Insulin Lispro

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere: Hypoglycemia [see Warnings and Precautions ( 5.3 )] . Hypokalemia [see Warnings and Precautions ( 5.6 )] . Adverse reactions associated with Insulin Lispro Injection include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, and rash. ( 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 designs, the adverse reaction rates reported in one clinical trial may not be easily compared with those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. The frequencies of Treatment-Emergent Adverse Events during Insulin Lispro Injection clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below. Table 1: Treatment-Emergent Adverse Events in Patients with Type 1 Diabetes Mellitus (adverse events with frequency ≥5%) Events, n (%) Insulin Lispro Injection (n=81) Regular human insulin (n=86) Flu syndrome 28 (34.6) 28 (32.6) Pharyngitis 27 (33.3) 29 (33.7) Rhinitis 20 (24.7) 25 (29.1) Headache 24 (29.6) 19 (22.1) Pain 16 (19.8) 14 (16.3) Cough increased 14 (17.3) 15 (17.4) Infection 11 (13.6) 18 (20.9) Nausea 5 (6.2) 13 (15.1) Accidental injury 7 (8.6) 10 (11.6) Surgical procedure 5 (6.2) 12 (14.0) Fever 5 (6.2) 10 (11.6) Abdominal pain 6 (7.4) 7 (8.1) Asthenia 6 (7.4) 7 (8.1) Bronchitis 6 (7.4) 6 (7.0) Diarrhea 7 (8.6) 5 (5.8) Dysmenorrhea 5 (6.2) 6 (7.0) Myalgia 6 (7.4) 5 (5.8) Urinary tract infection 5 (6.2) 4 (4.7) Table 2: Treatment-Emergent Adverse Events in Patients with Type 2 Diabetes Mellitus (adverse events with frequency ≥5%) Events, n (%) Insulin Lispro Injection (n=714) Regular human insulin (n=709) Headache 83 (11.6) 66 (9.3) Pain 77 (10.8) 71 (10.0) Infection 72 (10.1) 54 (7.6) Pharyngitis 47 (6.6) 58 (8.2) Rhinitis 58 (8.1) 47 (6.6) Flu syndrome 44 (6.2) 58 (8.2) Surgical procedure 53 (7.4) 48 (6.8) 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. Lipodystrophy Long-term use of insulin, including Insulin Lispro Injection, can cause lipodystrophy at the site of repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection or infusion sites within the same region to reduce the risk of lipodystrophy [see Dosage and Administration ( 2.2 )] . Weight gain Weight gain can occur with insulin therapy, including Insulin Lispro Injection, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Peripheral Edema Insulin, including Insulin Lispro Injection, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Adverse Reactions with Continuous Subcutaneous Insulin Infusion (CSII) In a 12-week, randomized, crossover study in adult patients with type 1 diabetes (n=39), the rates of catheter occlusions and infusion site reactions were similar for Insulin Lispro Injection and regular human insulin treated patients ( see Table 3 ). Table 3: Catheter Occlusions and Infusion Site Reactions Insulin Lispro Injection (n=38) Regular human insulin (n=39) Catheter occlusions/month 0.09 0.10 Infusion site reactions 2.6% (1/38) 2.6% (1/39) In a randomized, 16-week, open-label, parallel design study of children and adolescents with type 1 diabetes, adverse event reports related to infusion-site reactions were similar for Insulin Lispro Injection and insulin aspart (21% of 100 patients versus 17% of 198 patients, respectively). In both groups, the most frequently reported infusion site adverse events were infusion site erythema and infusion site reaction. Allergic Reactions Local Allergy — As with any insulin therapy, patients taking Insulin Lispro Injection may experience redness, swelling, or itching at the site of the injection. These minor reactions usually resolve in a few days to a few weeks, but in some occasions, may require discontinuation of Insulin Lispro Injection. In some instances, these reactions may be related to factors other than insulin, such as irritants in a skin cleansing agent or poor injection technique. Systemic Allergy — Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin, including Insulin Lispro Injection. Generalized allergy to insulin may cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis. In controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving regular human insulin (n=2969) and 30 patients receiving Insulin Lispro Injection (n=2944). Localized reactions and generalized myalgias have been reported with injected metacresol, which is an excipient in Insulin Lispro Injection [see Contraindications ( 4 )] . Antibody Production In large clinical trials with patients with type 1 (n=509) and type 2 (n=262) diabetes mellitus, anti-insulin antibody (insulin lispro-specific antibodies, insulin-specific antibodies, cross-reactive antibodies) formation was evaluated in patients receiving both regular human insulin and Insulin Lispro Injection (including patients previously treated with human insulin and naive patients). As expected, the largest increase in the antibody levels occurred in patients new to insulin therapy. The antibody levels peaked by 12 months and declined over the remaining years of the study. These antibodies do not appear to cause deterioration in glycemic control or necessitate an increase in insulin dose. There was no statistically significant relationship between the change in the total daily insulin dose and the change in percent antibody binding for any of the antibody types. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of Insulin Lispro Injection. 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 in which other insulins have been accidentally substituted for Insulin Lispro Injection have been identified during post-approval use [see Patient Counseling Information ( 17 )] . 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 Lispro Injection is contraindicated: during episodes of hypoglycemia in patients who are hypersensitive to Insulin Lispro Injection or to any of its excipients. Do not use during episodes of hypoglycemia. ( 4 ) Do not use in patients with hypersensitivity to Insulin Lispro Injection or any of its excipients. ( 4 )

11 DESCRIPTION Insulin Lispro Injection is a rapid-acting human insulin analog. Insulin lispro is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli . Insulin lispro differs from human insulin in that the amino acid proline at position B28 is replaced by lysine and the lysine in position B29 is replaced by proline. Chemically, it is Lys(B28), Pro(B29) human insulin analog and has the empirical formula C 257 H 383 N 65 O 77 S 6 and a molecular weight of 5808, both identical to that of human insulin. Insulin Lispro Injection has the following primary structure: Insulin Lispro Injection is a sterile, aqueous, clear, and colorless solution for subcutaneous or intravenous use. Each milliliter of Insulin Lispro Injection contains 100 units of insulin lispro, dibasic sodium phosphate (1.88 mg), glycerin (16 mg), Metacresol (3.15 mg), zinc oxide (content adjusted to provide 0.0197 mg zinc ion), trace amounts of phenol, and Water for Injection, USP. Insulin lispro has a pH of 7.0 to 7.8. The pH is adjusted by addition of aqueous solutions of hydrochloric acid 10% and/or sodium hydroxide 10%. Primary Structure

