DailyMed - INSULIN LISPRO injection, solution

NDC Code(s): 50090-5391-0
Packager: A-S Medication Solutions
This is a repackaged label.
Source NDC Code(s): 0002-7737

Category: HUMAN PRESCRIPTION DRUG LABEL
DEA Schedule: None
Marketing Status: Biologic Licensing Application

Drug Label Information

Updated May 31, 2024

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HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use INSULIN LISPRO safely and effectively. See full prescribing information for INSULIN LISPRO.

INSULIN LISPRO injection, for subcutaneous or intravenous use
Initial U.S. Approval: 1996
This product is HUMALOG® (insulin lispro).

INDICATIONS AND USAGE

Insulin Lispro is a rapid acting human insulin analog indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus. (1)
DOSAGE AND ADMINISTRATION
- See Full Prescribing Information for important administration instructions. (2.1, 2.2, 2.3, 2.4)
- Subcutaneous Injection (2.2):
  
  Administer Insulin Lispro by subcutaneous injection into the abdominal wall, thigh, upper arm, or buttocks within 15 minutes before a meal or immediately after a meal.
  
  Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis.
- Continuous subcutaneous infusion (Insulin Pump) (2.2):
  
  Refer to the insulin infusion pump user manual to see if Humalog can be used. Use in accordance with the insulin pump instructions for use.
  
  Administer Insulin Lispro by continuous subcutaneous infusion using an insulin pump in a region recommended in the instructions from the pump manufacturer.
  
  Rotate infusion sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis.
- Intravenous Infusion (2.2):
  
  Administer Insulin Lispro by intravenous infusion ONLY after dilution and under medical supervision.
- The dosage of Insulin Lispro must be individualized based on the route of administration and the individual's metabolic needs, blood glucose monitoring results and glycemic control goal. (2.3)
- Do not perform dose conversion when using the Insulin Lispro prefilled pens. The dose window shows the number of insulin units to be delivered and no conversion is needed. (2.1, 2.3)
DOSAGE FORMS AND STRENGTHS
Injection: 100 units/mL (U-100) is available as: (3)
- 10 mL multiple-dose vial
- 3 mL single-patient-use KwikPen® prefilled pen
- 3 mL single-patient-use Junior KwikPen® prefilled pen
CONTRAINDICATIONS
- Do not use during episodes of hypoglycemia. (4)
- Do not use in patients with hypersensitivity to Insulin Lispro or any of the excipients in Insulin Lispro. (4)
WARNINGS AND PRECAUTIONS
- Never share an Insulin Lispro prefilled pen or syringe between patients, even if the needle is changed. (5.1)
- Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen: Make changes to a patient's insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring. (5.2)
- Hypoglycemia: May be life-threatening. Monitor blood glucose and increase monitoring frequency with changes to insulin dosage, use of glucose lowering medications, meal pattern, physical activity; in patients with renal or hepatic impairment; and in patients with hypoglycemia unawareness. (5.3, 7, 8.6, 8.7)
- Hypoglycemia Due to Medication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection. (5.4)
- Hypersensitivity Reactions: May be life-threatening. Discontinue Insulin Lispro, monitor and treat if indicated. (5.5)
- Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated. (5.6)
- Fluid Retention and Heart Failure with Concomitant Use of Thiazolidinediones (TZDs): Observe for signs and symptoms of heart failure; consider dosage reduction or discontinuation if heart failure occurs. (5.7)
- Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction: Monitor glucose and administer Insulin Lispro by subcutaneous injection if pump malfunction occurs. (5.8)
ADVERSE REACTIONS

Adverse reactions associated with Insulin Lispro include hypoglycemia, allergic reactions, injection site reactions, lipodystrophy, pruritus, and rash. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
DRUG INTERACTIONS
- Drugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics (7).
- Drugs that may decrease the blood glucose lowering effect: atypical antipsychotics, corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones (7).
- Drugs that may increase or decrease the blood glucose lowering effect: alcohol, beta-blockers, clonidine, lithium salts, and pentamidine (7).
- Drugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine (7).
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.

Revised: 5/2024
Table of Contents

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

2.2 Administration Instructions for the Approved Routes of Administration

2.3 Dosage Recommendations

2.4 Dosage Modifications for Drug Interactions

2.5 Instructions for Mixing with Other Insulins

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Never Share an Insulin Lispro Prefilled Pen 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 Hypersensitivity Reactions

5.6 Hypokalemia

5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists

5.8 Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

14.1 Type 1 Diabetes – Adults and Pediatric Patients Aged 12 Years and Older

14.2 Type 1 Diabetes – Pediatric Patients

14.3 Type 1 Diabetes – Adults: Continuous Subcutaneous Insulin Infusion

14.4 Type 1 Diabetes – Pediatric Patients: Continuous Subcutaneous Insulin Infusion

14.5 Type 2 Diabetes – Adults

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

*

Sections or subsections omitted from the full prescribing information are not listed.
1 INDICATIONS AND USAGE

Insulin Lispro is indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus.

2 DOSAGE AND ADMINISTRATION

2.1 Important Administration Instructions

Always check insulin labels before administration. This product is HUMALOG (insulin lispro) [see Warnings and Precautions (5.4)].
Inspect Insulin Lispro visually before use. It should appear clear and colorless. Do not use Insulin Lispro if particulate matter or coloration is seen.
Use Insulin Lispro prefilled pens with caution in patients with visual impairment that may rely on audible clicks to dial their dose.
Do NOT mix Insulin Lispro with other insulins when using a continuous subcutaneous infusion pump.
Do NOT perform dose conversion when using any Insulin Lispro prefilled pens. The dose window shows the number of insulin units to be delivered and no conversion is needed.

2.2 Administration Instructions for the Approved Routes of Administration

Subcutaneous Injection

Administer the dose of Insulin Lispro within fifteen minutes before a meal or immediately after a meal by injection into the subcutaneous tissue of the abdominal wall, thigh, upper arm, or buttocks.
Rotate the injection site within the same region from one injection to the next (abdominal wall, thigh, upper arm, or buttocks) to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2) and Adverse Reactions (6)].
During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].
Insulin Lispro administered by subcutaneous injection should generally be used in regimens with an intermediate- or long-acting insulin.
The Insulin Lispro KwikPen dials in 1 unit increments and delivers a maximum dose of 60 units per injection.
The Insulin Lispro Junior KwikPen dials in 0.5 unit increments and delivers a maximum dose of 30 units per injection.

Subcutaneous Injection: Diluted Insulin Lispro

Insulin Lispro may be diluted with Sterile Diluent for Insulin Lispro for subcutaneous injection ONLY under medical supervision. Dilute one part Insulin Lispro to:
- Nine parts diluent to yield a concentration one-tenth that of Insulin Lispro (equivalent to U-10).
- One part diluent to yield a concentration one-half that of Insulin Lispro (equivalent to U-50).
Diluted Insulin Lispro for subcutaneous injection may be stored for 28 days when refrigerated at 41°F (5°C) and for 14 days at room temperature up to 86°F (30°C).

