Insulin Lispro Junior KwikPen

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 associated with Insulin Lispro 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 Trials 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. Common adverse reactions, excluding hypoglycemia, were defined as events that occurred in ≥5% of patients treated with Insulin Lispro or regular human insulin. The frequencies of adverse reactions during Insulin Lispro clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below. Table 1: Adverse Reactions That Occurred in ≥5% in Patients with Type 1 Diabetes Mellitus Insulin Lispro (%) (n=81) Regular human insulin (%) (n=86) Flu syndrome 34.6 32.6 Pharyngitis 33.3 33.7 Rhinitis 24.7 29.1 Headache 29.6 22.1 Pain 19.8 16.3 Cough increased 17.3 17.4 Infection 13.6 20.9 Nausea 6.2 15.1 Accidental injury 8.6 11.6 Surgical procedure 6.2 14.0 Fever 6.2 11.6 Abdominal pain 7.4 8.1 Asthenia 7.4 8.1 Bronchitis 7.4 7.0 Diarrhea 8.6 5.8 Dysmenorrhea 6.2 7.0 Myalgia 7.4 5.8 Urinary tract infection 6.2 4.7 Table 2: Adverse Reactions That Occurred in ≥5% in Patients with Type 2 Diabetes Mellitus Insulin Lispro (%) (n=714) Regular human insulin (%) (n=709) Headache 11.6 9.3 Pain 10.8 10.0 Infection 10.1 7.6 Pharyngitis 6.6 8.2 Rhinitis 8.1 6.6 Flu syndrome 6.2 8.2 Surgical procedure 7.4 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. Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including Insulin Lispro. Lipodystrophy Long-term use of insulin, including Insulin Lispro, 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 [see Dosage and Administration ( 2.2 )] . Weight gain Weight gain can occur with insulins, including Insulin Lispro, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Peripheral Edema Insulins, including Insulin Lispro, 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 and regular human insulin treated patients ( see Table 3 ). Table 3: Catheter Occlusions and Infusion Site Reactions Insulin Lispro (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 pediatric patients with type 1 diabetes, adverse reactions related to infusion-site reactions were similar for Insulin Lispro and insulin aspart (21% of 100 patients versus 17% of 198 patients, respectively). In both groups, the most frequently reported infusion site reactions were infusion site erythema and infusion site reaction. Allergic Reactions Local Allergy — As with any insulin, patients taking Insulin Lispro 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. Systemic Allergy — Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin, including Insulin Lispro. 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 (n=2944). Localized reactions and generalized myalgias have been reported with injected metacresol, which is an excipient in Insulin Lispro [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 (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. 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 have been identified during post-approval use. 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 is contraindicated: during episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] . in patients who are hypersensitive to Insulin Lispro or to any of the excipients in Insulin Lispro [see Warnings and Precautions ( 5.5 )] . Do not use during episodes of hypoglycemia. ( 4 ) Do not use in patients with hypersensitivity to Insulin Lispro or any of the excipients in Insulin Lispro. ( 4 )

