LYUMJEV

Indications and Usage ( 1 ) 10/2022

1 INDICATIONS AND USAGE LYUMJEV ® is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. LYUMJEV ® is a rapid-acting human insulin analog indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. ( 1 )

2 DOSAGE AND ADMINISTRATION See Full Prescribing Information for important administration instructions. ( 2.1 , 2.2 ) Subcutaneous Injection ( 2.2 ): Administer LYUMJEV U-100 or U-200 at the start of a meal or within 20 minutes after starting a meal subcutaneously into the abdomen, upper arm, thigh, or buttocks. Rotate injection sites within the same region to reduce risk of lipodystrophy and localized cutaneous amyloidosis. Should generally be used in regimens with an intermediate or long-acting insulin. Continuous subcutaneous infusion (Insulin Pump) ( 2.2 ): Refer to the insulin infusion pump user manual to see if LYUMJEV can be used. Use in accordance with the insulin pump instructions for use. Administer LYUMJEV U-100 by continuous subcutaneous infusion using an insulin pump 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 administer LYUMJEV U-200 by continuous subcutaneous infusion. Intravenous Infusion ( 2.2 ): Administer LYUMJEV U-100 intravenously only under medical supervision. DO NOT administer LYUMJEV U-200 by intravenous infusion. Dilute LYUMJEV U-100 to a concentration of 1 unit/mL. Individualize and adjust the dosage of LYUMJEV based on the patient's metabolic needs, glucose monitoring results, and glycemic control goal. ( 2.3 ) Dose adjustments may be needed when switching from another insulin, with changes in physical activity, changes in concomitant medications, changes in meal patterns (i.e., amount and type of food, timing of food intake), changes in renal or hepatic function, or during acute illness. ( 2.3 ) 2.1 Important Administration Instructions Always check insulin labels before administration [see Warnings and Precautions ( 5.4 )] . Inspect LYUMJEV visually before use. It should appear clear and colorless. Do not use LYUMJEV if particulate matter and discoloration is seen. Use LYUMJEV prefilled pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose. Do not perform dose conversion when using any LYUMJEV U-100 or U-200 prefilled pens. The dose window of LYUMJEV prefilled pens shows the number of units of LYUMJEV to be delivered and no conversion is needed . Do not transfer LYUMJEV U-200 from the prefilled pen to a syringe for administration [see Warnings and Precautions ( 5.4 )] . Do not mix LYUMJEV with any other insulin products. Do not administer LYUMJEV U-200 using continuous subcutaneous infusion insulin pump. Do not administer LYUMJEV U-200 intravenously. 2.2 Route of Administration Instructions Subcutaneous Injection for LYUMJEV U-100 or U-200 Administer LYUMJEV at the start of a meal or within 20 minutes after starting a meal subcutaneously into the abdomen, upper arm, thigh, 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 Adverse Reactions ( 6.1 , 6.2 )]. LYUMJEV given by subcutaneous injection should generally be used in regimens with intermediate or long-acting insulin. The LYUMJEV U-100 KwikPen, LYUMJEV U-100 Tempo Pen, and LYUMJEV U-200 KwikPen each dial in 1 unit increments and deliver a maximum dose of 60 units per injection. The LYUMJEV U-100 Junior KwikPen dials in 0.5 unit increments and delivers a maximum dose of 30 units per injection. Continuous Subcutaneous Insulin Infusion (Insulin Pump) for LYUMJEV U-100 Only Do not administer LYUMJEV U-200 using an insulin pump. Refer to the continuous subcutaneous insulin infusion pump user manual to see if LYUMJEV can be used with the insulin pump. Use LYUMJEV in accordance with the insulin pump system's instructions for use. Administer LYUMJEV U-100 by continuous subcutaneous infusion in a region recommended in the instructions from the pump manufacturer. …