Continuous Subcutaneous Infusion (Insulin Pump)

This Insulin Lispro product can be used with continuous subcutaneous insulin infusion pumps labeled for use with Humalog (insulin lispro). Refer to the insulin pump user manual to see if Humalog can be used. Use Insulin Lispro in accordance with the insulin pump system's instructions for use.
Administer Insulin Lispro by continuous subcutaneous infusion in a region recommended in the instructions from the pump manufacturer.
Rotate infusion sites within the same region to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2) and Adverse Reactions (6)].
Train patients using continuous subcutaneous insulin infusion therapy to administer insulin by injection and have alternate insulin therapy available in case of insulin pump failure [see Warnings and Precautions (5.8)].
During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)].
Change Insulin Lispro in the pump reservoir at least every 7 days or according to the pump user manual, whichever is shorter. Follow the Humalog-specific information for in-use time because Humalog-specific information may differ from general pump manual instructions.
Change the infusion set and the infusion set insertion site according to the manufacturer's user manual.
Do NOT dilute or mix Insulin Lispro when administering by continuous subcutaneous infusion.
Do NOT expose Insulin Lispro in the pump reservoir to temperatures greater than 98.6°F (37°C).

Intravenous Administration

Administer Insulin Lispro intravenously ONLY under medical supervision with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia [see Warnings and Precautions (5.3, 5.6) and How Supplied/Storage and Handling (16.4)].
Dilute Insulin Lispro to concentrations from 0.1 unit/mL to 1.0 unit/mL using 0.9% Sodium Chloride Injection, USP.
Infusion bags prepared with Insulin Lispro are stable when stored in a refrigerator (2° to 8°C [36° to 46°F]) for 48 hours and then may be used at room temperature for up to an additional 48 hours.

2.3 Dosage Recommendations

Individualize and adjust the dosage of Insulin Lispro based on route of administration, the individual's metabolic needs, blood glucose monitoring results and glycemic control goal.
When switching from another insulin to Insulin Lispro. a different dosage of Insulin Lispro may be needed [see Warnings and Precautions (5.2)].
Dosage modifications may be needed with changes in physical activity, changes in meal patterns (i.e., macronutrient content or timing of food intake), changes in renal or hepatic function or during acute illness [see Warnings and Precautions (5.2, 5.3) and Use in Specific Populations (8.6, 8.7)].
Do NOT perform dose conversion when using the Insulin Lispro prefilled pens. The dose window shows the number of insulin units to be delivered and no conversion is needed.

2.4 Dosage Modifications for Drug Interactions

Dosage modification may be needed when Insulin Lispro is used concomitantly with certain drugs [see Drug Interactions (7)].

2.5 Instructions for Mixing with Other Insulins

The table below includes administration instructions regarding mixing Insulin Lispro with other insulins.

Insulin Lispro subcutaneous injection route	Insulin Lispro may be mixed with NPH insulin preparations ONLY. If Insulin Lispro is mixed with NPH insulin, Insulin Lispro should be drawn into the syringe first. Injection should occur immediately after mixing.
Insulin Lispro continuous subcutaneous infusion route (Insulin Pump)	Do NOT mix Insulin Lispro with any other insulin.

3 DOSAGE FORMS AND STRENGTHS
Injection: 100 units/mL (U-100) clear and colorless solution available as:
- 10 mL multiple-dose vial
- 3 mL single-patient-use KwikPen prefilled pen
- 3 mL single-patient-use Junior KwikPen prefilled pen
4 CONTRAINDICATIONS
Insulin Lispro is contraindicated:
- during episodes of hypoglycemia [see Warnings and Precautions (5.3)].
- in patients who are hypersensitive to Insulin Lispro or to any of the excipients in Insulin Lispro [see Warnings and Precautions (5.5)].
5 WARNINGS AND PRECAUTIONS

5.1 Never Share an Insulin Lispro Prefilled Pen or Syringe Between Patients

Insulin Lispro prefilled pens must never be shared between patients, even if the needle is changed. Patients using Insulin Lispro 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 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)].

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 antidiabetic products may be needed.

5.3 Hypoglycemia

Hypoglycemia is the most common adverse reaction associated with insulins, including Insulin Lispro. Severe hypoglycemia can cause seizures, 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).

Hypoglycemia can happen suddenly, and symptoms may differ in each individual and change over time in the same individual. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic nerve disease, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7)], or in patients who experience recurrent hypoglycemia.

Risk Factors for 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. As with all insulins, the glucose lowering effect time course of Insulin Lispro 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 blood 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 blood glucose monitoring is recommended.

5.4 Hypoglycemia Due to Medication Errors

Accidental mix-ups between insulin products have been reported. To avoid medication errors between Insulin Lispro and other insulins, instruct patients to always check the insulin label before each injection.

5.5 Hypersensitivity Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including Insulin Lispro. If hypersensitivity reactions occur, discontinue Insulin Lispro; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6.1)]. Insulin Lispro is contraindicated in patients who have had hypersensitivity reactions to Insulin Lispro or any of the excipients in Insulin Lispro [see Contraindications (4)].

5.6 Hypokalemia

All insulins, including Insulin Lispro, 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).

5.7 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 Insulin Lispro, 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.

5.8 Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction

Malfunction of the insulin pump or insulin infusion set or insulin degradation can rapidly lead to hyperglycemia and ketoacidosis. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim subcutaneous injections with Insulin Lispro may be required. Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure [see How Supplied/Storage and Handling (16.2) and Patient Counseling Information (17)].

6 ADVERSE REACTIONS

The following adverse reactions are discussed elsewhere:

Hypoglycemia [see Warnings and Precautions (5.3)].
Hypoglycemia Due to Medication Errors [see Warnings and Precautions (5.4)].
Hypersensitivity Reactions [see Warnings and Precautions (5.5)].
Hypokalemia [see Warnings and Precautions (5.6)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying designs, the adverse reaction rates reported in one clinical trial may not be easily compared with those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice.

Common adverse reactions, excluding hypoglycemia, were defined as events that occurred in ≥5% of patients treated with Insulin Lispro or regular human insulin. The frequencies of adverse reactions during Insulin Lispro clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus are listed in the tables below.

Table 1: Adverse Reactions That Occurred in ≥5% in Patients with Type 1 Diabetes Mellitus
	Insulin Lispro (%) (n=81)	Regular human insulin (%) (n=86)
Flu syndrome	34.6	32.6
Pharyngitis	33.3	33.7
Rhinitis	24.7	29.1
Headache	29.6	22.1
Pain	19.8	16.3
Cough increased	17.3	17.4
Infection	13.6	20.9
Nausea	6.2	15.1
Accidental injury	8.6	11.6
Surgical procedure	6.2	14.0
Fever	6.2	11.6
Abdominal pain	7.4	8.1
Asthenia	7.4	8.1
Bronchitis	7.4	7.0
Diarrhea	8.6	5.8
Dysmenorrhea	6.2	7.0
Myalgia	7.4	5.8
Urinary tract infection	6.2	4.7

Table 2: Adverse Reactions That Occurred in ≥5% in Patients with Type 2 Diabetes Mellitus
	Insulin Lispro (%) (n=714)	Regular human insulin (%) (n=709)
Headache	11.6	9.3
Pain	10.8	10.0
Infection	10.1	7.6
Pharyngitis	6.6	8.2
Rhinitis	8.1	6.6
Flu syndrome	6.2	8.2
Surgical procedure	7.4	6.8

Insulin initiation and intensification of glucose control

Intensification or rapid improvement in glucose control has been associated with a transitory, reversible ophthalmologic refraction disorder, worsening of diabetic retinopathy, and acute painful peripheral neuropathy. However, long-term glycemic control decreases the risk of diabetic retinopathy and neuropathy.

Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including Insulin Lispro.

Lipodystrophy

Long-term use of insulin, including Insulin Lispro, can cause lipodystrophy at the site of repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption [see Dosage and Administration (2.2)].

Weight gain

Weight gain can occur with insulins, including Insulin Lispro, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.

Peripheral Edema

Insulins, including Insulin Lispro, may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.

Adverse Reactions with Continuous Subcutaneous Insulin Infusion (CSII)

In a 12-week, randomized, crossover study in adult patients with type 1 diabetes (n=39), the rates of catheter occlusions and infusion site reactions were similar for Insulin Lispro and regular human insulin treated patients (see Table 3).

Table 3: Catheter Occlusions and Infusion Site Reactions
	Insulin Lispro (n=38)	Regular human insulin (n=39)
Catheter occlusions/month	0.09	0.10
Infusion site reactions	2.6% (1/38)	2.6% (1/39)

In a randomized, 16-week, open-label, parallel design study of pediatric patients with type 1 diabetes, adverse reactions related to infusion-site reactions were similar for Insulin Lispro and insulin aspart (21% of 100 patients versus 17% of 198 patients, respectively). In both groups, the most frequently reported infusion site reactions were infusion site erythema and infusion site reaction.

Allergic Reactions

Local Allergy — As with any insulin, patients taking Insulin Lispro may experience redness, swelling, or itching at the site of the injection. These minor reactions usually resolve in a few days to a few weeks, but in some occasions, may require discontinuation of Insulin Lispro.

Systemic Allergy — Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin, including Insulin Lispro. Generalized allergy to insulin may cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis.

In controlled clinical trials, pruritus (with or without rash) was seen in 17 patients receiving regular human insulin (n=2969) and 30 patients receiving Insulin Lispro (n=2944).

Localized reactions and generalized myalgias have been reported with injected metacresol, which is an excipient in Insulin Lispro [see Contraindications (4)].

Antibody Production

In large clinical trials with patients with type 1 (n=509) and type 2 (n=262) diabetes mellitus, anti-insulin antibody (insulin lispro-specific antibodies, insulin-specific antibodies, cross-reactive antibodies) formation was evaluated in patients receiving both regular human insulin and Insulin Lispro (including patients previously treated with human insulin and naive patients). As expected, the largest increase in the antibody levels occurred in patients new to insulin therapy. The antibody levels peaked by 12 months and declined over the remaining years of the study. These antibodies do not appear to cause deterioration in glycemic control or necessitate an increase in insulin dose. There was no statistically significant relationship between the change in the total daily insulin dose and the change in percent antibody binding for any of the antibody types.

6.2 Postmarketing Experience

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

Medication errors in which other insulins have been accidentally substituted for Insulin Lispro have been identified during post-approval use.

Localized cutaneous amyloidosis at the injection site has occurred. 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

The table below includes clinically significant drug interactions with Insulin Lispro.

Drugs That May Increase the Risk of Hypoglycemia
Drugs:	Antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics.
Intervention:	Dose adjustment and increased frequency of glucose monitoring may be required when Insulin Lispro is co-administered with these drugs.
Drugs That May Decrease the Blood Glucose Lowering Effect of Insulin Lispro
Drugs:	Atypical antipsychotics (e.g., olanzapine and clozapine), corticosteroids, danazol, diuretics, estrogens, glucagon, isoniazid, niacin, oral contraceptives, phenothiazines, progestogens (e.g., in oral contraceptives), protease inhibitors, somatropin, sympathomimetic agents (e.g., albuterol, epinephrine, terbutaline), and thyroid hormones.
Intervention:	Dose adjustment and increased frequency of glucose monitoring may be required when Insulin Lispro is co-administered with these drugs.
Drugs That May Increase or Decrease the Blood Glucose Lowering Effect of Insulin Lispro
Drugs:	Alcohol, beta-blockers, clonidine, and lithium salts. Pentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.
Intervention:	Dose adjustment and increased frequency of glucose monitoring may be required when Insulin Lispro is co-administered with these drugs.
Drugs That May Blunt Signs and Symptoms of Hypoglycemia
Drugs:	Beta-blockers, clonidine, guanethidine and reserpine
Intervention:	Increased frequency of glucose monitoring may be required when Insulin Lispro is co-administered with these drugs.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Published studies with insulin lispro used during pregnancy have not reported an association between insulin lispro and the induction of major birth defects, miscarriage, or adverse maternal or fetal outcomes (see Data). There are risks to the mother and fetus associated with poorly controlled diabetes in pregnancy (see Clinical Considerations).

Pregnant rats and rabbits were exposed to insulin lispro in animal reproduction studies during organogenesis. No adverse effects on embryo/fetal viability or morphology were observed in offspring of rats exposed to insulin lispro at a dose approximately 3 times the human subcutaneous dose of 1 unit insulin lispro/kg/day. No adverse effects on embryo/fetal development were observed in offspring of rabbits exposed to insulin lispro at doses up to approximately 0.2 times the human subcutaneous dose of 1 unit/kg/day (see Data).

The estimated background risk of major birth defects is 6-10% in women with pre-gestational diabetes with a HbA1c >7 and has been reported to be as high as 20-25% in women with a HbA1c >10. The estimated background risk of miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, 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, miscarriage, 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

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.

8.2 Lactation

Risk Summary

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

8.4 Pediatric Use

The safety and effectiveness of Insulin Lispro to improve glycemic control have been established in pediatric patients with diabetes mellitus. Use of Insulin Lispro for this indication is supported by evidence from adequate and well-controlled studies in 831 pediatric patients with type 1 diabetes mellitus aged 3 years and older and from studies in adults with diabetes mellitus [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

8.5 Geriatric Use

Of the total number of patients (n=2,834) in eight clinical studies of Insulin Lispro, twelve percent (n=338) were 65 years of age or over. The majority of these patients had type 2 diabetes. HbA1c values and hypoglycemia rates did not differ by age. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of Insulin Lispro action have not been performed.

8.6 Renal Impairment

Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent Insulin Lispro dose adjustment and more frequent blood glucose monitoring [see Clinical Pharmacology (12.3)].

8.7 Hepatic Impairment

Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent Insulin Lispro dose adjustment and more frequent blood glucose monitoring [see Clinical Pharmacology (12.3)].
10 OVERDOSAGE

Excess insulin administration may cause hypoglycemia and hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with a glucagon product for emergency use 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 is a rapid-acting human insulin analog produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli. Insulin lispro 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 5.808 kDa, both identical to that of human insulin.

Insulin lispro has the following primary structure:

Insulin Lispro injection is a sterile, clear, and colorless solution for subcutaneous or intravenous use.

Each mL of Insulin Lispro contains 100 units of insulin lispro, and the inactive ingredients: dibasic sodium phosphate (1.0 mg), glycerin (16 mg), metacresol (3.15 mg), trace amounts of phenol, zinc oxide (content adjusted to provide 0.0197 mg zinc ion), and Water for Injection, USP.

Insulin Lispro has a pH of 7.0 to 7.8.

