Cre groups in the ORIGIN Tril [see Clinicl Studies (14)]. Percent of ptients Tble 5: Severe Symptomtic Hypoglycemi in the ORIGIN Tril ORIGIN Tril Medin durtion of follow-up: 6. yers, Stndrd Cre 100 units/ml (N=631) (N=673) 6 Allergic Rections Some ptients tking insulin therpy, including BASAGLAR hve experienced erythem, locl edem, nd pruritus t the site of injection. These conditions were usully self-limiting. Severe cses of generlized llergy (nphylxis) hve been reported [see Wrnings nd Precutions (5.5)]. Peripherl Edem Some ptients tking BASAGLAR hve experienced sodium retention nd edem, prticulrly if previously poor metbolic control is improved by intensified insulin therpy. Lipodystrophy Administrtion of insulin subcutneously, including BASAGLAR, hs resulted in lipotrophy (depression in the skin) or lipohypertrophy (enlrgement or thickening of tissue) in some ptients [see Dosge nd Administrtion (.1)]. Weight gin Weight gin hs occurred with some insulin therpies including BASAGLAR nd hs been ttributed to the nbolic effects of insulin nd the decrese in glycosuri. 6. Immunogenicity As with ll therpeutic proteins, there is potentil for immunogenicity. In 5-week study of type 1 dibetes ptients, 4% of ptients who received BASAGLAR once dily were positive for nti-drug ntibodies (ADA) t lest once during the study, including 17% tht were positive t bseline nd 5% of

6 6 ptients who developed ADA during the study. Sixty-five percent of the ADA positive ptients on BASAGLAR with ntibody testing t week 5 remined ADA positive t week 5. In 4-week study of type dibetes ptients, 17% of ptients who received BASAGLAR once dily were positive for ADA t lest once during the study. Among the subjects who were positive, 5% hd ADA t bseline nd 1% developed ntibodies during the study. The percent binding of ptients positive t bseline on BASAGLAR did not increse significntly during the study. Fifty-one percent of the ADA positive ptients on BASAGLAR with ntibody testing t week 4 remined ADA positive t week 4. There ws no evidence tht these ntibodies hd n impct on efficcy nd sfety outcomes. The detection of ntibody formtion is highly dependent on the sensitivity nd specificity of the ssy nd my be influenced by severl fctors such s: ssy methodology, smple hndling, timing of smple collection, concomitnt mediction, nd underlying disese. For these resons, comprison of the incidence of ntibodies to BASAGLAR with the incidence of ntibodies in other studies or to other products my be misleding. 6.3 Postmrketing Experience The following dverse rections hve been identified during post-pprovl use of nother insulin glrgine product, 100 units/ml. Becuse these rections re reported voluntrily from popultion of uncertin size, it is not lwys possible to estimte relibly their frequency or estblish cusl reltionship to drug exposure. Mediction errors hve been reported in which other insulin products, prticulrly rpid-cting insulins, hve been ccidentlly dministered insted of n insulin glrgine product. To void mediction errors between insulin glrgine products nd other insulin products, ptients should be instructed to lwys verify the insulin lbel before ech injection. 7 DRUG INTERACTIONS Tble 6 includes cliniclly significnt drug interctions with BASAGLAR Tble 6: Cliniclly Significnt Drug Interctions with BASAGLAR Drugs Tht My Increse the Risk of Hypoglycemi Antidibetic gents, ACE inhibitors, ngiotensin II receptor blocking gents, disopyrmide, fibrtes, fluoxetine, monomine oxidse inhibitors, pentoxifylline, prmlintide, Drugs: propoxyphene, slicyltes, somtosttin nlogs (e.g., octreotide), nd sulfonmide ntibiotics. Dose reductions nd incresed frequency of glucose monitoring my be required when Intervention: BASAGLAR is co-dministered with these drugs. Drugs Tht My Decrese the Blood Glucose Lowering Effect of BASAGLAR Atypicl ntipsychotics (e.g., olnzpine nd clozpine), corticosteroids, dnzol, diuretics, estrogens, glucgon, isonizid, nicin, orl contrceptives, phenothizines, Drugs: progestogens (e.g., in orl contrceptives), protese inhibitors, somtropin, sympthomimetic gents (e.g., lbuterol, epinephrine, terbutline), nd thyroid