NDC 0002-7726 Lyumjev
Insulin Lispro-aabc Injection, Solution Subcutaneous

Product Label Table of Contents

• 1 INDICATIONS AND USAGE
• 2.1 IMPORTANT ADMINISTRATION INSTRUCTIONS
• OTHER
• 2.3 GENERAL DOSAGE INSTRUCTIONS
• 3 DOSAGE FORMS AND STRENGTHS
• 4 CONTRAINDICATIONS
• 5.1 NEVER SHARE A LYUMJEV PREFILLED PEN, CARTRIDGE, OR SYRINGE BETWEEN PATIENTS
• 5.2 HYPERGLYCEMIA OR HYPOGLYCEMIA WITH CHANGES IN INSULIN REGIMEN
• 5.3 HYPOGLYCEMIA
• 5.4 HYPOGLYCEMIA DUE TO MEDICATION ERRORS
• 5.5 HYPOKALEMIA
• 5.6 HYPERSENSITIVITY AND ALLERGIC REACTIONS
• 5.7 FLUID RETENTION AND HEART FAILURE WITH CONCOMITANT USE OF PPAR-GAMMA AGONISTS
• 6 ADVERSE REACTIONS
• 6.1 CLINICAL TRIAL EXPERIENCE
• 6.2 IMMUNOGENICITY
• 6.3 POSTMARKETING EXPERIENCE
• 7 DRUG INTERACTIONS
• 8.4 PEDIATRIC USE
• 8.5 GERIATRIC USE
• 8.6 RENAL IMPAIRMENT
• 8.7 HEPATIC IMPAIRMENT
• 10 OVERDOSAGE
• 11 DESCRIPTION
• 12.1 MECHANISM OF ACTION
• 12.2 PHARMACODYNAMICS
• 13.1 CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY
• 14.1 OVERVIEW OF CLINICAL STUDIES
• 14.2 TYPE 1 DIABETES – ADULTS
• 14.3 TYPE 2 DIABETES – ADULTS
• 16.1 HOW SUPPLIED
• 16.2 STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
• SPL PATIENT PACKAGE INSERT
• INSTRUCTIONS FOR USE
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

1 Indications And Usage

LYUMJEV™ is indicated to improve glycemic control in adults with diabetes mellitus.

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 injected.
• Do not transfer LYUMJEV U-200 from the prefilled pen to a 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.

Other

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 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 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 Warnings and Precautions (5.3, 5.5)].
• Dilute LYUMJEV U-100 to a concentration of 1 unit/mL using 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP infusion solutions. Dilutions to concentrations below 1 unit/mL are not recommended.
• Diluted LYUMJEV may be stored for up to 4 days when refrigerated at 36°F to 46°F (2°C to 8°C) until time of use. The same solution may be stored for up to 12 hours at room temperature at 68°F to 77°F (20°C to 25°C).

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 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 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

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 treated with LYUMJEV in clinical trials are shown in Table 3 [see Clinical Studies (14)].

Table 3. Proportion of Patients with Type 1 Diabetes and Type 2 Diabetes Experiencing at Least One Episode of Severe Hypoglycemia in Adult Clinical Trials

a Severe hypoglycemia: an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or other resuscitative actions
	PRONTO-T1D (Type 1)		PRONTO-T2D (Type 2)
	Mealtime LYUMJEV + basal insulin (N=451) %	Postmeal LYUMJEV + basal insulin (N=329) %	Mealtime LYUMJEV + basal insulin (N=336) %
Severe hypoglycemiaa	5.5	4.6	0.9

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 Dosage and Administration (2.2)].

Injection Site Reactions

As with other insulin therapy, patients may experience rash, redness, inflammation, bruising, or itching at the site of LYUMJEV injection. Injection site reactions occurred in 2.7% of patients treated with LYUMJEV. These reactions were usually mild, with <0.1% of patients discontinuing from trials due to this event.

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.

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.

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.

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.

Absorption

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

• Insulin lispro-aabc appeared in circulation approximately 1 minute after injection of LYUMJEV.
• Time to 50% maximum insulin lispro-aabc concentration was 13 minutes.
• Time to maximum insulin lispro-aabc concentration was achieved at 57 minutes.

In healthy subjects, the day-to-day variability [CV%] within subjects of LYUMJEV was 10% for total exposure (AUC, 0-10h) and 16% for maximum insulin lispro-aabc concentration (Cmax).

Figure 2 - lyumjev uspi f2 v1

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

The absolute bioavailability of insulin lispro-aabc after subcutaneous administration of LYUMJEV in the abdomen, deltoid, and thigh was approximately 65%. The rate of absorption of insulin lispro-aabc is maintained regardless of injection site. Maximum concentration and time to maximum concentration were comparable for the abdomen and upper arm regions; time to maximum concentration was longer and maximum concentration was lower for the thigh.

Total insulin lispro-aabc exposure and maximum insulin lispro-aabc concentration increased proportionally with increasing subcutaneous doses of LYUMJEV within the therapeutic dose range.

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

Distribution

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

Elimination

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

Specific Populations

Age (18 to 77 years), 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-aabc. Insulin requirements may be reduced in the presence of renal or hepatic impairment.

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)].

Eli Lilly and Company, Indianapolis, IN 46285, USA
US License No. 1891
Copyright © 2020, Eli Lilly and Company. All rights reserved.

LUM-0001-USPI-20200615

2.3 General Dosage Instructions

• Individualize and adjust the dosage of LYUMJEV based on the patient's metabolic needs, glucose monitoring results, and glycemic control goal.
• If converting from another mealtime insulin to LYUMJEV, the change can be done on a unit-to-unit basis.
• Dosage adjustments may be needed when switching from another insulin, with changes in physical activity, changes in concomitant medications, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness to minimize the risk of hypoglycemia or hyperglycemia [see Warnings and Precautions (5.2, 5.3), Drug Interactions (7) and Use in Specific Populations (8.6, 8.7)].
• During changes to a patient's insulin regimen, increase the frequency of glucose monitoring [see Warnings and Precautions (5.2)].
• Instruct patients who forget a mealtime dose to monitor their glucose level to decide if an insulin dose is needed, and to resume their usual dosing schedule at the next meal.

3 Dosage Forms And Strengths

Injection: 100 units per mL (U-100) clear and colorless solution available as:

• 10 mL multiple-dose vial
• 3 mL single-patient-use LYUMJEV KwikPen
• 3 mL single-patient-use LYUMJEV Junior KwikPen
• 3 mL single-patient-use LYUMJEV Tempo Pen
• 3 mL single-patient-use cartridges

Injection: 200 units per mL (U-200) clear and colorless solution available as:

• 3 mL single-patient-use LYUMJEV KwikPen

4 Contraindications

LYUMJEV is contraindicated:

• during episodes of hypoglycemia.
• in patients with hypersensitivity to insulin lispro-aabc or one of the excipients in LYUMJEV.