Hydrochloric acid 10% and/or sodium hydroxide 10% is added to adjust the pH.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Regulation of glucose metabolism is the primary activity of insulins and insulin analogs, including insulin lispro. Insulins lower blood 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

Insulin Lispro has been shown to be equipotent to human insulin on a molar basis. One unit of Insulin Lispro has the same glucose-lowering effect as one unit of regular human insulin. Studies in normal volunteers and patients with diabetes demonstrated that Insulin Lispro has a more rapid onset of action and a shorter duration of activity than regular human insulin when given subcutaneously.

The time course of action of insulin and insulin analogs, such as Insulin Lispro, may vary considerably in different individuals or within the same individual. The parameters of Insulin Lispro activity (time of onset, peak time, and duration) as designated in Figure 1 should be considered only as general guidelines. The rate of insulin absorption, and consequently the onset of activity are known to be affected by the site of injection, exercise, and other variables [see Warnings and Precautions (5.2)].

Figure 1: Blood Glucose Levels After Subcutaneous Injection of Regular Human Insulin or Insulin Lispro (0.2 unit/kg) Immediately Before a High Carbohydrate Meal in 10 Patients with Type 1 Diabetesa.

a Baseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin.

Intravenous Administration — The glucose lowering effect of intravenously administered Insulin Lispro was tested in 21 patients with type 1 diabetes. For the study, the patients' usual doses of insulin were held and blood glucose concentrations were allowed to reach a stable range of 200 to 260 mg/dL during a one to three hours run-in phase. The run-in phase was followed by a 6-hour assessment phase. During the assessment phase, patients received intravenous Insulin Lispro at an initial infusion rate of 0.5 units/hour. The infusion rate of Insulin Lispro could be adjusted at regular timed intervals to achieve and maintain blood glucose concentrations between 100 to 160 mg/dL.

The mean blood glucose levels during the assessment phase for patients on Insulin Lispro therapy are summarized below in Table 4. All patients achieved the targeted glucose range at some point during the 6-hour assessment phase. At the endpoint, blood glucose was within the target range (100 to 160 mg/dL) for 17 of 20 patients treated with Insulin Lispro. The average time (±SE) required to attain near normoglycemia was 129 ± 14 minutes for Insulin Lispro.

Table 4: Mean Blood Glucose Concentrations (mg/dL) During Intravenous Infusions of Insulin Lispro
a Results shown as mean ± SD
Time from Start of Infusion (minutes)	Mean Blood Glucose (mg/dL) Intravenous
0	224 ± 16
30	205 ± 21
60	195 ± 20
120	165 ± 26
180	140 ± 26
240	123 ± 20
300	120 ± 27
360	122 ± 25

12.3 Pharmacokinetics

Absorption and Bioavailability — Studies in healthy volunteers and patients with diabetes demonstrated that Insulin Lispro is absorbed more quickly than regular human insulin. In healthy volunteers given subcutaneous doses of Insulin Lispro ranging from 0.1 to 0.4 unit/kg, peak serum levels were seen 30 to 90 minutes after dosing. When healthy volunteers received equivalent doses of regular human insulin, peak insulin levels occurred between 50 to 120 minutes after dosing. Similar results were seen in patients with type 1 diabetes (see Figure 2).

Figure 2: Serum Insulin Lispro and Insulin Levels After Subcutaneous Injection of Regular Human Insulin or Insulin Lispro (0.2 unit/kg) Immediately Before a High Carbohydrate Meal in 10 Patients with Type 1 Diabetesa.

a Baseline insulin concentration was maintained by infusion of 0.2 mU/min/kg human insulin.

Insulin Lispro was absorbed at a consistently faster rate than regular human insulin in healthy male volunteers given 0.2 unit/kg at abdominal, deltoid, or femoral subcutaneous sites. After Insulin Lispro was administered in the abdomen, serum drug levels were higher and the duration of action was slightly shorter than after deltoid or thigh administration. Bioavailability of Insulin Lispro is similar to that of regular human insulin. The absolute bioavailability after subcutaneous injection ranges from 55% to 77% with doses between 0.1 to 0.2 unit/kg, inclusive.

Distribution — When administered intravenously as bolus injections of 0.1 and 0.2 U/kg dose in two separate groups of healthy subjects, the mean volume of distribution of Insulin Lispro appeared to decrease with increase in dose (1.55 and 0.72 L/kg, respectively) in contrast to that of regular human insulin for which, the volume of distribution was comparable across the two dose groups (1.37 and 1.12 L/kg for 0.1 and 0.2 U/kg dose, respectively).

Metabolism — Human metabolism studies have not been conducted. However, animal studies indicate that the metabolism of Insulin Lispro is identical to that of regular human insulin.

Elimination — After subcutaneous administration of Insulin Lispro, the t1/2 is shorter than that of regular human insulin (1 versus 1.5 hours, respectively). When administered intravenously, Insulin Lispro and regular human insulin demonstrated similar dose-dependent clearance, with a mean clearance of 21.0 mL/min/kg and 21.4 mL/min/kg, respectively (0.1 unit/kg dose), and 9.6 mL/min/kg and 9.4 mL/min/kg, respectively (0.2 unit/kg dose). Accordingly, Insulin Lispro demonstrated a mean t1/2 of 0.85 hours (51 minutes) and 0.92 hours (55 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses, and regular human insulin mean t1/2 was 0.79 hours (47 minutes) and 1.28 hours (77 minutes), respectively for 0.1 unit/kg and 0.2 unit/kg doses.

Specific Populations

The effects of age, gender, race, obesity, pregnancy, or smoking on the pharmacokinetics of Insulin Lispro have not been studied.

Renal Impairment — Type 2 diabetic patients with varying degree of renal impairment showed no difference in pharmacokinetics of regular insulin and Insulin Lispro. However, the sensitivity of the patients to insulin did change, with an increased response to insulin as the renal function declined. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal impairment [see Use in Specific Populations (8.6)].

Hepatic Impairment — Type 2 diabetic patients with impaired hepatic function showed no effect on the pharmacokinetics of Insulin Lispro as compared to patients with no hepatic dysfunction. However, some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure [see Use in Specific Populations (8.7)].

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Standard 2-year carcinogenicity studies in animals have not been performed. 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.

13.2 Animal Toxicology and/or Pharmacology

In standard biological assays in fasted rabbits, 0.2 unit/kg of insulin lispro injected subcutaneously had the same glucose-lowering effect and had a more rapid onset of action as 0.2 unit/kg of regular human insulin.

14 CLINICAL STUDIES

The safety and efficacy of Insulin Lispro were studied in pediatric and adult patients with type 1 diabetes (n=789) and adult patients with type 2 diabetes (n=722).

14.1 Type 1 Diabetes – Adults and Pediatric Patients Aged 12 Years and Older

A 12-month, randomized, parallel, open-label, active-controlled study was conducted in patients with type 1 diabetes to assess the safety and efficacy of Insulin Lispro (n=81) compared with Humulin® R [insulin human injection (100 units/mL)] (n=86). Insulin Lispro was administered by subcutaneous injection immediately prior to meals and Humulin R was administered 30 to 45 minutes before meals. Humulin® U [ULTRALENTE® human insulin (rDNA origin) extended zinc suspension] was administered once or twice daily as the basal insulin. There was a 2- to 4-week run-in period with Humulin R and Humulin U before randomization. Most patients were Caucasian (97%). Forty-seven percent of the patients were male. The mean age was 31 years (range 12 to 70 years). Glycemic control, the total daily doses of Insulin Lispro and Humulin R, and the incidence of severe hypoglycemia (as determined by the number of events that were not self-treated) were similar in the two treatment groups. There were no episodes of diabetic ketoacidosis in either treatment group.