hormones Dose increses nd incresed frequency of glucose monitoring my be required when Intervention: BASAGLAR is co-dministered with these drugs. Drugs Tht My Increse or Decrese the Blood Glucose Lowering Effect of BASAGLAR Alcohol, bet-blockers, clonidine, nd lithium slts. Pentmidine my cuse Drugs: hypoglycemi, which my sometimes be followed by hyperglycemi. Dose djustment nd incresed frequency of glucose monitoring my be required when Intervention: BASAGLAR is co-dministered with these drugs. Drugs Tht My Blunt Signs nd Symptoms of Hypoglycemi Drugs: bet-blockers, clonidine, gunethidine, nd reserpine Incresed frequency of glucose monitoring my be required when BASAGLAR is cointervention: dministered with these drugs USE IN SPECIFIC POPULATIONS Pregnncy Pregnncy Ctegory C Risk Summry 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

7 7 ptients should be dvised to tell their physicins if they intend to become, or if they become pregnnt while tking BASAGLAR. Humn dt There re no well-controlled clinicl studies of the use of insulin glrgine in pregnnt women. Becuse niml reproduction studies re not lwys predictive of humn response, this drug should be used during pregnncy only if the potentil benefit justifies the potentil risk to the fetus. Animl dt Subcutneous reproduction nd tertology studies hve been performed with nother insulin glrgine product nd with regulr humn insulin in rts nd Himlyn rbbits. This other insulin glrgine product ws given to femle rts before mting, during mting, nd throughout pregnncy t dose up to 0.36 mg/kg/dy, which is pproximtely 7 times the recommended humn subcutneous strting dose of 10 units/dy (0.008 mg/kg/dy) bsed on mg/m. In rbbits, doses of 0.07 mg/kg/dy, which is pproximtely times the recommended humn subcutneous strting dose of 10 units/dy (0.008 mg/kg/dy), bsed on mg/m, were dministered during orgnogenesis. The effects of this other insulin glrgine product did not generlly differ from those observed with regulr humn insulin in rts nd rbbits. However, in rbbits, five fetuses from two litters of the high-dose group exhibited diltion of the cerebrl ventricles. Fertility nd erly embryonic development ppered norml. 8.3 Nursing Mothers Endogenous insulin is present in humn milk; it is unknown whether insulin glrgine is excreted in humn milk. Becuse mny drugs, including humn insulin, re excreted in humn milk, cution should be exercised when BASAGLAR is dministered to nursing womn. Use of BASAGLAR is comptible with brestfeeding, but women with dibetes who re lctting my require djustments of their insulin doses. 8.4 Peditric Use The sfety nd effectiveness of BASAGLAR hve been estblished in peditric ptients (ge 6 to 15 yers) with type 1 dibetes bsed on n dequte nd well-controlled tril of nother insulin glrgine product, 100 units/ml, in peditric ptients (ge 6 to 15 yers) with type 1 dibetes nd dditionl dt in dults with type 1 dibetes [see Clinicl Studies (14.)]. The sfety nd effectiveness of BASAGLAR in peditric ptients younger thn 6 yers of ge with type 1 dibetes nd peditric ptients with type dibetes hs not been estblished. The dosge recommendtion when chnging to BASAGLAR in peditric ptients (ge 6 to 15 yers) with type 1 dibetes is the sme s tht described for dults [see Dosge nd Administrtion (.3,.4) nd Clinicl Studies (14)]. As in dults, the dosge of BASAGLAR must be individulized in peditric ptients (ge 6 to 15 yers) with type 1 dibetes bsed on metbolic needs nd frequent monitoring of blood glucose. In the peditric clinicl tril, peditric ptients (ge 6 to 15 yers) with type 1 dibetes hd higher incidence of severe symptomtic hypoglycemi compred to the dults in trils with type 1 dibetes [see Adverse Rections (6.1)]. 