SPL PATIENT PACKAGE INSERT SECTION.

PATIENT INFORMATION. NovoLog(R) (NO-vo-log)(insulin aspart [rDNA origin] Injection)Important:Know your insulin. Do not change the type of insulin you use unless told to do so by your healthcare provider. The amount of insulin you take as well as the best time for you to take your insulin may need to change if you take different type of insulin.Make sure you know the type and strength of insulin prescribed for you.Read the Patient Information that comes with NovoLog(R) before you start taking it and each time you get refill. There may be new information. This leaflet does not take the place of talking with your healthcare provider about your diabetes or your treatment. Make sure you know how to manage your diabetes. Ask your healthcare provider if you have any questions about managing your diabetes.What is NovoLog(R)NovoLog(R) is man-made insulin that is used to control high blood sugar in adults and children with diabetes mellitus. Who should not use NovoLog(R)Do not take NovoLog(R) if:oYour blood sugar is too low (hypoglycemia).oYou are allergic to anything in NovoLog(R). See the end of this leaflet for complete list of ingredients in NovoLog(R). Check with your healthcare provider if you are not sure.Tell your healthcare provider:oabout all of your medical conditions. Medical conditions can affect your insulin needs and your dose of NovoLog(R).oif you are pregnant or breastfeeding. You and your healthcare provider should talk about the best way to manage your diabetes while you are pregnant or breastfeeding. NovoLog(R) has not been studied in nursing women.oabout all medicines you take, including prescriptions and non-prescription medicines, vitamins and herbal supplements. Your NovoLog(R) dose may change if you take other medicines.oif you take any other medicines, especially ones commonly called TZDs (thiazolidinediones).oif you have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with NovoLog(R).Know the medicines you take. Keep list of your medicines with you to show your healthcare providers when you get new medicine.How should take NovoLog(R)Only use NovoLog(R) if it appears clear and colorless. There may be air bubbles. This is normal. If it looks cloudy, thickened, or colored, or if it contains solid particles do not use it and call Novo Nordisk at 1-800-727-6500.NovoLog(R) comes in:o10 mL vials (small bottles) for use with syringeo3 mL PenFill(R) cartridges for use with the Novo Nordisk mL PenFill(R) cartridge compatible insulin delivery devices and NovoFine(R) disposable needles. The cartridge delivery device can be used with NovoPen(R) PenMate(R) o3 mL NovoLog(R) FlexPen(R) Read the instructions for use that come with your NovoLog(R) product. Talk to your healthcare provider if you have any questions. Your healthcare provider should show you how to inject NovoLog(R) before you start taking it.oTake NovoLog(R) exactly as prescribed. You should eat meal within to 10 minutes after using NovoLog(R) to avoid low blood sugar.oNovoLog(R) is fast-acting insulin. The effects of NovoLog(R) start working 10 to 20 minutes after injection or bolus pump infusion.oDo not inject NovoLog(R) if you do not plan to eat right after your injection or bolus pump infusion.oThe greatest blood sugar lowering effect is between and hours after the injection or infusion. This blood sugar lowering lasts for to hours.oWhile using NovoLog(R) you may have to change your total dose of insulin, your dose of longer-acting insulin, or the number of injections of longer-acting insulin you use. Pump users given NovoLog(R) may need to change the amount of total insulin given as basal infusion.oDo not mix NovoLog(R):with any other insulins when used in pumpwith any insulins other than NPH when used with injections by syringeIf your healthcare provider recommends diluting NovoLog(R), follow your healthcare providers instructions exactly so that you know:oHow to make NovoLog(R) more dilute (that is, smaller number of units of NovoLog(R) for given amount of liquid) andoHow to use this more dilute form of NovoLog(R). Do not use dilute insulin in pump.oInject NovoLog(R) into the skin of your stomach area, upper arms, buttocks or upper legs. NovoLog(R) may affect your blood sugar levels sooner if you inject it into the skin of your stomach area. Never inject NovoLog(R) into vein or into muscle. oChange (rotate) your injection site within the chosen area (for example, stomach or upper arm) with each dose. Do not inject into the exact same spot for each injection.oIf you take too much NovoLog(R) your blood sugar may fall low (hypoglycemia). You can treat mild low blood sugar (hypoglycemia) by drinking or eating something sugary right away (fruit juice, sugar candies, or glucose tablets). It is important to treat low blood sugar (hypoglycemia) right away because it could get worse and you could pass out (become unconscious). If you pass out you will need help from another person or emergency medical services right away, and will need treatment with glucagon injection or treatment at hospital. See What are the possible side effects of NovoLog(R) for more information on low blood sugar (hypoglycemia).oIf you forget to take your dose of NovoLog(R), your blood sugar may go too high (hyperglycemia). If high blood sugar (hyperglycemia) is not treated it can lead to serious problems, like loss of consciousness (passing out), coma or even death. Follow your healthcare providers instructions for treating high blood sugar. Know your symptoms of high blood sugar which may include:oincreased thirstofrequent urinationodrowsinessoloss of appetite oa hard time breathingofruity smell on the breathohigh amounts of sugar and ketones in your urineonausea, vomiting (throwing up) or stomach painCheck your blood sugar levels. Ask your healthcare provider what your blood sugars should be and when you should check your blood sugar levels. Your insulin dosage may need to change because of:oillnessostressoother medicines you takeochange in dietochange in physical activity or exercise What should avoid while using NovoLog(R)oAlcohol. Alcohol, including beer and wine, may affect your blood sugar when you take NovoLog(R).oDriving and operating machinery. You may have difficulty concentrating or reacting if you have low blood sugar (hypoglycemia). Be careful when you drive car or operate machinery. Ask your healthcare provider if it is alright to drive if you often have:low blood sugardecreased or no warning signs of low blood sugarWhat are the possible side effects of NovoLog(R)oLow blood sugar (hypoglycemia). Symptoms of low blood sugar may include:osweatingodizziness or lightheadednessoshakinessohungerofast heart beatotingling of lips and tongueotrouble concentrating or confusionoblurred visionoslurred speechoanxiety, irritability or mood changesoheadacheSevere low blood sugar can cause unconsciousness (passing out), seizures, and death. Know your symptoms of low blood sugar. Follow your healthcare providers instructions for treating low blood sugar. Talk to your healthcare provider if low blood sugar is problem for you.oSerious allergic reaction (whole body reaction). Get medical help right away, if you develop rash over your whole body, have trouble breathing, fast heartbeat, or sweating.oReactions at the injection site (local allergic reaction). You may get redness, swelling, and itching at the injection site. If you keep having skin reactions or they are serious talk to your healthcare provider. You may need to stop using NovoLog(R) and use different insulin. Do not inject insulin into skin that is red, swollen, or itchy.oSkin thickens or pits at the injection site (lipodystrophy). Change (rotate) where you inject your insulin to help to prevent these skin changes from happening. Do not inject insulin into this type of skin.oSwelling of your hands and feetoHeart Failure. Taking certain diabetes pills called thiazolidinediones or TZDs with NovoLog(R) may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with NovoLog(R). Your healthcare provider should monitor you closely while you are taking TZDs with NovoLog(R). Tell your healthcare provider if you have any new or worse symptoms of heart failure including:shortness of breathswelling of your ankles or feetsudden weight gain Treatment with TZDs and NovoLog(R) may need to be adjusted or stopped by your healthcare provider if you have new or worse heart failure.oVision changesoLow potassium in your blood (hypokalemia)oWeight gainThese are not all of the possible side effects from NovoLog(R). Ask your healthcare provider or pharmacist for more information.Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store NovoLog(R)All Unopened NovoLog(R):oKeep all unopened NovoLog(R) in the refrigerator between 36 to 46F (2 to 8C). oDo not freeze. Do not use NovoLog(R) if it has been frozen.oKeep unopened NovoLog(R) in the carton to protect from light.NovoLog(R) in use:oVialsKeep in the refrigerator or at room temperature below 86F (30C) for up to 28 days.Keep vials away from direct heat or light.Throw away an opened vial after 28 days of use, even if there is insulin left in the vial. Do not draw up NovoLog(R) into syringe and store for later use.Unopened vials can be used until the expiration date on the NovoLog(R) label, if the medicine has been stored in refrigerator.oPenFill(R) Cartridges or NovoLog(R) FlexPen(R) Keep at room temperature below 86F (30C) for up to 28 days.Do not store PenFill(R) cartridge or NovoLog(R) FlexPen(R) that you are using in the refrigerator.Keep PenFill(R) cartridges and NovoLog(R) FlexPen(R) away from direct heat or light.Throw away used PenFill(R) cartridge or NovoLog(R) FlexPen(R) after 28 days, even if there is insulin left in the cartridge or syringe.oNovoLog(R) in the pump reservoir and the complete external pump infusion set The infusion set and the infusion site should be changed at least every days. The insulin in the reservoir should be changed at least every days even if you have not used all of the insulin. Change the infusion set and the infusion site more often than every days if you have high blood sugar (hyperglycemia), the pump alarm sounds, or the insulin flow is blocked (occlusion).General advice about NovoLog(R) Medicines are sometimes prescribed for conditions that are not mentioned in the patient leaflet. Do not use NovoLog(R) for condition for which it was not prescribed. Do not give NovoLog(R) to other people, even if they have the same symptoms you have. It may harm them.This leaflet summarizes the most important information about NovoLog(R). If you would like more information about NovoLog(R) or diabetes, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about NovoLog(R) that is written for healthcare professionals. Call 1-800-727-6500 or visit www.novonordisk-us.com for more information.Helpful information for people with diabetes is published by the American Diabetes Association, 1701 Beauregard Street, Alexandria, VA 22311 and on www.diabetes.org.NovoLog(R) ingredients include:oinsulin aspartoglycerinophenolometacresolozincodisodium hydrogen phosphate dihydrateosodium chlorideowater for injectionAll NovoLog(R) vials, PenFill(R) cartridges and NovoLog(R) FlexPen(R) are latex free.Date of Issue: March 9, 2013Version: 12Novo Nordisk(R), NovoLog(R), PenFill(R), FlexPen(R), NovoPen(R), NovoFine(R), and PenMate(R) are registered trademarks of Novo Nordisk A/S.NovoLog(R) is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents pending.FlexPen(R) is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004, and other patents pending.PenFill(R) is covered by US Patent No. 5,693,027.(C) 2002-2013 Novo Nordisk Manufactured by:Novo Nordisk A/SDK-2880 Bagsvaerd, DenmarkFor information about NovoLog(R) contact:Novo Nordisk Inc.800 Scudders Mill RoadPlainsboro, New Jersey 08536PATIENT INSTRUCTIONS FOR USENovoLog(R) (NO-vo-log)(insulin aspart [rDNA origin] injection)10 mL vial (100 Units/mL, U-100)Read this Instructions for Use before you start taking NovoLog(R) 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(R) injection:o10 mL NovoLog(R) vialoinsulin syringe and needleoalcohol swabPreparing your NovoLog(R) dose:oWash your hands with soap and water.oBefore you start to prepare your injection, check the NovoLog(R) 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(R) should look clear and colorless. Do not use NovoLog(R) if it is thick, cloudy, or is colored. oDo not use NovoLog(R) past the expiration date printed on the label.Step 1: Pull off the tamper resistant cap (See Figure A). Step 2: Wipe the rubber stopper with an alcohol swab (See Figure B).Step 3: 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 C).Step 4: Push the needle through the rubber stopper of the NovoLog(R) vial (See Figure D).Step 5: Push the plunger all the way in. This puts air into the NovoLog(R) vial (See Figure E).Step 6: Turn the NovoLog(R) 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 F).oIf there are air bubbles, tap the syringe gently few times to let any air bubbles rise to the top (See Figure G).Step 7: Slowly push the plunger up until the black tip reaches the line for your NovoLog(R) dose (See Figure H).Step 8: Check the syringe to make sure you have the right dose of NovoLog(R).Step 9: Pull the syringe out of the vials rubber stopper (See Figure I).Giving your Injection:oInject your NovoLog(R) exactly as your healthcare provider has shown you. Your healthcare provider should tell you if you need to pinch the skin before injecting. oNovoLog(R) can be injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs or upper arms, infused in an insulin pump, or given through needle in your arm (intravenously) by your healthcare provider.oIf you inject NovoLog(R),change (rotate) your injection sites within the area you choose for each dose. Do not use the same injection site for each injection. oIf you use NovoLog(R) in an insulin pump, you should change your insertion site every days. The insulin in the reservoir should be changed at least every days even if you have not used all of the insulin.oIf you use NovoLog(R) in an insulin pump, see your insulin pump manual for instructions or talk to your healthcare provider.oNPH insulin is the only type of insulin that can be mixed with NovoLog(R). Do not mix NovoLog(R) with any other type of insulin. oNovoLog(R) should only be mixed with NPH insulin if it is going to be injected right away under your skin (subcutaneously). oNovoLog(R) should be drawn up into the syringe before you draw up your NPH insulin.oTalk to your healthcare provider if you are not sure about the right way to mix NovoLog(R) and NPH insulin.Step 10: Choose your injection site and wipe the skin with an alcohol swab. Let the injection site dry before you inject your dose (See Figure J).Step 11: Insert the needle into your skin. Push down on the plunger to inject your dose (See Figure K). Needle should remain in the skin for at least seconds to make sure you have injected all the insulin.Step 12: Pull the needle out of your skin. After that, you may see drop of NovoLog(R) at the needle tip. This is normal and does not affect the dose you just received (See Figure L).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. oThrow away empty insulin vials, used syringes, and needles in sharps container or some type of hard plastic or metal container with screw on cap such as detergent bottle or empty coffee can. Check with your healthcare provider about the right way to throw away the container. There may be local or state laws about how to throw away used syringes and needles. Do not throw away used syringes and needles in household trash or recycling bins. How should store NovoLog(R) Do not freeze NovoLog(R). Do not use NovoLog(R) if it has been frozen.oKeep NovoLog(R) away from heat or light.oStore opened and unopened NovoLog(R) vials in the refrigerator at 36OF to 46OF (2OC to 8OC). Opened NovoLog(R) vials can also be stored out of the refrigerator below 86OF (30OC). oUnopened vials may be used until the expiration date printed on the label, if they are kept in the refrigerator. oOpened NovoLog(R) vials should be thrown away after 28 days, even if they still have insulin left in them. General information about the safe and effective use of NovoLog(R) oAlways use new syringe and needle for each injection.oDo not share syringes or needles. oKeep NovoLog(R) 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 A/SDK-2880 Bagsvaerd, DenmarkNovoLog(R) is registered trademark of Novo Nordisk A/S.NovoLog(R) is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents pending.