LYUMJEV™ is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus.

Important Administration Instructions

•     Always check insulin labels before administration [see Special Warnings and Precautions for Use (4.4)].

•     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 injected.

•     Do not transfer LYUMJEV U-200 from the prefilled pen to a syringe for administration [see Special Warnings and Precautions for Use (4.4)].

•     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.

Route of Administration Instructions

Subcutaneous Injection

•     Administer LYUMJEV at the start of a meal or within 20 minutes after starting a meal subcutaneously into the abdomen, upper arm, thigh, or buttocks.

•     Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Undesirable Effects (4.8)].

•     LYUMJEV given by subcutaneous injection should generally be used in regimens with intermediate or long-acting insulin.

•     The LYUMJEV U-100 KwikPen, and LYUMJEV U-200 KwikPen each dial in 1 unit increments and deliver a maximum dose of 60 units per injection.

•     The LYUMJEV U-100 Junior KwikPen dials in 0.5 unit increments and delivers a maximum dose of 30 units per injection.

Intravenous Administration for LYUMJEV U-100 Only

•     Do not administer LYUMJEV U-200 intravenously.

•     Administer LYUMJEV U-100 intravenously only under medical supervision with close monitoring of glucose and potassium levels to avoid hypoglycemia and hypokalemia [see Special Warnings and Precautions for Use (4.4)].

•     Dilute LYUMJEV U-100 to a concentration of 1 unit/mL using 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP infusion solutions. Dilutions to concentrations below 1 unit/mL are not recommended.

•     Stable up to 14 days when diluted to concentrations of 0.1 to 1 U/mL in 5% Dextrose Injection or 0.9% Sodium Chloride Injection when stored in a refrigerator at 2°C to 8°C [36°F to 46°F] until time of use. The same solutions may be stored for up to 20 hours at room temperature at 20°C to 25°C [(68°F to 77°F)].

General Dosage Instructions

•     Individualize and adjust the dosage of LYUMJEV based on the patient’s metabolic needs, glucose monitoring results, and glycemic control goal.

•     If converting from another mealtime insulin to LYUMJEV, the change can be done on a unit-to-unit basis.

•     Dosage adjustments may be needed when switching from another insulin, with changes in physical activity, changes in concomitant medications, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness to minimize the risk of hypoglycemia or hyperglycemia [see Special Warnings and Precautions For Use (4.4), Interactions with other medicinal products and other forms of interaction (4.5) and Use in Specific Populations (5.2)].

•     During changes to a patient’s insulin regimen, increase the frequency of glucose monitoring [see Special Warnings and Precautions For Use (4.4)].

•     Instruct patients who forget a mealtime dose to monitor their glucose level to decide if an insulin dose is needed, and to resume their usual dosing schedule at the next meal.

Never Share a 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 a risk for transmission of blood-borne pathogens.

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 Special Warnings and Precautions For Use (4.4)] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and a sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia [see Undesirable Effects (4.8)].

Make any changes to a patient's 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 2 diabetes, dosage adjustments of concomitant anti-diabetic products may be needed.

Hypoglycemia

Hypoglycemia is the most common adverse reaction associated with insulins, including LYUMJEV [see Undesirable Effects (4.8)]. 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 (4.3)].

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 Interactions with other medicinal products and other forms of interaction (4.5)], or in patients who experience recurrent hypoglycemia.

Risk Factors for Hypoglycemia

The 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 insulin preparations, 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 Pharmacodynamic Properties (5.1)]. 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 Interactions with other medicinal products and other forms of interaction (4.5)]. Patients with renal or hepatic impairment may be at higher risk of hypoglycemia [see Use in Specific Populations (5.2)].

Risk Mitigation Strategies for Hypoglycemia

Patients 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.

Hypoglycemia Due to Medication Errors

Accidental mix-ups between basal insulin products and other insulins, particularly rapid-acting insulins, 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 a syringe. The markings on the insulin syringe will not measure the dose correctly and can result in overdosage and severe hypoglycemia [see Posology and method of administration (4.2) and Special Warnings and Precautions For Use (4.4)].

