MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are discussed elsewhere:Hypoglycemia [see Warnings and Precautions (5.3)] Hypersensitivity and allergic reactions [see Warnings and Precautions (5.5)] Hypokalemia [see Warnings and Precautions (5.6)] Hypoglycemia [see Warnings and Precautions (5.3)] Hypersensitivity and allergic reactions [see Warnings and Precautions (5.5)] Hypokalemia [see Warnings and Precautions (5.6)] Adverse reactions commonly associated with Insulin glargine include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, rash, edema, and weight gain. (6.1)To report SUSPECTED ADVERSE REACTIONS, contact sanofi-aventis at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.The data in Table reflect the exposure of 2327 patients with type diabetes to Insulin glargine or NPH. The type diabetes population had the following characteristics: Mean age was 38.5 years. Fifty-four percent were male, 96.9% were Caucasian, 1.8% were Black or African American and 2.7% were Hispanic. The mean BMI was 25.1 kg/m2.The data in Table reflect the exposure of 1563 patients with type diabetes to Insulin glargine or NPH. The type diabetes population had the following characteristics: Mean age was 59.3 years. Fifty-eight percent were male, 86.7% were Caucasian, 7.8% were Black or African American and 9% were Hispanic. The mean BMI was 29.2 kg/m2.The frequencies of adverse events during Insulin glargine clinical trials in patients with type diabetes mellitus and type diabetes mellitus are listed in the tables below.Table 1: Adverse Events in Pooled Clinical Trials up to 28 Weeks Duration in Adults with Type Diabetes (adverse events with frequency >=5%)Insulin glargine, (n=1257)NPH, %(n=1070)Upper respiratory tract infection22.423.1InfectionBody system not specified 9.410.3Accidental injury5.76.4Headache5.54.7Table 2: Adverse Events in Pooled Clinical Trials up to Year Duration in Adults with Type Diabetes (adverse events with frequency >=5%)Insulin glargine, %(n=849)NPH, %(n=714)Upper respiratory tract infection11.413.3InfectionBody system not specified 10.411.6Retinal vascular disorder5.87.4Table 3: Adverse Events in 5-Year Trial of Adults with Type Diabetes (adverse events with frequency >=10%)Insulin glargine, %(n=514)NPH, %(n=503)Upper respiratory tract infection29.033.6Edema peripheral20.022.7Hypertension19.618.9Influenza18.719.5Sinusitis18.517.9Cataract18.115.9Bronchitis15.214.1Arthralgia14.216.1Pain in extremity13.013.1Back pain12.812.3Cough12.17.4Urinary tract infection10.710.1Diarrhea10.710.3Depression10.59.7Headache10.39.3Table 4: Adverse Events in 28-Week Clinical Trial of Children and Adolescents with Type Diabetes (adverse events with frequency >=5%)Insulin glargine, %(n=174)NPH, %(n=175)InfectionBody system not specified 13.817.7Upper respiratory tract infection13.816.0Pharyngitis7.58.6Rhinitis5.25.1. Severe HypoglycemiaHypoglycemia is the most commonly observed adverse reaction in patients using insulin, including Insulin glargine [see Warnings and Precautions (5.3)]. Tables 5, 6, and summarize the incidence of severe hypoglycemia in the Insulin glargine individual clinical trials. Severe symptomatic hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either blood glucose below 50 mg/dL (<=56 mg/dL in the 5-year trial and <=36 mg/dL in the ORIGIN trial) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration.Percentages of Insulin glargine-treated adult patients experiencing severe symptomatic hypoglycemia in the Insulin glargine clinical trials [see Clinical Studies (14)] were comparable to percentages of NPH-treated patients for all treatment regimens (see Tables and 6). In the pediatric phase clinical trial, children and adolescents with type diabetes had higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to the adult trials with type diabetes.Table 5: Severe Symptomatic Hypoglycemia in Patients with Type DiabetesStudy AType DiabetesAdults 28 weeksIn combination with regular insulinStudy BType DiabetesAdults 28 weeksIn combination with regular insulinStudy CType DiabetesAdults 16 weeksIn combination with insulin lisproStudy DType Diabetes Pediatrics 26 weeksIn combination with regular insulinInsulin glargineN=292NPHN=293Insulin glargineN=264NPHN=270Insulin glargineN=310NPHN=309Insulin glargineN=174NPHN=175Percent of patients10.615.08.710.46.55.223.028.6Table 6: Severe Symptomatic Hypoglycemia in Patients with Type DiabetesStudy EType DiabetesAdults 52 weeksIn combination with oral agentsStudy FType DiabetesAdults 28 weeksIn combination with regular insulinStudy GType DiabetesAdults yearsIn combination with regular insulinInsulin glargineN=289NPHN=281Insulin glargineN=259NPHN=259Insulin glargineN=513NPHN=504Percent of patients1.71.10.42.37.811.9Table displays the proportion of patients experiencing severe symptomatic hypoglycemia in the Insulin glargine and Standard Care groups in the ORIGIN Trial [see Clinical Studies (14)].Table 7: Severe Symptomatic Hypoglycemia in the ORIGIN TrialORIGIN TrialMedian duration of follow-up: 6.2 yearsInsulin glargineN=6231Standard CareN=6273Percent of patients5.61.8. Peripheral EdemaSome patients taking Insulin glargine have experienced sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.. LipodystrophyAdministration of insulin subcutaneously, including Insulin glargine, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients [see Dosage and Administration (2.2)].. Insulin Initiation and Intensification of Glucose ControlIntensification or rapid improvement in glucose control has been associated with transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.. Weight GainWeight gain has occurred with some insulin therapies including Insulin glargine and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.. Allergic Reactions. Local allergyAs with any insulin therapy, patients taking Insulin glargine may experience injection site reactions, including redness, pain, itching, urticaria, edema, and inflammation. In clinical studies in adult patients, there was higher incidence of treatment-emergent injection site pain in Insulin glargine-treated patients (2.7%) compared to NPH insulin-treated patients (0.7%). The reports of pain at the injection site did not result in discontinuation of therapy.. Systemic allergySevere, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including Insulin glargine and may be life threatening.. 6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. All insulin products can elicit the formation of insulin antibodies. The presence of such insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase clinical trials of Insulin glargine, increases in titers of antibodies to insulin were observed in NPH insulin and Insulin glargine treatment groups with similar incidences.. 6.3 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of Insulin glargine. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Medication errors have been reported in which other insulins, particularly rapid-acting insulins, have been accidentally administered instead of Insulin glargine [see Patient Counseling Information (17)]. To avoid medication errors between Insulin glargine and other insulins, patients should be instructed to always verify the insulin label before each injection.Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with sudden change to an unaffected injection site.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In mice and rats, standard two-year carcinogenicity studies with insulin glargine were performed at doses up to 0.455 mg/kg, which was for the rat approximately 65 times the recommended human subcutaneous starting dose of 0.2 units/kg/day (0.007 mg/kg/day) on mg/kg basis. Histiocytomas were found at injection sites in male rats and mice in acid vehicle containing groups and are considered response to chronic tissue irritation and inflammation in rodents. These tumors were not found in female animals, in saline control, or insulin comparator groups using different vehicle.Insulin glargine was not mutagenic in tests for detection of gene mutations in bacteria and mammalian cells (Ames and HGPRT-test) and in tests for detection of chromosomal aberrations (cytogenetics in vitro in V79 cells and in vivo in Chinese hamsters).In combined fertility and prenatal and postnatal study in male and female rats at subcutaneous doses up to 0.36 mg/kg/day, which was approximately 50 times the recommended human subcutaneous starting dose of 0.2 units/kg/day (0.007 mg/kg/day) maternal toxicity due to dose-dependent hypoglycemia, including some deaths, was observed. Consequently, reduction of the rearing rate occurred in the high-dose group only. Similar effects were observed with NPH insulin.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The primary activity of insulin, including insulin glargine, is regulation of glucose metabolism. Insulin and its analogs lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis.. 12.2 Pharmacodynamics. In clinical studies, the glucose-lowering effect on molar basis (i.e., when given at the same doses) of intravenous insulin glargine is approximately the same as that for human insulin. Figure shows results from study in patients with type diabetes conducted for maximum of 24 hours after the injection. The median time between injection and the end of pharmacological effect was 14.5 hours (range: 9.5 to 19.3 hours) for NPH insulin, and 24 hours (range: 10.8 to >24.0 hours) (24 hours was the end of the observation period) for insulin glargine.Figure 1: Activity Profile in Patients with Type Diabetes Determined as amount of glucose infused to maintain constant plasma glucose levelsThe duration of action after abdominal, deltoid, or thigh subcutaneous administration was similar. The time course of action of insulins, including Insulin glargine, may vary between individuals and within the same individual.. Figure 1. 