CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Overview of Clinical Studies. The safety and efficacy of LYUMJEV was evaluated in randomized, active controlled trials of 26 weeks in adult patients with type diabetes (N=780) or type diabetes (N=336). The safety and efficacy of LYUMJEV in adults with type diabetes currently using continuous subcutaneous insulin infusion (N=432) was evaluated in randomized, active controlled 16 week trial.. 14.2 Type Diabetes Adults. PRONTO-T1D (NCT03214367) was 26 week, randomized (4:4:3), active controlled, treat-to-target, multinational trial that evaluated the efficacy of LYUMJEV in 1222 patients with type diabetes. Patients were randomized to either blinded mealtime LYUMJEV (N=451), blinded mealtime HUMALOG (N=442), or open-label postmeal LYUMJEV (N=329), all in combination with either insulin glargine or insulin degludec. Mealtime LYUMJEV or HUMALOG was injected to minutes before the meal and postmeal LYUMJEV was injected 20 minutes after the start of the meal.Patients had mean age of 44 years; mean duration of diabetes of 19 years; 56% were male; race: 77% White, 19% Asian, and 2% Black or African American. Eight percent of the randomized patients were Hispanic. The mean BMI was 26.6 kg/m2.At week 26, treatment with mealtime LYUMJEV provided mean reduction in HbA1c that met the pre-specified non-inferiority margin (0.4%) (see Table 7). In addition, postmeal LYUMJEV met the prespecified non-inferiority margin (0.4%) compared to mealtime HUMALOG. Insulin doses were similar in all treatment groups at baseline and at 26 weeks.Table 7. Results from Study PRONTO-T1D: 26 Week Trial of Mealtime LYUMJEV and Postmeal LYUMJEV compared with Mealtime HUMALOG, all in Combination with Basal Insulin in Adults with Type Diabetesa Analysis population: all randomized subjects regardless of adherence to treatment or availability of post-baseline assessment. Missing data at Week 26 were imputed by return to baseline approach. At week 26, primary efficacy assessment was missing for 3.8%, 4.8%, and 5.2% of subjects, for mealtime LYUMJEV, mealtime HUMALOG, and postmeal LYUMJEV, respectively.b Least-squares (LS) mean from ANCOVA adjusted for baseline value and other stratification factors.c Tested for non-inferiority.Mealtime LYUMJEV basal insulinMealtime HUMALOG basal insulinPostmeal LYUMJEV basal insulinNumber of randomized subjects (N)451442329HbA1c(%) (mean)a,b Baseline7.37.37.4 Adjusted mean change from baseline-0.12-0.040.1 Estimated treatment difference versus HUMALOG [95% CI]-0.08 [-0.16, 0.00]c 0.14 [0.05, 0.22]. 14.3 Type Diabetes Adults. PRONTO-T2D (NCT03214380) was 26-week, randomized (1:1), active controlled, treat-to-target, multinational trial that evaluated the efficacy of LYUMJEV in 673 patients with type diabetes who at study entry were on up to three oral anti-diabetic medications (OAMs), basal insulin and at least one prandial insulin injection or premixed insulin with at least two injections daily. Patients were allowed to continue on metformin and/or SGLT2 inhibitor and were randomized to either mealtime LYUMJEV (N=336) or to mealtime HUMALOG (N=337), both in combination with insulin glargine or insulin degludec in basal-bolus regimen. Mealtime LYUMJEV or mealtime HUMALOG was injected 0-2 minutes before the meal.Patients had mean age of 61 years; mean duration of diabetes of 17 years; 53% were male; race: 69% White, 24% Asian, and 5% Black or African American. Twenty-three percent of the randomized patients were Hispanic. The mean BMI was 32.3 kg/m2.At week 26, treatment with mealtime LYUMJEV provided mean reduction of HbA1c from baseline that met the pre-specified non-inferiority margin (0.4%) compared to mealtime HUMALOG (see Table 8). Insulin doses were similar in both treatment groups at baseline and at 26 weeks.Table 8. Results from Study PRONTO-T2D: 26 Week Trial of Mealtime LYUMJEV Compared with Mealtime HUMALOG, both in Combination with Basal Insulin in Adults with Type Diabetesa Analysis population: all randomized subjects regardless of adherence to treatment or availability of post-baseline assessment. Missing data at Week 26 were imputed by return to baseline approach. At week 26, primary efficacy assessment was missing for 4.8% of subjects for mealtime LYUMJEV and for 4.5% mealtime HUMALOG.b Least-squares (LS) mean from ANCOVA adjusted for baseline value and other stratification factors.c Tested for non-inferiority.Mealtime LYUMJEV basal insulinMealtime HUMALOG basal insulinNumber of randomized subjects (N)336337HbA1c(%)a,b Baseline mean7.37.3 Adjusted mean change from baseline-0.36-0.38 Estimated treatment difference versus HUMALOG [95% CI]c 0.03 [-0.08, 0.13]. 14.4 Type Diabetes Adults Continuous Subcutaneous Insulin Infusion (CSII). PRONTO-Pump-2 (NCT03830281) was 16 week randomized (1:1), active controlled, treat-to-target, multinational trial that evaluated the efficacy of LYUMJEV in 432 patients with type diabetes currently using continuous subcutaneous insulin infusion. Patients were randomized to either blinded LYUMJEV (N=215) or blinded HUMALOG (N= 217). Mealtime LYUMJEV or HUMALOG boluses were initiated to minutes before the meal.Patients had mean age of 46 years; mean duration of diabetes of 26 years; 45% were male; race: 95% White, 3% Black or African American, and 0.5% Asian. Eight percent of the randomized patients were Hispanic. The mean BMI was 27.1 kg/m2.At week 16, treatment with LYUMJEV provided mean reduction in HbA1c that met the pre-specified non-inferiority margin (0.4%) compared to mealtime HUMALOG (see Table 9). Total daily insulin doses were similar for both treatment groups at baseline and at 16 weeks.Table 9. Results from Study PRONTO-Pump-2: 16 Week Trial of LYUMJEV compared with HUMALOG in Adults with Type Diabetesa Analysis population: all randomized subjects regardless of adherence to treatment or availability of post-baseline assessment. Missing data at Week 16 were imputed by return to baseline approach. At week 16, primary efficacy assessment was missing for 7% and 4.6% of subjects, for LYUMJEV and HUMALOG, respectively.b Least-squares (LS) mean from ANCOVA adjusted for baseline value and other stratification factors.c Tested for non-inferiority.LYUMJEVHUMALOGNumber of randomized subjects (N)215217HbA1c(%)a,b Baseline mean7.67.5 Adjusted mean change from baseline-0.06-0.09 Estimated treatment difference versus HUMALOG [95% CI]c 0.03 [-0.05, 0.11].