Hypokalemia

All insulin products, including LYUMJEV, cause a 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).

Hypersensitivity and Allergic Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including LYUMJEV [see Undesirable Effects (4.8)]. 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 or any of its excipients [see Contraindications (4.2)].

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 a 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.

Table 1 includes clinically significant drug interactions with LYUMJEV.

Table 1. Clinically Significant Drug Interactions with LYUMJEV

Pregnancy

Risk Summary

Published studies with insulin lispro used during pregnancy have not reported an association between insulin lispro and the induction of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations). Pregnant rats and rabbits were exposed to insulin lispro in animal reproduction studies during organogenesis. No adverse effects on embryo/fetal viability or morphology were observed in offspring of rats exposed to insulin lispro at a dose approximately 3 times the human subcutaneous dose of 1 unit insulin lispro/kg/day. No adverse effects on embryo/fetal development were observed in offspring of rabbits exposed to insulin lispro at doses up to approximately 0.2 times the human subcutaneous dose of 1 unit/kg/day (see Data).

The estimated background risk of major birth defects is 6% to 10% in women with pre-gestational diabetes with a HbA_1c>7 and has been reported to be as high as 20% to 25% in women with a HbA_1c>10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated Maternal and/or Embryo-Fetal Risk

Poorly controlled diabetes in pregnancy increases the maternal risk for diabetic ketoacidosis, pre-eclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, stillbirth, and macrosomia related morbidity.

Data

Human Data

Published data from retrospective studies and meta-analyses do not report an association with insulin lispro and major birth defects, or adverse maternal or fetal outcomes when insulin lispro is used during pregnancy. However, these studies cannot definitely establish or exclude the absence of any risk because of methodological limitations including small sample size, selection bias, confounding by unmeasured factors, and some lacking comparator groups.

Animal Data

Animal reproduction studies have not been performed with LYUMJEV. However, subcutaneous reproduction and teratology studies have been conducted with insulin lispro. In a combined fertility and embryo-fetal development study, female rats were given subcutaneous insulin lispro injections of 1, 5, and 20 units/kg/day (0.2, 0.8, and 3 times the human subcutaneous dose of 1 unit insulin lispro/kg/day, based on units/body surface area, respectively) from 2 weeks prior to cohabitation through Gestation Day 19. There were no adverse effects on female fertility, implantation, or fetal viability and morphology. However, fetal growth retardation was produced at the 20 units/kg/day-dose as indicated by decreased fetal weight and an increased incidence of fetal runts/litter.

In an embryo-fetal development study in pregnant rabbits, insulin lispro doses of 0.1, 0.25, and 0.75 unit/kg/day (0.03, 0.08, and 0.2 times the human subcutaneous dose of 1 unit insulin lispro/kg/day, based on units/body surface area, respectively) were injected subcutaneously on Gestation Days 7 through 19. There were no adverse effects on fetal viability, weight, and morphology at any dose.

Lactation

Risk Summary

Available data from published literature suggests that exogenous human insulin products, including insulin lispro, are transferred into human milk. There are no adverse reactions reported in breastfed infants in the literature. There are no data on the effects of exogenous human insulin products, including insulin lispro, on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for insulin, any potential adverse effects on the breastfed child from LYUMJEV or from the underlying maternal condition.

The proper use of the correct therapeutic dose of insulins has no known effect on driving or the use of machinery. The patient’s ability to concentrate and react may be impaired as a result of hypoglycemia. This may constitute a risk in situations where these abilities are of special importance (e.g. driving a car or operating machinery).

The following adverse reactions are also discussed elsewhere:

•     Hypoglycemia [see Special Warnings and Precautions For Use (4.4)].

•     Hypokalemia [see Special Warnings and Precautions For Use (4.4)].

•     Hypersensitivity and Allergic Reactions [see Special Warnings and Precautions For Use (4.4)].

Clinical Trial Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates actually observed in clinical practice.

