Lyumjev Drug Information

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

Important

Administration Instructions Always check insulin labels before administration . Inspect LYUMJEV visually before use. It should appear clear and colorless. Do not use LYUMJEV if particulate matter and discoloration is seen.

Use LYUMJEV prefilled pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose. Do not perform dose conversion when using any LYUMJEV U-100 or U-200 prefilled pens. The dose window of LYUMJEV prefilled pens shows the number of units of LYUMJEV to be delivered and no conversion is needed.

Do not transfer LYUMJEV U-200 from the prefilled pen to a syringe for administration . 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.

Route of

Administration Instructions Subcutaneous Injection for LYUMJEV U-100 or U-200 Administer LYUMJEV at the start of a meal or within 20 minutes after starting a meal subcutaneously into the abdomen, upper arm, thigh, or buttocks. Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis.

LYUMJEV given by subcutaneous injection should generally be used in regimens with intermediate or long-acting insulin. The LYUMJEV U-100 KwikPen, LYUMJEV U-100 Tempo Pen, and LYUMJEV U-200 KwikPen each dial in 1 unit increments and deliver a maximum dose of 60 units per injection. The LYUMJEV U-100 Junior KwikPen dials in 0.5 unit increments and delivers a maximum dose of 30 units per injection.

Continuous Subcutaneous Insulin Infusion (Insulin Pump) for LYUMJEV U-100 Only Do not administer LYUMJEV U-200 using an insulin pump. Refer to the continuous subcutaneous insulin infusion pump user manual to see if LYUMJEV can be used with the insulin pump. Use LYUMJEV in accordance with the insulin pump system's instructions for use.

Administer LYUMJEV U-100 by continuous subcutaneous infusion in a region recommended in the instructions from the pump manufacturer. Rotate infusion sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not infuse into areas of lipodystrophy or localized cutaneous amyloidosis . Train patients using continuous subcutaneous insulin infusion (CSII) therapy to administer insulin by injection and have alternate insulin therapy available in case of insulin pump failure . Change LYUMJEV U-100 in the pump reservoir at least every 9 days or according to the pump user manual, whichever is shorter.

Change the infusion sets and the infusion set insertion site according to the manufacturer's user manual. Do not dilute or mix LYUMJEV U-100 when administering by CSII. Do not expose LYUMJEV in the pump reservoir to temperatures greater than 98.6°F (37°C). Intravenous Administration for LYUMJEV U-100 Only Do not administer LYUMJEV U-200 intravenously. Administer LYUMJEV U-100 intravenously only under medical supervision with close monitoring of glucose and potassium levels to avoid hypoglycemia and hypokalemia . Dilute LYUMJEV U-100 to a concentration of 1 unit/mL using 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP infusion solutions.

Dilutions to concentrations below 1 unit/mL are not recommended. Diluted LYUMJEV may be stored for up to 4 days when refrigerated or up to 12 hours at room temperature.

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 . During changes to a patient's insulin regimen, increase the frequency of glucose monitoring . 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.

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug, and may not reflect the rates actually observed in clinical practice. Adverse Reaction Database – Adult Patients with Type 1 and Type 2 Diabetes The data in Table 1 reflect the exposure of 780 adult patients with type 1 diabetes to LYUMJEV with a mean exposure duration of 26 weeks . The mean age was 44 years, the mean duration of diabetes was 19 years, 55% were male, 77% were White, 2% were Black or African American, and 9% were Hispanic. The mean BMI was 26.6 kg/m 2 and the mean HbA 1c at baseline was 7.3%. The data in Table 2 reflect the exposure of 336 adult patients with type 2 diabetes to LYUMJEV with a mean exposure duration of 26 weeks . The mean age was 60 years, the mean duration of diabetes was 16 years, 55% were male, 69% were White, 4% were Black or African American, and 24% were Hispanic.

