Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 KwikPen

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere in the labeling: 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 observed with Insulin Lispro Protamine and Insulin Lispro Mix75/25 include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, weight gain, edema, pruritus, and rash. ( 6 ) 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. Adverse Reactions from Clinical Studies or Postmarketing Reports The following adverse reactions have been identified during post-marketing use of Insulin Lispro Protamine and Insulin Lispro Mix75/25. Because some of 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. Adverse reactions associated with insulin initiation and glucose control intensification 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. Over the long-term, improved glycemic control decreases the risk of diabetic retinopathy and neuropathy. Hypersensitivity reactions Severe, life-threatening, generalized allergy, including anaphylaxis. Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in Insulin Lispro Protamine and Insulin Lispro Mix75/25. Hypokalemia Insulin Lispro Protamine and Insulin Lispro Mix75/25 can cause a shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Injection site reactions Insulin Lispro Protamine and Insulin Lispro Mix75/25 can cause local injection site reactions including redness, swelling, or itching at the site of injection. These reactions usually resolve in a few days to a few weeks, but in some occasions, may require discontinuation. Localized reactions and generalized myalgias have been reported with the use of meta-cresol, which is an excipient in Insulin Lispro Protamine and Insulin Lispro Mix75/25. Lipodystrophy Administration of insulin subcutaneously, including Insulin Lispro Protamine and Insulin Lispro Mix75/25, has resulted in lipoatrophy (depression in the skin) or lipohypertrophy (enlargement or thickening of tissue) [see Dosage and Administration ( 2.1 )] in some patients. Localized cutaneous amyloidosis 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. Medication Errors Medication errors in which other insulins have been accidentally substituted for Insulin Lispro Protamine and Insulin Lispro Mix75/25 have been identified during postapproval use. Peripheral Edema Insulins, including Insulin Lispro Protamine and Insulin Lispro Mix75/25, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Weight gain Weight gain can occur with insulins, including Insulin Lispro Protamine and Insulin Lispro Mix75/25, and has been attributed to the anabolic effects of insulin and the decrease in glycosuria. Immunogenicity As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The incidence of antibody formation with Insulin Lispro Protamine and Insulin Lispro Mix75/25 is unknown.

4 CONTRAINDICATIONS Insulin Lispro Protamine and Insulin Lispro Mix75/25 is contraindicated: during episodes of hypoglycemia [see Warnings and Precautions ( 5.3 )] in patients who have had hypersensitivity reactions to Insulin Lispro Protamine and Insulin Lispro Mix75/25 or to any of its excipients. [see Warnings and Precautions ( 5.5 )] Do not use during episodes of hypoglycemia. ( 4 ) Do not use in patients with hypersensitivity to Insulin Lispro Protamine and Insulin Lispro Mix75/25 or any of its excipients. ( 4 )

11 DESCRIPTION Insulin lispro is a rapid-acting 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 Protamine and Insulin Lispro Mix75/25 is a mixture of 75% insulin lispro protamine, an intermediate-acting human insulin analog, and 25% insulin lispro, a rapid-acting human insulin analog. Insulin lispro protamine suspension is a suspension of crystals produced from combining insulin lispro and protamine sulfate under appropriate conditions for crystal formation. Insulin lispro has the following primary structure: Insulin Lispro Protamine and Insulin Lispro Mix75/25 injectable suspension is a white and cloudy, sterile suspension for subcutaneous use. Each mL of Insulin Lispro Protamine and Insulin Lispro Mix75/25 contains 100 units of insulin lispro; dibasic sodium phosphate (2.0 mg), glycerin (16 mg), metacresol (1.76 mg), phenol (0.715 mg), protamine sulfate (0.28 mg), zinc oxide content adjusted to provide zinc ion (0.025 mg), and Water for Injection, USP. The pH is 7.0 to 7.8. Sodium hydroxide and/or hydrochloric acid is added during manufacture to adjust the pH. Primary Structure

