SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION. NovoLog(R) Mix 70/30 (NO-vo-log-MIX-SEV-en-tee-THIR-tee)(insulin aspart protamine and insulin aspart) injectable suspensionDo not share your NovoLog Mix 70/30 FlexPen with other people, even if the needle has been changed. You may give other people serious infection, or get serious infection from them.What is NovoLog Mix 70/30oNovoLog Mix 70/30 is man-made insulin that is used to control high blood sugar in people with diabetes mellitus.oIt is not known if NovoLog Mix 70/30 is safe and effective in children.Who should not take NovoLog Mix 70/30Do not take NovoLog Mix 70/30 if you:oare having an episode of low blood sugar (hypoglycemia).ohave an allergy to NovoLog Mix 70/30 or any of the ingredients in NovoLog Mix 70/30.Before taking NovoLog Mix 70/30, tell your healthcare provider about all your medical conditions including, if you are:opregnant, planning to become pregnant, or are breastfeeding.otaking new prescription or over-the-counter medicines, vitamins, or herbal supplements.Before you start taking NovoLog Mix 70/30, talk to your healthcare provider about low blood sugar and how to manage it.How should take NovoLog Mix 70/30oRead the Instructions for Use that come with your NovoLog Mix 70/30.oTake NovoLog Mix 70/30 exactly as your healthcare provider tells you to.oNovoLog Mix 70/30 starts acting fast. If you have Type diabetes, inject it up to 15 minutes before you eat meal. Do not inject NovoLog Mix 70/30 if you are not planning to eat within 15 minutes. If you have Type diabetes, you may inject NovoLog Mix 70/30 up to 15 minutes before or after starting your meal.oDo not mix NovoLog Mix 70/30 with other insulin products or use in an insulin pump.oKnow the type and strength of insulin you take. Do not change 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.oCheck your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels.oDo not reuse or share your needles or syringes with other people. You may give other people serious infection or get serious infection from them.oNovoLog Mix 70/30 is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs, or upper arms.oChange (rotate) your injection sites within the same area you choose with each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.oDo not use the exact same spot for each injection.oDo not inject where skin has pits, is thickened, or has lumps.oDo not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. What should avoid while taking NovoLog Mix 70/30While taking NovoLog Mix 70/30 do not:oDrive or operate heavy machinery, until you know how NovoLog Mix 70/30 affects you.oDrink alcohol or use prescription or over-the-counter medicines that contain alcohol.What are the possible side effects of NovoLog Mix 70/30NovoLog Mix 70/30 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:odizziness or light-headednessoblurred visionoanxiety, irritability, or mood changesosweatingoslurred speechohungeroconfusionoshakinessoheadacheofast heart beat Your insulin dose may need to change because of:ochange in level of physical activity or exerciseoincreased stressochange in dietoweight gain or lossoillnessOther common side effects of NovoLog Mix 70/30 may include:olow 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:otrouble 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 NovoLog Mix 70/30. 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 NovoLog Mix 70/30.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. You can ask your pharmacist or healthcare provider for information about NovoLog Mix 70/30 that is written for health professionals. Do not use NovoLog Mix 70/30 for condition for which it was not prescribed. Do not give NovoLog Mix 70/30 to other people, even if they have the same symptoms that you have. It may harm them.What are the ingredients in NovoLog Mix 70/30Active Ingredient: 70% insulin aspart protamine and 30% insulin aspart.Inactive Ingredients: disodium hydrogen phosphate dihydrate, glycerol, metacresol, phenol, protamine sulfate, sodium chloride, zinc, and Water for Injection, USP. Hydrochloric acid or sodium hydroxide may be added to adjust pH.Manufactured by: Novo Nordisk Inc., Plainsboro, NJ 08536 U.S. License Number 1261For more information, go to www.novonordisk-us.com or call 1-800-727-6500. This Patient Information has been approved by the U.S. Food and Drug AdministrationRevised: 4/2021INSTRUCTIONS FOR USENovoLog(R) Mix 70/30 (NO-vo-Log-MIX-SEV-en-tee-THIR-tee)(insulin aspart protamine and insulin aspart) injectable suspension10 mL multiple-dose vial (100 Units/mL, U-100)Read this Instructions for Use before you start taking NovoLog Mix 70/30 and each time you get 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 NovoLog Mix 70/30 injection:o10 mL NovoLog Mix 70/30 vialoinsulin syringe and needleoalcohol swabsPreparing your NovoLog Mix 70/30 dose:oWash your hands with soap and water.oBefore you start to prepare your injection, check the NovoLog Mix 70/30 label to make sure that you are taking the right type of insulin. This is especially important if you use more than type of insulin.oNovoLog Mix 70/30 should look white and cloudy after mixing. Do not use NovoLog Mix 70/30 if it looks clear or contains any lumps or particles. oNovoLog Mix 70/30 is easier to mix when it is at room temperature. oAfter mixing NovoLog Mix 70/30, inject your dose right away. If you wait to inject your dose, the insulin will need to be mixed again.oDo not use NovoLog Mix 70/30 past the expiration date printed on the label.Step 1: If you are using new vial, pull off the tamper-resistant cap (See Figure A).Step 2: Wipe the rubber stopper with an alcohol swab (See Figure B).Step 3: Roll the NovoLog Mix 70/30 vial between your hands 10 times. Keep the vial in horizontal (flat) position (See Figure C). Roll the vial between your hands until the NovoLog Mix 70/30 looks white and cloudy. Do not shake the vial.Step 4: Hold the syringe with the needle pointing up. Pull down on the plunger until the black tip reaches the line for the number of units for your prescribed dose (See Figure D).Step 5: Push the needle through the rubber stopper of the NovoLog Mix 70/30 vial (See Figure E).Step 6: Push the plunger all the way in. This puts air into the NovoLog Mix 70/30 vial (See Figure F).Step 7: Turn the NovoLog Mix 70/30 vial and syringe upside down and slowly pull the plunger down until the black tip is few units past the line for your dose (See Figure G).oIf there are air bubbles, tap the syringe gently few times to let any air bubbles rise to the top (See Figure H).Step 8: Slowly push the plunger up until the black tip reaches the line for your NovoLog Mix 70/30 dose (See Figure I).Step 9: Check the syringe to make sure you have the right dose of NovoLog Mix 70/30.Step 10: Pull the syringe out of the vials rubber stopper (See Figure J).Giving your injection:oInject your NovoLog Mix 70/30 exactly as your healthcare provider has shown you. Your healthcare provider should tell you if you need to pinch the skin before injecting. oNovoLog Mix 70/30 is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs, or upper arms.oChange (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. Do not use the same injection site for each injection. Do not inject where the skin has pits, thickened, or has lumps. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.Step 11: Choose your injection site and wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose (See Figure K).Step 12: Insert the needle into your skin. Push down on the plunger to inject your dose (See Figure L). The needle should remain in the skin for at least seconds to make sure you have injected all the insulin.Step 13: Pull the needle out of your skin. After that, you may see drop of NovoLog Mix 70/30 at the needle tip. This is normal and does not affect the dose you just received (See Figure M).oIf you see blood after you take the needle out of your skin, press the injection site lightly with piece of gauze or an alcohol swab. Do not rub the area.After your injection: oDo not recap the needle. Recapping the needle can lead to needle stick injury.oPut the empty insulin vials, used needles and syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.oIf you do not have FDA-cleared sharps disposal container, you may use household container that is:omade of heavy-duty plastic,ocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,oupright and stable during use,oleak-resistant, andoproperly labeled to warn of hazardous waste inside the container.oWhen 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 the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs website at: http://www.fda.gov/safesharpsdisposal.Do not dispose of your used sharps disposal container in your household trash unless your community guidelines permit this. Do not recycle your used sharps disposal container. How should store NovoLog Mix 70/30 