The data in Table 2 reflect the exposure of 780 adult patients with type 1 diabetes to LYUMJEV with a mean exposure duration of 26 weeks [see Pharmacodynamic Properties (5.1)]. 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 HbA_1c at baseline was 7.3%.

The data in Table 3 reflect the exposure of 336 adult patients with type 2 diabetes to LYUMJEV with a mean exposure duration of 26 weeks [Pharmacodynamic Properties (5.1)]. 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 HbA_1c at baseline was 7.3%.

The data in Table 4 reflect the exposure of 418 pediatric patients with type 1 diabetes to LYUMJEV with a mean exposure duration of 26 weeks [see Clinical Studies (5.1]. The mean age was 12 years, the mean duration of diabetes was 5 years, 50% were male, 91% were White, 1% were Black or African American, and 23% were Hispanic. The mean BMI was 20.5 kg/m2 and the mean HbA1c at baseline was 7.8%.

The data in Table 5 reflect the exposure of 215 adult patients with type 1 diabetes to LYUMJEV via CSII administration with a mean exposure duration of 16 weeks [see Clinical Studies (5.1)]. 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 HbA_1c 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^®-treated patients.

Table 2. Adverse Reactions Occurring in ≥5% of LYUMJEV-Treated Adult Patients with Type 1 Diabetes

Table 3. Adverse Reactions Occurring in ≥5% of LYUMJEV-Treated Adult Patients with Type 2 Diabetes

Table 4. Adverse Reactions Occurring in ≥5% of LYUMJEV-Treated Pediatric Patients with Type 1 Diabetes

Table 5. Adverse Reactions Occurring in ≥5% of LYUMJEV-Treated Adult Patients with Type 1 Diabetes Using Continuous Subcutaneous Insulin Infusion

Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including LYUMJEV. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for LYUMJEV with the incidence of hypoglycemia for other products may be misleading and also may not be representative of hypoglycemia rates that occur in clinical practice.

Incidence rates for severe hypoglycemia in adults with type 1 and type 2 diabetes mellitus and pediatric patients with type 1 diabetes mellitus treated with LYUMJEV in clinical trials are shown in Table 6 [See Pharmacodynamic Properties (5.1)].

Table 6. Proportion of Patients with Type 1 Diabetes and Type 2 Diabetes Experiencing at Least One Episode of Severe Hypoglycemia in Adult and Pediatric Clinical Trials

^a    Severe hypoglycemia: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions

Allergic Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LYUMJEV, and may be life threatening. Generalized hypersensitivity reactions such as skin rashes and hypersensitivity were reported in patients treated with LYUMJEV: eczema (0.4%), rash (0.4%), dermatitis (0.3%), hypersensitivity (0.2%), and pruritus (0.2%).

Lipodystrophy

Administration of insulin, including LYUMJEV, has resulted in lipohypertrophy (enlargement or thickening of tissue) and lipoatrophy (depression in the skin). Lipodystrophy was reported in 0.2% of patients treated with LYUMJEV [see Posology and method of administration (4.2)].

Injection/Infusion Site Reactions

Injection 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 (2.1)] 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.

In Study PRONTO-Peds, injection site-related reactions occurred in 6.2% of patients treated with LYUMJEV (mild in 5.7% and moderate in 0.5%), with <0.5% of patients discontinuing from treatment due to injection site-related reactions.

Continuous Subcutaneous Insulin Infusion (CSII) Site-Related Reactions:

In Study PRONTO-Pump-2, infusion site-related reactions were reported in 37.7% of 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 5.

Weight Gain

Weight gain can occur with insulin therapy, including LYUMJEV, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Patients with type 1 diabetes treated with LYUMJEV gained an average of 0.6 kg and patients with type 2 diabetes treated with LYUMJEV gained an average of 1.5 kg.

Peripheral Edema

Insulin, including LYUMJEV, may cause sodium retention and edema, particularly if previous poor metabolic control is improved by intensified insulin therapy. Peripheral edema occurred in 0.2% of patients treated with LYUMJEV.

