Insulin Lispro-Aabc

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. Rotate infusion sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not infuse into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.1 )] . Train patients using continuous subcutaneous insulin infusion (CSII) therapy to administer insulin by injection and have alternate insulin therapy available in case of insulin pump failure [see Warnings and Precautions ( 5.8 )] . Change LYUMJEV U-100 in the pump reservoir at least every 9 days or according to the pump user manual, whichever is shorter. Change the infusion sets and the infusion set insertion site according to the manufacturer's user manual. Do not dilute or mix LYUMJEV U-100 when administering by CSII. Do not expose LYUMJEV in the pump reservoir to temperatures greater than 98.6°F (37°C). Intravenous Administration for LYUMJEV U-100 Only Do not administer LYUMJEV U-200 intravenously. Administer LYUMJEV U-100 intravenously only under medical supervision with close monitoring of glucose and potassium levels to avoid hypoglycemia and hypokalemia [see Warnings and Precautions ( 5.3 , 5.5 )] . Dilute LYUMJEV U-100 to a concentration of 1 unit/mL using 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP infusion solutions. Dilutions to concentrations below 1 unit/mL are not recommended. Diluted LYUMJEV may be stored for up to 4 days when refrigerated or up to 12 hours at room temperature [see HOW SUPPLIED/STORAGE AND HANDLING ( 16.2 )]. 2.3 General Dosage Instructions Individualize and adjust the dosage of LYUMJEV based on the patient's metabolic needs, glucose monitoring results, and glycemic control goal. If converting from another mealtime insulin to LYUMJEV, the change can be done on a unit-to-unit basis. Dosage adjustments may be needed when switching from another insulin, with changes in physical activity, changes in concomitant medications, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness to minimize the risk of hypoglycemia or hyperglycemia [see Warnings and Precautions ( 5.2 , 5.3 ), Drug Interactions ( 7 ) and Use in Specific Populations ( 8.6 , 8.7 )] . During changes to a patient's insulin regimen, increase the frequency of glucose monitoring [see Warnings and Precautions ( 5.2 )] . Instruct patients who forget a mealtime dose to monitor their glucose level to decide if an insulin dose is needed, and to resume their usual dosing schedule at the next meal.

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 LYUMJEV + basal insulin (N=138) % Nasopharyngitis 8.2 5.1 Upper Respiratory Tract Infection 5.4 1.4 Hypoglycemia Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including LYUMJEV. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for LYUMJEV with the incidence of hypoglycemia for other products may be misleading and also may not be representative of hypoglycemia rates that occur in clinical practice. Incidence rates for severe hypoglycemia in adults with type 1 and type 2 diabetes mellitus and pediatric patients with type 1 diabetes mellitus treated with LYUMJEV in clinical trials are shown in Table 5 [see Clinical Studies ( 14 )] . Table 5. Proportion of Patients with Type 1 Diabetes and Type 2 Diabetes Who Experienced at Least One Episode of Severe Hypoglycemia in Adult and Pediatric Clinical Trials a Severe hypoglycemia: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions PRONTO-T1D (Adult Type 1) PRONTO-T2D (Adult Type 2) PRONTO-Pump-2 (Adult Type 1 CSII) PRONTO-Peds (Pediatric Type 1) Mealtime LYUMJEV + basal insulin (N=451) % Postmeal LYUMJEV + basal insulin (N=329) % Mealtime LYUMJEV + basal insulin (N=336) % LYUMJEV (N=215) % Mealtime LYUMJEV + basal insulin (N=280) % Postmeal LYUMJEV + basal insulin (N=298) % Severe hypoglycemia a 5.5 4.6 0.9 1.4 1.1 0 Allergic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LYUMJEV, and may be life threatening. Generalized hypersensitivity reactions such as skin rashes and hypersensitivity were reported in adult patients treated with LYUMJEV: eczema (0.4%), rash (0.4%), dermatitis (0.3%), hypersensitivity (0.2%), and pruritus (0.2%). Generalized hypersensitivity reactions reported in more than 1 pediatric patient treated with LYUMJEV included: rhinitis (0.7%), dermatitis (0.7%), rash (0.5%), and hypersensitivity (0.5%). Lipodystrophy Administration of insulin, including LYUMJEV, has resulted in lipohypertrophy (enlargement or thickening of tissue) and lipoatrophy (depression in the skin). Lipodystrophy was reported in 0.2% of adult and pediatric patients treated with LYUMJEV [see Dosage and Administration ( 2.2 )] . Injection/Infusion Site Reactions Injection or infusion site reactions can occur with insulin therapy. With LYUMJEV, adult and pediatric patients have experienced rash, redness, inflammation, pain, bruising, or itching at the site of LYUMJEV injection or infusion. LYUMJEV contains treprostinil sodium and sodium citrate dihydrate as inactive ingredients [see Description ( 11 )] which have been associated with infusion and injection site reactions with other non-insulin products. Subcutaneous Injection Site-Related Reactions : In studies PRONTO-T1D and PRONTO-T2D, injection site-related reactions occurred in 2.7% of adult patients treated with LYUMJEV (mild in 2.2% and moderate in 0.5%). with <0.1% of patients discontinuing from treatment due to injection site-related reactions. In Study PRONTO-Peds, injection site-related reactions occurred in 6.2% of pediatric patients treated with LYUMJEV (mild in 5.7% and moderate in 0.5%), with <0.5% of patients discontinuing from treatment due to injection site-related reactions. Continuous Subcutaneous Insulin Infusion (CSII) Site-Related Reactions: In Study PRONTO-Pump-2, infusion site-related reactions were reported in 37.7% of adult patients treated with LYUMJEV (mild in 27.9%, moderate in 7.9%, and severe in 1.9%), with 3.3% of patients discontinuing from treatment due to infusion site-related reactions. See Table 4 . Weight Gain Weight gain can occur with insulin therapy, including LYUMJEV, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Adult patients with type 1 diabetes treated with LYUMJEV gained an average of 0.6 kg and patients with type 2 diabetes treated with LYUMJEV gained an average of 1.5 kg. Peripheral Edema Insulin, including LYUMJEV, may cause sodium retention and edema, particularly if previous poor metabolic control is improved by intensified insulin therapy. Peripheral edema occurred in 0.2% of adult patients treated with LYUMJEV. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during post-approval use of insulin lispro. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Localized cutaneous amyloidosis at the injection site has occurred with insulin use. 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.

