INSULIN ASPART PROTAMINE AND INSULIN ASPART- insulin aspart injection, suspension.INSULIN ASPART PROTAMINE AND INSULIN ASPART- insulin aspart injection, suspension
For Healthcare Providers >

1. Patient Information
2. Distributed By:
3. What Is Insulin Aspart Protamine And Insulin Aspart?
4. Do Not Take Insulin Aspart Protamine And Insulin Aspart If You:
5. Before Taking Insulin Aspart Protamine And Insulin Aspart, Tell Your Healthcare Provider About All Your Medical Conditions Including, If You Are:
6. How Should I Take Insulin Aspart Protamine And Insulin Aspart?
7. While Taking Insulin Aspart Protamine And Insulin Aspart Do Not:
8. Insulin Aspart Protamine And Insulin Aspart May Cause Serious Side Effects That Can Lead To Death, Including:
9. Your Insulin Dose May Need To Change Because Of:
10. Other Common Side Effects Of Insulin Aspart Protamine And Insulin Aspart May Include:
11. Get Emergency Medical Help If You Have:
12. Active Ingredient:
13. Manufactured By:
14. Supplies You Will Need To Give Your Insulin Aspart Protamine And Insulin Aspart Injection:
15. Preparing Your Insulin Aspart Protamine And Insulin Aspart Dose:
16. All Unopened Vials:
17. After Vials Have Been Opened:
18. For Information Contact:
19. Make Sure You Have The Following Items:
20. Before Your First Injection With A New Insulin Aspart Protamine And Insulin Aspart Flexpen You Must Mix The Insulin:

Patient Information ⮝

Advise the patient to read theFDA-approved patient labeling(Patient Information and Instructions for Use).

Never Share a Insulin Aspart Protamine and Insulin Aspart FlexPen between Patients

Advise patients that they must never share Insulin Aspart Protamine and Insulin Aspart FlexPen device with another person even if the needle is changed. Advise patients using insulin aspart protamine and insulin aspart 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)].

Hypoglycemia

Inform patients that hypoglycemia is the most common adverse reaction with insulin. Instruct patients on self-management procedures including glucose monitoring, proper injection technique, and management of hypoglycemia and hyperglycemia, especially at initiation of insulin aspart protamine and insulin aspart 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[see Warnings and Precautions (5.3)].

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.

Hypoglycemia with Medication Errors

Instruct patients to always check the insulin 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 aspart protamine and insulin aspart. Inform patients of the symptoms of hypersensitivity reactions[see Warnings and Precautions (5.5)].

Administration

Advise patients to inspect insulin aspart protamine and insulin aspart visually before use. It should appear uniformly white and cloudy. Instruct them to not use it if it looks clear or contains solid particles.

Insulin aspart protamine and insulin aspart must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature.

Instruct patients when using the vial, to roll the vial gently in their hands in a horizontal position 10 times until the suspension appears uniformly white and cloudy. The patient should use immediately after resuspension.

Instruct patients when using Insulin Aspart Protamine and Insulin Aspart FlexPen, to roll Insulin Aspart Protamine and Insulin Aspart FlexPen gently between their hands in a horizontal position 10 times. Then, to turn Insulin Aspart Protamine and Insulin Aspart FlexPen upside down so that the glass ball moves from one end of the reservoir to the other 10 times until the suspension appears uniformly white and cloudy. The patient should use immediately after resuspension.

Instruct patients to administer insulin aspart protamine and insulin aspart by subcutaneous injection in the abdominal region, buttocks, thigh, or upper arm and to rotate injection sites within the same region to reduce the risk of lipodystrophy.

Version: 1

Novo Nordisk, FlexPen, and Novolinare registered trademarks of Novo NordiskA/S.

Patent Information:http://novonordisk-us.com/patients/products/product-patents.html

2002 2019 Novo Nordisk

Distributed By: ⮝

Novo Nordisk Pharma, Inc.
1-800-727-6500

What Is Insulin Aspart Protamine And Insulin Aspart? ⮝

Insulin aspart protamine and insulin aspart is a man-made insulin that is used to control high blood sugar in people with diabetes mellitus.

It is not known if insulin aspart protamine and insulin aspart is safe and effective in children.

Do Not Take Insulin Aspart Protamine And Insulin Aspart If You: ⮝

are having an episode of low blood sugar (hypoglycemia).

have an allergy to insulin aspart protamine and insulin aspart or any of the ingredients in insulin aspart protamine and insulin aspart.

Before Taking Insulin Aspart Protamine And Insulin Aspart, Tell Your Healthcare Provider About All Your Medical Conditions Including, If You Are: ⮝

pregnant, planning to become pregnant, or are breastfeeding.

taking new prescription or over-the-counter medicines, vitamins, or herbal supplements.

Before you start taking insulin aspart protamine and insulin aspart, talk to your healthcare provider about low blood sugar and how to manage it.

How Should I Take Insulin Aspart Protamine And Insulin Aspart? ⮝

Read the Instructions for Usethat come with your insulin aspart protamine and insulin aspart.

Take insulin aspart protamine and insulin aspart exactly as your healthcare provider tells you to.

Insulin aspart protamine and insulin aspart starts acting fast. If you have Type 1 diabetes, inject it up to 15 minutes before you eat a meal.Do not inject insulin aspart protamine and insulin aspart if you are not planning to eat within 15 minutes.If you have Type 2 diabetes, you may inject insulin aspart protamine and insulin aspart up to 15 minutes before or after starting your meal.

Do not mix insulin aspart protamine and insulin aspart with other insulin productsoruse in an insulin pump.

Know the type and strength of insulin you take.Do notchange the type 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 blood sugar levels.Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels.

Do not reuse or share your needles or syringes with other people.You may give other people a serious infection or get a serious infection from them.

While Taking Insulin Aspart Protamine And Insulin Aspart Do Not: ⮝

Drive or operate heavy machinery, until you know how insulin aspart protamine and insulin aspart affects you.

Drink alcohol or use prescription or over-the-counter medicines that contain alcohol.

Insulin Aspart Protamine And Insulin Aspart May Cause Serious Side Effects That Can Lead To Death, Including: ⮝

Low blood sugar (hypoglycemia).Signs and symptoms that may indicate low blood sugar include:

dizziness or light-headedness

blurred vision

anxiety, irritability, or mood changes

sweating

slurred speech

hunger

confusion

shakiness

headache

fast heart beat

Your Insulin Dose May Need To Change Because Of: ⮝

change in level of physical activity or exercise

increased stress

change in diet

weight gain or loss

illness

Other Common Side Effects Of Insulin Aspart Protamine And Insulin Aspart May Include: ⮝

low potassium in your blood (hypokalemia), reactions at the injection site, itching, rash, serious allergic reactions (whole body reactions), skin thickening or pits at the injection site (lipodystrophy), weight gain, and swelling of your hands and feet.

