Humulin r U-500

Dispensing Errors

Instruct patients to always inspect insulin vials to confirm that the correct insulin is dispensed including the correct insulin brand and concentration.

The HUMULIN R U-500 vial, which contains 20 mL, has a band of aqua coloring, a 500 units/mL concentration statement consisting of white lettering on a green rectangular background, and a green “U-500” statement prominently displayed next to the trade name. Additionally, the vial has a green flip top and a red warning on the front panel describing the highly concentrated dose and a statement advising use with only U-500 insulin syringes.

Please read these instructions before use.

Important Information

• Humulin R U-500 is a concentrated insulin.
• Know your dose. Your health care provider will tell you the number of insulin units that you should take.
• Always inject Humulin R U-500 insulin with a U-500 syringe. Other syringes will not measure your dose correctly.
• If you use the wrong syringe, you can give yourself a severe overdose. This can cause very low blood sugar, which may put your life in danger. For example, using a U-100 syringe can give you a 5 times overdose.
• If you do not have a U-500 syringe, you should contact your health care provider or pharmacist.

Additional Safety Information

• Each line on the U-500 syringe measures 5 units of U-500 insulin.
• You can give from 5 to 250 units in one injection.
• If your dose is more than 250 units, you will need to give more than 1 injection.
• Make sure you know how to draw up your dose with a U-500 syringe. If you need help, call your health care provider.
• Do not reuse your U-500 syringe.
• Do not share your U - 500 syringes with other people. You may give other people a serious infection or get a serious infection from them.
• Do not mix Humulin R U-500 with other insulins in the same syringe.
• You can get more instructions by calling Lilly at 1-800-LillyRx (1-800-545-5979).

Before You Start

• Check your vial. Make sure it says Humulin R U-500.
• Check the expiration date on the vial. Do not use it if it is expired. Throw away the opened vial after 40 days, even if there is still insulin left in the vial.
• See if the insulin in the vial is clear. Do not use if it is thick, cloudy, or colored or has solid particles.
• Make sure you have a new U-500 Syringe. Check for the green U-500 symbol and green Needle Shield.
• Check your supply. Make sure you have enough Humulin R U-500 insulin and U-500 syringes for several injections. Always reorder before you run out.
• Check with your health care provider if you have any questions.

Use only a U-500 syringe to inject Humulin R U-500 insulin

Prepare

• Wash your hands with soap and water.
• Always use a new syringe for each injection to help prevent infections and blocked needles.

Inject

• Inject your insulin exactly 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.

Disposal of used syringes

Storage and Handling

• Keep away from heat and out of direct light.
• Do not shake the vial.

Unopened vials:

• Store unopened vials in the refrigerator.
• Do not freeze Humulin R U-500. If it has been frozen, do not use it.
• If unopened vials have been stored in the refrigerator, you may use them until the expiration date.

After the vial has been opened:

• Store opened vials in the refrigerator or at room temperature (up to 86°F [30°C]) for up to 40 days.
• Throw away the opened vial after 40 days, even if there is still insulin left in the vial.

Frequently Asked Questions

• Why do I need to use a U-500 syringe?
  
  Humulin R U-500 insulin and a U-500 syringe work together to help you inject the correct dose. Using any other syringe may result in dosing mistakes. This may put your life in danger.
• Do I have to convert my Humulin R U-500 insulin dose when I use the U-500 syringe?
  
  No, you do not have to convert your dose. Your health care provider should tell you how much Humulin R U-500 insulin to take in units and when to take it. Your health care provider should show you how to draw up your dose using the U-500 syringe.
• What should I do if I run out of U-500 syringes?
  
  If you run out of U-500 syringes, do not use any other syringe to inject Humulin R U-500 insulin. Call your health care provider or pharmacist for help. You may also call Lilly at 1-800-Lilly-Rx (1-800-545-5979).

Where to get more information and help

• If you have any questions about Humulin R U-500 insulin or U-500 syringes, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979).
• You can also call your health care provider or pharmacist.
• For more information on Humulin R U-500 insulin, go to www.humulin.com

Scan this code to launch the humulin.com website

These Instructions for Use have been approved by the U.S. Food and Drug Administration.

Humulin^® is a trademark of Eli Lilly and Company.

Manufactured by:

Eli Lilly and Company, Indianapolis, IN 46285, USA

US License Number 1891

Copyright © 1996, 2022, Eli Lilly and Company. All rights reserved.