Immunogenicity

As with all therapeutic proteins, there is a 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 a 26-week study in type 1 diabetes patients, 49% were anti-drug (insulin lispro) antibody (ADA)-positive at baseline, 91% of which were cross-reactive with native insulin. A total of 33% of LYUMJEV-treated patients had treatment-emergent ADA post-baseline (i.e., either new ADA or a 57% increase in assay signal over baseline), 75% of which were cross-reactive with native insulin.

In a 26-week study in type 2 diabetes patients, 35% were ADA-positive at baseline, 81% of which were cross-reactive with native insulin. A total of 31% of LYUMJEV-treated patients had treatment-emergent ADA post-baseline (i.e., either new ADA or a 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 HbA_1c, or specific adverse reactions.

Postmarketing Experience

The following additional adverse reactions have been identified during post-approval use of insulin lispro. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Localized cutaneous amyloidosis at the injection site has occurred with insulin use. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with a sudden change to an unaffected injection site.

Pediatric Use

The safety and effectiveness of LYUMJEV in pediatric patients have been established to improve glycemic control in pediatric patients with diabetes mellitus. Use of LYUMJEV for this indication is supported by evidence from an adequate and well-controlled study in 716 pediatric patients with type 1 diabetes mellitus aged 1 to 17 years, and from clinical pharmacology studies in adult and pediatric patients with diabetes mellitus.

Other special population

Geriatric Use

In clinical trials, 187 of 1116 (16.8%) LYUMJEV-treated patients with type 1 or type 2 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.

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)].

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)].

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed here.

Excess insulin administration may cause hypoglycemia and hypokalemia [see Special Warnings and Precautions For Use (4.4)]. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.

Pharmacotherapeutic group: {Insulins and analogues for injection, fast-acting}, ATC code: {A10AB04}

Mechanism of Action

The primary activity of LYUMJEV is the regulation of glucose metabolism. Insulins, including insulin lispro, 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.

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 a euglycemic clamp study] for subcutaneous administration of 7, 15, and 30 units of LYUMJEV in 42 healthy subjects is shown in Figure 1 and key characteristics of the timing of the effect are described in Table 7 below.

Figure 1. Mean Insulin Effect Over Time After Subcutaneous Administration of 7, 15, and 30 units of LYUMJEV in Healthy Subjects.

Table 7. 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 1

On average, the pharmacodynamic effects of LYUMJEV, measured as area under the glucose infusion rate-time curve (AUC_GIR), 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 1 diabetes and 38 patients with type 2 diabetes given LYUMJEV subcutaneously as a 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 (AUC_GIR, 0-1h), 27% for the total glucose lowering (AUC_GIR, 0-10h), and 19% for maximum glucose lowering effect (GIR_max).

Postprandial Glucose Lowering

When given at the start of a meal or 20 minutes after the start of the meal, LYUMJEV reduced postprandial glucose during a standardized test meal over the complete 5-hour period [change from premeal AUC(0-5h)] in patients with type 1 or type 2 diabetes.

The maximum and total glucose lowering were comparable for a 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.

Clinical efficacy and safety

CLINICAL STUDIES

Overview of Clinical Studies

The safety and efficacy of LYUMJEV was evaluated in 2 randomized, active controlled trials of 26 weeks in adult patients with type 1 diabetes (N=780) or type 2 diabetes (N=336).

Type 1 Diabetes – Adults

PRONTO-T1D (NCT03214367) was a 26 week, randomized (4:4:3), active controlled, treat-to-target, multinational trial that evaluated the efficacy of LYUMJEV in 1222 patients with type 1 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 0 to 2  minutes before the meal and postmeal LYUMJEV was injected 20 minutes after the start of the meal.

Patients had a 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 a mean reduction in HbA_1c that met the pre-specified non-inferiority margin (0.4%) (see Table 8). 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 8. 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 1 Diabetes

^a    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.