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.

These are not all the possible side effects of insulin aspart protamine and insulin aspart. 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 aspart protamine and insulin aspart.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about insulin aspart protamine and insulin aspart that is written for health professionals. Do not use insulin aspart protamine and insulin aspart for a condition for which it was not prescribed. Do not give insulin aspart protamine and insulin aspart to other people, even if they have the same symptoms that you have. It may harm them.

Active Ingredient: ⮝

70% insulin aspart protamine and 30% insulin aspart.

Inactive Ingredients: glycerol, phenol, metacresol, zinc, disodium hydrogen phosphate dihydrate, sodium chloride, protamine sulfate, water for injection, hydrochloric acid or sodium hydroxide.

Manufactured By: ⮝

Novo Nordisk A/S; DK-2880 Bagsvaerd, Denmark

For more information call 1-800-727-6500.

This Patient Information has been approved by the U.S. Food and Drug Administration

Revised: 08/2019

INSTRUCTIONS FOR USE

Insulin Aspart Protamine and Insulin Aspart

Injectable Suspension

10 mL multiple-dose vial (100 Units/mL, U-100)

Read this Instructions for Use before you start taking insulin aspart protamine and insulin aspart and each time you get a refill. 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.

Supplies You Will Need To Give Your Insulin Aspart Protamine And Insulin Aspart Injection: ⮝

10 mL insulin aspart protamine and insulin aspart vial

insulin syringe and needle

alcohol swabs

Preparing Your Insulin Aspart Protamine And Insulin Aspart Dose: ⮝

Wash your hands with soap and water.

Before you start to prepare your injection, check the insulin aspart protamine and insulin aspart label to make sure that you are taking the right type of insulin. This is especially important if you use more than 1 type of insulin.

Insulin aspart protamine and insulin aspart should look white and cloudy after mixing.Do notuse insulin aspart protamine and insulin aspart if it looks clear or contains any lumps or particles.

Insulin aspart protamine and insulin aspart is easier to mix when it is at room temperature.

After mixing insulin aspart protamine and insulin aspart, inject your dose right away. If you wait to inject your dose, the insulin will need to be mixed again.

Do notuse insulin aspart protamine and insulin aspart past the expiration date printed on the label.

Step 1:If you are using a new vial, pull off the tamper-resistant cap (

Do notfreeze insulin aspart protamine and insulin aspart.Do notuse insulin aspart protamine and insulin aspart if it has been frozen.

Keep insulin aspart protamine and insulin aspart away from heat or light.

All Unopened Vials: ⮝

Store unopened insulin aspart protamine and insulin aspart vials in the refrigerator at 36OF to 46OF (2OC to 8OC).

Unopened vials may be used until the expiration date printed on the 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: ⮝

Opened insulin aspart protamine and insulin aspart vials can be stored in the refrigerator 36F to 46F (2C to 8C) or at room temperature below 86F (30C) for up to 28 days.

Throw away all opened insulin aspart protamine and insulin aspart vials after 28 days, even if they still have insulin left in them.

General information about the safe and effective use of insulin aspart protamine and insulin aspart

Always use a new syringe and needle for each injection.

Do not share syringes or needles.

Keep insulin aspart protamine and insulin aspart vials, syringes, and needles out of the reach of children.

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

For Information Contact: ⮝

Novo Nordisk Pharma, Inc.

1-800-727-6500

INSTRUCTIONS FOR USE

Insulin Aspart Protamine and Insulin AspartFlexPen

Injectable Suspension

Read the following instructions carefully before you start using your Insulin Aspart Protamine and Insulin Aspart FlexPen and each time you get a refill. There may be new information. You should read the instructions even if you have used Insulin Aspart Protamine and Insulin Aspart FlexPen before.

Do not share your Insulin Aspart Protamine and Insulin Aspart FlexPen 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 Aspart Protamine and Insulin Aspart FlexPen is a disposable, single-patient use, dial-a-dose insulin pen. You can select doses from 1 to 60 units in increments of 1 unit. Insulin Aspart Protamine and Insulin Aspart FlexPen is designed to be used with NovoFine, NovoFine Plus or NovoTwist needles.

Peoplewho are blind or have vision problems should not use Insulin Aspart Protamine and Insulin Aspart FlexPen without help from a person trained to use Insulin Aspart Protamine and Insulin Aspart FlexPen.

Getting ready

Make Sure You Have The Following Items: ⮝

Insulin Aspart Protamine and Insulin Aspart FlexPen

New NovoFine, NovoFine Plus or NovoTwist needle

Alcohol swabs

Preparing your Insulin Aspart Protamine and Insulin Aspart FlexPen

Wash your hands with soap and water.

Before you start to prepare your injection, check the label to make sure that you are taking the right type of insulin. This is especially important if you take more than 1 type of insulin. Insulin aspart protamine and insulin aspart should look cloudy after mixing.

Before Your First Injection With A New Insulin Aspart Protamine And Insulin Aspart Flexpen You Must Mix The Insulin: ⮝

A. Let the insulin reach room temperature before you use it. This makes it easier to mix.

Pull off the pen cap (

Do notfreeze insulin aspart protamine and insulin aspart.Do notuse insulin aspart protamine and insulin aspart if it has been frozen.

Keep insulin aspart protamine and insulin aspart away from heat or light.

Store the Insulin Aspart Protamine and Insulin Aspart FlexPen without the needle attached.

Unused Insulin Aspart Protamine and Insulin Aspart FlexPen:

o

Store unused Insulin Aspart Protamine and Insulin Aspart FlexPen in the refrigerator at 36 F to 46 F (2 C to 8 C).

o

Unused Insulin Aspart Protamine and Insulin Aspart FlexPen may be used until the expiration date printed on the label, if kept in the refrigerator.

o

Unused Insulin Aspart Protamine and Insulin Aspart FlexPen should be thrown away after 14 days, if it is stored at room temperature.

In-Use Insulin Aspart Protamine and Insulin Aspart FlexPen:

o

Store the FlexPen you are currently using at room temperature below 86 F (30 C) for up to 14 days.

o

The Insulin Aspart Protamine and Insulin Aspart FlexPen you are using should be thrown away after 14 days, even if it still has insulin left in it.