11 DESCRIPTION Insulin lispro is a rapid-acting human insulin analog 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 5.808 kDa, both identical to that of human insulin. Insulin lispro has the following primary structure: Insulin Lispro injection is a sterile, clear, and colorless solution for subcutaneous or intravenous use. Each mL of Insulin Lispro contains 100 units of insulin lispro, and the inactive ingredients: dibasic sodium phosphate (1.0 mg), glycerin (16 mg), metacresol (3.15 mg), trace amounts of phenol, zinc oxide (content adjusted to provide 0.0197 mg zinc ion), and Water for Injection, USP. Insulin Lispro has a pH of 7.0 to 7.8. Hydrochloric acid 10% and/or sodium hydroxide 10% is added to adjust the pH. 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 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 ): Refer to the insulin infusion pump user manual to see if Humalog can be used. Use in accordance with the insulin pump instructions for use. Administer Insulin Lispro 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 by intravenous infusion ONLY after dilution and under medical supervision. The dosage of Insulin Lispro 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 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. This product is HUMALOG (insulin lispro) [see Warnings and Precautions ( 5.4 )] . Inspect Insulin Lispro visually before use. It should appear clear and colorless. Do not use Insulin Lispro if particulate matter or coloration is seen. Use Insulin Lispro prefilled pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose. Do NOT mix Insulin Lispro with other insulins when using a continuous subcutaneous infusion pump. Do NOT perform dose conversion when using any Insulin Lispro prefilled pens. The dose window shows the number of insulin units to be delivered and no conversion is needed. 2.2 Administration Instructions for the Approved Routes of Administration Subcutaneous Injection Administer the dose of Insulin Lispro 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. Rotate the injection site within the same region from one injection to the next (abdominal wall, thigh, upper arm, or buttocks) 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 )] . Insulin Lispro administered by subcutaneous injection should generally be used in regimens with an intermediate- or long-acting insulin. The Insulin Lispro KwikPen dials in 1 unit increments and delivers a maximum dose of 60 units per injection. The Insulin Lispro Junior KwikPen dials in 0.5 unit increments and delivers a maximum dose of 30 units per injection. Subcutaneous Injection: Diluted Insulin Lispro Insulin Lispro may be diluted with Sterile Diluent for Insulin Lispro for subcutaneous injection ONLY under medical supervision. Dilute one part Insulin Lispro to: Nine parts diluent to yield a concentration one-tenth that of Insulin Lispro (equivalent to U-10). One part diluent to yield a concentration one-half that of Insulin Lispro (equivalent to U-50). Diluted Insulin Lispro for subcutaneous injection may be stored for 28 days when refrigerated at 41°F (5°C) and for 14 days at room temperature up to 86°F (30°C). Continuous Subcutaneous Infusion (Insulin Pump) This Insulin Lispro product can be used with continuous subcutaneous insulin infusion pumps labeled for use with Humalog (insulin lispro). Refer to the insulin pump user manual to see if Humalog can be used. Use Insulin Lispro in accordance with the insulin pump system's instructions for use. Administer Insulin Lispro 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 )] . Train patients using continuous subcutaneous insulin infusion therapy to administer insulin by injection and have alternate insulin therapy available in case of insulin pump failure [see Warnings and Precautions ( 5.8 )]. During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )] . Change Insulin Lispro in the pump reservoir at least every 7 days or according to the pump user manual, whichever is shorter. Follow the Humalog-specific information for in-use time because Humalog-specific information may differ from general pump manual instructions. Change the infusion set and the infusion set insertion site according to the manufacturer's user manual. Do NOT dilute or mix Insulin Lispro when administering by continuous subcutaneous infusion. Do NOT expose Insulin Lispro in the pump reservoir to temperatures greater than 98.6°F (37°C). Intravenous Administration Administer Insulin Lispro 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)] . Dilute Insulin Lispro to concentrations from 0.1 unit/mL to 1.0 unit/mL using 0.9% Sodium Chloride Injection, USP. Infusion bags prepared with Insulin Lispro are stable when stored in a refrigerator (2° to 8°C [36° to 46°F]) for 48 hours and then may be used at room temperature for up to an additional 48 hours. 2.3 Dosage Recommendations Individualize and adjust the dosage of Insulin Lispro based on route of administration, the individual's metabolic needs, blood glucose monitoring results and glycemic control goal. When switching from another insulin to Insulin Lispro. a different dosage of Insulin Lispro may be needed [see Warnings and Precautions ( 5.2 )]. Dosage modifications 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 prefilled pens. The dose window shows the number of insulin units to be delivered and no conversion is needed. 2.4 Dosage Modifications for Drug Interactions Dosage modification may be needed when Insulin Lispro is used concomitantly with certain drugs [see Drug Interactions ( 7 )] . 2.5 Instructions for Mixing with Other Insulins The table below includes administration instructions regarding mixing Insulin Lispro with other insulins. Insulin Lispro subcutaneous injection route Insulin Lispro may be mixed with NPH insulin preparations ONLY . If Insulin Lispro is mixed with NPH insulin, Insulin Lispro should be drawn into the syringe first. Injection should occur immediately after mixing. Insulin Lispro continuous subcutaneous infusion route (Insulin Pump) Do NOT mix Insulin Lispro with any other insulin.