5.1 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.

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 a 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 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.

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.

5.4 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 Dosage and Administration (2.1) and Warnings and Precautions (5.3)].

5.5 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).

5.6 Hypersensitivity And Allergic Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, 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 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.

6 Adverse Reactions

The following adverse reactions are also discussed elsewhere:

• Hypoglycemia [see Warnings and Precautions (5.3)].
• Hypokalemia [see Warnings and Precautions (5.5)].
• Hypersensitivity and Allergic Reactions [see Warnings and Precautions (5.6)]

6.1 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 1 reflect the exposure of 780 patients with type 1 diabetes to LYUMJEV with a mean exposure duration of 26 weeks [see Clinical Studies (14.2)]. The mean age was 44 years, the mean duration of diabetes was 19 years, 55% were male, 77% were White, 2% were Black or African American, and 9% were Hispanic. The mean BMI was 26.6 kg/m² and the mean HbA_1c at baseline was 7.3%.

The data in Table 2 reflect the exposure of 336 patients with type 2 diabetes to LYUMJEV with a mean exposure duration of 26 weeks [see Clinical Studies (14.3)]. The mean age was 60 years, the mean duration of diabetes was 16 years, 55% were male, 69% were White, 4% were Black or African American, and 24% were Hispanic. The mean BMI was 32.1 kg/m² and the mean HbA_1c at baseline was 7.3%.

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.

6.2 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-aabc) 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.

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 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.

7 Drug Interactions

Table 4 includes clinically significant drug interactions with LYUMJEV.

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 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.

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)].

10 Overdosage

Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.5)]. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.

11 Description

Insulin lispro-aabc is a rapid-acting human insulin analog used to lower blood glucose. Insulin lispro-aabc is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli. Insulin lispro-aabc differs from human insulin in that the amino acid proline at position B28 is replaced by lysine and the lysine in position B29 is replaced by proline. Chemically, it is Lys(B28), Pro(B29) human insulin analog and has the empirical formula C₂₅₇H₃₈₃N₆₅O₇₇S₆ and a molecular weight of 5808 daltons, both identical to that of human insulin.

Insulin lispro-aabc has the following primary structure:

Insulin Lispro-aabc Primary Structure - lyumjev uspi chem v1

LYUMJEV (insulin lispro-aabc) injection is a sterile, aqueous, clear, and colorless solution for subcutaneous or intravenous administration. Each mL of LYUMJEV U-100 contains 100 units of insulin lispro-aabc and the inactive ingredients: glycerol (12.1 mg), magnesium chloride hexahydrate (1.02 mg), metacresol (3.15 mg), sodium citrate dihydrate (4.41 mg), treprostinil sodium (1.06 mcg), zinc oxide (content adjusted to provide 39 mcg zinc ion), and Water for Injection, USP.

Each mL of LYUMJEV U-200 contains 200 units of insulin lispro-aabc and the inactive ingredients: glycerol (12.1 mg), magnesium chloride hexahydrate (1.02 mg), metacresol (3.15 mg), sodium citrate dihydrate (4.41 mg), treprostinil sodium (1.06 mcg), zinc oxide (content adjusted to provide 52 mcg zinc ion), and Water for Injection, USP.

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

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 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 5 below.

Figure 1 - lyumjev uspi f1 v1

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).

13.1 Carcinogenesis, Mutagenesis, Impairment Of Fertility

In Fischer 344 rats, a 12-month repeat-dose toxicity study was conducted with insulin lispro at subcutaneous 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.

14.1 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).

14.2 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 6). 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.

14.3 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 7). Insulin doses were similar in both treatment groups at baseline and at 26 weeks.

16.1 How Supplied

LYUMJEV (insulin lispro-aabc) injection is a clear and colorless solution available as shown in Table 8.

16.2 Storage And Handling

• Dispense in the original sealed carton with the enclosed Instructions for Use.
• Refrigerate unopened LYUMJEV vials, pens, and cartridges between 36°F to 46°F (2°C to 8°C) until time of use and keep in the original carton to protect from light. Do not freeze or use LYUMJEV if it has been frozen. Do not expose to direct heat. Discard opened or unopened LYUMJEV vials, pens, and cartridges stored at room temperature below 86°F (30°C) after 28 days.

The storage conditions for vials, pens, and cartridges are summarized in Table 9.

Table 9. Storage Conditions for Vials, Pens, and Cartridges

a In-use (opened) vials, whether or not refrigerated, must be used within 28 days.
b When stored at room temperature, LYUMJEV can only be used for a total of 28 days including both not in-use (unopened) and in-use (opened) storage time.
LYUMJEV Presentation	Not In-use (Unopened)		In-use (Opened)
	Room Temperature (below 86°F [30°C])	Refrigerated (36°F to 46°F [2°C to 8°C])	Room Temperature (below 86°F [30°C])	Refrigerated (36°F to 46°F [2°C to 8°C])
10 mL viala,b	28 days	Until expiration date	28 days	28 days
3 mL cartridgeb	28 days	Until expiration date	28 days	Do not refrigerate
3 mL LYUMJEV KwikPen (U-100 and U-200)b	28 days	Until expiration date	28 days	Do not refrigerate
3 mL LYUMJEV Junior KwikPenb	28 days	Until expiration date	28 days	Do not refrigerate
3 mL LYUMJEV Tempo Penb	28 days	Until expiration date	28 days	Do not refrigerate

Diluted LYUMJEV may be stored for up to 4 days when refrigerated at 36°F to 46°F (2°C to 8°C) and up to 12 hours at room temperature at 68°F to 77°F (20°C to 25°C) [see Dosage and Administration (2.2)].

17 Patient Counseling Information

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

Spl Patient Package Insert

LUM-0001-PPI-20200615

Instructions For Use

Instructions for Use

LYUMJEV™ (LOOM-jehv)

(insulin lispro-aabc) injection

for 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 a 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 a serious infection or get a serious infection from them.

Supplies needed to give your injection

• a multiple-dose LYUMJEV vial
• a U-100 insulin syringe and needle (Becton, Dickinson and Company syringes and needles recommended)
• 2 alcohol swabs
• gauze (optional)
• 1 sharps container for throwing away used syringes and needles. See “Disposing of used syringes and needles” at the end of these instructions.

Vial	Syringe
Figure - lyumjev u100 vial ifu f1 v1

Preparing your LYUMJEV dose

• 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 1 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 a 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 a 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 a 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 a 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 a syringe

• 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 a meal or within 20 minutes after you start a 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 5 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 a piece of gauze or an alcohol swab. Do not rub the area. Do not recap the needle. Recapping the needle can lead to a needle stick injury.