Maintenance

For the safe and proper use of your Insulin Aspart Protamine and Insulin Aspart FlexPen be sure to handle it with care. Avoid dropping your Insulin Aspart Protamine and Insulin Aspart FlexPen as it may damage it. If you are concerned that your Insulin Aspart Protamine and Insulin Aspart FlexPen is damaged, use a new one. You can clean the outside of your Insulin Aspart Protamine and Insulin Aspart FlexPen by wiping it with a damp cloth. Do not soak or wash your Insulin Aspart Protamine and Insulin Aspart FlexPen as it may damage it. Do not refill your Insulin Aspart Protamine and Insulin Aspart FlexPen.

Remove the needle from the Insulin Aspart Protamine and Insulin Aspart FlexPen after each injection. This helps to ensure sterility, prevent leakage of insulin, and will help to make sure you inject the right dose of insulin for future injections.

Be careful when handling used needles to avoid needle sticks and transfer of infectious diseases.

Keep your Insulin Aspart Protamine and Insulin Aspart FlexPen and needles out of the reach of children.

Use Insulin Aspart Protamine and Insulin Aspart FlexPen as directed to treat your diabetes.

Do notshare your Insulin Aspart Protamine and Insulin Aspart FlexPen or needles with other people. You may give other people a serious infection, or get a serious infection from them.

Always use a new needle for each injection.

Novo Nordisk is not responsible for harm due to using this insulin pen with products not recommended by Novo Nordisk.

As a precautionary measure, always carry a spare insulin delivery device in case your Insulin Aspart Protamine and Insulin Aspart FlexPen is lost or damaged.

Remember to keep the disposable Insulin Aspart Protamine and Insulin Aspart FlexPen with you. Do not leave it in a car or other location where it can get too hot or too cold.

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

Revised: 08/2019

1. Highlights Of Prescribing Information
2. Recent Major Changes
3. Indications And Usage
4. Dosage And Administration
5. Dosage Forms And Strengths
6. Contraindications
7. Warnings And Precautions
8. Adverse Reactions
9. Drug Interactions
10. 1 Indications And Usage
11. 2 Dosage And Administration
12. 3 Dosage Forms And Strengths
13. 4 Contraindications
14. 5 Warnings And Precautions
15. 6 Adverse Reactions
16. 7 Drug Interactions
17. 8 Use In Specific Populations
18. 10 Overdosage
19. 11 Description
20. 12 Clinical Pharmacology
21. 13 Nonclinical Toxicology
22. 14 Clinical Studies
23. 16 How Supplied/storage And Handling
24. Principal Display Panel - Vial 10ml
25. Principal Display Panel - Flexpen 3ml

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use insulin aspart protamine and insulin aspart safely and effectively. See full prescribing information for insulin aspart protamine and insulin aspart.

Insulin Aspart Protamine and Insulin Aspart Injectable Suspension, for subcutaneous use
Initial U.S. Approval: 2001

Recent Major Changes ⮝

Dosage and Administration (2.1, 2.2) ..12/2018

Indications And Usage ⮝

Insulin aspart protamine and insulin aspart is a mixture of insulin aspart protamine, an intermediate-acting human insulin analog, and insulin aspart, a rapid-acting human insulin analog, indicated to improve glycemic control in patients with diabetes mellitus.

Limitations of Use:

Not recommended for the treatment of diabetic ketoacidosis.

The proportions of rapid-acting and long-acting insulins are fixed and do not allow for basal versus prandial dose adjustments (1).

Dosage And Administration ⮝

Inject insulin aspart protamine and insulin aspart subcutaneously in the abdominal region, buttocks, thigh, or upper arm (2.1).

Administer the dose within 15 minutes before meal initiation. For patients with type 2 diabetes, the dose may also be given after meal initiation (2.1).

Rotate injection sites within the same region from one injection to the next (2.1).

Inspect visually before use. Appearance should be uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles (2.1).

Insulin aspart protamine and insulin aspart must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature (2.1).

Do not administer intravenously or use in insulin infusion pumps (2.1).

Insulin aspart protamine and insulin aspart is typically dosed twice-daily (with each dose intended to cover 2 meals or a meal and a snack) (2.2).

Individualize dosage based on metabolic needs, blood glucose monitoring results, glycemic control goal (2.2).

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 or during acute illness (2.2).

Dosage adjustment may be needed when switching from another insulin to insulin aspart protamine and insulin aspart (2.2).

Dosage Forms And Strengths ⮝

Injectable suspension: insulin aspart protamine and insulin aspart is 100 units per mL (U-100), 70% insulin aspart protamine and 30% insulin aspart, is available as: (3)

10 mL multiple-dose vial

3 mL single-patient-use Insulin Aspart Protamine and Insulin Aspart FlexPen

Contraindications ⮝

Do not use during episodes of hypoglycemia (4).

Do not use in patients with hypersensitivity to insulin aspart protamine and insulin aspart or one of its excipients (4).

Warnings And Precautions ⮝

Never share an Insulin Aspart Protamine and Insulin Aspart FlexPen between patients, even if the needle is changed (5.1).

Hyper- or hypoglycemia with changes in insulin regimen: Carry out under close medical supervision and increase frequency of blood glucose monitoring (5.2).

Hypoglycemia: May be life-threatening. Increase frequency of glucose monitoring with changes to: insulin dosage, co-administered glucose lowering medications, meal pattern, physical activity; and in patients with renal or hepatic impairments and hypoglycemia unawareness (5.3).

Medication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection (5.4).

Hypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, may occur. Discontinue insulin aspart protamine and insulin aspart, treat, and monitor, 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).

Adverse Reactions ⮝

Adverse reactions observed with insulin therapy include hypoglycemia, allergic reactions, local injection site reactions, lipodystrophy, rash and pruritus (6).

To report SUSPECTED ADVERSE REACTIONS, contact Novo Nordisk Pharma, Inc. at 1-800-727-6500 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, propoxyphene, 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: 9/2019

1 Indications And Usage ⮝

Insulin aspart protamine and insulin aspart is a mixture of insulin aspart protamine and insulin aspart indicated to improve glycemic control in patients with diabetes mellitus.

Limitations of Use:

Insulin aspart protamine and insulin aspart is not recommended for the treatment of diabetic ketoacidosis.

The proportions of rapid-acting and long-acting insulins in insulin aspart protamine and insulin aspart are fixed and do not allow for basal versus prandial dose adjustments.

2 Dosage And Administration ⮝

2.1 Important Administration Information

Always check insulin labels before administration [see Warnings and Precautions (5.4)].

Inject insulin aspart protamine and insulin aspart subcutaneously in the abdominal region, buttocks, thigh, or upper arm.

Administer the dose within 15 minutes before meal initiation. For patients with type 2 diabetes, the dose may also be given after meal initiation.

Rotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy [see Adverse Reactions (6.1)].

Inspect insulin aspart protamine and insulin aspart visually before use. It should appear uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles.

Insulin aspart protamine and insulin aspart must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature.

When using the vial, roll the vial gently in hands in a horizontal position 10 times until the suspension appears uniformly white and cloudy. Inject immediately.

When using Insulin Aspart Protamine and Insulin Aspart FlexPen, roll Insulin Aspart Protamine and Insulin Aspart FlexPen gently between hands in a horizontal position 10 times. Then, turn Insulin Aspart Protamine and Insulin Aspart FlexPen upside down so that the glass ball moves from one end of the reservoir to the other 10 times until the suspension appears uniformly white and cloudy. Inject immediately.

The Insulin Aspart Protamine and Insulin Aspart FlexPen dials in 1-unit increment.

Use Insulin Aspart Protamine and Insulin Aspart FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.

Do not administer insulin aspart protamine and insulin aspart intravenously or use in insulin infusion pumps.

Do not mix insulin aspart protamine and insulin aspart with any other insulins.

2.2 Dosage Information

Insulin aspart protamine and insulin aspart is typically dosed twice-daily (with each dose intended to cover 2 meals or a meal and a snack).

Individualize and adjust the dosage of insulin aspart protamine and insulin aspart based on the individual'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 or during acute illness [see Warnings and Precautions (5.3) and Use in Specific Populations (8.6, 8.7)].

Dosage adjustment may be needed when switching from another insulin to insulin aspart protamine and insulin aspart [see Warnings and Precautions (5.2)].

2.3 Dosage Adjustment Due to Drug Interactions

Dosage adjustment may be needed when insulin aspart protamine and insulin aspart is co-administered with certain drugs [see Drug Interactions (7)].

3 Dosage Forms And Strengths ⮝

Insulin aspart protamine and insulin aspart is 100 units per mL (U-100), 70% insulin aspart protamine and 30% insulin aspart, is available as a white and cloudy injectable suspension:

10 mL multiple-dose vial

3 mL single-patient-use Insulin Aspart Protamine and Insulin Aspart FlexPen

4 Contraindications ⮝

Insulin aspart protamine and insulin aspart is contraindicated

During episodes of hypoglycemia [see Warnings and Precautions (5.3)]

In patients with hypersensitivity to insulin aspart protamine and insulin aspart or one of its excipients [see Warnings and Precautions (5.5)]

5 Warnings And Precautions ⮝

5.1 Never Share Insulin Aspart Protamine and Insulin Aspart FlexPen Between Patients

Insulin Aspart Protamine and Insulin Aspart FlexPen should never be shared between patients, even if the needle is changed. Patients using insulin aspart protamine and insulin aspart 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 insulin strength, manufacturer, type, or method of administration may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions (5.3)]or hyperglycemia. These changes should be made cautiously and only under close medical supervision, and the frequency of blood glucose monitoring should be increased. For patients with type 2 diabetes, dosage adjustments of concomitant anti-diabetic products may be needed.

5.3 Hypoglycemia

Hypoglycemia is the most common adverse effect of all insulin therapies, including insulin aspart protamine and insulin aspart. Severe hypoglycemia can cause seizures, may lead to unconsciousness, may be life threatening or cause death. Hypoglycemia can impair concentration ability and reaction time; this may place an individual and others at risk in situations where these abilities are important (e.g., driving or operating other machinery).

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 insulin preparations, the glucose lowering effect time course of insulin aspart protamine and insulin aspart 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; increased frequency of blood glucose monitoring is recommended. 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 aspart protamine and insulin aspart and other insulin products have been reported. To avoid medication errors between insulin aspart protamine and insulin aspart and other insulins, instruct patients to always check the insulin label before each injection.

5.5 Hypersensitivity and Allergic Reactions

Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulin products, including insulin aspart protamine and insulin aspart. If hypersensitivity reactions occur, discontinue insulin aspart protamine and insulin aspart; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6)]. Insulin aspart protamine and insulin aspart is contraindicated in patients who have had hypersensitivity reactions to insulin aspart or one of the excipients [see Contraindications (4)].

5.6 Hypokalemia

All insulin products, including insulin aspart protamine and insulin aspart, can 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 concentration).

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 aspart protamine and insulin aspart, and a PPAR-gamma agonist should be observed for signs and symptoms of heart failure. If heart failure develops, it should be managed according to current standards of care, and discontinuation or dose reduction of the PPAR-gamma agonist must be considered.

6 Adverse Reactions ⮝

The following adverse reactions are also discussed elsewhere:

Hypoglycemia [see Warnings and Precautions (5.3)]

Hypersensitivity and allergic reactions [see Warnings and Precautions (5.5)]

Hypokalemia [see Warnings and Precautions (5.6)]

6.1 Clinical Trial Experience

Clinical trials are conducted under widely varying designs, therefore, the adverse reaction rates reported in one clinical trial may not be easily compared to those rates reported in another clinical trial, and may not reflect the rates actually observed in clinical practice. The data in Table 1 reflect the exposure of 55 patients with type 1 diabetes to insulin aspart protamine and insulin aspart with a mean exposure duration of three months. The mean age was 43.2 years. Sixty-four percent were male and 100% were Caucasian. The mean body mass index (BMI) was 26.1 kg/m2. The mean duration of diabetes was 14.9 years.

The data in Table 2 reflect the exposure of 85 patients with type 2 diabetes to insulin aspart protamine and insulin aspart with a mean exposure duration of three months. The mean age was 62.7 years. Fifty-four percent were male and 100% were Caucasian. The mean body mass index (BMI) was 28.1 kg/m2. The mean duration of diabetes was 15.0 years.

Common adverse reactions were defined as events occurring in 5%, excluding hypoglycemia, of the population studied. Common adverse events occurring at the same rate or greater for insulin aspart protamine and insulin aspart-treated subjects than on comparator-treated subjects during clinical trials in patients with type 1 diabetes mellitus and type 2 diabetes mellitus (other than hypoglycemia) are listed in Table 1 and Table 2, respectively. The trial was a three-month, open-label trial in patients with type 1 or type 2 diabetes who were treated twice daily (before breakfast and before supper) with insulin aspart protamine and insulin aspart.