12.3 Pharmacokinetics. Absorption and BioavailabilityAfter subcutaneous injection of Insulin glargine in healthy subjects and in patients with diabetes, the insulin serum concentrations indicated slower, more prolonged absorption and relatively constant concentration/time profile over 24 hours with no pronounced peak in comparison to NPH insulin.. Metabolism and EliminationA metabolism study in humans indicates that insulin glargine is partly metabolized at the carboxyl terminus of the chain in the subcutaneous depot to form two active metabolites with in vitro activity similar to that of human insulin, M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin). Unchanged drug and these degradation products are also present in the circulation.. Special Populations. Age, race, and genderEffect of age, race, and gender on the pharmacokinetics of Insulin glargine has not been evaluated. However, in controlled clinical trials in adults (n=3890) and controlled clinical trial in pediatric patients (n=349), subgroup analyses based on age, race, and gender did not show differences in safety and efficacy between Insulin glargine and NPH insulin [see Clinical Studies (14)].. ObesityEffect of Body Mass Index (BMI) on the pharmacokinetics of Insulin glargine has not been evaluated.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Overview of Clinical Studies The safety and effectiveness of Insulin glargine given once-daily at bedtime was compared to that of once-daily and twice-daily NPH insulin in open-label, randomized, active-controlled, parallel studies of 2,327 adult patients and 349 pediatric patients with type diabetes mellitus and 1,563 adult patients with type diabetes mellitus (see Tables 9-11). In general, the reduction in glycated hemoglobin (HbA1c) with Insulin glargine was similar to that with NPH insulin.. 14.2Clinical Studies in Adult and Pediatric Patients with Type Diabetes. In two clinical studies (Studies and B), patients with type diabetes (Study n=585, Study n=534) were randomized to 28 weeks of basal-bolus treatment with Insulin glargine or NPH insulin. Regular human insulin was administered before each meal. Insulin glargine was administered at bedtime. NPH insulin was administered either as once daily at bedtime or in the morning and at bedtime when used twice daily.In Study A, the average age was 39.2 years. The majority of patients were White (99%) and 55.7% were male. The mean BMI was approximately 24.9 kg/m2. The mean duration of diabetes was 15.5 years.In Study B, the average age was 38.5 years. The majority of patients were White (95.3%) and 50.6% were male. The mean BMI was approximately 25.8 kg/m2. The mean duration of diabetes was 17.4 years.In another clinical study (Study C), patients with type diabetes (n=619) were randomized to 16 weeks of basal-bolus treatment with Insulin glargine or NPH insulin. Insulin lispro was used before each meal. Insulin glargine was administered once daily at bedtime and NPH insulin was administered once or twice daily. The average age was 39.2 years. The majority of patients were White (96.9%) and 50.6% were male. The mean BMI was approximately 25.6 kg/m2. The mean duration of diabetes was 18.5 years.In these studies, Insulin glargine and NPH insulin had similar effects on HbA1c (Table 9) with similar overall rate of severe symptomatic hypoglycemia [see Adverse Reactions (6.1)].Table 9: Type Diabetes Mellitus AdultStudy AStudy BStudy CTreatment duration28 weeks28 weeks16 weeksTreatment in combination withRegular insulinRegular insulinInsulin lisproInsulin glargineNPHInsulin glargineNPHInsulin glargineNPHNumber of subjects treated292293264270310309HbA1cBaseline HbA1c8.08.07.77.77.67.7Adjusted mean change at trial end+0.2+0.1-0.2-0.2-0.1-0.1Treatment Difference (95% CI)+0.1 (0.0; +0.2)+0.1 (-0.1; +0.2)0.0 (-0.1; +0.1)Basal insulin doseBaseline mean212329292828Mean change from baseline-20-4+2-5+1Total insulin doseBaseline mean485250515050Mean change from baseline-100+4-30Fasting blood glucose (mg/dL)Baseline mean167166166175175173Adj. mean change from baseline-21-16-20-17-29-12Body weight (kg)Baseline mean73.274.875.575.074.875.6Mean change from baseline0.1-0.00.71.00.10.5. Type Diabetes Pediatric (see Table 10)In randomized, controlled clinical study (Study D), pediatric patients (age range to 15 years) with type diabetes (n=349) were treated for 28 weeks with basal-bolus insulin regimen where regular human insulin was used before each meal. Insulin glargine was administered once daily at bedtime and NPH insulin was administered once or twice daily. The average age was 11.7 years. The majority of patients were White (96.8%) and 51.9% were male. The mean BMI was approximately 18.9 kg/m2. The mean duration of diabetes was 4.8 years. Similar effects on HbA1c (Table 10) were observed in both treatment groups [see Adverse Reactions (6.1)].Table 10: Type Diabetes Mellitus PediatricStudy DTreatment duration28 weeksTreatment in combination withRegular insulinInsulin glargine Regular InsulinNPH Regular InsulinNumber of subjects treated174175HbA1cBaseline mean8.58.8Change from baseline (adjusted mean)+0.3+0.3Difference from NPH (adjusted mean)0.0(95% CI )(-0.2; +0.3)Basal insulin doseBaseline mean1919Mean change from baseline-1+2Total insulin doseBaseline mean4343Mean change from baseline+2+3Fasting blood glucose (mg/dL)Baseline mean194191Mean change from baseline-23-12Body weight (kg)Baseline mean45.544.6Mean change from baseline2.22.5. 14.3Clinical Studies in Adults with Type Diabetes In randomized, controlled clinical study (Study E) (n=570), Insulin glargine was evaluated for 52 weeks in combination with oral antidiabetic medications (a sulfonylurea, metformin, acarbose, or combinations of these drugs). The average age was 59.5 years. The majority of patients were White (92.8%) and 53.7% were male. The mean BMI was approximately 29.1 kg/m2. The mean duration of diabetes was 10.3 years. Insulin glargine administered once daily at bedtime was as effective as NPH insulin administered once daily at bedtime in reducing HbA1c and fasting glucose (Table 11). The rate of severe symptomatic hypoglycemia was similar in Insulin glargine and NPH insulin treated patients [see Adverse Reactions (6.1)].In randomized, controlled clinical study (Study F), in patients with type diabetes not using oral antidiabetic medications (n=518), basal-bolus regimen of Insulin glargine once daily at bedtime or NPH insulin administered once or twice daily was evaluated for 28 weeks. Regular human insulin was used before meals, as needed. The average age was 59.3 years. The majority of patients were White (80.7%) and 60% were male. The mean BMI was approximately 30.5 kg/m2. The mean duration of diabetes was 13.7 years. Insulin glargine had similar effectiveness as either once- or twice-daily NPH insulin in reducing HbA1c and fasting glucose (Table 11) with similar incidence of hypoglycemia [see Adverse Reactions (6.1)].In randomized, controlled clinical study (Study G), patients with type diabetes were randomized to years of treatment with once-daily Insulin glargine or twice-daily NPH insulin. For patients not previously treated with insulin, the starting dose of Insulin glargine or NPH insulin was 10 units daily. Patients who were already treated with NPH insulin either continued on the same total daily NPH insulin dose or started Insulin glargine at dose that was 80% of the total previous NPH insulin dose. The primary endpoint for this study was comparison of the progression of diabetic retinopathy by or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. HbA1c change from baseline was secondary endpoint. Similar glycemic control in the treatment groups was desired in order to not confound the interpretation of the retinal data. Patients or study personnel used an algorithm to adjust the Insulin glargine and NPH insulin doses to target fasting plasma glucose <=100 mg/dL. After the Insulin glargine or NPH insulin dose was adjusted, other antidiabetic agents, including premeal insulin were to be adjusted or added. The average age was 55.1 years. The majority of patients were White (85.3%) and 53.9% were male. The mean BMI was approximately 34.3 kg/m2. The mean duration of diabetes was 10.8 years. The Insulin glargine group had smaller mean reduction from baseline in HbA1c compared to the NPH insulin group, which may be explained by the lower daily basal insulin doses in the Insulin glargine group (Table 11). The incidences of severe symptomatic hypoglycemia were similar between groups [see Adverse Reactions (6.1)].Table 11: Type Diabetes Mellitus AdultStudy EStudy FStudy GTreatment duration52 weeks28 weeks5 yearsTreatment in combination withOral agentsRegular insulinRegular insulinInsulin glargineNPHInsulin glargineNPHInsulin glargineNPHNumber of subjects treated289281259259513504HbA1cBaseline