8.5 Geritric Use Of the totl number of subjects in clinicl studies of ptients with type dibetes who were treted with BASAGLAR or nother insulin glrgine product, 100 units/ml, ech in combintion with orl gents in controlled clinicl tril environment, 8.3% were 65 nd over, while 4.5% were 75 nd over. No overll differences in sfety or effectiveness were observed between these subjects nd younger subjects, nd other reported clinicl experience hs not identified differences in responses between the elderly nd younger ptients, but greter sensitivity of some older individuls cnnot be ruled out. Nevertheless, cution should be exercised when BASAGLAR is dministered to geritric ptients. In elderly ptients with dibetes, the initil dosing, dose increments, nd mintennce dosge should be conservtive to void hypoglycemic rections. Hypoglycemi my be difficult to recognize in the elderly. 8.6 Renl Impirment The effect of renl impirment on the phrmcokinetics of BASAGLAR hs not been studied. Some studies with humn insulin hve shown incresed circulting levels of insulin in ptients with renl filure. Frequent glucose monitoring nd dose djustment my be necessry for BASAGLAR in ptients with renl impirment [see Wrnings nd Precutions (5.3)]. 8.7 Heptic Impirment The effect of heptic impirment on the phrmcokinetics of BASAGLAR hs not been studied. However, s with ll insulin products, more frequent glucose monitoring nd dose djustment my be necessry for BASAGLAR in ptients with heptic impirment [see Wrnings nd Precutions (5.3)]. 8.8 Obesity In controlled clinicl trils, subgroup nlyses bsed on BMI did not show differences in sfety nd efficcy between BASAGLAR nd nother insulin glrgine product, 100 units/ml. 10 OVERDOSAGE

8 8 Excess insulin dministrtion reltive to food intke, energy expenditure, or both my led to severe nd sometimes prolonged nd life-thretening hypoglycemi nd hypoklemi [see Wrnings nd Precutions (5.3, 5.6)]. Mild episodes of hypoglycemi cn be treted with orl glucose. Adjustments in drug dosge, mel ptterns, or physicl ctivity level 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 BASAGLAR (insulin glrgine injection) is long-cting insulin for subcutneous use. glrgine is recombinnt humn insulin nlog [see Clinicl Phrmcology (1)]. BASAGLAR is produced by recombinnt DNA technology utilizing non-pthogenic lbortory strin of Escherichi coli (K1) s the production orgnism. glrgine differs from humn insulin in tht the mino cid sprgine t position A1 is replced by glycine nd two rginines re dded to the C-terminus of the B-chin. Chemiclly, insulin glrgine is 1A-Gly-30B--L-Arg-30Bb-L-Arghumn insulin nd hs the empiricl formul C67H404N7O78S6 nd moleculr weight of glrgine hs the following structurl formul: BASAGLAR is cler, colorless, sterile queous solution of insulin glrgine. Ech milliliter of BASAGLAR (insulin glrgine injection) contins 100 units ( mg) insulin glrgine. The 3 ml BASAGLAR KwikPen contins the following inctive ingredients per ml: 30 mcg zinc,.7 mg metcresol, 17 mg glycerin, nd wter for injection. The ph is djusted by ddition of queous solutions of hydrochloric cid nd sodium hydroxide. BASAGLAR hs ph of pproximtely CLINICAL PHARMACOLOGY Mechnism of Action The primry ctivity of insulin, including insulin glrgine, is regultion of glucose metbolism. nd its nlog lower blood glucose by stimulting peripherl glucose uptke, especilly by skeletl muscle nd ft, nd by inhibiting heptic glucose production. inhibits lipolysis nd proteolysis, nd enhnces protein synthesis. 1. Phrmcodynmics The phrmcodynmic profile for BASAGLAR ws determined fter subcutneous dministrtion of single 0.5 U/kg dose in euglycemic clmp study conducted in 91 helthy subjects. The medin time to mximum effect of BASAGLAR (mesured by the pek rte of glucose infusion) ws pproximtely 1.0 hours. The phrmcodynmic profile of BASAGLAR following subcutneous injection demonstrted sustined glucose lowering ctivity over 4 hours with no pronounced pek. The men re under the glucose infusion rte curves (mesure of overll phrmcodynmic effect) nd mximum glucose infusion rte were 1670 mg/kg nd.1 mg/kg/min, respectively. A euglycemic clmp study in 0 ptients with type 1 dibetes showed similr phrmcodynmic profile with sustined glucose lowering ctivity over 4 hours following single 0.3 U/kg subcutneous dose of BASAGLAR. After subcutneous injection of 0.3 units/kg of nother insulin glrgine product, 100 units/ml, in ptients with type 1 dibetes, the durtion of ction fter bdominl, deltoid, or thigh subcutneous dministrtion ws similr. The time course of ction of insulins, including insulin glrgine, my vry between individuls nd within the sme individul. 1.3 Phrmcokinetics Absorption nd Biovilbility The phrmcokinetic profile for BASAGLAR ws determined fter subcutneous dministrtion of single 0.5 U/kg dose in euglycemic clmp study conducted in 91 helthy subjects. The insulin serum concentrtions indicted