Table 1: Adverse Reactions Occurring in 5% of Type 1 Diabetes Mellitus Adult Patients treated with insulin aspart protamine and insulin aspart and at the same rate or greater on insulin aspart protamine and insulin aspart than on comparator

	insulin aspart protamine and insulin aspart (N=55)		Novolin 70/30 (N=49)
Preferred Term	N	%	N	%
Hypoglycemia	38	69	37	76
Headache	19	35	6	12
Influenza-like symptoms	7	13	1	2
Dyspepsia	5	9	3	6
Back pain	4	7	2	4
Diarrhea	4	7	3	6
Pharyngitis	4	7	1	2
Rhinitis	3	5	6	12
Skeletal pain	3	5	2	4
Upper respiratory tract infection	3	5	1	2

Table 2: Adverse reactions Occurring in 5% of Type 2 Diabetes Mellitus Adult Patients treated with insulin aspart protamine and insulin aspart and at the same rate or greater on insulin aspart protamine and insulin aspart than on comparator

	insulin aspart protamine and insulin aspart (N=85)		Novolin 70/30 (N=102)
Preferred Term	N	%	N	%
Hypoglycemia	40	47	51	50
Upper respiratory tract infection	10	12	6	6
Headache	8	9	8	8
Diarrhea	7	8	2	2
Neuropathy	7	8	2	2
Pharyngitis	5	6	4	4
Abdominal pain	4	5	0	0
Rhinitis	4	5	2	2

Severe Hypoglycemia

Hypoglycemia is the most commonly observed adverse reaction in patients using insulin, including insulin aspart protamine and insulin aspart [see Warnings and Precautions (5.3)]. The rates of reported hypoglycemia depend on the definition of hypoglycemia used, diabetes type, insulin dose, intensity of glucose control, background therapies, and other intrinsic and extrinsic patient factors. For these reasons, comparing rates of hypoglycemia in clinical trials for insulin aspart protamine and insulin aspart with the incidence of hypoglycemia for other products may be misleading and also, may not be representative of hypoglycemia rates that will occur in clinical practice.

Severe hypoglycemia requiring the assistance of another person and/or parenteral glucose infusion or glucagon administration has been observed in clinical trials with insulin, including trials with insulin aspart protamine and insulin aspart.

The incidence of severe hypoglycemia in adult patients receiving subcutaneous insulin aspart protamine and insulin aspart was 16% and 4% for type 1 and type 2 diabetes patients respectively at 12 weeks [see Clinical Studies (14)].

Allergic Reactions

Patients have experienced reactions such as erythema, edema or pruritus at the site of insulin aspart protamine and insulin aspart injection. These reactions usually resolve in a few days to a few weeks, but in some occasions, have required discontinuation of insulin aspart protamine and insulin aspart. Severe cases of generalized allergy (anaphylaxis) have been reported [see Warnings and Precautions (5.5)].

Insulin initiation and glucose control intensification

Intensification or rapid improvement in glucose control has been associated with 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.

Lipodystrophy

Long-term use of insulin, including insulin aspart protamine and insulin aspart, can cause lipodystrophy at the site of repeated insulin injections. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption [see Dosage and Administration (2.1)].

Weight gain

Weight gain can occur with some insulin therapies, including insulin aspart protamine and insulin aspart, and has been attributed to the anabolic effects of insulin and the decrease in glycosuria.

Peripheral Edema

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

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to insulin aspart protamine and insulin aspart in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.

In a 3-month study with an extension in adult subjects with type 2 diabetes, 100% of patients who received insulin aspart protamine and insulin aspart were positive for anti-insulin antibodies (AIA) at least once during the first 12 months of the study including 91.4% that were positive at baseline. A total of 91.4% of patients who received insulin aspart protamine and insulin aspart were positive for anti-drug antibodies (ADA) at least once during the first 12 months of the study, including 62.1% that were positive at baseline.

In a phase 3 type 2 diabetes clinical trial of insulin aspart protamine and insulin aspart, initial increase in titers of antibodies to insulin followed by a decrease approaching to baseline values was observed in insulin aspart protamine and insulin aspart and Novolin 70/30 treatment groups with similar incidences. These antibodies did not cause deterioration in glycemic control or necessitate increases in insulin dose.

6.3 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of insulin aspart protamine and insulin aspart. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is generally not 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 aspart protamine and insulin aspart have been reported [see Warnings and Precautions (5.4)].

7 Drug Interactions ⮝

Table 3: Clinically Significant Drug Interactions with insulin aspart protamine and insulin aspart

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 aspart protamine and insulin aspart is co-administered with these drugs.
Drugs that May Decrease the Blood Glucose Lowering Effect of insulin aspart protamine and insulin aspart
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 aspart protamine and insulin aspart is co-administered with these drugs.
Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of insulin aspart protamine and insulin aspart
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 aspart protamine and insulin aspart 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 aspart protamine and insulin aspart is co-administered with these drugs.

8 Use In Specific Populations ⮝

8.1 Pregnancy

Risk Summary

There are no available data with insulin aspart protamine and insulin aspart in pregnant women to inform a drug-associated risk for major birth defects and miscarriage. Available information from published randomized controlled trials with insulin aspart use during the second trimester of pregnancy have not reported an association with insulin aspart and major birth defects 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].

In animal reproduction studies, administration of subcutaneous insulin aspart to pregnant rats and rabbits during the period of organogenesis did not cause adverse developmental effects at exposures 8-times and equal to the human subcutaneous dose of 1 unit/kg/day, respectively. Pre- and post-implantation losses and visceral/skeletal abnormalities were seen at higher exposures, which are considered secondary to maternal hypoglycemia. These effects were similar to those observed in rats administered regular human insulin [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, preeclampsia, spontaneous abortions, preterm delivery, and delivery complications. Poorly controlled diabetes increases the fetal risk for major birth defects, still birth, and macrosomia related morbidity.

Data

Human Data

Published data from 5 randomized controlled trials of 441 pregnant women with diabetes mellitus treated with insulin aspart during the late 2nd trimester of pregnancy did not identify an association of insulin aspart with major birth defects or adverse maternal or fetal outcomes. However, these studies cannot definitely establish the absence of any risk because of methodological limitations, including a variable duration of treatment and small size of the majority of the trials.

Animal Data

Fertility, embryo-fetal and pre- and postnatal development studies have been performed with insulin aspart and regular human insulin in rats and rabbits. In a combined fertility and embryo-fetal development study in rats, insulin aspart was administered before mating, during mating, and throughout pregnancy. Further, in a pre- and postnatal development study insulin aspart was given throughout pregnancy and during lactation to rats. In an embryo-fetal development study insulin aspart was given to female rabbits during organogenesis. The effects of insulin aspart did not differ from those observed with subcutaneous regular human insulin. Insulin aspart, like human insulin, caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at a dose of 200 units/kg/day (approximately 32 times the human subcutaneous dose of 1 unit/kg/day, based on human exposure equivalents) and in rabbits at a dose of 10 units/kg/day (approximately three times the human subcutaneous dose of 1 unit/kg/day, based on human exposure equivalents). No significant effects were observed in rats at a dose of 50 units/kg/day and in rabbits at a dose of 3 units/kg/day. These doses are approximately 8 times the human subcutaneous dose of 1 unit/kg/day for rats and equal to the human subcutaneous dose of 1 unit/kg/day for rabbits, based on human exposure equivalents. The effects are considered secondary to maternal hypoglycemia.