oDo not freeze NovoLog Mix 70/30. Do not use NovoLog Mix 70/30 if it has been frozen.oKeep NovoLog Mix 70/30 away from heat or light. All unopened vials:oStore unopened NovoLog Mix 70/30 vials in the refrigerator at 36F to 46F (2C to 8C). oUnopened vials may be used until the expiration date printed on the label, if they have been stored in the refrigerator.oUnopened vials should be thrown away after 28 days, if they are stored at room temperature. After vials have been opened:oOpened NovoLog Mix 70/30 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.oThrow away all opened NovoLog Mix 70/30 vials after 28 days, even if they still have insulin left in them. General information about the safe and effective use of NovoLog Mix 70/30oAlways use new syringe and needle for each injection.oDo not share syringes or needles. oKeep NovoLog Mix 70/30 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.Manufactured by:Novo Nordisk Inc.800 Scudders Mill RoadPlainsboro, New Jersey 085361-800-727-6500U.S. License Number 1261Revised: 4/2021NovoLog(R) is registered trademark of Novo Nordisk A/S.PATENT Information: http://novonordisk-us.com/products/product-patents.html (C) 2002-2021 Novo NordiskFor information about NovoLog Mix 70/30 contact:Novo Nordisk Inc.800 Scudders Mill RoadPlainsboro, New Jersey 085361-800-727-6500www.novonordisk-us.comINSTRUCTIONS FOR USENovoLog(R) Mix 70/30 FlexPen(R) (NO-vo-Log-MIX-SEV-en-tee-THIR-tee)(insulin aspart protamine and insulin aspart) injectable suspensionRead the following instructions carefully before you start using your NovoLog Mix 70/30 FlexPen and each time you get refill. There may be new information. You should read the instructions even if you have used NovoLog Mix 70/30 FlexPen before.Do not share your NovoLog Mix 70/30 FlexPen with other people, even if the needle has been changed. You may give other people serious infection, or get serious infection from them.NovoLog Mix 70/30 FlexPen is disposable, single-patient-use dial-a-dose insulin pen. You can select doses from to 60 units in increments of unit. NovoLog Mix 70/30 FlexPen is designed to be used with NovoFine, NovoFine Plus or NovoTwist needles.People who are blind or have vision problems should not use NovoLog Mix 70/30 FlexPen without help from person trained to use NovoLog Mix 70/30 FlexPen.Getting readyMake sure you have the following texts:oNovoLog Mix 70/30 FlexPenoNew NovoFine, NovoFine Plus or NovoTwist needleoAlcohol swabsPreparing your NovoLog Mix 70/30 FlexPenoWash your hands with soap and water. oBefore 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 type of insulin. NovoLog Mix 70/30 should look cloudy after mixing. Before your first injection with new NovoLog Mix 70/30 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 (see diagram A).B. Roll the pen between your palms 10 times it is important that the pen is kept horizontal (see diagram B).C. Then gently move the pen up and down ten times between position and as shown, so the glass ball moves from one end of the cartridge to the other (see diagram C). Repeat rolling and moving the pen until the liquid appears white and cloudy. Do not use the pen if the liquid appears discolored or contains particles.For every following injection move the pen up and down between positions and at least ten times until the liquid appears white and cloudy.After mixing, complete all the following steps of the injection right away. If there is delay, the insulin will need to be mixed again.Wipe the rubber stopper with an alcohol swab.Before you inject, there must be at least 12 units of insulin left in the cartridge to make sure the remaining insulin is evenly mixed. If there are less than 12 units left, use new NovoLog Mix 70/30 FlexPen.Attaching the needleD. Remove the protective tab from disposable needle.Screw the needle tightly onto your NovoLog Mix 70/30 FlexPen. It is important that the needle is put on straight (see diagram D).Never place disposable needle on your NovoLog Mix 70/30 FlexPen until you are ready to take your injection. E. Pull off the big outer needle cap (see diagram E).F. Pull off the inner needle cap and throw it away (dispose of it) (see diagram F). Always use new needle for each injection to make sure the needle is free of germs (sterile) and to prevent blocked needles. Do not reuse or share your needles or syringes with other people. You may give other people serious infection, or get serious infection from them. Be careful not to bend or damage the needle before use. To reduce the risk of needle stick, never put the inner needle cap back on the needle. Giving the airshot before each injectionBefore each injection small amounts of air may collect in the cartridge during normal use. To avoid injecting air and to make sure you take the right dose of insulin: G. Turn the dose selector to select units (see diagram G).H. Hold your NovoLog Mix 70/30 FlexPen with the needle pointing up. Tap the cartridge gently with your finger few times to make any air bubbles collect at the top of the cartridge (see diagram H).I. Keep the needle pointing upwards, press the push-button all the way in (see diagram I). The dose selector returns to 0.A drop of insulin should appear at the needle tip. If not, change the needle and repeat the procedure no more than times.If you do not see drop of insulin after times, do not use the NovoLog Mix 70/30 FlexPen and contact Novo Nordisk at 1-800-727-6500.A small air bubble may remain at the needle tip, but it will not be injected. Selecting your doseCheck and make sure that the dose selector is set at 0. J. Turn the dose selector to the number of units you need to inject. The pointer should line up with your dose.The dose can be corrected either up or down by turning the dose selector in either direction until the correct dose lines up with the pointer (see diagram J). When turning the dose selector, be careful not to press the push-button as insulin will come out. You cannot select dose larger than the number of units left in the cartridge. You will hear click for every single unit dialed. Do not set the dose by counting the number of clicks you hear because you may get an incorrect dose.Do not use the cartridge scale printed on the cartridge to measure your dose of insulin. Giving the injectionoDo the injection exactly as shown to you by your healthcare provider. Your healthcare provider should tell you if you need to pinch the skin before injecting. Wipe the skin with an alcohol swab and let the area dry.oNovoLog Mix 70/30 can be injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs (thighs), or upper arms. oChange (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. Do not use the same injection site for each injection. Do not inject where the skin has pits, is thickened, or has lumps. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.K. Insert the needle into your skin.Inject the dose by pressing the push-button all the way in until the lines up with the pointer (see diagram K). Be careful only to push the button when injecting.Turning the dose selector will not inject insulin.L. Keep the needle in the skin for at least seconds, and keep the push-button pressed all the way in until the needle has been pulled out from the skin (see diagram L). This will make sure that the full dose has been given.You may see drop of insulin at the needle tip. This is normal and has no effect on the dose you just received. If blood appears after you take the needle out of your skin, press the injection site lightly with an alcohol swab. Do not rub the area. After the injectionDo not recap the needle. Recapping can lead to needle stick injury. Remove the needle from the NovoLog Mix 70/30 FlexPen after each injection and dispose of it. This helps to prevent infection, leakage of insulin, and will help to make sure you inject the right dose of insulin. oPut your used needles in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles in your household trash.oIf you do not have FDA-cleared sharps disposal container, carefully slip the needle into the outer needle cap and throw it away in household container that is:omade of heavy-duty plastic,ocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,oupright and stable during use,oleak-resistant, andoproperly labeled to warn of hazardous waste inside the containeroWhen 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 the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs 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.oWhen there is not enough medicine left in your NovoLog Mix 70/30 FlexPen for your prescribed dose, the NovoLog Mix 70/30 FlexPen may be thrown away in your household trash after you have removed the needle. The NovoLog Mix 70/30 FlexPen prevents the cartridge from being completely emptied. It is designed to deliver 300 units.M. Put the pen cap on the NovoLog Mix 70/30 FlexPen and store the NovoLog Mix 70/30 FlexPen without the