Disposing of used syringes and needles

• Put your used syringes and needles in a 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 a FDA-cleared sharps disposal container, you may use a household container that is:
  • – made of a heavy-duty plastic,
  • – can be closed with a 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 FDA's 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 I store LYUMJEV?

  All not in-use (unopened) vials:

  • Store all not in-use (unopened) vials in the refrigerator at 36°F to 46°F (2°C to 8°C).
  • 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 86°F (30°C) 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.

  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 launch

  www.lyumjev.com

  This Instructions for Use has been approved by the U.S. Food and Drug Administration.

  Manufactured by:
  Eli Lilly and Company
  Indianapolis, IN 46285, USA
  US License Number 1891

  LYUMJEV™ is a trademark of Eli Lilly and Company.

  Copyright © 2020, Eli Lilly and Company. All rights reserved.

  Issued: June 2020

  LUMVL-0001-IFU-20200615

  Instructions for Use

  LYUMJEV™ KwikPen^® (LOOM-jehv)

  (insulin lispro-aabc)

  injection, for subcutaneous use

  3 mL single-patient-use pen

  100 units/mL

  Read the Instructions for Use before you start taking LYUMJEV™ and each time you get another LYUMJEV KwikPen. 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 LYUMJEV KwikPen with other people, even if the needle has been changed. Do not reuse or share needles with other people. You may give other people a serious infection or get a serious infection from them.

  LYUMJEV KwikPen (“Pen”) is a disposable single-patient-use prefilled pen containing 300 units of LYUMJEV.

  • Your healthcare provider will tell you how many units to give as your dose and how to inject your prescribed dose of insulin.
  • You can give yourself more than 1 dose from the Pen.
  • Each turn of the dose knob dials 1 unit of insulin. You can give from 1 to 60 units in a single injection.
  • If your dose is more than 60 units, you will need to give yourself more than 1 injection. Always check the number in the dose window to make sure you dialed the correct dose.
  • The plunger only moves a little with each injection, and you may not notice that it moves. The plunger will only reach the end of the cartridge when you have used all 300 units in the Pen.

  People who are blind or have vision problems should not use the Pen without help from a person trained to use the Pen.

  How to recognize your LYUMJEV KwikPen

  Pen color:	Taupe
  Dose Knob:	Blue, with raised ridges on side
  Label:	Blue and white

  Supplies needed to give your injection

  • LYUMJEV KwikPen, 100 units/mL
  • KwikPen compatible needle (Becton, Dickinson and Company Pen needles recommended)
  • Alcohol swab
  • Gauze (optional)

  Preparing your Pen

  • Wash your hands with soap and water.
  • Check the Pen to make sure you are taking the right type of insulin. This is especially important if you use more than 1 type of insulin.
  • Do not use your Pen past the expiration date printed on the label or for more than 28 days after you first start using the Pen.
  • Always use a new needle for each injection to help prevent infections and blocked needles.
  Do not remove the Pen label.
  • Wipe the rubber seal with an alcohol swab.

  –

  Step 1: Pull the Pen cap straight off.
  Step 2: Check the liquid in the Pen. LYUMJEV should look clear and colorless. Do not use if it is cloudy, colored, or has particles or clumps in it.
  Step 3: Select a new needle. Pull off the paper tab from the outer needle shield.
  Step 4: Push the capped needle straight onto the Pen and twist the needle on until it is tight.
  Step 5: Pull off the outer needle shield. Do not throw it away. Pull off the inner needle shield and throw it away.

  Priming your Pen

  Prime before each injection.

  • Priming your Pen means removing the air from the needle and cartridge that may collect during normal use and ensures that your Pen is working correctly.
  • If you do not prime before each injection, you may get too much or too little insulin.
  If you do not see insulin, repeat priming steps 6 to 8, but not more than 4 times.
  If you still do not see insulin, change the needle and repeat priming steps 6 to 8.
  Small air bubbles are normal and will not affect your dose.

  –

  –

  Step 6: To prime your Pen, turn the dose knob to select 2 units.
  Step 7: Hold your Pen with the needle pointing up. Tap the cartridge holder gently to collect air bubbles at the top.
  Step 8: Continue holding your Pen with the needle pointing up. Push the dose knob in until it stops and “0” is seen in the dose window. Hold the dose knob in and count to 5 slowly. You should see insulin at the tip of the needle.

  Selecting your dose

  • You can give from 1 to 60 units in a single injection.
  • If your dose is more than 60 units, you will need to give more than 1 injection.
    • – If you need help with dividing up your dose the right way, ask your healthcare provider.
    • – Use a new needle for each injection and repeat the priming steps.
    The Pen dials 1 unit at a time.
    The dose knob clicks as you turn it.
    Do not dial your dose by counting the clicks. You may dial the wrong dose. This may lead to you getting too much insulin or not enough insulin.
    The dose can be corrected by turning the dose knob in either direction until the correct dose lines up with the dose indicator.
    The even numbers are printed on the dial. The example to the right shows 12 units in the dose window.
    The odd numbers, after the number 1, are shown as full lines between the numbers. The example to the right shows 25 units in the dose window.
    • Always check the number in the dose window to make sure you have dialed the correct dose.

    –

    –

    –

    –

    –

    –

    Step 9: Turn the dose knob to select the number of units you need to inject. The dose indicator should line up with your dose.

    Example: 12 units shown in the dose window Example: 25 units shown in the dose window

    • The Pen will not let you dial more than the number of units left in the Pen.
    • If you need to inject more than the number of units left in the Pen, you may either:
      • – inject the amount left in your Pen and then use a new Pen to give the rest of your dose,
        or
      • – get a new Pen and inject the full dose.
      • It is normal to see a small amount of insulin left in the Pen that you cannot inject.

      Giving your injection

      • Inject your insulin as your healthcare provider has shown you.
      • 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.
      • Do not try to change your dose while injecting.
      A drop of insulin at the needle tip is normal. It will not affect your dose.
      • Check the number in the dose window.
      If you see “0” in the dose window, you have received the full amount you dialed.
      If you do not see “0” in the dose window, you did not receive your full dose. Do not redial. Insert the needle into your skin and finish your injection.
      If you still do not think you received the full amount you dialed for your injection, do not start over or repeat that injection. Monitor your blood glucose as instructed by your healthcare provider.
      If you normally need to give 2 injections for your full dose, be sure to give your second injection. The plunger only moves a little with each injection, and you may not notice that it moves.
      If you see blood after you take the needle out of your skin, press the injection site lightly with a piece of gauze or an alcohol swab. Do not rub the area.
      

      –

      –

      –

      –

      –

      Step 10: Choose your injection site. LYUMJEV is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs or upper arms. Wipe your skin with an alcohol swab, and let your skin dry before you inject your dose.
      Step 11: Insert the needle into your skin. Push the dose knob all the way in.
      Continue to hold the dose knob in and slowly count to 5 before removing the needle. Do not try to inject your insulin by turning the dose knob. You will not receive your insulin by turning the dose knob.
      Step 12: Pull the needle out of your skin.