Table 5: Type 1 Diabetes Mellitus – Adults and Pediatric Patients Aged 12 years and Older
a Values are Mean ± SD
b Severe hypoglycemia refers to hypoglycemia for which patients were not able to self-treat.
Treatment Duration Treatment in Combination with:	12 months Humulin U
	Insulin Lispro	Humulin R
N	81	86
Baseline HbA1c (%)a	8.2 ± 1.4	8.3 ± 1.7
Change from baseline HbA1c (%)a	-0.1 ± 0.9	0.1 ± 1.1
Treatment Difference in HbA1c Mean (95% confidence interval)	0.4 (0.0, 0.8)
Baseline short-acting insulin dose (units/kg/day)	0.3 ± 0.1	0.3 ± 0.1
End-of-Study short-acting insulin dose (units/kg/day)	0.3 ± 0.1	0.3 ± 0.1
Change from baseline short-acting insulin dose (units/kg/day)	0.0 ± 0.1	0.0 ± 0.1
Baseline Body weight (kg)	72 ± 12.7	71 ± 11.3
Weight change from baseline (kg)	1.4 ± 3.6	1.0 ± 2.6
Patients with severe hypoglycemia (n, %)b	14 (17%)	18 (21%)

14.2 Type 1 Diabetes – Pediatric Patients

An 8-month, crossover study of pediatric patients with type 1 diabetes (n=463), aged 9 to 19 years, compared two subcutaneous multiple-dose treatment regimens: Insulin Lispro or Humulin R, both administered with Humulin N (NPH human insulin) as the basal insulin. Insulin Lispro achieved glycemic control comparable to Humulin R, as measured by HbA1c (see Table 6), and both treatment groups had a comparable incidence of hypoglycemia. In a 9-month, crossover study of pediatric patients (n=60) with type 1 diabetes, aged 3 to 11 years, Insulin Lispro administered immediately before meals, Insulin Lispro administered immediately after meals and Humulin R administered 30 minutes before meals resulted in similar glycemic control, as measured by HbA1c, and incidence of hypoglycemia, regardless of treatment group.

Table 6: Pediatric Subcutaneous Administration of Insulin Lispro in Type 1 Diabetes
a Values are Mean ± SD
b Severe hypoglycemia refers to hypoglycemia that required glucagon or glucose injection or resulted in coma.
		End point
	Baseline	Insulin Lispro + NPH	Humulin R + NPH
HbA1c (%)a	8.6 ± 1.5	8.7 ± 1.5	8.7 ± 1.6
Change from baseline HbA1c (%)a	—	0.1 ± 1.1	0.1 ± 1.3
Short-acting insulin dose (units/kg/day)a	0.5 ± 0.2	0.5 ± 0.2	0.5 ± 0.2
Change from baseline short-acting insulin dose (units/kg/day)a	—	0.01 ± 0.1	-0.01 ± 0.1
Body weight (kg)a	59.1 ± 13.1	61.1 ± 12.7	61.4 ± 12.9
Weight change from baseline (kg)a	—	2.0 ± 3.1	2.3 ± 3.0
Patients with severe hypoglycemia (n, %)b	—	5 (1.1%)	5 (1.1%)
Diabetic ketoacidosis (n, %)	—	11 (2.4%)	9 (1.9%)

14.3 Type 1 Diabetes – Adults: Continuous Subcutaneous Insulin Infusion

To evaluate the administration of Insulin Lispro via external insulin pumps, two open-label, crossover design studies were performed in patients with type 1 diabetes. One study involved 39 patients, ages 19 to 58 years, treated for 24 weeks with Insulin Lispro or regular human insulin. After 12 weeks of treatment, the mean HbA1c values decreased from 7.8% to 7.2% in the Insulin Lispro -treated patients and from 7.8% to 7.5% in the regular human insulin-treated patients. Another study involved 60 patients (mean age 39, range 15 to 58 years) treated for 24 weeks with either Insulin Lispro or buffered regular human insulin. After 12 weeks of treatment, the mean HbA1c values decreased from 7.7% to 7.4% in the Insulin Lispro-treated patients and remained unchanged from 7.7% in the buffered regular human insulin-treated patients. Rates of hypoglycemia were comparable between treatment groups in both studies.

14.4 Type 1 Diabetes – Pediatric Patients: Continuous Subcutaneous Insulin Infusion

A randomized, 16-week, open-label, parallel design, study of pediatric patients with type 1 diabetes (n=298) aged 4 to 18 years compared two subcutaneous infusion regimens administered via an external insulin pump: insulin aspart (n=198) or Insulin Lispro (n=100). These two treatments resulted in comparable changes from baseline in HbA1c and comparable rates of hypoglycemia after 16 weeks of treatment (see Table 7). Infusion site reactions were similar between groups.

Table 7: Pediatric Insulin Pump Study in Type 1 Diabetes (16 weeks; n=298)
a Values are Mean ± SD
b Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the intervention of another person or hospitalization.
	Insulin Lispro	Aspart
N	100	198
Baseline HbA1c (%)a	8.2 ± 0.8	8.0 ± 0.9
Change from Baseline HbA1c (%)	-0.1 ± 0.7	-0.1 ± 0.8
Treatment Difference in HbA1c, Mean (95% confidence interval)	0.1 (-0.3, 0.1)
Baseline insulin dose (units/kg/24 hours)a	0.9 ± 0.3	0.9 ± 0.3
End-of-Study insulin dose (units/kg/24 hours)a	0.9 ± 0.2	0.9 ± 0.2
Patients with severe hypoglycemia (n, %)b	8 (8%)	19 (10%)
Diabetic ketoacidosis (n, %)	0 (0)	1 (0.5%)
Baseline body weight (kg)a	55.5 ± 19.0	54.1 ± 19.7
Weight Change from baseline (kg)a	1.6 ± 2.1	1.8 ± 2.1

14.5 Type 2 Diabetes – Adults

A 6-month randomized, crossover, open-label, active-controlled study was conducted in insulin-treated patients with type 2 diabetes (n=722) to assess the safety and efficacy of Insulin Lispro for 3 months followed by Humulin R for 3 months or the reverse sequence. Insulin Lispro was administered by subcutaneous injection immediately before meals and Humulin R was administered 30 to 45 minutes before meals. Humulin® N [NPH human insulin (rDNA origin) isophane suspension] or Humulin U was administered once or twice daily as the basal insulin. All patients participated in a 2- to 4-week run-in period with Humulin R and Humulin N or Humulin U. Most of the patients were Caucasian (88%), and the numbers of men and women in each group were approximately equal. The mean age was 58.6 years (range 23.8 to 85 years). The average body mass index (BMI) was 28.2 kg/m2. During the study, the majority of patients used Humulin N (84%) compared with Humulin U (16%) as their basal insulin. The reductions from baseline in HbA1c and the incidence of severe hypoglycemia (as determined by the number of events that were not self-treated) were similar between the two treatments from the combined groups (see Table 8).