Literature revised: June 2022

LINR500VL-0004-IFU-20220627

Immunogenicity

As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The presence of antibodies that affect clinical efficacy may necessitate dose adjustments to correct for tendencies toward hyper- or hypoglycemia.

The incidence of antibody formation with HUMULIN R U-500 is unknown.

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.

Risk Summary

Available data from published literature suggests that exogenous human insulin products, including HUMULIN R U-500, 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 HUMULIN R U-500 on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for HUMULIN R U-500 and any potential adverse effects on the breastfed child from HUMULIN R U-500 or from the underlying maternal condition.

Insulin human is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli and has the empirical formula C₂₅₇H₃₈₃N₆₅O₇₇S₆ with a molecular weight of 5.808 kDa.

HUMULIN R U-500 (insulin human) injection is a sterile, aqueous, and colorless solution for subcutaneous use. HUMULIN R U-500 contains 500 units of insulin human in each milliliter. Each milliliter of HUMULIN R U-500 also contains glycerin (16 mg), metacresol (2.5 mg), zinc oxide to supplement the endogenous zinc to obtain a total zinc content of 0.017 mg/100 units, and Water for Injection. Sodium hydroxide and hydrochloric acid may be added during manufacture to adjust the pH. The pH is 7.0 to 7.8.

All insulins, including HUMULIN R U-500, 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. Use caution in patients who may be at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).

Hypoglycemia is the most common adverse reaction associated with insulins, including HUMULIN R U-500. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Severe hypoglycemia may develop as long as 18 to 24 hours after an injection of HUMULIN R U-500. Hypoglycemia can impair concentration ability and reaction time; this may place the patient 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 patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7.3, 7.4)], or in patients who experience recurrent hypoglycemia.

HUMULIN R U-500 (500 units/mL) injection is available in a clear, colorless solution as:

The HUMULIN R U-500 KwikPen dials in 5 unit increments.

The safety and effectiveness of HUMULIN R U-500 in pediatric patients with diabetes mellitus requiring more than 200 units of insulin per day to improve glycemic control have been established. Use of HUMULIN R U-500 for this indication is supported by evidence from studies with other insulin human in pediatric patients with type 1 diabetes mellitus and from studies in adults with diabetes mellitus. Standard precautions as applied to use of HUMULIN R U-500 in adults are appropriate for use in pediatric patients.

The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN R U-500 has not been studied. Caution should be exercised when HUMULIN R U-500 is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia.

HUMULIN R U-500 is contraindicated:

• During episodes of hypoglycemia [see Warnings and Precautions (5.4)]
• In patients who are hypersensitive to HUMULIN R U-500 or any of its excipients [see Warnings and Precautions (5.5)]

The following adverse reactions are discussed elsewhere:

• Hypoglycemia [see Warnings and Precautions (5.4)].
• Hypersensitivity Reactions [see Warnings and Precautions (5.5)].
• Hypokalemia [see Warnings and Precautions (5.6)].

The following additional adverse reactions have been identified during post-approval use of HUMULIN R U-500. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure.

Frequent glucose monitoring and insulin dose reduction may be required in patients with renal impairment.

The safety and efficacy of HUMULIN R U-500 used in combination with other insulins has not been determined.

The safety and efficacy of HUMULIN R U-500 delivered by continuous subcutaneous infusion has not been determined.

In a euglycemic clamp study of 24 healthy obese subjects (BMI=30-39 kg/m²), single doses of HUMULIN R U-500 at 50 units (0.4-0.6 unit/kg) and 100 units (0.8-1.3 unit/kg) resulted in a mean time of onset of action of less than 15 minutes at both doses and a mean duration of action of 21 hours (range 13-24 hours). The time action characteristics reflect both prandial and basal activity, consistent with clinical experience. This effect has been attributed to the high concentration of the preparation.

Figure 1 should be considered a representative example since the time course of action of insulin may vary in different individuals or within the same individual. The rate of insulin absorption and consequently the onset of activity is known to be affected by the site of injection, exercise, and other variables [see Warnings and Precautions (5.3)].

Frequent glucose monitoring and insulin dose reduction may be required in patients with hepatic impairment.

HUMULIN R U-500 is a concentrated human insulin indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus requiring more than 200 units of insulin per day.