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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.The data in Table reflect the exposure of 780 patients with type diabetes to LYUMJEV with 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/m2 and the mean HbA1c at baseline was 7.3%.The data in Table reflect the exposure of 336 patients with type diabetes to LYUMJEV with 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/m2 and the mean HbA1c at baseline was 7.3%.The data in Table reflect the exposure of 215 patients with type diabetes to LYUMJEV via CSII administration with 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/m2 and the mean HbA1c at baseline was 7.6%.Common adverse reactions, excluding hypoglycemia, were defined as events occurring in >=5% and occurring at the same rate or greater for LYUMJEV-treated patients than HUMALOG(R)-treated patients.Table 1. Adverse Reactions Occurring in >=5% of LYUMJEV-Treated Patients with Type DiabetesMealtime LYUMJEV basal insulin(N=451)%Postmeal LYUMJEV basal insulin(N=329)%Nasopharyngitis14.214.6Table 2. Adverse Reactions Occurring in >=5% of LYUMJEV-Treated Patients with Type DiabetesMealtime LYUMJEV basal insulin(N=336)%Nasopharyngitis12.5Upper Respiratory Tract Infection7.4Table 3. Adverse Reactions Occurring in >=5% of LYUMJEV-Treated Patients with Type Diabetes Using Continuous Subcutaneous Insulin InfusionCSII LYUMJEV administration(N=215)%Infusion site reaction19.1Infusion site pain15.8Nasopharyngitis6.0. HypoglycemiaHypoglycemia 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 and type diabetes mellitus treated with LYUMJEV in clinical trials are shown in Table [see Clinical Studies (14)].Table 4. Proportion of Patients with Type Diabetes and Type Diabetes Experiencing at Least One Episode of Severe Hypoglycemia in Adult Clinical Trialsa Severe hypoglycemia: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actionsPRONTO-T1D (Type 1)PRONTO-T2D (Type 2)PRONTO-Pump-2 (Type CSII)Mealtime LYUMJEV +basal insulin(N=451)%Postmeal LYUMJEV +basal insulin(N=329)%Mealtime LYUMJEV +basal insulin(N=336)%LYUMJEV(N=215)%Severe hypoglycemiaa 5.54.60.91.4. Allergic ReactionsSevere, 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 patients treated with LYUMJEV: eczema (0.4%), rash (0.4%), dermatitis (0.3%), hypersensitivity (0.2%), and pruritus (0.2%).. LipodystrophyAdministration 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 patients treated with LYUMJEV [see Dosage and Administration (2.2)].. Injection/Infusion Site ReactionsInjection or infusion site reactions can occur with insulin therapy. With LYUMJEV, 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 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.. Continuous Subcutaneous Insulin Infusion (CSII) Site-Related Reactions:In Study PRONTO-Pump-2, infusion site-related reactions were reported in 37.7% of 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 3.. Weight GainWeight gain can occur with insulin therapy, including LYUMJEV, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Patients with type diabetes treated with LYUMJEV gained an average of 0.6 kg and patients with type diabetes treated with LYUMJEV gained an average of 1.5 kg.. Peripheral EdemaInsulin, 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 patients treated with LYUMJEV.

ADVERSE REACTIONS SECTION.

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)].. 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 Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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.The data in Table reflect the exposure of 780 patients with type diabetes to LYUMJEV with 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/m2 and the mean HbA1c at baseline was 7.3%.The data in Table reflect the exposure of 336 patients with type diabetes to LYUMJEV with 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/m2 and the mean HbA1c at baseline was 7.3%.The data in Table reflect the exposure of 215 patients with type diabetes to LYUMJEV via CSII administration with 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/m2 and the mean HbA1c at baseline was 7.6%.Common adverse reactions, excluding hypoglycemia, were defined as events occurring in >=5% and occurring at the same rate or greater for LYUMJEV-treated patients than HUMALOG(R)-treated patients.Table 1. Adverse Reactions Occurring in >=5% of LYUMJEV-Treated Patients with Type DiabetesMealtime LYUMJEV basal insulin(N=451)%Postmeal LYUMJEV basal insulin(N=329)%Nasopharyngitis14.214.6Table 2. Adverse Reactions Occurring in >=5% of LYUMJEV-Treated Patients with Type DiabetesMealtime LYUMJEV basal insulin(N=336)%Nasopharyngitis12.5Upper Respiratory Tract Infection7.4Table 3. Adverse Reactions Occurring in >=5% of LYUMJEV-Treated Patients with Type Diabetes Using Continuous Subcutaneous Insulin InfusionCSII LYUMJEV administration(N=215)%Infusion site reaction19.1Infusion site pain15.8Nasopharyngitis6.0. HypoglycemiaHypoglycemia 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 and type diabetes mellitus treated with LYUMJEV in clinical trials are shown in Table [see Clinical Studies (14)].Table 4. Proportion of Patients with Type Diabetes and Type Diabetes Experiencing at Least One Episode of Severe Hypoglycemia in Adult Clinical Trialsa Severe hypoglycemia: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actionsPRONTO-T1D (Type 1)PRONTO-T2D (Type 2)PRONTO-Pump-2 (Type CSII)Mealtime LYUMJEV +basal insulin(N=451)%Postmeal LYUMJEV +basal insulin(N=329)%Mealtime LYUMJEV +basal insulin(N=336)%LYUMJEV(N=215)%Severe hypoglycemiaa 5.54.60.91.4. Allergic ReactionsSevere, 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 patients treated with LYUMJEV: eczema (0.4%), rash (0.4%), dermatitis (0.3%), hypersensitivity (0.2%), and pruritus (0.2%).. LipodystrophyAdministration 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 patients treated with LYUMJEV [see Dosage and Administration (2.2)].. Injection/Infusion Site ReactionsInjection or infusion site reactions can occur with insulin therapy. With LYUMJEV, 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 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.. Continuous Subcutaneous Insulin Infusion (CSII) Site-Related Reactions:In Study PRONTO-Pump-2, infusion site-related reactions were reported in 37.7% of 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 3.. Weight GainWeight gain can occur with insulin therapy, including LYUMJEV, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Patients with type diabetes treated with LYUMJEV gained an average of 0.6 kg and patients with type diabetes treated with LYUMJEV gained an average of 1.5 kg.. Peripheral EdemaInsulin, 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 patients treated with LYUMJEV.. 6.2 Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors such as assay methodology, sample handling, timing of sample collection, concomitant medication, and underlying disease. For these reasons, comparison of the incidence of antibodies to LYUMJEV in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.In 26-week study in type diabetes patients, 49% were anti-drug (insulin lispro-aabc) antibody (ADA)-positive at baseline, 91% of which were cross-reactive with native insulin. total of 33% of LYUMJEV-treated patients had treatment-emergent ADA post-baseline (i.e., either new ADA or 57% increase in assay signal over baseline), 75% of which were cross-reactive with native insulin.In 26-week study in type diabetes patients, 35% were ADA-positive at baseline, 81% of which were cross-reactive with native insulin. total of 31% of LYUMJEV-treated patients had treatment-emergent ADA post-baseline (i.e., either new ADA or 57% increase in assay signal over baseline), 68% of which were cross-reactive with native insulin.Presence of antibody did not correlate with reduced efficacy, as measured by HbA1c, or specific adverse reactions.. 6.3 Postmarketing Experience. The following additional adverse reactions have been identified during post-approval use of insulin lispro. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 sudden change to an unaffected injection site.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 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.. 