8.2 Lactation

Risk Summary

There are no data on the presence of insulin aspart protamine and insulin aspart in human milk, the effects on the breastfed infant, or the effect on milk production. One small published study reported that exogenous insulin, including insulin aspart, was present in human milk. However, there is insufficient information to determine the effects of insulin aspart on the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother s clinical need for insulin aspart protamine and insulin aspart, and any potential adverse effects on the breastfed infant from insulin aspart protamine and insulin aspart, or from the underlying maternal condition.

8.4 Pediatric Use

Safety and effectiveness of insulin aspart protamine and insulin aspart have not been established in pediatric patients.

8.5 Geriatric Use

Clinical studies of insulin aspart protamine and insulin aspart did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently than younger patients. In elderly patients with diabetes, the initial dosing, dose increments should be conservative to avoid hypoglycemic reactions. Hypoglycemia may be difficult to recognize in the elderly.

8.6 Renal Impairment

The effect of renal impairment on the pharmacokinetics of insulin aspart protamine and insulin aspart has not been studied. Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. Patients with renal impairment may be at increased risk of hypoglycemia and may require more frequent insulin aspart protamine and insulin aspart dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.3)].

8.7 Hepatic Impairment

The effect of hepatic impairment on the pharmacokinetics of insulin aspart protamine and insulin aspart has not been studied. Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent insulin aspart protamine and insulin aspart dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.3)].

10 Overdosage ⮝

Excess insulin administration may cause hypoglycemia and hypokalemia [see Warnings and Precautions (5.3,5.6)]. 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 intramuscular/subcutaneous glucagon or concentrated intravenous glucose. Sustained carbohydrate intake and observation may be necessary because hypoglycemia may recur after apparent clinical recovery. Hypokalemia must be corrected appropriately.

11 Description ⮝

Insulin aspart protamine and insulin aspart injection is a human insulin analog suspension containing 70% insulin aspart protamine crystals and 30% soluble insulin aspart. Insulin aspart protamine and insulin aspart is a blood-glucose-lowering agent with an earlier onset and an intermediate duration of action. Insulin aspart is homologous with regular human insulin with the exception of a single substitution of the amino acid proline by aspartic acid in position B28, and is produced by recombinant DNA technology utilizing Saccharomyces cerevisiae (baker s yeast). Insulin aspart has the empirical formula C256H381N65O79S6 and a molecular weight of 5825.8 Da.

Figure 1. Structural formula of insulin aspart

Insulin aspart protamine and insulin aspart is a uniform, white, sterile suspension that contains insulin aspart 100 units/mL.

Inactive ingredients are glycerol 16.0 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 19.6 g/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL, sodium chloride 0.877 mg/mL, and protamine sulfate 0.32 mg/mL. Insulin aspart protamine and insulin aspart has a pH of 7.20 - 7.44. Hydrochloric acid or sodium hydroxide may be added to adjust pH.

12 Clinical Pharmacology ⮝

12.1 Mechanism of Action

The primary activity of insulin, including insulin aspart protamine and insulin aspart is the regulation of glucose metabolism. Insulin and its analog lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits lipolysis and proteolysis, and enhances protein synthesis.

12.2 Pharmacodynamics

A euglycemic clamp study described below assessed glucose utilization after subcutaneous dosing of insulin aspart protamine and insulin aspart in healthy subjects (n = 24). Following a 0.3 units/kg single subcutaneous dose, the onset of action is between 10-20 minutes for insulin aspart protamine and insulin aspart compared to 30 minutes for Novolin 70/30. The mean SD time to peak activity for insulin aspart protamine and insulin aspart is 2.7 hr 0.9 hr compared to 4.3 hr 3.9 hr for Novolin 70/30. The duration of action may be as long as 24 hours (see Figure 2).

Figure 2. Pharmacodynamic Activity Profile of insulin aspart protamine and insulin aspart and Novolin 70/30 in healthy subjects after single 0.3 units/kg subcutaneous dose

12.3 Pharmacokinetics

The single substitution of the amino acid proline with aspartic acid at position B28 in insulin aspart reduces the molecule s tendency to form hexamers as observed with regular human insulin. The rapid absorption characteristics of insulin aspart are maintained by insulin aspart protamine and insulin aspart.

Absorption and Bioavailability

The 30% insulin aspart in the soluble component of insulin aspart protamine and insulin aspart is absorbed more rapidly from the subcutaneous layer than regular human insulin. The remaining 70% is in crystalline form as insulin aspart protamine which has a prolonged absorption profile after subcutaneous injection.

The relative bioavailability of insulin aspart protamine and insulin aspart compared to NOVOLOG and Novolin 70/30 indicates that the insulins are absorbed to similar extent. In a euglycemic clamp study in healthy subjects (n=24) after dosing with insulin aspart protamine and insulin aspart (0.3 units/kg), a mean maximum serum concentration (Cmax) of 61.3 20.1 milliunits/L was reached after 85 minutes. Serum insulin levels returned to baseline 16 to 20 hours after a subcutaneous dose of insulin aspart protamine and insulin aspart (see Fig. 3 for pharmacokinetic profiles).

Figure 3. Pharmacokinetic Profiles of insulin aspart protamine and insulin aspart and Novolin 70/30 after single 0.3 units/kg subcutaneous dose

Distribution and Elimination

Insulin aspart has a low binding affinity to plasma proteins (<10%), similar to that seen with regular human insulin.

13 Nonclinical Toxicology ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of insulin aspart protamine and insulin aspart. In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with NOVOLOG, the rapid-acting component of insulin aspart protamine and insulin aspart, at 10, 50, and 200 units/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of 1.0 unit/kg/day, based on units/body surface area, respectively). At a dose of 200 units/kg/day, insulin aspart increased the incidence of mammary gland tumors in females when compared to untreated controls. The relevance of these findings to humans is not known.

Insulin aspart was not genotoxic in the following tests: Ames test, mouse lymphoma cell forward gene mutation test, human peripheral blood lymphocyte chromosome aberration test, in vivo micronucleus test in mice, and in ex vivo UDS test in rat liver hepatocytes.