• Instruct patients to inject HUMULIN R U-500 subcutaneously usually two or three times daily approximately 30 minutes before meals.
• Individualize and titrate the dosage of HUMULIN R U-500 based on the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal.
• Dosage adjustments 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, changes in medications or during acute illness to minimize the risk of hypoglycemia or hyperglycemia [see Warnings and Precautions (5.3)].

Regulation of glucose metabolism is the primary activity of insulins, including HUMULIN R U-500. 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.

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

Protect from heat and light. Do not freeze. Do not use if it has been frozen. Do not shake the vial. See Table 2 below for storage conditions.

• Hyperglycemia, Hypoglycemia or Death due to Dosing Errors with Vial Presentation: Can be life-threatening. Overdose has occurred as a result of dispensing, prescribing or administration errors. Attention to details at all levels is required to prevent these errors. (2.1, 2.3, 2.4, 5.1)
• Never share a HUMULIN R U-500 KwikPen or U-500 insulin syringe between patients, even if the needle is changed. (5.2)
• 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. (5.3)
• Hypoglycemia: May be life-threatening. Increase monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness. (5.4)
• Hypersensitivity Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue HUMULIN R U-500, monitor, and treat if indicated. (5.5)
• Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk for 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)

• Adhere to administration instructions to reduce the risk of dosing errors. (2.1, 2.3, 2.4, 5.1)
• HUMULIN R U-500 is available as a single-patient-use KwikPen or multiple-dose vial. Patients using the vial must be prescribed the U-500 insulin syringe to avoid medication errors. (2.1)
• Individualize dose of HUMULIN R U-500 based on metabolic needs, blood glucose monitoring results and glycemic control goal. (2.2)
• Administer HUMULIN R U-500 subcutaneously two or three times daily 30 minutes before a meal into the thigh, upper arm, abdomen, or buttocks. Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. (2.1, 2.2)
• Do NOT mix HUMULIN R U-500 with other insulins. (2.1)
• Do NOT administer HUMULIN R U-500 intravenously (2.1)
• Do NOT perform dose conversion when using the HUMULIN R U-500 KwikPen. The dose window of the HUMULIN R U-500 KwikPen shows the number of units of HUMULIN R U-500 to be injected. (2.3)
• Do NOT transfer HUMULIN R U-500 from the HUMULIN R U-500 KwikPen into any syringe. (2.3)
• Do NOT perform dose conversion when using a U-500 insulin syringe. Use only a U-500 insulin syringe with the HUMULIN R U-500 vial. (2.4)

Injection: 500 units/mL (U-500) clear, colorless solution available as:

• 3 mL single-patient-use HUMULIN R U-500 KwikPen prefilled pen (containing 1,500 units of insulin)
• 20 mL multiple-dose vial (containing 10,000 units of insulin)

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including HUMULIN R U-500. If hypersensitivity reactions occur, discontinue HUMULIN R U-500; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6)].

See FDA-approved patient labeling.

Patients should be counseled that HUMULIN R U-500 is a 5-times concentrated insulin product. Extreme caution must be observed in the measurement of dosage because inadvertent overdose may result in serious adverse reaction or life-threatening hypoglycemia. Accidental mix-ups between insulin products have been reported. To avoid medication errors between HUMULIN R U-500 and other insulins, patients should be instructed to always check the insulin label before each injection [see Warnings and Precautions (5.1)].

If using the HUMULIN R U-500 KwikPen, patients should be counseled to dial and dose the prescribed number of units of insulin (no dose conversion is required) [see Dosage and Administration (2.3)].

When using HUMULIN R U-500 from a vial, patients should be counseled to use only a U-500 insulin syringe and be informed that no dose conversion is required [see Dosage and Administration (2.4)].

Patients should be instructed on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of HUMULIN R U-500 therapy. Patients must be instructed 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. 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. Refer patients to the HUMULIN R U-500 Patient Information Leaflet for additional information [see Warnings and Precautions (5)].

Do not dilute or mix HUMULIN R U-500 with any other insulin products or solutions [see Dosage and Administration (2.1)].

Literature Revised: February 2024

Manufactured by:

Eli Lilly and Company,

Indianapolis, IN 46285, USA

US License Number 1891

Copyright © 1997, 2024, Eli Lilly and Company. All rights reserved.