12.2 Pharmacodynamics. The time course of insulin action (i.e., glucose lowering) may vary considerably in different individuals or within the same individual. The average pharmacodynamic profile [i.e., glucose lowering effect measured as glucose infusion rate (GIR) in euglycemic clamp study] for subcutaneous administration of 7, 15, and 30 units of LYUMJEV in 42 healthy subjects is shown in Figure and key characteristics of the timing of the effect are described in Table below.Figure 1. Mean Insulin Effect Over Time After Subcutaneous Administration of 7, 15, and 30 units of LYUMJEV in Healthy Subjects.Table 6. Timing of Insulin Effect (i.e., Mean Pharmacodynamic Effect) After Subcutaneous Administration of 7, 15, and 30 Units of LYUMJEV in Healthy Subjects (N=42) and Corresponding to the Data Shown in Figure 1Parameter for Insulin EffectLYUMJEV7 unitsLYUMJEV15 unitsLYUMJEV30 unitsTime to first measurable effect~17 minutes~17 minutes~15 minutesTime to peak effect~120 minutes~138 minutes~174 minutesTime for effect to return to baseline~4.6 hours~6.2 hours~7.3 hoursOn average, the pharmacodynamic effects of LYUMJEV, measured as area under the glucose infusion rate-time curve (AUCGIR), was 1080 mg/kg, 1860 mg/kg, and 3030 mg/kg following administration of 7, 15, and 30 units of LYUMJEV in healthy subjects.Similar pharmacodynamic profiles were observed in separate studies conducted in 40 patients with type diabetes and 38 patients with type diabetes given LYUMJEV subcutaneously as single 15 unit dose.The onset and total glucose lowering were similar when LYUMJEV was administered in the abdomen, deltoid, or thigh. The day-to-day variability [percent coefficient of variation (CV%)] within subjects in the glucose-lowering-effect of LYUMJEV was 24% for the early glucose lowering (AUCGIR, 0-1h), 27% for the total glucose lowering (AUCGIR, 0-10h), and 19% for maximum glucose lowering effect (GIRmax).. Figure 1. Postprandial Glucose LoweringWhen given at the start of meal or 20 minutes after the start of the meal, LYUMJEV reduced postprandial glucose during standardized test meal over the complete 5-hour period [change from premeal AUC(0-5h)] in patients with type or type diabetes.The maximum and total glucose lowering were comparable for single 15 unit dose of LYUMJEV 200 units/mL or LYUMJEV 100 units/mL when administered subcutaneously to healthy subjects. The insulin time action profile with LYUMJEV 200 units/mL was the same as observed with LYUMJEV 100 units/mL.. 12.3 Pharmacokinetics. AbsorptionAbsorption 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 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 (Cmax).Figure 2. Mean Serum Insulin Lispro-aabc After Subcutaneous Injection of LYUMJEV (15 unit dose) in Healthy SubjectsThe 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 study in healthy subjects demonstrated that LYUMJEV 200 units/mL is bioequivalent to LYUMJEV 100 units/mL following administration of 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.. Insulin lispro-aabc appeared in circulation approximately 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.. Figure 2. DistributionFollowing 15 unit intravenous bolus injection of LYUMJEV in healthy subjects, the geometric mean (CV%) volume of distribution of insulin lispro-aabc (Vd) was 34 (30%).. EliminationFollowing 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 PopulationsAge (18 to 77 years), gender, and race did not affect the pharmacokinetics and pharmacodynamics of LYUMJEV.. Patients with Renal and Hepatic ImpairmentRenal 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.

DOSAGE & ADMINISTRATION SECTION.

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 meal or within 20 minutes after starting 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 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 concentration of unit/mL. Individualize and adjust the dosage of LYUMJEV based on the patients 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). 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 meal or within 20 minutes after starting 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. Administer LYUMJEV U-100 or U-200 at the start of meal or within 20 minutes after starting 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 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. 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 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 concentration of unit/mL. Administer LYUMJEV U-100 intravenously only under medical supervision. DO NOT administer LYUMJEV U-200 by intravenous infusion.. Dilute LYUMJEV U-100 to concentration of unit/mL.. Individualize and adjust the dosage of LYUMJEV based on the patients 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.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 syringe for administration [see Warnings and Precautions (5.4)].Use LYUMJEV prefilled pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose.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.. 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.. 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 syringe for administration [see Warnings and Precautions (5.4)].. Use LYUMJEV prefilled pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose.. 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 InjectionAdminister LYUMJEV at the start of meal or within 20 minutes after starting 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, 6.3)]. 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 unit increments and deliver maximum dose of 60 units per injection.The LYUMJEV U-100 Junior KwikPen dials in 0.5 unit increments and delivers maximum dose of 30 units per injection.. Administer LYUMJEV at the start of meal or within 20 minutes after starting 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, 6.3)]. 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 unit increments and deliver maximum dose of 60 units per injection.. The LYUMJEV U-100 Junior KwikPen dials in 0.5 unit increments and delivers maximum dose of 30 units per injection.. Continuous Subcutaneous Infusion (Insulin Pump) for LYUMJEV U-100 OnlyDo 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 systems instructions for use.Administer LYUMJEV U-100 by continuous subcutaneous infusion in 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 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 days or according to the pump user manual, whichever is shorter.Change the infusion sets and the infusion set insertion site according to the manufacturers user manual.Do not dilute or mix LYUMJEV U-100 when administering by continuous subcutaneous infusion.Do not expose LYUMJEV in the pump reservoir to temperatures greater than 98.6F (37C).. 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 systems instructions for use.. Administer LYUMJEV U-100 by continuous subcutaneous infusion in 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 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 days or according to the pump user manual, whichever is shorter.. Change the infusion sets and the infusion set insertion site according to the manufacturers user manual.. Do not dilute or mix LYUMJEV U-100 when administering by continuous subcutaneous infusion.. Do not expose LYUMJEV in the pump reservoir to temperatures greater than 98.6F (37C).. Intravenous Administration for LYUMJEV U-100 OnlyDo 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 concentration of unit/mL using 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP infusion solutions. Dilutions to concentrations below unit/mL are not recommended.Diluted LYUMJEV may be stored for up to days when refrigerated or up to 12 hours at room temperature [see HOW SUPPLIED/STORAGE AND HANDLING (16.2)]. 