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for important preparation and administration instructions. ( 2.1 ) Inject Insulin Lispro Protamine and Insulin Lispro Mix75/25 subcutaneously within 15 minutes before a meal in abdominal wall, thigh, upper arm, or buttocks and rotate injection sites to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. ( 2.1 , 2.2 ) Individualize and adjust dosage based on metabolic needs, blood glucose monitoring results and glycemic control goal. ( 2.2 ) Do not administer Insulin Lispro Protamine and Insulin Lispro Mix75/25 intravenously or by a continuous subcutaneous insulin infusion pump. ( 2.1 ) Insulin Lispro Protamine and Insulin Lispro Mix75/25 is typically dosed twice daily (with each dose intended to cover 2 meals or a meal and a snack). ( 2.2 ) 2.1 Important Preparation and Administration Instructions Preparation Instructions Always check insulin labels before administration. This product is HUMALOG Mix75/25 [see Warnings and Precautions ( 5.4 )] . Insulin Lispro Protamine and Insulin Lispro Mix75/25 is a suspension that must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature. To resuspend KwikPen, gently roll the KwikPen at least 10 times and then carefully invert the KwikPen at least 10 times until the suspension appears uniformly white and cloudy. Inspect Insulin Lispro Protamine and Insulin Lispro Mix75/25 visually before use. Do not use if discoloration or particulate matter is seen. Administration Instructions After resuspension, immediately administer Insulin Lispro Protamine and Insulin Lispro Mix75/25 by subcutaneous injection into the abdominal wall, thigh, upper arm, or buttocks. Rotate the injection site within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6 )] . The Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPen dials in 1 unit increments. Use Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPen with caution in patients with visual impairment that may rely on audible clicks to dial their dose. Do not administer Insulin Lispro Protamine and Insulin Lispro Mix75/25 intravenously or by a continuous subcutaneous insulin infusion pump. Do not mix Insulin Lispro Protamine and Insulin Lispro Mix75/25 with any other insulins or diluents. 2.2 Dosage Recommendations Individualize and adjust the dosage of Insulin Lispro Protamine and Insulin Lispro Mix75/25 based on the individual's metabolic needs, blood glucose monitoring results and glycemic control goal. Inject Insulin Lispro Protamine and Insulin Lispro Mix75/25 subcutaneously within 15 minutes before a meal. Insulin Lispro Protamine and Insulin Lispro Mix75/25 is typically dosed twice-daily (with each dose intended to cover 2 meals or a meal and a snack). 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 )] . When switching from another insulin to Insulin Lispro Protamine and Insulin Lispro Mix75/25, a different dosage of Insulin Lispro Protamine and Insulin Lispro Mix75/25 may be needed. During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.2 )] . 2.3 Dosage Modifications for Drug Interactions Dosage modification may be needed when Insulin Lispro Protamine and Insulin Lispro Mix75/25 is used concomitantly with certain drugs [see Drug Interactions ( 7 )] .

1 INDICATIONS AND USAGE Insulin Lispro Protamine and Insulin Lispro Mix75/25 is indicated to improve glycemic control in adults with diabetes mellitus. Insulin Lispro Protamine and Insulin Lispro Mix75/25™ is a mixture of insulin lispro protamine, an intermediate-acting human insulin analog, and insulin lispro, a rapid-acting human insulin analog indicated to improve glycemic control in adults with diabetes mellitus. ( 1 ) Limitations of Use: The proportions of rapid-acting and intermediate-acting insulins are fixed and do not allow for basal versus prandial dose adjustments. ( 1 ) Limitations of Use: The proportions of rapid-acting and intermediate-acting insulins in Insulin Lispro Protamine and Insulin Lispro Mix75/25 are fixed and do not allow for basal versus prandial dose adjustments.

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 [see Warnings and Precautions ( 5.3 , 5.6 )].