mean9.08.98.68.58.48.3Adjusted mean change from baseline-0.5-0.4-0.4-0.6-0.6-0.8Insulin glargine NPH-0.1+0.2+0.295% CI for Treatment difference(-0.3; +0.1)(0.0; +0.4)(+0.1; +0.4)Basal insulin doseIn Study G, the baseline dose of basal or total insulin was the first available on-treatment dose prescribed during the study (on visit month 1.5). Baseline mean141544.145.53944Mean change from baseline+12+9-1+7+23+30Total insulin dose Baseline mean141564674853Mean change from baseline+12+9+10+13+41+40Fasting blood glucose (mg/dL)Baseline mean179180164166190180Adj. mean change from baseline-49-46-24-22-45-44Body weight (kg)Baseline mean83.582.189.690.710099Adj. mean change from baseline2.01.90.41.43.74.8. Insulin Glargine Timing of Daily Dosing (see Table 12)The safety and efficacy of Insulin glargine administered pre-breakfast, pre-dinner, or at bedtime were evaluated in randomized, controlled clinical study in patients with type diabetes (Study H, n=378). Patients were also treated with insulin lispro at mealtime. The average age was 40.9 years. All patients were White (100%) and 53.7% were male. The mean BMI was approximately 25.3 kg/m2. The mean duration of diabetes was 17.3 years. Insulin glargine administered at different times of the day resulted in similar reductions in HbA1c compared to that with bedtime administration (see Table 12). In these patients, data are available from 8-point home glucose monitoring. The maximum mean blood glucose was observed just prior to injection of Insulin glargine regardless of time of administration. In this study, 5% of patients in the Insulin glargine-breakfast arm discontinued treatment because of lack of efficacy. No patients in the other two arms discontinued for this reason. The safety and efficacy of Insulin glargine administered pre-breakfast or at bedtime were also evaluated in randomized, active-controlled clinical study (Study I, n=697) in patients with type diabetes not adequately controlled on oral antidiabetic therapy. All patients in this study also received glimepiride mg daily. The average age was 60.8 years. The majority of patients were White (96.6%) and 53.7% were male. The mean BMI was approximately 28.7 kg/m2. The mean duration of diabetes was 10.1 years. Insulin glargine given before breakfast was at least as effective in lowering HbA1c as Insulin glargine given at bedtime or NPH insulin given at bedtime (see Table 12).Table 12: Insulin Glargine Timing of Daily Dosing in Type (Study H) and Type (Study I) Diabetes MellitusStudy HStudy ITreatment duration24 weeks24 weeksTreatment in combination withInsulin lisproGlimepirideInsulin glargineBreakfastInsulin glargineDinnerInsulin glargineBedtimeInsulin glargineBreakfastInsulin glargineBedtimeNPH BedtimeNumber of subjects treatedIntent-to-treat 112124128234226227HbA1cBaseline mean7.67.57.69.19.19.1Mean change from baseline-0.2-0.10.0-1.3-1.0-0.8Basal insulin dose (U)Baseline mean222321192019Mean change from baseline522111818Total insulin dose (U)NANot applicable NA NA Baseline mean525249---Mean change from baseline232---Body weight (kg)Baseline mean77.177.874.580.78281Mean change from baseline0.70.10.43.93.72.9. Five-Year Trial Evaluating the Progression of RetinopathyRetinopathy was evaluated in the Insulin glargine clinical studies by analysis of reported retinal adverse events and fundus photography. The numbers of retinal adverse events reported for Insulin glargine and NPH insulin treatment groups were similar for patients with type and type diabetes.Insulin glargine was compared to NPH insulin in 5-year randomized clinical trial that evaluated the progression of retinopathy as assessed with fundus photography using grading protocol derived from the Early Treatment Diabetic Retinopathy Scale (ETDRS). Patients had type diabetes (mean age 55 years) with no (86%) or mild (14%) retinopathy at baseline. Mean baseline HbA1c was 8.4%. The primary outcome was progression by or more steps on the ETDRS scale at study endpoint. Patients with prespecified postbaseline eye procedures (pan-retinal photocoagulation for proliferative or severe nonproliferative diabetic retinopathy, local photocoagulation for new vessels, and vitrectomy for diabetic retinopathy) were also considered as 3-step progressors regardless of actual change in ETDRS score from baseline. Retinopathy graders were blinded to treatment group assignment. The results for the primary endpoint are shown in Table 13 for both the per-protocol and intent-to-treat populations, and indicate similarity of Insulin glargine to NPH in the progression of diabetic retinopathy as assessed by this outcome.Table 13: Number (%) of Patients with or More Step Progression on ETDRS Scale at EndpointInsulin glargine (%)NPH (%)DifferenceDifference Insulin glargine NPH Using generalized linear model (SAS GENMOD) with treatment and baseline HbA1c strata (cutoff 9.0%) as the classified independent variables, and with binomial distribution and identity link function (SE)95% CI for differencePer-protocol53/374 (14.2%)57/363 (15.7%)-2.0% (2.6%)-7.0% to +3.1%Intent-to-Treat63/502 (12.5%)71/487 (14.6%)-2.1% (2.1%)-6.3% to +2.1%. The Origin StudyThe Outcome Reduction with Initial Glargine Intervention trial (i.e., ORIGIN) was an open-label, randomized, 2-by-2, factorial design study. One intervention in ORIGIN compared the effect of Insulin glargine to standard care on major adverse cardiovascular outcomes in 12,537 participants >=50 years of age with abnormal glucose levels (i.e., impaired fasting glucose [IFG] and/or impaired glucose tolerance [IGT]) or early type diabetes mellitus and established cardiovascular (i.e., CV) disease or CV risk factors at baseline.The objective of the trial was to demonstrate that Insulin glargine use could significantly lower the risk of major cardiovascular outcomes compared to standard care. Two coprimary composite cardiovascular endpoints were used in ORIGIN. The first coprimary endpoint was the time to first occurrence of major adverse cardiovascular event defined as the composite of CV death, nonfatal myocardial infarction, and nonfatal stroke. The second coprimary endpoint was the time to the first occurrence of CV death or nonfatal myocardial infarction or nonfatal stroke or revascularization procedure or hospitalization for heart failure.Participants were randomized to either Insulin glargine (N=6264) titrated to goal fasting plasma glucose of <=95 mg/dL or to standard care (N=6273). Anthropometric and disease characteristics were balanced at baseline. The mean age was 64 years and 8% of participants were 75 years of age or older. The majority of participants were male (65%). Fifty nine percent were Caucasian, 25% were Latin, 10% were Asian and 3% were Black. The median baseline BMI was 29 kg/m2. Approximately 12% of participants had abnormal glucose levels (IGT and/or IFG) at baseline and 88% had type diabetes. For patients with type diabetes, 59% were treated with single oral antidiabetic drug, 23% had known diabetes but were on no antidiabetic drug and 6% were newly diagnosed during the screening procedure. The mean HbA1c (SD) at baseline was 6.5% (1.0). Fifty-nine percent of participants had had prior cardiovascular event and 39% had documented coronary artery disease or other cardiovascular risk factors.Vital status was available for 99.9% and 99.8% of participants randomized to Insulin glargine and standard care respectively at end of trial. The median duration of follow-up was 6.2 years (range: days to 7.9 years). The mean HbA1c (SD) at the end of the trial was 6.5% (1.1) and 6.8% (1.2) in the Insulin glargine and standard care group respectively. The median dose of Insulin glargine at end of trial was 0.45 U/kg. Eighty-one percent of patients randomized to Insulin glargine were using Insulin glargine at end of the study. The mean change in body weight from baseline to the last treatment visit was 2.2 kg greater in the Insulin glargine group than in the standard care group.Overall, the incidence of major adverse cardiovascular outcomes was similar between groups (see Table 14). All-cause mortality was also similar between groups.Table 14: Cardiovascular Outcomes in ORIGIN Time to First Event AnalysesInsulin glargine N=6264Standard Care N=6273Insulin glargine vs Standard Caren(Events per 100 PY)n(Events per 100 PY)Hazard Ratio (95% CI)Coprimary endpointsCV death, nonfatal myocardial infarction, or nonfatal stroke1041(2.9)1013(2.9)1.02 (0.94, 1.11)CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure or revascularization procedure1792(5.5)1727(5.3)1.04 (0.97, 1.11)Components of coprimary endpointsCV death5805761.00 (0.89, 1.13)Myocardial Infarction (fatal or nonfatal)3363261.03 (0.88, 1.19)Stroke (fatal or nonfatal)3313191.03 (0.89, 1.21)Revascularizations9088601.06 (0.96, 1.16)Hospitalization for heart failure3103430.90 (0.77, 1.05)In the ORIGIN trial, the overall incidence of cancer (all types combined) or death from cancer (Table 15) was similar between treatment groups.Table 15: Cancer Outcomes in ORIGIN Time to First Event AnalysesInsulin glargine N=6264Standard Care N=6273Insulin glargine vs Standard Caren(Events per 100 PY)n(Events per 100 PY)Hazard Ratio (95% CI)Cancer endpointsAny cancer event (new or recurrent)559(1.56)561(1.56)0.99 (0.88, 1.11)New cancer events524(1.46)535(1.49)0.96 (0.85, 1.09)Death due to Cancer189(0.51)201(0.54)0.94 (0.77, 1.15).

