Humulin R U-500 KwikPen

1 INDICATIONS AND USAGE HUMULIN R U-500 is a concentrated human insulin indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus requiring more than 200 units of insulin per day. HUMULIN ® R U-500 is a concentrated human insulin indicated to improve glycemic control in adults and pediatric patients with diabetes mellitus requiring more than 200 units of insulin per day. ( 1 ) Limitation of Use: The safety and efficacy of HUMULIN R U-500 used in combination with other insulins has not been determined. The safety and efficacy of HUMULIN R U-500 delivered by continuous subcutaneous infusion has not been determined. ( 1.1 ) 1.1 Limitation of Use The safety and efficacy of HUMULIN R U-500 used in combination with other insulins has not been determined. The safety and efficacy of HUMULIN R U-500 delivered by continuous subcutaneous infusion has not been determined.

6 ADVERSE REACTIONS The following adverse reactions are discussed elsewhere: Hypoglycemia [see Warnings and Precautions ( 5.4 )] . Hypersensitivity Reactions [see Warnings and Precautions ( 5.5 )] . Hypokalemia [see Warnings and Precautions ( 5.6 )] . The following additional adverse reactions have been identified during post-approval use of HUMULIN R U-500. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. Adverse reactions associated with HUMULIN R U-500 include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, 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. Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including HUMULIN R U-500. Allergic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, rash, angioedema, bronchospasm, hypotension, and shock may occur with insulins, including HUMULIN R U-500 and may be life threatening. Lipodystrophy Long-term use of insulin, including HUMULIN R U-500, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue) and may affect insulin absorption. Rotate insulin injections sites within the same region to reduce the risk of lipodystrophy [see Dosage and Administration ( 2.1 )] . 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. Injection Site Reactions Patients taking HUMULIN R U-500 may experience injection site reactions, including injection site hematoma, pain, hemorrhage, erythema, nodules, swelling, discoloration, pruritus, warmth, and injection site mass. Weight Gain Weight gain can occur with insulins, including HUMULIN R U-500, and has been attributed to the anabolic effects of insulin. Peripheral Edema Insulins, including HUMULIN R U-500, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy. Immunogenicity As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The presence of antibodies that affect clinical efficacy may necessitate dose adjustments to correct for tendencies toward hyper- or hypoglycemia. The incidence of antibody formation with HUMULIN R U-500 is unknown.

4 CONTRAINDICATIONS HUMULIN R U-500 is contraindicated: During episodes of hypoglycemia [see Warnings and Precautions ( 5.4 )] In patients who are hypersensitive to HUMULIN R U-500 or 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 HUMULIN R U-500 or any of its excipients. ( 4 )

11 DESCRIPTION Insulin human is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli and has the empirical formula C 257 H 383 N 65 O 77 S 6 with a molecular weight of 5.808 kDa. HUMULIN R U-500 (insulin human) injection is a sterile, aqueous, and colorless solution for subcutaneous use. HUMULIN R U-500 contains 500 units of insulin human in each milliliter. Each milliliter of HUMULIN R U-500 also contains glycerin (16 mg), metacresol (2.5 mg), zinc oxide to supplement the endogenous zinc to obtain a total zinc content of 0.017 mg/100 units, and Water for Injection. Sodium hydroxide and hydrochloric acid may be added during manufacture to adjust the pH. The pH is 7.0 to 7.8.