The mean BMI was 32.1 kg/m 2 and the mean HbA 1c at baseline was 7.3%. The data in Table 3 reflect the exposure of 215 adult patients with type 1 diabetes to LYUMJEV via CSII administration with a mean exposure duration of 16 weeks . The mean age was 48 years, the mean duration of diabetes was 26 years, 44% were male, 94% were White, 3% were Black or African American, and 8% were Hispanic. The mean BMI was 27.0 kg/m 2 and the mean HbA 1c at baseline was 7.6%. Common adverse reactions, excluding hypoglycemia, were defined as events that occurred in ≥5% and at the same rate or greater for LYUMJEV-treated patients than HUMALOG-treated patients. Table 1. Adverse Reactions That Occurred in ≥5% of LYUMJEV-Treated Adult Patients with Type 1 Diabetes Mealtime LYUMJEV + basal insulin (N=451) % Postmeal LYUMJEV + basal insulin (N=329) % Nasopharyngitis 14.2

Table 2. Adverse Reactions That Occurred in ≥5% of

LYUMJEV-Treated Adult Patients with Type 2 Diabetes Mealtime LYUMJEV + basal insulin (N=336) % Nasopharyngitis

Upper Respiratory Tract Infection 7.4 Table 3. Adverse Reactions That Occurred in

≥5% of LYUMJEV-Treated Adult Patients with Type 1 Diabetes Using Continuous Subcutaneous Insulin Infusion CSII LYUMJEV administration (N=215) % Infusion site reaction

Infusion site pain 15.8 Nasopharyngitis 6.0 Adverse Reaction Database – Pediatric Patients

with Type 1 Diabetes The data in Table 4 reflect the exposure of 418 pediatric patients with type 1 diabetes to LYUMJEV with a mean exposure duration of 26 weeks . The mean age was 12 years; 50% were male, 91% were White, 1% were Black or African American; and 24% of the US subpopulation in this trial were Hispanic. The mean BMI was 20.5 kg/m 2, the mean duration of diabetes was 5 years, and the mean HbA 1c at baseline was 7.8%. Common adverse reactions, excluding hypoglycemia, were defined as events that occurred in ≥5% and at the same rate or greater for LYUMJEV-treated patients than HUMALOG-treated patients. Table 4. Adverse Reactions That Occurred in ≥5% of LYUMJEV-Treated Pediatric Patients with Type 1 Diabetes Mealtime LYUMJEV + basal insulin (N=280) % Postmeal LYUMJEV + basal insulin (N=138) % Nasopharyngitis 8.2

Upper Respiratory Tract Infection 5.4 1.4 Hypoglycemia Hypoglycemia is the most commonly

observed adverse reaction in patients using insulin, including LYUMJEV. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for LYUMJEV with the incidence of hypoglycemia for other products may be misleading and also may not be representative of hypoglycemia rates that occur in clinical practice. Incidence rates for severe hypoglycemia in adults with type 1 and type 2 diabetes mellitus and pediatric patients with type 1 diabetes mellitus treated with LYUMJEV in clinical trials are shown in Table 5 . Table 5. Proportion of Patients with Type 1 Diabetes and Type 2 Diabetes Who Experienced at Least One Episode of Severe Hypoglycemia in Adult and Pediatric Clinical Trials a Severe hypoglycemia: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions PRONTO-T1D (Adult Type 1) PRONTO-T2D (Adult Type 2) PRONTO-Pump-2 (Adult Type 1 CSII) PRONTO-Peds (Pediatric Type 1) Mealtime LYUMJEV + basal insulin (N=451) % Postmeal LYUMJEV + basal insulin (N=329) % Mealtime LYUMJEV + basal insulin (N=336) % LYUMJEV (N=215) % Mealtime LYUMJEV + basal insulin (N=280) % Postmeal LYUMJEV + basal insulin (N=298) % Severe hypoglycemia a 5.5 4.6 0.9 1.4 1.1 0 Allergic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, generalized skin reactions, angioedema, bronchospasm, hypotension, and shock may occur with any insulin, including LYUMJEV, and may be life threatening.