LINR500-0010-USPI-20240222

• Prescribe HUMULIN R U-500 ONLY to patients who require more than 200 units of insulin per day.
• HUMULIN R U-500 is available as a single-patient-use KwikPen or multiple-dose vial. Patients using the vial must be prescribed the U-500 insulin syringe to avoid medication errors.
• Instruct patients using the vial presentation to use only a U-500 insulin syringe and on how to correctly draw the prescribed dose of HUMULIN R U-500 into the U-500 insulin syringe. Confirm that the patient has understood these instructions and can correctly draw the prescribed dose of HUMULIN R U-500 with their syringe [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)].
• Instruct patients to always check the insulin label before administration to confirm the correct insulin product is being used [see Warnings and Precautions (5.1)].
• Inspect HUMULIN R U-500 visually for particulate matter and discoloration. Only use HUMULIN R U-500 if the solution appears clear and colorless.
• Instruct patients to inject HUMULIN R U-500 subcutaneously into the thigh, upper arm, abdomen, or buttocks.
• Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.3) and Adverse Reactions (6)].
• During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.3)].
• Use HUMULIN R U-500 KwikPen with caution in patients with visual impairment that may rely on audible clicks to dial their dose.
• DO NOT administer HUMULIN R U-500 intravenously.
• DO NOT dilute or mix HUMULIN R U-500 with any other insulin products or solutions.

NDC 0002-8501-01

20 mL

Humulin^® R U-500

(insulin human)

injection

10,000 units per 20 mL

500 units per mL

Rx only

500 units/mL

Warning - Highly Concentrated

IMPORTANT: Use only with a U-500 syringe.

20 mL multiple-dose vial

For subcutaneous use only

www.humulin.com

Lilly

Carcinogenicity and fertility studies were not performed with HUMULIN R U-500 in animals. Biosynthetic human insulin was not genotoxic in the in vivo sister chromatid exchange assay and the in vitro gradient plate and unscheduled DNA synthesis assays.

Dispense in this sealed carton

NDC 0002-8824-27

Humulin^®R U-500

KwikPen^®

(insulin human)

injection

For Single Patient Use Only

prefilled insulin delivery device

500 units/mL

500 units per mL

2 x 3 mL prefilled pens

Rx only

For subcutaneous use only.

Read Humulin^®R U-500 KwikPen^® Instructions for Use.

NEEDLES NOT INCLUDED

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

Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including HUMULIN R U-500, 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.

HUMULIN R U-500 KwikPens should never be shared between patients, even if the needle is changed. Patients using HUMULIN R U-500 vials should never share needles or U-500 insulin syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.

Medication errors associated with the HUMULIN R U-500 vial presentation resulting in patients experiencing hyperglycemia, hypoglycemia or death have been reported. The majority of errors occurred due to errors in dispensing, prescribing or administration. Attention to details at all levels may prevent these errors.

• DO NOT perform dose conversion when using a U-500 insulin syringe. The markings on the U-500 insulin syringe show the number of units of HUMULIN R U-500 to be injected.
• Each marking on the syringe represents 5 units of insulin.
• Prescribe patients a U-500 insulin syringe to administer HUMULIN R U-500 from the vial to avoid administration errors. DO NOT use any other type of syringe [see Warnings and Precautions (5.1)].

• The HUMULIN R U-500 KwikPen dials in 5 unit increments and delivers a maximum dose of 300 units per injection.
• DO NOT perform dose conversion when using the HUMULIN R U-500 KwikPen. The dose window of the HUMULIN R U-500 KwikPen shows the number of units of HUMULIN R U-500 to be injected and NO dose conversion is required.
• DO NOT transfer HUMULIN R U-500 from the HUMULIN R U-500 KwikPen into any syringe for administration as overdose and severe hypoglycemia can occur [see Warnings and Precautions (5.4)].

Dispensing Errors

Instruct patients to always inspect insulin vials to confirm that the correct insulin is dispensed including the correct insulin brand and concentration.

The HUMULIN R U-500 vial, which contains 20 mL, has a band of aqua coloring, a 500 units/mL concentration statement consisting of white lettering on a green rectangular background, and a green “U-500” statement prominently displayed next to the trade name. Additionally, the vial has a green flip top and a red warning on the front panel describing the highly concentrated dose and a statement advising use with only U-500 insulin syringes.

Please read these instructions before use.