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 concentration of unit/mL using 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP infusion solutions. Dilutions to concentrations below unit/mL are not recommended.. Diluted LYUMJEV may be stored for up to 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 patients metabolic needs, glucose monitoring results, and glycemic control goal.If converting from another mealtime insulin to LYUMJEV, the change can be done on 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 patients insulin regimen, increase the frequency of glucose monitoring [see Warnings and Precautions (5.2)].Instruct patients who forget 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.. Individualize and adjust the dosage of LYUMJEV based on the patients metabolic needs, glucose monitoring results, and glycemic control goal.. If converting from another mealtime insulin to LYUMJEV, the change can be done on 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 patients insulin regimen, increase the frequency of glucose monitoring [see Warnings and Precautions (5.2)].. Instruct patients who forget 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. LYUMJEV (insulin lispro-aabc) injection is clear and colorless solution available as shown in Table 10.Table 10. How Supplieda mL cartridge is for use in Eli Lilly and Companys HumaPen(R) Luxura(R) 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 component that allows for data connectivity when used with compatible transmitter.LYUMJEVNDC NumberConcentrationTotal Units in PresentationDose IncrementPackage SizeU-100 multiple-dose 10 mL vial0002-7728-01100 units/mL1,000 unitsn/a1 vialU-100 single-patient-use mL cartridgea 0002-7726-05100 units/mL300 unitsn/a5 cartridgesU-100 single-patient-use mL KwikPen0002-8207-05100 units/mL300 units1 unit5 pensU-100 single-patient-use mL Junior KwikPen0002-8351-05100 units/mL300 units0.5 unit5 pensU-100 single-patient-use mL Tempo Penb 0002-8235-05100 units/mL300 units1 unit5 pensU-200 single-patient-use mL KwikPen0002-8228-27200 units/mL600 units1 unit2 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 36F to 46F (2C to 8C) 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 86F (30C) after 28 days.The storage conditions for vials, pens, and cartridges are summarized in Table 11.Table 11. Storage Conditions for Vials, Pens, and Cartridgesa 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 total of 28 days including both not in-use (unopened) and in-use (opened) storage time.LYUMJEV PresentationNot In-use(Unopened)In-use(Opened)Room Temperature (below 86F [30C])Refrigerated(36F to 46F[2C to 8C])Room Temperature (below 86F [30C])Refrigerated(36F to 46F [2C to 8C])10 mL viala,b 28 daysUntil expiration date28 days28 days3 mL cartridgeb 28 daysUntil expiration date28 daysDo not refrigerate3 mL LYUMJEV KwikPen (U-100 and U-200)b 28 daysUntil expiration date28 daysDo not refrigerate3 mL LYUMJEV Junior KwikPenb 28 daysUntil expiration date28 daysDo not refrigerate3 mL LYUMJEV Tempo Penb 28 daysUntil expiration date28 daysDo not refrigerate. Dispense in the original sealed carton with the enclosed Instructions for Use.. Refrigerate unopened LYUMJEV vials, pens, and cartridges between 36F to 46F (2C to 8C) 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 86F (30C) after 28 days.. Storage of LYUMJEV in Insulin PumpChange the LYUMJEV U-100 in the pump reservoir at least every days, or according to the pump user manual, whichever is shorter, or after exposure to temperatures that exceed 98.6F (37C).. Storage of LYUMJEV in Intravenous Infusion FluidsDiluted LYUMJEV may be stored for up to days when refrigerated at 36F to 46F (2C to 8C) until time of use. The same solution may be stored up to 12 hours at room temperature at 68F to 77F (20C to 25C) [see Dosage and Administration (2.2)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-Approved Patient Labeling (Patient Information and Instructions for Use).. Never Share LYUMJEV Prefilled Pen, Cartridge, or Syringe Between PatientsAdvise patients that they must never share LYUMJEV prefilled pen or cartridge with another person, even if the needle is changed. Advise patients using LYUMJEV vials not to share needles or syringes with another person. Sharing poses risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)].. Hyperglycemia or HypoglycemiaInform 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 LYUMJEV therapy. Instruct patients on handling of special situations such as intercurrent conditions (illness, stress, or emotional disturbances), an inadequate or skipped insulin dose, inadvertent administration of an increased insulin dose, inadequate food intake, and skipped meals. Instruct patients on the management of hypoglycemia.Inform patients that their ability to concentrate and react may be impaired as result of hypoglycemia. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery [see Warnings and Precautions (5.3)].Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision [see Warnings and Precautions (5.2)].. Hypoglycemia due to Medication ErrorsInstruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products.Inform patients that LYUMJEV U-200 contains times as much insulin per mL as LYUMJEV U-100. The LYUMJEV U-200 KwikPen dose window shows the number of units of LYUMJEV U-200 to be injected so no dose conversion is required [see Dosage and Administration (2.1)].Instruct patients to not transfer LYUMJEV U-200 from the LYUMJEV U-200 KwikPen to syringe [see Warnings and Precautions (5.4)].. Hypersensitivity ReactionsAdvise patients that hypersensitivity reactions have occurred with LYUMJEV. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.6)].. Instructions for Patients Using Continuous Subcutaneous Infusion (Insulin Pump)Do not use LYUMJEV U-200 in an insulin pump.Train patients in intensive insulin therapy with multiple injections and in the function of their pump and pump accessories.Instruct patients to follow healthcare provider recommendations when setting pump basal rates and bolus settings.Refer to the continuous subcutaneous infusion pump user manual to see if LYUMJEV can be used with the pump. See recommended reservoir and infusion sets in the insulin pump user manual.Instruct patients to replace insulin in the reservoir at least every days, or according to the pump user manual whichever is shorter. By following this schedule, patients avoid insulin degradation, infusion set occlusion, and loss of the insulin preservative.Instruct patients to discard insulin exposed to temperatures higher than 98.6F (37C).Instruct patients to inform healthcare provider and select new site for infusion if infusion site becomes erythematous, pruritic, or thickened.Instruct patients on the risk of rapid hyperglycemia and ketosis due to pump malfunction, infusion set occlusion, leakage, disconnection or kinking, and degraded insulin. Instruct patients on the risk of hypoglycemia from pump malfunction. If these problems cannot be promptly corrected, instruct patients to resume therapy with subcutaneous insulin injection and contact their healthcare provider [see Warnings and Precautions (5) and How Supplied/Storage and Handling (16.2)].Eli Lilly and Company, Indianapolis, IN 46285, USAUS License No. 1891Copyright (C) 2020, 2021, Eli Lilly and Company. All rights reserved.LUM-0002-USPI-20210813. Do not use LYUMJEV U-200 in an insulin pump.. Train patients in intensive insulin therapy with multiple injections and in the function of their pump and pump accessories.. Instruct patients to follow healthcare provider recommendations when setting pump basal rates and bolus settings.. Refer to the continuous subcutaneous infusion pump user manual to see if LYUMJEV can be used with the pump. See recommended reservoir and infusion sets in the insulin pump user manual.. Instruct patients to replace insulin in the reservoir at least every days, or according to the pump user manual whichever is shorter. By following this schedule, patients avoid insulin degradation, infusion set occlusion, and loss of the insulin preservative.. Instruct patients to discard insulin exposed to temperatures higher than 98.6F (37C).. Instruct patients to inform healthcare provider and select new site for infusion if infusion site becomes erythematous, pruritic, or thickened.. Instruct patients on the risk of rapid hyperglycemia and ketosis due to pump malfunction, infusion set occlusion, leakage, disconnection or kinking, and degraded insulin. Instruct patients on the risk of hypoglycemia from pump malfunction. If these problems cannot be promptly corrected, instruct patients to resume therapy with subcutaneous insulin injection and contact their healthcare provider [see Warnings and Precautions (5) and How Supplied/Storage and Handling (16.2)].