7 DRUG INTERACTIONS Table 1 below presents clinically significant drug interactions with Insulin Lispro Protamine and Insulin Lispro Mix75/25. Table 1: Clinically Significant Drug Interactions with Insulin Lispro Protamine and Insulin Lispro Mix75/25 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 Protamine and Insulin Lispro Mix75/25 is co-administered with these drugs. Drugs that May Decrease the Blood Glucose Lowering Effect of Insulin Lispro Protamine and Insulin Lispro Mix75/25 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 Protamine and Insulin Lispro Mix75/25 is co-administered with these drugs. Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of Insulin Lispro Protamine and Insulin Lispro Mix75/25 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 Protamine and Insulin Lispro Mix75/25 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 Protamine and Insulin Lispro Mix75/25 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 The primary activity of insulin, including Insulin Lispro Protamine and Insulin Lispro Mix75/25, is the regulation of glucose metabolism. 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 In a glucose clamp study performed in 30 healthy subjects, the onset of action and glucose-lowering activity of HUMALOG, HUMALOG ® Mix50/50™, Insulin Lispro Protamine and Insulin Lispro Mix75/25, and insulin lispro protamine suspension (ILPS) were compared ( see Figure 1 ). Graphs of mean glucose infusion rate versus time showed a distinct insulin activity profile for each formulation. The rapid onset of glucose-lowering activity characteristic of HUMALOG was maintained in Insulin Lispro Protamine and Insulin Lispro Mix75/25. The median maximum pharmacologic effect of Insulin Lispro Protamine and Insulin Lispro Mix75/25 after administration of a 0.3 unit/kg dose to healthy subjects occurred at approximately 2 hours (range: 1-6 hours); glucose lowering activity was detectable for a median of 22 hours (range: 13 to 22 hours), which was the end of the clamp. In separate glucose clamp studies performed in healthy subjects, pharmacodynamics of Insulin Lispro Protamine and Insulin Lispro Mix75/25 and HUMULIN ® 70/30 were assessed and are presented in Figure 2 . Insulin Lispro Protamine and Insulin Lispro Mix75/25 has a duration of activity similar to that of HUMULIN 70/30. Figures 1 and 2 should be considered only as representative examples since the time course of action of insulin and insulin analogs, may vary in different individuals or within the same individual. Figure 1: Mean Insulin Activity Versus Time Profiles After Injection of 0.3 units/kg of HUMALOG, HUMALOG Mix50/50, Insulin Lispro Protamine and Insulin Lispro Mix75/25, or Insulin Lispro Protamine Suspension (ILPS) in 30 Healthy Subjects. Figure 2: Mean Insulin Activity Versus Time Profiles After Injection of 0.3 units/kg of Insulin Lispro Protamine and Insulin Lispro Mix75/25 or HUMULIN 70/30 in Healthy Subjects. Figure Figure 12.3 Pharmacokinetics Absorption — Insulin Lispro Protamine and Insulin Lispro Mix75/25 has two phases of absorption. The early phase represents insulin lispro and its distinct characteristics of rapid onset. The late phase represents the prolonged absorption of insulin lispro protamine suspension. In 31 healthy subjects given subcutaneous doses (0.3 unit/kg) of Insulin Lispro Protamine and Insulin Lispro Mix75/25, the median peak serum concentration was 60 minutes (range: 30 minutes to 4 hours) after dosing. Identical results were found in patients with type 1 diabetes. The rapid absorption characteristics of HUMALOG are maintained with Insulin Lispro Protamine and Insulin Lispro Mix75/25. Insulin Lispro Protamine and Insulin Lispro Mix75/25 has a more rapid absorption than HUMULIN 70/30, which has been confirmed in patients with type 1 diabetes. Metabolism — Human metabolism studies of Insulin Lispro Protamine and Insulin Lispro Mix75/25 have not been conducted. However, studies in animals indicate that the metabolism of HUMALOG, the rapid-acting component of Insulin Lispro Protamine and Insulin Lispro Mix75/25, is identical to that of regular human insulin. Elimination — Because of the absorption-rate limited kinetics of insulin mixtures, a true half-life cannot be accurately estimated from the terminal slope of the concentration versus time curve. Specific Populations The effects of age, race, obesity, pregnancy, smoking, or renal or hepatic impairment on the pharmacokinetics of Insulin Lispro Protamine and Insulin Lispro Mix75/25 have not been studied. Gender — Pharmacokinetic and pharmacodynamic comparisons between men and women administered Insulin Lispro Protamine and Insulin Lispro Mix75/25 showed no gender differences.