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for important administration instructions. ( 2.1 , 2.2 , 2.3 , 2.4 ) Subcutaneous injection ( 2.2 ): Administer Insulin Lispro Injection by subcutaneous injection into the abdominal wall, thigh, upper arm, or buttocks within 15 minutes before a meal or immediately after a meal. Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. Continuous subcutaneous infusion (Insulin Pump) ( 2.2 ): Administer Insulin Lispro Injection by continuous subcutaneous infusion using an insulin pump in a region recommended in the instructions from the pump manufacturer. Rotate infusion sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. Intravenous Infusion ( 2.2 ): Administer Insulin Lispro Injection by intravenous infusion ONLY after dilution and under medical supervision. The dosage of Insulin Lispro Injection must be individualized based on the route of administration and the individual's metabolic needs, blood glucose monitoring results and glycemic control goal. ( 2.3 ) Do not perform dose conversion when using the Insulin Lispro Injection prefilled pens. The dose window shows the number of insulin units to be delivered and no conversion is needed. ( 2.1 , 2.3 ) 2.1 Important Administration Instructions Always check insulin labels before administration [see Warnings and Precautions ( 5.4 )] . Inspect Insulin Lispro Injection visually before use. It should appear clear and colorless. Do not use Insulin Lispro Injection if particulate matter or coloration is seen. Use Insulin Lispro Injection prefilled pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose. Do NOT mix Insulin Lispro Injection with other insulins when administering using a continuous subcutaneous infusion pump. Do NOT perform dose conversion when using any Insulin Lispro Injection prefilled pens. The dose window shows the number of insulin units to be delivered and no conversion is needed. 2.2 Route of Administration Subcutaneous Injection Administer the dose of Insulin Lispro Injection within fifteen minutes before a meal or immediately after a meal by injection into the subcutaneous tissue of the abdominal wall, thigh, upper arm, or buttocks. To reduce the risk of lipodystrophy and localized cutaneous amyloidosis, rotate the injection site within the same region from one injection to the next. 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 )] . Insulin Lispro Injection administered by subcutaneous injection should generally be used in regimens with an intermediate- or long-acting insulin. The Insulin Lispro Injection KwikPen dials in 1 unit increments and delivers a maximum dose of 60 units per injection. The Insulin Lispro Injection Junior KwikPen dials in 0.5 unit increments and delivers a maximum dose of 30 units per injection. Continuous Subcutaneous Infusion (Insulin Pump) Administer Insulin Lispro Injection by continuous subcutaneous infusion in a region recommended in the instructions from the pump manufacturer. Rotate infusion sites within the same region 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 )] . Follow healthcare professional recommendations when setting basal and meal time infusion rate. Do NOT dilute or mix Insulin Lispro Injection when administering by continuous subcutaneous infusion. Change Insulin Lispro Injection in the pump reservoir at least every 7 days. Change the infusion sets and the infusion set insertion site at least every 3 days. Do NOT expose Insulin Lispro Injection in the pump reservoir to temperatures greater than 98.6°F (37°C). Use Insulin Lispro Injection in pump systems suitable for insulin infusion [see Patient Counseling Information ( 17 )] . Intravenous Administration Dilute Insulin Lispro Injection to concentrations from 0.1 unit/mL to 1.0 unit/mL using 0.9% Sodium Chloride Injection, USP. Administer Insulin Lispro Injection intravenously ONLY under medical supervision with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia [see Warnings and Precautions ( 5.3 , 5.6 ) and How Supplied/Storage and Handling ( 16.4 )] . 2.3 Dosage Information Individualize and adjust the dosage of Insulin Lispro Injection based on route of administration, 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), changes in renal or hepatic function or during acute illness [see Warnings and Precautions ( 5.2 , 5.3 ) and Use in Specific Populations ( 8.6 , 8.7 )] . Do NOT perform dose conversion when using the Insulin Lispro Injection prefilled pens. The dose window shows the number of insulin units to be delivered and no conversion is needed. 2.4 Dosage Adjustment Due to Drug Interactions Dosage adjustment may be needed when Insulin Lispro Injection is coadministered with certain drugs [see Drug Interactions ( 7 )] . Dosage adjustment may be needed when switching from another insulin to Insulin Lispro Injection [see Warnings and Precautions ( 5.2 )] . Instructions for Mixing with Other Insulins Insulin Lispro Injection subcutaneous injection route Insulin Lispro Injection may be mixed with NPH insulin preparations ONLY . If Insulin Lispro Injection is mixed with NPH insulin, Insulin Lispro Injection should be drawn into the syringe first. Injection should occur immediately after mixing. Insulin Lispro Injection continuous subcutaneous infusion route (Insulin Pump) Do NOT mix Insulin Lispro Injection with any other insulin.

1 INDICATIONS AND USAGE Insulin Lispro Injection is a rapid acting human insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus. Insulin Lispro Injection is a rapid acting human insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus. ( 1 )