1 INDICATIONS AND USAGE Insulin Lispro is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. Insulin Lispro is a rapid acting human insulin analog indicated to improve glycemic control in adult and pediatric patients 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 a glucagon product for emergency use 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 The table below includes clinically significant drug interactions with Insulin Lispro. 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 analog (e.g., octreotide), and sulfonamide antibiotics. Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when Insulin Lispro is co-administered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of Insulin Lispro 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 adjustment and increased frequency of glucose monitoring may be required when Insulin Lispro is co-administered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of Insulin Lispro 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 Lispro is co-administered 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 Lispro is co-administered with these drugs. Drugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics ( 7 ). Drugs that may decrease the blood glucose lowering effect: atypical antipsychotics, 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 ( 7 ). Drugs that may increase or decrease the blood glucose lowering effect: alcohol, beta-blockers, clonidine, lithium salts, and pentamidine ( 7 ). Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine ( 7 ).

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 has been shown to be equipotent to human insulin on a molar basis. One unit of Insulin Lispro 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 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, may vary considerably in different individuals or within the same individual. The parameters of Insulin Lispro 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 (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 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 at an initial infusion rate of 0.5 units/hour. The infusion rate of Insulin Lispro 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 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. The average time (±SE) required to attain near normoglycemia was 129 ± 14 minutes for Insulin Lispro. Table 4: Mean Blood Glucose Concentrations (mg/dL) During Intravenous Infusions of Insulin Lispro a Results shown as mean ± SD Time from Start of Infusion (minutes) Mean Blood Glucose (mg/dL) Intravenous 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 is absorbed more quickly than regular human insulin. In healthy volunteers given subcutaneous doses of Insulin Lispro 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 and Insulin Levels After Subcutaneous Injection of Regular Human Insulin or Insulin Lispro (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 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 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 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 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 is identical to that of regular human insulin. Elimination — After subcutaneous administration of Insulin Lispro, the t 1/2 is shorter than that of regular human insulin (1 versus 1.5 hours, respectively). When administered intravenously, Insulin Lispro 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 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 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. 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 [see Use in Specific Populations ( 8.6 )]. Hepatic Impairment — Type 2 diabetic patients with impaired hepatic function showed no effect on the pharmacokinetics of Insulin Lispro 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 [see Use in Specific Populations ( 8.7 )].

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 has been shown to be equipotent to human insulin on a molar basis. One unit of Insulin Lispro 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 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, may vary considerably in different individuals or within the same individual. The parameters of Insulin Lispro 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 (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 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 at an initial infusion rate of 0.5 units/hour. The infusion rate of Insulin Lispro 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 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. The average time (±SE) required to attain near normoglycemia was 129 ± 14 minutes for Insulin Lispro. Table 4: Mean Blood Glucose Concentrations (mg/dL) During Intravenous Infusions of Insulin Lispro a Results shown as mean ± SD Time from Start of Infusion (minutes) Mean Blood Glucose (mg/dL) Intravenous 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 is absorbed more quickly than regular human insulin. In healthy volunteers given subcutaneous doses of Insulin Lispro 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 and Insulin Levels After Subcutaneous Injection of Regular Human Insulin or Insulin Lispro (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 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 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 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 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 is identical to that of regular human insulin. Elimination — After subcutaneous administration of Insulin Lispro, the t 1/2 is shorter than that of regular human insulin (1 versus 1.5 hours, respectively). When administered intravenously, Insulin Lispro 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 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 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. 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 [see Use in Specific Populations ( 8.6 )]. Hepatic Impairment — Type 2 diabetic patients with impaired hepatic function showed no effect on the pharmacokinetics of Insulin Lispro 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 [see Use in Specific Populations ( 8.7 )].