12.1 Mechanism of Action The primary activity of insulin, including Insulin Lispro Protamine and Insulin Lispro Mix75/25, is the regulation of glucose metabolism. 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 In a glucose clamp study performed in 30 healthy subjects, the onset of action and glucose-lowering activity of HUMALOG, HUMALOG ® Mix50/50™, Insulin Lispro Protamine and Insulin Lispro Mix75/25, and insulin lispro protamine suspension (ILPS) were compared ( see Figure 1 ). Graphs of mean glucose infusion rate versus time showed a distinct insulin activity profile for each formulation. The rapid onset of glucose-lowering activity characteristic of HUMALOG was maintained in Insulin Lispro Protamine and Insulin Lispro Mix75/25. The median maximum pharmacologic effect of Insulin Lispro Protamine and Insulin Lispro Mix75/25 after administration of a 0.3 unit/kg dose to healthy subjects occurred at approximately 2 hours (range: 1-6 hours); glucose lowering activity was detectable for a median of 22 hours (range: 13 to 22 hours), which was the end of the clamp. In separate glucose clamp studies performed in healthy subjects, pharmacodynamics of Insulin Lispro Protamine and Insulin Lispro Mix75/25 and HUMULIN ® 70/30 were assessed and are presented in Figure 2 . Insulin Lispro Protamine and Insulin Lispro Mix75/25 has a duration of activity similar to that of HUMULIN 70/30. Figures 1 and 2 should be considered only as representative examples since the time course of action of insulin and insulin analogs, may vary in different individuals or within the same individual. Figure 1: Mean Insulin Activity Versus Time Profiles After Injection of 0.3 units/kg of HUMALOG, HUMALOG Mix50/50, Insulin Lispro Protamine and Insulin Lispro Mix75/25, or Insulin Lispro Protamine Suspension (ILPS) in 30 Healthy Subjects. Figure 2: Mean Insulin Activity Versus Time Profiles After Injection of 0.3 units/kg of Insulin Lispro Protamine and Insulin Lispro Mix75/25 or HUMULIN 70/30 in Healthy Subjects. Figure Figure

12.3 Pharmacokinetics Absorption — Insulin Lispro Protamine and Insulin Lispro Mix75/25 has two phases of absorption. The early phase represents insulin lispro and its distinct characteristics of rapid onset. The late phase represents the prolonged absorption of insulin lispro protamine suspension. In 31 healthy subjects given subcutaneous doses (0.3 unit/kg) of Insulin Lispro Protamine and Insulin Lispro Mix75/25, the median peak serum concentration was 60 minutes (range: 30 minutes to 4 hours) after dosing. Identical results were found in patients with type 1 diabetes. The rapid absorption characteristics of HUMALOG are maintained with Insulin Lispro Protamine and Insulin Lispro Mix75/25. Insulin Lispro Protamine and Insulin Lispro Mix75/25 has a more rapid absorption than HUMULIN 70/30, which has been confirmed in patients with type 1 diabetes. Metabolism — Human metabolism studies of Insulin Lispro Protamine and Insulin Lispro Mix75/25 have not been conducted. However, studies in animals indicate that the metabolism of HUMALOG, the rapid-acting component of Insulin Lispro Protamine and Insulin Lispro Mix75/25, is identical to that of regular human insulin. Elimination — Because of the absorption-rate limited kinetics of insulin mixtures, a true half-life cannot be accurately estimated from the terminal slope of the concentration versus time curve. Specific Populations The effects of age, race, obesity, pregnancy, smoking, or renal or hepatic impairment on the pharmacokinetics of Insulin Lispro Protamine and Insulin Lispro Mix75/25 have not been studied. Gender — Pharmacokinetic and pharmacodynamic comparisons between men and women administered Insulin Lispro Protamine and Insulin Lispro Mix75/25 showed no gender differences.