needle attached (see diagram M). Storing without the needle attached helps prevent leaking, blocking of the needle, and air from entering the Pen.How should store NovoLog Mix 70/30 FlexPenoDo not freeze NovoLog Mix 70/30. Do not use NovoLog Mix 70/30 if it has been frozen.oKeep NovoLog Mix 70/30 away from heat or light.oStore the NovoLog Mix 70/30 FlexPen without the needle attached.oUnused NovoLog Mix 70/30 FlexPen: oStore unused NovoLog Mix 70/30 FlexPen in the refrigerator at 36F to 46F (2C to 8C).oUnused NovoLog Mix 70/30 FlexPen may be used until the expiration date printed on the label, if kept in the refrigerator.oUnused NovoLog Mix 70/30 FlexPen should be thrown away after 14 days, if it is stored at room temperature.oIn-Use NovoLog Mix 70/30 FlexPen: oStore the FlexPen you are currently using at room temperature below 86F (30C) for up to 14 days.oThe NovoLog Mix 70/30 FlexPen you are using should be thrown away after 14 days, even if it still has insulin left in it.MaintenanceFor the safe and proper use of your NovoLog Mix 70/30 FlexPen be sure to handle it with care. Avoid dropping your NovoLog Mix 70/30 FlexPen as it may damage it. If you are concerned that your NovoLog Mix 70/30 FlexPen is damaged, use new one. You can clean the outside of your NovoLog Mix 70/30 FlexPen by wiping it with damp cloth. Do not soak or wash your NovoLog Mix 70/30 FlexPen as it may damage it. Do not refill your NovoLog Mix 70/30 FlexPen. Remove the needle from the NovoLog Mix 70/30 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 NovoLog Mix 70/30 FlexPen and needles out of the reach of children. Use NovoLog Mix 70/30 FlexPen as directed to treat your diabetes. Do not share your NovoLog Mix 70/30 FlexPen or needles with other people. You may give other people serious infection, or get serious infection from them. Always use 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 precautionary measure, always carry spare insulin delivery device in case your NovoLog Mix 70/30 FlexPen is lost or damaged. Remember to keep the disposable NovoLog Mix 70/30 FlexPen with you. Do not leave it in 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. Manufactured by:Novo Nordisk Inc.800 Scudders Mill RoadPlainsboro, New Jersey 085361-800-727-6500U.S. License Number 1261Revised: 4/2021. oNovoLog Mix 70/30 is man-made insulin that is used to control high blood sugar in people with diabetes mellitus.. oIt is not known if NovoLog Mix 70/30 is safe and effective in children.. oare having an episode of low blood sugar (hypoglycemia).. ohave an allergy to NovoLog Mix 70/30 or any of the ingredients in NovoLog Mix 70/30.. opregnant, planning to become pregnant, or are breastfeeding.. otaking new prescription or over-the-counter medicines, vitamins, or herbal supplements.. oRead the Instructions for Use that come with your NovoLog Mix 70/30.. oTake NovoLog Mix 70/30 exactly as your healthcare provider tells you to.. oNovoLog Mix 70/30 starts acting fast. If you have Type diabetes, inject it up to 15 minutes before you eat meal. Do not inject NovoLog Mix 70/30 if you are not planning to eat within 15 minutes. If you have Type diabetes, you may inject NovoLog Mix 70/30 up to 15 minutes before or after starting your meal.. oDo not mix NovoLog Mix 70/30 with other insulin products or use in an insulin pump.. oKnow the type and strength of insulin you take. Do not change 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.. oCheck your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels.. oDo not reuse or share your needles or syringes with other people. You may give other people serious infection or get serious infection from them.. oNovoLog Mix 70/30 is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs, or upper arms.. oChange (rotate) your injection sites within the same area you choose with each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites.oDo not use the exact same spot for each injection.oDo not inject where skin has pits, is thickened, or has lumps.oDo not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin. oDo not use the exact same spot for each injection.. oDo not inject where skin has pits, is thickened, or has lumps.. oDo not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.. oDrive or operate heavy machinery, until you know how NovoLog Mix 70/30 affects you.. oDrink alcohol or use prescription or over-the-counter medicines that contain alcohol.. odizziness or light-headedness. oblurred vision. oanxiety, irritability, or mood changes. osweating. oslurred speech. ohunger. oconfusion. oshakiness. oheadache. ofast heart beat ochange in level of physical activity or exercise. oincreased stress. ochange in diet. oweight gain or loss. oillness. olow 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. otrouble breathing, shortness of breath, fast heartbeat, swelling of your face, tongue, or throat, sweating, extreme drowsiness, dizziness, confusion.. o10 mL NovoLog Mix 70/30 vial. oinsulin syringe and needle. oalcohol swabs. oWash your hands with soap and water.. oBefore you start to prepare your injection, check the NovoLog Mix 70/30 label to make sure that you are taking the right type of insulin. This is especially important if you use more than type of insulin.. oNovoLog Mix 70/30 should look white and cloudy after mixing. Do not use NovoLog Mix 70/30 if it looks clear or contains any lumps or particles. oNovoLog Mix 70/30 is easier to mix when it is at room temperature. oAfter mixing NovoLog Mix 70/30, inject your dose right away. If you wait to inject your dose, the insulin will need to be mixed again.. oDo not use NovoLog Mix 70/30 past the expiration date printed on the label.. oIf there are air bubbles, tap the syringe gently few times to let any air bubbles rise to the top (See Figure H).. oInject your NovoLog Mix 70/30 exactly as your healthcare provider has shown you. Your healthcare provider should tell you if you need to pinch the skin before injecting. oNovoLog Mix 70/30 is injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs, or upper arms.. oChange (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. Do not use the same injection site for each injection. Do not inject where the skin has pits, thickened, or has lumps. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.. oIf you see blood after you take the needle out of your skin, press the injection site lightly with piece of gauze or an alcohol swab. Do not rub the area.. oDo not recap the needle. Recapping the needle can lead to needle stick injury.. oPut the empty insulin vials, used needles and syringes in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles and syringes in your household trash.. oIf you do not have FDA-cleared sharps disposal container, you may use household container that is:omade of heavy-duty plastic,ocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,oupright and stable during use,oleak-resistant, andoproperly labeled to warn of hazardous waste inside the container.. omade of heavy-duty plastic,. ocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,. oupright and stable during use,. oleak-resistant, and. oproperly labeled to warn of hazardous waste inside the container.. oWhen 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 the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs 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. oDo not freeze NovoLog Mix 70/30. Do not use NovoLog Mix 70/30 if it has been frozen.. oKeep NovoLog Mix 70/30 away from heat or light.. All unopened vials:. oStore unopened NovoLog Mix 70/30 vials in the refrigerator at 36F to 46F (2C to 8C). oUnopened vials may be used until the expiration date printed on the label, if they have been stored in the refrigerator.. oUnopened vials should be thrown away after 28 days, if they are stored at room temperature.. After vials have been opened:. oOpened NovoLog Mix 70/30 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.. oThrow away all opened NovoLog Mix 70/30 vials after 28 days, even if they still have insulin left in them. oAlways use new syringe and needle for each injection.. oDo not share syringes or needles. oKeep NovoLog Mix 70/30 vials, syringes, and needles out of the reach of children.. oNovoLog Mix 70/30 FlexPen. oNew NovoFine, NovoFine Plus or NovoTwist needle. oAlcohol swabs. oWash your hands with soap and water. oBefore 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 type of insulin. NovoLog Mix 70/30 should look cloudy after mixing. Always use new needle for each injection to make sure the needle is free of germs (sterile) and to prevent blocked needles. Do not reuse or share your needles or syringes with other people. You may give other people serious infection, or get serious infection from them.. oDo the injection exactly as shown to you by your healthcare provider. Your healthcare provider should tell you if you need to pinch the skin before injecting. Wipe