INSTRUCTIONS FOR USE SECTION.

Instructions for UseLYUMJEV(TM) (LOOM-jehv)(insulin lispro-aabc) injectionfor subcutaneous use(100 units/mL, 10 mL multiple-dose vial)Read the Instructions for Use before you start taking LYUMJEV and each time you get new vial. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.Do not share your syringes or needles with other people. You may give other people serious infection or get serious infection from them.Supplies needed to give your injectiona multiple-dose LYUMJEV viala U-100 insulin syringe and needle (Becton, Dickinson and Company syringes and needles recommended)2 alcohol swabsgauze (optional)1 sharps container for throwing away used syringes and needles. See Disposing of used syringes and needles at the end of these instructions.VialSyringePreparing your LYUMJEV doseWash your hands with soap and water.Check the LYUMJEV label to make sure you are taking the right type of insulin. This is especially important if you use more than type of insulin.LYUMJEV should look clear and colorless. Do not use LYUMJEV if it is thick, cloudy, or colored, or if you see lumps or particles in it.Do not use LYUMJEV past the expiration date printed on the label or 28 days after you first use it.Always use new syringe and needle for each injection to prevent infections and blocked needles.Do not mix LYUMJEV U-100 with other insulins.Step 1:If you are using new vial, pull off the plastic protective cap, but do not remove the rubber stopper.Step 2:Wipe the rubber stopper with an alcohol swab.Step 3:Remove the needle shield from the syringe by pulling the needle shield straight off. Hold the syringe with the needle pointing up. Pull down on the plunger until the plunger tip reaches the line for the number of units for your prescribed dose.(Example Dose: 20 units shown)Step 4:Push the needle through the rubber stopper of the vial.Step 5:Push the plunger all the way in. This puts air into the vial.Step 6:Turn the vial and syringe upside down and slowly pull the plunger down until the plunger tip is few units past the line for your prescribed dose.(Example Dose: 20 units, plunger is shown at 24 units)If there are air bubbles, tap the syringe gently few times to let any air bubbles rise to the top.Step 7:Slowly push the plunger up until the plunger tip reaches the line for your prescribed dose.Check the syringe to make sure that you have the right dose.(Example Dose: 20 units shown)Step 8:Pull the syringe out of the rubber stopper of the vial.Giving your LYUMJEV injection with syringeInject your insulin exactly as your healthcare provider has shown you. Your healthcare provider should tell you if you should pinch the skin before injecting.LYUMJEV starts acting fast, so give your injection at the start of meal or within 20 minutes after you start meal.Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.Do not use the exact same spot for each injection.Do not inject where the skin has pits, is thickened, or has lumps.Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.Step 9:Choose your injection site.LYUMJEV is injected under the skin (subcutaneously) of your stomach area (abdomen), buttocks, upper legs, or upper arms.Wipe your skin with an alcohol swab, and let your skin dry before you inject your dose.Step 10:Insert the needle into your skin.Step 11:Push down on the plunger to inject your dose.The needle should stay in your skin for at least seconds after pushing down on the plunger to make sure you have injected all of your insulin dose.Step 12:Pull the needle out of your skin.If you see blood after you take the needle out of your skin, press the injection site with piece of gauze or an alcohol swab. Do not rub the area.Do not recap the needle. Recapping the needle can lead to needle stick injury.Giving your LYUMJEV using an insulin pumpIf you have been prescribed an insulin pump, check the pump manufacturers user manual to see if LYUMJEV can be used with the pump.LYUMJEV should be given into an area of your body recommended in the instructions that come with your insulin pump.Change LYUMJEV in the pump reservoir at least every days or according to the pump user manual, whichever is shorter, even if you have not used all of the insulin.Change (rotate) your insertion sites within the area you choose for each insertion to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the insertion sites. Do not insert into the exact same spot for each insertion. Do not insert where the skin has pits, is thickened, or has lumps. Do not insert where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.Call your healthcare provider and choose new infusion site if the skin at the infusion site becomes red, itchy, or thickened.Your healthcare provider should provide recommendations for appropriate pump basal and meal-time infusion rates. Call your healthcare provider if you have any questions about using the insulin pump.Do not dilute or mix LYUMJEV with any other type of insulin in your insulin pump.You should be trained on how to give insulin by injection and have an alternative insulin delivery system in case of pump failure.Disposing of used syringes and needlesPut your used syringes and needles in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose syringes and needles in your household trash. If you do not have FDA-cleared sharps disposal container, you may use household container that is:-made of heavy-duty plastic,-can be closed with 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 syringes and needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal.Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.How should store LYUMJEVAll not in-use (unopened) vials:Store all not in-use (unopened) vials in the refrigerator at 36F to 46F (2C to 8C).Do not freeze. Do not use if LYUMJEV has been frozen.Keep away from direct heat and light.Not in-use (unopened) vials can be used until the expiration date on the carton and label, if they have been stored in the refrigerator.Not in-use (unopened) vials should be thrown away after 28 days, if they are stored at room temperature.After vials have been in-use (opened):Store in-use (opened) vials in the refrigerator or at room temperature below 86F (30C) for up to 28 days.Keep vials away from direct heat and light.Throw away all in-use (opened) vials after 28 days of use, even if there is insulin left in the vial.LYUMJEV in an insulin pump:Throw away LYUMJEV in the pump reservoir if it has been exposed to temperatures higher than 98.6F (37C).Keep LYUMJEV vials, syringes, needles and all medicines out of the sight and reach of children.If you have any questions or problems with your LYUMJEV, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider for help. For more information on LYUMJEV and insulin, go to www.lyumjev.com.Scan this code to launchwww.lyumjev.comManufactured by: Eli Lilly and CompanyIndianapolis, IN 46285, USAUS License Number 1891LYUMJEV(TM) is trademark of Eli Lilly and Company.Copyright (C) 2020, 2021, Eli Lilly and Company. All rights reserved.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Revised: August 2021LUMVL-0002-IFU-20210813. multiple-dose LYUMJEV vial. U-100 insulin syringe and needle (Becton, Dickinson and Company syringes and needles recommended). alcohol swabs. gauze (optional). sharps container for throwing away used syringes and needles. See Disposing of used syringes and needles at the end of these instructions.. Wash your hands with soap and water.. Check the LYUMJEV label to make sure you are taking the right type of insulin. This is especially important if you use more than type of insulin.. LYUMJEV should look clear and colorless. Do not use LYUMJEV if it is thick, cloudy, or colored, or if you see lumps or particles in it.. Do not use LYUMJEV past the expiration date printed on the label or 28 days after you first use it.. Always use new syringe and needle for each injection to prevent infections and blocked needles.. Do not mix LYUMJEV U-100 with other insulins.. Inject your insulin exactly as your healthcare provider has shown you. Your healthcare provider should tell you if you should pinch the skin before injecting.. LYUMJEV starts acting fast, so give your injection at the start of meal or within 20 minutes after you start meal.. Change (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.. Do not use the exact same spot for each injection.. 