Type 1 Diabetes – Pediatrics

PRONTO-Peds (NCT03740919) was a 26-week, randomized (2:2:1), active controlled, treat-to-target, multinational trial that evaluated the efficacy of LYUMJEV in 716 patients with type 1 diabetes. Patients were randomized to either blinded mealtime LYUMJEV (N=280), blinded mealtime HUMALOG (N=298), or open-label postmeal LYUMJEV (N=138), all in combination with basal insulin (insulin glargine, insulin degludec or insulin detemir). Mealtime LYUMJEV or HUMALOG was injected 0 to 2 minutes before the meal and postmeal LYUMJEV was injected within 20 minutes after the start of the meal.

Patients had a mean age of 12 years; mean duration of diabetes of 5 years; 51% were male; race: 89% White, 6% Asian, and 2% Black or African American. Twenty-four percent of the randomized patients were Hispanic. The mean BMI was 20.4 kg/m2.

At week 26, treatment with mealtime LYUMJEV provided a mean reduction in HbA1c that met the pre-specified non-inferiority margin (0.4%) (see Table 9). 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 9. Results from Study PRONTO-Peds: 26 Week Trial of Mealtime LYUMJEV and Postmeal LYUMJEV compared with Mealtime HUMALOG, all in Combination with Basal Insulin in Pediatrics with Type 1 Diabetes

^a             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 5.4%, 7.1%, and 5.1% 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.

Type 2 Diabetes – Adults

PRONTO-T2D (NCT03214380) was a 26-week, randomized (1:1), active controlled, treat-to-target, multinational trial that evaluated the efficacy of LYUMJEV in 673 patients with type 2 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 a 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 a basal-bolus regimen. Mealtime LYUMJEV or mealtime HUMALOG was injected 0-2 minutes before the meal.

Patients had a 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 a mean reduction of HbA_1c from baseline that met the pre-specified non-inferiority margin (0.4%) compared to mealtime HUMALOG (see Table 10). Insulin doses were similar in both treatment groups at baseline and at 26 weeks.

Table 10. 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 2 Diabetes

^a    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.

Type 1 Diabetes – Adults Continuous Subcutaneous Insulin Infusion (CSII)

PRONTO-Pump-2 (NCT03830281) was a 16 week randomized (1:1), active controlled, treat-to-target, multinational trial that evaluated the efficacy of LYUMJEV in 432 patients with type 1 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 0 to 2 minutes before the meal.

Patients had a 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 a mean reduction in HbA_1c that met the pre-specified non-inferiority margin (0.4%) compared to mealtime HUMALOG (see Table 11). Total daily insulin doses were similar for both treatment groups at baseline and at 16 weeks.

Table 11. Results from Study PRONTO-Pump-2: 16 Week Trial of LYUMJEV compared with HUMALOG in Adults with Type 1 Diabetes

^a    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.

5.2     Pharmacokinetic properties

Absorption

Absorption of insulin lispro was evaluated in healthy subjects (see Figure 2) and patients with diabetes following subcutaneous injection of LYUMJEV.

•     Insulin lispro appeared in circulation approximately 1 minute after injection of LYUMJEV.

•     Time to 50% maximum insulin lispro concentration was 13 minutes.

•     Time to maximum insulin lispro 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 concentration (Cmax).

Figure 2. Mean Serum Insulin Lispro After Subcutaneous Injection of LYUMJEV (15 unit dose) in Healthy Subjects

The absolute bioavailability of insulin lispro after subcutaneous administration of LYUMJEV in the abdomen, deltoid, and thigh was approximately 65%. The rate of absorption of insulin lispro 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 exposure and maximum insulin lispro concentration increased proportionally with increasing subcutaneous doses of LYUMJEV within the therapeutic dose range.

The results of a study in healthy subjects demonstrated that LYUMJEV 200 units/mL is bioequivalent to LYUMJEV 100 units/mL following administration of a single 15 unit dose for the area under the serum insulin lispro concentration-time curve from time zero to infinity and maximum insulin lispro concentration. The rate of insulin lispro absorption after administration of LYUMJEV 200 units/mL was similar as observed with LYUMJEV 100 units/mL.