20230721

8

3 DOSAGE FORMS AND STRENGTHS Injectable Suspension: 100 units/mL (U-100) of Insulin Lispro Protamine and Insulin Lispro, 75% insulin lispro protamine and 25% insulin lispro is a white and cloudy suspension available as: 3 mL single-patient-use KwikPen prefilled pen Injectable suspension: 100 units/mL (U-100) of Insulin Lispro Protamine and Insulin Lispro Mix75/25, 75% insulin lispro protamine and 25% insulin lispro available as: ( 3 ) 3 mL single-patient-use KwikPen ® prefilled pen

Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 KwikPen Insulin lispro Insulin lispro Insulin lispro Protamine sulfate Glycerin Sodium Phosphate, Dibasic, Unspecified Form Metacresol Zinc oxide Phenol Water Hydrochloric acid Sodium hydroxide

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Standard 2-year carcinogenicity studies in animals have not been performed with Insulin Lispro Protamine and Insulin Lispro Mix75/25. In Fischer 344 rats, a 12-month repeat-dose toxicity study was conducted with insulin lispro (a component of Insulin Lispro Protamine and Insulin Lispro Mix75/25) at subcutaneous doses of 20 and 200 units/kg/day (approximately 3 and 32 times the human subcutaneous dose of 1 unit insulin lispro/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 insulin lispro/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 insulin lispro/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 with Insulin Lispro Protamine and Insulin Lispro Mix75/25. In Fischer 344 rats, a 12-month repeat-dose toxicity study was conducted with insulin lispro (a component of Insulin Lispro Protamine and Insulin Lispro Mix75/25) at subcutaneous doses of 20 and 200 units/kg/day (approximately 3 and 32 times the human subcutaneous dose of 1 unit insulin lispro/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 insulin lispro/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 insulin lispro/kg/day, based on units/body surface area), mating and fertility were not adversely affected in either gender at any dose.

BLA021017

Insulin Lispro Protamine and Insulin Lispro Injectable Suspension Mix75/25 KwikPen

Insulin lispro

0002-8233

HUMAN PRESCRIPTION DRUG

SUBCUTANEOUS

PACKAGE CARTON – Insulin Lispro Protamine and Insulin Lispro Injectable Suspension KwikPen Mix75/25™ 5ct NDC 0002-8233-05 Insulin Lispro Protamine and Insulin Lispro KwikPen Mix75/25™ Injectable Suspension For Single Patient Use Only Dispense in this sealed carton. Needles not included 100 units per mL (U-100) This device is recommended for use with Becton, Dickinson and Company's insulin pen needles For subcutaneous use only. prefilled insulin delivery device Rx only This product is Humalog Mix75/25. 5 x 3 mL Prefilled Pens Read Insulin Delivery Device Instructions for Use PACKAGE CARTON – INSULIN LISPRO PROTAMINE AND ISULIN LISPRO INJECTABLE SUSPENSION KwikPen Mix75/25 5ct

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 Protamine and Insulin Lispro Mix75/25 KwikPen Between Patients Advise patients using Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPens not to share needles or KwikPens with another person. Sharing poses a risk for transmission of blood-borne pathogens [see Warnings and Precautions ( 5.1 )] . Hyperglycemia or Hypoglycemia Inform patients that hypoglycemia is the most common adverse reaction with insulin. Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of Insulin Lispro Protamine and Insulin Lispro Mix75/25 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 [see Warnings and Precautions ( 5.3 )]. 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. 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 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 Protamine and Insulin Lispro Mix75/25. Inform patients on the symptoms of hypersensitivity reactions and to seek medical attention if they occur [see Warnings and Precautions ( 5.5 )] . Manufactured by: Eli Lilly and Company Indianapolis, IN 46285, USA US License Number 1891 Humalog ® Mix75/25™ and KwikPen ® are trademarks of Eli Lilly and Company. Copyright © 1999, 2023, Eli Lilly and Company. All rights reserved. ILPILIS7525-0002-USPI-20230721

