Insulin Glargine Solostar

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) ] 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. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in clinical trials of a 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 1 reflect the exposure of 2327 patients with type 1 diabetes to Insulin glargine or NPH. The type 1 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/m 2 . The data in Table 2 reflect the exposure of 1563 patients with type 2 diabetes to Insulin glargine or NPH. The type 2 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/m 2 . The frequencies of adverse events during Insulin glargine clinical trials in patients with type 1 diabetes mellitus and type 2 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 1 Diabetes (adverse events with frequency ≥5%) Insulin glargine, % (n=1257) NPH, % (n=1070) Upper respiratory tract infection 22.4 23.1 Infection Body system not specified 9.4 10.3 Accidental injury 5.7 6.4 Headache 5.5 4.7 Table 2: Adverse Events in Pooled Clinical Trials up to 1 Year Duration in Adults with Type 2 Diabetes (adverse events with frequency ≥5%) Insulin glargine, % (n=849) NPH, % (n=714) Upper respiratory tract infection 11.4 13.3 Infection Body system not specified 10.4 11.6 Retinal vascular disorder 5.8 7.4 Table 3: Adverse Events in a 5-Year Trial of Adults with Type 2 Diabetes (adverse events with frequency ≥10%) Insulin glargine, % (n=514) NPH, % (n=503) Upper respiratory tract infection 29.0 33.6 Edema peripheral 20.0 22.7 Hypertension 19.6 18.9 Influenza 18.7 19.5 Sinusitis 18.5 17.9 Cataract 18.1 15.9 Bronchitis 15.2 14.1 Arthralgia 14.2 16.1 Pain in extremity 13.0 13.1 Back pain 12.8 12.3 Cough 12.1 7.4 Urinary tract infection 10.7 10.1 Diarrhea 10.7 10.3 Depression 10.5 9.7 Headache 10.3 9.3 Table 4: Adverse Events in a 28-Week Clinical Trial of Children and Adolescents with Type 1 Diabetes (adverse events with frequency ≥5%) Insulin glargine, % (n=174) NPH, % (n=175) Infection Body system not specified 13.8 17.7 Upper respiratory tract infection 13.8 16.0 Pharyngitis 7.5 8.6 Rhinitis 5.2 5.1 Severe Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including Insulin glargine [see Warnings and Precautions (5.3) ] . Tables 5, 6, and 7 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 a 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 5 and 6 ). In the pediatric phase 3 clinical trial, children and adolescents with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia in the two treatment groups compared to the adult trials with type 1 diabetes. Table 5: Severe Symptomatic Hypoglycemia in Patients with Type 1 Diabetes Study A Type 1 Diabetes Adults 28 weeks In combination with regular insulin Study B Type 1 Diabetes Adults 28 weeks In combination with regular insulin Study C Type 1 Diabetes Adults 16 weeks In combination with insulin lispro Study D Type 1 Diabetes Pediatrics 26 weeks In combination with regular insulin Insulin glargine N=292 NPH N=293 Insulin glargine N=264 NPH N=270 Insulin glargine N=310 NPH N=309 Insulin glargine N=174 NPH N=175 Percent of patients 10.6 15.0 8.7 10.4 6.5 5.2 23.0 28.6 Table 6: Severe Symptomatic Hypoglycemia in Patients with Type 2 Diabetes Study E Type 2 Diabetes Adults 52 weeks In combination with oral agents Study F Type 2 Diabetes Adults 28 weeks In combination with regular insulin Study G Type 2 Diabetes Adults 5 years In combination with regular insulin Insulin glargine N=289 NPH N=281 Insulin glargine N=259 NPH N=259 Insulin glargine N=513 NPH N=504 Percent of patients 1.7 1.1 0.4 2.3 7.8 11.9 Table 7 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 Trial ORIGIN Trial Median duration of follow-up: 6.2 years Insulin glargine N=6231 Standard Care N=6273 Percent of patients 5.6 1.8 Peripheral Edema Some patients taking Insulin glargine have experienced sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Lipodystrophy Administration 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 Control Intensification or rapid improvement in glucose control has been associated with a 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 Gain Weight 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 allergy As 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 a 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 allergy Severe, 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 3 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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a 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 a sudden change to an unaffected injection site.