(C) 2002-2013 Novo NordiskFor information about NovoLog(R) contact:Novo Nordisk Inc.800 Scudders Mill RoadPlainsboro, New Jersey 085361-800-727-6500www.novonordisk-us.comRevised: March 2013PATIENT INSTRUCTIONS FOR USENovoLog(R) mL PenFill(R) cartridge (100 Units/mL, U-100) Before using the NovoLog(R) cartridge1.Talk with your healthcare provider for information about where to inject NovoLog(R) (injection sites) and how to give an injection with your insulin delivery device.2.Read the instruction manual that comes with your insulin delivery device for complete instructions on how to use the PenFill(R) cartridge with the device.How to use the NovoLog(R) cartridge1.Check your insulin. Just before using your NovoLog(R) cartridge, check to make sure that you have the right type of insulin. This is especially important if you use different types of insulin.2.Carefully look at the cartridge and the insulin inside it. The insulin should be clear and colorless. The tamper-resistant foil should be in place before the first use. If the foil has been broken or removed before your first use of the cartridge, or if the insulin is cloudy or colored, do not use it. Call Novo Nordisk at 1-800-727-6500.3.Wash your hands well with soap and water. If you clean your injection site with an alcohol swab, let the injection site dry before you inject. Talk with your healthcare provider for guidance on injection sites and how to give an injection with your insulin delivery device.4.Gather your supplies for injecting NovoLog(R).5.Insert 3 mL cartridge into your Novo Nordisk mL PenFill(R) cartridge compatible insulin delivery device. Wipe the front rubber stopper of the mL PenFill(R) cartridge with an alcohol swab, then attach new needle. For NovoFine(R) needles, remove the big outer needle cap and the inner needle cap. Always use new needle for each injection to prevent infection.Giving the airshot before each injection:To prevent the injection of air and to make sure insulin is delivered, you must do an airshot before each injection. Hold the device with the needle pointing up and gently tap the PenFill(R) cartridge holder with your finger few times to raise any air bubbles to the top of the cartridge. Do the airshot as described in the device instruction manual. Giving the injection6. Dial the number of units on the insulin delivery device that you need to inject. Inject the right way as shown to you by your healthcare provider.7. Insert the needle into the skin. Inject the dose by pressing the push button all the way in. 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. This will make sure that the full dose has been given. You may see drop of NovoLog(R) 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 finger. Do not rub the area. After the injection8. Do not recap the needle. Recapping can lead to needle stick injury. 9. Remove the needle from the PenFill(R) cartridge after each injection. Keep the mL PenFill(R) cartridge in the insulin delivery device. The needle should not be attached to the mL PenFill(R) cartridge during storage. This will prevent infection or leakage of insulin and will help ensure that you receive the right dose of NovoLog(R).10. Put the used needle and cartridge in sharps container, or some type of hard plastic or metal container with screw on top such as detergent bottle or coffee can. Check with your healthcare provider about the right way to throw away used needles and cartridges. There may be local or state laws about how to throw away used needles and syringes. Do not throw used needles and cartridges in household trash or recycling bins.11. Put the pen cap back on the Novo Nordisk mL PenFill(R) cartridge compatible insulin delivery device.Date of Issue: March 2013Version: 9Novo Nordisk(R), NovoLog(R), PenFill(R), and NovoFine(R) are registered trademarks of Novo Nordisk A/S.NovoLog(R) is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents pending.PenFill(R) is covered by US Patent No. 5,693,027.(C) 2002-2013 Novo NordiskManufactured by:Novo Nordisk A/SDK-2880 Bagsvaerd, DenmarkFor information about NovoLog(R) contact:Novo Nordisk Inc.800 Scudders Mill RoadPlainsboro, New Jersey 08536PATIENT INSTRUCTIONS FOR USENovoLog(R) FlexPen(R)IntroductionPlease read the following instructions carefully before using your NovoLog(R) FlexPen(R).NovoLog FlexPen is disposable dial-a-dose insulin pen. You can select doses from to 60 units in increments of unit. NovoLog FlexPen is designed to be used with NovoFine(R) needles. NovoLog FlexPen should not be used by people who are blind or have severe visual problems without the help of person who has good eyesight and who is trained to use the NovoLog FlexPen the right way.Getting readyMake sure you have the following texts:oNovoLog FlexPenoNew NovoFine needleoAlcohol swabPreparing Your NovoLog FlexPenWash your hands with soap and water. Before you start to prepare your injection, check the label to make sure that you are taking the right type of insulin. This is especially important if you take more than type of insulin. NovoLog should look clear.A. Pull off the pen cap (see diagram A).Wipe the rubber stopper with an alcohol swab.B. Attaching the needle Remove the protective tab from disposable needle.Screw the needle tightly onto your FlexPen. It is important that the needle is put on straight (see diagram B).Never place disposable needle on your NovoLog FlexPen until you are ready to take your injection.C. Pull off the big outer needle cap (see diagram C).D. Pull off the inner needle cap and dispose of it (see diagram D). Always use new needle for each injection to help ensure sterility and prevent blocked needles. Be careful not to bend or damage the needle before use. To reduce the risk of unexpected needle sticks, 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 ensure proper dosing:E. Turn the dose selector to select units (see diagram E).F. Hold your NovoLog 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 F).G. Keep the needle pointing upwards, press the push-button all the way in (see diagram G). 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 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.H. 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 H). 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. Do not use the cartridge scale printed on the cartridge to measure your dose of insulin.Giving the injectionDo 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.I. 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 I). Be careful only to push the button when injecting.Turning the dose selector will not inject insulin.J. 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 J). This will make sure that the full dose has been given.You may see drop of NovoLog 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 finger. 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 FlexPen after each injection. This helps to prevent infection, leakage of insulin, and will help to make sure you inject the right dose of insulin. Put the needle and any empty NovoLog FlexPen or any used NovoLog FlexPen still containing insulin in sharps container or some type of hard plastic or metal container with screw top such as detergent bottle or empty coffee can. These containers should be sealed and thrown away the right way. Check with your healthcare provider about the right way to throw away used syringes and needles. There may be local or state laws about how to throw away used needles and syringes. Do not throw away used needles and syringes in household trash or recycling bins.The NovoLog FlexPen prevents the cartridge from being completely emptied. It is designed to deliver 300 units.K. Put the pen cap on the NovoLog FlexPen and store the NovoLog FlexPen without the needle attached (see diagram K).Function CheckL. If your NovoLog FlexPen is not working the right way, follow the steps below:oScrew on new NovoFine needle.oRemove the big outer needle cap and the inner needle cap.oDo an airshot as described in Giving the airshot before each injection.oPut the big outer needle cap onto the needle. Do not put on the inner needle cap.oTurn the dose selector so the dose indicator window shows 20 units.oHold the NovoLog FlexPen so the needle is pointing down.oPress the push-button all the way in.The insulin should fill the lower part of the big outer needle cap (see diagram L). If the NovoLog FlexPen has released too much or too little insulin, do the function check again. If the same problem happens again, do not use your NovoLog FlexPen and contact Novo Nordisk at 1-800-727-6500.MaintenanceYour FlexPen is designed to work accurately and safely. It must be handled with care. Avoid dropping your FlexPen as it may damage it. If you are concerned that your FlexPen is damaged, use new one. You can clean the outside of your FlexPen by wiping it with damp cloth. Do not soak or wash your FlexPen as it may damage it. Do not refill your FlexPen. Remove the needle from the NovoLog 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 FlexPen and needles out of the reach of children. Use NovoLog FlexPen as directed to treat your diabetes. Needles and NovoLog FlexPen must not be shared. 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 FlexPen is lost or damaged. Remember to keep the disposable NovoLog FlexPen with you. Do not leave it in car or other location where it can get too hot or too cold.. oYour blood sugar is too low (hypoglycemia).. oYou are allergic to anything in NovoLog(R). See the end of this leaflet for complete list of ingredients in NovoLog(R). Check with your healthcare provider if you are not sure.. oabout all of your medical conditions. Medical conditions can affect your insulin needs and your dose of NovoLog(R).. oif you are pregnant or breastfeeding. You and your healthcare provider should talk about the best way to manage your diabetes while you are pregnant or breastfeeding. NovoLog(R) has not been studied in nursing women.. oabout all medicines you take, including prescriptions and non-prescription medicines, vitamins and herbal supplements. Your NovoLog(R) dose may change if you take other medicines.. oif you take any other medicines, especially ones commonly called TZDs (thiazolidinediones).. oif you have heart failure or other heart problems. If you have heart failure, it may get worse while you take TZDs with NovoLog(R).. o10 mL vials (small bottles) for use with syringe. o3 mL PenFill(R) cartridges for use with the Novo Nordisk mL PenFill(R) cartridge compatible insulin delivery devices and NovoFine(R) disposable needles. The cartridge delivery device can be used with NovoPen(R) PenMate(R) o3 mL NovoLog(R) FlexPen(R) oTake NovoLog(R) exactly as prescribed. You should eat meal within to 10 minutes after using NovoLog(R) to avoid low blood sugar.. oNovoLog(R) is fast-acting insulin. The effects of NovoLog(R) start working 10 to 20 minutes after injection or bolus pump infusion.. oDo not inject NovoLog(R) if you do not plan to eat right after your injection or bolus pump infusion.. oThe greatest blood sugar lowering effect is between and hours after the injection or infusion. This blood sugar lowering lasts for to hours.. oWhile using NovoLog(R) you may have to change your total dose of insulin, your dose of longer-acting insulin, or the number of injections of longer-acting insulin you use. Pump users given NovoLog(R) may need to change the amount of total insulin given as basal infusion.. oDo not mix NovoLog(R):with any other insulins when used in pumpwith any insulins other than NPH when used with injections by syringe. with any other insulins when used in pump. with any insulins other than NPH when used with injections by syringe. oHow to make NovoLog(R) more dilute (that is, smaller number of units of NovoLog(R) for given amount of liquid) and. oHow to use this more dilute form of NovoLog(R). Do not use dilute insulin in pump.. oInject NovoLog(R) into the skin of your stomach area, upper arms, buttocks or upper legs. NovoLog(R) may affect your blood sugar levels sooner if you inject it into the skin of your stomach area. Never inject NovoLog(R) into vein or into muscle. oChange (rotate) your injection site within the chosen area (for example, stomach or upper arm) with each dose. Do not inject into the exact same spot for each injection.. oIf you take too much NovoLog(R) your blood sugar may fall low (hypoglycemia). You can treat mild low blood sugar (hypoglycemia) by drinking or eating something sugary right away (fruit juice, sugar candies, or glucose tablets). It is important to treat low blood sugar (hypoglycemia) right away because it could get worse and you could pass out (become unconscious). If you pass out you will need help from another person or emergency medical services right away, and will need treatment with glucagon injection or treatment at hospital. See What are the possible side effects of NovoLog(R) for more information on low blood sugar (hypoglycemia).. oIf you forget to take your dose of NovoLog(R), your blood sugar may go too high (hyperglycemia). If high blood sugar (hyperglycemia) is not treated it can lead to serious problems, like loss of consciousness (passing out), coma or even death. Follow your healthcare providers instructions for treating high blood sugar. Know your symptoms of high blood sugar which may include:. oincreased thirst. ofrequent urination. odrowsiness. oloss of appetite oa hard time breathing. ofruity smell on the breath. ohigh amounts of sugar and ketones in your urine. onausea, vomiting (throwing up) or stomach pain. oillness. ostress. oother medicines you take. ochange in diet. ochange in physical activity or exercise oAlcohol. Alcohol, including beer and wine, may affect your blood sugar when you take NovoLog(R).. oDriving and operating machinery. You may have difficulty concentrating or reacting if you have low blood sugar (hypoglycemia). Be careful when you drive car or operate machinery. Ask your healthcare provider if it is alright to drive if you often have:low blood sugardecreased or no warning signs of low blood sugar. low blood sugar. decreased or no warning signs of low blood sugar. oLow blood sugar (hypoglycemia). Symptoms of low blood sugar may include:. osweating. odizziness or lightheadedness. oshakiness. ohunger. ofast heart beat. otingling of lips and tongue. otrouble concentrating or confusion. oblurred vision. oslurred speech. oanxiety, irritability or mood changes. oheadache. oSerious allergic reaction (whole body reaction). Get medical help right away, if you develop rash over your whole body, have trouble breathing, fast heartbeat, or sweating.. oReactions at the injection site (local allergic reaction). You may get redness, swelling, and itching at the injection site. If you keep having skin reactions or they are serious talk to your healthcare provider. You may need to stop using NovoLog(R) and use different insulin. Do not inject insulin into skin that is red, swollen, or itchy.. oSkin thickens or pits at the injection site (lipodystrophy). Change (rotate) where you inject your insulin to help to prevent these skin changes from happening. Do not inject insulin into this type of skin.. oSwelling of your hands and feet. oHeart