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

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

Insulin lispro

0002-7752

HUMAN PRESCRIPTION DRUG

SUBCUTANEOUS

PACKAGE CARTON – Insulin Lispro Injection 10 mL vial NDC 0002-7737-01 Insulin Lispro Injection 100 units per mL (U-100) For subcutaneous or intrevenous use 10 mL multiple-dose vial Use only with a U-100 syringe This product is Humalog. Rx only Lilly PACKAGE CARTON – Insulin Lispro Injection 10 mL vial 1ct

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 Prefilled Pen or Syringe Between Patients Advise patients that they must never share an Insulin Lispro prefilled pen with another person, even if the needle is changed. Advise patients using Insulin Lispro 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 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 )] . Hypoglycemia due to Medication Errors Instruct patients to always check the insulin container label before each injection to avoid mix-ups between insulin products [see Warnings and Precautions ( 5.4 )] . Hypersensitivity Reactions Advise patients that hypersensitivity reactions have occurred with Insulin Lispro. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions ( 5.5 )] . Instructions For Patients Using Continuous Subcutaneous Insulin Pumps Train patients in intensive insulin therapy with multiple injections and in the function of their pump and pump accessories. Instruct patients to follow healthcare provider recommendations when setting pump basal rates and bolus settings. This Insulin Lispro product can be used with continuous subcutaneous insulin infusion pumps labeled for use with Humalog (insulin lispro) – refer to the insulin pump user manual to see if Humalog can be used. See recommended reservoir and infusion sets in the insulin pump user manual. Instruct patients to replace insulin in the reservoir at least every 7 days, or according to the pump user manual, whichever is shorter; infusion sets and infusion set insertion sites should be changed in accordance with the manufacturers' user manual. By following this schedule, patients avoid insulin degradation, infusion set occlusion, and loss of the insulin preservative. Instruct patients to discard insulin exposed to temperatures higher than 98.6°F (37°C). 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. Instruct patients to inform healthcare provider and select a new site for infusion if infusion site becomes erythematous, pruritic, or thickened. Instruct patients on the risk of rapid hyperglycemia and ketosis due to pump malfunction, infusion set occlusion, leakage, disconnection or kinking, and degraded insulin. Instruct patients on the risk of hypoglycemia from pump malfunction. If these problems cannot be promptly corrected, instruct patients to resume therapy with subcutaneous insulin injection and contact their healthcare provider [see Warnings and Precautions ( 5 ) and How Supplied/Storage and Handling ( 16.2 )] . Manufactured by: Eli Lilly and Company Indianapolis, IN 46285, USA US License Number 1891 Humalog ® and KwikPen ® are registered trademarks of Eli Lilly and Company. Copyright © 1996, 2023, Eli Lilly and Company. All rights reserved. LIS-0008-USPI-20230921