9 9 slow nd prolonged bsorption nd reltively constnt concentrtion/time profile over 4 hours with no pronounced pek. The medin time to mximum serum insulin concentrtion ws 1 hours fter injection. On verge, serum insulin concentrtions declined to bseline by pproximtely 4 hours. The men observed re under the serum insulin concentrtion-time curve from time zero to 4 hours nd pek serum insulin concentrtion were 170 pmol*hr/l nd 103 pmol/l, respectively. Metbolism nd Elimintion After subcutneous injection of nother insulin glrgine product, 100 units/ml, in dibetic ptients, insulin glrgine is metbolized t the crboxyl terminus of the Bet chin with formtion of two ctive metbolites M1 (1A-Gly-insulin) nd M (1A-Gly-des-30B-Thr-insulin). The in vitro ctivity of M1 nd M were similr to tht of insulin. Specific Popultions Age, Rce, nd Gender: Effect of ge, rce, nd gender on the phrmcokinetics of BASAGLAR hs not been evluted. Obesity: Effect of BMI on the phrmcokinetics of BASAGLAR hs not been evluted NONCLINICAL TOXICOLOGY Crcinogenesis, Mutgenesis, Impirment of Fertility In mice nd rts, stndrd two-yer crcinogenicity studies with nother insulin glrgine product were performed t doses up to mg/kg, which ws for the rt pproximtely 10 times nd for the mouse pproximtely 5 times the recommended humn subcutneous strting dose of 10 units/dy (0.008 mg/kg/dy), bsed on mg/m. The findings in femle mice were not conclusive due to excessive mortlity in ll dose groups during the study. Histiocytoms were found t injection sites in mle rts (sttisticlly significnt) nd mle mice (not sttisticlly significnt) in cid vehicle contining groups. These tumors were not found in femle nimls, in sline control, or insulin comprtor groups using different vehicle. The relevnce of these findings to humns is unknown. insulin glrgine product ws not mutgenic in tests for detection of gene muttions in bcteri nd mmmlin cells (Ames- nd HGPRT-test) nd in tests for detection of chromosoml berrtions (cytogenetics in vitro in V79 cells nd in vivo in Chinese hmsters). In combined fertility nd prentl nd postntl study of nother insulin glrgine product in mle nd femle rts t subcutneous doses up to 0.36 mg/kg/dy, which ws pproximtely 7 times the recommended humn subcutneous strting dose of 10 units/dy (0.008 mg/kg/dy), bsed on mg/m, mternl toxicity due to dose-dependent hypoglycemi, including some deths, ws observed. Consequently, reduction of the rering rte occurred in the high-dose group only. Similr effects were observed with NPH insulin CLINICAL STUDIES Overview of Clinicl Studies The sfety nd effectiveness of nother insulin glrgine product, 100 units/ml, given once-dily t bedtime ws compred to tht of once-dily nd twice-dily NPH insulin in open-lbel, rndomized, ctive-controlled, prllel studies of,37 dults nd 349 peditric ptients with type 1 dibetes mellitus nd 1,563 dult ptients with type dibetes mellitus (see Tbles 8, 9, 11, nd 1). In generl, the reduction in glycted hemoglobin (HbA1c) with this other insulin glrgine product ws similr to tht with NPH insulin. 14. Clinicl Studies in Adult nd Peditric Ptients with Type 1 Dibetes Ptients with indequtely controlled type 1 dibetes prticipted in 4-week open-lbel, ctive-controlled study with 8 week extension to evlute the glucose lowering effect of once-dily BASAGLAR compred to tht of once-dily dministrtion of nother insulin glrgine product, 100 units/ml, or non-u.s.-pproved insulin glrgine product, 100 units/ml, (comprtor insulin glrgine products, 100 units/ml) both in combintion with meltime insulin lispro. Rndomized were 535 dults with type 1 dibetes. Men ge ws 41. yers nd men durtion of dibetes ws yers. 57.9% were mle. 74.5% were Cucsin,.1% Blck or Africn Americn nd 4.3% Americn Indin or Alskn ntive. 3.9% were Hispnic percent of ptients hd GFR>90 ml/min/1.73m. The men BMI ws pproximtely 5.54 kg/m. At week 4, tretment with BASAGLAR provided men reduction in HbA1c tht ws non-inferior to tht chieved with comprtor insulin glrgine products, 100 units/ml (see Tble 7). Tble 7: Type 1 Dibetes Mellitus Adult (BASAGLAR plus Meltime insulin versus Comprtor s, 100 units/ml, plus Meltime ) BASAGLAR + insulin Comprtor lispro s, (N=68 ) 100 units/mlb + insulin Efficcy Prmeter lispro (N=67) HbA1c (%)