Important Information

• Humulin R U-500 is a concentrated insulin.
• Know your dose. Your health care provider will tell you the number of insulin units that you should take.
• Always inject Humulin R U-500 insulin with a U-500 syringe. Other syringes will not measure your dose correctly.
• If you use the wrong syringe, you can give yourself a severe overdose. This can cause very low blood sugar, which may put your life in danger. For example, using a U-100 syringe can give you a 5 times overdose.
• If you do not have a U-500 syringe, you should contact your health care provider or pharmacist.

Additional Safety Information

• Each line on the U-500 syringe measures 5 units of U-500 insulin.
• You can give from 5 to 250 units in one injection.
• If your dose is more than 250 units, you will need to give more than 1 injection.
• Make sure you know how to draw up your dose with a U-500 syringe. If you need help, call your health care provider.
• Do not reuse your U-500 syringe.
• Do not share your U - 500 syringes with other people. You may give other people a serious infection or get a serious infection from them.
• Do not mix Humulin R U-500 with other insulins in the same syringe.
• You can get more instructions by calling Lilly at 1-800-LillyRx (1-800-545-5979).

Before You Start

• Check your vial. Make sure it says Humulin R U-500.
• Check the expiration date on the vial. Do not use it if it is expired. Throw away the opened vial after 40 days, even if there is still insulin left in the vial.
• See if the insulin in the vial is clear. Do not use if it is thick, cloudy, or colored or has solid particles.
• Make sure you have a new U-500 Syringe. Check for the green U-500 symbol and green Needle Shield.
• Check your supply. Make sure you have enough Humulin R U-500 insulin and U-500 syringes for several injections. Always reorder before you run out.
• Check with your health care provider if you have any questions.

Use only a U-500 syringe to inject Humulin R U-500 insulin

Prepare

• Wash your hands with soap and water.
• Always use a new syringe for each injection to help prevent infections and blocked needles.

Inject

• Inject your insulin exactly 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.

Disposal of used syringes

Storage and Handling

• Keep away from heat and out of direct light.
• Do not shake the vial.

Unopened vials:

• Store unopened vials in the refrigerator.
• Do not freeze Humulin R U-500. If it has been frozen, do not use it.
• If unopened vials have been stored in the refrigerator, you may use them until the expiration date.

After the vial has been opened:

• Store opened vials in the refrigerator or at room temperature (up to 86°F [30°C]) for up to 40 days.
• Throw away the opened vial after 40 days, even if there is still insulin left in the vial.

Frequently Asked Questions

• Why do I need to use a U-500 syringe?
  
  Humulin R U-500 insulin and a U-500 syringe work together to help you inject the correct dose. Using any other syringe may result in dosing mistakes. This may put your life in danger.
• Do I have to convert my Humulin R U-500 insulin dose when I use the U-500 syringe?
  
  No, you do not have to convert your dose. Your health care provider should tell you how much Humulin R U-500 insulin to take in units and when to take it. Your health care provider should show you how to draw up your dose using the U-500 syringe.
• What should I do if I run out of U-500 syringes?
  
  If you run out of U-500 syringes, do not use any other syringe to inject Humulin R U-500 insulin. Call your health care provider or pharmacist for help. You may also call Lilly at 1-800-Lilly-Rx (1-800-545-5979).

Where to get more information and help

• If you have any questions about Humulin R U-500 insulin or U-500 syringes, contact Lilly at 1-800-Lilly-Rx (1-800-545-5979).
• You can also call your health care provider or pharmacist.
• For more information on Humulin R U-500 insulin, go to www.humulin.com

Scan this code to launch the humulin.com website

These Instructions for Use have been approved by the U.S. Food and Drug Administration.

Humulin^® is a trademark of Eli Lilly and Company.

Manufactured by:

Eli Lilly and Company, Indianapolis, IN 46285, USA

US License Number 1891

Copyright © 1996, 2022, Eli Lilly and Company. All rights reserved.

Literature revised: June 2022

LINR500VL-0004-IFU-20220627

Immunogenicity

As with all therapeutic proteins, insulin administration may cause anti-insulin antibodies to form. The presence of antibodies that affect clinical efficacy may necessitate dose adjustments to correct for tendencies toward hyper- or hypoglycemia.

The incidence of antibody formation with HUMULIN R U-500 is unknown.

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.

Risk Summary

Available data from published literature suggests that exogenous human insulin products, including HUMULIN R U-500, 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 HUMULIN R U-500 on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for HUMULIN R U-500 and any potential adverse effects on the breastfed child from HUMULIN R U-500 or from the underlying maternal condition.