Vial Instructions for Use INSTRUCTIONS FOR USE Insulin Lispro [IHN-soo-lihn LIYS-proh] injection, for subcutaneous use 10 mL multiple-dose vial (100 units per mL, U-100) This product is HUMALOG ® (insulin lispro). Read this Instructions for Use before you start taking Insulin Lispro 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 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 dose Wash your hands with soap and water. Check the Insulin Lispro 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 should look clear and colorless. Do not use Insulin Lispro if it is thick, cloudy, or colored, or if you see lumps or particles in it. Do not use Insulin Lispro 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 with NPH insulin: NPH insulin is the only type of insulin that can be mixed with Insulin Lispro. Do not mix Insulin Lispro with any other type of insulin. Insulin Lispro 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 and NPH insulin. Give your injection right away. Giving your Insulin Lispro 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 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 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 using an insulin pump Insulin Lispro should be given into an area of your body recommended in the instructions that come with your insulin pump. Change your infusion set and rotate the infusion set insertion site according to the manufacturer's user manual. 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. This Insulin Lispro product can be used with the continuous subcutaneous insulin infusion pumps labeled for use with Humalog (insulin lispro) – refer to the insulin pump user manual to see if Humalog can be used. Change the insulin in the reservoir at least every 7 days or according to the pump user manual, whichever is shorter, even if you have not used all of the insulin. Do not dilute or mix Insulin Lispro 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? 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 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 up to 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. Insulin Lispro in an insulin pump: Throw away Insulin Lispro in the pump reservoir if it has been exposed to temperatures higher than 98.6°F (37°C). Keep Insulin Lispro vials, syringes, needles and all medicines out of the reach of children. If you have any questions or problems with your Insulin Lispro, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider for help. Manufactured by: Eli Lilly and Company Indianapolis, IN 46285, USA US License Number 1891 This Instructions for Use has been approved by the U.S. Food and Drug Administration. Humalog ® is a registered trademark of Eli Lilly and Company. Instructions for Use revised: July/2023 Copyright © 1996, 2023, Eli Lilly and Company. All rights reserved. LISVL-0006-IFU-20230721 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 were studied in pediatric 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 Pediatric Patients Aged 12 Years and Older 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 (n=81) compared with Humulin ® R [insulin human injection (100 units/mL)] (n=86). Insulin Lispro 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 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 Pediatric Patients Aged 12 years and Older 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 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 1 Diabetes – Pediatric Patients An 8-month, crossover study of pediatric patients with type 1 diabetes (n=463), aged 9 to 19 years, compared two subcutaneous multiple-dose treatment regimens: Insulin Lispro or Humulin R, both administered with Humulin N (NPH human insulin) as the basal insulin. Insulin Lispro achieved glycemic control comparable to Humulin R, as measured by HbA 1c ( see Table 6 ), and both treatment groups had a comparable incidence of hypoglycemia. In a 9-month, crossover study of pediatric patients (n=60) with type 1 diabetes, aged 3 to 11 years, Insulin Lispro administered immediately before meals, Insulin Lispro 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 6: Pediatric Subcutaneous Administration of Insulin Lispro 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 + 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%) 14.3 Type 1 Diabetes – Adults: Continuous Subcutaneous Insulin Infusion To evaluate the administration of Insulin Lispro 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 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 -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 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-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. 14.4 Type 1 Diabetes – Pediatric Patients: Continuous Subcutaneous Insulin Infusion A randomized, 16-week, open-label, parallel design, study of pediatric patients 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 (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 7 ). Infusion site reactions were similar between groups. Table 7: 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 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 14.5 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 for 3 months followed by Humulin R for 3 months or the reverse sequence. Insulin Lispro 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 8 ). Table 8: 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 + 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%)

8.5 Geriatric Use Of the total number of patients (n=2,834) in eight clinical studies of Insulin Lispro, twelve percent (n=338) were 65 years of age or over. The majority of these patients 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 action have not been performed.

8.4 Pediatric Use The safety and effectiveness of Insulin Lispro to improve glycemic control have been established in pediatric patients with diabetes mellitus. Use of Insulin Lispro for this indication is supported by evidence from adequate and well-controlled studies in 831 pediatric patients with type 1 diabetes mellitus aged 3 years and older and from studies in adults with diabetes mellitus [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14 )] .