10 10 Bseline (men) Chnge from bseline (djusted menc,d) Difference from comprtor (djusted menc,d) (95% CI) (-0.00, 0.19) Proportion of ptients chieving HbA1c <7%d 34.5% 3.% One ptient rndomized to the BASAGLAR group ws not included in the Full Anlysis Set. b Comprtor insulin glrgine products, 100 units/ml refers to nother insulin glrgine product, 100 units/ml, nd nonu.s.-pproved insulin glrgine product, 100 units/ml, used in this study. c ANCOVA Model includes tretment, country nd time of bseline bsl insulin injection (dytime or evening/bedtime) s fixed effects nd bseline HbA1c s covrite. d The results were clculted bsed on the number of ptients in the Full Anlysis Set using their lst observed postbseline vlue of HbA1c. Observed HbA1c dt t 4 weeks were vilble from 56 (95.5%) nd 58 (96.6%) subjects rndomized to the BASAGLAR nd comprtor insulin glrgine products, 100 units/ml, groups, respectively. In two clinicl studies (Studies A nd B), ptients with type 1 dibetes (Study A; n=585, Study B; n=534) were rndomized to 8 weeks of bsl-bolus tretment with nother insulin glrgine product, 100 units/ml, or NPH insulin. Regulr humn insulin ws dministered before ech mel. This other insulin glrgine product ws dministered t bedtime. NPH insulin ws dministered once dily t bedtime or in the morning nd t bedtime when used twice dily. In Study A, the verge ge ws 39. yers. The mjority of ptients were Cucsin (99%) nd 55.7% were mle. The men BMI ws pproximtely 4.9 kg/m. The men durtion of dibetes ws 15.5 yers. In Study B, the verge ge ws 38.5 yers. The mjority of ptients were Cucsin (95.3%) nd 50.6% were mle. The men BMI ws pproximtely 5.8 kg/m. The men durtion of dibetes ws 17.4 yers. In nother clinicl study (Study C), ptients with type 1 dibetes (n=619) were rndomized to 16 weeks of bslbolus tretment with nother insulin glrgine product, 100 units/ml, or NPH insulin. lispro ws used before ech mel. This other insulin glrgine product ws dministered once dily t bedtime nd NPH insulin ws dministered once or twice dily. The verge ge ws 39. yers. The mjority of ptients were Cucsin (96.9%) nd 50.6% were mle. The men BMI ws pproximtely 5.6 kg/m. The men durtion of dibetes ws 18.5 yers. In these 3 studies, nother insulin glrgine product, 100 units/ml, nd NPH insulin hd similr effects on HbA1c (see Tble 8) with similr overll rte of hypoglycemi [see Adverse Rections (6.1)]. Tble 8: Type 1 Dibetes Mellitus Adult (, 100 units/ml, versus NPH) Study A Study B Study C 8 weeks 8 weeks 16 weeks Regulr insulin Regulr insulin lispro Tretment durtion Tretment in combintion with Number of subject treted HbA1c (%) Bseline (men) Adjusted men chnge t tril end Tretment Difference (95% CI) Fsting blood glucose (mg/dl) Bseline (men) Adjusted men chnge t tril end 9 NPH NPH NPH (0.0; + 0.) (-0.1; + 0.) (+0.1; + 0.1) Type 1 Dibetes Peditric (see Tble 9) The efficcy of BASAGLAR to improve glycemic control in peditric ptients with type 1 dibetes mellitus is bsed on n dequte nd well-controlled tril of nother insulin glrgine product, 100 units/ml, in peditric ptients with type 1 dibetes mellitus (Study D). In this rndomized, ctive-controlled clinicl study (Study D), peditric ptients (ge rnge 6 to 15 yers) with type 1 dibetes (n=349) were treted for 8 weeks with bsl-bolus insulin regimen where regulr humn insulin ws used before ech mel. Ptients were rndomized to either this other insulin glrgine product dministered once dily t bedtime or NPH insulin dministered once or twice dily. The verge ge ws 11.7 yers. The mjority of ptients were Cucsin (96.8%) nd 51.9% were mle. The men BMI ws pproximtely 18.9 kg/m. The men durtion of dibetes ws 4.8 yers. Similr effects on HbA1c (see Tble 9) were observed in both tretment groups.