10 OVERDOSAGE Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.

7 DRUG INTERACTIONS Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may be needed. ( 7.1 , 7.2 , 7.3 ) Anti-Adrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent. ( 5.3 , 7.4 ) 7.1 Drugs That May Increase the Risk of Hypoglycemia The risk of hypoglycemia associated with Insulin Lispro Injection use may be increased when co-administered with antidiabetic agents, salicylates, sulfonamide antibiotics, monoamine oxidase inhibitors, fluoxetine, pramlintide, disopyramide, fibrates, pentoxifylline, ACE inhibitors, angiotensin II receptor blocking agents, and somatostatin analogs (e.g., octreotide). Dose adjustment and increased frequency of glucose monitoring may be required when Insulin Lispro Injection is co-administered with these drugs. 7.2 Drugs That May Decrease the Blood Glucose Lowering Effect of Insulin Lispro Injection The glucose lowering effect of Insulin Lispro Injection may be decreased when co-administered with corticosteroids, isoniazid, niacin, estrogens, oral contraceptives, phenothiazines, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, albuterol, terbutaline), somatropin, atypical antipsychotics, glucagon, protease inhibitors, and thyroid hormones. Dose adjustment and increased frequency of glucose monitoring may be required when Insulin Lispro Injection is co-administered with these drugs. 7.3 Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of Insulin Lispro Injection The glucose lowering effect of Insulin Lispro Injection may be increased or decreased with co-administered with beta-blockers, clonidine, lithium salts, and alcohol. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia. Dose adjustment and increased frequency of glucose monitoring may be required when Insulin Lispro Injection is co-administered with these drugs. 7.4 Drugs That May Blunt Signs and Symptoms of Hypoglycemia The signs and symptoms of hypoglycemia [see Warnings and Precautions ( 5.3 )] may be blunted when beta-blockers, clonidine, guanethidine, and reserpine are co-administered with Insulin Lispro Injection.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Regulation of glucose metabolism is the primary activity of insulins and insulin analogs, including insulin lispro. Insulins lower blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis. 12.2 Pharmacodynamics Insulin Lispro Injection has been shown to be equipotent to human insulin on a molar basis. One unit of Insulin Lispro Injection has the same glucose-lowering effect as one unit of regular human insulin. Studies in normal volunteers and patients with diabetes demonstrated that Insulin Lispro Injection has a more rapid onset of action and a shorter duration of activity than regular human insulin when given subcutaneously. The time course of action of insulin and insulin analogs, such as Insulin Lispro Injection, may vary considerably in different individuals or within the same individual. The parameters of Insulin Lispro Injection activity (time of onset, peak time, and duration) as designated in Figure 1 should be considered only as general guidelines. The rate of insulin absorption, and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables [see Warnings and Precautions ( 5.2 )] . Figure 1: Blood Glucose Levels After Subcutaneous Injection of Regular Human Insulin or Insulin Lispro Injection (0.2 unit/kg) Immediately Before a High Carbohydrate Meal in 10 Patients with Type 1 Diabetes a . a Baseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin. Figure 1 Intravenous Administration — The glucose lowering effect of intravenously administered Insulin Lispro Injection was tested in 21 patients with type 1 diabetes. For the study, the patients' usual doses of insulin were held and blood glucose concentrations were allowed to reach a stable range of 200 to 260 mg/dL during a one to three hours run-in phase. The run-in phase was followed by a 6-hour assessment phase. During the assessment phase, patients received intravenous Insulin Lispro Injection at an initial infusion rate of 0.5 units/hour. The infusion rate of Insulin Lispro Injection could be adjusted at regular timed intervals to achieve and maintain blood glucose concentrations between 100 to 160 mg/dL. The mean blood glucose levels during the assessment phase for patients on Insulin Lispro Injection therapy are summarized below in Table 4 . All patients achieved the targeted glucose range at some point during the 6-hour assessment phase. At the endpoint, blood glucose was within the target range (100 to 160 mg/dL) for 17 of 20 patients treated with Insulin Lispro Injection. The average time (±SE) required to attain near normoglycemia was 129 ± 14 minutes for Insulin Lispro Injection. Table 4: Mean Blood Glucose Concentrations (mg/dL) During Intravenous Infusions of Insulin Lispro Injection a Results shown as mean ± SD Time from Start of Infusion (minutes) Mean Blood Glucose (mg/dL) Intravenous a 0 224 ± 16 30 205 ± 21 60 195 ± 20 120 165 ± 26 180 140 ± 26 240 123 ± 20 300 120 ± 27 360 122 ± 25 12.3 Pharmacokinetics Absorption and Bioavailability — Studies in healthy volunteers and patients with diabetes demonstrated that Insulin Lispro Injection is absorbed more quickly than regular human insulin. In healthy volunteers given subcutaneous doses of Insulin Lispro Injection ranging from 0.1 to 0.4 unit/kg, peak serum levels were seen 30 to 90 minutes after dosing. When healthy volunteers received equivalent doses of regular human insulin, peak insulin levels occurred between 50 to 120 minutes after dosing. Similar results were seen in patients with type 1 diabetes ( see Figure 2 ). Figure 2: Serum Insulin Lispro Injection and Insulin Levels After Subcutaneous Injection of Regular Human Insulin or Insulin Lispro Injection (0.2 unit/kg) Immediately Before a High Carbohydrate Meal in 10 Patients with Type 1 Diabetes a . a Baseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin. Insulin Lispro Injection was absorbed at a consistently faster rate than regular human insulin in healthy male volunteers given 0.2 unit/kg at abdominal, deltoid, or femoral subcutaneous sites. After Insulin Lispro Injection was administered in the abdomen, serum drug levels were higher and the duration of action was slightly shorter than after deltoid or thigh administration. Bioavailability of Insulin Lispro Injection is similar to that of regular human insulin. The absolute bioavailability after subcutaneous injection ranges from 55% to 77% with doses between 0.1 to 0.2 unit/kg, inclusive. Figure 2 Distribution — When administered intravenously as bolus injections of 0.1 and 0.2 U/kg dose in two separate groups of healthy subjects, the mean volume of distribution of Insulin Lispro Injection appeared to decrease with increase in dose (1.55 and 0.72 L/kg, respectively) in contrast to that of regular human insulin for which, the volume of distribution was comparable across the two dose groups (1.37 and 1.12 L/kg for 0.1 and 0.2 U/kg dose, respectively). Metabolism — Human metabolism studies have not been conducted. However, animal studies indicate that the metabolism of Insulin Lispro Injection is identical to that of regular human insulin. Elimination — After subcutaneous administration of Insulin Lispro Injection, the t 1/2 is shorter than that of regular human insulin (1 versus 1.5 hours, respectively). When administered intravenously, Insulin Lispro Injection and regular human insulin demonstrated similar dose-dependent clearance, with a mean clearance of 21.0 mL/min/kg and 21.4 mL/min/kg, respectively (0.1 unit/kg dose), and 9.6 mL/min/kg and 9.4 mL/min/kg, respectively (0.2 unit/kg dose). Accordingly, Insulin Lispro Injection demonstrated a mean t 1/2 of 0.85 hours (51 minutes) and 0.92 hours (55 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses, and regular human insulin mean t 1/2 was 0.79 hours (47 minutes) and 1.28 hours (77 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses. Specific Populations The effects of age, gender, race, obesity, pregnancy, or smoking on the pharmacokinetics of Insulin Lispro Injection have not been studied. Renal Impairment — Type 2 diabetic patients with varying degree of renal impairment showed no difference in pharmacokinetics of regular insulin and Insulin Lispro Injection. However, the sensitivity of the patients to insulin did change, with an increased response to insulin as the renal function declined. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal impairment. Careful glucose monitoring and dose adjustments of insulin, including Insulin Lispro Injection, may be necessary in patients with renal dysfunction. Hepatic Impairment — Type 2 diabetic patients with impaired hepatic function showed no effect on the pharmacokinetics of Insulin Lispro Injection as compared to patients with no hepatic dysfunction. However, some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure. Careful glucose monitoring and dose adjustments of insulin, including Insulin Lispro Injection, may be necessary in patients with hepatic dysfunction.

12.1 Mechanism of Action Regulation of glucose metabolism is the primary activity of insulins and insulin analogs, including insulin lispro. Insulins lower blood glucose by stimulating peripheral glucose uptake by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulins inhibit lipolysis and proteolysis, and enhance protein synthesis.