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 LYUMJEV KwikPen 3 mL single-patient-use LYUMJEV Junior KwikPen 3 mL single-patient-use LYUMJEV Tempo Pen 3 mL single-patient-use cartridges Injection: 200 units/mL (U-200) clear and colorless solution available as: 3 mL single-patient-use LYUMJEV KwikPen Injection: 100 units/mL (U-100) available as: 10 mL multiple-dose vial ( 3 ) 3 mL single-patient-use KwikPen ® ( 3 ) 3 mL single-patient-use Junior KwikPen ® ( 3 ) 3 mL single-patient-use Tempo Pen ® ( 3 ) 3 mL single-patient-use cartridges ( 3 ) Injection: 200 units/mL (U-200) available as: 3 mL single-patient-use KwikPen ® ( 3 )

4 CONTRAINDICATIONS LYUMJEV is contraindicated: during episodes of hypoglycemia. in patients with hypersensitivity to insulin lispro-aabc or any of the excipients in LYUMJEV. During episodes of hypoglycemia. ( 4 ) Hypersensitivity to insulin lispro-aabc or any of the excipients in LYUMJEV. ( 4 )

6 ADVERSE REACTIONS The following adverse reactions are also discussed elsewhere: Hypoglycemia [see Warnings and Precautions ( 5.3 )] . Hypoglycemia Due to Medication Errors [see Warnings and Precautions ( 5.4 )] Hypokalemia [see Warnings and Precautions ( 5.5 )] . Hypersensitivity Reactions [see Warnings and Precautions ( 5.6 )] . Adverse reactions observed with LYUMJEV include hypoglycemia, injection/infusion site reactions, allergic reactions, rash, pruritus, lipodystrophy, and weight gain. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates actually observed in clinical practice. Adverse Reaction Database – Adult Patients with Type 1 and Type 2 Diabetes The data in Table 1 reflect the exposure of 780 adult patients with type 1 diabetes to LYUMJEV with a mean exposure duration of 26 weeks [see Clinical Studies ( 14.2 )] . The mean age was 44 years, the mean duration of diabetes was 19 years, 55% were male, 77% were White, 2% were Black or African American, and 9% were Hispanic. The mean BMI was 26.6 kg/m 2 and the mean HbA 1c at baseline was 7.3%. The data in Table 2 reflect the exposure of 336 adult patients with type 2 diabetes to LYUMJEV with a mean exposure duration of 26 weeks [see Clinical Studies ( 14.3 )] . The mean age was 60 years, the mean duration of diabetes was 16 years, 55% were male, 69% were White, 4% were Black or African American, and 24% were Hispanic. The mean BMI was 32.1 kg/m 2 and the mean HbA 1c at baseline was 7.3%. The data in Table 3 reflect the exposure of 215 adult patients with type 1 diabetes to LYUMJEV via CSII administration with a mean exposure duration of 16 weeks [see Clinical Studies ( 14.4 )] . The mean age was 48 years, the mean duration of diabetes was 26 years, 44% were male, 94% were White, 3% were Black or African American, and 8% were Hispanic. The mean BMI was 27.0 kg/m 2 and the mean HbA 1c at baseline was 7.6%. Common adverse reactions, excluding hypoglycemia, were defined as events that occurred in ≥5% and at the same rate or greater for LYUMJEV-treated patients than HUMALOG-treated patients. Table 1. Adverse Reactions That Occurred in ≥5% of LYUMJEV-Treated Adult Patients with Type 1 Diabetes Mealtime LYUMJEV + basal insulin (N=451) % Postmeal LYUMJEV + basal insulin (N=329) % Nasopharyngitis 14.2 14.6 Table 2. Adverse Reactions That Occurred in ≥5% of LYUMJEV-Treated Adult Patients with Type 2 Diabetes Mealtime LYUMJEV + basal insulin (N=336) % Nasopharyngitis 12.5 Upper Respiratory Tract Infection 7.4 Table 3. Adverse Reactions That Occurred in ≥5% of LYUMJEV-Treated Adult Patients with Type 1 Diabetes Using Continuous Subcutaneous Insulin Infusion CSII LYUMJEV administration (N=215) % Infusion site reaction 19.1 Infusion site pain 15.8 Nasopharyngitis 6.0 Adverse Reaction Database – Pediatric Patients with Type 1 Diabetes The data in Table 4 reflect the exposure of 418 pediatric patients with type 1 diabetes to LYUMJEV with a mean exposure duration of 26 weeks [see Clinical Studies ( 14.5 )] . The mean age was 12 years; 50% were male, 91% were White, 1% were Black or African American; and 24% of the US subpopulation in this trial were Hispanic. The mean BMI was 20.5 kg/m 2 , the mean duration of diabetes was 5 years, and the mean HbA 1c at baseline was 7.8%. Common adverse reactions, excluding hypoglycemia, were defined as events that occurred in ≥5% and at the same rate or greater for LYUMJEV-treated patients than HUMALOG-treated patients. Table 4. Adverse Reactions That Occurred in ≥5% of LYUMJEV-Treated Pediatric Patients with Type 1 Diabetes Mealtime LYUMJEV + basal insulin (N=280) % Postmeal …