      After your injection

      Step 13: Carefully replace the outer needle shield.
      Step 14: Unscrew the capped needle and throw it away (see Disposing of Pens and needles section). Do not store the Pen with the needle attached to prevent leaking, blocking the needle, and air from entering the Pen.
      Step 15: Replace the Pen cap by lining up the cap clip with the dose indicator and pushing straight on.

      Disposing of Pens and needles

      • Put your used needles in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles in your household trash.
      • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
        • – made of a heavy-duty plastic,
        • – can be closed with a 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 needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's 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.
        • The used Pen may be discarded in your household trash after you have removed the needle.

        Storing your Pen

        Unused Pens

        • Store unused Pens in the refrigerator at 36°F to 46°F (2°C to 8°C).
        • Do not freeze LYUMJEV. Do not use if it has been frozen.
        • Unused Pens may be used until the expiration date printed on the label if the Pen has been kept in the refrigerator.

        In-use Pen

        • Store the Pen you are currently using at room temperature [up to 86°F (30°C)]. Keep away from heat and light.
        • Throw away the LYUMJEV KwikPen you are using after 28 days, even if it still has insulin left in it.

        General information about the safe and effective use of your Pen

        • Keep your Pen and needles out of the sight and reach of children.
        • Do not use your Pen if any part looks broken or damaged.
        • Always carry an extra Pen in case yours is lost or damaged.

        Troubleshooting

        • If you cannot remove the Pen cap, gently twist the cap back and forth, and then pull the cap straight off.
        • If the dose knob is hard to push:
          • – pushing the dose knob more slowly will make it easier to inject.
          • – your needle may be blocked. Put on a new needle and prime the Pen.
          • – you may have dust, food, or liquid inside the Pen. Throw the Pen away and get a new Pen.

          If you have any questions or problems with your LYUMJEV KwikPen, contact Lilly at 1-800-545-5979 or call your healthcare provider for help. For more information on LYUMJEV KwikPen and insulin, go to www.lyumjev.com.

          Scan this code to launch

          www.lyumjev.com

          This Instructions for Use has been approved by the U.S. Food and Drug Administration.

          Manufactured by:
          Eli Lilly and Company
          Indianapolis, IN 46285, USA
          US License Number 1891

          LYUMJEV™ and LYUMJEV™ KwikPen^® are trademarks of Eli Lilly and Company.

          Copyright © 2020, Eli Lilly and Company. All rights reserved.

          LYUMJEV KwikPen meets the current dose accuracy and functional requirements of ISO 11608-1.

          Issued: June 2020

          LUMKP-0001-IFU-20200615

          Instructions for Use

          LYUMJEV™ Junior KwikPen^® (LOOM-jehv)

          (insulin lispro-aabc)

          injection, for subcutaneous use

          3 mL single-patient-use pen

          100 units/mL

          Read the Instructions for Use before you start taking LYUMJEV™ and each time you get another LYUMJEV Junior KwikPen. 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 LYUMJEV Junior KwikPen with other people, even if the needle has been changed. Do not reuse or share needles with other people. You may give other people a serious infection or get a serious infection from them.

          LYUMJEV Junior KwikPen (“Pen”) is a disposable single-patient-use prefilled pen containing 300 units of LYUMJEV.

          • Your healthcare provider will tell you how many units to give as your dose and how to inject your prescribed dose of insulin.
          • You can give yourself more than 1 dose from the Pen.
          • Each turn of the dose knob dials 0.5 (½) unit of insulin. You can give from 0.5 (½) to 30 units in a single injection.
          • If your dose is more than 30 units, you will need to give yourself more than 1 injection. Always check the number in the dose window to make sure you dialed the correct dose.
          • The plunger only moves a little with each injection, and you may not notice that it moves. The plunger will only reach the end of the cartridge when you have used all 300 units in the Pen.

          People who are blind or have vision problems should not use the Pen without help from a person trained to use the Pen.

          How to recognize your LYUMJEV Junior KwikPen

          Pen color:	Taupe
          Dose knob:	Peach, with raised ridges on end and side
          Label:	White with a peach color bar, and peach, light blue and dark blue color band

          Supplies needed to give your injection

          • LYUMJEV Junior KwikPen, 100 units/mL
          • KwikPen compatible needle (Becton, Dickinson and Company Pen needles recommended)
          • Alcohol swab
          • Gauze (optional)

          Preparing your Pen

          • Wash your hands with soap and water.
          • Check the Pen to make sure you are taking the right type of insulin. This is especially important if you use more than 1 type of insulin.
          • Do not use your Pen past the expiration date printed on the label or for more than 28 days after you first start using the Pen.
          • Always use a new needle for each injection to help prevent infections and blocked needles.
          Do not remove the Pen label.
          • Wipe the rubber seal with an alcohol swab.

          –

          Step 1: Pull the Pen cap straight off.
          Step 2: Check the liquid in the Pen. LYUMJEV should look clear and colorless. Do not use if it is cloudy, colored, or has particles or clumps in it.
          Step 3: Select a new needle. Pull off the paper tab from the outer needle shield.
          Step 4: Push the capped needle straight onto the Pen and twist the needle on until it is tight.
          Step 5: Pull off the outer needle shield. Do not throw it away. Pull off the inner needle shield and throw it away.

          Priming your Pen

          Prime before each injection.

          • Priming your Pen means removing the air from the needle and cartridge that may collect during normal use and ensures that your Pen is working correctly.
          • If you do not prime before each injection, you may get too much or too little insulin.
          If you do not see insulin, repeat priming steps 6 to 8, but not more than 4 times.
          If you still do not see insulin, change the needle and repeat priming steps 6 to 8. Small air bubbles are normal and will not affect your dose.
          

          –

          –

          Step 6: To prime your Pen, turn the dose knob to select 2 units.
          Step 7: Hold your Pen with the needle pointing up. Tap the cartridge holder gently to collect air bubbles at the top.
          Step 8: Continue holding your Pen with the needle pointing up. Push the dose knob in until it stops and “0” is seen in the dose window. Hold the dose knob in and count to 5 slowly. You should see insulin at the tip of the needle.