CLINICAL TRIALS EXPERIENCE SECTION.

6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of drug cannot be directly compared to rates in the clinical trial of another drug and may not reflect the rates observed in practice.The data in Table reflect the exposure of 2327 patients with type diabetes to Insulin glargine or NPH. The type diabetes population had the following characteristics: Mean age was 38.5 years. Fifty-four percent were male, 96.9% were Caucasian, 1.8% were Black or African American and 2.7% were Hispanic. The mean BMI was 25.1 kg/m2.The data in Table reflect the exposure of 1563 patients with type diabetes to Insulin glargine or NPH. The type diabetes population had the following characteristics: Mean age was 59.3 years. Fifty-eight percent were male, 86.7% were Caucasian, 7.8% were Black or African American and 9% were Hispanic. The mean BMI was 29.2 kg/m2.The frequencies of adverse events during Insulin glargine clinical trials in patients with type diabetes mellitus and type diabetes mellitus are listed in the tables below.Table 1: Adverse Events in Pooled Clinical Trials up to 28 Weeks Duration in Adults with Type Diabetes (adverse events with frequency >=5%)Insulin glargine, (n=1257)NPH, %(n=1070)Upper respiratory tract infection22.423.1InfectionBody system not specified 9.410.3Accidental injury5.76.4Headache5.54.7Table 2: Adverse Events in Pooled Clinical Trials up to Year Duration in Adults with Type Diabetes (adverse events with frequency >=5%)Insulin glargine, %(n=849)NPH, %(n=714)Upper respiratory tract infection11.413.3InfectionBody system not specified 10.411.6Retinal vascular disorder5.87.4Table 3: Adverse Events in 5-Year Trial of Adults with Type Diabetes (adverse events with frequency >=10%)Insulin glargine, %(n=514)NPH, %(n=503)Upper respiratory tract infection29.033.6Edema peripheral20.022.7Hypertension19.618.9Influenza18.719.5Sinusitis18.517.9Cataract18.115.9Bronchitis15.214.1Arthralgia14.216.1Pain in extremity13.013.1Back pain12.812.3Cough12.17.4Urinary tract infection10.710.1Diarrhea10.710.3Depression10.59.7Headache10.39.3Table 4: Adverse Events in 28-Week Clinical Trial of Children and Adolescents with Type Diabetes (adverse events with frequency >=5%)Insulin glargine, %(n=174)NPH, %(n=175)InfectionBody system not specified 13.817.7Upper respiratory tract infection13.816.0Pharyngitis7.58.6Rhinitis5.25.1. Severe HypoglycemiaHypoglycemia is the most commonly observed adverse reaction in patients using insulin, including Insulin glargine [see Warnings and Precautions (5.3)]. Tables 5, 6, and summarize the incidence of severe hypoglycemia in the Insulin glargine individual clinical trials. Severe symptomatic hypoglycemia was defined as an event with symptoms consistent with hypoglycemia requiring the assistance of another person and associated with either blood glucose below 50 mg/dL (<=56 mg/dL in the 5-year trial and <=36 mg/dL in the ORIGIN trial) or prompt recovery after oral carbohydrate, intravenous glucose, or glucagon administration.Percentages of Insulin glargine-treated adult patients experiencing severe symptomatic hypoglycemia in the Insulin glargine clinical trials [see Clinical Studies (14)] were comparable to percentages of NPH-treated patients for all treatment regimens (see Tables and 6). In the pediatric phase clinical trial, children and adolescents with type diabetes had higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to the adult trials with type diabetes.Table 5: Severe Symptomatic Hypoglycemia in Patients with Type DiabetesStudy AType DiabetesAdults 28 weeksIn combination with regular insulinStudy BType DiabetesAdults 28 weeksIn combination with regular insulinStudy CType DiabetesAdults 16 weeksIn combination with insulin lisproStudy DType Diabetes Pediatrics 26 weeksIn combination with regular insulinInsulin glargineN=292NPHN=293Insulin glargineN=264NPHN=270Insulin glargineN=310NPHN=309Insulin glargineN=174NPHN=175Percent of patients10.615.08.710.46.55.223.028.6Table 6: Severe Symptomatic Hypoglycemia in Patients with Type DiabetesStudy EType DiabetesAdults 52 weeksIn combination with oral agentsStudy FType DiabetesAdults 28 weeksIn combination with regular insulinStudy GType DiabetesAdults yearsIn combination with regular insulinInsulin glargineN=289NPHN=281Insulin glargineN=259NPHN=259Insulin glargineN=513NPHN=504Percent of patients1.71.10.42.37.811.9Table displays the proportion of patients experiencing severe symptomatic hypoglycemia in the Insulin glargine and Standard Care groups in the ORIGIN Trial [see Clinical Studies (14)].Table 7: Severe Symptomatic Hypoglycemia in the ORIGIN TrialORIGIN TrialMedian duration of follow-up: 6.2 yearsInsulin glargineN=6231Standard CareN=6273Percent of patients5.61.8. Peripheral EdemaSome patients taking Insulin glargine have experienced sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.. LipodystrophyAdministration of insulin subcutaneously, including Insulin glargine, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients [see Dosage and Administration (2.2)].. Insulin Initiation and Intensification of Glucose ControlIntensification or rapid improvement in glucose control has been associated with transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.. Weight GainWeight gain has occurred with some insulin therapies including Insulin glargine and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.. Allergic Reactions. Local allergyAs with any insulin therapy, patients taking Insulin glargine may experience injection site reactions, including redness, pain, itching, urticaria, edema, and inflammation. In clinical studies in adult patients, there was higher incidence of treatment-emergent injection site pain in Insulin glargine-treated patients (2.7%) compared to NPH insulin-treated patients (0.7%). The reports of pain at the injection site did not result in discontinuation of therapy.. Systemic allergySevere, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including Insulin glargine and may be life threatening.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Insulin glargine is contraindicated:during episodes of hypoglycemia [see Warnings and Precautions (5.3)] in patients with hypersensitivity to Insulin glargine or one of its excipients [see Warnings and Precautions (5.5)] during episodes of hypoglycemia [see Warnings and Precautions (5.3)] in patients with hypersensitivity to Insulin glargine or one of its excipients [see Warnings and Precautions (5.5)] During episodes of hypoglycemia (4)Hypersensitivity to Insulin glargine or one of its excipients (4). During episodes of hypoglycemia (4). Hypersensitivity to Insulin glargine or one of its excipients (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Insulin glargine (insulin glargine injection) is sterile solution of insulin glargine for subcutaneous use. Insulin glargine is recombinant human insulin analog that is long-acting, parenteral blood-glucose-lowering agent [see Clinical Pharmacology (12)]. Insulin glargine has low aqueous solubility at neutral pH. At pH insulin glargine is completely soluble. After injection into the subcutaneous tissue, the acidic solution is neutralized, leading to formation of microprecipitates from which small amounts of insulin glargine are slowly released, resulting in relatively constant concentration/time profile over 24 hours with no pronounced peak. This profile allows once-daily dosing as basal insulin. Insulin glargine is produced by recombinant DNA technology utilizing non-pathogenic laboratory strain of Escherichia coli (K12) as the production organism. Insulin glargine differs from human insulin in that the amino acid asparagine at position A21 is replaced by glycine and two arginines are added to the C-terminus of the B-chain. Chemically, insulin glargine is 21A-Gly-30Ba-L-Arg-30Bb-L-Arg-human insulin and has the empirical formula C267H404N72O78S6 and molecular weight of 6063. Insulin glargine has the following structural formula:Insulin glargine consists of insulin glargine dissolved in clear aqueous fluid. Each milliliter of insulin glargine injection contains 100 units (3.6378 mg) insulin glargine.The 10 mL vial presentation contains the following inactive ingredients per mL: 30 mcg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, 20 mcg polysorbate 20, and water for injection.The mL prefilled pen presentation contains the following inactive ingredients per mL: 30 mcg zinc, 2.7 mg m-cresol, 20 mg glycerol 85%, and water for injection.The pH is adjusted by addition of aqueous solutions of hydrochloric acid and sodium hydroxide. Insulin glargine has pH of approximately 4.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Individualize dosage based on metabolic needs, blood glucose monitoring, glycemic control, type of diabetes, and prior insulin use. (2.1, 2.3, 2.4)Administer subcutaneously into the abdominal area, thigh, or deltoid once daily at any time of day, but at the same time every day. (2.1)Do not dilute or mix with any other insulin or solution. (2.1)Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. (2.2)Closely monitor glucose when changing to Insulin glargine and during initial weeks thereafter. (2.4). Individualize dosage based on metabolic needs, blood glucose monitoring, glycemic control, type of diabetes, and prior insulin use. (2.1, 2.3, 2.4). Administer subcutaneously into the abdominal area, thigh, or deltoid once daily at any time of day, but at the same time every day. (2.1). Do not dilute or mix with any other insulin or solution. (2.1). Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. (2.2). Closely monitor glucose when changing to Insulin glargine and during initial weeks thereafter. (2.4). 2.1Important Administration Instructions. Administer Insulin glargine subcutaneously once daily at any time of day but at the same time every day.Prior to initiation of Insulin glargine, train patients on proper use and injection technique.Patient should follow the Instructions for Use to correctly administer Insulin glargine.Administer Insulin glargine subcutaneously into the abdominal area, thigh, or deltoid, and rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2), Adverse Reactions (6)].During changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].Visually inspect Insulin glargine vials and SoloStar prefilled pens for particulate matter and discoloration prior to administration. Only use if the solution is clear and colorless with no visible particles.The Insulin glargine SoloStar prefilled pen dials in 1-unit increments.Use Insulin glargine SoloStar prefilled pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.Refrigerate unused (unopened) Insulin glargine vials and SoloStar(R) prefilled pens.Do not administer intravenously or via an insulin pump.Do not dilute or mix Insulin glargine with any other insulin or solution.The SoloStar prefilled pen is for single patient use only [see Warnings and Precautions (5.1)].. Administer Insulin glargine subcutaneously once daily at any time of day but at the same time every day.. Prior to initiation of Insulin glargine, train patients on proper use and injection technique.. Patient should follow the Instructions for Use to correctly administer Insulin glargine.. Administer Insulin glargine subcutaneously into the abdominal area, thigh, or deltoid, and rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2), Adverse Reactions (6)].. During changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].. Visually inspect Insulin glargine vials and SoloStar prefilled pens for particulate matter and discoloration prior to administration. Only use if the solution is clear and colorless with no visible particles.. The Insulin glargine SoloStar prefilled pen dials in 1-unit increments.. Use Insulin glargine SoloStar prefilled pen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.. Refrigerate unused (unopened) Insulin glargine vials and SoloStar(R) prefilled pens.. Do not administer intravenously or via an insulin pump.. Do not dilute or mix Insulin glargine with any other insulin or solution.. The SoloStar prefilled pen is for single patient use only [see Warnings and Precautions (5.1)].. 2.2General Dosing Instructions. Individualize and adjust the dosage of Insulin glargine based on the individuals metabolic needs, blood glucose monitoring results and glycemic control goal.Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), during acute illness, or changes in renal or hepatic function. Dosage adjustments should only be made under medical supervision with appropriate glucose monitoring [see Warnings and Precautions (5.2)].. Individualize and adjust the dosage of Insulin glargine based on the individuals metabolic needs, blood glucose monitoring results and glycemic control goal.. Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), during acute illness, or changes in renal or hepatic function. Dosage adjustments should only be made under medical supervision with appropriate glucose monitoring [see Warnings and Precautions (5.2)].. 2.3Initiation of Insulin Glargine Therapy Type DiabetesIn patients with type diabetes, Insulin glargine must be used concomitantly with short-acting insulin. The recommended starting dose of Insulin glargine in patients with type diabetes should be approximately one-third of the total daily insulin requirements. Short-acting, premeal insulin should be used to satisfy the remainder of the daily insulin requirements.. In patients with type diabetes, Insulin glargine must be used concomitantly with short-acting insulin. The recommended starting dose of Insulin glargine in patients with type diabetes should be approximately one-third of the total daily insulin requirements. Short-acting, premeal insulin should be used to satisfy the remainder of the daily insulin requirements.. Type DiabetesThe recommended starting dose of Insulin glargine in patients with type diabetes who are not currently treated with insulin is 0.2 units/kg or up to 10 units once daily. One may need to adjust the amount and timing of short- or rapid-acting insulins and dosages of any oral antidiabetic drugs.. The recommended starting dose of Insulin glargine in patients with type diabetes who are not currently treated with insulin is 0.2 units/kg or up to 10 units once daily. One may need to adjust the amount and timing of short- or rapid-acting insulins and dosages of any oral antidiabetic drugs.. 2.4Changing to Insulin Glargine from Other Insulin Therapies. If changing patients from once-daily TOUJEO (insulin glargine) 300 units/mL to once-daily Insulin glargine, the recommended initial Insulin glargine dose is 80% of the TOUJEO dose that is being discontinued. This dose reduction will lower the likelihood of hypoglycemia [see Warnings and Precautions (5.3)]. If changing from treatment regimen with an intermediate or long-acting insulin to regimen with Insulin glargine, change in the dose of the basal insulin may be required and the amount and timing of the shorter-acting insulins and doses of any oral antidiabetic drugs may need to be adjusted.If changing patients from once-daily NPH insulin to once-daily Insulin glargine, the recommended initial Insulin glargine dose is the same as the dose of NPH that is being discontinued.If changing patients from twice-daily NPH insulin to once-daily Insulin glargine, the recommended initial Insulin glargine dosage is 80% of the total NPH dose that is being discontinued. This dosage reduction will lower the likelihood of hypoglycemia [see Warnings and Precautions (5.3)]. If changing patients from once-daily TOUJEO (insulin glargine) 300 units/mL to once-daily Insulin glargine, the recommended initial Insulin glargine dose is 80% of the TOUJEO dose that is being discontinued. This dose reduction will lower the likelihood of hypoglycemia [see Warnings and Precautions (5.3)]. If changing from treatment regimen with an intermediate or long-acting insulin to regimen with Insulin glargine, change in the dose of the basal insulin may be required and the amount and timing of the shorter-acting insulins and doses of any oral antidiabetic drugs may need to be adjusted.. If changing patients from once-daily NPH insulin to once-daily Insulin glargine, the recommended initial Insulin glargine dose is the same as the dose of NPH that is being discontinued.. If changing patients from twice-daily NPH insulin to once-daily Insulin glargine, the recommended initial Insulin glargine dosage is 80% of the total NPH dose that is being discontinued. This dosage reduction will lower the likelihood of hypoglycemia [see Warnings and Precautions (5.3)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injection: 100 units per mL (U-100) available as:10 mL multiple-dose vial (1,000 units/10 mL)3 mL single-patient-use SoloStar prefilled pen (300 units/3 mL). 10 mL multiple-dose vial (1,000 units/10 mL). mL single-patient-use SoloStar prefilled pen (300 units/3 mL). Injection: 100 units/mL (U-100) available as:10 mL multiple-dose vial (3)3 mL single-patient-use SoloStar prefilled pen (3). 10 mL multiple-dose vial (3). mL single-patient-use SoloStar prefilled pen (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table includes clinically significant drug interactions with Insulin glargine.Table 8: Clinically Significant Drug Interactions with Insulin GlargineDrugs that May Increase the Risk of HypoglycemiaDrugs:Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. Intervention:Dose reductions and increased frequency of glucose monitoring may be required when Insulin glargine is coadministered with these drugs.Drugs that May Decrease the Blood Glucose Lowering Effect of Insulin GlargineDrugs:Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.Intervention:Dose increases and increased frequency of glucose monitoring may be required when Insulin glargine is coadministered with these drugs.Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of Insulin GlargineDrugs:Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Intervention:Dose adjustment and increased frequency of glucose monitoring may be required when Insulin glargine is coadministered with these drugs. Drugs that May Blunt Signs and Symptoms of Hypoglycemia Drugs:Beta-blockers, clonidine, guanethidine, and reserpine.Intervention:Increased frequency of glucose monitoring may be required when Insulin glargine is coadministered with these drugs. Drugs that affect glucose metabolism: Adjustment of insulin dosage may be needed; closely monitor blood glucose. (7)Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent. (7). Drugs that affect glucose metabolism: Adjustment of insulin dosage may be needed; closely monitor blood glucose. (7). Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent. (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the total number of subjects in controlled clinical studies of patients with type and type diabetes who were treated with Insulin glargine, 15% were >=65 years of age and 2% were >=75 years of age. The only difference in safety or effectiveness in the subpopulation of patients >=65 years of age compared to the entire study population was higher incidence of cardiovascular events typically seen in an older population in the Insulin glargine and NPH treatment groups.Nevertheless, caution should be exercised when Insulin glargine is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly.