the skin with an alcohol swab and let the area dry.. oNovoLog Mix 70/30 can be injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs (thighs), or upper arms. oChange (rotate) your injection sites within the area you choose for each dose to reduce your risk of getting lipodystrophy (pits in skin or thickened skin) and localized cutaneous amyloidosis (skin with lumps) at the injection sites. Do not use the same injection site for each injection. Do not inject where the skin has pits, is thickened, or has lumps. Do not inject where the skin is tender, bruised, scaly or hard, or into scars or damaged skin.. oPut your used needles in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) loose needles in your household trash.. oIf you do not have FDA-cleared sharps disposal container, carefully slip the needle into the outer needle cap and throw it away in household container that is:omade of heavy-duty plastic,ocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,oupright and stable during use,oleak-resistant, andoproperly labeled to warn of hazardous waste inside the container. omade of heavy-duty plastic,. ocan be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,. oupright and stable during use,. oleak-resistant, and. oproperly labeled to warn of hazardous waste inside the container. oWhen 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 the safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDAs 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.. oWhen there is not enough medicine left in your NovoLog Mix 70/30 FlexPen for your prescribed dose, the NovoLog Mix 70/30 FlexPen may be thrown away in your household trash after you have removed the needle. The NovoLog Mix 70/30 FlexPen prevents the cartridge from being completely emptied. It is designed to deliver 300 units.. oDo not freeze NovoLog Mix 70/30. Do not use NovoLog Mix 70/30 if it has been frozen.. oKeep NovoLog Mix 70/30 away from heat or light.. oStore the NovoLog Mix 70/30 FlexPen without the needle attached.. oUnused NovoLog Mix 70/30 FlexPen: oStore unused NovoLog Mix 70/30 FlexPen in the refrigerator at 36F to 46F (2C to 8C).oUnused NovoLog Mix 70/30 FlexPen may be used until the expiration date printed on the label, if kept in the refrigerator.oUnused NovoLog Mix 70/30 FlexPen should be thrown away after 14 days, if it is stored at room temperature.. oStore unused NovoLog Mix 70/30 FlexPen in the refrigerator at 36F to 46F (2C to 8C).. oUnused NovoLog Mix 70/30 FlexPen may be used until the expiration date printed on the label, if kept in the refrigerator.. oUnused NovoLog Mix 70/30 FlexPen should be thrown away after 14 days, if it is stored at room temperature.. oIn-Use NovoLog Mix 70/30 FlexPen: oStore the FlexPen you are currently using at room temperature below 86F (30C) for up to 14 days.oThe NovoLog Mix 70/30 FlexPen you are using should be thrown away after 14 days, even if it still has insulin left in it.. oStore the FlexPen you are currently using at room temperature below 86F (30C) for up to 14 days.. oThe NovoLog Mix 70/30 FlexPen you are using should be thrown away after 14 days, even if it still has insulin left in it.. Vial Figure. Hand Vial Figure. Figure & Figure B. Figure C. Figure D. Figure E. Figure F. Figure G. Figure H. Figure I. Figure J. Image of possible injection sites.. Figure L. Figure M. Important. FlexPen components. Needle components.. Pull off the pen cap.. Roll the pen between your palms.. Move the pen up and down.. Important. Figure D: Screw needle on.. Figure E: Pull off outer needle cap.. Figure F: Pull off inner needle cap.. Important. Important. Important. Turn the dose selector to units.. Tap the needle.. Press the push-button.. Select your dose.. Important. Press the push button to inject.. Keep the needle in the skin for at least seconds.. Replace the pen cap.. Important. Important. Important. Important. Important. Important. Important. Important. Important.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. NOVOLOG MIX 70/30 is mixture of insulin aspart protamine and insulin aspart indicated to improve glycemic control in adult patients with diabetes mellitus.Limitations of Use:oNOVOLOG MIX 70/30 is not recommended for the treatment of diabetic ketoacidosis.oThe proportions of rapid-acting and long-acting insulins in NOVOLOG MIX 70/30 are fixed and do not allow for basal versus prandial dose adjustments.. oNOVOLOG MIX 70/30 is not recommended for the treatment of diabetic ketoacidosis.. oThe proportions of rapid-acting and long-acting insulins in NOVOLOG MIX 70/30 are fixed and do not allow for basal versus prandial dose adjustments.. NOVOLOG MIX 70/30 is mixture of insulin aspart protamine, an intermediate-acting human insulin analog, and insulin aspart, rapid-acting human insulin analog, indicated to improve glycemic control in adult patients with diabetes mellitus.Limitations of Use:oNot recommended for the treatment of diabetic ketoacidosis.oThe proportions of rapid-acting and long-acting insulins are fixed and do not allow for basal versus prandial dose adjustments (1).. oNot recommended for the treatment of diabetic ketoacidosis.. oThe proportions of rapid-acting and long-acting insulins are fixed and do not allow for basal versus prandial dose adjustments (1).

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following adverse reactions are also discussed elsewhere:oHypoglycemia [see Warnings and Precautions (5.3)]oHypoglycemia Due to Medication Errors [see Warnings and Precautions (5.4)]oHypersensitivity reactions [see Warnings and Precautions (5.5)]oHypokalemia [see Warnings and Precautions (5.6)]. oHypoglycemia [see Warnings and Precautions (5.3)]. oHypoglycemia Due to Medication Errors [see Warnings and Precautions (5.4)]. oHypersensitivity reactions [see Warnings and Precautions (5.5)]. oHypokalemia [see Warnings and Precautions (5.6)]. 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 Inc. at 1-800-727-6500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 reflect the exposure of 55 patients with type diabetes to NOVOLOG MIX 70/30 with mean exposure duration of three months. The mean age was 43.2 years. Sixty-four percent were male and 100% were White. The mean body mass index (BMI) was 26.1 kg/m2. The mean duration of diabetes was 14.9 years. The data in Table reflect the exposure of 85 patients with type diabetes to NOVOLOG MIX 70/30 with mean exposure duration of three months. The mean age was 62.7 years. Fifty-four percent were male and 100% were White. 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 for NOVOLOG MIX 70/30-treated subjects in patients with type diabetes mellitus and type diabetes mellitus are listed in Table and Table 2, respectively. The trial was three-month, open-label trial in patients with type or type diabetes who were treated twice daily (before breakfast and before supper) with NOVOLOG MIX 70/30.Table 1: Adverse Reactions Occurring in >= 5% of Type Diabetes Mellitus Adult Patients treated with NOVOLOG MIX 70/30NOVOLOG MIX 70/30(n=55)Preferred TermN%Hypoglycemia3869Headache1935Influenza-like symptoms713Dyspepsia59Back pain47Diarrhea47Pharyngitis47Rhinitis35Skeletal pain35Upper respiratory tract infection35Table 2: Adverse reactions Occurring in >= 5% of Type Diabetes Mellitus Adult Patients treated with NOVOLOG MIX 70/30 NOVOLOG MIX 70/30(n=85)Preferred TermN%Hypoglycemia4047Upper respiratory tract infection1012Headache89Diarrhea78Neuropathy78Pharyngitis56Abdominal pain45Rhinitis45Severe HypoglycemiaHypoglycemia is the most commonly observed adverse reaction in patients using insulin, including NOVOLOG MIX 70/30. 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 NOVOLOG MIX 70/30 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 NOVOLOG MIX 70/30. The incidence of severe hypoglycemia in adult patients receiving subcutaneous NOVOLOG MIX 70/30 was 16% and 4% for type and type diabetes patients respectively at 12 weeks [see Clinical Studies (14)]. Allergic ReactionsPatients have experienced reactions such as erythema, edema or pruritus at the site of NOVOLOG MIX 70/30 injection. These reactions usually resolve in few days to few weeks, but in some occasions, have required discontinuation of NOVOLOG MIX 70/30. Severe cases of generalized allergy (anaphylaxis) have been reported.Insulin initiation and glucose control intensificationIntensification 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.LipodystrophyLong-term use of insulin, including NOVOLOG MIX 70/30, 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 gainWeight gain can occur with insulins, including NOVOLOG MIX 70/30, and has been attributed to the anabolic effects of insulin and the decrease in glycosuria.Peripheral EdemaInsulins, including NOVOLOG MIX 70/30, 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 NOVOLOG MIX 70/30 in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.In 3-month study with an extension in adult patients with type diabetes, 100% of patients who received NOVOLOG MIX 70/30 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. total of 91.4% of patients who received NOVOLOG MIX 70/30 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 type diabetes clinical trial of NOVOLOG MIX 70/30, initial increase in titers of antibodies to insulin followed by decrease approaching to baseline values was observed in NOVOLOG MIX 70/30 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 NOVOLOG MIX 70/30. Because these adverse reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency or establish causal relationship to drug exposure. Medication errors in which other insulins have been accidentally substituted for NOVOLOG MIX 70/30 have been reported.Localized cutaneous amyloidosis at the injection site has occurred with insulin aspart. Hyperglycemia has been reported with repeated insulin injections into areas of localized cutaneous amyloidosis; hypoglycemia has been reported with sudden change to an unaffected injection site.