Table 8: Type 2 Diabetes Mellitus — Adults
a Values are Mean ± SD
b Severe hypoglycemia refers to hypoglycemia for which patients were not able to self-treat.
		End point
	Baseline	Insulin Lispro + Basal	Humulin R + Basal
HbA1c (%)a	8.9 ± 1.7	8.2 ± 1.3	8.2 ± 1.4
Change from baseline HbA1c (%)a	—	-0.7 ± 1.4	-0.7 ± 1.3
Short-acting insulin dose (units/kg/day)a	0.3 ± 0.2	0.3 ± 0.2	0.3 ± 0.2
Change from baseline short-acting insulin dose (units/kg/day)a	—	0.0 ± 0.1	0.0 ± 0.1
Body weight (kg)a	80 ± 15	81 ± 15	81 ± 15
Weight change from baseline	—	0.8 ± 2.7	0.9 ± 2.6
Patients with severe hypoglycemia (n, %)b	—	15 (2%)	16 (2%)

16 HOW SUPPLIED/STORAGE AND HANDLING

Product: 50090-5391

NDC: 50090-5391-0 10 mL in a VIAL / 1 in a CARTON
17 PATIENT COUNSELING INFORMATION
Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

Never Share an Insulin Lispro Prefilled Pen or Syringe Between Patients

Advise patients that they must never share an Insulin Lispro prefilled pen with another person, even if the needle is changed. Advise patients using Insulin Lispro 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

Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of Insulin Lispro 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 container label before each injection to avoid mix-ups between insulin products [see Warnings and Precautions (5.4)].

Hypersensitivity Reactions

Advise patients that hypersensitivity reactions have occurred with Insulin Lispro. Inform patients on the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.5)].
Instructions For Patients Using Continuous Subcutaneous Insulin Pumps
- Train patients in intensive insulin therapy with multiple injections and in the function of their pump and pump accessories.
- Instruct patients to follow healthcare provider recommendations when setting pump basal rates and bolus settings.
- This Insulin Lispro product can be used with continuous subcutaneous insulin infusion pumps labeled for use with Humalog (insulin lispro) – refer to the insulin pump user manual to see if Humalog can be used. See recommended reservoir and infusion sets in the insulin pump user manual.
- Instruct patients to replace insulin in the reservoir at least every 7 days, or according to the pump user manual, whichever is shorter; infusion sets and infusion set insertion sites should be changed in accordance with the manufacturers' user manual. By following this schedule, patients avoid insulin degradation, infusion set occlusion, and loss of the insulin preservative.
- Instruct patients to discard insulin exposed to temperatures higher than 98.6°F (37°C). The temperature of the insulin may exceed ambient temperature when the pump housing, cover, tubing or sport case is exposed to sunlight or radiant heat.
- Instruct patients to inform healthcare provider and select a new site for infusion if infusion site becomes erythematous, pruritic, or thickened.
- Instruct patients on the risk of rapid hyperglycemia and ketosis due to pump malfunction, infusion set occlusion, leakage, disconnection or kinking, and degraded insulin. Instruct patients on the risk of hypoglycemia from pump malfunction. If these problems cannot be promptly corrected, instruct patients to resume therapy with subcutaneous insulin injection and contact their healthcare provider [see Warnings and Precautions (5) and How Supplied/Storage and Handling (16.2)].
Manufactured by:
Eli Lilly and Company
Indianapolis, IN 46285, USA
US License Number 1891

Humalog® and KwikPen® are registered trademarks of Eli Lilly and Company.

Copyright © 1996, 2023, Eli Lilly and Company. All rights reserved.

LIS-0008-USPI-20230921

Patient Package Insert

This Patient Information has been approved by the U.S. Food and Drug Administration		Revised: July 2023
PATIENT INFORMATION Insulin Lispro [IHN-soo-lihn LIYS-proh] injection, for subcutaneous or intravenous use 100 units per mL This product is HUMALOG® (insulin lispro).
Do not share your Insulin Lispro prefilled pens or syringes with other people, even if the needle has been changed. You may give other people a serious infection or get a serious infection from them.
What is Insulin Lispro? Insulin Lispro is a man-made fast-acting insulin used to control high blood sugar in adults and children with diabetes mellitus.
Who should not take Insulin Lispro? Do not take Insulin Lispro if you: are having an episode of low blood sugar (hypoglycemia). have an allergy to Insulin Lispro or any of the ingredients in Insulin Lispro. See the end of this Patient Information leaflet for a complete list of ingredients in Insulin Lispro.
What should I tell my healthcare provider before taking Insulin Lispro? Before taking Insulin Lispro, tell your healthcare provider about all of your medical conditions, including if you: have kidney or liver problems. take any other medicines, especially ones called TZDs (thiazolidinediones). have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with Insulin Lispro. are pregnant or plan to become pregnant. Talk with your healthcare provider about the best way to control your blood sugar if you plan to become pregnant or while you are pregnant. are breastfeeding or plan to breastfeed. Talk with your healthcare provider about the best way to feed your baby while taking Insulin Lispro.
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Before you start taking Insulin Lispro, talk to your healthcare provider about low blood sugar and how to manage it.
How should I take Insulin Lispro? Read the Instructions for Use that comes with your Insulin Lispro. Take Insulin Lispro exactly as your healthcare provider tells you to. Your healthcare provider should tell you how much Insulin Lispro to take and when to take it. Insulin Lispro starts acting fast. Inject Insulin Lispro within 15 minutes before or right after you eat a meal. Know the type, strength and amount of insulin you take. Do not change the type or amount of insulin you take unless your healthcare provider tells you to. The amount of insulin and the best time for you to take your insulin may need to change if you take different types of insulin. Check your insulin label each time you give your injection to make sure you are taking the correct insulin. Inject Insulin Lispro under the skin (subcutaneously) of your stomach area, buttocks, upper legs or upper arms, or by continuous infusion under the skin (subcutaneously) through an insulin pump into an area of your body recommended in the instructions that come with your insulin pump. Change (rotate) your injection sites within the area you choose with 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. Always use a new needle for each injection to help prevent infections and blocked needles. Do not reuse or share your needles with other people. You may give other people a serious infection or get a serious infection from them. Check your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels.
Keep Insulin Lispro and all medicines out of the reach of children.
Your dose of Insulin Lispro may need to change because of a: change in physical activity or exercise, weight gain or loss, increased stress, illness, change in diet, or because of other medicines you take.
What should I avoid while taking Insulin Lispro? While taking Insulin Lispro do not: drive or operate heavy machinery, until you know how Insulin Lispro affects you. drink alcohol or take prescription or over-the-counter medicines that contain alcohol.
What are the possible side effects of Insulin Lispro? Insulin Lispro may cause serious side effects that can lead to death, including: low blood sugar (hypoglycemia). Signs and symptoms of low blood sugar may include:
dizziness or light-headedness sweating confusion headache blurred vision	slurred speech shakiness fast heartbeat anxiety, irritability or mood changes hunger
Your healthcare provider may prescribe a glucagon product for emergency use so that someone else can give you glucagon if your blood sugar becomes too low (severe hypoglycemia) and you are unable to take sugar by mouth. serious allergic reactions (whole body allergic reaction). Get medical help right away, if you have any of these signs or symptoms of a severe allergic reaction:
a rash over your whole body trouble breathing a fast heartbeat	sweating feel faint
low potassium in your blood (hypokalemia). heart failure. Taking certain diabetes pills called thiazolidinediones or “TZDs” with Insulin Lispro may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with Insulin Lispro. Your healthcare provider should monitor you closely while you are taking TZDs with Insulin Lispro. Tell your healthcare provider if you have any new or worse symptoms of heart failure including:
shortness of breath swelling of your ankles or feet	sudden weight gain
Treatment with TZDs and Insulin Lispro may need to be adjusted or stopped by your healthcare provider if you have new or worse heart failure. Get emergency medical help if you have:
trouble breathing shortness of breath fast heartbeat swelling of your face, tongue, or throat	sweating extreme drowsiness dizziness confusion
The most common side effects of Insulin Lispro include:
low blood sugar (hypoglycemia) reactions at your injection site skin thickening or pits at the injection site (lipodystrophy)	weight gain swelling in your hands or feet itching rash
These are not all the possible side effects of Insulin Lispro. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
General information about the safe and effective use of Insulin Lispro. Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not take Insulin Lispro for a condition for which it was not prescribed. Do not give Insulin Lispro to other people, even if they have the same symptoms that you have. It may harm them. This Patient Information leaflet summarizes the most important information about Insulin Lispro. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Insulin Lispro that is written for health professionals.
What are the ingredients in Insulin Lispro? Active ingredient: insulin lispro Inactive ingredients: dibasic sodium phosphate, glycerin, hydrochloric acid, metacresol, trace amounts of phenol, sodium hydroxide, zinc oxide (zinc ion), and Water for Injection, USP. Humalog® is a registered trademark of Eli Lilly and Company. Manufactured by: Eli Lilly and Company, Indianapolis, IN 46285, USA, US License Number 1891 Copyright © 1996, 2023, Eli Lilly and Company. All rights reserved. For more information, call 1-800-545-5979.