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 ( 4 ) Hypersensitivity to Insulin glargine or one of its excipients ( 4 )

11 DESCRIPTION Insulin glargine (insulin glargine injection) is a sterile solution of insulin glargine for subcutaneous use. Insulin glargine is a recombinant human insulin analog that is a long-acting, parenteral blood-glucose-lowering agent [see Clinical Pharmacology (12) ] . Insulin glargine has low aqueous solubility at neutral pH. At pH 4 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 a relatively constant concentration/time profile over 24 hours with no pronounced peak. This profile allows once-daily dosing as a basal insulin. Insulin glargine is produced by recombinant DNA technology utilizing a 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 21 A -Gly-30 B a-L-Arg-30 B b-L-Arg-human insulin and has the empirical formula C 267 H 404 N 72 O 78 S 6 and a molecular weight of 6063. Insulin glargine has the following structural formula: Insulin glargine consists of insulin glargine dissolved in a 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 3 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 a pH of approximately 4. Chemical Structure

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 ) 2.1 Important 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 a patient's 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 ® 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) ] . 2.2 General Dosing Instructions Individualize and adjust the dosage of Insulin glargine based on the individual's 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) ] . 2.3 Initiation of Insulin Glargine Therapy Type 1 Diabetes In patients with type 1 diabetes, Insulin glargine must be used concomitantly with short-acting insulin. The recommended starting dose of Insulin glargine in patients with type 1 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 2 Diabetes The recommended starting dose of Insulin glargine in patients with type 2 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. 2.4 Changing 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 a treatment regimen with an intermediate or long-acting insulin to a regimen with Insulin glargine, a 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) ].

1 INDICATIONS AND USAGE Insulin glargine is indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. Insulin glargine is a long-acting human insulin analog indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. ( 1 ) Limitations of Use Not recommended for treating diabetic ketoacidosis. ( 1 ) Limitations of Use Insulin glargine is not recommended for the treatment of diabetic ketoacidosis.

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.

7 DRUG INTERACTIONS Table 8 includes clinically significant drug interactions with Insulin glargine. Table 8: Clinically Significant Drug Interactions with Insulin Glargine Drugs that May Increase the Risk of Hypoglycemia Drugs : 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 Glargine Drugs : 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 Glargine Drugs : 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 )

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 a molar basis (i.e., when given at the same doses) of intravenous insulin glargine is approximately the same as that for human insulin. Figure 1 shows results from a study in patients with type 1 diabetes conducted for a 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 1 Diabetes * Determined as amount of glucose infused to maintain constant plasma glucose levels The 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 Bioavailability After subcutaneous injection of Insulin glargine in healthy subjects and in patients with diabetes, the insulin serum concentrations indicated a slower, more prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak in comparison to NPH insulin. Metabolism and Elimination A metabolism study in humans indicates that insulin glargine is partly metabolized at the carboxyl terminus of the B chain in the subcutaneous depot to form two active metabolites with in vitro activity similar to that of human insulin, M1 (21 A -Gly-insulin) and M2 (21 A -Gly-des-30 B -Thr-insulin). Unchanged drug and these degradation products are also present in the circulation. Special Populations Age, race, and gender Effect 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 a 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) ] . Obesity Effect of Body Mass Index (BMI) on the pharmacokinetics of Insulin glargine has not been evaluated.

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 a molar basis (i.e., when given at the same doses) of intravenous insulin glargine is approximately the same as that for human insulin. Figure 1 shows results from a study in patients with type 1 diabetes conducted for a 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 1 Diabetes * Determined as amount of glucose infused to maintain constant plasma glucose levels The 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 Bioavailability After subcutaneous injection of Insulin glargine in healthy subjects and in patients with diabetes, the insulin serum concentrations indicated a slower, more prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak in comparison to NPH insulin. Metabolism and Elimination A metabolism study in humans indicates that insulin glargine is partly metabolized at the carboxyl terminus of the B chain in the subcutaneous depot to form two active metabolites with in vitro activity similar to that of human insulin, M1 (21 A -Gly-insulin) and M2 (21 A -Gly-des-30 B -Thr-insulin). Unchanged drug and these degradation products are also present in the circulation. Special Populations Age, race, and gender Effect 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 a 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) ] . Obesity Effect of Body Mass Index (BMI) on the pharmacokinetics of Insulin glargine has not been evaluated.

20231101

3

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) Injection: 100 units/mL (U-100) available as: 10 mL multiple-dose vial ( 3 ) 3 mL single-patient-use SoloStar prefilled pen ( 3 )

Insulin Glargine Solostar insulin glargine INSULIN GLARGINE INSULIN GLARGINE ZINC METACRESOL GLYCERIN WATER HYDROCHLORIC ACID SODIUM HYDROXIDE

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 a mg/kg basis. Histiocytomas were found at injection sites in male rats and mice in acid vehicle containing groups and are considered a 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 a 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 a 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, a reduction of the rearing rate occurred in the high-dose group only. Similar effects were observed with NPH insulin.