KWIKPEN INSTRUCTIONS FOR USE INSTRUCTIONS FOR USE Insulin Lispro Protamine and Insulin Lispro [IHN-soo-lihn LIYS-proh] Mix75/25™ KwikPen ® injectable suspension, for subcutaneous use 3 mL single-patient-use pen (100 units per mL) This product is HUMALOG ® Mix75/25™ (insulin lispro protamine and insulin lispro). Read this Instructions for Use before you start taking Insulin Lispro Protamine and Insulin Lispro Mix75/25 and each time you get another KwikPen. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment. Do not share your Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPen 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. Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPen (“Pen”) is a disposable single-patient-use prefilled pen containing 300 units of Insulin Lispro Protamine and Insulin Lispro Mix75/25. You can give yourself more than 1 dose from the Pen. By turning the Dose Knob, you can dial doses from 1 to 60 units in 1 unit increments. If your dose is more than 60 units, you will need to give yourself more than 1 injection. The Plunger only moves a little with each injection, and you may not notice that it moves. The Plunger will only reach the end of the cartridge when you have used all 300 units in the Pen. People who are blind or have vision problems should not use this Pen without help from a person trained to use the Pen. How to recognize your Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPen Pen color: Dark blue Dose Knob: Dark blue Labels: White label with yellow stripe Supplies you will need to give your injection Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPen KwikPen compatible Needle (Becton, Dickinson and Company Pen Needles recommended) Alcohol swab Gauze Preparing your Pen Wash your hands with soap and water. Check your Pen to make sure you are taking the right type of insulin. This is especially important if you use more than 1 type of insulin. Always use a new needle for each injection to help prevent infections and blocked needles. Do not reuse or share your needles with other people. You may give other people a serious infection or get a serious infection from them. Step 1: Pull the Pen Cap straight off. - Do not remove the Pen Label. Wipe the Rubber Seal with an alcohol swab. - Do not attach the Needle before mixing. Step 2: Gently roll the Pen between your hands at least 10 times. Step 3: Move the Pen up and down (invert) at least 10 times. Mixing by rolling and inverting the Pen is important to make sure you get the right dose. After mixing Insulin Lispro Protamine and Insulin Lispro Mix75/25, inject your dose right away. If you wait to inject your dose, the insulin will need to be mixed again. Step 4: Check the liquid in the Pen. Insulin Lispro Protamine and Insulin Lispro Mix75/25 should look white and cloudy after mixing. Do not use if it looks clear or has any lumps or particles in it. Step 5: Select a new Needle. Pull off the Paper Tab from the Outer Needle Shield. Step 6: Push the capped Needle straight onto the Pen and twist the Needle on until it is tight. Step 7: Pull off the Outer Needle Shield. Do not throw it away. Pull off the Inner Needle Shield and throw it away. Priming your Pen Prime your Pen before each injection. Priming your Pen means removing the air from the Needle and Cartridge that may collect during normal use and ensures that the Pen is working correctly. If you do not prime before each injection, you may get too much or too little insulin. Step 8: To prime your Pen, turn the Dose Knob to select 2 units. Step 9: Hold your Pen with the Needle pointing up. Tap the Cartridge Holder gently to collect air bubbles at the top. Step 10: Continue holding your Pen with Needle pointing up. Push the Dose Knob in until it stops, and “0” is seen in the Dose Window. Hold the Dose Knob in and count to 5 slowly . You should see insulin at the tip of the Needle. - If you do not see insulin, repeat priming steps 8 to 10, no more than 4 times. - If you still do not see insulin, change the Needle and repeat priming steps 8 to 10. Small air bubbles are normal and will not affect your dose. Selecting your dose You can give from 1 to 60 units in a single injection. If your dose is more than 60 units, you will need to give more than one injection. - If you need help with dividing up your dose the right way, ask your healthcare provider. - Use a new Needle for each injection and repeat the priming steps. Step 11: Turn the Dose Knob to select the number of units you need to inject. The Dose Indicator should line up with your dose. - The Pen dials 1 unit at a time. - The Dose Knob clicks as you turn it. - Do not dial your dose by counting the clicks. You may dial the wrong dose. This may lead to you getting too much insulin or not enough insulin. - The dose can be corrected by turning the Dose Knob in either direction until the correct dose lines up