HEPATIC IMPAIRMENT SUBSECTION.

8.6 Hepatic Impairment. The effect of hepatic impairment on the pharmacokinetics of Insulin glargine has not been studied. Frequent glucose monitoring and dose adjustment may be necessary for Insulin glargine in patients with hepatic impairment [see Warnings and Precautions (5.3)].

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1How Supplied. Insulin glargine injection is supplied as clear solution containing 100 units per mL (U-100) available in:Insulin glargine injectionTotal volumeConcentrationTotal units available in presentationNDC numberPackage sizeMultiple-dose vial10 mL100 units/mL1,000 units0955-1729-011 vial per cartonSoloStar single-patient-use prefilled pen3 mL100 units/mL300 units0955-1728-055 pens per cartonThe insulin glargine SoloStar prefilled pen dials in 1-unit increments.Needles are not included in the packs.BD Ultra-Fine(R) needlesOther brands listed are the trademarks of their respective owners and are not trademarks of sanofi-aventis U.S. LLC to be used in conjunction with SoloStar prefilled pens are sold separately and are manufactured by BD.. 16.2 Storage. Dispense in the original sealed carton with the enclosed Instructions for Use.Insulin glargine should not be stored in the freezer and should not be allowed to freeze. Discard Insulin glargine if it has been frozen. Protect Insulin glargine from direct heat and light.Storage conditions are summarized in the following table.Not in-use (unopened)RefrigeratedNot in-use (unopened)Room TemperatureIn-use (opened)(36F-46F [2C-8C])(below 86F [30C])(see temperature below)10 mL multiple-dose vialUntil expiration date28 days28 daysRefrigerated or room temperature3 mL single-patient-use SoloStar prefilled penUntil expiration date28 days28 daysRoom temperature only(Do not refrigerate).

IMMUNOGENICITY.

6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. All insulin products can elicit the formation of insulin antibodies. The presence of such insulin antibodies may increase or decrease the efficacy of insulin and may require adjustment of the insulin dose. In phase clinical trials of Insulin glargine, increases in titers of antibodies to insulin were observed in NPH insulin and Insulin glargine treatment groups with similar incidences.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Insulin glargine is indicated to improve glycemic control in adults and pediatric patients with type diabetes mellitus and in adults with type diabetes mellitus.. Insulin glargine is long-acting human insulin analog indicated to improve glycemic control in adults and pediatric patients with type diabetes mellitus and in adults with type diabetes mellitus. (1)Limitations of UseNot recommended for treating diabetic ketoacidosis. (1). Limitations of UseInsulin glargine is not recommended for the treatment of diabetic ketoacidosis.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).. Never Share an Insulin Glargine SoloStar Prefilled Pen or Syringe Between PatientsAdvise patients that they must never share an Insulin glargine SoloStar prefilled pen with another person, even if the needle is changed. Advise patients using Insulin glargine vials not to re-use or share needles or syringes with another person. Sharing carries risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)].. Hyperglycemia or HypoglycemiaInform patients that hypoglycemia is the most common adverse reaction with insulin. Inform patients of the symptoms of hypoglycemia. Inform patients that the ability to concentrate and react may be impaired as result of hypoglycemia. This may present risk in situations where these abilities are especially important, such as driving or operating other machinery. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery [see Warnings and Precautions (5.3)]. Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions (5.2)].. Medications ErrorsInstruct patients to always check the insulin label before each injection [see Warnings and Precautions (5.4)].. AdministrationAdvise patients that Insulin glargine must NOT be diluted or mixed with any other insulin or solution and that Insulin glargine must only be used if the solution is clear and colorless with no particles visible [see Dosage and Administration (2)].

INSTRUCTIONS FOR USE SECTION.