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 a mg/kg basis. Histiocytomas were found at injection sites in male rats and mice in acid vehicle containing groups and are considered a 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 a 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 a 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, a reduction of the rearing rate occurred in the high-dose group only. Similar effects were observed with NPH insulin.

BLA021081

Insulin Glargine Solostar

insulin glargine

50090-6178

HUMAN PRESCRIPTION DRUG

SUBCUTANEOUS

INSULIN GLARGINE Label Image

Winthrop U.S., a business of sanofi-aventis U.S. LLC Bridgewater, NJ 08807 A SANOFI COMPANY ©2021 sanofi-aventis U.S. LLC TOUJEO and SoloStar are registered trademarks of sanofi-aventis U.S. LLC.

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 Patients Advise 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 a risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1) ] . Hyperglycemia or Hypoglycemia Inform 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 a result of hypoglycemia. This may present a 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 Errors Instruct patients to always check the insulin label before each injection [see Warnings and Precautions (5.4) ] . Administration Advise 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 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 a 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 a serious infection, or get a serious infection from them. Supplies needed to give your injection: an Insulin glargine 10 mL vial a U-100 insulin syringe and needle 2 alcohol swabs 1 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 1 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 a syringe that is marked for U-100 insulin . If you use a syringe other than a U-100 insulin syringe, you may get the wrong dose of insulin. Always use a 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 a serious infection or get a serious infection from them. Step 1: If you are using a 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 a needle stick injury. Disposing of used needles and syringes: Put your used needles and syringes in a 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 a FDA-cleared sharps container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a 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 FDA's 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 I store Insulin glargine? Store unused Insulin glargine vials in the refrigerator between 36°F to 46°F (2°C to 8°C). Store in-use (opened) Insulin glargine vials in a refrigerator or at room temperature below 86°F (30°C). Do not freeze Insulin glargine. Keep Insulin glargine out of direct heat and light. If a 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. LLC Bridgewater, NJ 08807 A SANOFI COMPANY ©2020 sanofi-aventis U.S. LLC Image Image Image Image Image Image Image