Distribution

Following a 15 unit intravenous bolus injection of LYUMJEV in healthy subjects, the geometric mean (CV%) volume of distribution of insulin lispro (Vd) was 34 L (30%).

Elimination

Following a 15 unit intravenous bolus injection of LYUMJEV in healthy subjects, the geometric mean (CV%) clearance of insulin lispro was 32 L/hour (22%) and the median half-life of insulin lispro was 44 minutes.

Specific Populations

Age, gender, and race did not affect the pharmacokinetics and pharmacodynamics of LYUMJEV.

Patients with Renal and Hepatic Impairment

Renal and hepatic impairment is not known to impact the pharmacokinetics of insulin lispro. Insulin requirements may be reduced in the presence of renal or hepatic impairment.

 Absorption

Absorption of insulin lispro was evaluated in healthy subjects (see Figure 2) and patients with diabetes following subcutaneous injection of LYUMJEV.

•     Insulin lispro appeared in circulation approximately 1 minute after injection of LYUMJEV.

•     Time to 50% maximum insulin lispro concentration was 13 minutes.

•     Time to maximum insulin lispro 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 concentration (Cmax).

Figure 2. Mean Serum Insulin Lispro After Subcutaneous Injection of LYUMJEV (15 unit dose) in Healthy Subjects

The absolute bioavailability of insulin lispro after subcutaneous administration of LYUMJEV in the abdomen, deltoid, and thigh was approximately 65%. The rate of absorption of insulin lispro 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 exposure and maximum insulin lispro concentration increased proportionally with increasing subcutaneous doses of LYUMJEV within the therapeutic dose range.

The results of a study in healthy subjects demonstrated that LYUMJEV 200 units/mL is bioequivalent to LYUMJEV 100 units/mL following administration of a single 15 unit dose for the area under the serum insulin lispro concentration-time curve from time zero to infinity and maximum insulin lispro concentration. The rate of insulin lispro absorption after administration of LYUMJEV 200 units/mL was similar as observed with LYUMJEV 100 units/mL.

Distribution

Following a 15 unit intravenous bolus injection of LYUMJEV in healthy subjects, the geometric mean (CV%) volume of distribution of insulin lispro (Vd) was 34 L (30%).

Elimination

Following a 15 unit intravenous bolus injection of LYUMJEV in healthy subjects, the geometric mean (CV%) clearance of insulin lispro was 32 L/hour (22%) and the median half-life of insulin lispro was 44 minutes.

Specific Populations

Age, gender, and race did not affect the pharmacokinetics and pharmacodynamics of LYUMJEV.

Patients with Renal and Hepatic Impairment

Renal and hepatic impairment is not known to impact the pharmacokinetics of insulin lispro. Insulin requirements may be reduced in the presence of renal or hepatic impairment.

NONCLINICAL TOXICOLOGY

Carcinogenesis, Mutagenesis, Impairment of Fertility

In Fischer 344 rats, a 12-month repeat-dose toxicity study was conducted with insulin lispro at subcutaneaaaous doses of 20 and 200 units/kg/day (approximately 3 and 32 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area). Insulin lispro did not produce important target organ toxicity including mammary tumors at any dose.

Insulin lispro was not mutagenic in the following genetic toxicity assays: bacterial mutation, unscheduled DNA synthesis, mouse lymphoma, chromosomal aberration, and micronucleus assays.

Male fertility was not compromised when male rats given subcutaneous insulin lispro injections of 5 and 20 units/kg/day (0.8 and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area) for 6 months were mated with untreated female rats. In a combined fertility, perinatal, and postnatal study in male and female rats given 1, 5, and 20 units/kg/day subcutaneously (0.2, 0.8, and 3 times the human subcutaneous dose of 1 unit/kg/day, based on units/body surface area), mating and fertility were not adversely affected in either gender at any dose.

glycerol (12.1 mg),

magnesium chloride hexahydrate (1.02 mg),

metacresol (3.15 mg),

sodium citrate dihydrate (4.41 mg),

treprostinil sodium (1.06 mcg),

zinc oxide (content adjusted to provide 39 mcg of zinc ion for 100units/mL and 52 mcg for 200units/ml),

and Water for Injection, USP.