2 DOSAGE AND ADMINISTRATION Adhere to administration instructions to reduce the risk of dosing errors. ( 2.1 , 2.3 , 2.4 , 5.1 ) HUMULIN R U-500 is available as a single-patient-use KwikPen or multiple-dose vial. Patients using the vial must be prescribed the U-500 insulin syringe to avoid medication errors. ( 2.1 ) Individualize dose of HUMULIN R U-500 based on metabolic needs, blood glucose monitoring results and glycemic control goal. ( 2.2 ) Administer HUMULIN R U-500 subcutaneously two or three times daily 30 minutes before a meal into the thigh, upper arm, abdomen, or buttocks. Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. ( 2.1 , 2.2 ) Do NOT mix HUMULIN R U-500 with other insulins. ( 2.1 ) Do NOT administer HUMULIN R U-500 intravenously ( 2.1 ) Do NOT perform dose conversion when using the HUMULIN R U-500 KwikPen. The dose window of the HUMULIN R U-500 KwikPen shows the number of units of HUMULIN R U-500 to be injected. ( 2.3 ) Do NOT transfer HUMULIN R U-500 from the HUMULIN R U-500 KwikPen into any syringe. ( 2.3 ) Do NOT perform dose conversion when using a U-500 insulin syringe. Use only a U-500 insulin syringe with the HUMULIN R U-500 vial. ( 2.4 ) 2.1 Important Administration Instructions Prescribe HUMULIN R U-500 ONLY to patients who require more than 200 units of insulin per day. HUMULIN R U-500 is available as a single-patient-use KwikPen or multiple-dose vial. Patients using the vial must be prescribed the U-500 insulin syringe to avoid medication errors. Instruct patients using the vial presentation to use only a U-500 insulin syringe and on how to correctly draw the prescribed dose of HUMULIN R U-500 into the U-500 insulin syringe. Confirm that the patient has understood these instructions and can correctly draw the prescribed dose of HUMULIN R U-500 with their syringe [see Dosage and Administration ( 2.4 ) and Warnings and Precautions ( 5.1 )] . Instruct patients to always check the insulin label before administration to confirm the correct insulin product is being used [see Warnings and Precautions ( 5.1 )] . Inspect HUMULIN R U-500 visually for particulate matter and discoloration. Only use HUMULIN R U-500 if the solution appears clear and colorless. Instruct patients to inject HUMULIN R U-500 subcutaneously into the thigh, upper arm, abdomen, or buttocks. Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions ( 5.3 ) and Adverse Reactions ( 6 )] . During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions ( 5.3 )] . Use HUMULIN R U-500 KwikPen with caution in patients with visual impairment that may rely on audible clicks to dial their dose. DO NOT administer HUMULIN R U-500 intravenously. DO NOT dilute or mix HUMULIN R U-500 with any other insulin products or solutions. 2.2 Dosing Instructions Instruct patients to inject HUMULIN R U-500 subcutaneously usually two or three times daily approximately 30 minutes before meals. Individualize and titrate the dosage of HUMULIN R U-500 based on the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal. Dosage adjustments may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function, changes in medications or during acute illness to minimize the risk of hypoglycemia or hyperglycemia [see Warnings and Precautions ( 5.3 )] . 2.3 Delivery of HUMULIN R U-500 Using the HUMULIN R U-500 Disposable Prefilled KwikPen Device The HUMULIN R U-500 KwikPen dials in 5 unit increments and delivers a maximum dose of 300 units per injection. DO NOT perform dose conversion when using the HUMULIN R U-500 KwikPen. The dose window of the HUMULIN R U-500 KwikPen shows the number of units of HUMULIN R U-500 to be injected and NO dose conversion is required . DO NOT transfer HUMULIN R U-500 from the HUMULIN R U-500 KwikPen into any syringe for administration as overdose and severe hypoglycemia can occur [see Warnings and Precautions ( 5.4 )]. 2.4 Delivery of HUMULIN R U-500 Using the Vial Presentation and the U-500 Insulin Syringe DO NOT perform dose conversion when using a U-500 insulin syringe. The markings on the U-500 insulin syringe show the number of units of HUMULIN R U-500 to be injected. Each marking on the syringe represents 5 units of insulin. Prescribe patients a U-500 insulin syringe to administer HUMULIN R U-500 from the vial to avoid administration errors. DO NOT use any other type of syringe [see Warnings and Precautions ( 5.1 )] .

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 Table 1: Clinically Significant Drug Interactions with HUMULIN R U-500 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 HUMULIN R U-500 is co-administered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of HUMULIN R U 500 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 HUMULIN R U-500 is co-administered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of HUMULIN R U 500 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 HUMULIN R U-500 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 HUMULIN R U-500 is co-administered with these drugs. Drugs that Affect Glucose Metabolism: Adjustment of insulin dosage may be needed. ( 7 ) Antiadrenergic Drugs (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Signs and symptoms of hypoglycemia may be reduced or absent. ( 5.3 , 7 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Regulation of glucose metabolism is the primary activity of insulins, including HUMULIN R U-500. 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 euglycemic clamp study of 24 healthy obese subjects (BMI=30-39 kg/m 2 ), single doses of HUMULIN R U-500 at 50 units (0.4-0.6 unit/kg) and 100 units (0.8-1.3 unit/kg) resulted in a mean time of onset of action of less than 15 minutes at both doses and a mean duration of action of 21 hours (range 13-24 hours). The time action characteristics reflect both prandial and basal activity, consistent with clinical experience. This effect has been attributed to the high concentration of the preparation. Figure 1 should be considered a representative example since the time course of action of insulin may vary in different individuals or within the same individual. The rate of insulin absorption and consequently the onset of activity is known to be affected by the site of injection, exercise, and other variables [see Warnings and Precautions ( 5.3 )] . Figure 1: Mean Insulin Activity Versus Time Profiles After Subcutaneous Injection of a 100 U Dose of HUMULIN R U-500 in Healthy Obese Subjects Figure 1 12.3 Pharmacokinetics Absorption — In a euglycemic clamp study of 24 healthy obese subjects, the median peak insulin level occurred between 4 hours (50 unit dose) and 8 hours (100 unit dose) with a range of 0.5-8 hours. Metabolism — The uptake and degradation of insulin occurs predominantly in liver, kidney, muscle, and adipocytes, with the liver being the major organ involved in the clearance of insulin. Elimination — Mean apparent half-life after subcutaneous administration of single doses of 50 units and 100 units to healthy obese subjects (N≥21) was approximately 4.5 hours (range=1.9-10 hours) for HUMULIN R U-500. Figure 2: Mean Serum Insulin Concentrations Versus Time After Subcutaneous Injection of a 100 U Dose of HUMULIN R U-500 Healthy Obese Subjects Figure 2