with the Dose Indicator. - The even numbers (for example, 12) are printed on the dial. - The odd numbers, (for example, 25) after the number 1, are shown as full lines. Always check the number in the Dose Window to make sure you have dialed the correct dose. (Example: 12 units shown in the Dose Window) (Example: 25 units shown in the Dose Window) The Pen will not let you dial more than the number of units left in the Pen. If you need to inject more than the number of units left in the Pen, you may either: - inject the amount left in your Pen and then use a new Pen to give the rest of your dose, or - get a new Pen and inject the full dose. It is normal to see a small amount of insulin left in the Pen that you can not inject. Giving your injection Inject your insulin as your healthcare provider has shown you. 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. Do not try to change your dose while injecting. Step 12: Choose your injection site. Insulin Lispro Protamine and Insulin Lispro Mix75/25 is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs or upper arms. Wipe your skin with an alcohol swab, and let your skin dry before you inject your dose. Step 13: Insert the Needle into your skin. Push the Dose Knob all the way in. Continue to hold the Dose Knob in and slowly count to 5 before removing the Needle. Do not try to inject your insulin by turning the Dose Knob. You will not receive your insulin by turning the Dose Knob. Step 14: Pull the Needle out of your skin. A drop of insulin at the Needle tip is normal. It will not affect your dose. Check the number in the Dose Window. - If you see “0” in the Dose Window, you have received the full amount you dialed. - If you do not see “0” in the Dose Window, do not redial. Insert the Needle into your skin and finish your injection. - If you still do not think you received the full amount you dialed for your injection, do not start over or repeat the injection. Monitor your blood glucose as instructed by your healthcare provider. - If you normally need to give 2 injections for your full dose, be sure to give your second injection. The Plunger only moves a little with each injection, and you may not notice that it moves. If you see blood after you take the Needle out of your skin, press the injection site lightly with a piece of gauze or an alcohol swab. Do not rub the area. After your injection Step 15: Carefully replace the Outer Needle Shield. Step 16: Unscrew the capped Needle and throw it away (see Disposing of Pens and Needles section). Do not store the Pen with the Needle attached to prevent leaking, blocking the Needle, and air from entering the Pen. Step 17: Replace the Pen Cap by lining up the Cap Clip with the Dose Indicator and pushing straight on. Disposing of Pens and Needles The used Pen may be discarded in your household trash after you have removed the needle. Put your used needles in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles 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. Storing your Pen Unused Pens Store unused Pens in the refrigerator at 36°F to 46°F (2°C to 8°C). Do not freeze your insulin. Do not use if Insulin Lispro Protamine and Insulin Lispro Mix75/25 has been frozen. Unused Pens may be used until the expiration date printed on the Label, if the Pen has been kept in the refrigerator. Unused Pens stored at room temperature, up to 86°F (30°C), should be thrown away after 10 days. In-use Pen Store the Pen you are currently using at room temperature [up to 86°F (30°C)]. Keep away from heat and light. Throw away the Insulin Lispro Protamine and Insulin Lispro Mix75/25 Pen you are using after 10 days, even if it still has insulin left in it. General information about the safe and effective use of your Pen Keep your Pen and needles out of the reach of children. Do not use your Pen if any part looks broken or damaged. Always carry an extra Pen in case yours is lost or damaged. Troubleshooting If you can not remove the Pen Cap, gently twist the cap back and forth, and then pull the cap straight off. If the Dose Knob is hard to push: - Pushing the Dose Knob more slowly will make it easier to inject. - Your Needle may be blocked. Put on a new Needle and prime the Pen. - You may have dust, food, or liquid inside the Pen. Throw the Pen away and get a new Pen. If you have any questions or problems with your Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPen, contact Lilly at 1-800-LillyRx (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. Revised: 07/2023 Humalog ® Mix75/25™ and KwikPen ® are trademarks of Eli Lilly and Company. Copyright © 2007, 2023, Eli Lilly and Company. All rights reserved. Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPen meets the current dose accuracy and functional requirements of ISO 11608-1. ILPILIS7525KP-0003-IFU-20230721 Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure Figure