14 CLINICAL STUDIES 14.1 Overview 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 1 diabetes mellitus and 1,563 adult patients with type 2 diabetes mellitus (see Tables 9–11). In general, the reduction in glycated hemoglobin (HbA1c) with Insulin glargine was similar to that with NPH insulin. 14.2 Clinical Studies in Adult and Pediatric Patients with Type 1 Diabetes In two clinical studies (Studies A and B), patients with type 1 diabetes (Study A n=585, Study B 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/m 2 . 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/m 2 . The mean duration of diabetes was 17.4 years. In another clinical study (Study C), patients with type 1 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/m 2 . The mean duration of diabetes was 18.5 years. In these 3 studies, Insulin glargine and NPH insulin had similar effects on HbA1c (Table 9) with a similar overall rate of severe symptomatic hypoglycemia [see Adverse Reactions (6.1) ] . Table 9: Type 1 Diabetes Mellitus – Adult Study A Study B Study C Treatment duration 28 weeks 28 weeks 16 weeks Treatment in combination with Regular insulin Regular insulin Insulin lispro Insulin glargine NPH Insulin glargine NPH Insulin glargine NPH Number of subjects treated 292 293 264 270 310 309 HbA1c Baseline HbA1c 8.0 8.0 7.7 7.7 7.6 7.7 Adjusted mean change at trial end +0.2 +0.1 -0.2 -0.2 -0.1 -0.1 Treatment Difference (95% CI) +0.1 (0.0; +0.2) +0.1 (-0.1; +0.2) 0.0 (-0.1; +0.1) Basal insulin dose Baseline mean 21 23 29 29 28 28 Mean change from baseline -2 0 -4 +2 -5 +1 Total insulin dose Baseline mean 48 52 50 51 50 50 Mean change from baseline -1 0 0 +4 -3 0 Fasting blood glucose (mg/dL) Baseline mean 167 166 166 175 175 173 Adj. mean change from baseline -21 -16 -20 -17 -29 -12 Body weight (kg) Baseline mean 73.2 74.8 75.5 75.0 74.8 75.6 Mean change from baseline 0.1 -0.0 0.7 1.0 0.1 0.5 Type 1 Diabetes – Pediatric (see Table 10 ) In a randomized, controlled clinical study (Study D), pediatric patients (age range 6 to 15 years) with type 1 diabetes (n=349) were treated for 28 weeks with a 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/m 2 . 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 1 Diabetes Mellitus – Pediatric Study D Treatment duration 28 weeks Treatment in combination with Regular insulin Insulin glargine + Regular Insulin NPH + Regular Insulin Number of subjects treated 174 175 HbA1c Baseline mean 8.5 8.8 Change from baseline (adjusted mean) +0.3 +0.3 Difference from NPH (adjusted mean) 0.0 (95% CI ) (-0.2; +0.3) Basal insulin dose Baseline mean 19 19 Mean change from baseline -1 +2 Total insulin dose Baseline mean 43 43 Mean change from baseline +2 +3 Fasting blood glucose (mg/dL) Baseline mean 194 191 Mean change from baseline -23 -12 Body weight (kg) Baseline mean 45.5 44.6 Mean change from baseline 2.2 2.5 14.3 Clinical Studies in Adults with Type 2 Diabetes In a 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/m 2 . 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 a randomized, controlled clinical study (Study F), in patients with type 2 diabetes not using oral antidiabetic medications (n=518), a 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/m 2 . 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 a similar incidence of hypoglycemia [see Adverse Reactions (6.1) ] . In a randomized, controlled clinical study (Study G), patients with type 2 diabetes were randomized to 5 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 a dose that was 80% of the total previous NPH insulin dose. The primary endpoint for this study was a comparison of the progression of diabetic retinopathy by 3 or more steps on the Early Treatment Diabetic Retinopathy Study (ETDRS) scale. HbA1c change from baseline was a secondary endpoint. Similar glycemic control in the 2 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 a 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/m 2 . The mean duration of diabetes was 10.8 years. The Insulin glargine group had a 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 2 Diabetes Mellitus – Adult Study E Study F Study G Treatment duration 52 weeks 28 weeks 5 years Treatment in combination with Oral agents Regular insulin Regular insulin Insulin glargine NPH Insulin glargine NPH Insulin glargine NPH Number of subjects treated 289 281 259 259 513 504 HbA1c Baseline mean 9.0 8.9 8.6 8.5 8.4 8.3 Adjusted mean change from baseline -0.5 -0.4 -0.4 -0.6 -0.6 -0.8 Insulin glargine – NPH -0.1 +0.2 +0.2 95% CI for Treatment difference (-0.3; +0.1) (0.0; +0.4) (+0.1; +0.4) Basal insulin dose In 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 mean 14 15 44.1 45.5 39 44 Mean change from baseline +12 +9 -1 +7 +23 +30 Total insulin dose Baseline mean 14 15 64 67 48 53 Mean change from baseline +12 +9 +10 +13 +41 +40 Fasting blood glucose (mg/dL) Baseline mean 179 180 164 166 190 180 Adj. mean change from baseline -49 -46 -24 -22 -45 -44 Body weight (kg) Baseline mean 83.5 82.1 89.6 90.7 100 99 Adj. mean change from baseline 2.0 1.9 0.4 1.4 3.7 4.8 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 a randomized, controlled clinical study in patients with type 1 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/m 2 . 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 a randomized, active-controlled clinical study (Study I, n=697) in patients with type 2 diabetes not adequately controlled on oral antidiabetic therapy. All patients in this study also received glimepiride 3 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/m 2 . 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 1 (Study H) and Type 2 (Study I) Diabetes Mellitus Study H Study I Treatment duration 24 weeks 24 weeks Treatment in combination with Insulin lispro Glimepiride Insulin glargine Breakfast Insulin glargine Dinner Insulin glargine Bedtime Insulin glargine Breakfast Insulin glargine Bedtime NPH Bedtime Number of subjects treated Intent-to-treat 112 124 128 234 226 227 HbA1c Baseline mean 7.6 7.5 7.6 9.1 9.1 9.1 Mean change from baseline -0.2 -0.1 0.0 -1.3 -1.0 -0.8 Basal insulin dose (U) Baseline mean 22 23 21 19 20 19 Mean change from baseline 5 2 2 11 18 18 Total insulin dose (U) NA Not applicable NA NA Baseline mean 52 52 49 – – – Mean change from baseline 2 3 2 – – – Body weight (kg) Baseline mean 77.1 77.8 74.5 80.7 82 81 Mean change from baseline 0.7 0.1 0.4 3.9 3.7 2.9 Five-Year Trial Evaluating the Progression of Retinopathy Retinopathy 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 1 and type 2 diabetes. Insulin glargine was compared to NPH insulin in a 5-year randomized clinical trial that evaluated the progression of retinopathy as assessed with fundus photography using a grading protocol derived from the Early Treatment Diabetic Retinopathy Scale (ETDRS). Patients had type 2 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 3 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 3 or More Step Progression on ETDRS Scale at Endpoint Insulin glargine (%) NPH (%) Difference Difference = Insulin glargine – NPH , Using a 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 difference Per-protocol 53/374 (14.2%) 57/363 (15.7%) -2.0% (2.6%) -7.0% to +3.1% Intent-to-Treat 63/502 (12.5%) 71/487 (14.6%) -2.1% (2.1%) -6.3% to +2.1% The Origin Study The 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 2 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 a 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 a 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/m 2 . Approximately 12% of participants had abnormal glucose levels (IGT and/or IFG) at baseline and 88% had type 2 diabetes. For patients with type 2 diabetes, 59% were treated with a 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 a 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: 8 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 Analyses Insulin glargine N=6264 Standard Care N=6273 Insulin glargine vs Standard Care n (Events per 100 PY) n (Events per 100 PY) Hazard Ratio (95% CI) Coprimary endpoints CV death, nonfatal myocardial infarction, or nonfatal stroke 1041 (2.9) 1013 (2.9) 1.02 (0.94, 1.11) CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure or revascularization procedure 1792 (5.5) 1727 (5.3) 1.04 (0.97, 1.11) Components of coprimary endpoints CV death 580 576 1.00 (0.89, 1.13) Myocardial Infarction (fatal or nonfatal) 336 326 1.03 (0.88, 1.19) Stroke (fatal or nonfatal) 331 319 1.03 (0.89, 1.21) Revascularizations 908 860 1.06 (0.96, 1.16) Hospitalization for heart failure 310 343 0.90 (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 Analyses Insulin glargine N=6264 Standard Care N=6273 Insulin glargine vs Standard Care n (Events per 100 PY) n (Events per 100 PY) Hazard Ratio (95% CI) Cancer endpoints Any cancer event (new or recurrent) 559 (1.56) 561 (1.56) 0.99 (0.88, 1.11) New cancer events 524 (1.46) 535 (1.49) 0.96 (0.85, 1.09) Death due to Cancer 189 (0.51) 201 (0.54) 0.94 (0.77, 1.15)