11 Tble 9: Type 1 Dibetes Mellitus Peditric (, 100 units/ml, plus Regulr versus NPH plus Regulr ) 11 Study D Number of subjects treted HbA1c Bseline men Chnge from bseline (djusted men) Difference from NPH (djusted men) (95% CI) Fsting blood glucose (mg/dl) Bseline men Men chnge from bseline + Regulr NPH + Regulr (-0.; +0.3) Clinicl Studies in Adults with Type Dibetes Ptients with type dibetes prticipted in double-blind, ctive-controlled study to evlute the glucose lowering effect of once-dily BASAGLAR plus orl ntidibetic mediction (OAM) compred to tht of nother insulin glrgine product, 100 units/ml, or non-u.s.-pproved insulin glrgine product, 100 units/ml (comprtor insulin glrgine products, 100 units/ml) dministered once-dily long with OAMs. Ptients were either insulin nïve (pproximtely 60%) nd hd filed to chieve dequte glycemic control on t lest OAMs, or were lredy on nother insulin glrgine product, 100 units/ml, or non-u.s.-pproved insulin glrgine product, 100 units/ml, long with t lest OAMs with dequte or indequte glycemic control (pproximtely 40%). A totl of 759 ptients were rndomized. Three ptients rndomized to BASAGLAR did not receive study drug nd were not included in efficcy nlysis. The verge ge ws pproximtely 59 yers. The mjority of ptients were White (78%) nd 50% of the ptients were mle. Sixty-eight percent of ptients hd GFR>90 ml/min/1.73m. The men BMI ws pproximtely 3 kg/m. At week 4, tretment with BASAGLAR provided men reduction in HbA1c tht ws non-inferior to tht chieved with comprtor insulin glrgine products, 100 units/ml (see Tble 10). Tble 10: Type Dibetes Mellitus Adult (BASAGLAR plus Orl Antidibetic Medictions versus Comprtor s, 100 units/ml, plus Orl Antidibetic Medictions) Comprtor BASAGLAR + Orl s, Antidibetic 100 units/mlb + Orl Mediction Antidibetic (N=376) Mediction (N=380) HbA1c (%) Bseline (men) Chnge from bseline (djusted menc,d) Difference from comprtor (djusted menc,d) 0.05 (95% CI) (-0.07, 0.17) Proportion of ptients chieving HbA1c <7%d 48.8% 5.5% Three ptients rndomized to BASAGLAR did not receive study drug nd were not included in the Full Anlysis Set. b Comprtor insulin glrgine products, 100 units/ml refers to nother insulin glrgine product, 100 units/ml, nd nonu.s.-pproved insulin glrgine product, 100 units/ml, used in this study. c ANCOVA Model includes tretment, country, sulfonylure use nd time of bseline bsl insulin injection (dytime or evening/bedtime) s fixed effects nd bseline HbA1c s covrite. d The results were clculted bsed on the number of ptients in the Full Anlysis Set using their lst observed postbseline vlue of HbA1c. Observed HbA1c dt t 4 weeks were vilble from 331 (88%) nd 39 (87%) subjects rndomized to the BASAGLAR nd comprtor insulin glrgine products, 100 units/ml, groups, respectively. In rndomized, controlled clinicl study (Study E) (n=570), nother insulin glrgine product, 100 units/ml, ws evluted for 5 weeks in combintion with orl nti-dibetic medictions ( sulfonylure, metformin, crbose, or combintion of these drugs). The verge ge ws 59.5 yers. The mjority of ptients were Cucsin (9.8%) nd 53.7% were mle. The men BMI ws pproximtely 9.1 kg/m. The men durtion of dibetes ws 10.3 yers. This other insulin glrgine product dministered once dily t bedtime ws s effective s NPH insulin dministered once dily