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.. If you see blood after you take the needle out of your skin, press the injection site with piece of gauze or an alcohol swab. Do not rub the area.. Do not recap the needle. Recapping the needle can lead to needle stick injury.. If you have been prescribed an insulin pump, check the pump manufacturers user manual to see if LYUMJEV can be used with the pump.. LYUMJEV should be given into an area of your body recommended in the instructions that come with your insulin pump.. Change LYUMJEV in the pump reservoir at least every days or according to the pump user manual, whichever is shorter, even if you have not used all of the insulin.. Change (rotate) your insertion sites within the area you choose for each insertion to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the insertion sites. Do not insert into the exact same spot for each insertion. Do not insert where the skin has pits, is thickened, or has lumps. Do not insert where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.. Call your healthcare provider and choose new infusion site if the skin at the infusion site becomes red, itchy, or thickened.. Your healthcare provider should provide recommendations for appropriate pump basal and meal-time infusion rates. Call your healthcare provider if you have any questions about using the insulin pump.. Do not dilute or mix LYUMJEV with any other type of insulin in your insulin pump.. You should be trained on how to give insulin by injection and have an alternative insulin delivery system in case of pump failure.. Put your used syringes and needles in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose syringes and needles in your household trash. If you do not have FDA-cleared sharps disposal container, you may use household container that is:-made of heavy-duty plastic,-can be closed with 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. -made of heavy-duty plastic,. -can be closed with 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 syringes and needles. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs 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.. Store all not in-use (unopened) vials in the refrigerator at 36F to 46F (2C to 8C).. Do not freeze. Do not use if LYUMJEV has been frozen.. Keep away from direct heat and light.. Not in-use (unopened) vials can be used until the expiration date on the carton and label, if they have been stored in the refrigerator.. Not in-use (unopened) vials should be thrown away after 28 days, if they are stored at room temperature.. Store in-use (opened) vials in the refrigerator or at room temperature below 86F (30C) for up to 28 days.. Keep vials away from direct heat and light.. Throw away all in-use (opened) vials after 28 days of use, even if there is insulin left in the vial.. Throw away LYUMJEV in the pump reservoir if it has been exposed to temperatures higher than 98.6F (37C).. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. QR Code.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. AbsorptionAbsorption 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 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 (Cmax).Figure 2. Mean Serum Insulin Lispro-aabc After Subcutaneous Injection of LYUMJEV (15 unit dose) in Healthy SubjectsThe 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 study in healthy subjects demonstrated that LYUMJEV 200 units/mL is bioequivalent to LYUMJEV 100 units/mL following administration of 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.. Insulin lispro-aabc appeared in circulation approximately 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.. Figure 2. DistributionFollowing 15 unit intravenous bolus injection of LYUMJEV in healthy subjects, the geometric mean (CV%) volume of distribution of insulin lispro-aabc (Vd) was 34 (30%).. EliminationFollowing 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 PopulationsAge (18 to 77 years), gender, and race did not affect the pharmacokinetics and pharmacodynamics of LYUMJEV.. Patients with Renal and Hepatic ImpairmentRenal 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryPublished 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 dose approximately times the human subcutaneous dose of 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 unit/kg/day (see Data).The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with HbA1c>7 and has been reported to be as high as 20% to 25% in women with 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% to 4% and 15% to 20%, respectively.. Clinical Considerations. Disease-associated Maternal and/or Embryo-Fetal RiskPoorly 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 DataPublished 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 DataAnimal reproduction studies have not been performed with LYUMJEV. However, subcutaneous reproduction and teratology studies have been conducted with insulin lispro. In 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 times the human subcutaneous dose of unit insulin lispro/kg/day, based on units/body surface area, respectively) from 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 unit insulin lispro/kg/day, based on units/body surface area, respectively) were injected subcutaneously on Gestation Days through 19. There were no adverse effects on fetal viability, weight, and morphology at any dose.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug AdministrationRevised: August 2021Patient InformationLYUMJEV(TM) (LOOM-jehv)(insulin lispro-aabc)injection, for subcutaneous or intravenous useDo not share your LYUMJEV with other people, even if the needle has been changed. You may give other people serious infection, or get serious infection from them.What is LYUMJEVLYUMJEV is man-made fast-acting insulin used to control high blood sugar in adults with diabetes mellitus.It is not known if LYUMJEV is safe and effective in children.Do not take LYUMJEV if you:are having an episode of low blood sugar (hypoglycemia).have an allergy to insulin lispro-aabc or any of the ingredients in LYUMJEV. See the end of this Patient Information leaflet for complete list of ingredients in LYUMJEV.Before taking LYUMJEV, tell your healthcare provider about all of your medical conditions, including if you:have kidney or liver problems.take any other medicines, especially ones called thiazolidinediones (TZDs).have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with LYUMJEV.are pregnant or plan to become pregnant. Talk with your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.are breastfeeding or plan to breastfeed. It is not known if LYUMJEV passes into your breast milk. You and your healthcare provider should decide if you will take LYUMJEV while you breastfeed.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.Before you start taking LYUMJEV, talk to your healthcare provider about low blood sugar and how to manage it.How should take LYUMJEVRead the Instructions for Use that come with your LYUMJEV.Take LYUMJEV exactly as your healthcare provider tells you to. Your healthcare provider will tell you how much LYUMJEV to take and when to take it.LYUMJEV starts acting fast. Inject LYUMJEV at the beginning of meal or within 20 minutes after you start eating meal.Know the type and strength of insulin you take. Do not change the type or amount of insulin you take unless your healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin may need to change if you take different types of insulin.Check your insulin label each time you give your injection to make sure you are using the correct insulin.Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar level.LYUMJEV comes in U-100 (100 units/mL) and U-200 (200 units/mL) insulin strengths. LYUMJEV U-200 contains times as much insulin (200 units/mL) in mL as LYUMJEV U-100 (100 units/mL).LYUMJEV U-100 and LYUMJEV U-200 can be injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs, or upper arms.LYUMJEV U-100 can be given by continuous infusion under the skin (subcutaneously) through an insulin pump into an area of your body recommended in the instructions that come with your insulin pump. LYUMJEV U-200 cannot be given through an insulin pump.LYUMJEV U-100 can also be given in your vein (intravenously) by your healthcare provider. LYUMJEV U-200 cannot be given in your vein.Change (rotate) your injection sites within the area you choose with each dose to reduce your risk of getting pits in skin or thickened skin (lipodystrophy) and skin with lumps (localized cutaneous amyloidosis) at the injection sites.Do not use the exact same spot for each injection.