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Standard 2-year carcinogenicity studies in animals have not been performed to evaluate the carcinogenic potential of NOVOLOG MIX 70/30. In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with NOVOLOG, the rapid-acting component of NOVOLOG MIX 70/30, 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 dose of 200 units/kg/day, NOVOLOG increased the incidence of mammary gland tumors in females when compared to untreated controls. The relevance of these findings to humans is not known.NOVOLOG 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, NOVOLOG 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.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The primary activity of insulin, including NOVOLOG MIX 70/30 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. euglycemic clamp study described below assessed glucose utilization after subcutaneous dosing of NOVOLOG MIX 70/30 in healthy subjects (n 24). Following 0.3 units/kg single subcutaneous dose of NOVOLOG MIX 70/30, the onset of action is between 10-20 minutes and the mean +- SD time to peak activity is 2.7 hr +- 0.9 hr. The duration of action may be as long as 24 hours (see Figure 2).Figure 2. Pharmacodynamic Activity Profile of NOVOLOG MIX 70/30 in healthy subjects after single 0.3 units/kg subcutaneous dose. Graph showing glucose infusion rate for NovoLog Mix 0/30. 12.3 Pharmacokinetics. The single substitution of the amino acid proline with aspartic acid at position B28 in insulin aspart (NOVOLOG) reduces the molecules tendency to form hexamers as observed with regular human insulin. The rapid absorption characteristics of NOVOLOG are maintained by NOVOLOG MIX 70/30.Absorption and Bioavailability The 30% insulin aspart in the soluble component of NOVOLOG MIX 70/30 is absorbed rapidly from the subcutaneous layer. The remaining 70% is in crystalline form as insulin aspart protamine which has prolonged absorption profile after subcutaneous injection.The relative bioavailability of NOVOLOG MIX 70/30 compared to NOVOLOG indicates that the insulins are absorbed to similar extent. In euglycemic clamp study in healthy subjects (n=24) after dosing with NOVOLOG MIX 70/30 (0.3 units/kg), 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 subcutaneous dose of NOVOLOG MIX 70/30 (see Fig. for pharmacokinetic profiles).Figure 3. Pharmacokinetic Profile of NOVOLOG MIX 70/30 after single 0.3 units/kg subcutaneous doseDistribution and EliminationInsulin aspart has low binding affinity to plasma proteins (<10%), similar to that seen with regular human insulin.. Graph showing mean serum insulin for NovoLog Mix 70/30.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Clinical Studies in Adult Patients with Type and Type Diabetes. In three-month, open-label trial, patients with type (n=104) or type (n=187) diabetes were treated twice daily (before breakfast and before supper) with NOVOLOG MIX 70/30 or Novolin 70/30. Patients had received insulin for at least 24 months before the study. Oral hypoglycemic agents were not allowed within 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 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 White for type and type 2. The mean body mass index (BMI) was 26.1 kg/m2 for type and 28.1 kg/m2 for type 2. The mean duration of diabetes was 14.9 years for type and 15.0 years for type 2.Table 4: Glycemic Parameters at the End of Treatment [Mean +- SD (n subjects)]NOVOLOG MIX 70/30Novolin 70/30Type 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 (%) Baseline8.4 +- 1.2 (51)8.5 +- 1.1 (46) HbA1c (%) Week 128.4 +- 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 (%) Baseline8.1 +- 1.2 (82)8.2 +- 1.3 (98) HbA1c (%) Week 127.9 +- 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. 14.2 Clinical Studies in Adult Patients with Type Diabetes with Insulin and Oral Antidiabetic Agents. Trial 1:In 34-week, open-label trial, insulin-naive patients with type diabetes currently treated with 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 NOVOLOG MIX 70/30 twice daily added on to the metformin and pioglitazone regimen or continue the current optimized metformin and pioglitazone therapy. NOVOLOG MIX 70/30 was started at dose of IU twice daily (before breakfast and before supper). Insulin doses were titrated to 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 Diabetes Mellitus [Mean (SD)]Treatment duration 24-weeks NOVOLOG MIX 70/30 Metformin PioglitazoneMetformin PioglitazoneHbA1c Baseline mean +- SD (n)8.1 +- 1.0 (102)8.1 +- 1.0 (98) End-of-study mean +- SD (n) LOCF6.6 +- 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) LOCF130 +- 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) Hour Post Breakfast138 +- 42.8 (86)188 +- 57.7 (74) Hour Post Lunch150 +- 41.5 (86)176 +- 56.5 (74) Hour Post Dinner141 +- 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 28-week, open-label trial, insulin-naive patients with type diabetes with fasting plasma glucose above 140 mg/dL currently treated with metformin +- thiazolidinedione therapy were randomized to receive either NOVOLOG MIX 70/30 twice daily [before breakfast and before supper] or insulin glargine once daily (see Table 6). NOVOLOG MIX 70/30 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 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 White (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 White, 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 Diabetes Mellitus [Mean (SD)] Treatment duration 28-weeks NOVOLOG MIX 70/30 Metformin +- PioglitazoneInsulin Glargine Metformin +- Pioglitazone Number of patients117116 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%. 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 28-week, open-label trial, insulin-naive patients with type diabetes with fasting plasma glucose above 140 mg/dL currently treated with metformin +- thiazolidinedione therapy were randomized to receive either NOVOLOG MIX 70/30 twice daily [before breakfast and before supper] or insulin glargine once daily (see Table 6). NOVOLOG MIX 70/30 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 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 White (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 White, 15% Black, 27% were Hispanic, 2% were Asian and 2% were Other. The mean BMI was approximately 31.5 kg/m2.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. NOVOLOG MIX 70/30 is contraindicated oDuring episodes of hypoglycemia [see Warnings and Precautions (5.3)]oIn patients with hypersensitivity to NOVOLOG MIX 70/30 or one of its excipients [see Warnings and Precautions (5.5)]. oDuring episodes of hypoglycemia [see Warnings and Precautions (5.3)]. oIn patients with hypersensitivity to NOVOLOG MIX 70/30 or one of its excipients [see Warnings and Precautions (5.5)]. oDo not use during episodes of hypoglycemia (4).oDo not use in patients with hypersensitivity to NOVOLOG MIX 70/30 or one of its excipients (4).. oDo not use during episodes of hypoglycemia (4).. oDo not use in patients with hypersensitivity to NOVOLOG MIX 70/30 or one of its excipients (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Insulin aspart protamine and insulin aspart is human insulin analog containing 70% insulin aspart protamine crystals and 30% soluble insulin aspart. Insulin aspart is homologous with regular human insulin with the exception of single substitution of the amino acid proline by aspartic acid in position B28, and is produced by recombinant DNA technology utilizing Saccharomyces cerevisiae (bakers yeast). Insulin aspart has the empirical formula C256H381N65O79S6 and molecular weight of 5825.8 Da. In vitro assay confirms the minimum potency of insulin aspart to be NLT 15 units/mg.Figure 1. Structural formula of insulin aspartNOVOLOG MIX 70/30 (insulin aspart protamine and insulin aspart) injectable suspension is uniform, white and cloudy, sterile suspension for subcutaneous use. Each mL contains 100 units of insulin aspart and the inactive ingredients: disodium hydrogen phosphate dihydrate (1.25 mg), glycerol (16.0 mg), metacresol (1.72 mg), phenol (1.50 mg), protamine sulfate (0.32 mg), sodium chloride (0.877 mg), zinc (19.6 mcg), and Water for Injection, USP. NOVOLOG MIX 70/30 has pH of 7.20 7.44. Hydrochloric acid or sodium hydroxide may be added to adjust pH.. Molecular chain of insulin aspart.