LIS-0007-PPI-20230721

Vial Instructions for Use

INSTRUCTIONS FOR USE

Insulin Lispro [IHN-soo-lihn LIYS-proh]

injection, for subcutaneous use

10 mL multiple-dose vial (100 units per mL, U-100)

This product is HUMALOG® (insulin lispro).

Read this Instructions for Use before you start taking Insulin Lispro 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 needles or syringes with other people, even if the needle has been changed. You may give other people a serious infection or get a serious infection from them.

Supplies needed to give your injection

a multiple-dose Insulin Lispro vial
a U-100 insulin syringe and needle
2 alcohol swabs
gauze
1 sharps container for throwing away used needles and syringes. See “Disposing of used needles and syringes” at the end of these instructions.

Vial	Syringe

Preparing your Insulin Lispro dose

Wash your hands with soap and water.
Check the Insulin Lispro 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.
Insulin Lispro should look clear and colorless. Do not use Insulin Lispro if it is thick, cloudy, or colored, or if you see lumps or particles in it.
Do not use Insulin Lispro 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 reuse or share your syringes or needles with other people. You may give other people a serious infection or get a serious infection from them.

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.

If you use Insulin Lispro with NPH insulin:

NPH insulin is the only type of insulin that can be mixed with Insulin Lispro. Do not mix Insulin Lispro with any other type of insulin.
Insulin Lispro should be drawn up into the syringe first, before you draw up your NPH insulin. Talk to your healthcare provider if you are not sure about the right way to mix Insulin Lispro and NPH insulin.
Give your injection right away.

Giving your Insulin Lispro 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.
Insulin Lispro starts acting fast, so give your injection within 15 minutes before or right after you eat 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 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. Insulin Lispro is injected under the skin (subcutaneously) of your stomach area (abdomen), buttocks, upper legs or upper arms. Wipe the skin with an alcohol swab. Let the injection site 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 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.

Giving your Insulin Lispro using an insulin pump

Insulin Lispro should be given into an area of your body recommended in the instructions that come with your insulin pump.
Change your infusion set and rotate the infusion set insertion site according to the manufacturer's user manual.
Change (rotate) your insertion sites within the area you choose for each insertion to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the insertion sites. Do not insert into the exact same spot for each insertion. Do not insert where the skin has pits, is thickened, or has lumps. Do not insert where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.
This Insulin Lispro product can be used with the continuous subcutaneous insulin infusion pumps labeled for use with Humalog (insulin lispro) – refer to the insulin pump user manual to see if Humalog can be used.
Change the insulin in the reservoir at least every 7 days or according to the pump user manual, whichever is shorter, even if you have not used all of the insulin.
Do not dilute or mix Insulin Lispro with any other type of insulin in your insulin pump.
See your insulin pump manual for instructions or talk to your healthcare provider.

Disposing of used needles and syringes

Put your used needles and syringes in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes 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.

How should I store Insulin Lispro?

All unopened vials:

Store all unopened vials in the refrigerator at 36°F to 46°F (2°C to 8°C).
Do not freeze. Do not use if Insulin Lispro has been frozen.
Keep away from heat and out of direct light.
Unopened vials can be used until the expiration date on the carton and label, if they have been stored in the refrigerator.
Unopened vials should be thrown away after 28 days, if they are stored at room temperature.

After vials have been opened:

Store opened vials in the refrigerator or at room temperature up to 86°F (30°C) for up to 28 days.
Keep vials away from heat and out of direct light.
Throw away all opened vials after 28 days of use, even if there is insulin left in the vial.

Insulin Lispro in an insulin pump:

Throw away Insulin Lispro in the pump reservoir if it has been exposed to temperatures higher than 98.6°F (37°C).

Keep Insulin Lispro vials, syringes, needles and all medicines out of the reach of children.

If you have any questions or problems with your Insulin Lispro, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979) or call your healthcare provider for help.

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

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

Humalog® is a registered trademark of Eli Lilly and Company.

Instructions for Use revised: July/2023

LISVL-0006-IFU-20230721

KwikPen (U-100) Instructions for Use

INSTRUCTIONS FOR USE

Insulin Lispro [IHN-soo-lihn LIYS-proh]

KwikPen®

injection, for subcutaneous use

3 mL single-patient-use pen (100 units per mL)

This product is HUMALOG® (insulin lispro).

Read the Instructions for Use before you start taking Insulin Lispro and each time you get another 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 Insulin Lispro KwikPen with other people, even if the needle has been changed. You may give other people a serious infection or get a serious infection from them.

Insulin Lispro KwikPen (“Pen”) is a disposable single-patient-use prefilled pen containing 300 units of insulin lispro. You can give yourself more than 1 dose from the Pen. Each turn (click) 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. 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 Insulin Lispro KwikPen

Pen color: Dark blue
Dose Knob: Dark blue
Labels: White label with burgundy stripe

Supplies you will need to give your injection

Insulin Lispro KwikPen
KwikPen compatible Needle (Becton, Dickinson and Company Pen Needles recommended)
Alcohol swab
Gauze

Preparing your Pen

Wash your hands with soap and water.
Check your 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 reuse or share your needles with other people. You may give other people a serious infection or get a serious infection from them.