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. If you miss dose of LYUMJEV, monitor your blood sugar levels to decide if an insulin dose is needed. Continue with your regular dosing schedule at the next meal.LYUMJEV comes in vial, single-patient-use prefilled pen, or in cartridge. Do not use syringe to remove LYUMJEV from your single-patient-use prefilled pen or cartridge. Keep LYUMJEV and all medicines out of the reach of children.Your dose of LYUMJEV may need to change because of:a change in level of physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take.What should avoid while taking LYUMJEVWhile taking LYUMJEV do not:drive or operate heavy machinery, until you know how LYUMJEV affects you.drink alcohol or take other medicines that contain alcohol.What are the possible side effects of LYUMJEVLYUMJEV may cause serious side effects that can lead to death, including:low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include: dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, hunger, anxiety, irritability, or mood changes.low potassium in your blood (hypokalemia).serious allergic reactions (whole body allergic reaction). Get emergency medical help right away, if you have any of these symptoms of severe allergic reaction: rash over your whole body, trouble breathing, fast heartbeat, swelling of your face, tongue, or throat, sweating, or feeling faint.heart failure. Taking certain diabetes pills called thiazolidinediones (TZDs) with LYUMJEV may cause heart failure in some people. This can happen even if you have never had heart failure or heart failure problems before. If you already have heart failure it may get worse while you take TZDs with LYUMJEV. Your healthcare provider should monitor you closely while you are taking TZDs with LYUMJEV. Tell your healthcare provider if you have any new or worse symptoms of heart failure including: shortness of breath, swelling of your ankles or feet, or sudden weight gain. Treatment with TZDs and LYUMJEV may need to be adjusted or stopped by your healthcare provider if you have new or worse heart failure.sudden onset of high blood sugar (hyperglycemia) and high amounts of ketones in the blood or urine (ketoacidosis) due to insulin pump problems. If LYUMEV is given through an insulin pump and the pump is not working the right way or in case of handling errors, you may not get the right amount of insulin, which can cause sudden onset of high blood sugar and high amounts of ketones in the blood or urine. Get emergency medical help if you have:trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue or throat, sweating, extreme drowsiness, dizziness, or confusion.The most common side effects of LYUMJEV include:low blood sugar (hypoglycemia)allergic reactionsrashitching (pruritus)thickening or pits at the injection or infusion site (lipodystrophy)weight gainreactions or pain at the site of injection or at the site of infusion with insulin pump use (treprostinil sodium and sodium citrate dihydrate are inactive ingredients in LYUMJEV that have been known to cause reactions and pain at the infusion and injection sites in other non-insulin medicines)These are not all the possible side effects of LYUMJEV. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of LYUMJEV.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not take LYUMJEV for condition for which it was not prescribed. Do not give LYUMJEV to other people, even if they have the same symptoms that you have. It may harm them.You can ask your pharmacist or healthcare provider for information about LYUMJEV that is written for health professionals.What are the ingredients in LYUMJEVActive ingredient: insulin lispro-aabc Inactive ingredients: glycerol, magnesium chloride hexahydrate, metacresol, sodium citrate dihydrate, treprostinil sodium, zinc oxide (zinc ion), and Water for Injection, USPLYUMJEV(TM) is trademark of Eli Lilly and Company. Eli Lilly and Company Indianapolis, IN 46285, USA US License Number 1891 Copyright (C) 2020, 2021, Eli Lilly and Company. All rights reserved.For more information, go to www.lilly.com or call 1-800-545-5979.LUM-0002-PPI-20210813. LYUMJEV is man-made fast-acting insulin used to control high blood sugar in adults with diabetes mellitus.. It is not known if LYUMJEV is safe and effective in children.. are having an episode of low blood sugar (hypoglycemia).. have an allergy to insulin lispro-aabc or any of the ingredients in LYUMJEV. See the end of this Patient Information leaflet for complete list of ingredients in LYUMJEV.. have kidney or liver problems.. take any other medicines, especially ones called thiazolidinediones (TZDs).. have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with LYUMJEV.. are pregnant or plan to become pregnant. Talk with your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant.. are breastfeeding or plan to breastfeed. It is not known if LYUMJEV passes into your breast milk. You and your healthcare provider should decide if you will take LYUMJEV while you breastfeed.. Read the Instructions for Use that come with your LYUMJEV.. Take LYUMJEV exactly as your healthcare provider tells you to. Your healthcare provider will tell you how much LYUMJEV to take and when to take it.. LYUMJEV starts acting fast. Inject LYUMJEV at the beginning of meal or within 20 minutes after you start eating meal.. Know the type and strength of insulin you take. Do not change the type or amount of insulin you take unless your healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin may need to change if you take different types of insulin.. Check your insulin label each time you give your injection to make sure you are using the correct insulin.. Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar level.. LYUMJEV comes in U-100 (100 units/mL) and U-200 (200 units/mL) insulin strengths. LYUMJEV U-200 contains times as much insulin (200 units/mL) in mL as LYUMJEV U-100 (100 units/mL).. LYUMJEV U-100 and LYUMJEV U-200 can be injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs, or upper arms.. LYUMJEV U-100 can be given by continuous infusion under the skin (subcutaneously) through an insulin pump into an area of your body recommended in the instructions that come with your insulin pump. LYUMJEV U-200 cannot be given through an insulin pump.. LYUMJEV U-100 can also be given in your vein (intravenously) by your healthcare provider. LYUMJEV U-200 cannot be given in your vein.. Change (rotate) your injection sites within the area you choose with each dose to reduce your risk of getting pits in skin or thickened skin (lipodystrophy) and skin with lumps (localized cutaneous amyloidosis) at the injection sites.Do not use the exact same spot for each injection.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 use the exact same spot for each injection.. 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.. If you miss dose of LYUMJEV, monitor your blood sugar levels to decide if an insulin dose is needed. Continue with your regular dosing schedule at the next meal.. LYUMJEV comes in vial, single-patient-use prefilled pen, or in cartridge. Do not use syringe to remove LYUMJEV from your single-patient-use prefilled pen or cartridge. drive or operate heavy machinery, until you know how LYUMJEV affects you.. drink alcohol or take other medicines that contain alcohol.. low blood sugar (hypoglycemia). Signs and symptoms that may indicate low blood sugar include: dizziness or light-headedness, sweating, confusion, headache, blurred vision, slurred speech, shakiness, fast heartbeat, hunger, anxiety, irritability, or mood changes.. low potassium in your blood (hypokalemia).. serious allergic reactions (whole body allergic reaction). Get emergency medical help right away, if you have any of these symptoms of severe allergic reaction: rash over your whole body, trouble breathing, fast heartbeat, swelling of your face, tongue, or throat, sweating, or feeling faint.. heart failure. Taking certain diabetes pills called thiazolidinediones (TZDs) with LYUMJEV may cause heart failure in some people. This can happen even if you have never had heart failure or heart failure problems before. If you already have heart failure it may get worse while you take TZDs with LYUMJEV. Your healthcare provider should monitor you closely while you are taking TZDs with LYUMJEV. Tell your healthcare provider if you have any new or worse symptoms of heart failure including: shortness of breath, swelling of your ankles or feet, or sudden weight gain. Treatment with TZDs and LYUMJEV may need to be adjusted or stopped by your healthcare provider if you have new or worse heart failure.. sudden onset of high blood sugar (hyperglycemia) and high amounts of ketones in the blood or urine (ketoacidosis) due to insulin pump problems. If LYUMEV is given through an insulin pump and the pump is not working the right way or in case of handling errors, you may not get the right amount of insulin, which can cause sudden onset of high blood sugar and high amounts of ketones in the blood or urine. trouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue or throat, sweating, extreme drowsiness, dizziness, or confusion.. low blood sugar (hypoglycemia). allergic reactions. rash. itching (pruritus). thickening or pits at the injection or infusion site (lipodystrophy). weight gain. reactions or pain at the site of injection or at the site of infusion with insulin pump use (treprostinil sodium and sodium citrate dihydrate are inactive ingredients in LYUMJEV that have been known to cause reactions and pain at the infusion and injection sites in other non-insulin medicines).

