1. Indications and Usage for Humulin R U-500

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.

2. Humulin R U-500 Dosage and Administration

3. Dosage Forms and Strengths

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)

4. Contraindications

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)]

5. Warnings and Precautions

6. Adverse Reactions/Side Effects

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.

7. Drug Interactions

8. Use In Specific Populations

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. Humulin R U-500 Description

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.

12. Humulin R U-500 - Clinical Pharmacology

13. Nonclinical Toxicology

16. How is Humulin R U-500 supplied

17. Patient Counseling Information

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: June 2022

Manufactured by:
Eli Lilly and Company,
Indianapolis, IN 46285, USA
US License Number 1891
Copyright © 1997, 2022, Eli Lilly and Company. All rights reserved.

LINR500-0009-USPI-20220627

Please read these instructions before use.

Warnings
For your safety, always inject Humulin® R U-500 insulin with a U-500 syringe. If you use another kind of syringe, you may get a dangerous overdose.
U-500 syringe – for single injection only The U-500 syringe has a green U-500 symbol and a green Needle Shield on the syringe.

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).

Supplies
Humulin R U-500 multiple-dose vial U-500 Syringe (BD [Becton, Dickinson and Company] syringes recommended) 2 alcohol swabs 1 sharps container

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.

Step 1: Find the line on the U-500 syringe that matches your prescribed dose. This is your Dose Line. Each line is 5 units.	(Example: Arrow shows Dose Line at 85 units)
Step 2: If you are using a new vial, pull off the plastic Protective Cap. Do not remove the Rubber Stopper.
Step 3: Wipe the Rubber Stopper with an alcohol swab.
Step 4: Hold the syringe with the Needle pointing up. Pull down on the Plunger Rod until the Plunger Tip reaches your Dose Line.	(Example Dose: 85 units shown)
Step 5: Push the Needle through the Rubber Stopper of the vial.
Step 6: Push the Plunger all the way in. This puts air into the vial.
Step 7: Turn the vial and syringe upside down and slowly pull the Plunger down until the Plunger Tip is past your Dose Line.	(Example Dose: 85 units Plunger is shown at 100 units)
If there are air bubbles, tap the syringe gently a few times. This lets the air bubbles rise to the top.
Step 8: Slowly push the Plunger up until the Plunger Tip reaches your Dose Line. Check the syringe to make sure that you have the right dose.	(Example Dose: 85 units shown)
Step 9: Pull the syringe out of the vial's Rubber Stopper.

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.

Step 10: Choose your injection site. Humulin R U-500 is injected under the skin (subcutaneously). You may inject into your stomach area, buttocks, upper legs, or upper arms. Wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose.
Step 11: Insert the Needle into your skin.
Step 12: Push down on the Plunger to inject your dose. Then keep the Needle in your skin for at least 5 seconds, to make sure you have injected all of your dose.
Step 13: Pull the Needle out of your skin. You may see blood after you take the Needle out of your skin. This is normal. Press the injection site lightly with a piece of gauze or an alcohol swab. Do not rub the area. Do not put the Needle Shield back on the Needle, because you may get a needle stick injury.

Disposal of used syringes

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

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.

General Information

Always use a U-500 syringe to inject Humulin R U-500 insulin. Never use other syringes. The lines and numbers on other syringes will not measure your dose correctly. You can give yourself the wrong dose if you use any other syringe, such as a U-100, tuberculin or allergy syringe. For example, a U-100 syringe is made to measure U-100 insulin. If you use a U-100 Syringe for your U-500 dose, you can give yourself a 5 times overdose. Do not make any changes to your dose or the type of insulin you use unless you are told to do so by your health care provider. Keep your vials and syringes out of the sight and reach of children.

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

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

Literature revised: June 2022

LINR500VL-0004-IFU-20220627

Instructions for Use
HUMULIN® R U-500 KwikPen®

(insulin human)
injection, for subcutaneous use
3 mL single-patient-use pen (500 units/mL, U-500)

Read the Instructions for Use before you start taking HUMULIN R U-500 and each time you get another Pen. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or your treatment.

Do not share your HUMULIN R U-500 Pen 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.

HUMULIN R U-500 KwikPen (“Pen”) is a disposable single-patient-use prefilled pen containing 1500 units of HUMULIN R. You can give yourself more than 1 dose from the Pen. Each turn (click) of the Dose Knob dials 5 units of insulin. You can give from 5 to 300 units in a single 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 1500 units in the Pen.