12.1 Mechanism of Action Regulation of glucose metabolism is the primary activity of insulins, including HUMULIN R U-500. 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 euglycemic clamp study of 24 healthy obese subjects (BMI=30-39 kg/m 2 ), single doses of HUMULIN R U-500 at 50 units (0.4-0.6 unit/kg) and 100 units (0.8-1.3 unit/kg) resulted in a mean time of onset of action of less than 15 minutes at both doses and a mean duration of action of 21 hours (range 13-24 hours). The time action characteristics reflect both prandial and basal activity, consistent with clinical experience. This effect has been attributed to the high concentration of the preparation. Figure 1 should be considered a representative example since the time course of action of insulin may vary in different individuals or within the same individual. The rate of insulin absorption and consequently the onset of activity is known to be affected by the site of injection, exercise, and other variables [see Warnings and Precautions ( 5.3 )] . Figure 1: Mean Insulin Activity Versus Time Profiles After Subcutaneous Injection of a 100 U Dose of HUMULIN R U-500 in Healthy Obese Subjects Figure 1

12.3 Pharmacokinetics Absorption — In a euglycemic clamp study of 24 healthy obese subjects, the median peak insulin level occurred between 4 hours (50 unit dose) and 8 hours (100 unit dose) with a range of 0.5-8 hours. Metabolism — The uptake and degradation of insulin occurs predominantly in liver, kidney, muscle, and adipocytes, with the liver being the major organ involved in the clearance of insulin. Elimination — Mean apparent half-life after subcutaneous administration of single doses of 50 units and 100 units to healthy obese subjects (N≥21) was approximately 4.5 hours (range=1.9-10 hours) for HUMULIN R U-500. Figure 2: Mean Serum Insulin Concentrations Versus Time After Subcutaneous Injection of a 100 U Dose of HUMULIN R U-500 Healthy Obese Subjects Figure 2

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3 DOSAGE FORMS AND STRENGTHS Injection: 500 units/mL (U-500) clear, colorless solution available as: 3 mL single-patient-use HUMULIN R U-500 KwikPen prefilled pen (containing 1,500 units of insulin) 20 mL multiple-dose vial (containing 10,000 units of insulin) Injection: 500 units/mL (U-500) available as: ( 3 ) 3 mL single-patient-use HUMULIN ® R U-500 KwikPen ® prefilled pen (containing 1,500 units of insulin) 20 mL multiple-dose vial (containing 10,000 units of insulin)

Humulin R U-500 Insulin human Insulin human Insulin human Glycerin Metacresol Zinc Water Hydrochloric acid Sodium hydroxide Humulin R U-500 KwikPen Insulin human Insulin human Insulin human Glycerin Metacresol Zinc Water Hydrochloric acid Sodium hydroxide

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity and fertility studies were not performed with HUMULIN R U-500 in animals. Biosynthetic human insulin was not genotoxic in the in vivo sister chromatid exchange assay and the in vitro gradient plate and unscheduled DNA synthesis assays.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity and fertility studies were not performed with HUMULIN R U-500 in animals. Biosynthetic human insulin was not genotoxic in the in vivo sister chromatid exchange assay and the in vitro gradient plate and unscheduled DNA synthesis assays.

