Insulin Glargine

1 INDICATIONS AND USAGE BASAGLAR ® is indicated to improve glycemic control in adults and pediatric patients with type 1 diabetes mellitus and in adults with type 2 diabetes mellitus. BASAGLAR ® 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 BASAGLAR is not recommended for the treatment of diabetic ketoacidosis.

2 DOSAGE AND ADMINISTRATION Individualize dosage based on metabolic needs, blood glucose monitoring, glycemic control, type of diabetes, prior insulin use. ( 2.2 , 2.3 , 2.4 ) Administer subcutaneously once daily at any time of day, but at the same time every day. ( 2.2 ) Rotate injection sites into the abdominal area, thigh, or deltoid to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. ( 2.1 ) Closely monitor glucose when converting to BASAGLAR and during initial weeks thereafter. ( 2.2 ) Do not dilute or mix with any other insulin or solution. ( 2.1 ) 2.1 Important Administration Instructions Always check insulin labels before administration [see Warnings and Precautions ( 5.4 )] . Visually inspect BASAGLAR prefilled pens for particulate matter and discoloration prior to administration. Only use if the solution is clear and colorless with no visible particles. Administer BASAGLAR 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 ) and Adverse Reactions ( 6 )] . During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )] . Use BASAGLAR with caution in patients with visual impairment that may rely on audible clicks to dial their dose. Do not dilute or mix BASAGLAR with any other insulin or solution. Do not administer intravenously or via an insulin pump. 2.2 General Dosing Instructions In patients with type 1 diabetes, BASAGLAR must be used concomitantly with short-acting insulin. Inject BASAGLAR subcutaneously once daily at any time of day but at the same time every day. Individualize and adjust the dosage of BASAGLAR 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 )] . The BASAGLAR prefilled pens each dials in 1 unit increments and delivers a maximum dose of 80 units per injection. 2.3 Initiation of BASAGLAR Therapy The recommended starting dose of BASAGLAR in patients with type 1 diabetes should be approximately one-third of the total daily insulin requirements. Short- or rapid-acting, pre-meal insulin should be used to satisfy the remainder of the daily insulin requirements. The recommended starting dose of BASAGLAR in patients with type 2 diabetes is 0.2 units/kg or up to 10 units once daily. 2.4 Changing to BASAGLAR from Other Insulin Therapies If changing patients from another insulin glargine product, 100 units/mL, to BASAGLAR, the dose of BASAGLAR should be the same as the other insulin glargine product, 100 units/mL. If changing patients from a once-daily insulin glargine product, 300 units/mL, to once-daily BASAGLAR, the recommended initial BASAGLAR dosage is 80% of the insulin glargine product, 300 units/mL [see Warnings and Precautions ( 5.2 )] . If changing from a treatment regimen with an intermediate- or long-acting insulin to a regimen with BASAGLAR, a change in the dose of the basal insulin may be required. If changing patients from twice-daily NPH insulin to once-daily BASAGLAR, the recommended initial BASAGLAR dosage is 80% of the total daily NPH dosage [see Warnings and Precautions ( 5.2 )] .