In fertility studies in male and female rats, insulin aspart at subcutaneous doses up to 200 units/kg/day (approximately 32 times the human subcutaneous dose, based on units/body surface area) had no direct adverse effects on male and female fertility, or on general reproductive performance of animals.

13.2 Animal Toxicology and/or Pharmacology

In standard biological assays in mice and rabbits, one unit of insulin aspart has the same glucose-lowering effect as one unit of regular human insulin.

14 Clinical Studies ⮝

14.1 Clinical Studies in Adult Patients with Type 1 and Type 2 Diabetes

In a three-month, open-label trial, patients with type 1 (n=104) or type 2 (n=187) diabetes were treated twice daily (before breakfast and before supper) with insulin aspart protamine and insulin aspart or Novolin 70/30. Patients had received insulin for at least 24 months before the study. Oral hypoglycemic agents were not allowed within 1 month prior to the study or during the study. The small changes in HbA1c were comparable across the treatment groups (see Table 4).

The mean age of the trial population for type 1 was 43.2 years and 62.7 for type 2. For type 1, 64% were male and for type 2, 54% were male and 100% were Caucasian for type 1 and type 2. The mean body mass index (BMI) was 26.1 kg/m2 for type 1 and 28.1 kg/m2 for type 2. The mean duration of diabetes was 14.9 years for type 1 and 15.0 years for type 2.

Table 4: Glycemic Parameters at the End of Treatment [Mean SD (N subjects)]

	insulin aspart protamine and insulin aspart	Novolin 70/30
Type 1, N=104
Fasting Blood Glucose (mg/dL)	174 64 (48)	142 59 (44)
1.5 Hour Post Breakfast (mg/dL)	187 82 (48)	200 82 (42)
1.5 Hour Post Dinner (mg/dL)	162 77 (47)	171 66 (41)
HbA1c (%) Baseline	8.4 1.2 (51)	8.5 1.1 (46)
HbA1c (%) Week 12	8.4 1.1 (51)	8.3 1.0 (47)
Type 2, N=187
Fasting Blood Glucose (mg/dL)	153 40 (76)	152 69 (93)
1.5 Hour Post Breakfast (mg/dL)	182 65 (75)	200 80 (92)
1.5 Hour Post Dinner (mg/dL)	168 51 (75)	191 65 (93)
HbA1c (%) Baseline	8.1 1.2 (82)	8.2 1.3 (98)
HbA1c (%) Week 12	7.9 1.0 (81)	8.1 1.1 (96)

The significance, with respect to the long-term clinical sequelae of diabetes, of the differences in postprandial hyperglycemia between treatment groups has not been established.

Specific anti-insulin antibodies as well as cross-reacting anti-insulin antibodies were monitored in the 3-month, open-label comparator trial as well as in a long-term extension trial.

14.2 Clinical Studies in Adult Patients with Type 2 Diabetes with Insulin and Oral Antidiabetic Agents

Trial 1:

In a 34-week, open-label trial, insulin-na ve patients with type 2 diabetes currently treated with 2 oral antidiabetic agents were switched to treatment with metformin and pioglitazone. The mean age of the trial population was 53.4 years and mean duration of diabetes was 9.2 years. Forty-six percent were male. Eighty-five percent were White, 12% were Black and 3% were Asian. The mean BMI was approximately 32.4 kg/m2. During an 8-week optimization period metformin and pioglitazone were increased to 2500 mg per day and 30 or 45 mg per day, respectively. After the optimization period, subjects were randomized to receive either insulin aspart protamine and insulin aspart twice daily added on to the metformin and pioglitazone regimen or continue the current optimized metformin and pioglitazone therapy. Insulin aspart protamine and insulin aspart was started at a dose of 6 IU twice daily (before breakfast and before supper). Insulin doses were titrated to a pre-meal glucose goal of 80-110 mg/dL. The total daily insulin dose at the end of the study was 56.9 30.5 IU.

Table 5: Combination Therapy with Oral Agents and Insulin in Patients with Type 2 Diabetes Mellitus [Mean (SD)]

Treatment duration 24-weeks	insulin aspart protamine and insulin aspart + Metformin + Pioglitazone	Metformin + Pioglitazone
HbA1c
Baseline mean SD (n)	8.1 1.0 (102)	8.1 1.0 (98)
End-of-study mean SD (n) - LOCF	6.6 1.0 (93)	7.8 1.2 (87)
Adjusted Mean change from baseline SE (n)*	-1.6 0.1 (93)	-0.3 0.1 (87)
Treatment difference mean SE* 95% CI*	-1.3 0.1 (-1.6, -1.0)
Percentage of subjects reaching HbA1c <7.0%	76%	24%
Percentage of subjects reaching HbA1c 6.5%	59%	12%
Fasting Blood Glucose (mg/dL)
Baseline Mean SD (n)	173 39.8 (93)	163 35.4 (88)
End of Study Mean SD (n) - LOCF	130 50.0 (90)	162 40.8 (84)
Adjusted Mean change from baseline SE (n)*	-43.0 5.3 (90)	-3.9 5.3 (84)
End-of-Study Blood Glucose (Plasma) (mg/dL)
2 Hour Post Breakfast	138 42.8 (86)	188 57.7 (74)
2 Hour Post Lunch	150 41.5 (86)	176 56.5 (74)
2 Hour Post Dinner	141 57.8 (86)	195 60.1 (74)

*Adjusted mean per group, treatment difference, and 95% CI were obtained based on an ANCOVA model with treatment, FPG stratum, and secretagogue stratum as fixed factors and baseline HbA1c as the covariate.

Trial 2:

In a 28-week, open-label trial, insulin-na ve patients with type 2 diabetes with fasting plasma glucose above 140 mg/dL currently treated with metformin thiazolidinedione therapy were randomized to receive either insulin aspart protamine and insulin aspart twice daily [before breakfast and before supper] or insulin glargine once daily (see Table 6). Insulin aspart protamine and insulin aspart was started at an average dose of 5-6 IU (0.07 0.03 IU/kg) twice daily (before breakfast and before supper), and bedtime insulin glargine was started at 10-12 IU (0.13 0.03 IU/kg). Insulin doses were titrated weekly by decrements or increments of -2 to +6 units per injection to a pre-meal glucose goal of 80-110 mg/dL. The metformin dose was adjusted to 2550 mg/day. Approximately one-third of the patients in each group were also treated with pioglitazone (30 mg/day). Insulin secretagogues were discontinued in order to reduce the risk of hypoglycemia. Most patients were Caucasian (53%), and the mean initial weight was 90 kg.