BLA018780

Humulin R U-500 KwikPen

Insulin human

0002-8824

HUMAN PRESCRIPTION DRUG

SUBCUTANEOUS

VIAL PACKAGE CARTON – HUMULIN R U-500 Vial 20 mL 1ct NDC 0002-8501-01 20 mL Humulin ® R U-500 (insulin human) injection 10,000 units per 20 mL 500 units per mL Rx only 500 units/mL Warning - Highly Concentrated IMPORTANT: Use only with a U-500 syringe. 20 mL multiple-dose vial For subcutaneous use only www.humulin.com Lilly PACKAGE CARTON – HUMULIN R U-500 Vial 20 mL 1ct

17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling . Patients should be counseled that HUMULIN R U-500 is a 5-times concentrated insulin product. Extreme caution must be observed in the measurement of dosage because inadvertent overdose may result in serious adverse reaction or life-threatening hypoglycemia. Accidental mix-ups between insulin products have been reported. To avoid medication errors between HUMULIN R U-500 and other insulins, patients should be instructed to always check the insulin label before each injection [see Warnings and Precautions ( 5.1 )] . If using the HUMULIN R U-500 KwikPen, patients should be counseled to dial and dose the prescribed number of units of insulin (no dose conversion is required) [see Dosage and Administration ( 2.3 )] . When using HUMULIN R U-500 from a vial, patients should be counseled to use only a U-500 insulin syringe and be informed that no dose conversion is required [see Dosage and Administration ( 2.4 )] . Patients should be instructed on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of HUMULIN R U-500 therapy. Patients must be instructed 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. 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. Refer patients to the HUMULIN R U-500 Patient Information Leaflet for additional information [see Warnings and Precautions ( 5 )] . Do not dilute or mix HUMULIN R U-500 with any other insulin products or solutions [see Dosage and Administration ( 2.1 )] . Literature Revised: February 2024 Manufactured by: Eli Lilly and Company, Indianapolis, IN 46285, USA US License Number 1891 Copyright © 1997, 2024, Eli Lilly and Company. All rights reserved. LINR500-0010-USPI-20240222