7 DRUG INTERACTIONS Table 6 includes clinically significant drug interactions with LYUMJEV. Table 6. Clinically Significant Drug Interactions with LYUMJEV 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 analogs (e.g., octreotide), and sulfonamide antibiotics. Intervention: Dose reductions and increased frequency of glucose monitoring may be required when LYUMJEV is co-administered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of LYUMJEV 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 increases and increased frequency of glucose monitoring may be required when LYUMJEV is co-administered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of LYUMJEV 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 LYUMJEV 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 LYUMJEV is co-administered with these drugs. Drugs that Increase Hypoglycemia Risk or Increase or Decrease Blood Glucose Lowering Effect: Adjustment of dosage may be needed; closely monitor blood glucose. ( 7 ) Drugs that Blunt Hypoglycemia Signs and Symptoms (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Increased frequency of glucose monitoring may be required. ( 7 )

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% to 10% in women with pre-gestational diabetes with a HbA 1c >7 and has been reported to be as high as 20% to 25% in women with a HbA 1c >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% to 4% and 15% to 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, 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 LYUMJEV. However, subcutaneous reproduction and teratology studies have been conducted with insulin lispro. 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 LYUMJE …

12.1 Mechanism of Action The primary activity of LYUMJEV is the regulation of glucose metabolism. Insulins, including insulin lispro-aabc, exert their specific action through binding to insulin receptors. Receptor-bound insulin lowers 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.

11 DESCRIPTION Insulin lispro-aabc is a rapid-acting human insulin analog used to lower blood glucose. Insulin lispro-aabc is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli . Insulin lispro-aabc differs from human insulin in that the amino acid proline at position B28 is replaced by lysine and the lysine in position B29 is replaced by proline. Chemically, it is Lys(B28), Pro(B29) human insulin analog and has the empirical formula C 257 H 383 N 65 O 77 S 6 and a molecular weight of 5808 daltons, both identical to that of human insulin. Insulin lispro-aabc has the following primary structure: LYUMJEV (insulin lispro-aabc) injection is a sterile, aqueous, clear, and colorless solution for subcutaneous or intravenous administration. Each mL of LYUMJEV U-100 contains 100 units of insulin lispro-aabc and the inactive ingredients: glycerol (12.1 mg), magnesium chloride hexahydrate (1.02 mg), metacresol (3.15 mg), sodium citrate dihydrate (4.41 mg), treprostinil sodium (1.06 mcg), zinc oxide (content adjusted to provide 39 mcg zinc ion), and Water for Injection, USP. Each mL of LYUMJEV U-200 contains 200 units of insulin lispro-aabc and the inactive ingredients: glycerol (12.1 mg), magnesium chloride hexahydrate (1.02 mg), metacresol (3.15 mg), sodium citrate dihydrate (4.41 mg), treprostinil sodium (1.06 mcg), zinc oxide (content adjusted to provide 52 mcg zinc ion), and Water for Injection, USP. Hydrochloric acid and/or sodium hydroxide may be added to adjust the pH. LYUMJEV has a pH of 7.0 to 7.8. Primary Structure