          Selecting your dose

          • You can give from 0.5 (½) to 30 units in a single injection.
          • If your dose is more than 30 units, you will need to give more than 1 injection.
            • – If you need help with dividing up your dose the right way, ask your healthcare provider.
            • – Use a new needle for each injection and repeat the priming steps.
            • – If you usually need more than 30 units, ask your healthcare provider if a different LYUMJEV Pen would be better for you.
            The Pen dials 0.5 (½) unit at a time.
            The dose knob clicks as you turn it.
            Do not dial your dose by counting the clicks. You may dial the wrong dose. This may lead to you getting too much insulin or not enough insulin.
            The dose can be corrected by turning the dose knob in either direction until the correct dose lines up with the dose indicator.
            The whole unit numbers are printed on the dial. The example to the right shows 4 units in the dose window.
            The half units are shown as lines between the whole unit numbers. The example to the right shows 10.5 units in the dose window.
            • Always check the number in the dose window to make sure you have dialed the correct dose.

            –

            –

            –

            –

            –

            –

            Step 9: Turn the dose knob to select the number of units you need to inject. The dose indicator should line up with your dose.

            Example: 4 units shown in the dose window Example: 10.5 (10 ½) units shown in the dose window

            • The Pen will not let you dial more than the number of units left in the Pen.
            • If you need to inject more than the number of units left in the Pen, you may either:
              • – inject the amount left in your Pen and then use a new Pen to give the rest of your dose,
                or
              • – get a new Pen and inject the full dose.
              • It is normal to see a small amount of insulin left in the Pen that you cannot inject.

              Giving your injection

              • Inject your insulin as your healthcare provider has shown you.
              • 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.
              • Do not try to change your dose while injecting.
              A drop of insulin at the needle tip is normal. It will not affect your dose.
              • Check the number in the dose window.
              If you see “0” in the dose window, you have received the full amount you dialed.
              If you do not see “0” in the dose window, you did not receive your full dose. Do not redial. Insert the needle into your skin and finish your injection.
              If you still do not think you received the full amount you dialed for your injection, do not start over or repeat that injection. Monitor your blood glucose as instructed by your healthcare provider.
              If you normally need to give 2 injections for your full dose, be sure to give your second injection. The plunger only moves a little with each injection, and you may not notice that it moves.
              If you see blood after you take the needle out of your skin, press the injection site lightly with a piece of gauze or an alcohol swab. Do not rub the area.
              

              –

              –

              –

              –

              –

              Step 10: Choose your injection site. LYUMJEV is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs or upper arms. Wipe your skin with an alcohol swab, and let your skin dry before you inject your dose.
              Step 11: Insert the needle into your skin. Push the dose knob all the way in.
              Continue to hold the dose knob in and slowly count to 5 before removing the needle. Do not try to inject your insulin by turning the dose knob. You will not receive your insulin by turning the dose knob.
              Step 12: Pull the needle out of your skin.

              After your injection

              Step 13: Carefully replace the outer needle shield.
              Step 14: Unscrew the capped needle and throw it away (see Disposing of Pens and needles section). Do not store the Pen with the needle attached to prevent leaking, blocking the needle, and air from entering the Pen.
              Step 15: Replace the Pen cap by lining up the cap clip with the dose indicator and pushing straight on.

              Disposing of Pens and needles

              • Put your used needles in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles in your household trash.
              • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
                • – made of a heavy-duty plastic,
                • – can be closed with a 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 needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's 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.
                • The used Pen may be discarded in your household trash after you have removed the needle.

                Storing your Pen

                Unused Pens

                • Store unused Pens in the refrigerator at 36°F to 46°F (2°C to 8°C).
                • Do not freeze LYUMJEV. Do not use if it has been frozen.
                • Unused Pens may be used until the expiration date printed on the label if the Pen has been kept in the refrigerator.

                In-use Pen

                • Store the Pen you are currently using at room temperature [up to 86°F (30°C)]. Keep away from heat and light.
                • Throw away the LYUMJEV Junior KwikPen you are using after 28 days, even if it still has insulin left in it.

                General information about the safe and effective use of your Pen

                • Keep your Pen and needles out of the sight and reach of children.
                • Do not use your Pen if any part looks broken or damaged.
                • Always carry an extra Pen in case yours is lost or damaged.

                Troubleshooting

                • If you cannot remove the Pen cap, gently twist the cap back and forth, and then pull the cap straight off.
                • If the dose knob is hard to push:
                  • – pushing the dose knob more slowly will make it easier to inject.
                  • – your needle may be blocked. Put on a new needle and prime the Pen.
                  • – you may have dust, food, or liquid inside the Pen. Throw the Pen away and get a new Pen.

                  If you have any questions or problems with your LYUMJEV Junior KwikPen, contact Lilly at 1-800-545-5979 or call your healthcare provider for help. For more information on LYUMJEV Junior KwikPen and insulin, go to www.lyumjev.com.

                  Scan this code to launch

                  www.lyumjev.com

                  This Instructions for Use has been approved by the U.S. Food and Drug Administration.

                  Manufactured by:
                  Eli Lilly and Company
                  Indianapolis, IN 46285, USA
                  US License Number 1891

                  LYUMJEV™ and LYUMJEV™ Junior KwikPen^® are trademarks of Eli Lilly and Company.

                  Copyright © 2020, Eli Lilly and Company. All rights reserved.

                  LYUMJEV Junior KwikPen meets the current dose accuracy and functional requirements of ISO 11608-1.

                  Issued: June 2020

                  LUMJRKP-0001-IFU-20200615

                  Instructions for Use

                  LYUMJEV™ Tempo Pen™ (LOOM-jehv)

                  (insulin lispro-aabc)

                  injection, for subcutaneous use

                  3 mL single-patient-use pen

                  100 units/mL

                  Read the Instructions for Use before you start taking LYUMJEV™ and each time you get another LYUMJEV Tempo Pen. 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 LYUMJEV Tempo Pen with other people, even if the needle has been changed. Do not reuse or share needles with other people. You may give other people a serious infection or get a serious infection from them.

                  LYUMJEV Tempo Pen (“Pen”) is a disposable single-patient-use prefilled pen containing 300 units of LYUMJEV.

                  • Your healthcare provider will tell you how many units to give as your dose and how to inject your prescribed dose of insulin.
                  • You can give yourself more than 1 dose from the Pen.
                  • Each turn of the dose knob dials 1 unit of insulin. You can give from 1 to 60 units in a single injection.
                  • If your dose is more than 60 units, you will need to give yourself more than 1 injection. Always check the number in the dose window to make sure you dialed the correct dose.
                  • The plunger only moves a little with each injection, and you may not notice that it moves. The plunger will only reach the end of the cartridge when you have used all 300 units in the Pen.
                  • This LYUMJEV Tempo Pen contains a component that allows for data connectivity when used with a compatible transmitter.

                  People who are blind or have vision problems should not use the Pen without help from a person trained to use the Pen.