Instructions for Use Humulin ® R U-500 (insulin human) injection, for subcutaneous use 20 mL multiple-dose vial (500 units/mL) Please read these instructions before use. Warnings For your safety, always inject Humulin ® R U - 500 insulin with a U - 500 syringe. If you use another kind of syringe, you may get a dangerous overdose. U-500 syringe – for single injection only The U-500 syringe has a green U-500 symbol and a green Needle Shield on the syringe. Important Information Humulin R U-500 is a concentrated insulin. Know your dose. Your health care provider will tell you the number of insulin units that you should take. Always inject Humulin R U-500 insulin with a U-500 syringe. Other syringes will not measure your dose correctly. If you use the wrong syringe, you can give yourself a severe overdose. This can cause very low blood sugar, which may put your life in danger. For example, using a U-100 syringe can give you a 5 times overdose. If you do not have a U-500 syringe, you should contact your health care provider or pharmacist. Additional Safety Information Each line on the U-500 syringe measures 5 units of U-500 insulin. You can give from 5 to 250 units in one injection. If your dose is more than 250 units, you will need to give more than 1 injection. Make sure you know how to draw up your dose with a U-500 syringe. If you need help, call your health care provider. Do not reuse your U-500 syringe. Do not share your U - 500 syringes with other people. You may give other people a serious infection or get a serious infection from them. Do not mix Humulin R U-500 with other insulins in the same syringe. You can get more instructions by calling Lilly at 1-800-LillyRx (1-800-545-5979). Supplies Humulin R U-500 multiple-dose vial U-500 Syringe (BD [Becton, Dickinson and Company] syringes recommended) 2 alcohol swabs 1 sharps container Before You Start Check your vial. Make sure it says Humulin R U-500. Check the expiration date on the vial. Do not use it if it is expired. Throw away the opened vial after 40 days, even if there is still insulin left in the vial. See if the insulin in the vial is clear. Do not use if it is thick, cloudy, or colored or has solid particles. Make sure you have a new U-500 Syringe. Check for the green U-500 symbol and green Needle Shield. Check your supply. Make sure you have enough Humulin R U-500 insulin and U-500 syringes for several injections. Always reorder before you run out. Check with your health care provider if you have any questions. Use only a U-500 syringe to inject Humulin R U-500 insulin Prepare Wash your hands with soap and water. Always use a new syringe for each injection to help prevent infections and blocked needles. Step 1: Find the line on the U-500 syringe that matches your prescribed dose. This is your Dose Line. Each line is 5 units. (Example: Arrow shows Dose Line at 85 units) Step 2: If you are using a new vial, pull off the plastic Protective Cap. Do not remove the Rubber Stopper. Step 3: Wipe the Rubber Stopper with an alcohol swab. Step 4: Hold the syringe with the Needle pointing up. Pull down on the Plunger Rod until the Plunger Tip reaches your Dose Line. (Example Dose: 85 units shown) Step 5: Push the Needle through the Rubber Stopper of the vial. Step 6: Push the Plunger all the way in. This puts air into the vial. Step 7: Turn the vial and syringe upside down and slowly pull the Plunger down until the Plunger Tip is past your Dose Line. (Example Dose: 85 units Plunger is shown at 100 units) If there are air bubbles, tap the syringe gently a few times. This lets the air bubbles rise to the top. Step 8: Slowly push the Plunger up until the Plunger Tip reaches your Dose Line. Check the syringe to make sure that you have the right dose. (Example Dose: 85 units shown) Step 9: Pull the syringe out of the vial's Rubber Stopper. Inject Inject your insulin exactly 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. Step 10: Choose your injection site. Humulin R U-500 is injected under the skin (subcutaneously). You may inject into your stomach area, buttocks, upper legs, or upper arms. Wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose. Step 11: Insert the Needle into your skin. Step 12: Push down on the Plunger to inject your dose. Then keep the Needle in your skin for at least 5 seconds, to make sure you have injected all of your dose. Step 13: Pull the Needle out of your skin. You may see blood after you take the Needle out of your skin. This is normal. Press the injection site lightly with a piece of gauze or an alcohol swab. Do not rub the area. Do not put the Needle Shield back on the Needle, because you may get a needle stick injury. Disposal of used syringes Put your used syringes in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) 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. Storage and Handling Keep away from heat and out of direct light. Do not shake the vial. Unopened vials: Store unopened vials in the refrigerator. Do not freeze Humulin R U-500. If it has been frozen, do not use it. If unopened vials have been stored in the refrigerator, you may use them until the expiration date. After the vial has been opened: Store opened vials in the refrigerator or at room temperature (up to 86°F [30°C]) for up to 40 days. Throw away the opened vial after 40 days, even if there is still insulin left in the vial. General Information Always use a U-500 syringe to inject Humulin R U-500 insulin. Never use other syringes. The lines and numbers on other syringes will not measure your dose correctly. You can give yourself the wrong dose if you use any other syringe, such as a U-100, tuberculin or allergy syringe. For example, a U-100 syringe is made to measure U-100 insulin. If you use a U-100 Syringe for your U-500 dose, you can give yourself a 5 times overdose. Do not make any changes to your dose or the type of insulin you use unless you are told to do so by your health care provider. Keep your vials and syringes out of the sight and reach of children. Frequently Asked Questions Why do I need to use a U-500 syringe? Humulin R U-500 insulin and a U-500 syringe work together to help you inject the correct dose. Using any other syringe may result in dosing mistakes. This may put your life in danger. Do I have to convert my Humulin R U-500 insulin dose when I use the U-500 syringe? No, you do not have to convert your dose. Your health care provider should tell you how much Humulin R U-500 insulin to take in units and when to take it. Your health care provider should show you how to draw up your dose using the U-500 syringe. What should I do if I run out of U-500 syringes? If you run out of U-500 syringes, do not use any other syringe to inject Humulin R U-500 insulin. Call your health care provider or pharmacist for help. You may also call Lilly at 1-800-Lilly-Rx (1-800-545-5979). Where to get more information and help If you have any questions about Humulin R U-500 insulin or U-500 syringes, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979). You can also call your health care provider or pharmacist. For more information on Humulin R U-500 insulin, go to www.humulin.com Scan this code to launch the humulin.com website These Instructions for Use have been approved by the U.S. Food and Drug Administration. Humulin ® is a trademark of Eli Lilly and Company. Manufactured by: Eli Lilly and Company, Indianapolis, IN 46285, USA US License Number 1891 Copyright © 1996, 2022, Eli Lilly and Company. All rights reserved. Literature revised: June 2022 LINR500VL-0004-IFU-20220627 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 The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN R U-500 has not been studied. Caution should be exercised when HUMULIN R U-500 is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia.