12.2 Pharmacodynamics Insulin Lispro Injection has been shown to be equipotent to human insulin on a molar basis. One unit of Insulin Lispro Injection has the same glucose-lowering effect as one unit of regular human insulin. Studies in normal volunteers and patients with diabetes demonstrated that Insulin Lispro Injection has a more rapid onset of action and a shorter duration of activity than regular human insulin when given subcutaneously. The time course of action of insulin and insulin analogs, such as Insulin Lispro Injection, may vary considerably in different individuals or within the same individual. The parameters of Insulin Lispro Injection activity (time of onset, peak time, and duration) as designated in Figure 1 should be considered only as general guidelines. The rate of insulin absorption, and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables [see Warnings and Precautions ( 5.2 )] . Figure 1: Blood Glucose Levels After Subcutaneous Injection of Regular Human Insulin or Insulin Lispro Injection (0.2 unit/kg) Immediately Before a High Carbohydrate Meal in 10 Patients with Type 1 Diabetes a . a Baseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin. Figure 1 Intravenous Administration — The glucose lowering effect of intravenously administered Insulin Lispro Injection was tested in 21 patients with type 1 diabetes. For the study, the patients' usual doses of insulin were held and blood glucose concentrations were allowed to reach a stable range of 200 to 260 mg/dL during a one to three hours run-in phase. The run-in phase was followed by a 6-hour assessment phase. During the assessment phase, patients received intravenous Insulin Lispro Injection at an initial infusion rate of 0.5 units/hour. The infusion rate of Insulin Lispro Injection could be adjusted at regular timed intervals to achieve and maintain blood glucose concentrations between 100 to 160 mg/dL. The mean blood glucose levels during the assessment phase for patients on Insulin Lispro Injection therapy are summarized below in Table 4 . All patients achieved the targeted glucose range at some point during the 6-hour assessment phase. At the endpoint, blood glucose was within the target range (100 to 160 mg/dL) for 17 of 20 patients treated with Insulin Lispro Injection. The average time (±SE) required to attain near normoglycemia was 129 ± 14 minutes for Insulin Lispro Injection. Table 4: Mean Blood Glucose Concentrations (mg/dL) During Intravenous Infusions of Insulin Lispro Injection a Results shown as mean ± SD Time from Start of Infusion (minutes) Mean Blood Glucose (mg/dL) Intravenous a 0 224 ± 16 30 205 ± 21 60 195 ± 20 120 165 ± 26 180 140 ± 26 240 123 ± 20 300 120 ± 27 360 122 ± 25

12.3 Pharmacokinetics Absorption and Bioavailability — Studies in healthy volunteers and patients with diabetes demonstrated that Insulin Lispro Injection is absorbed more quickly than regular human insulin. In healthy volunteers given subcutaneous doses of Insulin Lispro Injection ranging from 0.1 to 0.4 unit/kg, peak serum levels were seen 30 to 90 minutes after dosing. When healthy volunteers received equivalent doses of regular human insulin, peak insulin levels occurred between 50 to 120 minutes after dosing. Similar results were seen in patients with type 1 diabetes ( see Figure 2 ). Figure 2: Serum Insulin Lispro Injection and Insulin Levels After Subcutaneous Injection of Regular Human Insulin or Insulin Lispro Injection (0.2 unit/kg) Immediately Before a High Carbohydrate Meal in 10 Patients with Type 1 Diabetes a . a Baseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin. Insulin Lispro Injection was absorbed at a consistently faster rate than regular human insulin in healthy male volunteers given 0.2 unit/kg at abdominal, deltoid, or femoral subcutaneous sites. After Insulin Lispro Injection was administered in the abdomen, serum drug levels were higher and the duration of action was slightly shorter than after deltoid or thigh administration. Bioavailability of Insulin Lispro Injection is similar to that of regular human insulin. The absolute bioavailability after subcutaneous injection ranges from 55% to 77% with doses between 0.1 to 0.2 unit/kg, inclusive. Figure 2 Distribution — When administered intravenously as bolus injections of 0.1 and 0.2 U/kg dose in two separate groups of healthy subjects, the mean volume of distribution of Insulin Lispro Injection appeared to decrease with increase in dose (1.55 and 0.72 L/kg, respectively) in contrast to that of regular human insulin for which, the volume of distribution was comparable across the two dose groups (1.37 and 1.12 L/kg for 0.1 and 0.2 U/kg dose, respectively). Metabolism — Human metabolism studies have not been conducted. However, animal studies indicate that the metabolism of Insulin Lispro Injection is identical to that of regular human insulin. Elimination — After subcutaneous administration of Insulin Lispro Injection, the t 1/2 is shorter than that of regular human insulin (1 versus 1.5 hours, respectively). When administered intravenously, Insulin Lispro Injection and regular human insulin demonstrated similar dose-dependent clearance, with a mean clearance of 21.0 mL/min/kg and 21.4 mL/min/kg, respectively (0.1 unit/kg dose), and 9.6 mL/min/kg and 9.4 mL/min/kg, respectively (0.2 unit/kg dose). Accordingly, Insulin Lispro Injection demonstrated a mean t 1/2 of 0.85 hours (51 minutes) and 0.92 hours (55 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses, and regular human insulin mean t 1/2 was 0.79 hours (47 minutes) and 1.28 hours (77 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses. Specific Populations The effects of age, gender, race, obesity, pregnancy, or smoking on the pharmacokinetics of Insulin Lispro Injection have not been studied. Renal Impairment — Type 2 diabetic patients with varying degree of renal impairment showed no difference in pharmacokinetics of regular insulin and Insulin Lispro Injection. However, the sensitivity of the patients to insulin did change, with an increased response to insulin as the renal function declined. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal impairment. Careful glucose monitoring and dose adjustments of insulin, including Insulin Lispro Injection, may be necessary in patients with renal dysfunction. Hepatic Impairment — Type 2 diabetic patients with impaired hepatic function showed no effect on the pharmacokinetics of Insulin Lispro Injection as compared to patients with no hepatic dysfunction. However, some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure. Careful glucose monitoring and dose adjustments of insulin, including Insulin Lispro Injection, may be necessary in patients with hepatic dysfunction.