Instructions for Use. Insulin glargine (IN-su-lin-GLAR-gine)injection for subcutaneous use 10 mL Vial (100 Units/mL, U-100)Read the Instructions for Use before you start taking Insulin glargine and each time you get new Insulin glargine vial. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.Do not share your Insulin glargine syringes with other people even if the needle has been changed. You may give other people serious infection, or get serious infection from them.Supplies needed to give your injection:an Insulin glargine 10 mL viala U-100 insulin syringe and needle2 alcohol swabs1 sharps container for throwing away used needles and syringes. See Disposing of used needles and syringes at the end of these instructions.Preparing your Insulin glargine dose:Wash your hands with soap and water or with alcohol.Check the Insulin glargine label to make sure you are taking the right type of insulin. This is especially important if you use more than type of insulin.Check the insulin to make sure it is clear and colorless. Do not use Insulin glargine if it is colored or cloudy, or if you see particles in the solution.Do not use Insulin glargine after the expiration date stamped on the label or 28 days after you first use it.Always use syringe that is marked for U-100 insulin. If you use syringe other than U-100 insulin syringe, you may get the wrong dose of insulin.Always use new syringe or needle for each injection. Do not re-use or share your syringes or needles with other people. You may give other people serious infection or get serious infection from them.Step 1:If you are using new vial, remove the protective cap. Do not remove the stopper.Step 2:Wipe the top of the vial with an alcohol swab. You do not have to shake the vial of Insulin glargine before use.Step 3:Draw air into the syringe equal to your insulin dose. Put the needle through the rubber top of the vial and push the plunger to inject the air into the vial.Step 4:Leave the syringe in the vial and turn both upside down. Hold the syringe and vial firmly in one hand. Make sure the tip of the needle is in the insulin. With your free hand, pull the plunger to withdraw the correct dose into the syringe.Step 5:Before you take the needle out of the vial, check the syringe for air bubbles. If bubbles are in the syringe, hold the syringe straight up and tap the side of the syringe until the bubbles float to the top. Push the bubbles out with the plunger and draw insulin back in until you have the correct dose. Step 6:Remove the needle from the vial. Do not let the needle touch anything. You are now ready to inject.Giving your Insulin glargine injection:Inject your insulin exactly as your healthcare provider has shown you.Inject your insulin under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen).Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in the skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.Do not inject where the skin has pits, is thickened, or has lumps.Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.Step 7:Choosing your injection site: Insulin glargine is injected under the skin (subcutaneously) of your upper arm, thigh, or stomach area (abdomen). Wipe the skin with an alcohol swab to clean the injection site. Let the injection site dry before you inject your dose.Step 8:Pinch the skin. Insert the needle in the way your healthcare provider showed you. Release the skin.Slowly push in the plunger of the syringe all the way, making sure you have injected all the insulin. Leave the needle in the skin for about 10 seconds. Step 9:Pull the needle straight out of your skin.Gently press the injection site for several seconds. Do not rub the area.Do not recap the used needle. Recapping the needle can lead to needle stick injury.Disposing of used needles and syringes:Put your used needles and syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash. If you do not have FDA-cleared sharps container, you may use household container that is:made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak resistant, andproperly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal.Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.How should store Insulin glargineStore unused Insulin glargine vials in the refrigerator between 36F to 46F (2C to 8C). Store in-use (opened) Insulin glargine vials in refrigerator or at room temperature below 86F (30C).Do not freeze Insulin glargine. Keep Insulin glargine out of direct heat and light.If vial has been frozen or overheated, throw it away.The Insulin glargine vials you are using should be thrown away after 28 days, even if it still has insulin left in it.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Revised: December 2020 Winthrop U.S.,a business of sanofi-aventis U.S. LLCBridgewater, NJ 08807A SANOFI COMPANY(C)2020 sanofi-aventis U.S. LLC. an Insulin glargine 10 mL vial. U-100 insulin syringe and needle. alcohol swabs. sharps container for throwing away used needles and syringes. See Disposing of used needles and syringes at the end of these instructions.. Wash your hands with soap and water or with alcohol.. Check the Insulin glargine label to make sure you are taking the right type of insulin. This is especially important if you use more than type of insulin.. Check the insulin to make sure it is clear and colorless. Do not use Insulin glargine if it is colored or cloudy, or if you see particles in the solution.. Do not use Insulin glargine after the expiration date stamped on the label or 28 days after you first use it.. Always use syringe that is marked for U-100 insulin. If you use syringe other than U-100 insulin syringe, you may get the wrong dose of insulin.. Always use new syringe or needle for each injection. Do not re-use or share your syringes or needles with other people. You may give other people serious infection or get serious infection from them.. Inject your insulin exactly as your healthcare provider has shown you.. Inject your insulin under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen).. Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in the skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.. Do not inject where the skin has pits, is thickened, or has lumps.. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.. Pinch the skin. Insert the needle in the way your healthcare provider showed you. Release the skin.. Slowly push in the plunger of the syringe all the way, making sure you have injected all the insulin. Leave the needle in the skin for about 10 seconds. Pull the needle straight out of your skin.. Gently press the injection site for several seconds. Do not rub the area.. Do not recap the used needle. Recapping the needle can lead to needle stick injury.. Put your used needles and syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash. If you do not have FDA-cleared sharps container, you may use household container that is:made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak resistant, andproperly labeled to warn of hazardous waste inside the container. made of heavy-duty plastic,. can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,. upright and stable during use,. leak resistant, and. properly labeled to warn of hazardous waste inside the container.. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal.. Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.. Store unused Insulin glargine vials in the refrigerator between 36F to 46F (2C to 8C). Store in-use (opened) Insulin glargine vials in refrigerator or at room temperature below 86F (30C).. Do not freeze Insulin glargine. Keep Insulin glargine out of direct heat and light.. If vial has been frozen or overheated, throw it away.. The Insulin glargine vials you are using should be thrown away after 28 days, even if it still has insulin left in it.. Image. Image. Image. Image. Image. Image. Image.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere are either no or only limited data on the presence of insulin glargine in human milk, the effects on breastfed infant, or the effects on milk production. Endogenous insulin is present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for insulin glargine, and any potential adverse effects on the breastfed child from insulin glargine or from the underlying maternal condition.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. In mice and rats, standard two-year carcinogenicity studies with insulin glargine were performed at doses up to 0.455 mg/kg, which was for the rat approximately 65 times the recommended human subcutaneous starting dose of 0.2 units/kg/day (0.007 mg/kg/day) on mg/kg basis. Histiocytomas were found at injection sites in male rats and mice in acid vehicle containing groups and are considered response to chronic tissue irritation and inflammation in rodents. These tumors were not found in female animals, in saline control, or insulin comparator groups using different vehicle.Insulin glargine was not mutagenic in tests for detection of gene mutations in bacteria and mammalian cells (Ames and HGPRT-test) and in tests for detection of chromosomal aberrations (cytogenetics in vitro in V79 cells and in vivo in Chinese hamsters).In combined fertility and prenatal and postnatal study in male and female rats at subcutaneous doses up to 0.36 mg/kg/day, which was approximately 50 times the recommended human subcutaneous starting dose of 0.2 units/kg/day (0.007 mg/kg/day) maternal toxicity due to dose-dependent hypoglycemia, including some deaths, was observed. Consequently, reduction of the rearing rate occurred in the high-dose group only. Similar effects were observed with NPH insulin.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.6)]. Mild episodes of hypoglycemia can usually be treated with oral carbohydrates. Adjustments in drug dosage, meal patterns, or exercise may be needed.More severe episodes of hypoglycemia with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. After apparent clinical recovery from hypoglycemia, continued observation and additional carbohydrate intake may be necessary to avoid recurrence of hypoglycemia. Hypokalemia must be corrected appropriately.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL One 10 mL Vial Carton. NDC 0955-1729-01Rx onlyWinthropA SANOFI COMPANYInsulin glargineinjection100 units/mL(U-100)For subcutaneous injection onlyDo not mix with other insulinsUse only if solution is clear andcolorless with no particles visibleUse with U-100 syringe onlyOne 10 mL multiple-dose vialSANOFI. PRINCIPAL DISPLAY PANEL One 10 mL Vial Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of Insulin glargine have been established in pediatric patients (age to 15 years) with type diabetes [see Clinical Studies (14.2)]. The safety and effectiveness of Insulin glargine in pediatric patients younger than years of age with type diabetes and pediatric patients with type diabetes have not been established.The dosage recommendation when changing to Insulin glargine in pediatric patients (age to 15 years) with type diabetes is the same as that described for adults [see Dosage and Administration (2.2, 2.4) Clinical Studies (14)]. As in adults, the dosage of Insulin glargine must be individualized in pediatric patients (age to 15 years) with type diabetes based on metabolic needs and frequent monitoring of blood glucose.In the pediatric clinical trial, pediatric patients (age to 15 years) with type diabetes had higher incidence of severe symptomatic hypoglycemia compared to the adults in trials with type diabetes [see Adverse Reactions (6.1)].

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. In clinical studies, the glucose-lowering effect on molar basis (i.e., when given at the same doses) of intravenous insulin glargine is approximately the same as that for human insulin. Figure shows results from study in patients with type diabetes conducted for maximum of 24 hours after the injection. The median time between injection and the end of pharmacological effect was 14.5 hours (range: 9.5 to 19.3 hours) for NPH insulin, and 24 hours (range: 10.8 to >24.0 hours) (24 hours was the end of the observation period) for insulin glargine.Figure 1: Activity Profile in Patients with Type Diabetes Determined as amount of glucose infused to maintain constant plasma glucose levelsThe duration of action after abdominal, deltoid, or thigh subcutaneous administration was similar. The time course of action of insulins, including Insulin glargine, may vary between individuals and within the same individual.. Figure 1.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Absorption and BioavailabilityAfter subcutaneous injection of Insulin glargine in healthy subjects and in patients with diabetes, the insulin serum concentrations indicated slower, more prolonged absorption and relatively constant concentration/time profile over 24 hours with no pronounced peak in comparison to NPH insulin.. Metabolism and EliminationA metabolism study in humans indicates that insulin glargine is partly metabolized at the carboxyl terminus of the chain in the subcutaneous depot to form two active metabolites with in vitro activity similar to that of human insulin, M1 (21A-Gly-insulin) and M2 (21A-Gly-des-30B-Thr-insulin). Unchanged drug and these degradation products are also present in the circulation.. Special Populations. Age, race, and genderEffect of age, race, and gender on the pharmacokinetics of Insulin glargine has not been evaluated. However, in controlled clinical trials in adults (n=3890) and controlled clinical trial in pediatric patients (n=349), subgroup analyses based on age, race, and gender did not show differences in safety and efficacy between Insulin glargine and NPH insulin [see Clinical Studies (14)].. ObesityEffect of Body Mass Index (BMI) on the pharmacokinetics of Insulin glargine has not been evaluated.