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryPublished 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 dose approximately times the human subcutaneous dose of 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 unit/kg/day (see Data).The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with HbA1c>7 and has been reported to be as high as 20% to 25% in women with 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% to 4% and 15% to 20%, respectively.. Clinical Considerations. Disease-associated Maternal and/or Embryo-Fetal RiskPoorly 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 DataPublished 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 DataAnimal reproduction studies have not been performed with LYUMJEV. However, subcutaneous reproduction and teratology studies have been conducted with insulin lispro. In 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 times the human subcutaneous dose of unit insulin lispro/kg/day, based on units/body surface area, respectively) from 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 unit insulin lispro/kg/day, based on units/body surface area, respectively) were injected subcutaneously on Gestation Days through 19. There were no adverse effects on fetal viability, weight, and morphology at any dose.. 8.2 Lactation. Risk SummaryAvailable 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 mothers clinical need for insulin, any potential adverse effects on the breastfed child from LYUMJEV or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of LYUMJEV in pediatric patients have not been established.. 8.5 Geriatric Use. In clinical trials, 187 of 1116 (16.8%) LYUMJEV-treated patients with type or type diabetes were >=65 years of age and 18 of 1116 (1.6%) were >=75 years of age. No overall differences in safety or effectiveness were observed between these elderly patients and younger adult patients.. 8.6 Renal Impairment. Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent LYUMJEV dose adjustment and more frequent glucose monitoring [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].. 8.7 Hepatic Impairment. Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent LYUMJEV dose adjustment and more frequent glucose monitoring [see Warnings and Precautions (5.3) and Clinical Pharmacology (12.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Never share LYUMJEV prefilled pen or cartridge between patients, even if the needle is changed. (5.1)Hyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to patients insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of glucose monitoring. (5.2)Hypoglycemia: May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness. (5.3)Hypoglycemia due to medication errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. Do not transfer LYUMJEV U-200 from the LYUMJEV KwikPen to syringe as overdosage and severe hypoglycemia can result. (5.4)Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated. (5.5)Hypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue LYUMJEV, monitor, and treat if indicated. (5.6)Fluid retention and heart failure with concomitant use of thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation of TZD if heart failure occurs. (5.7)Hyperglycemia and ketoacidosis due to insulin pump device malfunction: Monitor glucose and administer LYUMJEV by subcutaneous injection if pump malfunction occurs. (5.8). Never share LYUMJEV prefilled pen or cartridge between patients, even if the needle is changed. (5.1). Hyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to patients insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of glucose monitoring. (5.2). Hypoglycemia: May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness. (5.3). Hypoglycemia due to medication errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. Do not transfer LYUMJEV U-200 from the LYUMJEV KwikPen to syringe as overdosage and severe hypoglycemia can result. (5.4). Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk for hypokalemia and treat if indicated. (5.5). Hypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue LYUMJEV, monitor, and treat if indicated. (5.6). Fluid retention and heart failure with concomitant use of thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation of TZD if heart failure occurs. (5.7). Hyperglycemia and ketoacidosis due to insulin pump device malfunction: Monitor glucose and administer LYUMJEV by subcutaneous injection if pump malfunction occurs. (5.8). 5.1 Never Share LYUMJEV Prefilled Pen, Cartridge, or Syringe Between Patients. LYUMJEV prefilled pens or cartridges should never be shared between patients, even if the needle is changed. Patients using LYUMJEV vials must never share needles or syringes with another person. Sharing poses risk for transmission of blood-borne pathogens.. 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen. Changes in an insulin regimen (e.g., insulin, insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions (5.3)] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions (6.1)].Make any changes to patients insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type diabetes, dosage adjustments of concomitant anti-diabetic products may be needed.. 5.3 Hypoglycemia. Hypoglycemia is the most common adverse reaction associated with insulins, including LYUMJEV [see Adverse Reactions (6.1)]. Severe hypoglycemia can cause seizures, may lead to unconsciousness, may be life-threatening, or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery). LYUMJEV, or any insulin, should not be used during episodes of hypoglycemia [see Contraindications (4)].Hypoglycemia can happen suddenly and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7)], or in patients who experience recurrent hypoglycemia.. Risk Factors for HypoglycemiaThe risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulation. As with all insulins, the glucose lowering effect time course of LYUMJEV may vary in different individuals or at different times in the same individual and depends on many conditions, including the area of injection as well as the injection site blood supply and temperature [see Clinical Pharmacology (12.2)]. Other factors which may increase the risk of hypoglycemia include changes in meal pattern (e.g., macronutrient content or timing of meals), changes in level of physical activity, or changes to co-administered medication [see Drug Interactions (7)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (8.6, 8.7)].. Risk Mitigation Strategies for HypoglycemiaPatients and caregivers must be educated to recognize and manage hypoglycemia. Self-monitoring of glucose plays an essential role in the prevention and management of hypoglycemia. In patients at higher risk for hypoglycemia and patients who have reduced symptomatic awareness of hypoglycemia, increased frequency of glucose monitoring is recommended.. 5.4 Hypoglycemia Due to Medication Errors. Accidental mix-ups between insulin products have been reported. To avoid medication errors between LYUMJEV and other insulins, instruct patients to always check the insulin label before each injection.Do not transfer LYUMJEV U-200 from the LYUMJEV KwikPen to syringe. The markings on the insulin syringe will not measure the dose correctly and can result in overdosage and severe hypoglycemia [see Dosage and Administration (2.1) and Warnings and Precautions (5.3)].. 5.5 Hypokalemia. All insulins, including LYUMJEV, cause shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia. Untreated hypokalemia may cause respiratory paralysis, ventricular arrhythmia, and death. Monitor potassium levels in patients at risk for hypokalemia if indicated (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).. 5.6 Hypersensitivity Reactions. Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including LYUMJEV [see Adverse Reactions (6.1)]. If hypersensitivity reactions occur, discontinue LYUMJEV; treat per standard of care and monitor until symptoms and signs resolve. LYUMJEV is contraindicated in patients who have had hypersensitivity reactions to insulin lispro-aabc or any of its excipients [see Contraindications (4)].. 5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-Gamma Agonists. Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including LYUMJEV, and PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.. 5.8 Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction. Pump or infusion set malfunctions can lead to rapid onset of hyperglycemia and ketoacidosis. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim therapy with subcutaneous injection of LYUMJEV may be required. Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure [see Dosage and Administration (2.2), How Supplied/Storage and Handling (16.2), and Patient Counseling Information (17)].