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3 DOSAGE FORMS AND STRENGTHS Injection: 100 units per mL (U-100) clear and colorless solution available as: 10 mL multiple-dose vial 3 mL single-patient-use Insulin Lispro Injection KwikPen 3 mL single-patient-use Insulin Lispro Injection Junior KwikPen Injection: 100 units/mL (U-100) is available as: ( 3 ) 10 mL multiple-dose vial 3 mL single-patient-use Insulin Lispro Injection KwikPen ® 3 mL single-patient-use Insulin Lispro Injection Junior KwikPen ®

Insulin Lispro Insulin lispro INSULIN LISPRO INSULIN LISPRO Glycerin Sodium Phosphate, Dibasic, Unspecified Form Metacresol Zinc Phenol Water Hydrochloric acid Sodium hydroxide

13.2 Animal Toxicology and/or Pharmacology In standard biological assays in fasted rabbits, 0.2 unit/kg of insulin lispro injected subcutaneously had the same glucose-lowering effect and had a more rapid onset of action as 0.2 unit/kg of regular human insulin.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Standard 2-year carcinogenicity studies in animals have not been performed. In Fischer 344 rats, a 12-month repeat-dose toxicity study was conducted with insulin lispro at subcutaneous doses of 20 and 200 units/kg/day (approximately 3 and 32 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area). Insulin lispro did not produce important target organ toxicity including mammary tumors at any dose. Insulin lispro was not mutagenic in the following genetic toxicity assays: bacterial mutation, unscheduled DNA synthesis, mouse lymphoma, chromosomal aberration and micronucleus assays. Male fertility was not compromised when male rats given subcutaneous insulin lispro injections of 5 and 20 units/kg/day (0.8 and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area) for 6 months were mated with untreated female rats. In a combined fertility, perinatal, and postnatal study in male and female rats given 1, 5, and 20 units/kg/day subcutaneously (0.2, 0.8, and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area), mating and fertility were not adversely affected in either gender at any dose.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Standard 2-year carcinogenicity studies in animals have not been performed. In Fischer 344 rats, a 12-month repeat-dose toxicity study was conducted with insulin lispro at subcutaneous doses of 20 and 200 units/kg/day (approximately 3 and 32 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area). Insulin lispro did not produce important target organ toxicity including mammary tumors at any dose. Insulin lispro was not mutagenic in the following genetic toxicity assays: bacterial mutation, unscheduled DNA synthesis, mouse lymphoma, chromosomal aberration and micronucleus assays. Male fertility was not compromised when male rats given subcutaneous insulin lispro injections of 5 and 20 units/kg/day (0.8 and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area) for 6 months were mated with untreated female rats. In a combined fertility, perinatal, and postnatal study in male and female rats given 1, 5, and 20 units/kg/day subcutaneously (0.2, 0.8, and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area), mating and fertility were not adversely affected in either gender at any dose. 13.2 Animal Toxicology and/or Pharmacology In standard biological assays in fasted rabbits, 0.2 unit/kg of insulin lispro injected subcutaneously had the same glucose-lowering effect and had a more rapid onset of action as 0.2 unit/kg of regular human insulin.

BLA020563

Insulin Lispro

Insulin lispro

50090-5391

HUMAN PRESCRIPTION DRUG

INTRAVENOUS,SUBCUTANEOUS

Insulin lispro Label Image

Dosage and Administration ( 2.2 ) 11/2019 Warnings and Precautions ( 5.2 ) 11/2019

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Never Share an Insulin Lispro Injection Prefilled Pen or Syringe Between Patients Advise patients that they must never share an Insulin Lispro Injection prefilled pen with another person, even if the needle is changed. Advise patients using Insulin Lispro Injection vials not to share needles or syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens [see Warnings and Precautions ( 5.1 )] . Hyperglycemia or Hypoglycemia Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of Insulin Lispro Injection therapy. Instruct patients on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals. Instruct patients on the management of hypoglycemia. Inform patients that their ability to concentrate and react may be impaired as a result of hypoglycemia. 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 )] . Hypersensitivity Reactions Advise patients that hypersensitivity reactions have occurred with Insulin Lispro Injection. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions ( 5.5 )] . Medication Errors Instruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products. Instructions For Patients Using Continuous Subcutaneous Insulin Pumps Patients using external pump infusion therapy should be trained appropriately. The following insulin pumps have been tested in Insulin Lispro Injection clinical trials conducted by Eli Lilly and Company. Disetronic ® H-Tron ® plus V100, D-Tron ® and D-Tronplus ® with Disetronic Rapid infusion sets 1 MiniMed ® Models 506, 507 and 508 and Polyfin ® infusion sets 2 Insulin Lispro Injection is recommended for use in pump systems suitable for insulin infusion such as MiniMed, Disetronic, and other equivalent pumps. Before using Insulin Lispro Injection in a pump system, read the pump label to make sure the pump is indicated for continuous delivery of fast-acting insulin. Insulin Lispro Injection is recommended for use in any reservoir and infusion sets that are compatible with insulin and the specific pump. Please see recommended reservoir and infusion sets in the pump manual. To avoid insulin degradation, infusion set occlusion, and loss of the preservative (metacresol), insulin in the reservoir should be replaced at least every 7 days; infusion sets and infusion set insertion sites should be changed at least every 3 days. Insulin exposed to temperatures higher than 98.6°F (37°C) should be discarded. The temperature of the insulin may exceed ambient temperature when the pump housing, cover, tubing or sport case is exposed to sunlight or radiant heat. Infusion sites that are erythematous, pruritic, or thickened should be reported to the healthcare professional, and a new site selected because continued infusion may increase the skin reaction or alter the absorption of Insulin Lispro Injection. Pump or infusion set malfunctions or insulin degradation can lead to rapid hyperglycemia and ketosis. This is especially pertinent for rapid acting insulin analogs that are more rapidly absorbed through skin and have a shorter duration of action. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Problems include pump malfunction, infusion set occlusion, leakage, disconnection or kinking, and degraded insulin. Less commonly, hypoglycemia from pump malfunction may occur. If these problems cannot be promptly corrected, patients should resume therapy with subcutaneous insulin injection and contact their healthcare professionals [see Dosage and Administration ( 2.2 ) and How Supplied/Storage and Handling ( 16.2 )] . ____________ KwikPen ® is a trademark of Eli Lilly and Company. 1 Disetronic ® , H-Tron ® , D-Tron ® , and D-Tronplus ® are registered trademarks of Roche Diagnostics GmbH. 2 MiniMed ® and Polyfin ® are registered trademarks of MiniMed, Inc. Other product and company names may be the trademarks of their respective owners. Literature revised February 2020 Manufactured by Eli Lilly and Company Indianapolis, IN 46285, USA Copyright © 1996, 2020, Eli Lilly and Company. All rights reserved. LIS-0006-USPI-20200212