12 1 t bedtime in reducing HbA1c nd fsting glucose (see Tble 11). The rte of hypoglycemi ws similr in this other insulin glrgine product nd NPH insulin treted ptients [see Adverse Rections (6.1)]. In rndomized, controlled clinicl study (Study F), in ptients with type dibetes not using orl nti-dibetic medictions (n=518), bsl-bolus regimen of nother insulin glrgine product, 100 units/ml, once dily t bedtime or NPH insulin dministered once or twice dily ws evluted for 8 weeks. Regulr humn insulin ws used before mels, s needed. The verge ge ws 59.3 yers. The mjority of ptients were Cucsin (80.7%) nd 60% were mle. The men BMI ws pproximtely 30.5 kg/m. The men durtion of dibetes ws 13.7 yers. This other insulin glrgine product hd similr effectiveness s either once- or twice dily NPH insulin in reducing HbA1c nd fsting glucose (see Tble 11) with similr incidence of hypoglycemi [see Adverse Rections (6.1)]. In rndomized, controlled clinicl study (Study G), ptients with type dibetes were rndomized to 5 yers of tretment with nother insulin glrgine product, 100 units/ml, once-dily or twice-dily NPH insulin. For ptients not previously treted with insulin, the strting dose of this other insulin glrgine product or NPH insulin ws 10 units dily. Ptients who were lredy treted with NPH insulin either continued on the sme totl dily NPH insulin dose or strted this other insulin glrgine product t dose tht ws 80% of the totl previous NPH insulin dose. The primry endpoint for this study ws comprison of the progression of dibetic retinopthy by 3 or more steps on the ETDRS scle. HbA1c chnge from bseline ws secondry endpoint. Similr glycemic control in the tretment groups ws desired in order to not confound the interprettion of the retinl dt. Ptients or study personnel used n lgorithm to djust this other insulin glrgine product nd NPH insulin doses to trget fsting plsm glucose 100 mg/dl. After this other insulin glrgine product or NPH insulin dose ws djusted, other nti-dibetic gents, including pre-mel insulin were to be djusted or dded. The verge ge ws 55.1 yers. The mjority of ptients were Cucsin (85.3%) nd 53.9% were mle. The men BMI ws pproximtely 34.3 kg/m. The men durtion of dibetes ws 10.8 yers. This other insulin glrgine product group hd smller men reduction from bseline in HbA1c compred to the NPH insulin group, which my be explined by the lower dily bsl insulin doses in this other insulin glrgine product group (see Tble 11). Both tretment groups hd similr incidence of reported symptomtic hypoglycemi. The incidence of severe symptomtic hypoglycemi in the ORIGIN Tril is given in Tble 5 [see Adverse Rections (6.1)]. Tble 11: Type Dibetes Mellitus Adult (, 100 units/ml, versus NPH) Study E Study F Study G 5 weeks 8 weeks 5 yers Orl gents Regulr insulin Regulr insulin Tretment durtion Tretment in combintion with NPH NPH NPH Number of subjects treted HbA1c Bseline men Adjusted men chnge from bseline insulin glrgine product, units/ml NPH 95% CI for Tretment difference (-0.3; +0.1) (0.0; +0.4) (+0.1; +0.4) Fsting blood glucose (mg/dl) Bseline men Adjusted men chnge from bseline, 100 units/ml, Timing of Dily Dosing (see Tble 1) The sfety nd efficcy of this other insulin glrgine product dministered pre-brekfst, pre-dinner, or t bedtime were evluted in rndomized, controlled clinicl study in ptients with type 1 dibetes (Study H; n=378). Ptients were lso treted with insulin lispro t meltime. The verge ge ws 40.9 yers. All ptients were Cucsin (100%) nd 53.7% were mle. The men BMI ws pproximtely 5.3 kg/m. The men durtion of dibetes ws 17.3 yers. This other insulin glrgine product dministered t different times of the dy resulted in similr reductions in HbA1c compred to tht with bedtime dministrtion (see Tble 1). In these ptients, dt re vilble from 8-point home glucose monitoring. The mximum men blood glucose ws observed just prior to injection of this other insulin glrgine product regrdless of time of dministrtion. In this study, 5% of ptients in this other insulin glrgine product-brekfst rm discontinued tretment becuse of lck of efficcy. No ptients in the other two rms discontinued for this reson. The sfety nd efficcy of this other insulin glrgine product dministered pre-brekfst or t bedtime were lso evluted in rndomized, ctive-controlled clinicl