Insulin human is produced by recombinant DNA technology utilizing a non-pathogenic laboratory strain of Escherichia coli and has the empirical formula C₂₅₇H₃₈₃N₆₅O₇₇S₆ with a molecular weight of 5.808 kDa.

HUMULIN R U-500 (insulin human) injection is a sterile, aqueous, and colorless solution for subcutaneous use. HUMULIN R U-500 contains 500 units of insulin human in each milliliter. Each milliliter of HUMULIN R U-500 also contains glycerin (16 mg), metacresol (2.5 mg), zinc oxide to supplement the endogenous zinc to obtain a total zinc content of 0.017 mg/100 units, and Water for Injection. Sodium hydroxide and hydrochloric acid may be added during manufacture to adjust the pH. The pH is 7.0 to 7.8.

All insulins, including HUMULIN R U-500, 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. Use caution in patients who may be at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations).

Hypoglycemia is the most common adverse reaction associated with insulins, including HUMULIN R U-500. Severe hypoglycemia can cause seizures, may be life-threatening or cause death. Severe hypoglycemia may develop as long as 18 to 24 hours after an injection of HUMULIN R U-500. Hypoglycemia can impair concentration ability and reaction time; this may place the patient 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 patient and change over time in the same patient. Symptomatic awareness of hypoglycemia may be less pronounced in patients with longstanding diabetes, in patients with diabetic neuropathy, in patients using medications that block the sympathetic nervous system (e.g., beta-blockers) [see Drug Interactions (7.3, 7.4)], or in patients who experience recurrent hypoglycemia.

HUMULIN R U-500 (500 units/mL) injection is available in a clear, colorless solution as:

The HUMULIN R U-500 KwikPen dials in 5 unit increments.

The safety and effectiveness of HUMULIN R U-500 in pediatric patients with diabetes mellitus requiring more than 200 units of insulin per day to improve glycemic control have been established. Use of HUMULIN R U-500 for this indication is supported by evidence from studies with other insulin human in pediatric patients with type 1 diabetes mellitus and from studies in adults with diabetes mellitus. Standard precautions as applied to use of HUMULIN R U-500 in adults are appropriate for use in pediatric patients.

The effect of age on the pharmacokinetics and pharmacodynamics of HUMULIN R U-500 has not been studied. Caution should be exercised when HUMULIN R U-500 is administered to geriatric patients. In elderly patients with diabetes, the initial dosing, dose increments, and maintenance dosage should be conservative to avoid hypoglycemia.

HUMULIN R U-500 is contraindicated:

• During episodes of hypoglycemia [see Warnings and Precautions (5.4)]
• In patients who are hypersensitive to HUMULIN R U-500 or any of its excipients [see Warnings and Precautions (5.5)]

The following adverse reactions are discussed elsewhere:

• Hypoglycemia [see Warnings and Precautions (5.4)].
• Hypersensitivity Reactions [see Warnings and Precautions (5.5)].
• Hypokalemia [see Warnings and Precautions (5.6)].

The following additional adverse reactions have been identified during post-approval use of HUMULIN R U-500. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure.

Frequent glucose monitoring and insulin dose reduction may be required in patients with renal impairment.

The safety and efficacy of HUMULIN R U-500 used in combination with other insulins has not been determined.

The safety and efficacy of HUMULIN R U-500 delivered by continuous subcutaneous infusion has not been determined.

In a euglycemic clamp study of 24 healthy obese subjects (BMI=30-39 kg/m²), single doses of HUMULIN R U-500 at 50 units (0.4-0.6 unit/kg) and 100 units (0.8-1.3 unit/kg) resulted in a mean time of onset of action of less than 15 minutes at both doses and a mean duration of action of 21 hours (range 13-24 hours). The time action characteristics reflect both prandial and basal activity, consistent with clinical experience. This effect has been attributed to the high concentration of the preparation.

Figure 1 should be considered a representative example since the time course of action of insulin may vary in different individuals or within the same individual. The rate of insulin absorption and consequently the onset of activity is known to be affected by the site of injection, exercise, and other variables [see Warnings and Precautions (5.3)].

Frequent glucose monitoring and insulin dose reduction may be required in patients with hepatic impairment.

HUMULIN R U-500 is a concentrated human insulin indicated to improve glycemic control in adult and pediatric patients with diabetes mellitus requiring more than 200 units of insulin per day.