Instructions for Use Insulin Lispro Injection Read this Instructions for Use before you start taking Insulin Lispro Injection and each time you get a new 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 needles or 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 a multiple-dose Insulin Lispro Injection vial a U-100 insulin syringe and needle 2 alcohol swabs gauze 1 sharps container for throwing away used needles and syringes. See “Disposing of used needles and syringes” at the end of these instructions. Vial Syringe Preparing your Insulin Lispro Injection dose Wash your hands with soap and water. Check the Insulin Lispro Injection 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. Insulin Lispro Injection should look clear and colorless. Do not use Insulin Lispro Injection if it is thick, cloudy, or colored, or if you see lumps or particles in it. Do not use Insulin Lispro Injection past the expiration date printed on the label or 28 days after you first use it. Always use a new syringe and needle for each injection to prevent infections and blocked needles. Do not reuse 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, pull off the plastic Protective Cap, but do not remove the Rubber Stopper. Step 2: Wipe the Rubber Stopper with an alcohol swab. Step 3: Remove the Needle Shield from the syringe by pulling the Needle Shield straight off. Hold the syringe with the needle pointing up. Pull down on the Plunger until the Plunger Tip reaches the line for the number of units for your prescribed dose. (Example Dose: 20 units shown) Step 4: Push the needle through the Rubber Stopper of the vial. Step 5: Push the Plunger all the way in. This puts air into the vial. Step 6: Turn the vial and syringe upside down and slowly pull the Plunger down until the Plunger Tip is a few units past the line for your prescribed dose. (Example Dose: 20 units Plunger is shown at 24 units) If there are air bubbles, tap the syringe gently a few times to let any air bubbles rise to the top. Step 7: Slowly push the Plunger up until the Plunger Tip reaches the line for your prescribed dose. Check the syringe to make sure that you have the right dose. (Example Dose: 20 units shown) Step 8: Pull the syringe out of the Rubber Stopper of the vial. If you use Insulin Lispro Injection with NPH insulin: NPH insulin is the only type of insulin that can be mixed with Insulin Lispro Injection. Do not mix Insulin Lispro Injection with any other type of insulin. Insulin Lispro Injection should be drawn up into the syringe first, before you draw up your NPH insulin. Talk to your healthcare provider if you are not sure about the right way to mix Insulin Lispro Injection and NPH insulin. Give your injection right away. Giving your Insulin Lispro Injection with a syringe Inject your insulin exactly as your healthcare provider has shown you. Your healthcare provider should tell you if you should pinch the skin before injecting. Insulin Lispro Injection starts acting fast, so give your injection within 15 minutes before or right after you eat a meal. Change (rotate) your injection sites within the area you choose for 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 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 9: Choose your injection site. Insulin Lispro Injection is injected under the skin (subcutaneously) of your stomach area (abdomen), buttocks, upper legs or upper arms. Wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose. Step 10: Insert the needle into your skin. Step 11: Push down on the Plunger to inject your dose. The needle should stay in your skin for at least 5 seconds to make sure you have injected all of your insulin dose. Step 12: Pull the needle out of your skin. If you see blood after you take the needle out of your skin, press the injection site with a piece of gauze or an alcohol swab. Do not rub the area. Do not recap the needle. Recapping the needle can lead to a needle stick injury. Giving your Insulin Lispro Injection using an insulin pump Insulin Lispro Injection should be given into an area of your body recommended in the instructions that come with your insulin pump. Change (rotate) your insertion site every 3 days. Change (rotate) your insertion sites within the area you choose for each insertion to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the insertion sites. Do not insert into the exact same spot for each insertion. Do not insert where the skin has pits, is thickened, or has lumps. Do not insert where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. Change the insulin in the reservoir at least every 7 days, even if you have not used all of the insulin. Do not dilute or mix Insulin Lispro Injection with any other type of insulin in your insulin pump. See your insulin pump manual for instructions or talk to your healthcare provider. 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 disposal 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 Lispro Injection? All unopened vials: Store all unopened vials in the refrigerator at 36°F to 46°F (2°C to 8°C). Do not freeze. Do not use if Insulin Lispro Injection has been frozen. Keep away from heat and out of direct light. Unopened vials can be used until the expiration date on the carton and label, if they have been stored in the refrigerator. Unopened vials should be thrown away after 28 days, if they are stored at room temperature. After vials have been opened: Store opened vials in the refrigerator or at room temperature below 86°F (30°C) for up to 28 days. Keep vials away from heat and out of direct light. Throw away all opened vials after 28 days of use, even if there is insulin left in the vial. Keep Insulin Lispro Injection vials, syringes, needles and all medicines out of the reach of children. If you have any questions or problems with your Insulin Lispro Injection, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider for help. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Instructions for Use revised: February 2020 Manufactured by Eli Lilly and Company Indianapolis, IN 46285, USA Copyright © 1996, 2020, Eli Lilly and Company. All rights reserved. LISVL-0005-IFU-20200212 Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure