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere: Hypoglycemia [see Warnings and Precautions ( 5.3 )] . Hypoglycemia Due to Medication Errors [see Warnings and Precautions ( 5.4 )] . Hypersensitivity Reactions [see Warnings and Precautions ( 5.5 )] . Hypokalemia [see Warnings and Precautions ( 5.6 )] . Adverse reactions commonly (≥5%) associated with insulin glargine products are: Hypoglycemia, allergic reactions, injection site reaction, lipodystrophy, pruritus, rash, edema, and weight gain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Two clinical trials with BASAGLAR were conducted: one in type 1 diabetes and one in type 2 diabetes. The type 1 diabetes population had the following characteristics: Mean age was 41 years and mean duration of diabetes was 16 years. 58% were male. 75% were Caucasian, 2% Black or African American and 4% American Indian or Alaskan native. 4% were Hispanic. At baseline, mean eGFR was 109 mL/min/1.73m 2 . 73.5 percent of patients had eGFR>90 mL/min/1.73m 2 . The mean BMI was approximately 26 kg/m 2 . HbA 1c at baseline was 7.8%. The data in Table 1 reflect exposure of 268 patients to BASAGLAR with a mean exposure duration of 49 weeks. The type 2 diabetes population had the following characteristics: Mean age was 59 years and mean duration of diabetes was 11 years. 50% were male. 78% were Caucasian, 8% Black or African American and 5% American Indian or Alaskan native. 28% were Hispanic. At baseline, mean eGFR was 109 mL/min/1.73m 2 . 67.5 percent of patients had eGFR>90 mL/min/1.73m 2 . The mean BMI was approximately 32 kg/m 2 . HbA 1c at baseline was 8.3%. The data in Table 2 reflect exposure of 376 patients to BASAGLAR with a mean exposure duration of 22 weeks. Common adverse reactions were defined as reactions occurring in ≥5% of the population studied. Common adverse reactions during clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus (other than hypoglycemia) are listed in Table 1 and Table 2 , respectively. Table 1: Adverse reactions occurring in ≥5% of adult patients with type 1 diabetes treated with BASAGLAR in a 52-week trial a Infections other than nasopharyngitis or upper respiratory tract infection. BASAGLAR + Insulin Lispro, % (n=268) Infection a 24 Nasopharyngitis 16 Upper respiratory tract infection 8 Table 2: Adverse reactions occurring in ≥5% of adult patients with type 2 diabetes treated with BASAGLAR in a 24-week trial a Infections other than nasopharyngitis or upper respiratory tract infection. BASAGLAR + Oral Antidiabetic Medication, % (n=376) Infection a 17 Nasopharyngitis 6 Upper respiratory tract infection 5 The frequencies of adverse reactions during a clinical trial of 5 years duration with another insulin glargine product, 100 units/mL, in patients with type 2 diabetes mellitus are listed in Table 3 . Table 3: Common adverse reactions in 5-year trial of adult patients with type 2 diabetes (adverse reactions with incidence ≥10% and higher with another insulin glargine product, 100 units/mL, than comparator) Another Insulin Glargine Product, % (n=514) NPH, % (n=503) Hypertension 20 19 Sinusitis 19 18 Cataract 18 16 Bronchitis 15 14 Back pain 13 12 Cough 12 7 Urinary tract infection 11 10 Diarrhea 11 10 Depression 11 10 Headache 10 9 The frequencies of adverse reactions during clinical trials with another insulin glargine product, 100 units/mL, in children and adolescents with type 1 diabetes mellitus are listed in Table 4 . Table 4: Adverse reactions in a 28-week clinical trial of pediatric patients with type 1 diabetes (adverse reactions with frequency ≥5% and the same or higher with another insulin glargine product, 100 units/mL, than comparator) Another Insulin Glargine Product, % (n=174) NPH, % (n=175) Rhinitis 5 5 Severe Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including BASAGLAR. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for BASAGLAR with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice. 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. The incidence of severe symptomatic hypoglycemia in patients receiving BASAGLAR with type 1 diabetes mellitus and type 2 diabetes mellitus [see Clinical Studies ( 14 )] was 4% at 52 weeks and 1% at 24 weeks, respectively. The incidence of severe symptomatic hypoglycemia in a clinical trial with another insulin glargine product, 100 units/mL, in children and adolescents age 6 to 15 years with type 1 diabetes [see Clinical Studies ( 14 )] was 23% at 26 weeks. Table 5 displays the proportion of patients experiencing severe symptomatic hypoglycemia in another insulin glargine product, 100 units/mL, and Standard Care groups in the ORIGIN Trial [see Clinical Studies ( 14 )] . Table 5: Severe Symptomatic Hypoglycemia in the ORIGIN Trial ORIGIN Trial Median duration of follow-up: 6.2 years Another Insulin Glargine Product, 100 units/mL (N=6231) Standard Care (N=6273) Percent of patients 6 2 Allergic Reactions Some patients taking insulins, including BASAGLAR have experienced erythema, local edema, and pruritus at the site of injection. These conditions were usually self-limiting. Severe cases of generalized allergy (anaphylaxis) have been reported. Peripheral Edema Some patients taking BASAGLAR have experienced sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Lipodystrophy Administration of insulins subcutaneously, including BASAGLAR, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) in some patients [see Dosage and Administration ( 2.1 )] . Weight gain Weight gain has occurred with insulins, including BASAGLAR, and has been attributed to the anabolic effects of insulin and the decrease in glycosuria. 6.2 Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. In a 52-week study of type 1 diabetes patients, 42% of patients who received BASAGLAR once daily were positive for anti-drug antibodies (ADA) at least once during the study, including 17% that were positive at baseline and 25% of patients who developed ADA during the study. Sixty-five percent of the ADA positive patients on BASAGLAR with antibody testing at week 52 remained ADA positive at week 52. In a 24-week study of type 2 diabetes patients, 17% of patients who received BASAGLAR once daily were positive for ADA at least once during the study. Among the subjects who were positive, 5% had ADA at baseline and 12% developed antibodies during the study. The percent binding of patients positive at baseline on BASAGLAR did not increase significantly during the study. Fifty-one percent of the ADA positive patients on BASAGLAR with antibody testing at week 24 remained ADA positive at week 24. There was no evidence that these antibodies had an impact on efficacy and safety outcomes. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as: assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to BASAGLAR with the incidence of antibodies in other studies or to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post-approval use of insulin glargine. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Medication errors have been reported in which other insulin products, particularly rapid-acting insulins, have been accidentally administered instead of insulin glargine. 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.

12.3 Pharmacokinetics Absorption and Bioavailability The pharmacokinetic profile for BASAGLAR was determined after subcutaneous administration of a single 0.5 U/kg dose in a euglycemic clamp study conducted in 91 healthy subjects. The insulin serum concentrations indicated a slow and prolonged absorption and a relatively constant concentration/time profile over 24 hours with no pronounced peak. The median time to maximum serum insulin concentration was 12 hours after injection. On average, serum insulin concentrations declined to baseline by approximately 24 hours. The mean observed area under the serum insulin concentration-time curve from time zero to 24 hours and peak serum insulin concentration were 1720 pmol*hr/L and 103 pmol/L, respectively. Metabolism and Elimination After subcutaneous injection of another insulin glargine product, 100 units/mL, in diabetic patients, insulin glargine is metabolized at the carboxyl terminus of the Beta chain with formation of two active metabolites M1 (21 A -Gly-insulin) and M2 (21 A -Gly-des-30 B -Thr-insulin). The in vitro activity of M1 and M2 were similar to that of insulin. Specific Populations Age, Race, and Gender: Effect of age, race, and gender on the pharmacokinetics of BASAGLAR has not been evaluated. Obesity: Effect of BMI on the pharmacokinetics of BASAGLAR has not been evaluated.