POSTMARKETING EXPERIENCE SECTION.

6.3 Postmarketing Experience. The following adverse reactions have been identified during postapproval use of Insulin glargine. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Medication errors have been reported in which other insulins, particularly rapid-acting insulins, have been accidentally administered instead of Insulin glargine [see Patient Counseling Information (17)]. To avoid medication errors between Insulin glargine and other insulins, patients should be instructed to always verify the insulin label before each injection.Localized cutaneous amyloidosis at the injection site has occurred. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with sudden change to an unaffected injection site.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryPublished studies with use of insulin glargine during pregnancy have not reported clear association with insulin glargine and adverse developmental outcomes [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].Rats and rabbits were exposed to insulin glargine in animal reproduction studies during organogenesis, respectively 50 times and 10 times the human subcutaneous dose of 0.2 units/kg/day. Overall, the effects of insulin glargine did not generally differ from those observed with regular human insulin [see Data].The estimated background risk of major birth defects is 6% to 10% in women with pregestational diabetes with an HbA1c >7 and has been reported to be as high as 20% to 25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo-fetal riskPoorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.. Data. Human dataPublished data do not report clear association with insulin glargine and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin glargine is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations including small sample size and some lacking comparator groups.. Animal dataSubcutaneous reproduction and teratology studies have been performed with insulin glargine and regular human insulin in rats and Himalayan rabbits. Insulin glargine was given to female rats before mating, during mating, and throughout pregnancy at doses up to 0.36 mg/kg/day, which is approximately 50 times the recommended human subcutaneous starting dose of 0.2 units/kg/day (0.007 mg/kg/day), on mg/kg basis. In rabbits, doses of 0.072 mg/kg/day, which is approximately 10 times the recommended human subcutaneous starting dose of 0.2 units/kg/day on mg/kg basis, were administered during organogenesis. The effects of insulin glargine did not generally differ from those observed with regular human insulin in rats or rabbits. However, in rabbits, five fetuses from two litters of the high-dose group exhibited dilation of the cerebral ventricles. Fertility and early embryonic development appeared normal.

RENAL IMPAIRMENT SUBSECTION.

8.7 Renal Impairment. The effect of renal impairment on the pharmacokinetics of Insulin glargine has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. Frequent glucose monitoring and dose adjustment may be necessary for Insulin glargine in patients with renal impairment [see Warnings and Precautions (5.3)].

SPL PATIENT PACKAGE INSERT SECTION.

Patient InformationInsulin glargine (IN-su-lin-GLAR-gine)(insulin glargine injection) for subcutaneous use, 100 Units/mL (U-100)This Patient Information has been approved by the U.S. Food and Drug AdministrationRevised: December 2020Do not share your syringes with other people, even if the needle has been changed. You may give other people serious infection, or get serious infection from them.What is Insulin glargineInsulin glargine is long-acting man-made-insulin used to control high blood sugar in adults with diabetes mellitus. Insulin glargine is not for use to treat diabetic ketoacidosis.It is not known if Insulin glargine is safe and effective in children less than years of age with type diabetes.It is not known if Insulin glargine is safe and effective in children with type diabetes.Who should not use Insulin glargineDo not use Insulin glargine if you:are having an episode of low blood sugar (hypoglycemia).have an allergy to insulin glargine or any of the ingredients in Insulin glargine. See the end of this Patient Information leaflet for complete list of ingredients in Insulin glargine.What should tell my healthcare provider before using Insulin glargineBefore using Insulin glargine, tell your healthcare provider about all your medical conditions including if you:have liver or kidney problems. take other medicines, especially ones called TZDs (thiazolidinediones).have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with Insulin glargine.are pregnant, planning to become pregnant, or are breastfeeding. It is not known if Insulin glargine may harm your unborn baby or breastfeeding baby.Tell your healthcare provider about all the medicines you take including prescription and over-the-counter medicines, vitamins, and herbal supplements.Before you start using Insulin glargine, talk to your healthcare provider about low blood sugar and how to manage it.How should use Insulin glargineRead the detailed Instructions for Use that come with your Insulin glargine insulin.Use Insulin glargine exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much Insulin glargine to use and when to use it.Know the amount of Insulin glargine you use. Do not change the amount of Insulin glargine you use unless your healthcare provider tells you to.Check your insulin label each time you give your injection to make sure you are using the correct insulin.Do not re-use needles. Always use new needle for each injection. Re-use of needles increases your risk of having blocked needles, which may cause you to get the wrong dose of Insulin glargine. Using new needle for each injection lowers your risk of getting an infection.You may take Insulin glargine at any time during the day but you must take it at the same time every day.Only use Insulin glargine that is clear and colorless. If your Insulin glargine is cloudy or slightly colored, return it to your pharmacy for replacement.Insulin glargine is injected under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen).Do not use Insulin glargine in an insulin pump or inject Insulin glargine into your vein (intravenously).Change (rotate) injection sites within the area you chose with each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.Do not use the exact same spot for each injection.Do not inject where the skin has pits, is thickened, or has lumps.Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. Do not mix Insulin glargine with any other type of insulin or liquid medicine.Check your blood sugar levels. Ask your healthcare provider what your blood sugar should be and when you should check your blood sugar levels.Keep Insulin glargine and all medicines out of the reach of children.Your dose of Insulin glargine may need to change because of:a change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of the medicines you take.What should avoid while using Insulin glargineWhile using Insulin glargine do not: drive or operate heavy machinery, until you know how Insulin glargine affects you.drink alcohol or use over-the-counter medicines that contain alcohol. What are the possible side effects of Insulin glargine and other insulinsInsulin glargine may cause serious side effects that can lead to death, including:low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include:dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood change, hunger. severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or symptoms of severe allergic reaction:a rash over your whole body, trouble breathing, fast heartbeat, or sweating.low potassium in your blood (hypokalemia).Heart failure. Taking certain diabetes pills called TZDs (thiazolidinediones) with Insulin glargine may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with Insulin glargine. Your healthcare provider should monitor you closely while you are taking TZDs with Insulin glargine. Tell your healthcare provider if you have any new or worse symptoms of heart failure including:shortness of breath, swelling of your ankles or feet, sudden weight gain.Treatment with TZDs and Insulin glargine may need to be changed or stopped by your healthcare provider if you have new or worse heart failure.Get emergency medical help if you have:trouble breathing; shortness of breath; fast heartbeat; swelling of your face, tongue, or throat; sweating; extreme drowsiness; dizziness; confusion.The most common side effects of Insulin glargine include:low blood sugar (hypoglycemia); weight gain; allergic reactions, including reactions at your injection site; skin thickening or pits at the injection site (lipodystrophy).These are not all the possible side effects of Insulin glargine. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of Insulin glargine.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use Insulin glargine for condition for which it was not prescribed. Do not give Insulin glargine to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about Insulin glargine. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Insulin glargine that is written for healthcare professionals. For more information, go to www.winthropus.com or call 1-800-633-1610.What are the ingredients in Insulin glargineActive ingredient: insulin glargine10 mL vial inactive ingredients: zinc, m-cresol, glycerol, polysorbate, and water for injectionManufactured by: Winthrop U.S., business of sanofi-aventis U.S. LLC, Bridgewater, NJ 08807. Insulin glargine is not for use to treat diabetic ketoacidosis.. It is not known if Insulin glargine is safe and effective in children less than years of age with type diabetes.. It is not known if Insulin glargine is safe and effective in children with type diabetes.. are having an episode of low blood sugar (hypoglycemia).. have an allergy to insulin glargine or any of the ingredients in Insulin glargine. See the end of this Patient Information leaflet for complete list of ingredients in Insulin glargine.. have liver or kidney problems. take other medicines, especially ones called TZDs (thiazolidinediones).. have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with Insulin glargine.. are pregnant, planning to become pregnant, or are breastfeeding. It is not known if Insulin glargine may harm your unborn baby or breastfeeding baby.. Read the detailed Instructions for Use that come with your Insulin glargine insulin.. Use Insulin glargine exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much Insulin glargine to use and when to use it.. Know the amount of Insulin glargine you use. Do not change the amount of Insulin glargine you use unless your healthcare provider tells you to.. Check your insulin label each time you give your injection to make sure you are using the correct insulin.. Do not re-use needles. Always use new needle for each injection. Re-use of needles increases your risk of having blocked needles, which may cause you to get the wrong dose of Insulin glargine. Using new needle for each injection lowers your risk of getting an infection.. You may take Insulin glargine at any time during the day but you must take it at the same time every day.. Only use Insulin glargine that is clear and colorless. If your Insulin glargine is cloudy or slightly colored, return it to your pharmacy for replacement.. Insulin glargine is injected under the skin (subcutaneously) of your upper legs (thighs), upper arms, or stomach area (abdomen).. Do not use Insulin glargine in an insulin pump or inject Insulin glargine into your vein (intravenously).. Change (rotate) injection sites within the area you chose with each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.Do not use the exact same spot for each injection.Do not inject where the skin has pits, is thickened, or has lumps.Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. Do not use the exact same spot for each injection.. Do not inject where the skin has pits, is thickened, or has lumps.. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.. Do not mix Insulin glargine with any other type of insulin or liquid medicine.. Check your blood sugar levels. Ask your healthcare provider what your blood sugar should be and when you should check your blood sugar levels.. change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of the medicines you take.. drive or operate heavy machinery, until you know how Insulin glargine affects you.. drink alcohol or use over-the-counter medicines that contain alcohol.. low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include:dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood change, hunger. dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, anxiety, irritability or mood change, hunger.. severe allergic reaction (whole body reaction). Get medical help right away if you have any of these signs or symptoms of severe allergic reaction:a rash over your whole body, trouble breathing, fast heartbeat, or sweating.. rash over your whole body, trouble breathing, fast heartbeat, or sweating.. low potassium in your blood (hypokalemia).. Heart failure. Taking certain diabetes pills called TZDs (thiazolidinediones) with Insulin glargine may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with Insulin glargine. Your healthcare provider should monitor you closely while you are taking TZDs with Insulin glargine. Tell your healthcare provider if you have any new or worse symptoms of heart failure including:shortness of breath, swelling of your ankles or feet, sudden weight gain.Treatment with TZDs and Insulin glargine may need to be changed or stopped by your healthcare provider if you have new or worse heart failure.. shortness of breath, swelling of your ankles or feet, sudden weight gain.. trouble breathing; shortness of breath; fast heartbeat; swelling of your face, tongue, or throat; sweating; extreme drowsiness; dizziness; confusion.. low blood sugar (hypoglycemia); weight gain; allergic reactions, including reactions at your injection site; skin thickening or pits at the injection site (lipodystrophy).. Active ingredient: insulin glargine. 10 mL vial inactive ingredients: zinc, m-cresol, glycerol, polysorbate, and water for injection.