• Instruct patients to inject HUMULIN R U-500 subcutaneously usually two or three times daily approximately 30 minutes before meals.
• Individualize and titrate the dosage of HUMULIN R U-500 based on the patient's metabolic needs, blood glucose monitoring results, and glycemic control goal.
• Dosage adjustments 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, changes in medications or during acute illness to minimize the risk of hypoglycemia or hyperglycemia [see Warnings and Precautions (5.3)].

Regulation of glucose metabolism is the primary activity of insulins, including HUMULIN R U-500. 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.

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

Protect from heat and light. Do not freeze. Do not use if it has been frozen. Do not shake the vial. See Table 2 below for storage conditions.

• Hyperglycemia, Hypoglycemia or Death due to Dosing Errors with Vial Presentation: Can be life-threatening. Overdose has occurred as a result of dispensing, prescribing or administration errors. Attention to details at all levels is required to prevent these errors. (2.1, 2.3, 2.4, 5.1)
• Never share a HUMULIN R U-500 KwikPen or U-500 insulin syringe between patients, even if the needle is changed. (5.2)
• 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. (5.3)
• Hypoglycemia: May be life-threatening. Increase monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; and in patients with renal impairment or hepatic impairment or hypoglycemia unawareness. (5.4)
• Hypersensitivity Reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, can occur. Discontinue HUMULIN R U-500, monitor, and treat if indicated. (5.5)
• Hypokalemia: May be life-threatening. Monitor potassium levels in patients at risk for 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)

• Adhere to administration instructions to reduce the risk of dosing errors. (2.1, 2.3, 2.4, 5.1)
• HUMULIN R U-500 is available as a single-patient-use KwikPen or multiple-dose vial. Patients using the vial must be prescribed the U-500 insulin syringe to avoid medication errors. (2.1)
• Individualize dose of HUMULIN R U-500 based on metabolic needs, blood glucose monitoring results and glycemic control goal. (2.2)
• Administer HUMULIN R U-500 subcutaneously two or three times daily 30 minutes before a meal into the thigh, upper arm, abdomen, or buttocks. Rotate injection sites to reduce risk of lipodystrophy and localized cutaneous amyloidosis. (2.1, 2.2)
• Do NOT mix HUMULIN R U-500 with other insulins. (2.1)
• Do NOT administer HUMULIN R U-500 intravenously (2.1)
• Do NOT perform dose conversion when using the HUMULIN R U-500 KwikPen. The dose window of the HUMULIN R U-500 KwikPen shows the number of units of HUMULIN R U-500 to be injected. (2.3)
• Do NOT transfer HUMULIN R U-500 from the HUMULIN R U-500 KwikPen into any syringe. (2.3)
• Do NOT perform dose conversion when using a U-500 insulin syringe. Use only a U-500 insulin syringe with the HUMULIN R U-500 vial. (2.4)

Injection: 500 units/mL (U-500) clear, colorless solution available as:

• 3 mL single-patient-use HUMULIN R U-500 KwikPen prefilled pen (containing 1,500 units of insulin)
• 20 mL multiple-dose vial (containing 10,000 units of insulin)

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including HUMULIN R U-500. If hypersensitivity reactions occur, discontinue HUMULIN R U-500; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6)].

See FDA-approved patient labeling.

Patients should be counseled that HUMULIN R U-500 is a 5-times concentrated insulin product. Extreme caution must be observed in the measurement of dosage because inadvertent overdose may result in serious adverse reaction or life-threatening hypoglycemia. Accidental mix-ups between insulin products have been reported. To avoid medication errors between HUMULIN R U-500 and other insulins, patients should be instructed to always check the insulin label before each injection [see Warnings and Precautions (5.1)].

If using the HUMULIN R U-500 KwikPen, patients should be counseled to dial and dose the prescribed number of units of insulin (no dose conversion is required) [see Dosage and Administration (2.3)].

When using HUMULIN R U-500 from a vial, patients should be counseled to use only a U-500 insulin syringe and be informed that no dose conversion is required [see Dosage and Administration (2.4)].

Patients should be instructed on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of HUMULIN R U-500 therapy. Patients must be instructed 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. 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. Refer patients to the HUMULIN R U-500 Patient Information Leaflet for additional information [see Warnings and Precautions (5)].

Do not dilute or mix HUMULIN R U-500 with any other insulin products or solutions [see Dosage and Administration (2.1)].