8.4 Pediatric Use The safety and effectiveness of HUMULIN R U-500 in pediatric patients with diabetes mellitus requiring more than 200 units of insulin per day to improve glycemic control have been established. Use of HUMULIN R U-500 for this indication is supported by evidence from studies with other insulin human in pediatric patients with type 1 diabetes mellitus and from studies in adults with diabetes mellitus. Standard precautions as applied to use of HUMULIN R U-500 in adults are appropriate for use in pediatric patients.

8.1 Pregnancy Risk Summary Available data from published studies over decades have not established an association with human insulin use during pregnancy and 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). Animal reproduction studies were not performed. 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 While available studies cannot definitively establish the absence of risk, published data from retrospective studies, open-label, randomized, parallel studies and meta-analyses over decades have not established an association with human insulin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. All available studies have methodological limitations, including lack of blinding, unclear methods or randomization, and small sample size.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data from published studies over decades have not established an association with human insulin use during pregnancy and 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). Animal reproduction studies were not performed. 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 While available studies cannot definitively establish the absence of risk, published data from retrospective studies, open-label, randomized, parallel studies and meta-analyses over decades have not established an association with human insulin use during pregnancy and major birth defects, miscarriage, or adverse maternal or fetal outcomes. All available studies have methodological limitations, including lack of blinding, unclear methods or randomization, and small sample size. 8.2 Lactation Risk Summary Available data from published literature suggests that exogenous human insulin products, including HUMULIN R U-500, 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 HUMULIN R U-500 on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for HUMULIN R U-500 and any potential adverse effects on the breastfed child from HUMULIN R U-500 or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of HUMULIN R U-500 in pediatric patients with diabetes mellitus requiring more than 200 units of insulin per day to improve glycemic control have been established. Use of HUMULIN R U-500 for this indication is supported by evidence from studies with other insulin human in pediatric patients with type 1 diabetes mellitus and from studies in adults with diabetes mellitus. Standard precautions as applied to use of HUMULIN R U-500 in adults are appropriate for use in pediatric patients. 8.5 Geriatric Use The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN R U-500 has not been studied. Caution should be exercised when HUMULIN R U-500 is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia. 8.6 Renal Impairment Frequent glucose monitoring and insulin dose reduction may be required in patients with renal impairment. 8.7 Hepatic Impairment Frequent glucose monitoring and insulin dose reduction may be required in patients with hepatic impairment.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied HUMULIN R U-500 (500 units/mL) injection is available in a clear, colorless solution as: 2 x 3 mL single-patient-use HUMULIN R U-500 KwikPen NDC 0002-8824-27 20 mL multiple-dose vial NDC 0002-8501-01 The HUMULIN R U-500 KwikPen dials in 5 unit increments. 16.2 Storage and Handling Dispense in the original sealed carton with the enclosed Instructions for Use. Protect from heat and light. Do not freeze. Do not use if it has been frozen. Do not shake the vial. See Table 2 below for storage conditions. Table 2: Storage Conditions for HUMULIN R U-500 Vials and Pens a When stored at room temperature, HUMULIN R U-500 vial can only be used for a total of 40 days, including both not in-use (unopened) and in-use (opened) storage time. b When stored at room temperature, HUMULIN R U-500 KwikPen 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) In-use (Opened) Room Temperature (up to 86°F [30°C]) Refrigerated (36° to 46°F [2° to 8°C]) Room Temperature (up to 86°F [30°C]) Refrigerated (36° to 46°F [2° to 8°C]) 20 mL multiple-dose vial a 40 days Until expiration date 40 days 40 days 3 mL single-patient-use HUMULIN R U-500 KwikPen b 28 days Until expiration date 28 days Do not refrigerate.

16.2 Storage and Handling Dispense in the original sealed carton with the enclosed Instructions for Use. Protect from heat and light. Do not freeze. Do not use if it has been frozen. Do not shake the vial. See Table 2 below for storage conditions. Table 2: Storage Conditions for HUMULIN R U-500 Vials and Pens a When stored at room temperature, HUMULIN R U-500 vial can only be used for a total of 40 days, including both not in-use (unopened) and in-use (opened) storage time. b When stored at room temperature, HUMULIN R U-500 KwikPen 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) In-use (Opened) Room Temperature (up to 86°F [30°C]) Refrigerated (36° to 46°F [2° to 8°C]) Room Temperature (up to 86°F [30°C]) Refrigerated (36° to 46°F [2° to 8°C]) 20 mL multiple-dose vial a 40 days Until expiration date 40 days 40 days 3 mL single-patient-use HUMULIN R U-500 KwikPen b 28 days Until expiration date 28 days Do not refrigerate.