14 CLINICAL STUDIES The safety and efficacy of Insulin Lispro Injection were studied in children, adolescent, and adult patients with type 1 diabetes (n=789) and adult patients with type 2 diabetes (n=722). 14.1 Type 1 Diabetes – Adults and Adolescents A 12-month, randomized, parallel, open-label, active-controlled study was conducted in patients with type 1 diabetes to assess the safety and efficacy of Insulin Lispro Injection (n=81) compared with Humulin ® R [insulin human injection (100 units per mL)] (n=86). Insulin Lispro Injection was administered by subcutaneous injection immediately prior to meals and Humulin R was administered 30 to 45 minutes before meals. Humulin ® U [ULTRALENTE ® human insulin (rDNA origin) extended zinc suspension] was administered once or twice daily as the basal insulin. There was a 2- to 4-week run-in period with Humulin R and Humulin U before randomization. Most patients were Caucasian (97%). Forty-seven percent of the patients were male. The mean age was 31 years (range 12 to 70 years). Glycemic control, the total daily doses of Insulin Lispro Injection and Humulin R, and the incidence of severe hypoglycemia (as determined by the number of events that were not self-treated) were similar in the two treatment groups. There were no episodes of diabetic ketoacidosis in either treatment group. Table 5: Type 1 Diabetes Mellitus – Adults and Adolescents a Values are Mean ± SD b Severe hypoglycemia refers to hypoglycemia for which patients were not able to self-treat. Treatment Duration Treatment in Combination with: 12 months Humulin U Insulin Lispro Injection Humulin R N 81 86 Baseline HbA 1c (%) a 8.2 ± 1.4 8.3 ± 1.7 Change from baseline HbA 1c (%) a -0.1 ± 0.9 0.1 ± 1.1 Treatment Difference in HbA 1c Mean (95% confidence interval) 0.4 (0.0, 0.8) Baseline short-acting insulin dose (units/kg/day) 0.3 ± 0.1 0.3 ± 0.1 End-of-Study short-acting insulin dose (units/kg/day) 0.3 ± 0.1 0.3 ± 0.1 Change from baseline short-acting insulin dose (units/kg/day) 0.0 ± 0.1 0.0 ± 0.1 Baseline Body weight (kg) 72 ± 12.7 71 ± 11.3 Weight change from baseline (kg) 1.4 ± 3.6 1.0 ± 2.6 Patients with severe hypoglycemia (n, %) b 14 (17%) 18 (21%) 14.2 Type 2 Diabetes – Adults A 6-month randomized, crossover, open-label, active-controlled study was conducted in insulin-treated patients with type 2 diabetes (n=722) to assess the safety and efficacy of Insulin Lispro Injection for 3 months followed by Humulin R for 3 months or the reverse sequence. Insulin Lispro Injection was administered by subcutaneous injection immediately before meals and Humulin R was administered 30 to 45 minutes before meals. Humulin ® N [NPH human insulin (rDNA origin) isophane suspension] or Humulin U was administered once or twice daily as the basal insulin. All patients participated in a 2- to 4-week run-in period with Humulin R and Humulin N or Humulin U. Most of the patients were Caucasian (88%), and the numbers of men and women in each group were approximately equal. The mean age was 58.6 years (range 23.8 to 85 years). The average body mass index (BMI) was 28.2 kg/m 2 . During the study, the majority of patients used Humulin N (84%) compared with Humulin U (16%) as their basal insulin. The reductions from baseline in HbA 1c and the incidence of severe hypoglycemia (as determined by the number of events that were not self-treated) were similar between the two treatments from the combined groups ( see Table 6 ). Table 6: Type 2 Diabetes Mellitus — Adults a Values are Mean ± SD b Severe hypoglycemia refers to hypoglycemia for which patients were not able to self-treat. End point Baseline Insulin Lispro Injection + Basal Humulin R + Basal HbA 1c (%) a 8.9 ± 1.7 8.2 ± 1.3 8.2 ± 1.4 Change from baseline HbA 1c (%) a — -0.7 ± 1.4 -0.7 ± 1.3 Short-acting insulin dose (units/kg/day) a 0.3 ± 0.2 0.3 ± 0.2 0.3 ± 0.2 Change from baseline short-acting insulin dose (units/kg/day) a — 0.0 ± 0.1 0.0 ± 0.1 Body weight (kg) a 80 ± 15 81 ± 15 81 ± 15 Weight change from baseline — 0.8 ± 2.7 0.9 ± 2.6 Patients with severe hypoglycemia (n, %) b — 15 (2%) 16 (2%) 14.3 Type 1 Diabetes – Pediatric and Adolescents An 8-month, crossover study of adolescents with type 1 diabetes (n=463), aged 9 to 19 years, compared two subcutaneous multiple-dose treatment regimens: Insulin Lispro Injection or Humulin R, both administered with Humulin N (NPH human insulin) as the basal insulin. Insulin Lispro Injection achieved glycemic control comparable to Humulin R, as measured by HbA 1c ( see Table 7 ), and both treatment groups had a comparable incidence of hypoglycemia. In a 9-month, crossover study of prepubescent children (n=60) with type 1 diabetes, aged 3 to 11 years, Insulin Lispro Injection administered immediately before meals, Insulin Lispro Injection administered immediately after meals and Humulin R administered 30 minutes before meals resulted in similar glycemic control, as measured by HbA 1c , and incidence of hypoglycemia, regardless of treatment group. Table 7: Pediatric Subcutaneous Administration of Insulin Lispro Injection in Type 1 Diabetes a Values are Mean ± SD b Severe hypoglycemia refers to hypoglycemia that required glucagon or glucose injection or resulted in coma. End point Baseline Insulin Lispro Injection + NPH Humulin R + NPH HbA 1c (%) a 8.6 ± 1.5 8.7 ± 1.5 8.7 ± 1.6 Change from baseline HbA 1c (%) a — 0.1 ± 1.1 0.1 ± 1.3 Short-acting insulin dose (units/kg/day) a 0.5 ± 0.2 0.5 ± 0.2 0.5 ± 0.2 Change from baseline short-acting insulin dose (units/kg/day) a — 0.01 ± 0.1 -0.01 ± 0.1 Body weight (kg) a 59.1 ± 13.1 61.1 ± 12.7 61.4 ± 12.9 Weight change from baseline (kg) a — 2.0 ± 3.1 2.3 ± 3.0 Patients with severe hypoglycemia (n, %) b — 5 (1.1%) 5 (1.1%) Diabetic ketoacidosis (n, %) — 11 (2.4%) 9 (1.9%) 14.4 Type 1 Diabetes – Adults Continuous Subcutaneous Insulin Infusion To evaluate the administration of Insulin Lispro Injection via external insulin pumps, two open-label, crossover design studies were performed in patients with type 1 diabetes. One study involved 39 patients, ages 19 to 58 years, treated for 24 weeks with Insulin Lispro Injection or regular human insulin. After 12 weeks of treatment, the mean HbA 1c values decreased from 7.8% to 7.2% in the Insulin Lispro Injection-treated patients and from 7.8% to 7.5% in the regular human insulin-treated patients. Another study involved 60 patients (mean age 39, range 15 to 58 years) treated for 24 weeks with either Insulin Lispro Injection or buffered regular human insulin. After 12 weeks of treatment, the mean HbA 1c values decreased from 7.7% to 7.4% in the Insulin Lispro Injection-treated patients and remained unchanged from 7.7% in the buffered regular human insulin-treated patients. Rates of hypoglycemia were comparable between treatment groups in both studies. 14.5 Type 1 Diabetes – Pediatric Continuous Subcutaneous Insulin Infusion A randomized, 16-week, open-label, parallel design, study of children and adolescents with type 1 diabetes (n=298) aged 4 to 18 years compared two subcutaneous infusion regimens administered via an external insulin pump: insulin aspart (n=198) or Insulin Lispro Injection (n=100). These two treatments resulted in comparable changes from baseline in HbA 1c and comparable rates of hypoglycemia after 16 weeks of treatment ( see Table 8 ). Infusion site reactions were similar between groups. Table 8: Pediatric Insulin Pump Study in Type 1 Diabetes (16 weeks; n=298) a Values are Mean ± SD b Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the intervention of another person or hospitalization. Insulin Lispro Injection Aspart N 100 198 Baseline HbA 1c (%) a 8.2 ± 0.8 8.0 ± 0.9 Change from Baseline HbA 1c (%) -0.1 ± 0.7 -0.1 ± 0.8 Treatment Difference in HbA 1c , Mean (95% confidence interval) 0.1 (-0.3, 0.1) Baseline insulin dose (units/kg/24 hours) a 0.9 ± 0.3 0.9 ± 0.3 End-of-Study insulin dose (units/kg/24 hours) a 0.9 ± 0.2 0.9 ± 0.2 Patients with severe hypoglycemia (n, %) b 8 (8%) 19 (10%) Diabetic ketoacidosis (n, %) 0 (0) 1 (0.5%) Baseline body weight (kg) a 55.5 ± 19.0 54.1 ± 19.7 Weight Change from baseline (kg) a 1.6 ± 2.1 1.8 ± 2.1

8.5 Geriatric Use Of the total number of subjects (n=2834) in eight clinical studies of Insulin Lispro Injection, twelve percent (n=338) were 65 years of age or over. The majority of these had type 2 diabetes. HbA 1c values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of Insulin Lispro Injection action have not been performed.