Inject HUMULIN R U-500 only with your Pen. Do not transfer insulin from your Pen to a syringe.

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 HUMULIN R U-500 KwikPen

Pen color: Aqua Dose Knob: Aqua with raised ridges on the end Label: HUMULIN R U-500 and 500 units/mL in a green box

Supplies needed to give your injection

• HUMULIN R U-500 KwikPen
• KwikPen compatible Needle (Becton, Dickinson and Company Pen Needles recommended)
• Alcohol swab

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 KwikPen Label. Wipe the Rubber Seal with an alcohol swab. HUMULIN R U-500 should look clear and colorless. Do not use if it is cloudy, colored, or has particles or clumps in it.
Step 2: Select a new Needle. Pull off the Paper Tab from the Outer Needle Shield.
Step 3: Push the capped Needle straight onto the Pen and twist the Needle on until it is tight.
Step 4: 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 5: To prime your pen, turn the Dose Knob to select 5 units.
Step 6: Hold your Pen with the Needle pointing up. Tap the Cartridge Holder gently to collect air bubbles at the top.
Step 7: 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 5 to 7, no more than 8 times. – If you still do not see insulin, change the Needle and repeat priming steps 5 to 7. Small air bubbles are normal and will not affect your dose.

Selecting your dose

This Pen has been made to deliver the dose in insulin units that is shown in the Dose Window. Ask your healthcare provider what your dose should be for this Pen.

• You can give from 5 to 300 units in a single injection.
• If your dose is more than 300 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 8: Turn the Dose Knob to select the number of units you need to inject. The Dose Indicator should line up with your dose. – The Dose Knob clicks as you turn it. Each click of the Dose Knob dials 5 insulin units at a time. – 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, 80) are printed on the dial. – The odd numbers (for example, 125) are shown as lines between the even numbers. Always check the number in the Dose Window to make sure you have dialed the correct dose.

Example: 80 units shown in Dose Window Example: 125 units shown in Dose Window

• The Pen will not let you dial more than the number of units left in the Pen.
• If your dose is 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 your full dose.

• It is normal to see a small amount of insulin left in the Pen that you cannot inject. Do not transfer this to a syringe. Severe overdose can happen.

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 9: Choose your injection site. HUMULIN 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 10: 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 11: 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 your injection. Monitor your blood glucose as instructed by your healthcare provider. 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 12: Carefully replace the Outer Needle Shield.
Step 13: 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 14: Replace the Pen Cap by lining up the Cap Clip with the Dose Indicator and pushing straight on.

• Put your used Needles in a FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose Needles in your household trash.
• If you do not have a FDA-cleared sharps disposal container, you may use a household container that is:

  –

  made of a heavy-duty plastic,

  –

  can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out,

  –

  upright and stable during use,

  –

  leak-resistant, and

  –

  properly labeled to warn of hazardous waste inside the container.

• When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal
• Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container.
• The used Pen may be discarded in your household trash after you have removed the needle.

Storing your Pen

Unused Pens

• Store unused Pens in the refrigerator at 36°F to 46°F (2°C to 8°C).
• Do not freeze HUMULIN R U-500. 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 Pen you are using after 28 days, even if it still has insulin left in it.

What you should know if you are switching to HUMULIN R U-500 KwikPen

Ask your healthcare provider what your dose should be for your Pen in insulin units. Always follow your healthcare provider's instructions for dosing.

General information about the safe and effective use of your Pen

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

Troubleshooting

• If you cannot remove the Pen Cap, gently twist the cap back and forth, and then pull the cap straight off.
• If it is hard to push the Dose Knob:

  –

  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 HUMULIN R U-500 KwikPen, contact Lilly at 1-800-LillyRx (1-800-545-5979) or call your healthcare provider for help. For more information on HUMULIN R U-500 KwikPen and insulin, go to www.humulin.com.

Scan this code to launch www.humulin.com

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

HUMULIN® and HUMULIN® KwikPen® are trademarks of Eli Lilly and Company.

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

Copyright © 2015, 2022, Eli Lilly and Company. All rights reserved.

Document revision date: June 2022

LINR500KP-0005-IFU-20220627

VIAL PACKAGE CARTON – HUMULIN R U-500 Vial 20 mL 1ct

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

KWIKPEN PACKAGE CARTON – HUMULIN R U-500 KwikPen 3 mL (500 Units per mL)

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.