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oInject NOVOLOG MIX 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm (2.1).oAdminister the dose within 15 minutes before meal initiation. For patients with type diabetes, the dose may also be given after meal initiation (2.1).oRotate injection sites within the same region from one injection to the next to reduce risk of lipodystrophy and localized cutaneous amyloidosis (2.1).oInspect 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).oNOVOLOG MIX 70/30 must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature (2.1).oDo not administer intravenously or use in insulin infusion pumps (2.1).oNOVOLOG MIX 70/30 is typically dosed twice-daily (with each dose intended to cover meals or meal and snack) (2.2).oIndividualize dosage based on metabolic needs, blood glucose monitoring results, glycemic control goal (2.2).oDosage 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).oDosage adjustment may be needed when switching from another insulin to NOVOLOG MIX 70/30 (2.2).. oInject NOVOLOG MIX 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm (2.1).. oAdminister the dose within 15 minutes before meal initiation. For patients with type diabetes, the dose may also be given after meal initiation (2.1).. oRotate injection sites within the same region from one injection to the next to reduce risk of lipodystrophy and localized cutaneous amyloidosis (2.1).. oInspect 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).. oNOVOLOG MIX 70/30 must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature (2.1).. oDo not administer intravenously or use in insulin infusion pumps (2.1).. oNOVOLOG MIX 70/30 is typically dosed twice-daily (with each dose intended to cover meals or meal and snack) (2.2).. oIndividualize dosage based on metabolic needs, blood glucose monitoring results, glycemic control goal (2.2).. oDosage 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).. oDosage adjustment may be needed when switching from another insulin to NOVOLOG MIX 70/30 (2.2).. 2.1 Important Administration Information. oAlways check insulin labels before administration [see Warnings and Precautions (5.4)].oInject NOVOLOG MIX 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm.oAdminister the dose within 15 minutes before meal initiation. For patients with type diabetes, the dose may also be given after meal initiation.oRotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2) and Adverse Reactions (6.1, 6.3)].oDuring changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)]. oInspect NOVOLOG MIX 70/30 visually before use. It should appear uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles.oNOVOLOG MIX 70/30 must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature.oWhen using the vial, roll the vial gently in hands in horizontal position 10 times until the suspension appears uniformly white and cloudy. Inject immediately.oWhen using NOVOLOG MIX 70/30 FlexPen, roll NOVOLOG MIX 70/30 FlexPen gently between hands in horizontal position 10 times. Then, turn NOVOLOG MIX 70/30 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.oThe NOVOLOG MIX 70/30 FlexPen dials in 1-unit increments.oUse NOVOLOG MIX 70/30 FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.oDo not administer NOVOLOG MIX 70/30 intravenously or use in insulin infusion pumps.oDo not mix NOVOLOG MIX 70/30 with any other insulins.. oAlways check insulin labels before administration [see Warnings and Precautions (5.4)].. oInject NOVOLOG MIX 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm.. oAdminister the dose within 15 minutes before meal initiation. For patients with type diabetes, the dose may also be given after meal initiation.. oRotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2) and Adverse Reactions (6.1, 6.3)].. oDuring changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)]. oInspect NOVOLOG MIX 70/30 visually before use. It should appear uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles.. oNOVOLOG MIX 70/30 must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature.. oWhen using the vial, roll the vial gently in hands in horizontal position 10 times until the suspension appears uniformly white and cloudy. Inject immediately.. oWhen using NOVOLOG MIX 70/30 FlexPen, roll NOVOLOG MIX 70/30 FlexPen gently between hands in horizontal position 10 times. Then, turn NOVOLOG MIX 70/30 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.. oThe NOVOLOG MIX 70/30 FlexPen dials in 1-unit increments.. oUse NOVOLOG MIX 70/30 FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.. oDo not administer NOVOLOG MIX 70/30 intravenously or use in insulin infusion pumps.. oDo not mix NOVOLOG MIX 70/30 with any other insulins.. 2.2 Dosage Information. oNOVOLOG MIX 70/30 is typically dosed twice-daily (with each dose intended to cover meals or meal and snack).oIndividualize and adjust the dosage of NOVOLOG MIX 70/30 based on the individuals metabolic needs, blood glucose monitoring results and glycemic control goal.oDosage 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)] .oDosage adjustment may be needed when switching from another insulin to NOVOLOG MIX 70/30 [see Warnings and Precautions (5.2)].. oNOVOLOG MIX 70/30 is typically dosed twice-daily (with each dose intended to cover meals or meal and snack).. oIndividualize and adjust the dosage of NOVOLOG MIX 70/30 based on the individuals metabolic needs, blood glucose monitoring results and glycemic control goal.. oDosage 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)] .. oDosage adjustment may be needed when switching from another insulin to NOVOLOG MIX 70/30 [see Warnings and Precautions (5.2)].. 2.3 Dosage Adjustment Due to Drug Interactions oDosage adjustment may be needed when NOVOLOG MIX 70/30 is co-administered with certain drugs [see Drug Interactions (7)].. oDosage adjustment may be needed when NOVOLOG MIX 70/30 is co-administered with certain drugs [see Drug Interactions (7)].

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Injectable suspension: 100 units/mL (U-100) of NOVOLOG MIX 70/30, 70% insulin aspart protamine and 30% insulin aspart, is white and cloudy suspension available as: o10 mL multiple-dose vial o3 mL single-patient-use NOVOLOG MIX 70/30 FlexPen. o10 mL multiple-dose vial o3 mL single-patient-use NOVOLOG MIX 70/30 FlexPen. Injectable suspension: 100 units/mL (U-100) of NOVOLOG MIX 70/30, 70% insulin aspart protamine and 30% insulin aspart available as: o10 mL multiple-dose vial (3)o3 mL single-patient-use NOVOLOG MIX 70/30 FlexPen (3). o10 mL multiple-dose vial (3). o3 mL single-patient-use NOVOLOG MIX 70/30 FlexPen (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table 3: Clinically Significant Drug Interactions with NOVOLOG MIX 70/30Drugs that May Increase the Risk of HypoglycemiaDrugs: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 antibioticsIntervention:Dose adjustment and increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is co-administered with these drugs. Drugs that May Decrease the Blood Glucose Lowering Effect of NOVOLOG MIX 70/30Drugs: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 NOVOLOG MIX 70/30 is co-administered with these drugs.Drugs that May Increase or Decrease the Blood Glucose Lowering Effect of NOVOLOG MIX 70/30Drugs: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 NOVOLOG MIX 70/30 is co-administered with these drugs.Drugs that May Blunt Signs and Symptoms of HypoglycemiaDrugs:Beta-blockers, clonidine, guanethidine, and reserpineIntervention:Increased frequency of glucose monitoring may be required when NOVOLOG MIX 70/30 is co-administered with these drugs.. oDrugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics (7).oDrugs 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).oDrugs that may increase or decrease the blood glucose lowering effect: alcohol, beta-blockers, clonidine, lithium salts, and pentamidine (7).oDrugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine (7).. oDrugs that may increase the risk of hypoglycemia: antidiabetic agents, ACE inhibitors, angiotensin II receptor blocking agents, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, pentoxifylline, pramlintide, salicylates, somatostatin analog (e.g., octreotide), and sulfonamide antibiotics (7).. oDrugs 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).. oDrugs that may increase or decrease the blood glucose lowering effect: alcohol, beta-blockers, clonidine, lithium salts, and pentamidine (7).. oDrugs that may blunt the signs and symptoms of hypoglycemia: beta-blockers, clonidine, guanethidine, and reserpine (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of NOVOLOG MIX 70/30 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. NOVOLOG MIX 70/30 (insulin aspart protamine and insulin aspart) injectable suspension is white and cloudy suspension of 100 units/mL (U-100) of 70% insulin aspart protamine and 30% insulin aspart available as:10 mL multiple-dose vialNDC 0169-3685-12ReliOn(R) brandNDC 0169-2200-113 mL single-patient-use FlexPen NDC 0169-3696-19ReliOn(R) brandNDC 0169-2201-25 The NOVOLOG MIX 70/30 FlexPen dials in 1-unit increments.. The NOVOLOG MIX 70/30 FlexPen dials in 1-unit increments.. 