Generalized hypersensitivity reactions such as skin rashes and hypersensitivity were reported in adult patients treated with LYUMJEV: eczema (0.4%), rash (0.4%), dermatitis (0.3%), hypersensitivity (0.2%), and pruritus (0.2%). Generalized hypersensitivity reactions reported in more than 1 pediatric patient treated with LYUMJEV included: rhinitis (0.7%), dermatitis (0.7%), rash (0.5%), and hypersensitivity (0.5%). Lipodystrophy Administration of insulin, including LYUMJEV, has resulted in lipohypertrophy (enlargement or thickening of tissue) and lipoatrophy (depression in the skin). Lipodystrophy was reported in 0.2% of adult and pediatric patients treated with LYUMJEV . Injection/Infusion Site Reactions Injection or infusion site reactions can occur with insulin therapy. With LYUMJEV, adult and pediatric patients have experienced rash, redness, inflammation, pain, bruising, or itching at the site of LYUMJEV injection or infusion. LYUMJEV contains treprostinil sodium and sodium citrate dihydrate as inactive ingredients which have been associated with infusion and injection site reactions with other non-insulin products.

Subcutaneous Injection Site-Related Reactions : In studies PRONTO-T1D and PRONTO-T2D, injection site-related reactions occurred in 2.7% of adult patients treated with LYUMJEV (mild in 2.2% and moderate in 0.5%). with <0.1% of patients discontinuing from treatment due to injection site-related reactions. In Study PRONTO-Peds, injection site-related reactions occurred in 6.2% of pediatric patients treated with LYUMJEV (mild in 5.7% and moderate in 0.5%), with <0.5% of patients discontinuing from treatment due to injection site-related reactions. Continuous Subcutaneous Insulin Infusion (CSII) Site-Related Reactions: In Study PRONTO-Pump-2, infusion site-related reactions were reported in 37.7% of adult patients treated with LYUMJEV (mild in 27.9%, moderate in 7.9%, and severe in 1.9%), with 3.3% of patients discontinuing from treatment due to infusion site-related reactions.

See Table 4. Weight Gain Weight gain can occur with insulin therapy, including LYUMJEV, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria. Adult patients with type 1 diabetes treated with LYUMJEV gained an average of 0.6 kg and patients with type 2 diabetes treated with LYUMJEV gained an average of 1.5 kg. Peripheral Edema Insulin, including LYUMJEV, may cause sodium retention and edema, particularly if previous poor metabolic control is improved by intensified insulin therapy.

Peripheral edema occurred in 0.2% of adult patients treated with LYUMJEV.

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.

Table 6 includes clinically significant drug interactions with LYUMJEV. Table 6. Clinically Significant Drug Interactions with LYUMJEV Drugs That May Increase the Risk of Hypoglycemia Drugs: Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analogs (e.g., octreotide), and sulfonamide antibiotics. Intervention: Dose reductions and increased frequency of glucose monitoring may be required when LYUMJEV is co-administered with these drugs. Drugs That May Decrease the Blood Glucose Lowering Effect of LYUMJEV Drugs: Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.

Intervention: Dose increases and increased frequency of glucose monitoring may be required when LYUMJEV is co-administered with these drugs. Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of LYUMJEV Drugs: Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.

Intervention: Dose adjustment and increased frequency of glucose monitoring may be required when LYUMJEV is co-administered with these drugs. Drugs That May Blunt Signs and Symptoms of Hypoglycemia Drugs: Beta-blockers, clonidine, guanethidine, and reserpine. Intervention: Increased frequency of glucose monitoring may be required when LYUMJEV is co-administered with these drugs.

Drugs that Increase Hypoglycemia Risk or Increase or Decrease Blood Glucose Lowering Effect: Adjustment of dosage may be needed; closely monitor blood glucose. Drugs that Blunt Hypoglycemia Signs and Symptoms (e.g., beta-blockers, clonidine, guanethidine, and reserpine): Increased frequency of glucose monitoring may be required.

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.

Pediatric Use The safety and effectiveness of LYUMJEV to improve glycemic control in pediatric patients with diabetes mellitus have been established. 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 year and older, and from studies in adult and pediatric patients with diabetes mellitus . LYUMJEV-treated pediatric patients reported a higher incidence of subcutaneous injection site-related reactions compared to LYUMJEV-treated adults . It is expected that LYUMJEV-treated pediatric patients who receive continuous subcutaneous insulin infusion (CSII) are more likely to have infusion site-related adverse reactions than those who receive subcutaneous injections . Monitor injection and infusion sites closely when initiating therapy with LYUMJEV in pediatric patients. If persistent injection or infusion site reactions occur, discontinue LYUMJEV and initiate therapy with an alternative insulin.

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

Excess insulin administration may cause hypoglycemia and hypokalemia . Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with 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.