8.5 Geriatric Use Of the total number of subjects in controlled clinical studies of patients with type 1 and type 2 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 a 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.

8.4 Pediatric Use The safety and effectiveness of Insulin glargine have been established in pediatric patients (age 6 to 15 years) with type 1 diabetes [see Clinical Studies (14.2) ] . The safety and effectiveness of Insulin glargine in pediatric patients younger than 6 years of age with type 1 diabetes and pediatric patients with type 2 diabetes have not been established. The dosage recommendation when changing to Insulin glargine in pediatric patients (age 6 to 15 years) with type 1 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 6 to 15 years) with type 1 diabetes based on metabolic needs and frequent monitoring of blood glucose. In the pediatric clinical trial, pediatric patients (age 6 to 15 years) with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia compared to the adults in trials with type 1 diabetes [see Adverse Reactions (6.1) ] .

8.1 Pregnancy Risk Summary Published studies with use of insulin glargine during pregnancy have not reported a 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 a 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 risk Poorly 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 data Published data do not report a 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 data Subcutaneous 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 a 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 a 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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Published studies with use of insulin glargine during pregnancy have not reported a 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 a 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 risk Poorly 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 data Published data do not report a 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 data Subcutaneous 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 a 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 a 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 Summary There 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 mother's 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 6 to 15 years) with type 1 diabetes [see Clinical Studies (14.2) ] . The safety and effectiveness of Insulin glargine in pediatric patients younger than 6 years of age with type 1 diabetes and pediatric patients with type 2 diabetes have not been established. The dosage recommendation when changing to Insulin glargine in pediatric patients (age 6 to 15 years) with type 1 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 6 to 15 years) with type 1 diabetes based on metabolic needs and frequent monitoring of blood glucose. In the pediatric clinical trial, pediatric patients (age 6 to 15 years) with type 1 diabetes had a higher incidence of severe symptomatic hypoglycemia compared to the adults in trials with type 1 diabetes [see Adverse Reactions (6.1) ] . 8.5 Geriatric Use Of the total number of subjects in controlled clinical studies of patients with type 1 and type 2 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 a 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) ]. 8.8 Obesity In controlled clinical trials, subgroup analyses based on BMI did not show differences in safety and efficacy between Insulin glargine and NPH.

16 HOW SUPPLIED/STORAGE AND HANDLING Product: 50090-6178 NDC: 50090-6178-0 3 mL in a SYRINGE / 5 in a CARTON