16.2 Recommended Storage. Dispense in the original sealed carton with the enclosed Instructions for Use.Unused NOVOLOG MIX 70/30 should be stored in refrigerator between 2C and 8C (36F to 46F). Do not freeze NOVOLOG MIX 70/30 or use NOVOLOG MIX 70/30 if it has been frozen. Do not expose NOVOLOG MIX 70/30 to excessive heat or light.Always remove the needle after each injection and store NOVOLOG MIX 70/30 FlexPen without needle attached. The storage conditions are summarized in the following table:Table 7: Storage conditions for NOVOLOG MIX 70/30 vial and FlexPenNot in-use (unopened)Room Temperature(up to 30C [86F])Not in-use (unopened)Refrigerated(2C 8C [36F 46F])In-use (opened)Room Temperature(up to 30C [86F])10 mL multiple-dose vial28 daysUntil expiration date28 days (refrigerated/room temperature)3 mL single-patient-use NOVOLOG MIX 70/30 FlexPen14 daysUntil expiration date14 days (Do not refrigerate).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).Never Share NOVOLOG MIX 70/30 FlexPen between PatientsAdvise patients that they must never share NOVOLOG MIX 70/30 FlexPen device with another person even if the needle is changed. Advise patients using NOVOLOG MIX 70/30 vials not to share needles or syringes with another person. Sharing poses risk for transmission of blood-borne pathogens [see Warnings and Precautions (5.1)]. Hyperglycemia or HypoglycemiaInform 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 NOVOLOG MIX 70/30 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 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.Advise patients that changes in insulin regimen can predispose to hyperglycemia or hypoglycemia and that changes in insulin regimen should be made under close medical supervision see Warnings and Precautions (5.2)].Hypoglycemia with Medication ErrorsInstruct patients to always check the insulin label before each injection to avoid mix-ups between insulin products [see Warnings and Precautions (5.4)].Hypersensitivity ReactionsAdvise patients that hypersensitivity reactions have occurred with NOVOLOG MIX 70/30. Inform patients of the symptoms of hypersensitivity reactions [see Warnings and Precautions (5.5)].Version: 17Novo Nordisk(R), NOVOLOG(R), FlexPen(R), and Novolin(R) are registered trademarks of Novo Nordisk(R) A/S. ReliOn(R) is registered trademark of Walmart Inc. and is used under license by Novo Nordisk Inc.Patent Information: http://novonordisk-us.com/products/product-patents.html (C) 2021 Novo Nordisk Manufactured by: Novo Nordisk Inc.800 Scudders Mill RoadPlainsboro, NJ 085361-800-727-6500U.S. License Number 1261For information about NOVOLOG MIX 70/30 contact:Novo Nordisk Inc.800 Scudders Mill RoadPlainsboro, NJ 085361-800-727-6500 (Se Habla espanol)www.novonordisk-us.com.

LACTATION SECTION.

8.2 Lactation Risk SummaryThere are no data on the presence of NOVOLOG MIX 70/30 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 mothers clinical need for NOVOLOG MIX 70/30, and any potential adverse effects on the breastfed infant from NOVOLOG MIX 70/30, or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The primary activity of insulin, including NOVOLOG MIX 70/30 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.

NONCLINICAL TOXICOLOGY SECTION.

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 NOVOLOG MIX 70/30. In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with NOVOLOG, the rapid-acting component of NOVOLOG MIX 70/30, 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 dose of 200 units/kg/day, NOVOLOG increased the incidence of mammary gland tumors in females when compared to untreated controls. The relevance of these findings to humans is not known.NOVOLOG 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, NOVOLOG 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.

OVERDOSAGE SECTION.

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.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL VIAL 10ML. NDC 0169-3685-12List 368512NovoLog(R) Mix 70/30(insulin aspart protamine andinsulin aspart) injectable suspension100 units/mL (U-100)For subcutaneous use.Shake carefully before using. See enclosed insert for proper technique.Rx onlyUse only with U-100 syringe.10 mL multiple-dose vial. NovoLog Mix 70/30 vial carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. Safety and effectiveness of NOVOLOG MIX 70/30 have not been established in pediatric patients.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. euglycemic clamp study described below assessed glucose utilization after subcutaneous dosing of NOVOLOG MIX 70/30 in healthy subjects (n 24). Following 0.3 units/kg single subcutaneous dose of NOVOLOG MIX 70/30, the onset of action is between 10-20 minutes and the mean +- SD time to peak activity is 2.7 hr +- 0.9 hr. The duration of action may be as long as 24 hours (see Figure 2).Figure 2. Pharmacodynamic Activity Profile of NOVOLOG MIX 70/30 in healthy subjects after single 0.3 units/kg subcutaneous dose. Graph showing glucose infusion rate for NovoLog Mix 0/30.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The single substitution of the amino acid proline with aspartic acid at position B28 in insulin aspart (NOVOLOG) reduces the molecules tendency to form hexamers as observed with regular human insulin. The rapid absorption characteristics of NOVOLOG are maintained by NOVOLOG MIX 70/30.Absorption and Bioavailability The 30% insulin aspart in the soluble component of NOVOLOG MIX 70/30 is absorbed rapidly from the subcutaneous layer. The remaining 70% is in crystalline form as insulin aspart protamine which has prolonged absorption profile after subcutaneous injection.The relative bioavailability of NOVOLOG MIX 70/30 compared to NOVOLOG indicates that the insulins are absorbed to similar extent. In euglycemic clamp study in healthy subjects (n=24) after dosing with NOVOLOG MIX 70/30 (0.3 units/kg), 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 subcutaneous dose of NOVOLOG MIX 70/30 (see Fig. for pharmacokinetic profiles).Figure 3. Pharmacokinetic Profile of NOVOLOG MIX 70/30 after single 0.3 units/kg subcutaneous doseDistribution and EliminationInsulin aspart has low binding affinity to plasma proteins (<10%), similar to that seen with regular human insulin.. Graph showing mean serum insulin for NovoLog Mix 70/30.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no available data with NOVOLOG MIX 70/30 in pregnant women to inform 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 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 HbA1c >7% and has been reported to be as high as 20-25% in women with 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 ConsiderationsDisease-Associated Maternal and/or Embryo-Fetal RiskPoorly 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.DataHuman DataPublished data from 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 variable duration of treatment and small size of the majority of the trials.Animal DataFertility, embryo-fetal and pre- and postnatal development studies have been performed with insulin aspart and regular human insulin in rats and rabbits. In combined fertility and embryo-fetal development study in rats, insulin aspart was administered before mating, during mating, and throughout pregnancy. Further, in 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 dose of 200 units/kg/day (approximately 32 times the human subcutaneous dose of unit/kg/day, based on human exposure equivalents) and in rabbits at dose of 10 units/kg/day (approximately three times the human subcutaneous dose of unit/kg/day, based on human exposure equivalents). No significant effects were observed in rats at dose of 50 units/kg/day and in rabbits at dose of units/kg/day. These doses are approximately times the human subcutaneous dose of unit/kg/day for rats and equal to the human subcutaneous dose of unit/kg/day for rabbits, based on human exposure equivalents. The effects are considered secondary to maternal hypoglycemia.

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions (5.3, 5.4, 5.5, 5.6)................................ 04/2021.

SPL UNCLASSIFIED SECTION.