8.4 Pediatric Use Insulin Lispro Injection is approved for use in children for subcutaneous daily injections [see Clinical Studies ( 14 )]. Insulin Lispro Injection is approved for use in children by continuous subcutaneous infusion in insulin pumps. Insulin Lispro Injection has not been studied in pediatric patients younger than 3 years of age. Insulin Lispro Injection has not been studied in pediatric patients with type 2 diabetes. As in adults, the dosage of Insulin Lispro Injection must be individualized in pediatric patients based on metabolic needs and results of frequent monitoring of blood glucose.

8.1 Pregnancy Risk Summary The limited available data with Insulin Lispro Injection in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Published studies with insulin lispro used during pregnancy have not reported an association between insulin lispro and the induction of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ) . There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations) . Pregnant rats and rabbits were exposed to insulin lispro in animal reproduction studies during organogenesis. No adverse effects on embryo/fetal viability or morphology were observed in offspring of rats exposed to insulin lispro at a dose approximately 3 times the human subcutaneous dose of 1 unit insulin lispro/kg/day. No adverse effects on embryo/fetal development were observed in offspring of rabbits exposed to insulin lispro at doses up to approximately 0.2 times the human subcutaneous dose of 1 unit/kg/day (see Data) . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% 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 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, 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 from retrospective studies and meta-analyses do not report an association with insulin lispro and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin lispro is used during pregnancy. However, these studies cannot definitely establish or exclude the absence of any risk because of methodological limitations including small sample size, selection bias, confounding by unmeasured factors, and some lacking comparator groups. Animal Data In a combined fertility and embryo-fetal development study, female rats were given subcutaneous insulin lispro injections of 1, 5, and 20 units/kg/day (0.2, 0.8, and 3 times the human subcutaneous dose of 1 unit insulin lispro/kg/day, based on units/body surface area, respectively) from 2 weeks prior to cohabitation through Gestation Day 19. There were no adverse effects on female fertility, implantation, or fetal viability and morphology. However, fetal growth retardation was produced at the 20 units/kg/day-dose as indicated by decreased fetal weight and an increased incidence of fetal runts/litter. In an embryo-fetal development study in pregnant rabbits, insulin lispro doses of 0.1, 0.25, and 0.75 unit/kg/day (0.03, 0.08, and 0.2 times the human subcutaneous dose of 1 unit insulin lispro/kg/day, based on units/body surface area, respectively) were injected subcutaneously on Gestation days 7 through 19. There were no adverse effects on fetal viability, weight, and morphology at any dose.

8 USE IN SPECIFIC POPULATIONS Pediatrics: Not studied in children with type 2 diabetes or in children with type 1 diabetes <3 years of age. ( 8.4 ) 8.1 Pregnancy Risk Summary The limited available data with Insulin Lispro Injection in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Published studies with insulin lispro used during pregnancy have not reported an association between insulin lispro and the induction of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data ) . There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations) . Pregnant rats and rabbits were exposed to insulin lispro in animal reproduction studies during organogenesis. No adverse effects on embryo/fetal viability or morphology were observed in offspring of rats exposed to insulin lispro at a dose approximately 3 times the human subcutaneous dose of 1 unit insulin lispro/kg/day. No adverse effects on embryo/fetal development were observed in offspring of rabbits exposed to insulin lispro at doses up to approximately 0.2 times the human subcutaneous dose of 1 unit/kg/day (see Data) . The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% 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 2-4% and 15-20%, respectively. Clinical Considerations Disease-associated maternal and/or embryo/fetal risk Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, 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 from retrospective studies and meta-analyses do not report an association with insulin lispro and major birth defects, miscarriage, or adverse maternal or fetal outcomes when insulin lispro is used during pregnancy. However, these studies cannot definitely establish or exclude the absence of any risk because of methodological limitations including small sample size, selection bias, confounding by unmeasured factors, and some lacking comparator groups. Animal Data In a combined fertility and embryo-fetal development study, female rats were given subcutaneous insulin lispro injections of 1, 5, and 20 units/kg/day (0.2, 0.8, and 3 times the human subcutaneous dose of 1 unit insulin lispro/kg/day, based on units/body surface area, respectively) from 2 weeks prior to cohabitation through Gestation Day 19. There were no adverse effects on female fertility, implantation, or fetal viability and morphology. However, fetal growth retardation was produced at the 20 units/kg/day-dose as indicated by decreased fetal weight and an increased incidence of fetal runts/litter. In an embryo-fetal development study in pregnant rabbits, insulin lispro doses of 0.1, 0.25, and 0.75 unit/kg/day (0.03, 0.08, and 0.2 times the human subcutaneous dose of 1 unit insulin lispro/kg/day, based on units/body surface area, respectively) were injected subcutaneously on Gestation days 7 through 19. There were no adverse effects on fetal viability, weight, and morphology at any dose. 8.2 Lactation Risk Summary There are no data on the presence of Insulin Lispro Injection in human milk, the effects on the breastfed infant, or the effect on milk production. One small published study reported that exogenous insulin was present in human milk. However, there is insufficient information to determine the effects of Insulin Lispro Injection on the breastfed infant and no available information on the effects of Insulin Lispro Injection on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for insulin, any potential adverse effects on the breastfed child from Insulin Lispro Injection or from the underlying maternal condition. 8.4 Pediatric Use Insulin Lispro Injection is approved for use in children for subcutaneous daily injections [see Clinical Studies ( 14 )]. Insulin Lispro Injection is approved for use in children by continuous subcutaneous infusion in insulin pumps. Insulin Lispro Injection has not been studied in pediatric patients younger than 3 years of age. Insulin Lispro Injection has not been studied in pediatric patients with type 2 diabetes. As in adults, the dosage of Insulin Lispro Injection must be individualized in pediatric patients based on metabolic needs and results of frequent monitoring of blood glucose. 8.5 Geriatric Use Of the total number of subjects (n=2834) in eight clinical studies of Insulin Lispro Injection, twelve percent (n=338) were 65 years of age or over. The majority of these had type 2 diabetes. HbA 1c values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of Insulin Lispro Injection action have not been performed. 8.6 Renal Impairment Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent Insulin Lispro Injection dose adjustment and more frequent blood glucose monitoring [see Clinical Pharmacology ( 12.3 )] . 8.7 Hepatic Impairment Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent Insulin Lispro Injection dose adjustment and more frequent blood glucose monitoring [see Clinical Pharmacology ( 12.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING Product: 50090-5391 NDC: 50090-5391-0 10 mL in a VIAL / 1 in a CARTON