Failure. Taking certain diabetes pills called thiazolidinediones or TZDs with NovoLog(R) may cause heart failure in some people. This can happen even if you have never had heart failure or heart problems before. If you already have heart failure it may get worse while you take TZDs with NovoLog(R). Your healthcare provider should monitor you closely while you are taking TZDs with NovoLog(R). Tell your healthcare provider if you have any new or worse symptoms of heart failure including:shortness of breathswelling of your ankles or feetsudden weight gain shortness of breath. swelling of your ankles or feet. sudden weight gain. Treatment with TZDs and NovoLog(R) may need to be adjusted or stopped by your healthcare provider if you have new or worse heart failure.. oVision changes. oLow potassium in your blood (hypokalemia). oWeight gain. oKeep all unopened NovoLog(R) in the refrigerator between 36 to 46F (2 to 8C). oDo not freeze. Do not use NovoLog(R) if it has been frozen.. oKeep unopened NovoLog(R) in the carton to protect from light.. oVialsKeep in the refrigerator or at room temperature below 86F (30C) for up to 28 days.Keep vials away from direct heat or light.Throw away an opened vial after 28 days of use, even if there is insulin left in the vial. Do not draw up NovoLog(R) into syringe and store for later use.Unopened vials can be used until the expiration date on the NovoLog(R) label, if the medicine has been stored in refrigerator.. Keep in the refrigerator or at room temperature below 86F (30C) for up to 28 days.. Keep vials away from direct heat or light.. Throw away an opened vial after 28 days of use, even if there is insulin left in the vial. Do not draw up NovoLog(R) into syringe and store for later use.. Unopened vials can be used until the expiration date on the NovoLog(R) label, if the medicine has been stored in refrigerator.. oPenFill(R) Cartridges or NovoLog(R) FlexPen(R) Keep at room temperature below 86F (30C) for up to 28 days.Do not store PenFill(R) cartridge or NovoLog(R) FlexPen(R) that you are using in the refrigerator.Keep PenFill(R) cartridges and NovoLog(R) FlexPen(R) away from direct heat or light.Throw away used PenFill(R) cartridge or NovoLog(R) FlexPen(R) after 28 days, even if there is insulin left in the cartridge or syringe.. Keep at room temperature below 86F (30C) for up to 28 days.. Do not store PenFill(R) cartridge or NovoLog(R) FlexPen(R) that you are using in the refrigerator.. Keep PenFill(R) cartridges and NovoLog(R) FlexPen(R) away from direct heat or light.. Throw away used PenFill(R) cartridge or NovoLog(R) FlexPen(R) after 28 days, even if there is insulin left in the cartridge or syringe.. oNovoLog(R) in the pump reservoir and the complete external pump infusion set The infusion set and the infusion site should be changed at least every days. The insulin in the reservoir should be changed at least every days even if you have not used all of the insulin. Change the infusion set and the infusion site more often than every days if you have high blood sugar (hyperglycemia), the pump alarm sounds, or the insulin flow is blocked (occlusion).. The infusion set and the infusion site should be changed at least every days. The insulin in the reservoir should be changed at least every days even if you have not used all of the insulin. Change the infusion set and the infusion site more often than every days if you have high blood sugar (hyperglycemia), the pump alarm sounds, or the insulin flow is blocked (occlusion).. oinsulin aspart. oglycerin. ophenol. ometacresol. ozinc. odisodium hydrogen phosphate dihydrate. osodium chloride. owater for injection. o10 mL NovoLog(R) vial. oinsulin syringe and needle. oalcohol swab. oWash your hands with soap and water.. oBefore you start to prepare your injection, check the NovoLog(R) 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(R) should look clear and colorless. Do not use NovoLog(R) if it is thick, cloudy, or is colored. oDo not use NovoLog(R) 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 G).. Giving your Injection:. oInject your NovoLog(R) exactly as your healthcare provider has shown you. Your healthcare provider should tell you if you need to pinch the skin before injecting. oNovoLog(R) can be injected under the skin (subcutaneously) of your stomach area, buttocks, upper legs or upper arms, infused in an insulin pump, or given through needle in your arm (intravenously) by your healthcare provider.. oIf you inject NovoLog(R),change (rotate) your injection sites within the area you choose for each dose. Do not use the same injection site for each injection. oIf you use NovoLog(R) in an insulin pump, you should change your insertion site every days. The insulin in the reservoir should be changed at least every days even if you have not used all of the insulin.. oIf you use NovoLog(R) in an insulin pump, see your insulin pump manual for instructions or talk to your healthcare provider.. oNPH insulin is the only type of insulin that can be mixed with NovoLog(R). Do not mix NovoLog(R) with any other type of insulin. oNovoLog(R) should only be mixed with NPH insulin if it is going to be injected right away under your skin (subcutaneously). oNovoLog(R) should be drawn up into the syringe before you draw up your NPH insulin.. oTalk to your healthcare provider if you are not sure about the right way to mix NovoLog(R) and NPH insulin.. 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. oThrow away empty insulin vials, used syringes, and needles in sharps container or some type of hard plastic or metal container with screw on cap such as detergent bottle or empty coffee can. Check with your healthcare provider about the right way to throw away the container. There may be local or state laws about how to throw away used syringes and needles. Do not throw away used syringes and needles in household trash or recycling bins. oKeep NovoLog(R) away from heat or light.. oStore opened and unopened NovoLog(R) vials in the refrigerator at 36OF to 46OF (2OC to 8OC). Opened NovoLog(R) vials can also be stored out of the refrigerator below 86OF (30OC). oUnopened vials may be used until the expiration date printed on the label, if they are kept in the refrigerator. oOpened NovoLog(R) vials should be thrown away 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(R) vials, syringes, and needles out of the reach of children.. 1.Talk with your healthcare provider for information about where to inject NovoLog(R) (injection sites) and how to give an injection with your insulin delivery device.. 2.Read the instruction manual that comes with your insulin delivery device for complete instructions on how to use the PenFill(R) cartridge with the device.. 1.Check your insulin. Just before using your NovoLog(R) cartridge, check to make sure that you have the right type of insulin. This is especially important if you use different types of insulin.. 2.Carefully look at the cartridge and the insulin inside it. The insulin should be clear and colorless. The tamper-resistant foil should be in place before the first use. If the foil has been broken or removed before your first use of the cartridge, or if the insulin is cloudy or colored, do not use it. Call Novo Nordisk at 1-800-727-6500.. 3.Wash your hands well with soap and water. If you clean your injection site with an alcohol swab, let the injection site dry before you inject. Talk with your healthcare provider for guidance on injection sites and how to give an injection with your insulin delivery device.. 4.Gather your supplies for injecting NovoLog(R).. 5.Insert 3 mL cartridge into your Novo Nordisk mL PenFill(R) cartridge compatible insulin delivery device. Wipe the front rubber stopper of the mL PenFill(R) cartridge with an alcohol swab, then attach new needle. For NovoFine(R) needles, remove the big outer needle cap and the inner needle cap. Always use new needle for each injection to prevent infection.. NovoLog FlexPen should not be used by people who are blind or have severe visual problems without the help of person who has good eyesight and who is trained to use the NovoLog FlexPen the right way.. oNovoLog FlexPen. oNew NovoFine needle. oAlcohol swab. Always use new needle for each injection to help ensure sterility and prevent blocked needles.. Be careful not to bend or damage the needle before use.. To reduce the risk of unexpected needle sticks, never put the inner needle cap back on the needle.. Do not use the cartridge scale printed on the cartridge to measure your dose of insulin.. Put the needle and any empty NovoLog FlexPen or any used NovoLog FlexPen still containing insulin in sharps container or some type of hard plastic or metal container with screw top such as detergent bottle or empty coffee can. These containers should be sealed and thrown away the right way. Check with your healthcare provider about the right way to throw away used syringes and needles. There may be local or state laws about how to throw away used needles and syringes. Do not throw away used needles and syringes in household trash or recycling bins.. oScrew on new NovoFine needle.. oRemove the big outer needle cap and the inner needle cap.. oDo an airshot as described in Giving the airshot before each injection.. oPut the big outer needle cap onto the needle. Do not put on the inner needle cap.. oTurn the dose selector so the dose indicator window shows 20 units.. oHold the NovoLog FlexPen so the needle is pointing down.. oPress the push-button all the way in.. Vial figure. Hand and vial figure. Figure and Figure B. Figure C. Figure D. Figure E. Figure F. Figure G. Figure H. Figure I. Figure J. Figure K. Figure L. Instructions For Use NovoLog FlexPen. - Preparing the NovoLog FlexPen. - Attaching the Needle. - Pulling off the big outer needle cap. - Pulling off the inner needle cap. - Giving the airshot before each injection- Turn the dose selector to select units. - Giving the airshot before each injection Tap the cartridge to make air bubbles collect at the top of the cartridge. - Giving the airshot before each injection Press the push-button all the way in. The dose selector returns to 0. - Selecting the dose I Giving the injection. - Giving the injection Making sure that the full dose has been given. - After the injection Storing NovoLog FlexPen. - Function Check.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. oNovoLog is an insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus (1.1).. oNovoLog is an insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus (1.1).. 1.1 Treatment of Diabetes Mellitus. NovoLog is an insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. [See FDA-Approved Patient Labeling (17.3)]. 17.1 Physician Instructions. Maintenance of normal or near-normal glucose control is treatment goal in diabetes mellitus and has been associated with reduction in diabetic complications. Patients should be informed about potential risks and benefits of NovoLog therapy including the possible adverse reactions. Patients should also be offered continued education and advice on insulin therapies, injection technique, life-style management, regular glucose monitoring, periodic glycosylated hemoglobin testing, recognition and management of hypo- and hyperglycemia, adherence to meal planning, complications of insulin therapy, timing of dose, instruction in the use of injection or subcutaneous infusion devices, and proper storage of insulin. Patients should be informed that frequent, patient-performed blood glucose measurements are needed to achieve optimal glycemic control and avoid both hyper- and hypoglycemia.The patients ability to concentrate and react may be impaired as result of hypoglycemia. This may present risk in situations where these abilities are especially important, such as driving or operating other machinery. Patients who have frequent hypoglycemia or reduced or absent warning signs of hypoglycemia should be advised to use caution when driving or operating machinery.Accidental substitutions between NovoLog and other insulin products have been reported. Patients should be instructed to always carefully check that they are administering the appropriate insulin to avoid medication errors between NovoLog and any other insulin. The written prescription for NovoLog should be written clearly, to avoid confusion with other insulin products, for example, NovoLog Mix 70/30. 17.2 Patients Using Pumps. Patients using external pump infusion therapy should be trained in intensive insulin therapy with multiple injections and in the function of their pump and pump accessories.The following insulin pumps+ have been used in NovoLog clinical or in vitro studies conducted by Novo Nordisk, the manufacturer of NovoLog:oMedtronic Paradigm(R) 512 and 712oMiniMed 508oDisetronic(R) D-TRON(R) and H-TRON(R) Before using another insulin pump with NovoLog, read the pump label to make sure the pump has been evaluated with NovoLog. NovoLog is recommended for use in any reservoir and infusion sets that are compatible with insulin and the specific pump. Please see recommended reservoir and infusion sets in the pump manual.To avoid insulin degradation, infusion set occlusion, and loss of the preservative (metacresol), insulin in the reservoir should be replaced at least every days; infusion sets and infusion set insertion sites should be changed at least every days. Insulin exposed to temperatures higher than 37C (98.6F) should be discarded. The temperature of the insulin may exceed ambient temperature when the pump housing, cover, tubing, or sport case is exposed to sunlight or radiant heat. Infusion sites that are erythematous, pruritic, or thickened should be reported to medical personnel, and new site selected because continued infusion may increase the skin reaction and/or alter the absorption of NovoLog. Pump or infusion set malfunctions or insulin degradation can lead to hyperglycemia and ketosis in short time because of the small subcutaneous depot of insulin. This is especially pertinent for rapid-acting insulin analogs that are more rapidly absorbed through skin and have shorter duration of action. These differences are particularly relevant when patients are switched from multiple injection therapy. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Problems include pump malfunction, infusion set occlusion, leakage, disconnection or kinking, and degraded insulin. Less commonly, hypoglycemia from pump malfunction may occur. If these problems cannot be promptly corrected, patients should resume therapy with subcutaneous insulin injection and contact their physician [see Dosage and Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling (16.2) ].. oMedtronic Paradigm(R) 512 and 712. oMiniMed 508. oDisetronic(R) D-TRON(R) and H-TRON(R) 17.3 FDA-Approved Patient Labeling See separate leaflet.Rx OnlyDate of Issue: March 9, 2013Version: 20Novo Nordisk(R), NovoLog(R), NovoPen(R) 3, PenFill(R), Novolin(R), FlexPen(R), PenMate(R) and NovoFine(R) are registered trademarks of Novo Nordisk A/S.NovoLog(R) is covered by US Patent Nos. 5,618,913, 5,866,538, and other patents pending.FlexPen(R) is covered by US Patent Nos. 6,582,404, 6,004,297, 6,235,004, and other patents pending.PenFill(R) is covered by US Patent No. 5,693,027.+The brands listed are the registered trademarks of their respective owners and are not trademarks of Novo Nordisk A/S.(C) 2002-2013 Novo NordiskManufactured by:Novo Nordisk A/SDK-2880 Bagsvaerd, DenmarkFor information about NovoLog contact:Novo Nordisk Inc.Plainsboro, New Jersey 085361-800-727-6500www.novonordisk-us.com.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. The primary activity of NovoLog is the regulation of glucose metabolism. Insulins, including NovoLog, bind to the insulin receptors on muscle and fat cells and lower blood glucose by facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose from the liver.

ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Clinical Trial ExperienceBecause clinical trials are conducted under widely varying designs, 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.oHypoglycemiaHypoglycemia is the most commonly observed adverse reaction in patients using insulin, including NovoLog [see Warnings and Precautions (5) ].oInsulin 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.oLipodystrophyLong-term use of insulin, including NovoLog, can cause lipodystrophy at the site of repeated insulin injections or infusion. Lipodystrophy includes lipohypertrophy (thickening of adipose tissue) and lipoatrophy (thinning of adipose tissue), and may affect insulin absorption. Rotate insulin injection or infusion sites within the same region to reduce the risk of lipodystrophy.oWeight gainWeight gain can occur with some insulin therapies, including NovoLog, and has been attributed to the anabolic effects of insulin and the decrease in glucosuria.oPeripheral EdemaInsulin may cause sodium retention and edema, particularly if previously poor metabolic control is improved by intensified insulin therapy.oFrequencies of adverse drug reactions The frequencies of adverse drug reactions during NovoLog clinical trials in patients with type diabetes mellitus and type diabetes mellitus are listed in the tables below.Table 1: Treatment-Emergent Adverse Events in Patients with Type Diabetes Mellitus (Adverse events with frequency >= 5% and occurring more frequently with NovoLog compared to human regular insulin are listed)NovoLog NPHN= 596Human Regular Insulin NPHN= 286Preferred TermN(%)N(%)HypoglycemiaHypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms. See Section 14 for the incidence of serious hypoglycemia in the individual clinical trials. 44875%20572%Headache7012%2810%Injury accidental6511%2910%Nausea437%135%Diarrhea285%93%Table 2: Treatment-Emergent Adverse Events in Patients with Type Diabetes Mellitus (except for hypoglycemia, adverse events with frequency >= 5% and occurring more frequently with NovoLog compared to human regular insulin are listed)NovoLog NPHN= 91Human Regular Insulin NPHN= 91N(%)N(%)HypoglycemiaHypoglycemia is defined as an episode of blood glucose concentration <45 mg/dL, with or without symptoms. See Section 14 for the incidence of serious hypoglycemia in the individual clinical trials. 2527%3336%Hyporeflexia1011%67%Onychomycosis910%55%Sensory disturbance89%67%Urinary tract infection78%67%Chest pain55%33%Headache55%33%Skin disorder55%22%Abdominal pain55%11%Sinusitis55%11%Postmarketing DataThe following additional adverse reactions have been identified during postapproval use of NovoLog. Because these adverse reactions are reported voluntarily from population of uncertain size, it is generally not possible to reliably estimate their frequency. Medication errors in which other insulins have been accidentally substituted for NovoLog have been identified during postapproval use [see Patient Counseling Information (17) ].. oHypoglycemia. oInsulin initiation and glucose control intensification. oLipodystrophy. oWeight gain. oPeripheral Edema. oFrequencies of adverse drug reactions Adverse reactions observed with NovoLog 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.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. In standard biological assays in mice and rabbits, one unit of NovoLog has the same glucose-lowering effect as one unit of regular human insulin. In humans, the effect of NovoLog is more rapid in onset and of shorter duration, compared to regular human insulin, due to its faster absorption after subcutaneous injection (see Section 12 CLINICAL PHARMACOLOGY Figure and Figure 4).