SPL UNCLASSIFIED SECTION.

Limitations of UseInsulin glargine is not recommended for the treatment of diabetic ketoacidosis.

STORAGE AND HANDLING SECTION.

16.2 Storage. Dispense in the original sealed carton with the enclosed Instructions for Use.Insulin glargine should not be stored in the freezer and should not be allowed to freeze. Discard Insulin glargine if it has been frozen. Protect Insulin glargine from direct heat and light.Storage conditions are summarized in the following table.Not in-use (unopened)RefrigeratedNot in-use (unopened)Room TemperatureIn-use (opened)(36F-46F [2C-8C])(below 86F [30C])(see temperature below)10 mL multiple-dose vialUntil expiration date28 days28 daysRefrigerated or room temperature3 mL single-patient-use SoloStar prefilled penUntil expiration date28 days28 daysRoom temperature only(Do not refrigerate).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryPublished studies with use of insulin glargine during pregnancy have not reported clear association with insulin glargine and adverse developmental outcomes [see Data]. There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy [see Clinical Considerations].Rats and rabbits were exposed to insulin glargine in animal reproduction studies during organogenesis, respectively 50 times and 10 times the human subcutaneous dose of 0.2 units/kg/day. Overall, the effects of insulin glargine did not generally differ from those observed with regular human insulin [see Data].The estimated background risk of major birth defects is 6% to 10% in women with pregestational diabetes with an HbA1c >7 and has been reported to be as high as 20% to 25% in women with HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.. Clinical Considerations. Disease-associated maternal and/or embryo-fetal riskPoorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia-related morbidity.. Data. Human dataPublished data do not report clear association with insulin glargine and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin glargine is used during pregnancy. However, these studies cannot definitely establish the absence of any risk because of methodological limitations including small sample size and some lacking comparator groups.. Animal dataSubcutaneous reproduction and teratology studies have been performed with insulin glargine and regular human insulin in rats and Himalayan rabbits. Insulin glargine was given to female rats before mating, during mating, and throughout pregnancy at doses up to 0.36 mg/kg/day, which is approximately 50 times the recommended human subcutaneous starting dose of 0.2 units/kg/day (0.007 mg/kg/day), on mg/kg basis. In rabbits, doses of 0.072 mg/kg/day, which is approximately 10 times the recommended human subcutaneous starting dose of 0.2 units/kg/day on mg/kg basis, were administered during organogenesis. The effects of insulin glargine did not generally differ from those observed with regular human insulin in rats or rabbits. However, in rabbits, five fetuses from two litters of the high-dose group exhibited dilation of the cerebral ventricles. Fertility and early embryonic development appeared normal.. 8.2 Lactation. Risk SummaryThere are either no or only limited data on the presence of insulin glargine in human milk, the effects on breastfed infant, or the effects on milk production. Endogenous insulin is present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mothers clinical need for insulin glargine, and any potential adverse effects on the breastfed child from insulin glargine or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of Insulin glargine have been established in pediatric patients (age to 15 years) with type diabetes [see Clinical Studies (14.2)]. The safety and effectiveness of Insulin glargine in pediatric patients younger than years of age with type diabetes and pediatric patients with type diabetes have not been established.The dosage recommendation when changing to Insulin glargine in pediatric patients (age to 15 years) with type diabetes is the same as that described for adults [see Dosage and Administration (2.2, 2.4) Clinical Studies (14)]. As in adults, the dosage of Insulin glargine must be individualized in pediatric patients (age to 15 years) with type diabetes based on metabolic needs and frequent monitoring of blood glucose.In the pediatric clinical trial, pediatric patients (age to 15 years) with type diabetes had higher incidence of severe symptomatic hypoglycemia compared to the adults in trials with type diabetes [see Adverse Reactions (6.1)].. 8.5 Geriatric Use. Of the total number of subjects in controlled clinical studies of patients with type and type diabetes who were treated with Insulin glargine, 15% were >=65 years of age and 2% were >=75 years of age. The only difference in safety or effectiveness in the subpopulation of patients >=65 years of age compared to the entire study population was higher incidence of cardiovascular events typically seen in an older population in the Insulin glargine and NPH treatment groups.Nevertheless, caution should be exercised when Insulin glargine is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly.. 8.6 Hepatic Impairment. The effect of hepatic impairment on the pharmacokinetics of Insulin glargine has not been studied. Frequent glucose monitoring and dose adjustment may be necessary for Insulin glargine in patients with hepatic impairment [see Warnings and Precautions (5.3)].. 8.7 Renal Impairment. The effect of renal impairment on the pharmacokinetics of Insulin glargine has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. Frequent glucose monitoring and dose adjustment may be necessary for Insulin glargine in patients with renal impairment [see Warnings and Precautions (5.3)]. 8.8Obesity. In controlled clinical trials, subgroup analyses based on BMI did not show differences in safety and efficacy between Insulin glargine and NPH.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Never share an Insulin glargine SoloStar prefilled pen between patients, even if the needle is changed. (5.1)Hyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to patients insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. (5.2)Hypoglycemia: May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, coadministered glucose lowering medications, meal pattern, physical activity; and in patients with renal or hepatic impairment and hypoglycemia unawareness. (5.3, 6.1)Medication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. (5.4, 6.3)Hypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue Insulin glargine. Monitor and treat if indicated. (5.5, 6.1)Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. (5.6)Fluid retention and heart failure with concomitant use of thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation of TZD if heart failure occurs. (5.7). Never share an Insulin glargine SoloStar prefilled pen between patients, even if the needle is changed. (5.1). Hyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to patients insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. (5.2). Hypoglycemia: May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, coadministered glucose lowering medications, meal pattern, physical activity; and in patients with renal or hepatic impairment and hypoglycemia unawareness. (5.3, 6.1). Medication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. (5.4, 6.3). Hypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue Insulin glargine. Monitor and treat if indicated. (5.5, 6.1). Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. (5.6). Fluid retention and heart failure with concomitant use of thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation of TZD if heart failure occurs. (5.7). 5.1Never Share an Insulin Glargine SoloStar Prefilled Pen, Syringe, or Needle Between Patients. Insulin glargine SoloStar prefilled pens must never be shared between patients, even if the needle is changed. Patients using Insulin glargine vials must never re-use or share needles or syringes with another person. Sharing poses risk for transmission of blood-borne pathogens.. 5.2Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen. Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions (5.3)] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and sudden change in the injection site (to unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions (6)].Make any changes to patients insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type diabetes, dosage adjustments of concomitant oral and antidiabetic products may be needed.. 5.3Hypoglycemia Hypoglycemia is the most common adverse reaction associated with insulin, including Insulin glargine. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7)], or in patients who experience recurrent hypoglycemia.. Risk Factors for HypoglycemiaThe risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulin preparations, the glucose lowering effect time course of Insulin glargine may vary in different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature [see Clinical Pharmacology (12.2)]. Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to coadministered medication [see Drug Interactions (7)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].. Risk Mitigation Strategies for HypoglycemiaPatients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of blood glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of blood glucose monitoring is recommended.The long-acting effect of Insulin glargine may delay recovery from hypoglycemia.. 5.4Medication Errors Accidental mix-ups among insulin products, particularly between long-acting insulins and rapid-acting insulins, have been reported. To avoid medication errors between Insulin glargine and other insulins, instruct patients to always check the insulin label before each injection [see Adverse Reactions (6.3)].. 5.5Hypersensitivity and Allergic Reactions. Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including Insulin glargine. If hypersensitivity reactions occur, discontinue Insulin glargine; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6.1)]. Insulin glargine is contraindicated in patients who have had hypersensitivity reactions to insulin glargine or one of the excipients [see Contraindications (4)].. 5.6Hypokalemia. All insulin products, including Insulin glargine, cause shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia, if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).. 5.7Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists. Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including Insulin glargine, and PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.