                  How to recognize your LYUMJEV Tempo Pen

                  Pen color:	Taupe
                  Dose Knob:	Blue, with raised ridges around the entire side
                  Label:	Blue and white

                  Supplies needed to give your injection

                  • LYUMJEV Tempo Pen, 100 units/mL
                  • Tempo Pen compatible needle (Becton, Dickinson and Company Pen needles recommended)
                  • Alcohol swab
                  • Gauze (optional)

                  Preparing your Pen

                  • Wash your hands with soap and water.
                  • Check the Pen to make sure you are taking the right type of insulin. This is especially important if you use more than 1 type of insulin.
                  • Do not use your Pen past the expiration date printed on the label or for more than 28 days after you first start using the Pen.
                  • Always use a new needle for each injection to help prevent infections and blocked needles.
                  Do not remove the Pen label.
                  • Wipe the rubber seal with an alcohol swab.

                  –

                  Step 1: Pull the Pen cap straight off.
                  Step 2: Check the liquid in the Pen. LYUMJEV should look clear and colorless. Do not use if it is cloudy, colored, or has particles or clumps in it.
                  Step 3: Select a new needle. Pull off the paper tab from the outer needle shield.
                  Step 4: Push the capped needle straight onto the Pen and twist the needle on until it is tight.
                  Step 5: Pull off the outer needle shield. Do not throw it away. Pull off the inner needle shield and throw it away.

                  Priming your Pen

                  Prime before each injection.

                  • Priming your Pen means removing the air from the needle and cartridge that may collect during normal use and ensures that your Pen is working correctly.
                  • If you do not prime before each injection, you may get too much or too little insulin.
                  If you do not see insulin, repeat priming steps 6 to 8, but not more than 4 times.
                  If you still do not see insulin, change the needle and repeat priming steps 6 to 8. Small air bubbles are normal and will not affect your dose.
                  

                  –

                  –

                  Step 6: To prime your Pen, turn the dose knob to select 2 units.
                  Step 7: Hold your Pen with the needle pointing up. Tap the cartridge holder gently to collect air bubbles at the top.
                  Step 8: Continue holding your Pen with the needle pointing up. Push the dose knob in until it stops and “0” is seen in the dose window. Hold the dose knob in and count to 5 slowly. You should see insulin at the tip of the needle.

                  Selecting your dose

                  • You can give from 1 to 60 units in a single injection.
                  • If your dose is more than 60 units, you will need to give more than 1 injection.
                    • – If you need help with dividing up your dose the right way, ask your healthcare provider.
                    • – Use a new needle for each injection and repeat the priming steps.
                    The Pen dials 1 unit at a time.
                    The dose knob clicks as you turn it.
                    Do not dial your dose by counting the clicks. You may dial the wrong dose. This may lead to you getting too much insulin or not enough insulin.
                    The dose can be corrected by turning the dose knob in either direction until the correct dose lines up with the dose indicator.
                    The even numbers are printed on the dial. The example to the right shows 12 units in the dose window.
                    The odd numbers, after the number 1, are shown as full lines between the numbers. The example to the right shows 25 units in the dose window.
                    • Always check the number in the dose window to make sure you have dialed the correct dose.

                    –

                    –

                    –

                    –

                    –

                    –

                    Step 9: Turn the dose knob to select the number of units you need to inject. The dose indicator should line up with your dose.

                    Example: 12 units shown in the dose window Example: 25 units shown in the dose window

                    • The Pen will not let you dial more than the number of units left in the Pen.
                    • If you need to inject more than the number of units left in the Pen, you may either:
                      • – inject the amount left in your Pen and then use a new Pen to give the rest of your dose,
                        or
                      • – get a new Pen and inject the full dose.
                      • It is normal to see a small amount of insulin left in the Pen that you cannot inject.

                      Giving your injection

                      • Inject your insulin as your healthcare provider has shown you.
                      • 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.
                      • Do not try to change your dose while injecting.
                      A drop of insulin at the needle tip is normal. It will not affect your dose.
                      • Check the number in the dose window.
                      If you see “0” in the dose window, you have received the full amount you dialed.
                      If you do not see “0” in the dose window, you did not receive your full dose. Do not redial. Insert the needle into your skin and finish your injection.
                      If you still do not think you received the full amount you dialed for your injection, do not start over or repeat that injection. Monitor your blood glucose as instructed by your healthcare provider.
                      If you normally need to give 2 injections for your full dose, be sure to give your second injection.
                      
                      
                      
                      
                      The plunger only moves a little with each injection, and you may not notice that it moves.
                      If you see blood after you take the needle out of your skin, press the injection site lightly with a piece of gauze or an alcohol swab. Do not rub the area.
                      

                      –

                      –

                      –

                      –

                      –

                      Step 10: Choose your injection site. LYUMJEV is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs or upper arms. Wipe your skin with an alcohol swab, and let your skin dry before you inject your dose.
                      Step 11: Insert the needle into your skin. Push the dose knob all the way in.
                      Continue to hold the dose knob in and slowly count to 5 before removing the needle. Do not try to inject your insulin by turning the dose knob. You will not receive your insulin by turning the dose knob.
                      Step 12: Pull the needle out of your skin.

                      After your injection

                      Step 13: Carefully replace the outer needle shield.
                      Step 14: Unscrew the capped needle and throw it away (see Disposing of Pens and needles section). Do not store the Pen with the needle attached to prevent leaking, blocking the needle, and air from entering the Pen.
                      Step 15: Replace the Pen cap by lining up the cap clip with the dose indicator and pushing straight on.

                      Disposing of Pens and needles

                      • Put your used needles in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles in your household trash.
                      • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
                        • – made of a heavy-duty plastic,
                        • – can be closed with a 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 needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's 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.
                        • The used Pen may be discarded in your household trash after you have removed the needle.

                        Storing your Pen

                        Unused Pens

                        • Store unused Pens in the refrigerator at 36°F to 46°F (2°C to 8°C).
                        • Do not freeze LYUMJEV. Do not use if it has been frozen.
                        • Unused Pens may be used until the expiration date printed on the label if the Pen has been kept in the refrigerator.

                        In-use Pen

                        • Store the Pen you are currently using at room temperature [up to 86°F (30°C)]. Keep away from heat and light.
                        • Throw away the LYUMJEV Tempo Pen you are using after 28 days, even if it still has insulin left in it.

                        General information about the safe and effective use of your Pen

                        • Keep your Pen and needles out of the sight and reach of children.
                        • Do not use your Pen if any part looks broken or damaged.
                        • Always carry an extra Pen in case yours is lost or damaged.

                        Troubleshooting

                        • If you cannot remove the Pen cap, gently twist the cap back and forth, and then pull the cap straight off.
                        • If the dose knob is hard to push:
                          • – pushing the dose knob more slowly will make it easier to inject.
                          • – your needle may be blocked. Put on a new needle and prime the Pen.
                          • – you may have dust, food, or liquid inside the Pen. Throw the Pen away and get a new Pen.