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. In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with NovoLog at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area, respectively). At dose of 200 U/kg/day, NovoLog increased the incidence of mammary gland tumors in females when compared to untreated controls. The incidence of mammary tumors for NovoLog was not significantly different than for regular human insulin. 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, at subcutaneous doses up to 200 U/kg/day (approximately 32 times the human subcutaneous dose, based on U/body surface area), no direct adverse effects on male and female fertility, or general reproductive performance of animals was observed.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. The primary activity of NovoLog is the regulation of glucose metabolism. Insulins, including NovoLog, bind to the insulin receptors on muscle and fat cells and lower blood glucose by facilitating the cellular uptake of glucose and simultaneously inhibiting the output of glucose from the liver.. 12.2 Pharmacodynamics. Studies in normal volunteers and patients with diabetes demonstrated that subcutaneous administration of NovoLog has more rapid onset of action than regular human insulin.In study in patients with type diabetes (n=22), the maximum glucose-lowering effect of NovoLog occurred between and hours after subcutaneous injection (see Figure 2). The duration of action for NovoLog is to hours. The time course of action of insulin and insulin analogs such as NovoLog may vary considerably in different individuals or within the same individual. The parameters of NovoLog activity (time of onset, peak time and duration) as designated in Figure should be considered only as general guidelines. The rate of insulin absorption and onset of activity is affected by the site of injection, exercise, and other variables [see Warnings and Precautions (5.1) ].Figure 2. Serial mean serum glucose collected up to hours following single pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched curve) injected immediately before meal in 22 patients with type diabetes. double-blind, randomized, two-way cross-over study in 16 patients with type diabetes demonstrated that intravenous infusion of NovoLog resulted in blood glucose profile that was similar to that after intravenous infusion with regular human insulin. NovoLog or human insulin was infused until the patients blood glucose decreased to 36 mg/dL, or until the patient demonstrated signs of hypoglycemia (rise in heart rate and onset of sweating), defined as the time of autonomic reaction (R) (see Figure 3).Figure 3. Mean blood glucose profiles following intravenous infusion of NovoLog (hatched curve) and regular human insulin (solid curve) in 16 patients with type diabetes. represents the time of autonomic reaction. Fig. - Pharmacodynamics Graph showing Maximum Glucose-Lowering Effect of NovoLog. Fig. - Pharmacodynamics Graph Time of Autonomic Reaction. 12.3 Pharmacokinetics. The single substitution of the amino acid proline with aspartic acid at position B28 in NovoLog reduces the molecules tendency to form hexamers as observed with regular human insulin. NovoLog is, therefore, more rapidly absorbed after subcutaneous injection compared to regular human insulin.In randomized, double-blind, crossover study 17 healthy Caucasian male subjects between 18 and 40 years of age received an intravenous infusion of either NovoLog or regular human insulin at 1.5 mU/kg/min for 120 minutes. The mean insulin clearance was similar for the two groups with mean values of 1.2 l/h/kg for the NovoLog group and 1.2 l/h/kg for the regular human insulin group.Bioavailability and Absorption NovoLog has faster absorption, faster onset of action, and shorter duration of action than regular human insulin after subcutaneous injection (see Figure and Figure 4). The relative bioavailability of NovoLog compared to regular human insulin indicates that the two insulins are absorbed to similar extent.Figure 4. Serial mean serum free insulin concentration collected up to hours following single pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched curve) injected immediately before meal in 22 patients with type diabetes. In studies in healthy volunteers (total n=107) and patients with type diabetes (total n=40), NovoLog consistently reached peak serum concentrations approximately twice as fast as regular human insulin. The median time to maximum concentration in these trials was 40 to 50 minutes for NovoLog versus 80 to 120 minutes for regular human insulin. In clinical trial in patients with type diabetes, NovoLog and regular human insulin, both administered subcutaneously at dose of 0.15 U/kg body weight, reached mean maximum concentrations of 82 and 36 mU/L, respectively. Pharmacokinetic/pharmacodynamic characteristics of insulin aspart have not been established in patients with type diabetes.The intra-individual variability in time to maximum serum insulin concentration for healthy male volunteers was significantly less for NovoLog than for regular human insulin. The clinical significance of this observation has not been established.In clinical study in healthy non-obese subjects, the pharmacokinetic differences between NovoLog and regular human insulin described above, were observed independent of the site of injection (abdomen, thigh, or upper arm).Distribution and Elimination NovoLog has low binding to plasma proteins (<10%), similar to that seen with regular human insulin. After subcutaneous administration in normal male volunteers (n=24), NovoLog was more rapidly eliminated than regular human insulin with an average apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.Specific PopulationsChildren and Adolescents The pharmacokinetic and pharmacodynamic properties of NovoLog and regular human insulin were evaluated in single dose study in 18 children (6-12 years, n=9) and adolescents (13-17 years [Tanner grade 2], n=9) with type diabetes. The relative differences in pharmacokinetics and pharmacodynamics in children and adolescents with type diabetes between NovoLog and regular human insulin were similar to those in healthy adult subjects and adults with type diabetes.Gender In healthy volunteers, no difference in insulin aspart levels was seen between men and women when body weight differences were taken into account. There was no significant difference in efficacy noted (as assessed by HbAlc) between genders in trial in patients with type diabetes.Obesity A single subcutaneous dose of 0.1 U/kg NovoLog was administered in study of 23 patients with type diabetes and wide range of body mass index (BMI, 22-39 kg/m2). The pharmacokinetic parameters, AUC and Cmax, of NovoLog were generally unaffected by BMI in the different groups BMI 19-23 kg/m2 (N=4); BMI 23-27 kg/m2 (N=7); BMI 27-32 kg/m2 (N=6) and BMI >32 kg/m2 (N=6). Clearance of NovoLog was reduced by 28% in patients with BMI >32 kg/m2 compared to patients with BMI <23 kg/m2.Renal Impairment Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. single subcutaneous dose of 0.08 U/kg NovoLog was administered in study to subjects with either normal (N=6) creatinine clearance (CLcr) (> 80 ml/min) or mild (N=7; CLcr 50-80 ml/min), moderate (N=3; CLcr 30-50 ml/min) or severe (but not requiring hemodialysis) (N=2; CLcr <30 ml/min) renal impairment. In this small study, there was no apparent effect of creatinine clearance values on AUC and Cmax of NovoLog. Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be necessary in patients with renal dysfunction [see Warnings and Precautions (5.4) ].Hepatic Impairment Some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure. single subcutaneous dose of 0.06 U/kg NovoLog was administered in an open-label, single-dose study of 24 subjects (N=6/group) with different degree of hepatic impairment (mild, moderate and severe) having Child-Pugh Scores ranging from (healthy volunteers) to 12 (severe hepatic impairment). In this small study, there was no correlation between the degree of hepatic failure and any NovoLog pharmacokinetic parameter. Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be necessary in patients with hepatic dysfunction [see Warnings and Precautions (5.5) ].The effect of age, ethnic origin, pregnancy and smoking on the pharmacokinetics and pharmacodynamics of NovoLog has not been studied.. Fig. - Pharmacokinetics Graph showing Bioavailability and Absorption of NovoLog.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1 Subcutaneous Daily Injections Two six-month, open-label, active-controlled studies were conducted to compare the safety and efficacy of NovoLog to Novolin in adult patients with type diabetes. Because the two study designs and results were similar, data are shown for only one study (see Table 3). NovoLog was administered by subcutaneous injection immediately prior to meals and regular human insulin was administered by subcutaneous injection 30 minutes before meals. NPH insulin was administered as the basal insulin in either single or divided daily doses. Changes in HbA1c and the incidence rates of severe hypoglycemia (as determined from the number of events requiring intervention from third party) were comparable for the two treatment regimens in this study (Table 3) as well as in the other clinical studies that are cited in this section. Diabetic ketoacidosis was not reported in any of the adult studies in either treatment group.Table 3. Subcutaneous NovoLog Administration in Type Diabetes (24 weeks; n=882)NovoLog NPHNovolin + NPHN596286Baseline HbA1c (%)Values are Mean +- SD 7.9 +-1.18.0 +- 1.2Change from Baseline HbA1c (%)-0.1 +- 0.80.0 +- 0.8Treatment Difference in HbA1c Mean (95% confidence interval)-0.2 (-0.3, -0.1)Baseline insulin dose (IU/kg/24 hours) 0.7 +- 0.20.7 +- 0.2End-of-Study insulin dose (IU/kg/24 hours) 0.7 +- 0.20.7 +- 0.2Patients with severe hypoglycemia (n, %)Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the intervention of another person or hospitalization. 104 (17%)54 (19%)Baseline body weight (kg) Weight Change from baseline (kg) 75.3 +- 14.50.5 +- 3.375.9 +- 13.10.9 +- 2.9A 24-week, parallel-group study of children and adolescents with type diabetes (n 283) aged to 18 years compared two subcutaneous multiple-dose treatment regimens: NovoLog (n 187) or Novolin (n 96). NPH insulin was administered as the basal insulin. NovoLog achieved glycemic control comparable to Novolin R, as measured by change in HbA1c (Table 4) and both treatment groups had comparable incidence of hypoglycemia. Subcutaneous administration of NovoLog and regular human insulin have also been compared in children with type diabetes (n=26) aged to years with similar effects on HbA1c and hypoglycemia.Table 4. Pediatric Subcutaneous Administration of NovoLog in Type Diabetes (24 weeks; n=283)NovoLog NPHNovolin + NPHN18796Baseline HbA1c (%)Values are Mean +- SD 8.3 +- 1.28.3 +- 1.3Change from Baseline HbA1c (%)0.1+- 1.00.1+- 1.1Treatment Difference in HbA1c, Mean (95% confidence interval) 0.1 (-0.5, 0.1)Baseline insulin dose (IU/kg/24 hours) 0.4 +- 0.20.6 +- 0.2End-of-Study insulin dose (IU/kg/24 hours) 0.4 +- 0.20.7 +- 0.2Patients with severe hypoglycemia (n, %)Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the intervention of another person or hospitalization. 11 (6%)9 (9%)Diabetic ketoacidosis (n, %)10 (5%)2 (2%)Baseline body weight (kg) Weight Change from baseline (kg) 50.6 +- 19.62.7 +- 3.548.7 +- 15.82.4 +- 2.6One six-month, open-label, active-controlled study was conducted to compare the safety and efficacy of NovoLog to Novolin in patients with type diabetes (Table 5). NovoLog was administered by subcutaneous injection immediately prior to meals and regular human insulin was administered by subcutaneous injection 30 minutes before meals. NPH insulin was administered as the basal insulin in either single or divided daily doses. Changes in HbAlc and the rates of severe hypoglycemia (as determined from the number of events requiring intervention from third party) were comparable for the two treatment regimens.Table 5. Subcutaneous NovoLog Administration in Type Diabetes (6 months; n=176)NovoLog NPHNovolin + NPHN9086Baseline HbA1c (%)Values are Mean +- SD 8.1 +- 1.27.8 +- 1.1Change from Baseline HbA1c (%)-0.3 +- 1.0-0.1 +- 0.8Treatment Difference in HbA1c, Mean (95% confidence interval)- 0.1 (-0.4, -0.1)Baseline insulin dose (IU/kg/24 hours) 0.6 +- 0.30.6 +- 0.3End-of-Study insulin dose (IU/kg/24 hours) 0.7 +- 0.30.7 +- 0.3Patients with severe hypoglycemia (n, %)Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the intervention of another person or hospitalization. (10%)5 (8%)Baseline body weight (kg) Weight Change from baseline (kg) 88.4 +- 13.31.2 +- 3.085.8 +- 14.80.4 +- 3.1. 14.2 Continuous Subcutaneous Insulin Infusion (CSII) by External Pump. Two open-label, parallel design studies (6 weeks [n=29] and 16 weeks [n=118]) compared NovoLog to buffered regular human insulin (Velosulin) in adults with type diabetes receiving subcutaneous infusion with an external insulin pump. The two treatment regimens had comparable changes in HbA1c and rates of severe hypoglycemia.Table 6. Adult Insulin Pump Study in Type Diabetes (16 weeks; n=118)NovoLogBuffered human insulinN5959Baseline HbA1c (%)Values are Mean +- SD 7.3 +- 0.77.5 +- 0.8Change from Baseline HbA1c (%)0.0 +- 0.50.2 +- 0.6Treatment Difference in HbA1c, Mean (95% confidence interval)0.3 (-0.1, 0.4)Baseline insulin dose (IU/kg/24 hours) 0.7 +- 0.80.6 +- 0.2End-of-Study insulin dose (IU/kg/24 hours) 0.7 +- 0.70.6 +- 0.2Patients with severe hypoglycemia (n, %)Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the intervention of another person or hospitalization. (2%)2 (3%)Baseline body weight (kg) Weight Change from baseline (kg) 77.4 +- 16.10.1 +- 3.574.8 +- 13.8-0.0 +- 1.7A randomized, 16-week, open-label, parallel design study of children and adolescents with type diabetes (n=298) aged 4-18 years compared two subcutaneous infusion regimens administered via an external insulin pump: NovoLog (n=198) or insulin lispro (n=100). These two treatments resulted in comparable changes from baseline in HbA1c and comparable rates of hypoglycemia after 16 weeks of treatment (see Table 7).Table 7. Pediatric Insulin Pump Study in Type Diabetes (16 weeks; n=298)NovoLogLisproN198100Baseline HbA1c (%)Values are Mean +- SD 8.0 +- 0.98.2 +- 0.8Change from Baseline HbA1c (%)-0.1 +- 0.8-0.1 +- 0.7Treatment Difference in HbA1c, Mean (95% confidence interval)-0.1 (-0.3, 0.1)Baseline insulin dose (IU/kg/24 hours) 0.9 +- 0.30.9 +- 0.3End-of-Study insulin dose (IU/kg/24 hours) 0.9 +- 0.20.9 +- 0.2Patients with severe hypoglycemia (n, %)Severe hypoglycemia refers to hypoglycemia associated with central nervous system symptoms and requiring the intervention of another person or hospitalization. 19 (10%)8 (8%)Diabetic ketoacidosis (n, %)1 (0.5%)0 (0)Baseline body weight (kg) Weight Change from baseline (kg) 54.1 +- 19.71.8 +- 2.155.5 +- 19.01.6 +- 2.1An open-label, 16-week parallel design trial compared pre-prandial NovoLog injection in conjunction with NPH injections to NovoLog administered by continuous subcutaneous infusion in 127 adults with type diabetes. The two treatment groups had similar reductions in HbA1c and rates of severe hypoglycemia (Table 8) [see Indications and Usage (1), Dosage and Administration (2), Warnings and Precautions (5) and How Supplied/Storage and Handling (16.2) ].Table 8. Pump Therapy in Type Diabetes (16 weeks; n=127)NovoLog pumpNovoLog NPHN6661Baseline HbA1c (%)Values are Mean +- SD 8.2 +- 1.48.0 +- 1.1Change from Baseline HbA1c (%)-0.6 +- 1.1-0.5 +- 0.9Treatment Difference in HbA1c, Mean (95% confidence interval)0.1 (0.4, 0.3)Baseline insulin dose (IU/kg/24 hours) 0.7 +- 0.30.8 +- 0.5End-of-Study insulin dose (IU/kg/24 hours) 0.9 +- 0.40.9 +- 0.5Baseline body weight (kg) Weight Change from baseline (kg) 96.4 +- 17.01.7 +- 3.796.9 +- 17.90.7 +- 4.1. 14.3 Intravenous Administration of NovoLog See Section 12.2 CLINICAL PHARMACOLOGY/Pharmacodynamics.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. NovoLog is contraindicatedoduring episodes of hypoglycemiaoin patients with hypersensitivity to NovoLog or one of its excipients.. oduring episodes of hypoglycemia. oin patients with hypersensitivity to NovoLog or one of its excipients.. oDo not use during episodes of hypoglycemia (4).oDo not use in patients with hypersensitivity to NovoLog or one of its excipients.. oDo not use during episodes of hypoglycemia (4).. oDo not use in patients with hypersensitivity to NovoLog or one of its excipients.