12.3 Pharmacokinetics Absorption Absorption of insulin lispro-aabc was evaluated in healthy subjects (see Figure 2 ) and patients with diabetes following subcutaneous injection of LYUMJEV. Insulin lispro-aabc appeared in circulation approximately 1 minute after injection of LYUMJEV. Time to 50% maximum insulin lispro-aabc concentration was 13 minutes. Time to maximum insulin lispro-aabc concentration was achieved at 57 minutes. In healthy subjects, the day-to-day variability [CV%] within subjects of LYUMJEV was 10% for total exposure (AUC, 0-10h) and 16% for maximum insulin lispro-aabc concentration (C max ). Figure 2. Mean Serum Insulin Lispro-aabc After Subcutaneous Injection of LYUMJEV (15 unit dose) in Healthy Subjects The absolute bioavailability of insulin lispro-aabc after subcutaneous administration of LYUMJEV in the abdomen, deltoid, and thigh was approximately 65%. The rate of absorption of insulin lispro-aabc is maintained regardless of injection site. Maximum concentration and time to maximum concentration were comparable for the abdomen and upper arm regions; time to maximum concentration was longer and maximum concentration was lower for the thigh. Total insulin lispro-aabc exposure and maximum insulin lispro-aabc concentration increased proportionally with increasing subcutaneous doses of LYUMJEV within the therapeutic dose range. The results of a study in healthy subjects demonstrated that LYUMJEV 200 units/mL is bioequivalent to LYUMJEV 100 units/mL following administration of a single 15 unit dose for the area under the serum insulin lispro-aabc concentration-time curve from time zero to infinity and maximum insulin lispro-aabc concentration. The rate of insulin lispro-aabc absorption after administration of LYUMJEV 200 units/mL was similar as observed with LYUMJEV 100 units/mL. Figure 2 Distribution Following a 15 unit intravenous bolus injection of LYUMJEV in healthy subjects, the geometric mean (CV%) volume of distribution of insulin lispro-aabc (Vd) was 34 L (30%). Elimination Following a 15 unit intravenous bolus injection of LYUMJEV in healthy subjects, the geometric mean (CV%) clearance of insulin lispro-aabc was 32 L/hour (22%) and the median half-life of insulin lispro-aabc was 44 minutes. Specific Populations Age, biological sex, and race did not affect the pharmacokinetics and pharmacodynamics of LYUMJEV. Patients with Renal and Hepatic Impairment Renal and hepatic impairment is not known to impact the pharmacokinetics of insulin lispro-aabc. Insulin requirements may be reduced in the presence of renal or hepatic impairment.