10 OVERDOSAGE Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions ( 5.3 , 5.5 )] . 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 glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied LYUMJEV (insulin lispro-aabc) injection is a clear and colorless solution available as shown in Table 12 . Table 12. How Supplied a 3 mL cartridge is for use in Eli Lilly and Company's HumaPen ® Luxura ® HD insulin delivery device. Patients need to check their device manual to determine if the LYUMJEV cartridge is compatible for use in other devices. b Tempo Pen contains a component that allows for data connectivity when used with a compatible transmitter. LYUMJEV NDC Number Concentration Total Units in Presentation Dose Increment Package Size U-100 multiple-dose 10 mL vial 0002-7728-01 100 units/mL 1,000 units n/a 1 vial U-100 single-patient-use 3 mL cartridge a 0002-7726-05 100 units/mL 300 units n/a 5 cartridges U-100 single-patient-use 3 mL KwikPen 0002-8207-05 100 units/mL 300 units 1 unit 5 pens U-100 single-patient-use 3 mL Junior KwikPen 0002-8351-05 100 units/mL 300 units 0.5 unit 5 pens U-100 single-patient-use 3 mL Tempo Pen b 0002-8235-05 100 units/mL 300 units 1 unit 5 pens U-200 single-patient-use 3 mL KwikPen 0002-8228-27 200 units/mL 600 units 1 unit 2 pens 16.2 Storage and Handling Dispense in the original sealed carton with the enclosed Instructions for Use. Refrigerate unopened LYUMJEV vials, pens, and cartridges between 36°F to 46°F (2°C to 8°C) until time of use and keep in the original carton to protect from light. Do not freeze or use LYUMJEV if it has been frozen. Do not expose to direct heat. Discard opened or unopened LYUMJEV vials, pens, and cartridges stored at room temperature below 86°F (30°C) after 28 days. The storage conditions for vials, pens, and cartridges are summarized in Table 13 . Table 13. Storage Conditions for Vials, Pens, and Cartridges a In-use (opened) vials, whether or not refrigerated, must be used within 28 days. b When stored at room temperature, LYUMJEV can only be used for a total of 28 days including both not in-use (unopened) and in-use (opened) storage time. LYUMJEV Presentation Not In-use (Unopened) In-use (Opened) Room Temperature (below 86°F [30°C]) Refrigerated (36°F to 46°F [2°C to 8°C]) Room Temperature (below 86°F [30°C]) Refrigerated (36°F to 46°F [2°C to 8°C]) 10 mL vial a,b 28 days Until expiration date 28 days 28 days 3 mL cartridge b 28 days Until expiration date 28 days Do not refrigerate 3 mL LYUMJEV KwikPen (U-100 and U-200) b 28 days Until expiration date 28 days Do not refrigerate 3 mL LYUMJEV Junior KwikPen b 28 days Until expiration date 28 days Do not refrigerate 3 mL LYUMJEV Tempo Pen b 28 days Until expiration date 28 days Do not refrigerate Storage of LYUMJEV in Insulin Pump Change the LYUMJEV U-100 in the pump reservoir at least every 9 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 LYUMJEV in Intravenous Infusion Fluids Diluted LYUMJEV may be stored for up to 4 days when refrigerated at 36°F to 46°F (2°C to 8°C) until time of use. The same solution may be stored up to 12 hours at room temperature at 68°F to 77°F (20°C to 25°C) [see Dosage and Administration ( 2.2 )].

16.1 How Supplied LYUMJEV (insulin lispro-aabc) injection is a clear and colorless solution available as shown in Table 12 . Table 12. How Supplied a 3 mL cartridge is for use in Eli Lilly and Company's HumaPen ® Luxura ® HD insulin delivery device. Patients need to check their device manual to determine if the LYUMJEV cartridge is compatible for use in other devices. b Tempo Pen contains a component that allows for data connectivity when used with a compatible transmitter. LYUMJEV NDC Number Concentration Total Units in Presentation Dose Increment Package Size U-100 multiple-dose 10 mL vial 0002-7728-01 100 units/mL 1,000 units n/a 1 vial U-100 single-patient-use 3 mL cartridge a 0002-7726-05 100 units/mL 300 units n/a 5 cartridges U-100 single-patient-use 3 mL KwikPen 0002-8207-05 100 units/mL 300 units 1 unit 5 pens U-100 single-patient-u …