Hydrochloric acid and/or sodium hydroxide may be added to adjust the pH. LYUMJEV has a pH of 7.0 to 7.8.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.

•     Dispense in the original sealed carton with the enclosed Instructions for Use.

Cartridges and Pens Special Precautions for Storage

·       Protect from direct heat and light [or sunlight]

·       DO NOT FREEZE

·       Store not in-use (unopened) cartridges and pens in a refrigerator at 2°C to 8°C [36°F to 46°F] until time of use

·       Do not store in-use cartridges and pens (after the disc seal has been punctured) in a refrigerator

·       Store in-use cartridges and pens for up to 28 days at a maximum temperature of 30˚C [86˚F]

·       Lilly 3 mL cartridges: Designed and tested for use only with Lilly pens

10 mL Vial (100 units/mL Only) Special Precautions for Storage

·       Protect from direct heat and light [or sunlight]

·       DO NOT FREEZE

·       Store drug product in a refrigerator at 2°C to 8°C [36°F to 46°F] until time of use.

·       Store in-use vials (after the stopper has been punctured) refrigerated for up to 28 days. If refrigeration is not possible, an in-use vial can be kept unrefrigerated for up to 28 days at a maximum temperature of 30°C [86°F]. In-use vials can only be used for a total of 28 days, including both refrigerated and unrefrigerated storage time.

·       [Drug product in a pump can be used for a maximum of 9 days. Tubings in which the inner surface materials are made of polyethylene or polyolefin have been evaluated and found compatible with pump use.]

Handling of Prepared Dosing Solution – IV Use

Stable up to 14 days when diluted to concentrations of 0.1 to 1 U/mL in 5% Dextrose Injection or 0.9% Sodium Chloride Injection when stored in a refrigerator at 2°C to 8°C [36°F to 46°F] until time of use. The same solutions may be stored for up to 20 hours at room temperature at 20°C to 25°C [(68°F to 77°F)].

The storage conditions for vials, pens, and cartridges are summarized in Table 12.

Table 12. Storage Conditions for Vials, Pens, and Cartridges

^a    In-use (opened) vials, whether or not refrigerated, must be used within 28 days.

^b    When stored at room temperature, LYUMJEV can only be used for a total of 28 days including both not in-use (unopened) and in-use (opened) storage time.

Storage of LYUMJEV in Insulin Pump

Change the LYUMJEV U-100 in the pump reservoir at least every 9 days, or according to the pump user manual, whichever is shorter, or after exposure to temperatures that exceed 37°C (98.6°F).

Storage of LYUMJEV in Intravenous Infusion Fluids

Diluted LYUMJEV may be stored for up to 4 days when refrigerated at 36°F to 46°F (2°C to 8°C) until time of use. The same solution may be stored up to 12 hours at room temperature at 68°F to 77°F (20°C to 25°C) [see Dosage and Administration (4.2)].

LYUMJEV (insulin lispro) injection is a clear and colorless solution available as shown in Table 13.

Table 13. How Supplied

^a    3 mL cartridge is for use in Eli Lilly and Company's insulin delivery device. Patients need to check their device manual to determine if the LYUMJEV cartridge is compatible for use in other devices.

Not all pack sizes may be marketed.

No special requirements for disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-Approved Patient Labeling (Patient Information and Instructions for Use).

Never Share a LYUMJEV Prefilled Pen, Cartridge, or Syringe Between Patients

Advise patients that they must never share a 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 a risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)].

Hyperglycemia or Hypoglycemia

Inform patients that hypoglycemia is the most common adverse reaction with insulin. Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of 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 a result of hypoglycemia. Advise patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia to use caution when driving or operating machinery [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 Errors

Instruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products.

Inform patients that LYUMJEV U-200 contains 2 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 a syringe [see Warnings and Precautions (5.4)].

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions have occurred with LYUMJEV. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.6)].