13 13 study (Study I, n=697) in ptients with type dibetes not dequtely controlled on orl nti-dibetic therpy. All ptients in this study lso received glimepiride 3 mg dily. The verge ge ws 60.8 yers. The mjority of ptients were Cucsin (96.6%) nd 53.7% were mle. The men BMI ws pproximtely 8.7 kg/m. The men durtion of dibetes ws 10.1 yers. This other insulin glrgine product given before brekfst ws t lest s effective in lowering HbA1c s this other insulin glrgine product given t bedtime or NPH insulin given t bedtime (see Tble 1). Tble 1: Type 1 Dibetes Mellitus Adults (, 100 units/ml, plus Lispro) nd Type Dibetes Mellitus Adults (, 100 units/ml, plus Glimepiride versus NPH plus Glimepiride) Study H Study I 4 weeks 4 weeks lispro Glimepiride Tretment durtion Tretment in combintion with NPH Brekfst Dinner Bedtime Brekfst Bedtime Bedtime Number of subjects treted HbA1c Bseline men Men chnge from bseline Intent to tret. b Totl number of ptients evluble for sfety. c Not pplicble. Five-yer Tril Evluting the Progression of Retinopthy Retinopthy ws evluted in clinicl studies with nother insulin glrgine product, 100 units/ml, by nlysis of reported retinl dverse events nd fundus photogrphy. The numbers of retinl dverse events reported for this other insulin glrgine product nd NPH insulin tretment groups were similr for ptients with type 1 nd type dibetes. insulin glrgine product, 100 units/ml, ws compred to NPH insulin in 5-yer rndomized clinicl tril tht evluted the progression of retinopthy s ssessed with fundus photogrphy using grding protocol derived from the Erly Tretment Dibetic Retinopthy Scle (ETDRS). Ptients hd type dibetes (men ge 55 yers) with no (86%) or mild (14%) retinopthy t bseline. Men bseline HbA1c ws 8.4%. The primry outcome ws progression by 3 or more steps on the ETDRS scle t study endpoint. Ptients with pre-specified post-bseline eye procedures (pnretinl photocogultion for prolifertive or severe nonprolifertive dibetic retinopthy, locl photocogultion for new vessels, nd vitrectomy for dibetic retinopthy) were lso considered s 3-step progressions regrdless of ctul chnge in ETDRS score from bseline. Retinopthy grders were blinded to tretment group ssignment. The results for the primry endpoint re shown in Tble 13 for both the per-protocol nd Intent-to-Tret popultions, nd indicte similrity of this other insulin glrgine product to NPH in the progression of dibetic retinopthy s ssessed by this outcome. Tble 13: Number (%) of Ptients with 3 or More Step Progression on ETDRS Scle t Endpoint, 100 units/ml (%) NPH (%) Difference,b (SE) 95% CI for difference Per-protocol 53/374 (14.%) 57/363 (15.5%) -.0% (.6%) -7.0% to +3.1% Intent-to-Tret 63/50 (1.5%) 71/487 (14.6%) -.1% (.1%) -6.3% to +.1% Difference = nother insulin glrgine product, 100 units/ml NPH. b Using generlized liner model (SAS GENMOD) with tretment nd bseline HbA1c strt (cutoff 9.0%) s the clssified independent vribles, nd with binomil distribution nd identity link function. The ORIGIN Study The Outcome Reduction with Initil Intervention tril (i.e., ORIGIN) ws n open-lbel, rndomized, -by, fctoril design study. One intervention in ORIGIN compred the effect of nother insulin glrgine product, 100 units/ml, to stndrd cre on mjor dverse crdiovsculr outcomes in 1,537 prticipnts 50 yers of ge with bnorml glucose levels [i.e., impired fsting glucose (IFG) nd/or impired glucose tolernce (IGT)] or erly type dibetes mellitus nd estblished crdiovsculr (i.e., CV) disese or CV risk fctors t bseline. The objective of the tril ws to demonstrte tht use of this other insulin glrgine product could significntly lower the risk of mjor crdiovsculr outcomes compred to stndrd cre. Two co-primry composite crdiovsculr