Step 1: Pull the Pen Cap straight off. - Do not remove the Pen Label. Wipe the Rubber Seal with an alcohol swab. Step 2: Check the liquid in the Pen. Insulin Lispro 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 the Pen is working correctly.
If you do not prime before each injection, you may get too much or too little insulin.

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 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. - If you do not see insulin, repeat priming steps 6 to 8, no 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.

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 step.

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.

-

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 (for example, 12) are printed on the dial.

-

The odd numbers, (for example, 25) after the number 1, are shown as full lines.
Always check the number in the Dose Window to make sure you have dialed the correct 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 can not 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 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.

Step 10: Choose your injection site. Insulin Lispro 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. 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, 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 the 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.

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

The used Pen may be discarded in your household trash after you have removed the needle.
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.

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 your insulin. 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 Insulin Lispro 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 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 can not 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 Insulin Lispro KwikPen, contact Lilly at 1-800-LillyRx (1-800-545-5979) or call your healthcare provider for help.

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

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

Revised: July/2023

Humalog® and KwikPen® are registered trademarks of Eli Lilly and Company.

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

LISKP-0006-IFU-20230721

Junior KwikPen (U-100) Instructions for Use

INSTRUCTIONS FOR USE

Insulin Lispro [IHN-soo-lihn LIYS-proh]

Junior KwikPen®

injection, for subcutaneous use

3 mL single-patient-use pen (100 units per mL)

This product is HUMALOG® (insulin lispro).

Read the Instructions for Use before you start taking Insulin Lispro and each time you get another Insulin Lispro 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 Insulin Lispro Junior KwikPen with other people, even if the needle has been changed. You may give other people a serious infection or get a serious infection from them.

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

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.
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 Insulin Lispro Junior KwikPen:

Pen color: Blue
Dose Knob: Blue, with raised ridges on end and side
Label: White with an orange color bar and orange-to-yellow color band

Supplies needed to give your injection:

Insulin Lispro Junior KwikPen
KwikPen compatible Needle (BD [Becton, Dickinson and Company] Pen Needles recommended)
Alcohol swab
Gauze

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 reuse or share your needles with other people. You may give other people a serious infection or get a serious infection from them.

Step 1: Pull the Pen Cap straight off. – Do not remove the Pen Label. Wipe the Rubber Seal with an alcohol swab. Step 2: Check the liquid in the Pen. Insulin Lispro 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 the Pen is working correctly.
If you do not prime before each injection, you may get too much or too little insulin.

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. – If you do not see insulin, repeat the priming steps 6 to 8, but not more than 4 times. – If you still do not see insulin, change the Needle and repeat the priming steps 6 to 8. Small air bubbles are normal and will not affect your dose.

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.

–

You must use a new Needle for each injection and repeat the priming step.

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.

–

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 (for example, 4) are printed on the dial.

–

The half units are shown as lines between the whole unit numbers.
Always check the number in the Dose Window to make sure you have dialed the correct 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 can not 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 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.

Step 10: Choose your injection site. Insulin Lispro 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. – 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, 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.

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

The used Pen may be discarded in your household trash after you have removed the needle.
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. 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 the container.

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 your insulin. 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 Insulin Lispro 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 can not 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 Insulin Lispro Junior KwikPen, contact Lilly at 1-800-LillyRx (1-800-545-5979) or call your healthcare provider for help.

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

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

Revised: July/2023

Humalog® and KwikPen® are registered trademarks of Eli Lilly and Company.

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

LIS-JRKP-0002-IFU-20230721

Insulin lispro

INGREDIENTS AND APPEARANCE

INSULIN LISPRO
insulin lispro injection, solution

Product Information
Product Type	HUMAN PRESCRIPTION DRUG	Item Code (Source)	NDC:50090-5391(NDC:0002-7737)
Route of Administration	INTRAVENOUS, SUBCUTANEOUS

Ingredient Name	Basis of Strength	Strength
Active Ingredient/Active Moiety
INSULIN LISPRO (UNII: GFX7QIS1II) (INSULIN LISPRO - UNII:GFX7QIS1II)	INSULIN LISPRO	100 [iU] in 1 mL

Ingredient Name	Strength
Inactive Ingredients
Glycerin (UNII: PDC6A3C0OX)	16 mg in 1 mL
Sodium Phosphate, Dibasic, Unspecified Form (UNII: GR686LBA74)	1.88 mg in 1 mL
Metacresol (UNII: GGO4Y809LO)	3.15 mg in 1 mL
Zinc (UNII: J41CSQ7QDS)	.0197 mg in 1 mL
Phenol (UNII: 339NCG44TV)
Water (UNII: 059QF0KO0R)
Hydrochloric acid (UNII: QTT17582CB)
Sodium hydroxide (UNII: 55X04QC32I)

#	Item Code	Package Description	Marketing Start Date
Packaging
1	NDC:50090-5391-0	1 in 1 CARTON	11/24/2020
1		10 mL in 1 VIAL; Type 0: Not a Combination Product

Marketing Category	Application Number or Monograph Citation	Marketing Start Date	Marketing End Date
Marketing Information
BLA	BLA020563	02/12/2020

Labeler - A-S Medication Solutions (830016429)

Name	Address	ID/FEI	Business Operations
Establishment
A-S Medication Solutions		830016429	RELABEL(50090-5391)

View All Sections

Published Date (What is this?)	Version	Files
Jun 3, 2024	7 (current)	download
Sep 1, 2023	5	download
Feb 8, 2023	3	download
Dec 1, 2020	1	download

	RxCUI	RxNorm NAME	RxTTY
1	242120	insulin lispro 100 UNT/ML Injectable Solution	PSN
2	242120	insulin lispro 100 UNT/ML Injectable Solution	SCD
3	242120	insulin, analog lispro 100 UNT/ML Injectable Solution	SY

Label: INSULIN LISPRO injection, solution

Drug Label Information

INDICATIONS AND USAGE

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

DRUG INTERACTIONS

FULL PRESCRIBING INFORMATION: CONTENTS*

2.1 Important Administration Instructions

2.2 Administration Instructions for the Approved Routes of Administration

2.3 Dosage Recommendations

2.4 Dosage Modifications for Drug Interactions

2.5 Instructions for Mixing with Other Insulins

5.1 Never Share an Insulin Lispro Prefilled Pen 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 Hypersensitivity Reactions

5.6 Hypokalemia

5.7 Fluid Retention and Heart Failure with Concomitant Use of PPAR-gamma Agonists

5.8 Hyperglycemia and Ketoacidosis Due to Insulin Pump Device Malfunction

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14.1 Type 1 Diabetes – Adults and Pediatric Patients Aged 12 Years and Older

14.2 Type 1 Diabetes – Pediatric Patients

14.3 Type 1 Diabetes – Adults: Continuous Subcutaneous Insulin Infusion

14.4 Type 1 Diabetes – Pediatric Patients: Continuous Subcutaneous Insulin Infusion

14.5 Type 2 Diabetes – Adults

Find additional resources

Safety

Related Resources

More Info on this Drug

INSULIN LISPRO injection, solution

Number of versions: 4

INSULIN LISPRO injection, solution

INSULIN LISPRO injection, solution

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INSULIN LISPRO injection, solution

If this SPL contains inactivated NDCs listed by the FDA initiated compliance action, they will be specified as such.