DESCRIPTION SECTION.

11 DESCRIPTION. NovoLog (insulin aspart [rDNA origin] injection) is rapid-acting human insulin analog used to lower blood glucose. NovoLog 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 C256H381N65079S6 and molecular weight of 5825.8.Figure 1. Structural formula of insulin aspart. NovoLog is sterile, aqueous, clear, and colorless solution, that contains insulin aspart 100 Units/mL, glycerin 16 mg/mL, phenol 1.50 mg/mL, metacresol 1.72 mg/mL, zinc 19.6 mcg/mL, disodium hydrogen phosphate dihydrate 1.25 mg/mL, sodium chloride 0.58 mg/mL and water for injection. NovoLog has pH of 7.2-7.6. Hydrochloric acid 10% and/or sodium hydroxide 10% may be added to adjust pH.. Fig. - Structural Formula of Insulin Aspart.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oThe dosage of NovoLog must be individualized.oSubcutaneous injection: NovoLog should generally be given immediately (within 5-10 minutes) prior to the start of meal (2.2).oUse in pumps: Change the NovoLog in the reservoir at least every days, change the infusion set, and the infusion set insertion site at least every days. NovoLog should not be mixed with other insulins or with diluent when it is used in the pump (2.3).oIntravenous use: NovoLog should be used at concentrations from 0.05 U/mL to 1.0 U/mL insulin aspart in infusion systems using polypropylene infusion bags. NovoLog has been shown to be stable in infusion fluids such as 0.9% sodium chloride (2.4).. oThe dosage of NovoLog must be individualized.. oSubcutaneous injection: NovoLog should generally be given immediately (within 5-10 minutes) prior to the start of meal (2.2).. oUse in pumps: Change the NovoLog in the reservoir at least every days, change the infusion set, and the infusion set insertion site at least every days. NovoLog should not be mixed with other insulins or with diluent when it is used in the pump (2.3).. oIntravenous use: NovoLog should be used at concentrations from 0.05 U/mL to 1.0 U/mL insulin aspart in infusion systems using polypropylene infusion bags. NovoLog has been shown to be stable in infusion fluids such as 0.9% sodium chloride (2.4).. 2.1 Dosing NovoLog is an insulin analog with an earlier onset of action than regular human insulin. The dosage of NovoLog must be individualized. NovoLog given by subcutaneous injection should generally be used in regimens with an intermediate or long-acting insulin [see Warnings and Precautions (5), How Supplied/Storage and Handling (16.2) ]. The total daily insulin requirement may vary and is usually between 0.5 to 1.0 units/kg/day. When used in meal-related subcutaneous injection treatment regimen, 50 to 70% of total insulin requirements may be provided by NovoLog and the remainder provided by an intermediate-acting or long-acting insulin. Because of NovoLogs comparatively rapid onset and short duration of glucose lowering activity, some patients may require more basal insulin and more total insulin to prevent pre-meal hyperglycemia when using NovoLog than when using human regular insulin.Do not use NovoLog that is viscous (thickened) or cloudy; use only if it is clear and colorless. NovoLog should not be used after the printed expiration date.. 2.2 Subcutaneous Injection. NovoLog should be administered by subcutaneous injection in the abdominal region, buttocks, thigh, or upper arm. Because NovoLog has more rapid onset and shorter duration of activity than human regular insulin, it should be injected immediately (within 5-10 minutes) before meal. Injection sites should be rotated within the same region to reduce the risk of lipodystrophy. As with all insulins, the duration of action of NovoLog will vary according to the dose, injection site, blood flow, temperature, and level of physical activity.NovoLog may be diluted with Insulin Diluting Medium for NovoLog for subcutaneous injection. Diluting one part NovoLog to nine parts diluent will yield concentration one-tenth that of NovoLog (equivalent to U-10). Diluting one part NovoLog to one part diluent will yield concentration one-half that of NovoLog (equivalent to U-50).. 2.3 Continuous Subcutaneous Insulin Infusion (CSII) by External Pump. NovoLog can also be infused subcutaneously by an external insulin pump [see Warnings and Precautions (5.8, 5.9), How Supplied/Storage and Handling (16.2)]. Diluted insulin should not be used in external insulin pumps. Because NovoLog has more rapid onset and shorter duration of activity than human regular insulin, pre-meal boluses of NovoLog should be infused immediately (within 5-10 minutes) before meal. Infusion sites should be rotated within the same region to reduce the risk of lipodystrophy. The initial programming of the external insulin infusion pump should be based on the total daily insulin dose of the previous regimen. Although there is significant interpatient variability, approximately 50% of the total dose is usually given as meal-related boluses of NovoLog and the remainder is given as basal infusion. Change the NovoLog in the reservoir at least every days, change the infusion sets and the infusion set insertion site at least every days. The following insulin pumps+ have been used in NovoLog clinical or in vitro studies conducted by Novo Nordisk, the manufacturer of NovoLog:oMedtronic Paradigm(R) 512 and 712oMiniMed 508oDisetronic(R) D-TRON(R) and H-TRON(R)Before using different insulin pump with NovoLog, read the pump label to make sure the pump has been evaluated with NovoLog. oMedtronic Paradigm(R) 512 and 712. oMiniMed 508. oDisetronic(R) D-TRON(R) and H-TRON(R). 2.4 Intravenous Use. NovoLog can be administered intravenously under medical supervision for glycemic control with close monitoring of blood glucose and potassium levels to avoid hypoglycemia and hypokalemia [see Warnings and Precautions (5), How Supplied/Storage and Handling (16.2) ]. For intravenous use, NovoLog should be used at concentrations from 0.05 U/mL to 1.0 U/mL insulin aspart in infusion systems using polypropylene infusion bags. NovoLog has been shown to be stable in infusion fluids such as 0.9% sodium chloride.Inspect NovoLog for particulate matter and discoloration prior to parenteral administration.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. NovoLog is available in the following package sizes: each presentation contains 100 units of insulin aspart per mL (U-100).o10 mL vialso3 mL PenFill cartridges for the mL PenFill cartridge delivery device (with or without the addition of NovoPen(R) PenMate(R)) with NovoFine(R) disposable needleso3 mL NovoLog FlexPen. o10 mL vials. o3 mL PenFill cartridges for the mL PenFill cartridge delivery device (with or without the addition of NovoPen(R) PenMate(R)) with NovoFine(R) disposable needles. o3 mL NovoLog FlexPen. Each presentation contains 100 Units of insulin aspart per mL (U-100)o10 mL vials (3)o3 mL PenFill(R) cartridges for the mL PenFill cartridge device (3)o3 mL NovoLog FlexPen(R) (3). o10 mL vials (3). o3 mL PenFill(R) cartridges for the mL PenFill cartridge device (3). o3 mL NovoLog FlexPen(R) (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. number of substances affect glucose metabolism and may require insulin dose adjustment and particularly close monitoring.oThe following are examples of substances that may increase the blood-glucose-lowering effect and susceptibility to hypoglycemia: oral antidiabetic products, pramlintide, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g., octreotide), sulfonamide antibiotics.oThe following are examples of substances that may reduce the blood-glucose-lowering effect: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives), atypical antipsychotics.oBeta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin.oPentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.oThe signs of hypoglycemia may be reduced or absent in patients taking sympatholytic products such as beta-blockers, clonidine, guanethidine, and reserpine.. oThe following are examples of substances that may increase the blood-glucose-lowering effect and susceptibility to hypoglycemia: oral antidiabetic products, pramlintide, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase (MAO) inhibitors, propoxyphene, salicylates, somatostatin analog (e.g., octreotide), sulfonamide antibiotics.. oThe following are examples of substances that may reduce the blood-glucose-lowering effect: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives), atypical antipsychotics.. oBeta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin.. oPentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia.. oThe signs of hypoglycemia may be reduced or absent in patients taking sympatholytic products such as beta-blockers, clonidine, guanethidine, and reserpine.. oThe following may increase the blood-glucose-lowering effect and susceptibility to hypoglycemia: oral antidiabetic products, pramlintide, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, propoxyphene, salicylates, somatostatin analogs, sulfonamide antibiotics (7).oThe following may reduce the blood-glucose-lowering effect: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives), atypical antipsychotics (7).oBeta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin (7). oPentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia (7).oThe signs of hypoglycemia may be reduced or absent in patients taking sympatholytic products such as beta-blockers, clonidine, guanethidine, and reserpine (7).. oThe following may increase the blood-glucose-lowering effect and susceptibility to hypoglycemia: oral antidiabetic products, pramlintide, ACE inhibitors, disopyramide, fibrates, fluoxetine, monoamine oxidase inhibitors, propoxyphene, salicylates, somatostatin analogs, sulfonamide antibiotics (7).. oThe following may reduce the blood-glucose-lowering effect: corticosteroids, niacin, danazol, diuretics, sympathomimetic agents (e.g., epinephrine, salbutamol, terbutaline), isoniazid, phenothiazine derivatives, somatropin, thyroid hormones, estrogens, progestogens (e.g., in oral contraceptives), atypical antipsychotics (7).. oBeta-blockers, clonidine, lithium salts, and alcohol may either potentiate or weaken the blood-glucose-lowering effect of insulin (7). oPentamidine may cause hypoglycemia, which may sometimes be followed by hyperglycemia (7).. oThe signs of hypoglycemia may be reduced or absent in patients taking sympatholytic products such as beta-blockers, clonidine, guanethidine, and reserpine (7).

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the total number of patients (n= 1,375) treated with NovoLog in controlled clinical studies, 2.6% (n=36) were 65 years of age or over. One-half of these patients had type diabetes (18/1285) and the other half had type diabetes (18/90). The HbA1c response to NovoLog, as compared to human insulin, did not differ by age, particularly in patients with type diabetes. Additional studies in larger populations of patients 65 years of age or over are needed to permit conclusions regarding the safety of NovoLog in elderly compared to younger patients. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of NovoLog action have not been performed.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. 16.1 How Supplied. NovoLog is available in the following package sizes: each presentation containing 100 Units of insulin aspart per mL (U-100).10 mL vialsNDC 0169-7501-113 mL PenFill cartridgesNovoLog PenFill cartridges are designed for use with Novo Nordisk mL PenFill cartridge compatible insulin delivery devices (with or without the addition of NovoPen PenMate) with NovoFine disposable needles. NDC 0169-3303-123 mL NovoLog FlexPenNDC 0169-6339-10. 16.2 Recommended Storage. Unused NovoLog should be stored in refrigerator between and 8C (36 to 46F). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze NovoLog and do not use NovoLog if it has been frozen. NovoLog should not be drawn into syringe and stored for later use.Vials: After initial use vial may be kept at temperatures below 30C (86F) for up to 28 days, but should not be exposed to excessive heat or sunlight. Opened vials may be refrigerated.Unpunctured vials can be used until the expiration date printed on the label if they are stored in refrigerator. Keep unused vials in the carton so they will stay clean and protected from light.PenFill cartridges or NovoLog FlexPen:Once cartridge or NovoLog FlexPen is punctured, it should be kept at temperatures below 30C (86F) for up to 28 days, but should not be exposed to excessive heat or sunlight. NovoLog FlexPen or cartridge in use must NOT be stored in the refrigerator. Keep the NovoLog FlexPen and all PenFill cartridges away from direct heat and sunlight. Unpunctured NovoLog FlexPen and PenFill cartridges can be used until the expiration date printed on the label if they are stored in refrigerator. Keep unused NovoLog FlexPen and PenFill cartridges in the carton so they will stay clean and protected from light. Always remove the needle after each injection and store the mL PenFill cartridge delivery device or NovoLog FlexPen without needle attached. This prevents contamination and/or infection, or leakage of insulin, and will ensure accurate dosing. Always use new needle for each injection to prevent contamination.Pump:NovoLog in the pump reservoir should be discarded after at least every days of use or after exposure to temperatures that exceed 37C (98.6F). The infusion set and the infusion set insertion site should be changed at least every days.Summary of Storage Conditions:The storage conditions are summarized in the following table:Table 9. Storage conditions for vial, PenFill cartridges and NovoLog FlexPenNovoLogpresentationNot in-use (unopened) Room Temperature (below 30C)Not in-use (unopened) RefrigeratedIn-use (opened) Room Temperature (below 30C)10 mL vial28 daysUntil expiration date28 days (refrigerated/room temperature)3 mL PenFill cartridges28 daysUntil expiration date28 days (Do not refrigerate)3 mL NovoLog FlexPen28 daysUntil expiration date28 days (Do not refrigerate)Storage of Diluted NovoLogNovoLog diluted with Insulin Diluting Medium for NovoLog to concentration equivalent to U-10 or equivalent to U-50 may remain in patient use at temperatures below 30C (86F) for 28 days.Storage of NovoLog in Infusion FluidsInfusion bags prepared as indicated under Dosage and Administration (2) are stable at room temperature for 24 hours. Some insulin will be initially adsorbed to the material of the infusion bag.

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. In 52-week studies, Sprague-Dawley rats were dosed subcutaneously with NovoLog at 10, 50, and 200 U/kg/day (approximately 2, 8, and 32 times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area, respectively). At dose of 200 U/kg/day, NovoLog increased the incidence of mammary gland tumors in females when compared to untreated controls. The incidence of mammary tumors for NovoLog was not significantly different than for regular human insulin. 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, at subcutaneous doses up to 200 U/kg/day (approximately 32 times the human subcutaneous dose, based on U/body surface area), no direct adverse effects on male and female fertility, or general reproductive performance of animals was observed.. 13.2 Animal Toxicology and/or Pharmacology. In standard biological assays in mice and rabbits, one unit of NovoLog has the same glucose-lowering effect as one unit of regular human insulin. In humans, the effect of NovoLog is more rapid in onset and of shorter duration, compared to regular human insulin, due to its faster absorption after subcutaneous injection (see Section 12 CLINICAL PHARMACOLOGY Figure and Figure 4).