8.5 Geriatric Use Clinical studies of Insulin Lispro Protamine and Insulin Lispro Mix75/25 did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. In patients aged 65 and over with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.3 )].

8.4 Pediatric Use Safety and effectiveness of Insulin Lispro Protamine and Insulin Lispro Mix75/25 in pediatric patients have not been established.

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, still birth, 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 Animal reproduction studies have not been performed with Insulin Lispro Protamine and Insulin Lispro Mix75/25. However, subcutaneous reproduction and teratology studies have been conducted with insulin lispro (a component of Insulin Lispro Protamine and Insulin Lispro Mix75/25). 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, still birth, 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 Animal reproduction studies have not been performed with Insulin Lispro Protamine and Insulin Lispro Mix75/25. However, subcutaneous reproduction and teratology studies have been conducted with insulin lispro (a component of Insulin Lispro Protamine and Insulin Lispro Mix75/25). 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 Protamine and Insulin Lispro Mix75/25, 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 Protamine and Insulin Lispro Mix75/25, 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 Protamine and Insulin Lispro Mix75/25 or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness of Insulin Lispro Protamine and Insulin Lispro Mix75/25 in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of Insulin Lispro Protamine and Insulin Lispro Mix75/25 did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. In patients aged 65 and over with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to reduce the risk of hypoglycemia [see Warnings and Precautions ( 5.3 )]. 8.6 Renal Impairment The effect of renal impairment on the pharmacokinetics of Insulin Lispro Protamine and Insulin Lispro Mix75/25 has not been studied. Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent Insulin Lispro Protamine and Insulin Lispro Mix75/25 dose adjustment and more frequent glucose monitoring [see Warnings and Precautions ( 5.3 )] . 8.7 Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of Insulin Lispro Protamine and Insulin Lispro Mix75/25 has not been studied. Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent Insulin Lispro Protamine and Insulin Lispro Mix75/25 dose adjustment and more frequent glucose monitoring [see Warnings and Precautions ( 5.3 )] .

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Insulin Lispro Protamine and Insulin Lispro, injectable suspension, is a white and cloudy suspension of 100 units/mL (U-100) of 75% insulin lispro protamine and 25% insulin lispro available as: 3 mL single-patient-use KwikPen prefilled pen NDC 0002-8233-05 Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPens must never be shared between patients, even if the needle is changed. Always use a new needle for each injection to prevent contamination. The Insulin Lispro Protamine and Insulin Lispro Mix75/25 KwikPen dials in 1 unit increments. 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 storage table below: Not In-Use (Unopened) Refrigerated (36° to 46°F [2° to 8°C]) Not In Use (Unopened) Room Temperature (up to 86°F [30°C]) In-Use (Opened) (see temperature below) 3 mL single-patient-use KwikPen Until expiration date 10 days 10 days Room temperature only (Do not refrigerate)

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 storage table below: Not In-Use (Unopened) Refrigerated (36° to 46°F [2° to 8°C]) Not In Use (Unopened) Room Temperature (up to 86°F [30°C]) In-Use (Opened) (see temperature below) 3 mL single-patient-use KwikPen Until expiration date 10 days 10 days Room temperature only (Do not refrigerate)