8.1 Pregnancy Risk Summary 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 8.1 Pregnancy Risk Summary 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 Available data from published literature suggests that exogenous human insulin products, including insulin lispro, are transferred into human milk. There are no adverse reactions reported in breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including insulin lispro, 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 or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of Insulin Lispro to improve glycemic control have been established in pediatric patients with diabetes mellitus. Use of Insulin Lispro for this indication is supported by evidence from adequate and well-controlled studies in 831 pediatric patients with type 1 diabetes mellitus aged 3 years and older and from studies in adults with diabetes mellitus [see Adverse Reactions ( 6.1 ), Clinical Pharmacology ( 12.3 ), and Clinical Studies ( 14 )] . 8.5 Geriatric Use Of the total number of patients (n=2,834) in eight clinical studies of Insulin Lispro, twelve percent (n=338) were 65 years of age or over. The majority of these patients 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 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 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 dose adjustment and more frequent blood glucose monitoring [see Clinical Pharmacology ( 12.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Insulin Lispro injection is a clear and colorless solution available as: Insulin Lispro Total Volume Concentration NDC Number Package Size U-100 multiple-dose vial 10 mL 100 units/mL 0002-7737-01 1 vial U-100 single-patient-use KwikPen 3 mL 100 units/mL 0002-8222-59 5 pens U-100 single-patient-use Junior KwikPen 3 mL 100 units/mL 0002-7752-05 5 pens The KwikPen dials in 1-unit increments. The Junior KwikPen dials in 0.5-unit increments. Each Insulin Lispro prefilled pen is for single-patient-use only. Insulin Lispro prefilled pens must never be shared between patients, even if the needle is changed. Patients using Insulin Lispro vials must never share needles or syringes with another person. 16.2 Storage and Handling Dispense in the original sealed carton with the enclosed Instructions for Use. Protect from direct heat and light. Do not freeze and do not use if it has been frozen. See table below for storage information: * When stored at room temperature, Insulin Lispro can only be used for a total of 28 days, including both not in-use (unopened) and in-use (opened) storage time. Not In-Use (Unopened) Room Temperature (Up to 86°F [30°C]) Not In-Use (Unopened) Refrigerated (36° to 46°F [2° to 8°C]) In-Use (Opened) (see temperature below*) 10 mL multiple-dose vial 28 days Until expiration date 28 days Refrigerated or room temperature. 3 mL single-patient-use Insulin Lispro KwikPen 28 days Until expiration date 28 days Room temperature only (Do not refrigerate) 3 mL single-patient-use Insulin Lispro Junior KwikPen 28 days Until expiration date 28 days Room temperature only (Do not refrigerate) Use in an External Insulin Pump — Change the Insulin Lispro in the reservoir at least every 7 days, or according to the pump user manual, whichever is shorter, or after exposure to temperatures that exceed 98.6°F (37°C). Storage of Diluted Insulin Lispro for Subcutaneous Injection — Diluted Insulin Lispro for subcutaneous injection may be stored for 28 days when refrigerated at 41°F (5°C) and 14 days at room temperature up to 86°F (30°C) [see Dosage and Administration ( 2.2 )] . Do not dilute Insulin Lispro used in an external insulin pump. Storage of Intravenous Infusion Preparations with Insulin Lispro Intravenous infusion bags prepared with Insulin Lispro maybe stored for 48 hours when refrigerated at 36° to 46°F (2° to 8°C). The prepared intravenous bags may then be used at room temperature for up to an additional 48 hours [see Dosage and Administration ( 2.2 )] .

16.2 Storage and Handling Dispense in the original sealed carton with the enclosed Instructions for Use. Protect from direct heat and light. Do not freeze and do not use if it has been frozen. See table below for storage information: * When stored at room temperature, Insulin Lispro can only be used for a total of 28 days, including both not in-use (unopened) and in-use (opened) storage time. Not In-Use (Unopened) Room Temperature (Up to 86°F [30°C]) Not In-Use (Unopened) Refrigerated (36° to 46°F [2° to 8°C]) In-Use (Opened) (see temperature below*) 10 mL multiple-dose vial 28 days Until expiration date 28 days Refrigerated or room temperature. 3 mL single-patient-use Insulin Lispro KwikPen 28 days Until expiration date 28 days Room temperature only (Do not refrigerate) 3 mL single-patient-use Insulin Lispro Junior KwikPen 28 days Until expiration date 28 days Room temperature only (Do not refrigerate) Use in an External Insulin Pump — Change the Insulin Lispro in the reservoir at least every 7 days, or according to the pump user manual, whichever is shorter, or after exposure to temperatures that exceed 98.6°F (37°C). Storage of Diluted Insulin Lispro for Subcutaneous Injection — Diluted Insulin Lispro for subcutaneous injection may be stored for 28 days when refrigerated at 41°F (5°C) and 14 days at room temperature up to 86°F (30°C) [see Dosage and Administration ( 2.2 )] . Do not dilute Insulin Lispro used in an external insulin pump. Storage of Intravenous Infusion Preparations with Insulin Lispro Intravenous infusion bags prepared with Insulin Lispro maybe stored for 48 hours when refrigerated at 36° to 46°F (2° to 8°C). The prepared intravenous bags may then be used at room temperature for up to an additional 48 hours [see Dosage and Administration ( 2.2 )] .