NURSING MOTHERS SECTION.

8.3 Nursing Mothers. It is unknown whether insulin aspart is excreted in human milk. Use of NovoLog is compatible with breastfeeding, but women with diabetes who are lactating may require adjustments of their insulin doses.

OVERDOSAGE SECTION.

10 OVERDOSAGE. Excess insulin administration may cause hypoglycemia and, particularly when given intravenously, hypokalemia. Mild episodes of hypoglycemia usually can be treated with oral glucose. Adjustments in drug dosage, meal patterns, or exercise, may be needed. More severe episodes with coma, seizure, or neurologic impairment may be treated with 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 3 mL NovoLog FlexPen. NDC 68258-8899-03NovoLog(R) FlexPen(R) Prefilled SyringeInsulin aspart Injection (rDNA origin)100 units/mL (U-100)5 3 mL Prefilled Insulin SyringesRx onlySingle patient use onlyFor use with NovoFine(R) disposable needles.Keep in cold place. Avoid freezing.Protect from light.. NDC 68258-8899-03.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. NovoLog is approved for use in children for subcutaneous daily injections and for subcutaneous continuous infusion by external insulin pump. NovoLog has not been studied in pediatric patients younger than years of age. NovoLog has not been studied in pediatric patients with type diabetes. Please see Section 14 CLINICAL STUDIES for summaries of clinical studies.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Studies in normal volunteers and patients with diabetes demonstrated that subcutaneous administration of NovoLog has more rapid onset of action than regular human insulin.In study in patients with type diabetes (n=22), the maximum glucose-lowering effect of NovoLog occurred between and hours after subcutaneous injection (see Figure 2). The duration of action for NovoLog is to hours. The time course of action of insulin and insulin analogs such as NovoLog may vary considerably in different individuals or within the same individual. The parameters of NovoLog activity (time of onset, peak time and duration) as designated in Figure should be considered only as general guidelines. The rate of insulin absorption and onset of activity is affected by the site of injection, exercise, and other variables [see Warnings and Precautions (5.1) ].Figure 2. Serial mean serum glucose collected up to hours following single pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched curve) injected immediately before meal in 22 patients with type diabetes. double-blind, randomized, two-way cross-over study in 16 patients with type diabetes demonstrated that intravenous infusion of NovoLog resulted in blood glucose profile that was similar to that after intravenous infusion with regular human insulin. NovoLog or human insulin was infused until the patients blood glucose decreased to 36 mg/dL, or until the patient demonstrated signs of hypoglycemia (rise in heart rate and onset of sweating), defined as the time of autonomic reaction (R) (see Figure 3).Figure 3. Mean blood glucose profiles following intravenous infusion of NovoLog (hatched curve) and regular human insulin (solid curve) in 16 patients with type diabetes. represents the time of autonomic reaction. Fig. - Pharmacodynamics Graph showing Maximum Glucose-Lowering Effect of NovoLog. Fig. - Pharmacodynamics Graph Time of Autonomic Reaction.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The single substitution of the amino acid proline with aspartic acid at position B28 in NovoLog reduces the molecules tendency to form hexamers as observed with regular human insulin. NovoLog is, therefore, more rapidly absorbed after subcutaneous injection compared to regular human insulin.In randomized, double-blind, crossover study 17 healthy Caucasian male subjects between 18 and 40 years of age received an intravenous infusion of either NovoLog or regular human insulin at 1.5 mU/kg/min for 120 minutes. The mean insulin clearance was similar for the two groups with mean values of 1.2 l/h/kg for the NovoLog group and 1.2 l/h/kg for the regular human insulin group.Bioavailability and Absorption NovoLog has faster absorption, faster onset of action, and shorter duration of action than regular human insulin after subcutaneous injection (see Figure and Figure 4). The relative bioavailability of NovoLog compared to regular human insulin indicates that the two insulins are absorbed to similar extent.Figure 4. Serial mean serum free insulin concentration collected up to hours following single pre-meal dose of NovoLog (solid curve) or regular human insulin (hatched curve) injected immediately before meal in 22 patients with type diabetes. In studies in healthy volunteers (total n=107) and patients with type diabetes (total n=40), NovoLog consistently reached peak serum concentrations approximately twice as fast as regular human insulin. The median time to maximum concentration in these trials was 40 to 50 minutes for NovoLog versus 80 to 120 minutes for regular human insulin. In clinical trial in patients with type diabetes, NovoLog and regular human insulin, both administered subcutaneously at dose of 0.15 U/kg body weight, reached mean maximum concentrations of 82 and 36 mU/L, respectively. Pharmacokinetic/pharmacodynamic characteristics of insulin aspart have not been established in patients with type diabetes.The intra-individual variability in time to maximum serum insulin concentration for healthy male volunteers was significantly less for NovoLog than for regular human insulin. The clinical significance of this observation has not been established.In clinical study in healthy non-obese subjects, the pharmacokinetic differences between NovoLog and regular human insulin described above, were observed independent of the site of injection (abdomen, thigh, or upper arm).Distribution and Elimination NovoLog has low binding to plasma proteins (<10%), similar to that seen with regular human insulin. After subcutaneous administration in normal male volunteers (n=24), NovoLog was more rapidly eliminated than regular human insulin with an average apparent half-life of 81 minutes compared to 141 minutes for regular human insulin.Specific PopulationsChildren and Adolescents The pharmacokinetic and pharmacodynamic properties of NovoLog and regular human insulin were evaluated in single dose study in 18 children (6-12 years, n=9) and adolescents (13-17 years [Tanner grade 2], n=9) with type diabetes. The relative differences in pharmacokinetics and pharmacodynamics in children and adolescents with type diabetes between NovoLog and regular human insulin were similar to those in healthy adult subjects and adults with type diabetes.Gender In healthy volunteers, no difference in insulin aspart levels was seen between men and women when body weight differences were taken into account. There was no significant difference in efficacy noted (as assessed by HbAlc) between genders in trial in patients with type diabetes.Obesity A single subcutaneous dose of 0.1 U/kg NovoLog was administered in study of 23 patients with type diabetes and wide range of body mass index (BMI, 22-39 kg/m2). The pharmacokinetic parameters, AUC and Cmax, of NovoLog were generally unaffected by BMI in the different groups BMI 19-23 kg/m2 (N=4); BMI 23-27 kg/m2 (N=7); BMI 27-32 kg/m2 (N=6) and BMI >32 kg/m2 (N=6). Clearance of NovoLog was reduced by 28% in patients with BMI >32 kg/m2 compared to patients with BMI <23 kg/m2.Renal Impairment Some studies with human insulin have shown increased circulating levels of insulin in patients with renal failure. single subcutaneous dose of 0.08 U/kg NovoLog was administered in study to subjects with either normal (N=6) creatinine clearance (CLcr) (> 80 ml/min) or mild (N=7; CLcr 50-80 ml/min), moderate (N=3; CLcr 30-50 ml/min) or severe (but not requiring hemodialysis) (N=2; CLcr <30 ml/min) renal impairment. In this small study, there was no apparent effect of creatinine clearance values on AUC and Cmax of NovoLog. Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be necessary in patients with renal dysfunction [see Warnings and Precautions (5.4) ].Hepatic Impairment Some studies with human insulin have shown increased circulating levels of insulin in patients with liver failure. single subcutaneous dose of 0.06 U/kg NovoLog was administered in an open-label, single-dose study of 24 subjects (N=6/group) with different degree of hepatic impairment (mild, moderate and severe) having Child-Pugh Scores ranging from (healthy volunteers) to 12 (severe hepatic impairment). In this small study, there was no correlation between the degree of hepatic failure and any NovoLog pharmacokinetic parameter. Careful glucose monitoring and dose adjustments of insulin, including NovoLog, may be necessary in patients with hepatic dysfunction [see Warnings and Precautions (5.5) ].The effect of age, ethnic origin, pregnancy and smoking on the pharmacokinetics and pharmacodynamics of NovoLog has not been studied.. Fig. - Pharmacokinetics Graph showing Bioavailability and Absorption of NovoLog.

PREGNANCY SECTION.

8.1 Pregnancy. Pregnancy Category B. All pregnancies have background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is essential in these patients. Therefore, female patients should be advised to tell their physician if they intend to become, or if they become pregnant while taking NovoLog.An open-label, randomized study compared the safety and efficacy of NovoLog (n=157) versus regular human insulin (n=165) in 322 pregnant women with type diabetes. Two-thirds of the enrolled patients were already pregnant when they entered the study. Because only one-third of the patients enrolled before conception, the study was not large enough to evaluate the risk of congenital malformations. Both groups achieved mean HbA1c of 6% during pregnancy, and there was no significant difference in the incidence of maternal hypoglycemia.Subcutaneous reproduction and teratology studies have been performed with NovoLog and regular human insulin in rats and rabbits. In these studies, NovoLog was given to female rats before mating, during mating, and throughout pregnancy, and to rabbits during organogenesis. The effects of NovoLog did not differ from those observed with subcutaneous regular human insulin. NovoLog, like human insulin, caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at dose of 200 U/kg/day (approximately 32 times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area) and in rabbits at dose of 10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area). The effects are probably secondary to maternal hypoglycemia at high doses. No significant effects were observed in rats at dose of 50 U/kg/day and in rabbits at dose of U/kg/day. These doses are approximately times the human subcutaneous dose of 1.0 U/kg/day for rats and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits, based on U/body surface area.

RECENT MAJOR CHANGES SECTION.

oWarnings and Precautions (5.10) 3/2013. oWarnings and Precautions (5.10) 3/2013.

SPL UNCLASSIFIED SECTION.

1.1 Treatment of Diabetes Mellitus. NovoLog is an insulin analog indicated to improve glycemic control in adults and children with diabetes mellitus.

STORAGE AND HANDLING SECTION.