2.1 Important Administration Information. oAlways check insulin labels before administration [see Warnings and Precautions (5.4)].oInject NOVOLOG MIX 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm.oAdminister the dose within 15 minutes before meal initiation. For patients with type diabetes, the dose may also be given after meal initiation.oRotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2) and Adverse Reactions (6.1, 6.3)].oDuring changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)]. oInspect NOVOLOG MIX 70/30 visually before use. It should appear uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles.oNOVOLOG MIX 70/30 must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature.oWhen using the vial, roll the vial gently in hands in horizontal position 10 times until the suspension appears uniformly white and cloudy. Inject immediately.oWhen using NOVOLOG MIX 70/30 FlexPen, roll NOVOLOG MIX 70/30 FlexPen gently between hands in horizontal position 10 times. Then, turn NOVOLOG MIX 70/30 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.oThe NOVOLOG MIX 70/30 FlexPen dials in 1-unit increments.oUse NOVOLOG MIX 70/30 FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.oDo not administer NOVOLOG MIX 70/30 intravenously or use in insulin infusion pumps.oDo not mix NOVOLOG MIX 70/30 with any other insulins.. oAlways check insulin labels before administration [see Warnings and Precautions (5.4)].. oInject NOVOLOG MIX 70/30 subcutaneously in the abdominal region, buttocks, thigh, or upper arm.. oAdminister the dose within 15 minutes before meal initiation. For patients with type diabetes, the dose may also be given after meal initiation.. oRotate injection sites within the same region from one injection to the next to reduce the risk of lipodystrophy and localized cutaneous amyloidosis. Do not inject into areas of lipodystrophy or localized cutaneous amyloidosis [see Warnings and Precautions (5.2) and Adverse Reactions (6.1, 6.3)].. oDuring changes to patients insulin regimen, increase the frequency of blood glucose monitoring [see Warnings and Precautions (5.2)]. oInspect NOVOLOG MIX 70/30 visually before use. It should appear uniformly white and cloudy. Do not use it if it looks clear or if it contains solid particles.. oNOVOLOG MIX 70/30 must be resuspended immediately before use. Resuspension is easier when the insulin has reached room temperature.. oWhen using the vial, roll the vial gently in hands in horizontal position 10 times until the suspension appears uniformly white and cloudy. Inject immediately.. oWhen using NOVOLOG MIX 70/30 FlexPen, roll NOVOLOG MIX 70/30 FlexPen gently between hands in horizontal position 10 times. Then, turn NOVOLOG MIX 70/30 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.. oThe NOVOLOG MIX 70/30 FlexPen dials in 1-unit increments.. oUse NOVOLOG MIX 70/30 FlexPen with caution in patients with visual impairment who may rely on audible clicks to dial their dose.. oDo not administer NOVOLOG MIX 70/30 intravenously or use in insulin infusion pumps.. oDo not mix NOVOLOG MIX 70/30 with any other insulins.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no available data with NOVOLOG MIX 70/30 in pregnant women to inform 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 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 HbA1c >7% and has been reported to be as high as 20-25% in women with 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 ConsiderationsDisease-Associated Maternal and/or Embryo-Fetal RiskPoorly 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.DataHuman DataPublished data from 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 variable duration of treatment and small size of the majority of the trials.Animal DataFertility, embryo-fetal and pre- and postnatal development studies have been performed with insulin aspart and regular human insulin in rats and rabbits. In combined fertility and embryo-fetal development study in rats, insulin aspart was administered before mating, during mating, and throughout pregnancy. Further, in 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 dose of 200 units/kg/day (approximately 32 times the human subcutaneous dose of unit/kg/day, based on human exposure equivalents) and in rabbits at dose of 10 units/kg/day (approximately three times the human subcutaneous dose of unit/kg/day, based on human exposure equivalents). No significant effects were observed in rats at dose of 50 units/kg/day and in rabbits at dose of units/kg/day. These doses are approximately times the human subcutaneous dose of unit/kg/day for rats and equal to the human subcutaneous dose of unit/kg/day for rabbits, based on human exposure equivalents. The effects are considered secondary to maternal hypoglycemia.. 8.2 Lactation Risk SummaryThere are no data on the presence of NOVOLOG MIX 70/30 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 mothers clinical need for NOVOLOG MIX 70/30, and any potential adverse effects on the breastfed infant from NOVOLOG MIX 70/30, or from the underlying maternal condition.. 8.4 Pediatric Use. Safety and effectiveness of NOVOLOG MIX 70/30 have not been established in pediatric patients.. 8.5 Geriatric Use. Clinical studies of NOVOLOG MIX 70/30 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 NOVOLOG MIX 70/30 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 NOVOLOG MIX 70/30 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 NOVOLOG MIX 70/30 has not been studied. Patients with hepatic impairment may be at increased risk of hypoglycemia and may require more frequent NOVOLOG MIX 70/30 dose adjustment and more frequent blood glucose monitoring [see Warnings and Precautions (5.3)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oNever share NOVOLOG MIX 70/30 FlexPen between patients, even if the needle is changed (5.1).oHyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to patients insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring (5.2).oHypoglycemia: 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).oMedication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection (5.4).oHypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, may occur. Discontinue NOVOLOG MIX 70/30, treat, and monitor, if indicated (5.5).oHypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated (5.6).oFluid 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).. oNever share NOVOLOG MIX 70/30 FlexPen between patients, even if the needle is changed (5.1).. oHyperglycemia or hypoglycemia with changes in insulin regimen: Make changes to patients insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) under close medical supervision with increased frequency of blood glucose monitoring (5.2).. oHypoglycemia: 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).. oMedication Errors: Accidental mix-ups between insulin products can occur. Instruct patients to check insulin labels before injection (5.4).. oHypersensitivity reactions: Severe, life-threatening, generalized allergy, including anaphylaxis, may occur. Discontinue NOVOLOG MIX 70/30, treat, and monitor, if indicated (5.5).. oHypokalemia: May be life-threatening. Monitor potassium levels in patients at risk of hypokalemia and treat if indicated (5.6).. oFluid 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).. 5.1 Never Share NOVOLOG MIX 70/30 FlexPen Between Patients. NOVOLOG MIX 70/30 FlexPen should never be shared between patients, even if the needle is changed. Patients using NOVOLOG MIX 70/30 vials must never share needles or syringes with another person. Sharing poses risk for transmission of blood-borne pathogens.. 5.2 Hyperglycemia or Hypoglycemia with Changes in Insulin Regimen. Changes in an insulin regimen (e.g., insulin strength, manufacturer, type, injection site or method of administration) may affect glycemic control and predispose to hypoglycemia [see Warnings and Precautions (5.3)] or hyperglycemia. Repeated insulin injections into areas of lipodystrophy or localized cutaneous amyloidosis have been reported to result in hyperglycemia; and sudden change in the injection site (to an unaffected area) has been reported to result in hypoglycemia [see Adverse Reactions 6.1 6.3)]. Make any changes to patients insulin regimen under close medical supervision with increased frequency of blood glucose monitoring. Advise patients who have repeatedly injected into areas of lipodystrophy or localized cutaneous amyloidosis to change the injection site to unaffected areas and closely monitor for hypoglycemia. For patients with type diabetes, dosage adjustments of concomitant anti-diabetic products may be needed. 5.3 Hypoglycemia. Hypoglycemia is the most common adverse effect of all insulins, including NOVOLOG MIX 70/30. 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 HypoglycemiaThe risk of hypoglycemia after an injection is related to the duration of action of the insulin and, in general, is highest when the glucose lowering effect of the insulin is maximal. As with all insulins, the glucose lowering effect time course of NOVOLOG MIX 70/30 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 HypoglycemiaPatients 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 products have been reported. To avoid medication errors between NOVOLOG MIX 70/30 and other insulins, instruct patients to always check the insulin label before each injection.. 5.5 Hypersensitivity Reactions. Severe, life-threatening, generalized allergy, including anaphylaxis, can occur with insulins, including NOVOLOG MIX 70/30. If hypersensitivity reactions occur, discontinue NOVOLOG MIX 70/30; treat per standard of care and monitor until symptoms and signs resolve [see Adverse Reactions (6)]. NOVOLOG MIX 70/30 is contraindicated in patients who have had hypersensitivity reactions to insulin aspart or one of the excipients [see Contraindications (4)]. 5.6 Hypokalemia. All insulins, including NOVOLOG MIX 70/30, can cause 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 NOVOLOG MIX 70/30, and 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.