                          If you have any questions or problems with your LYUMJEV Tempo Pen, contact Lilly at 1-800-545-5979 or call your healthcare provider for help. For more information on LYUMJEV Tempo Pen and insulin, go to www.lyumjev.com.

                          Scan this code to launch

                          www.lyumjev.com

                          This Instructions for Use has been approved by the U.S. Food and Drug Administration.

                          Manufactured by:
                          Eli Lilly and Company
                          Indianapolis, IN 46285, USA
                          US License Number 1891

                          LYUMJEV™ and LYUMJEV™ Tempo Pen™ are trademarks of Eli Lilly and Company.

                          Copyright © 2020, Eli Lilly and Company. All rights reserved.

                          LYUMJEV Tempo Pen meets the current dose accuracy and functional requirements of ISO 11608-1.

                          Issued: June 2020

                          LUMTP-0001-IFU-20200615

                          Instructions for Use

                          LYUMJEV™ KwikPen^® (LOOM-jehv)

                          (insulin lispro-aabc)

                          injection, for subcutaneous use

                          3 mL single-patient-use pen

                          200 units/mL

                          Read the Instructions for Use before you start taking LYUMJEV™ and each time you get another LYUMJEV KwikPen. 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 LYUMJEV KwikPen with other people, even if the needle has been changed. Do not reuse or share needles with other people. You may give other people a serious infection or get a serious infection from them.

                          LYUMJEV KwikPen (“Pen”) is a disposable single-patient-use prefilled pen containing 600 units of LYUMJEV.

                          • Your healthcare provider will tell you how many units to give as your dose and how to inject your prescribed dose of insulin.
                          • You can give yourself more than 1 dose from the Pen.
                          • Each turn of the dose knob dials 1 unit of insulin. You can give from 1 to 60 units in a single injection.
                          • If your dose is more than 60 units, you will need to give yourself more than 1 injection. Always check the number in the dose window to make sure you dialed the correct dose.
                          • The plunger only moves a little with each injection, and you may not notice that it moves. The plunger will only reach the end of the cartridge when you have used all 600 units in the Pen.

                          LYUMJEV KwikPen is available in two strengths, 100 units/mL and 200 units/mL. Inject LYUMJEV 200 units/mL only with your Pen. Do not transfer insulin from your Pen to a syringe. Syringes will not measure 200 units/mL of insulin correctly. A severe overdose can result, causing very low blood sugar which may put your life in danger.

                          People who are blind or have vision problems should not use the Pen without help from a person trained to use the Pen.

                          How to recognize your LYUMJEV KwikPen

                          Pen color:	Taupe
                          Dose Knob:	Taupe, with raised ridges on side
                          Label:	White with a blue color bar and checkerboard design with “200 units per mL (U-200)” in a yellow stripe. Yellow warning on cartridge holder.

                          Supplies needed to give your injection

                          • LYUMJEV KwikPen, 200 units/mL
                          • KwikPen compatible needle (Becton, Dickinson and Company Pen needles recommended)
                          • Alcohol swab
                          • Gauze (optional)

                          Preparing your Pen

                          • Wash your hands with soap and water.
                          • Check the Pen to make sure you are taking the right type of insulin. This is especially important if you use more than 1 type of insulin.
                          • Do not use your Pen past the expiration date printed on the label or for more than 28 days after you first start using the Pen.
                          • Always use a new needle for each injection to help prevent infections and blocked needles.
                          Do not remove the Pen label.
                          • Wipe the rubber seal with an alcohol swab.

                          –

                          Step 1: Pull the Pen cap straight off.
                          Step 2: Check the liquid in the Pen. LYUMJEV should look clear and colorless. Do not use if it is cloudy, colored, or has particles or clumps in it.
                          Step 3: Select a new needle. Pull off the paper tab from the outer needle shield.
                          Step 4: Push the capped needle straight onto the Pen and twist the needle on until it is tight.
                          Step 5: Pull off the outer needle shield. Do not throw it away. Pull off the inner needle shield and throw it away.

                          Priming your Pen

                          Prime before each injection.

                          • Priming your Pen means removing the air from the needle and cartridge that may collect during normal use and ensures that your Pen is working correctly.
                          • If you do not prime before each injection, you may get too much or too little insulin.
                          If you do not see insulin, repeat priming steps 6 to 8, but not more than 8 times.
                          If you still do not see insulin, change the needle and repeat priming steps 6 to 8. Small air bubbles are normal and will not affect your dose.
                          

                          –

                          –

                          Step 6: To prime your Pen, turn the dose knob to select 2 units.
                          Step 7: Hold your Pen with the needle pointing up. Tap the cartridge holder gently to collect air bubbles at the top.
                          Step 8: Continue holding your Pen with the needle pointing up. Push the dose knob in until it stops and “0” is seen in the dose window. Hold the dose knob in and count to 5 slowly. You should see insulin at the tip of the needle.

                          Selecting your dose

                          This Pen has been designed to deliver the dose that is shown in the dose window. Dial your usual dose as instructed by your healthcare provider.

                          • You can give from 1 to 60 units in a single injection.
                          • If your dose is more than 60 units, you will need to give more than 1 injection.
                            • – If you need help dividing up your dose the right way, ask your healthcare provider.
                            • – Use a new needle for each injection and repeat the priming steps.
                            The Pen dials 1 unit at a time.
                            The dose knob clicks as you turn it.
                            Do not dial your dose by counting the clicks. You may dial the wrong dose. This may lead to you getting too much insulin or not enough insulin.
                            The dose can be corrected by turning the dose knob in either direction until the correct dose lines up with the dose indicator.
                            The even numbers are printed on the dial. The example to the right shows 12 units in the dose window.
                            The odd numbers, after the number 1, are shown as full lines between the numbers. The example to the right shows 25 units in the dose window.
                            • Always check the number in the dose window to make sure you have dialed the correct dose.

                            –

                            –

                            –

                            –

                            –

                            –

                            Step 9: Turn the dose knob to select the number of units you need to inject. The dose indicator should line up with your dose.

                            Example: 12 units shown in the dose window Example: 25 units shown in the dose window

                            • The Pen will not let you dial more than the number of units left in the Pen.
                            • If you need to inject more than the number of units left in the Pen, you may either:
                              • – inject the amount left in your Pen and then use a new Pen to give the rest of your dose,
                                or
                              • – get a new Pen and inject the full dose.
                              • It is normal to see a small amount of insulin left in the Pen that you cannot inject. Do not transfer this to a syringe. Severe overdose can result.