16.2 Recommended Storage. Unused NovoLog should be stored in refrigerator between and 8C (36 to 46F). Do not store in the freezer or directly adjacent to the refrigerator cooling element. Do not freeze NovoLog and do not use NovoLog if it has been frozen. NovoLog should not be drawn into syringe and stored for later use.Vials: After initial use vial may be kept at temperatures below 30C (86F) for up to 28 days, but should not be exposed to excessive heat or sunlight. Opened vials may be refrigerated.Unpunctured vials can be used until the expiration date printed on the label if they are stored in refrigerator. Keep unused vials in the carton so they will stay clean and protected from light.PenFill cartridges or NovoLog FlexPen:Once cartridge or NovoLog FlexPen is punctured, it should be kept at temperatures below 30C (86F) for up to 28 days, but should not be exposed to excessive heat or sunlight. NovoLog FlexPen or cartridge in use must NOT be stored in the refrigerator. Keep the NovoLog FlexPen and all PenFill cartridges away from direct heat and sunlight. Unpunctured NovoLog FlexPen and PenFill cartridges can be used until the expiration date printed on the label if they are stored in refrigerator. Keep unused NovoLog FlexPen and PenFill cartridges in the carton so they will stay clean and protected from light. Always remove the needle after each injection and store the mL PenFill cartridge delivery device or NovoLog FlexPen without needle attached. This prevents contamination and/or infection, or leakage of insulin, and will ensure accurate dosing. Always use new needle for each injection to prevent contamination.Pump:NovoLog in the pump reservoir should be discarded after at least every days of use or after exposure to temperatures that exceed 37C (98.6F). The infusion set and the infusion set insertion site should be changed at least every days.Summary of Storage Conditions:The storage conditions are summarized in the following table:Table 9. Storage conditions for vial, PenFill cartridges and NovoLog FlexPenNovoLogpresentationNot in-use (unopened) Room Temperature (below 30C)Not in-use (unopened) RefrigeratedIn-use (opened) Room Temperature (below 30C)10 mL vial28 daysUntil expiration date28 days (refrigerated/room temperature)3 mL PenFill cartridges28 daysUntil expiration date28 days (Do not refrigerate)3 mL NovoLog FlexPen28 daysUntil expiration date28 days (Do not refrigerate)Storage of Diluted NovoLogNovoLog diluted with Insulin Diluting Medium for NovoLog to concentration equivalent to U-10 or equivalent to U-50 may remain in patient use at temperatures below 30C (86F) for 28 days.Storage of NovoLog in Infusion FluidsInfusion bags prepared as indicated under Dosage and Administration (2) are stable at room temperature for 24 hours. Some insulin will be initially adsorbed to the material of the infusion bag.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. oPediatric: Has not been studied in children with type diabetes. Has not been studied in children with type diabetes <2 years of age (8.4).. oPediatric: Has not been studied in children with type diabetes. Has not been studied in children with type diabetes <2 years of age (8.4).. 8.1 Pregnancy. Pregnancy Category B. All pregnancies have background risk of birth defects, loss, or other adverse outcome regardless of drug exposure. This background risk is increased in pregnancies complicated by hyperglycemia and may be decreased with good metabolic control. It is essential for patients with diabetes or history of gestational diabetes to maintain good metabolic control before conception and throughout pregnancy. Insulin requirements may decrease during the first trimester, generally increase during the second and third trimesters, and rapidly decline after delivery. Careful monitoring of glucose control is essential in these patients. Therefore, female patients should be advised to tell their physician if they intend to become, or if they become pregnant while taking NovoLog.An open-label, randomized study compared the safety and efficacy of NovoLog (n=157) versus regular human insulin (n=165) in 322 pregnant women with type diabetes. Two-thirds of the enrolled patients were already pregnant when they entered the study. Because only one-third of the patients enrolled before conception, the study was not large enough to evaluate the risk of congenital malformations. Both groups achieved mean HbA1c of 6% during pregnancy, and there was no significant difference in the incidence of maternal hypoglycemia.Subcutaneous reproduction and teratology studies have been performed with NovoLog and regular human insulin in rats and rabbits. In these studies, NovoLog was given to female rats before mating, during mating, and throughout pregnancy, and to rabbits during organogenesis. The effects of NovoLog did not differ from those observed with subcutaneous regular human insulin. NovoLog, like human insulin, caused pre- and post-implantation losses and visceral/skeletal abnormalities in rats at dose of 200 U/kg/day (approximately 32 times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area) and in rabbits at dose of 10 U/kg/day (approximately three times the human subcutaneous dose of 1.0 U/kg/day, based on U/body surface area). The effects are probably secondary to maternal hypoglycemia at high doses. No significant effects were observed in rats at dose of 50 U/kg/day and in rabbits at dose of U/kg/day. These doses are approximately times the human subcutaneous dose of 1.0 U/kg/day for rats and equal to the human subcutaneous dose of 1.0 U/kg/day for rabbits, based on U/body surface area.. 8.3 Nursing Mothers. It is unknown whether insulin aspart is excreted in human milk. Use of NovoLog is compatible with breastfeeding, but women with diabetes who are lactating may require adjustments of their insulin doses.. 8.4 Pediatric Use. NovoLog is approved for use in children for subcutaneous daily injections and for subcutaneous continuous infusion by external insulin pump. NovoLog has not been studied in pediatric patients younger than years of age. NovoLog has not been studied in pediatric patients with type diabetes. Please see Section 14 CLINICAL STUDIES for summaries of clinical studies.. 8.5 Geriatric Use. Of the total number of patients (n= 1,375) treated with NovoLog in controlled clinical studies, 2.6% (n=36) were 65 years of age or over. One-half of these patients had type diabetes (18/1285) and the other half had type diabetes (18/90). The HbA1c response to NovoLog, as compared to human insulin, did not differ by age, particularly in patients with type diabetes. Additional studies in larger populations of patients 65 years of age or over are needed to permit conclusions regarding the safety of NovoLog in elderly compared to younger patients. Pharmacokinetic/pharmacodynamic studies to assess the effect of age on the onset of NovoLog action have not been performed.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oHypoglycemia is the most common adverse effect of insulin therapy. Glucose monitoring is recommended for all patients with diabetes. Any change of insulin dose should be made cautiously and only under medical supervision (5.1, 5.2).oInsulin, particularly when given intravenously or in settings of poor glycemic control, can cause hypokalemia. Use caution in patients predisposed to hypokalemia (5.3).oLike all insulins, NovoLog requirements may be reduced in patients with renal impairment or hepatic impairment (5.4, 5.5).oSevere, life-threatening, generalized allergy, including anaphylaxis, may occur with insulin products, including NovoLog (5.6).oFluid retention and heart failure can occur with concomitant use of thiazolidinediones (TZDs), which are PPAR-gamma agonists, and insulin, including NovoLog (5.10).. oHypoglycemia is the most common adverse effect of insulin therapy. Glucose monitoring is recommended for all patients with diabetes. Any change of insulin dose should be made cautiously and only under medical supervision (5.1, 5.2).. oInsulin, particularly when given intravenously or in settings of poor glycemic control, can cause hypokalemia. Use caution in patients predisposed to hypokalemia (5.3).. oLike all insulins, NovoLog requirements may be reduced in patients with renal impairment or hepatic impairment (5.4, 5.5).. oSevere, life-threatening, generalized allergy, including anaphylaxis, may occur with insulin products, including NovoLog (5.6).. oFluid retention and heart failure can occur with concomitant use of thiazolidinediones (TZDs), which are PPAR-gamma agonists, and insulin, including NovoLog (5.10).. 5.1 Administration. NovoLog has more rapid onset of action and shorter duration of activity than regular human insulin. An injection of NovoLog should immediately be followed by meal within 5-10 minutes. Because of NovoLogs short duration of action, longer acting insulin should also be used in patients with type diabetes and may also be needed in patients with type diabetes. Glucose monitoring is recommended for all patients with diabetes and is particularly important for patients using external pump infusion therapy.Any change of insulin dose should be made cautiously and only under medical supervision. Changing from one insulin product to another or changing the insulin strength may result in the need for change in dosage. As with all insulin preparations, the time course of NovoLog action may vary in different individuals or at different times in the same individual and is dependent on many conditions, including the site of injection, local blood supply, temperature, and physical activity. Patients who change their level of physical activity or meal plan may require adjustment of insulin dosages. Insulin requirements may be altered during illness, emotional disturbances, or other stresses.Patients using continuous subcutaneous insulin infusion pump therapy must be trained to administer insulin by injection and have alternate insulin therapy available in case of pump failure.Needles and NovoLog FlexPen must not be shared.. 5.2 Hypoglycemia. Hypoglycemia is the most common adverse effect of all insulin therapies, including NovoLog. Severe hypoglycemia may lead to unconsciousness and/or convulsions and may result in temporary or permanent impairment of brain function or death. 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.The timing of hypoglycemia usually reflects the time-action profile of the administered insulin formulations [see Clinical Pharmacology (12) ]. Other factors such as changes in food intake (e.g., amount of food or timing of meals), injection site, exercise, and concomitant medications may also alter the risk of hypoglycemia [see Drug Interactions (7) ]. As with all insulins, use caution in patients with hypoglycemia unawareness and in patients who may be predisposed to hypoglycemia (e.g., patients who are fasting or have erratic food intake). The patients ability to concentrate and react may be impaired as result of hypoglycemia. This may present risk in situations where these abilities are especially important, such as driving or operating other machinery.Rapid changes in serum glucose levels may induce symptoms of hypoglycemia in persons with diabetes, regardless of the glucose value. Early warning symptoms of hypoglycemia may be different or less pronounced under certain conditions, such as longstanding diabetes, diabetic nerve disease, use of medications such as beta-blockers, or intensified diabetes control [see Drug Interactions (7) ]. These situations may result in severe hypoglycemia (and, possibly, loss of consciousness) prior to the patients awareness of hypoglycemia. Intravenously administered insulin has more rapid onset of action than subcutaneously administered insulin, requiring more close monitoring for hypoglycemia.. 5.3 Hypokalemia. All insulin products, including NovoLog, cause shift in potassium from the extracellular to intracellular space, possibly leading to hypokalemia that, if left untreated, may cause respiratory paralysis, ventricular arrhythmia, and death. Use caution in patients who may be at risk for hypokalemia (e.g., patients using potassium-lowering medications, patients taking medications sensitive to serum potassium concentrations, and patients receiving intravenously administered insulin).. 5.4 Renal Impairment. As with other insulins, the dose requirements for NovoLog may be reduced in patients with renal impairment [see Clinical Pharmacology (12.3) ].. 5.5 Hepatic Impairment. As with other insulins, the dose requirements for NovoLog may be reduced in patients with hepatic impairment [see Clinical Pharmacology (12.3) ].. 5.6 Hypersensitivity and Allergic Reactions. Local Reactions As with other insulin therapy, patients may experience redness, swelling, or itching at the site of NovoLog injection. These reactions usually resolve in few days to few weeks, but in some occasions, may require discontinuation of NovoLog. In some instances, these reactions may be related to factors other than insulin, such as irritants in skin cleansing agent or poor injection technique. Localized reactions and generalized myalgias have been reported with injected metacresol, which is an excipient in NovoLog.Systemic Reactions Severe, life-threatening, generalized allergy, including anaphylaxis, may occur with any insulin product, including NovoLog. Anaphylactic reactions with NovoLog have been reported post-approval. Generalized allergy to insulin may also cause whole body rash (including pruritus), dyspnea, wheezing, hypotension, tachycardia, or diaphoresis. In controlled clinical trials, allergic reactions were reported in of 735 patients (0.4%) treated with regular human insulin and 10 of 1394 patients (0.7%) treated with NovoLog. In controlled and uncontrolled clinical trials, of 2341 (0.1%) NovoLog-treated patients discontinued due to allergic reactions.. 5.7 Antibody Production. Increases in anti-insulin antibody titers that react with both human insulin and insulin aspart have been observed in patients treated with NovoLog. Increases in anti-insulin antibodies are observed more frequently with NovoLog than with regular human insulin. Data from 12-month controlled trial in patients with type diabetes suggest that the increase in these antibodies is transient, and the differences in antibody levels between the regular human insulin and insulin aspart treatment groups observed at and months were no longer evident at 12 months. The clinical significance of these antibodies is not known. These antibodies do not appear to cause deterioration in glycemic control or necessitate increases in insulin dose.. 5.8 Mixing of Insulins. oMixing NovoLog with NPH human insulin immediately before injection attenuates the peak concentration of NovoLog, without significantly affecting the time to peak concentration or total bioavailability of NovoLog. If NovoLog is mixed with NPH human insulin, NovoLog should be drawn into the syringe first, and the mixture should be injected immediately after mixing.oThe efficacy and safety of mixing NovoLog with insulin preparations produced by other manufacturers have not been studied.oInsulin mixtures should not be administered intravenously.. oMixing NovoLog with NPH human insulin immediately before injection attenuates the peak concentration of NovoLog, without significantly affecting the time to peak concentration or total bioavailability of NovoLog. If NovoLog is mixed with NPH human insulin, NovoLog should be drawn into the syringe first, and the mixture should be injected immediately after mixing.. oThe efficacy and safety of mixing NovoLog with insulin preparations produced by other manufacturers have not been studied.. oInsulin mixtures should not be administered intravenously.. 5.9 Continuous Subcutaneous Insulin Infusion by External Pump. When used in an external subcutaneous insulin infusion pump, NovoLog should not be mixed with any other insulin or diluent. When using NovoLog in an external insulin pump, the NovoLog-specific information should be followed (e.g., in-use time, frequency of changing infusion sets) because NovoLog-specific information may differ from general pump manual instructions.Pump or infusion set malfunctions or insulin degradation can lead to rapid onset of hyperglycemia and ketosis because of the small subcutaneous depot of insulin. This is especially pertinent for rapid-acting insulin analogs that are more rapidly absorbed through skin and have shorter duration of action. Prompt identification and correction of the cause of hyperglycemia or ketosis is necessary. Interim therapy with subcutaneous injection may be required [see Dosage and Administration (2.3), Warnings and Precautions (5.8, 5.9), How Supplied/Storage and Handling (16.2), and Patient Counseling Information (17.2) ].NovoLog should not be exposed to temperatures greater than 37C (98.6F). NovoLog that will be used in pump should not be mixed with other insulin or with diluent [see Dosage and Administration (2.3), Warnings and Precautions (5.8, 5.9), How Supplied/Storage and Handling (16.2), and Patient Counseling Information (17.2) ].. 5.10 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, 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.