The mean age of the trial population was 52.6 years and mean duration of diabetes was 9.5 years. Fifty three percent were male. Fifty-five percent were Caucasian, 15% Black, 27% were Hispanic, 2% were Asian and 2% were Other. The mean BMI was approximately 31.5 kg/m2.

Table 6: Combination Therapy with Oral Agents and Two Types of Insulin in Patients with Type 2 Diabetes Mellitus [Mean (SD)]

Treatment duration 28-weeks	insulin aspart protamine and insulin aspart+ Metformin Pioglitazone	Insulin Glargine + Metformin Pioglitazone
Number of patients	117	116
HbA1c
Baseline mean (%)	9.7 1.5 (117)	9.8 1.4 (114)
End-of-study mean ( SD)	6.9 1.2 (108)	7.4 1.2 (114)
Mean change from baseline	-2.7 1.6 (108)	-2.4 1.5 (114)
Percentage of subjects reaching HbA1c <7.0%	66%	40%

16 How Supplied/storage And Handling ⮝

16.1 How Supplied

Insulin aspart protamine and insulin aspart 100 units per mL (U-100), 70% insulin aspart protamine and 30% insulin aspart, is available as a white and cloudy injectable suspension:

10 mL multiple-dose vial NDC 73070-200-11

3 mL single-patient-use Insulin Aspart Protamine and Insulin Aspart FlexPen NDC 73070-203-15

The Insulin Aspart Protamine and Insulin Aspart FlexPen dials in 1-unit increment.

16.2 Recommended Storage

Unused insulin aspart protamine and insulin aspart should be stored in a refrigerator between 2 C and 8 C (36 F to 46 F). Do not freeze insulin aspart protamine and insulin aspart or use insulin aspart protamine and insulin aspart if it has been frozen. Do not expose insulin aspart protamine and insulin aspart to excessive heat or light.

Always remove the needle after each injection and store Insulin Aspart Protamine and Insulin Aspart FlexPen without a needle attached. This prevents contamination and/or infection, or leakage of insulin, and will ensure accurate dosing. Always use a new needle for each injection to prevent contamination.

The storage conditions are summarized in the following table:

Table 7: Storage conditions for Insulin Aspart Protamine and Insulin Aspart vial and FlexPen

	Not in-use (unopened) Room Temperature (below 30 C [86 F])	Not in-use (unopened) Refrigerated (2 C - 8 C [36 F - 46 F])	In-use (opened) Room Temperature (below 30 C [86 F])
10 mL vial	28 days	Until expiration date	28 days (refrigerated/room temperature)
3 mL Insulin Aspart Protamine and Insulin Aspart FlexPen	14 days	Until expiration date	14 days (Do not refrigerate)

Principal Display Panel - Vial 10ml ⮝

NDC 73070-200-11

List 020011

Insulin Aspart Protamine and Insulin Aspart

Injectable Suspension

One 10 mL multi-dose vial

100 units/mL (U-100)

Shake carefully before using.

See enclosed insert for proper technique.

Rx only

novo nordisk

Principal Display Panel - Flexpen 3ml ⮝

NDC 73070-203-15List 020315

Insulin Aspart Protamine and Insulin Aspart

FlexPen Prefilled Syringe

Injectable Suspension

For Single Patient Use Only

100 units/mL (U-100)

5x3 mL Prefilled insulin Syringes

Shake carefully before using.

See enclosed insert for proper technique.

Rx only

For use with NovoFine ,
NovoFine Plus or NovoTwist
disposable needles.

Keep in a refrigerator at 36oF to 46oF (2oC to 8oC) until first use. After first use store out of the refrigerator below 86oF (30oC) for up to 28 days.

Avoid freezing.
Protect from light.

novo nordisk

INSULIN ASPART PROTAMINE AND INSULIN ASPART insulin aspart injection, suspension

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:73070-200 Route of Administration SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength INSULIN ASPART (UNII: D933668QVX) (insulin aspart - UNII:D933668QVX) INSULIN ASPART 100 [iU] in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM PHOSPHATE, DIBASIC, DIHYDRATE (UNII: 94255I6E2T) 1.25 mg in 1 mL HYDROCHLORIC ACID (UNII: QTT17582CB) GLYCERIN (UNII: PDC6A3C0OX) 16.0 mg in 1 mL METACRESOL (UNII: GGO4Y809LO) 1.72 mg in 1 mL PHENOL (UNII: 339NCG44TV) 1.5 mg in 1 mL PROTAMINE SULFATE (UNII: 0DE9724IHC) 0.32 mg in 1 mL SODIUM CHLORIDE (UNII: 451W47IQ8X) 0.877 mg in 1 mL SODIUM HYDROXIDE (UNII: 55X04QC32I) ZINC (UNII: J41CSQ7QDS) 19.6 ug in 1 mL

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:73070-200-11 1 in 1 CARTON 09/10/2019 1 10 mL in 1 VIAL, GLASS; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA authorized generic NDA021172 11/01/2001

.INSULIN ASPART PROTAMINE AND INSULIN ASPART insulin aspart injection, suspension

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:73070-203 Route of Administration SUBCUTANEOUS

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength INSULIN ASPART (UNII: D933668QVX) (insulin aspart - UNII:D933668QVX) INSULIN ASPART 100 [iU] in 1 mL

Inactive Ingredients Ingredient Name Strength SODIUM PHOSPHATE, DIBASIC, DIHYDRATE (UNII: 94255I6E2T) 1.25 mg in 1 mL GLYCERIN (UNII: PDC6A3C0OX) 16 mg in 1 mL HYDROCHLORIC ACID (UNII: QTT17582CB) METACRESOL (UNII: GGO4Y809LO) 1.72 mg in 1 mL PHENOL (UNII: 339NCG44TV) 1.5 mg in 1 mL PROTAMINE SULFATE (UNII: 0DE9724IHC) 0.32 mg in 1 mL SODIUM CHLORIDE (UNII: 451W47IQ8X) 0.877 mg in 1 mL SODIUM HYDROXIDE (UNII: 55X04QC32I) ZINC (UNII: J41CSQ7QDS) 19.6 ug in 1 mL

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:73070-203-15 5 in 1 CARTON 09/10/2019 1 NDC:73070-203-10 3 mL in 1 SYRINGE, PLASTIC; Type 2: Prefilled Drug Delivery Device/System (syringe, patch, etc.)

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA authorized generic NDA021172 09/11/2002

Labeler - Novo Nordisk Pharma, Inc. (117032563)

Revised: 9/2019 Document Id: a0905c12-b088-49cc-bc08-12e201ac8860 34391-3 Set id: fc94baa4-3606-48bc-a781-9617ab6960ef Version: 3 Effective Time: 20190904 Novo Nordisk Pharma, Inc.