                              Giving your injection

                              • Inject your insulin as your healthcare provider has shown you.
                              • 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.
                              • Do not try to change your dose while injecting.
                              A drop of insulin at the needle tip is normal. It will not affect your dose.
                              • Check the number in the dose window.
                              If you see “0” in the dose window, you have received the full amount you dialed.
                              If you do not see “0” in the dose window, you did not receive your full dose. Do not redial. Insert the needle into your skin and finish your injection.
                              If you still do not think you received the full amount you dialed for your injection, do not start over or repeat that injection. Monitor your blood glucose as instructed by your healthcare provider.
                              If you normally need to give 2 injections for your full dose, be sure to give your second injection. The plunger only moves a little with each injection, and you may not notice that it moves.
                              If you see blood after you take the needle out of your skin, press the injection site lightly with a piece of gauze or an alcohol swab. Do not rub the area.
                              

                              –

                              –

                              –

                              –

                              –

                              Step 10: Choose your injection site. LYUMJEV is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs or upper arms. Wipe your skin with an alcohol swab, and let your skin dry before you inject your dose.
                              Step 11: Insert the needle into your skin. Push the dose knob all the way in.
                              Continue to hold the dose knob in and slowly count to 5 before removing the needle. Do not try to inject your insulin by turning the dose knob. You will not receive your insulin by turning the dose knob.
                              Step 12: Pull the needle out of your skin.

                              After your injection

                              Step 13: Carefully replace the outer needle shield
                              Step 14: Unscrew the capped needle and throw it away (see Disposing of Pens and needles section). Do not store the Pen with the needle attached to prevent leaking, blocking the needle, and air from entering the Pen.
                              Step 15: Replace the Pen cap by lining up the cap clip with the dose indicator and pushing straight on.

                              Disposing of Pens and needles

                              • Put your used needles in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles in your household trash.
                              • If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:
                                • – made of a heavy-duty plastic,
                                • – can be closed with a 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 needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's 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.
                                • The used Pen may be discarded in your household trash after you have removed the needle.

                                Storing your Pen

                                Unused Pens

                                • Store unused Pens in the refrigerator at 36°F to 46°F (2°C to 8°C).
                                • Do not freeze LYUMJEV. Do not use if it has been frozen.
                                • Unused Pens may be used until the expiration date printed on the label if the Pen has been kept in the refrigerator.

                                In-use Pen

                                • Store the Pen you are currently using at room temperature [up to 86°F (30°C)]. Keep away from heat and light.
                                • Throw away the LYUMJEV KwikPen you are using after 28 days, even if it still has insulin left in it.

                                General information about the safe and effective use of your Pen

                                • Keep your Pen and needles out of the sight and reach of children.
                                • Do not use your Pen if any part looks broken or damaged.
                                • Always carry an extra Pen in case yours is lost or damaged.

                                Troubleshooting

                                • If you cannot remove the Pen cap, gently twist the cap back and forth, and then pull the cap straight off.
                                • If the dose knob is hard to push:
                                  • – pushing the dose knob more slowly will make it easier to inject.
                                  • – your needle may be blocked. Put on a new needle and prime the Pen.
                                  • – you may have dust, food, or liquid inside the Pen. Throw the Pen away and get a new Pen.

                                  If you have any questions or problems with your LYUMJEV KwikPen, contact Lilly at 1-800-545-5979 or call your healthcare provider for help. For more information on LYUMJEV KwikPen and insulin, go to www.lyumjev.com.

                                  Scan this code to launch

                                  www.lyumjev.com

                                  This Instructions for Use has been approved by the U.S. Food and Drug Administration.

                                  Manufactured by:
                                  Eli Lilly and Company
                                  Indianapolis, IN 46285, USA
                                  US License Number 1891

                                  LYUMJEV™ and LYUMJEV™ KwikPen^® are trademarks of Eli Lilly and Company.

                                  Copyright © 2020, Eli Lilly and Company. All rights reserved.

                                  LYUMJEV KwikPen meets the current dose accuracy and functional requirements of ISO 11608-1.

                                  Issued: June 2020

                                  LUMKP200-0001-IFU-20200615

                                  
                                  

Package Label.Principal Display Panel

PACKAGE LABEL – LYUMJEV U100 Vial Carton

NDC 0002-7728-01

LYUMJEV^TM

(insulin lispro-aabc)

injection

100 units per mL (U-100)

for subcutaneous or intravenous use

10 mL multiple-dose vial

Rx only

www.lyumjev.com

Lilly

PACKAGE LABEL – LYUMJEV U100 Vial Carton - lyumjev u100 vial 044 00

PACKAGE LABEL – LYUMJEV U100 Cartridges 5 Count Carton

NDC 0002-7726-05

5 x 3 mL Cartridges

LYUMJEV^TM

(insulin lispro-aabc)

injection

For Single Patient Use Only

100 units per mL (U-100)

For subcutaneous use

5 x 3 mL prefilled pens

Rx only

For use in Eli Lilly and Company's HumaPen^® LUXURA^®HD and other compatible insulin delivery devices.

www.lyumjev.com

Lilly

PACKAGE LABEL – LYUMJEV U100 KwikPen 5 Count Carton

Dispense in this sealed carton.

NDC 0002-8207-05

LYUMJEV^TM KwikPen^®

(insulin lispro-aabc)

injection

For Single Patient Use Only

100 units per mL (U-100)

For subcutaneous use

5 x 3 mL prefilled pens

Rx only

Needles not included

This device is recommended for use with Becton, Dickinson and Company's insulin pen needles.

Lilly

PACKAGE LABEL – LYUMJEV U100 Junior KwikPen 5 Count Carton

Dispense in this sealed carton.

NDC 0002-8351-05

LYUMJEV^TM

Junior KwikPen^®

(insulin lispro-aabc)

injection

For Single Patient Use Only

100 units per mL (U-100)

This pen can deliver 0.5 (1/2) to 30 units in one injection.

5 x 3 mL prefilled pens

For subcutaneous use

Rx only

Needles not included

This device is recommended for use with Becton, Dickinson and Company's insulin pen needles.

Lilly

PACKAGE LABEL – LYUMJEV U100 Tempo Pen 5 Count Carton

Dispense in this sealed carton.

NDC 0002-8235-05

LYUMJEV^TM Tempo Pen^TM

(insulin lispro-aabc)

injection

For Single Patient Use Only

100 units per mL (U-100)

For subcutaneous use

5 x 3 mL prefilled pens

Rx only

Needles not included

This device is recommended for use with Becton, Dickinson and Company's insulin pen needles.

Lilly

PACKAGE LABEL – LYUMJEV U200 KwikPen 5 Count Carton

Dispense in this sealed carton.

NDC 0002-8228-27

LYUMJEV^TM KwikPen^®

(insulin lispro-aabc)

injection

For Single Patient Use Only

200 units per mL (U-200)

For subcutaneous use

2 x 3 mL prefilled pens

Rx only

Needles not included

This device is recommended for use with Becton, Dickinson and Company's insulin pen needles.

Lilly

DO NOT TRANSFER TO A SYRINGE SEVERE OVERDOSE CAN RESULT