Literature Revised: February 2024

Manufactured by:

Eli Lilly and Company,

Indianapolis, IN 46285, USA

US License Number 1891

Copyright © 1997, 2024, Eli Lilly and Company. All rights reserved.

LINR500-0010-USPI-20240222

• Prescribe HUMULIN R U-500 ONLY to patients who require more than 200 units of insulin per day.
• HUMULIN R U-500 is available as a single-patient-use KwikPen or multiple-dose vial. Patients using the vial must be prescribed the U-500 insulin syringe to avoid medication errors.
• Instruct patients using the vial presentation to use only a U-500 insulin syringe and on how to correctly draw the prescribed dose of HUMULIN R U-500 into the U-500 insulin syringe. Confirm that the patient has understood these instructions and can correctly draw the prescribed dose of HUMULIN R U-500 with their syringe [see Dosage and Administration (2.4) and Warnings and Precautions (5.1)].
• Instruct patients to always check the insulin label before administration to confirm the correct insulin product is being used [see Warnings and Precautions (5.1)].
• Inspect HUMULIN R U-500 visually for particulate matter and discoloration. Only use HUMULIN R U-500 if the solution appears clear and colorless.
• Instruct patients to inject HUMULIN R U-500 subcutaneously into the thigh, upper arm, abdomen, or buttocks.
• Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.3) and Adverse Reactions (6)].
• During changes to a patient's insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.3)].
• Use HUMULIN R U-500 KwikPen with caution in patients with visual impairment that may rely on audible clicks to dial their dose.
• DO NOT administer HUMULIN R U-500 intravenously.
• DO NOT dilute or mix HUMULIN R U-500 with any other insulin products or solutions.

NDC 0002-8501-01

20 mL

Humulin^® R U-500

(insulin human)

injection

10,000 units per 20 mL

500 units per mL

Rx only

500 units/mL

Warning - Highly Concentrated

IMPORTANT: Use only with a U-500 syringe.

20 mL multiple-dose vial

For subcutaneous use only

www.humulin.com

Lilly

Carcinogenicity and fertility studies were not performed with HUMULIN R U-500 in animals. Biosynthetic human insulin was not genotoxic in the in vivo sister chromatid exchange assay and the in vitro gradient plate and unscheduled DNA synthesis assays.

Dispense in this sealed carton

NDC 0002-8824-27

Humulin^®R U-500

KwikPen^®

(insulin human)

injection

For Single Patient Use Only

prefilled insulin delivery device

500 units/mL

500 units per mL

2 x 3 mL prefilled pens

Rx only

For subcutaneous use only.

Read Humulin^®R U-500 KwikPen^® Instructions for Use.

NEEDLES NOT INCLUDED

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

Thiazolidinediones (TZDs), which are peroxisome proliferator-activated receptor (PPAR)-gamma agonists, can cause dose-related fluid retention, when used in combination with insulin. Fluid retention may lead to or exacerbate heart failure. Patients treated with insulin, including HUMULIN R U-500, 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.

HUMULIN R U-500 KwikPens should never be shared between patients, even if the needle is changed. Patients using HUMULIN R U-500 vials should never share needles or U-500 insulin syringes with another person. Sharing poses a risk for transmission of blood-borne pathogens.

Medication errors associated with the HUMULIN R U-500 vial presentation resulting in patients experiencing hyperglycemia, hypoglycemia or death have been reported. The majority of errors occurred due to errors in dispensing, prescribing or administration. Attention to details at all levels may prevent these errors.

• DO NOT perform dose conversion when using a U-500 insulin syringe. The markings on the U-500 insulin syringe show the number of units of HUMULIN R U-500 to be injected.
• Each marking on the syringe represents 5 units of insulin.
• Prescribe patients a U-500 insulin syringe to administer HUMULIN R U-500 from the vial to avoid administration errors. DO NOT use any other type of syringe [see Warnings and Precautions (5.1)].

• The HUMULIN R U-500 KwikPen dials in 5 unit increments and delivers a maximum dose of 300 units per injection.
• DO NOT perform dose conversion when using the HUMULIN R U-500 KwikPen. The dose window of the HUMULIN R U-500 KwikPen shows the number of units of HUMULIN R U-500 to be injected and NO dose conversion is required.
• DO NOT transfer HUMULIN R U-500 from the HUMULIN R U-500 KwikPen into any syringe for administration as overdose and severe hypoglycemia can occur [see Warnings and Precautions (5.4)].